Antimicrobials

Klin Khir, 1997, (1), 17 - 8
{Clinical and morphological aspects of Helicobacter pylori invasion in reflux esophagitis}; Galimov OV et al.; The mucosal biopsies morphological investigation of the lower third of esophagus were conducted for Helicobacter pylori detection in 43 patients with reflux-esophagitis . Helicobacter pylori were detected in 66.7%, gastric metaplasia-in 83.3% of patients . Helicobacter pylori plays an important role in reflux-esophagitis pathogenesis . Surgical treatment is indicated if the combined antireflux and antibacterial therapy is ineffective.

Stomatologiia (Mosk), 1997, 76(3), 18 - 22
{A clinical and experimental validation of the use of Stimuloss in patients with chronic generalized periodontitis}; Fedosenko TD et al.; The pharmacological effect of hydroxyapatite and a composition based on it in the form of Stimulos sponge has been studied in human osteogenic tissue culture . Hydroxyapatite stimulated the biosynthetic processes in the cells . Addition of chlorohexidine and thymogen to the composition in order to increase its antibacterial activity did not decrease the osteoinductive properties of the drug . Trials of Stimulos in 66 patients with chronic generalized periodontitis demonstrated its high efficacy, particularly of the compositions containing immunostimulants: inflammation disappeared and the height of alveolar osseous tissue increased, as did bone compactness.

Stomatologiia (Mosk), 1997, 76(3), 12 - 7
{The functional morphology of the epithelial barrier of the oral mucosa}; Bykov VL; Modern notions on the morphology and function of the epithelial barrier of the buccal mucosa are discussed . The basis of this barrier is the epithelial layer, partially covered with horny layer, of a regular thickness and permeability, constantly regenerating, and casting off the injured superficial layers . Nonspecific antibacterial humoral factors (produced by the epithelium and salivary glands) play an important role in the barrier mechanisms, as well as nonspecific cellular mechanisms of defense, due to the presence of intraepithelial granulocytes and monocytes, specific immune humoral and cellular mechanisms including the system of antigen-presenting dendrite cells and lymphocytes, and flow of the saliva containing nonspecific and specific antibacterial factors . The barrier function of the epithelium is provided for by constant interactions between various specific and nonspecific cellular and humoral defense mechanisms.

Probl Tuberk, 1997, (2), 54 - 6
{Antibacterial effectiveness of long-acting isoniazid in the experiment}; Shkurupii VA et al.; The therapeutical efficiency of the long-acting lysosomotropic, complex drug isoniazid (LALCI) was tested in vivo and its antibacterial activity was studied in vitro . LALCI treatment of mice inoculated by virulent Mycobacterium tuberculosis was found to increase their life by 33% as compared with isoniazid . The findings suggest that the higher antibacterial effect of LALCI was due to the dextran matrix that potentiates the antibacterial activity of macrophages by acting on phagosomal and lysosomal cohesion.

Ter Arkh, 1997, 69(3), 19 - 23
{The characteristics of the clinical course and treatment of chronic obstructive lung diseases against a background of lymphoproliferative diseases}; Provotorov VM et al.; The authors studied expectoration, cough clearance and immunity in 48 patients with exacerbation of chronic obstructive pulmonary affections (COPA) associated with lymphoproliferative diseases (chronic lymphoid leukemia, lymphocytic lymphoma, myeloma) versus 16 control patients suffering from COPA alone . patients of the test group received cytostatics and steroids according to standard schemes . They are shown to develop aggravation of immune defects with emergence of persistent secondary immunodeficiency, more marked disturbance of tracheobronchial clearance with more frequent occurrence of persistent ciliary dyskinesia . This resulted in slower relief of clinical symptoms, more severe course dictating the necessity of longer treatment, the addition of immunocorrectors, antibacterial drugs without immunosuppressive action.

Lik Sprava, 1997 Jan-Feb, (1), 84 - 7
{The use of thienam for the emergency antibacterial therapy of acute suppurative pyelonephritis}; Pasiechnikov SP et al.; Results of a clinical and microbiological investigation designed to study thienam permit recommending this drug as an urgent agent of choice in acute purulent pyelonephritis . The drug is well tolerated . Among other benefits is extremely high sensitivity of bacteria (pathogenic and conditionally pathogenic) to the medication, achievement of an expected clinical effect within a short time since its therapy institution.

Lik Sprava, 1997 Jan-Feb, (1), 80 - 1
{Body nonspecific resistance in patients with gastric and duodenal peptic ulcer}; Pryima OB et al.; The present study focuses on bodily resistance to Helicobacter pylori infection . A decline is shown in factors of unspecific resistance, in particular, leucocyte content of non-enzymic cationic proteins in the phase of exacerbation of the ulcer process . Weakening of resistance is accompanied by a decline in the activity of phagocytosis . Thus, compromised antibacterial defence of the organism during the phase of exacerbation of the ulcer process contributes to the development of Helicobacter pylori in the gastroduodenal zone.

J Drug Target, 1997, 4(5), 265 - 70
Development and characterization of a mini capsular extrusion system for enteric delivery of metronidazole bearing liposomes; Singh R et al.; A capsular extrusion system was developed for enteric delivery of metronidazole loaded liposomes . The system is essentially based on a miniosmotic pump except that the extrusion in the present system is brought about by the swelling of a swellable polymer which raises the vestibule and extrudes out the contents through a deliver orifice . Drug reservoir of the system contained freeze dried liposomes which become hydrated prior to extrusion . Extruded liposomes were uniform in size with 45-68% incorporation of metronidazole . When tested for in vitro antiamoebic and antibacterial activity it was found that the effectiveness of liposomal metronidazole was significantly higher as compared to the unformulated drug.

Crit Rev Oral Biol Med, 1997, 8(2), 164 - 74
Subgingival delivery of therapeutic agents in the treatment of periodontal diseases; Soskolne WA; This article reviews the current status of controlled local delivery of antibacterial agents in the treatment of periodontitis . The principle of local intrapocket delivery of antibacterial agents and their delivery are discussed . The dosage forms include fibers, film/slabs, and injectable systems, some of which are degradable, while others are not and need to be removed at the termination of the treatment . The antibacterial agents used cover a range of antibiotics as well as antiseptics, and the composition of the delivery systems, their reported use, and the clinical results are summarized . The use of these systems in clinical practice is relatively recent, and therefore their application and integration into the dental office are not yet clearly defined . Clinical applications that have been tested are critically reviewed, and clinical situations in which controlled delivery of antibacterial agents may prove to be clinically useful are suggested for scientific evaluation.

Probl Tuberk, 1997, (1), 40 - 1
{Treatment and outcomes of disseminated pulmonary tuberculosis}; Rzhavskov IV et al.; The efficiency of treating 163 patients with first detected disseminated pulmonary tuberculosis in the past 30 years is analyzed . The efficiency of antibacterial therapy has been reducing with each decade owing to the detection of advanced diseases with multiple destructive changes, patient incompliance due to alcoholism, rare uses of intravenous and inhalation route of administering antituberculous drugs.

J Pept Res, 1997 Jan, 49(1), 89 - 102
Design of active analogues of a 15-residue peptide using D-optimal design, QSAR and a combinatorial search algorithm; Mee RP et al.; This report describes the rational design of novel analogues of a 15-residue antibacterial peptide CAMEL0 . A constrained D-optimal design was carried out to derive a training set of 60 analogues . Partial least squares (PLS) models describing quantitative structure-activity relationships (QSARs) were initially derived for the peptides using two published and one novel parameter set . The novel "Design parameters' were based on key structural features identified in hypothetical models of the mechanisms by which peptides interact with cell membranes . In an extension of the PLS method, influence statistics were used to decrease the weighting of compounds having a large effect on model predictions . A combinatorial search algorithm was developed which used PLS models as predictors to select a test set of 39 peptides with high predicted potencies . Within this set, the most potent analogue CAMEL135, which contained seven point mutations from CAMEL0, was identified . For a panel of 24 bacteria, the mean MIC value of CAMEL135 was approximately half of that for CAMEL0 . For the parameter sets tested, covariance functions derived from Z-scales gave highest Q2-values for the training set, whilst the model using the the 'Design parameters' gave least error when predicting the activity of the test set . The predictive ability of a third published set of peptide parameters was found to compare favourably with that of the parameters used in the design . Analysis of the PLS models indicates that hydrophobicity and amphipathicity are the most important features influencing activity for this class of compound.

J Mal Vasc, 1997 Mar, 22(1), 29 - 34
{Post-infectious systemic vasculitis: recovery without corticotherapy}; Cacoub P et al.; In the most cases the causes of systemic vasculitis are unknown and treatment is symptomatic (corticosteroids often associated with immunosuppressive agents) . We report three cases of systemic vasculitis associated with infections for which dramatic improvement was observed without cortico-therapy (in two patients) . CASE REPORT 1: A previously overweight 72-year-old woman was admitted because of a one-year history of fever, fourteen kilogram weight loss, vascular purpura, and polyneuropathy . Abnormal laboratory values included inflammatory syndrome {erythrocyte sedimentation rate (ESR): 80mm/first hour, thrombocytosis: 500,000/microliter, hypereosinophilia (1200/microliter) and positive perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) {anti-myelo-peroxydase antibodies: 30 U (normal < 7)} . Neuromuscular biopsy showed necrotizing vasculitis involving small and medium arteries . Further studies revealed a florid diverticulosis of the colon and no other severe visceral involvement . Treatment was started then with sigmoidectomy . Within six weeks her general condition improved dramatically without corticotherapy: regression of all systemic manifestations, the ESR normalized, and p-ANCA became negative . Ten months later she was still asymptomatic . CASE REPORT 2: An 50-year-old-man developed a progressive fifteen-kilogram weight loss (within 2 months), severe polyneuropathy of all four limbs . His ESR was 120 mm/first hour, and C-reactive protein 200 mg/l . Neuromuscular biopsy showed necrotizing vasculitis affecting small vessels in the nerve and no immune deposits . Stomatologic examination revealed a multiple foci of dental infections . The extraction of all these foci of infections associated with antibiotics improved dramatically all systemic manifestations (within eight weeks), once more without corticotherapy . Eight months later the patient remained asymptomatic . CASE REPORT 3: A 30-year-old-woman was admitted because of five-week history of fever, myalgias, polyarthritis, and cutaneous nodules in her limbs . Abnormal laboratory values included inflammatory syndrome, proteinuria of 0.7 g/day, and a significant rise in Chlamydia trachomatis antibodies titres from 1/64 to 1/256 over a 5 week period . She had a previous history of genital condyloma . The prednisone initialed (0.5 mg/kg/day) twelve days prior to admission was gradually reduced (stopped within 2 months) and treatment with doxycycline (200 mg/day) was initiated . Within six weeks of antibacterial treatment we assisted to a total regression of the initial clinical manifestations and laboratory values became normalized . Ten months later she remained asymptomatic . CONCLUSION: In systemic vasculitis, investigations in a search of foci of infections are of dual interest: possible etiologic agent like our case reports (strong evidence for an infectious association) and, from a therapeutic perspective, we must identify the microbes behind vasculitis syndromes, since treatment with corticosteroids may have serious consequences if the patient has an active infectious disease.

Radiats Biol Radioecol, 1997 Jan-Feb, 37(1), 61 - 7
{The use of recombinant human interleukin-1 alpha and -1 beta as agents in the early treatment of acute radiation sickness in an experiment}; Rogacheva SA et al.; Human recombinant interleukins 1 alpha and 1 beta (IL-1 alpha and IL-1 beta) have a good dose-dependent therapeutic effect for an acute radiation damage . For mice, the optimum therapy dose of IL-1 is 100.0 micrograms/kg-1 (survival rates: CD70--50%, CD100--17%; p < 0.05) . For dogs, the dose is 1.0 microgram/kg-1 (survival rate: CD100 in combination with antibacterial therapy-up to 80%; p < 0.05).

Arch Immunol Ther Exp (Warsz), 1997, 45(1), 67 - 72
Effect of bacterial extract, IRS-19, on the concentration of hydrogen peroxide and myeloperoxidase activity in nasal washings of patients with chronic bronchitis; Nowak D et al.; Twenty eight adult patients of both sexes with chronic bronchitis participated in an open study to determine the effect of intranasal treatment with IRS-19, an immunomodulating agent, on the number of polymorphonuclear leukocytes (PMNL), H2O2 concentration and myeloperoxidase (MPO) activity in nasal washings . The number of PMNL recovered from nasal spaces increased from 4460 +/- 3960 to 10,490 +/- 10,950 cells/ml (p < 0.02) after two month administration of IRS-19 . It was accompanied by 2.6- and 1.4-fold increase (p < 0.001) in MPO activity and H2O2 concentration, respectively . However, no correlation was found between increments in these three variables . Since PMNL and MPO-H2O2-Cl- system are involved in the first line of defense against invading pathogens it is suggested that above mentioned changes may represent one among mechanisms leading to enhancement of antibacterial defence in the airways in response to treatment with IRS-19.

Fold Des, 1997, 2(1), 47 - 52
Molecular modeling of amoebapore and NK-lysin: a four-alpha-helix bundle motif of cytolytic peptides from distantly related organisms; Dandekar T et al.; BACKGROUND: Amoebapore of the protozoan Entamoeba histolytica and NK-lysin of porcine cytotoxic lymphocytes are effector peptides from organisms separated extremely early in their evolutionary paths . The peptides intrigued us, however, with indications of some functional similarity . We thus wanted to derive and compare predictions for their as yet unknown three-dimensional structures as a guide for and to be tested by further experiments . RESULTS: Molecular models were generated by use of a genetic algorithm that selects according to basic protein structure principles exploiting available information such as the primary structures, secondary structure predictions and positions of disulfide bonds . Topological differences aside, the structural motif of an antiparallel four-alpha-helix bundle with adjacent connections and intramolecular crosslinks is predicted for both types of peptides . It combines the feature of amphipathic alpha-helices with a disulfide-bonded compact structure known from the beta-sheeted defensins and small toxins . CONCLUSIONS: The models presented here strengthen the notion that amoebapore and NK-lysin are particular among cytolytic and antibacterial polypeptides and share a similar function and structural motif . They also allow experimental testing and a better comparison of the two proteins in view of the predicted similarities and differences of their respective folds.

In Vivo, 1997 Jan-Feb, 11(1), 13 - 6
Induction of a protective immunity in mice against Escherichia coli by phenothiazines, 10-{n-(phthalimido)alkyl}-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1 -ureas ; Komatsu N et al.; Abilities of five phenothiazines, six 10-{n-(phthalimido)alkyl}-2-substituted-10H-phenothiazines and six 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1- ureas to induce anti-Escherichia coli activity in mice were compared . Seventeen compounds tested in this study had no antibacterial effect in direct contact with Escherichia coli using the disk diffusion method except chlorpromazine (4) with low growth inhibitory action . The pretreatment of mice with several phenothiazines, 10-{n-(phthalimido)alkyl}-2-substituted-10H-phenothiazines or 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1- ureas protected the animals from lethal infection of Escherichia coli to various extents . On the basis of these experiments, we assume that the protective effect against Escherichia coli infection might be due to the immunopotentiation or macrophage inducing activity by the compounds, or inactivation of lymphokines induced by the bacteria . Since the infection preventing effect of the tested phenothiazines depends on the chemical structures, the specificity of the biological process can be assumed.

J Antibiot (Tokyo), 1997 Jan, 50(1), 32 - 44
Cladinose analogues of sixteen-membered macrolide antibiotics . III . Efficient synthesis of 4-O-alkyl-L-cladinose analogues: improved antibacterial activities compatible with pharmacokinetics; Kurihara K et al.; The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as a neutral sugar are described . These potent novel derivatives have been efficiently synthesized avoiding glycosylations . Two hydroxyl groups in mycarose of the tri-(tert-butyldimethylsilyl) ether intermediate were successively alkylated . Sequential deprotections of silyl groups afforded 4-O-alkyl-L-cladinose analogues and 3,4-di-O-alkyl-L-mycarose analogues of leucomycin V . Some 4-O-alkyl-L-cladinose analogues exhibited potent antibacterial activities . The most active derivative, 3"-O-methyl-4"-O-(3-methylbutyl)leucomycin V, showed improved metabolic stability in rat plasma in vitro and extremely high concentrations in serum after oral administrations in mice and in hamsters.

J Antibiot (Tokyo), 1997 Jan, 50(1), 13 - 7
Benesudon, a new antibiotic fungal metabolite from cultures of Mollisia benesuada (Tul.) Phill; Thines E et al.; A novel metabolite, benesudon, possessing antibacterial, antifungal, cytotoxic and phytotoxic activities, was isolated from submerged cultures of the ascomycete Mollisia benesuada . Benesudon contains a reactive alpha-methyleneketone moiety which is believed to be responsible for its antibiotic activities, it reacts with cysteine and the reaction products are devoid of biological activities . Benesudon is the first secondary metabolite described from Mollisia benesuada, and its structure was determined by spectroscopic techniques.

Ophthalmologica, 1997, 211 Suppl 1, 2 - 8
Antibacterial protection of the ocular surface; Pleyer U et al.; The outer surface of the eye is constantly exposed to a wide array of microorganisms . To protect the integrity or the ocular surface and to retain corneal transparency, a number of defense mechanisms have evolved . This article discusses the host mechanisms of the eyelids-, tears, cornea and conjunctiva . These host defense mechanisms are identified as either a native, nonspecific defense or a specifically acquired immunological defense requiring previous exposure to an antigen and the development of specific immunity . Nonspecific components that protect the eye include the eyelids, ocular surface epithelium, normal flora and tear proteins . Specifically acquired immunity in tears, cornea and conjunctiva involves the interaction of antigen-presenting cells, lymphocytes and humoral components of the immune system.

Toxicol Pathol, 1997 Jan-Feb, 25(1), 53 - 60
Cationic amphiphilic drug-induced phospholipidosis; Halliwell WH; Phospholipidosis, a phospholipid storage disorder, defines an excessive accumulation of intracellular phospholipids . Phospholipids are structural components of mammalian cytoskeleton and cell membranes . The metabolism of this essential cell component is regulated by the individual cell and may be altered by drugs that interact with phospholipids or the enzymes that affect their metabolism . Xenobiotics or their metabolites that induce phospholipidosis include a wide variety of pharmacologic agents, including antibacterials, antipsychotics, antidepressants, antiarrhythmics, antianginals, antimalarials, anorexic agents, cholesterol-lowering agents, and others . Each of these drugs shares several common physiochemical properties: hydrophobic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group, hence the class term cationic amphiphilic drugs (CADs) . This paper reviews the phospholipid metabolism, physiochemical characteristics of CADs, specificity of phospholipidosis in animals and humans, functional effects of phospholipidosis, interaction of CADs with biologic membranes and lysosome metabolism, influence of CADs on phospholipases and phospholipid synthesis, and a proposed mechanism for induction of phospholipidosis in the lung . In human risk assessment, investigators should consider the many factors in evaluating a drug that induces phospholipidosis in animals . These include: the therapeutic class of drug, presence of active metabolites, tissue or organ selectivity in animals and humans, influence of concurrently administered drugs, reversibility of effect, and other factors that increase or decrease the induction of phospholipidosis . Generalities regarding the etiology, incidence, and effect of the drug on a specific host may not be made . Each drug must be evaluated separately to identify the risk when administered for therapeutic effect in humans.

J Pak Med Assoc, 1997 Jan, 47(1), 29 - 32
Paediatric prescribing in Karachi; Nizami SQ et al.; To assess amount of drug overuse we studied drug prescribing for common childhood problems by 65 general practitioners (GPs) and 29 paediatricians . A total of 2433 encounters between GPs or paediatricians and children under five years of age were observed . The presenting complaints were fever in 18%, cough in 9%, both fever and cough in 21%, vomiting in 20% and diarrhoea in 41% of encounters . Antibacterials were prescribed in 49% of encounters, analgesics and antipyretics in 29%, antiemetics in 8% and injectables in 15% . Antidiarrhoeals were prescribed in 41% encounters with children reported to have diarrhoea . Ampicillin and cotrimoxazole were the two common antibacterials prescribed by both GPs and paediatricians . Antibacterials were prescribed in significantly larger number of encounters with GPs than in those with paediatricians . Mean encounter time of patients with GPs was 3.4+/-2.7 minutes and with paediatricians 9.7+/-4.1 minutes.

Annu Rev Entomol, 1997, 42, 611 - 43
Biological mediators of insect immunity; Gillespie JP et al.; Infection in insects stimulates a complex defensive response . Recognition of pathogens may be accomplished by plasma or hemocyte b1p4eins that bind specifically to bacterial or fungal polysaccharides . Several morphologically distinct hemocyte cell types cooperate in the immune response . Hemocytes attach to invading organisms and then isolate them by phagocytosis, by trapping them in hemocyte aggregates called nodules, or by forming an organized multicellular capsule around large parasites . These responses are often accompanied by proteolytic activation of the phenoloxidase zymogen that is present in the hemolymph . A component of insect immune responses to bacteria is the synthesis by fat body and hemocytes of a variety of antibacterial proteins and peptides, which are secreted into the hemolymph . These molecules attack bacteria by several mechanisms . Inducible antifungal proteins have also been recently discovered in insect hemolymph . The promoters for several antibacterial protein genes in insects are regulated by transcription factors similar to those involved in mammalian acute phase responses.

Leukemia, 1997 Jan, 11(1), 97 - 105
Identification and functional analysis of multiple murine myeloperoxidase (MPO) promoters and comparison with the human MPO promoter region; Zhao WG et al.; Myeloperoxidase (MPO) is an important component of the oxidative antibacterial defense system of granulocytes . Mammalian MPO gene expression has been most extensively studied in human and murine cells . Transcription of the human MPO gene appears to begin at a single initiation site and we have recently described the isolation and characterization of the corresponding human MPO promoter . On the other hand, MPO transcripts in murine myeloid cells show several distinct 5'-termini, suggesting the existence of multiple murine MPO promoters . However, significant levels of endogenous murine MPO promoter activity have not been demonstrated heretofore, although several murine MPO enhancers have been described . We now report the identification and preliminary functional characterization of four distinct murine MPO promoters . Sequence comparison of the human and murine MPO promoter regions reveals homologues of three out of four of these murine promoters within the human MPO gene . However, only one of these sites appears to be functionally active in human myeloid cells, possibly because of the interposition of Alu sequences between the putative promoter sites in the human gene.

Semin Nephrol, 1997 Jan, 17(1), 27 - 33
Aminoglycoside nephrotoxicity; Swan SK; Aminoglycoside antibiotics maintain a leading role in antibacterial therapy of severe gram-negative infections despite nephrotoxicity complicating 10% to 20% of therapeutic courses . Risk factors for aminoglycoside-induced renal injury have been identified . A variety of maneuvers to protect renal function and minimize toxicity have been suggested, but few have been accepted for clinical use . Aminoglycosides are eliminated by glomerular filtration, but a fraction is reabsorbed in the proximal tubule . Polycationic aminoglycosides bind to anionic, brush-border, phospholipid membranes and are transported intracellularly . Disruption of normal phospholipid trafficking within the cell is evidenced by the presence of myeloid bodies, electron-dense concretions of phospholipid material . Although consistent with aminoglycoside injury, such biochemical and histological changes are observed with other drug exposures in which renal failure does not occur . Therapeutic drug monitoring services have failed to reduce aminoglycoside toxicity over the years, although two pharmacological parameters are imperative . The first is that peak aminoglycoside levels correlate with efficacy, as these agents display concentration-dependent bacterial killing . Second, trough levels reflect nephrotoxicity; the kidney is unable to excrete the dose of aminoglycoside within the dosing interval owing to impaired function . These two points have led to numerous reports evaluating once-daily dosing of aminoglycosides in which the cumulative dose for a 24-hour period would be administered as a single dose . This would take advantage of concentration-dependent "bug" killing as well as the post-antibiotic effect while minimizing repeated exposure and potential nephrotoxicity . Further trials are warranted to establish specific guidelines for once-daily as well as every 36- to 48-hour dosing regimens in patients with established renal impairment for specific organisms and specific types of infection.

Ann Pharmacother, 1997 Jan, 31(1), 39 - 44
Amphotericin B enzyme-linked immunoassay for clinical use: comparison with bioassay and HPLC; Cleary JD et al.; OBJECTIVE: To evaluate a new enzyme-linked immunosorbent assay (ELISA) for amphotericin B in serum samples . Results are compared with those obtained by HPLC and bioassay . DESIGN: Comparison of results obtained by ELISA, HPLC, and bioassay . METHODS: We developed a new ELISA using a polyclonal rabbit antibody to measure serum amphotericin B concentrations . Blinded samples of amphotericin B in concentrations of 0.15-78 micrograms/mL were prepared in human serum and assayed simultaneously by the ELISA, HPLC, and bioassay . The results of each assay were derived from standard curves and evaluated by using the Table Curve 2D computer program . These data were compared by using correlation analysis with evaluation of Pearson's correlation coefficient by Student's t-test . RESULTS: ELISA and bioassay compared favorably at amphotericin B concentrations of 0.3-20 micrograms/mL with a correlation coefficient of r = 0.993, while ELISA and HPLC compared with a correlation coefficient of r = 0.944 . The average coefficient of variation over the range 0.3-20.0 micrograms/mL was 28% +/- 7% for HPLC, 26% +/- 9% for ELISA, and 13% +/- 4% for bioassay . Comparison of all three assays revealed the highest correlation with the ELISA assay (r = 0.998) for the range of concentrations (0.3-20 micrograms/mL) routinely achieved . Samples containing concentrations in excess of 20 micrograms/mL could be diluted . Desiccation for concentrations less than 0.3 microgram/mL was not tested . CONCLUSION: The determination of serum amphotericin B concentrations by ELISA gave results similar to those obtained by a bioassay and HPLC technique . Although variability appears greater with ELISA, the ease of performing yjis assay expedites the evaluation of amphotericin B concentrations from lipid formulations without interference from coadministered antibacterials of azole antifungals.

Clin Infect Dis, 1997 Jan, 24 Suppl 1, S63 - 6
Increases in rates of resistance to trimethoprim; Huovinen P; Trimethoprim alone or in combination with a sulfonamide is an effective and relatively inexpensive antibacterial medication . However, a dramatic increase in the rate of resistance to trimethoprim along with high-level resistance to sulfonamides has been seen during the past two decades . The mechanisms of resistance show a remarkable evolutionary adaptation.

Clin Infect Dis, 1997 Jan, 24 Suppl 1, S9 - 16
The population genetics of antibiotic resistance; Levin BR et al.; Mathematical models are used to ascertain the relationship between the incidence of antibiotic treatment and the frequency of resistant bacteria in the commensal flora of human hosts, as well as the rates at which these frequencies would decline following a cessation of antibiotic use . Recent studies of the population biology of plasmid-encoded and chromosomal antibiotic resistance are reviewed for estimates of the parameters of these models and to evaluate other factors contributing to the fate of antibiotic-resistant bacteria in human hosts . The implications of these theoretical and empirical results to the future of antibacterial chemotherapy are discussed.

Antimicrob Agents Chemother, 1997 Jan, 41(1), 66 - 71
Molecular interactions of a semisynthetic glycopeptide antibiotic with D-alanyl-D-alanine and D-alanyl-D-lactate residues; Allen NE et al.; LY191145 is an N-alkylated glycopeptide antibiotic (the p-chlorobenzyl derivative of LY264826) with activity against vancomycin-susceptible and -resistant bacteria . Similar to vancomycin, LY191145 inhibited polymerization of peptidoglycan when muramyl pentapeptide served as a substrate but not when muramyl tetrapeptide was used, signifying a substrate-dependent mechanism of inhibition . Examination of ligand binding affinities for LY191145 and the effects of this agent on R39 D,D-carboxypeptidase action showed that, similar to vancomycin, LY191145 had an 800-fold greater affinity for N,N'-diacetyl-L-Lys-D-Ala-D-Ala than for N,N'-diacetyl-L-Lys-D-Ala-D-Lac . The antibacterial activity of LY191145 was antagonized by N,N'-diacetyl-L-Lys-D-Ala-D-Ala, but the molar excess required for complete suppression exceeded that needed to suppress inhibition by vancomycin . LY191145 is strongly dimerized and the p-chlorobenzyl side chain facilitates interactions with bacterial membranes . These findings are consistent with a mechanism of inhibition where interactions between antibiotic and D-Ala-D-Ala or D-Ala-D-Lac residues depend on intramolecular effects occurring at the subcellular target site.

Antimicrob Agents Chemother, 1997 Jan, 41(1), 54 - 9
Antibacterial activity in bovine lactoferrin-derived peptides; Hoek KS et al.; Several peptides sharing high sequence homology with lactoferricin B (Lf-cin B) were generated from bovine lactoferrin (Lf) with recombinant chymosin . Two peptides were copurified, one identical to Lf-cin B and another differing from Lf-cin B by the inclusion of a C-terminal alanine (lactoferricin) . Two other peptides were copurified from chymosin-hydrolyzed Lf, one differing from Lf-cin B by the inclusion of C-terminal alanyl-leucine and the other being a heterodimer linked by a disulfide bond . These peptides were isolated in a single step from chymosin-hydrolyzed Lf by membrane ion-exchange chromatography and were purified by reverse-phase high-pressure liquid chromatography (HPLC) . They were characterized by N-terminal Edman sequencing, mass spectrometry, and antibacterial activity determination . Pure lactoferricin, prepared from pepsin-hydrolyzed Lf, was purified by standard chromatography techniques . This peptide was analyzed against a number of gram-positive and gram-negative bacteria before and after reduction of its disulfide bond or cleavage after its single methionine residue and was found to inhibit the growth of all the test bacteria at a concentration of 8 microM or less . Subfragments of lactoferricin were isolated from reduced and cleaved peptide by reverse-phase HPLC . Subfragment 1 (residues 1 to 10) was active against most of the test microorganisms at concentrations of 10 to 50 microM . Subfragment 2 (residues 11 to 26) was active against only a few microorganisms at concentrations up to 100 microM . These antibacterial studies indicate that the activity of lactoferricin is mainly, but not wholly, due to its N-terminal region.

Science, 1996 Dec 20, 274(5295), 2107 - 10
A mechanism of drug action revealed by structural studies of enoyl reductase; Baldock C et al.; Enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis, is the target for antibacterial diazaborines and the front-line antituberculosis drug isoniazid . Analysis of the structures of complexes of Escherichia coli ENR with nicotinamide adenine dinucleotide and either thienodiazaborine or benzodiazaborine revealed the formation of a covalent bond between the 2' hydroxyl of the nicotinamide ribose and a boron atom in the drugs to generate a tight, noncovalently bound bisubstrate analog . This analysis has implications for the structure-based design of inhibitors of ENR, and similarities to other oxidoreductases suggest that mimicking this molecular linkage may have generic applications in other areas of medicinal chemistry.

Eur J Biochem, 1996 Dec 15, 242(3), 689 - 94
The enoyl-{acyl-carrier-protein} reductase (FabI) of Escherichia coli, which catalyzes a key regulatory step in fatty acid biosynthesis, accepts NADH and NADPH as cofactors and is inhibited by palmitoyl-CoA; Bergler H et al.; Reduction of enoyl-acyl-carrier-protein (ACP) substrates by enoyl-ACP reductase is a key regulatory step in fatty acid elongation of Escherichia coli . Two enoyl-ACP reductase activities have been described in E . coli, one specific for NADH, the other for NADPH as cofactor . Because of their distinct enzymatic properties, these activities were ascribed to two different proteins . The NADH-dependent enoyl-ACP reductase of E . coli has previously been identified as the FabI protein, which is the target of a group of antibacterial compounds, the diazaborines . We now demonstrate that both enoyl-ACP reductase activities reside in FabI . In crude cell extracts of FabI-overproducing strains, both NADH-dependent and NADPH-dependent enoyl-ACP reductase activities are increased . Mutations in the fabI gene that lead either to temperature-sensitive growth or diazaborine resistance result in the reduction of both activities . When FabI is purified in pH 6.5 buffers, the protein exhibits NADH-dependent and NADPH-dependent reductase activities . Both enzymatic activities are inhibited by diazaborine . The NADPH-dependent enoyl-ACP reductase activity, however, turned out to be approximately eight times more resistant to diazaborine . The difference in sensitivity indicates that binding of either NADPH or NADH to FabI results in distinct changes in the configuration of the protein or, alternatively, it is different due to the different charge of the cofactors . These effects might be responsible for the differences in the enzymatic properties . Both reductase activities of the FabI protein are inhibited by physiologically relevant concentrations of palmitoyl-CoA, which might be important in regulating endogenous fatty acid biosynthesis in E . coli in the presence of exogenous fatty acids.

Eur J Biochem, 1996 Dec 15, 242(3), 665 - 73
Biosynthesis of acylpeptidolactones of the daptomycin type . A comparative analysis of peptide synthetases forming A21978C and A54145; Wessels P et al.; A21978C and A54145 are antibacterial 13-residue peptides with a medium-chain-acylated amino terminus and a 10-residue lactone ring; they are produced by strains of Streptomyces roseosporus and Streptomyces fradiae, respectively . The structural differences in their peptide chains, which include amino acid replacements and modifications (L-Glu2-->L-Asn, L-Asn(OH)3-->L-Asp, Sar5-->Gly, L-Ala6-->L-Orn, L-Lys8-->D-Ala, L-Asp(OMe)9-->L-Asp, L-Asn11-->D-Ser, and L-lle13-->L-Kyn; Sar = sarcosine; L-Orn = L-ornithine, L-Kyn = L-kynurenine), reside in the multienzymatic templates directing their biosynthesis . We have examined the peptide synthetases employing immunodetection and substrate activation detected by the amino-acid-dependent ATP-PP1-exchange reaction . Two different antibodies specific for actinomycin synthetase 2 and a peptide sequence characteristic of acyl-CoA-synthetases/peptide synthetases were applied . For the A21978 system two peptide synthetases of 670 and 240 kDa were detected, together with two similar proteins of 630 and 440 kDa occurring in varying amounts . The latter are suggested to be degradation products of an unstable multienzyme . Activation of L-Asp, L-Thr, Gly, L-Orn, L-Ala and L-Ser were assigned to the high-molecular-mass components of 670, 630 and 440 kDa . The 240-kDa protein was purified to homogeneity and shown to catalyse activation of L-kynurenine . The A54145 system consisted of three peptide synthetases of 690, 590 and 250 kDa . Activations of L-Asn . L-Thr and Gly were found . The 250-kDa synthetase was capable of activating isoleucine and valine . Both systems thus show a comparable organisation; implications for the modular construction of their peptide synthetases are discussed.

Arch Biochem Biophys, 1996 Dec 15, 336(2), 283 - 9
High level expression of Ricinus communis casbene synthase in Escherichia coli and characterization of the recombinant enzyme; Hill AM et al.; Casbene synthase catalyzes the cyclization of geranylgeranyl diphosphate (2) to casbene (1), a diterpene phytoalexin with antibacterial and antifungal activity that is produced by seedlings of castor bean (Ricinus communis L.) in response to fungal attack . We report the high-level expression of casbene synthase cDNA in Escherichia coli as insoluble inclusion bodies, the solubilization and refolding of active casbene synthase, and the kinetic and product analysis of the recombinant enzyme . To overcome problems apparently associated with the presence in the casbene synthase gene of rare Arg codons, as well as the intrinsic antibacterial activity of casbene itself, the casbene synthase gene was expressed in an E . coli host harboring the pSM102 vector that encodes the dnaY gene for tArg(AGA/G), using an expression vector, pET-21d(+), carrying the tightly controlled T7lac promoter.

Pharmacoeconomics, 1997 Jan, 11(1), 64 - 74
Cost-effectiveness of abbreviating the duration of intravenous antibacterial therapy with oral fluoroquinolones; Jensen KM et al.; Comprehensive economic analyses should include outpatient as well as inpatient resources . A healthcare system that includes both inpatient and outpatient care, such as prescriptions, physician care, laboratory tests and multiple other items, has been termed an Integrated Healthcare Network (IHN) . Thus, cost-effectiveness analyses from the perspective of an IHN are necessary . We report a cost-effectiveness analysis from an IHN perspective on 187 evaluable hospitalised patients with serious infection who participated in randomised clinical trials that evaluated either: (i) standard regimens of intravenous (i.v.) antibacterial therapy, usually followed by oral antibacterial therapy; or (ii) an abbreviated regimen of intravenous antibacterials for 2 to 4 days, followed by either oral ciprofloxacin or oral enoxacin as early switch therapy . Clinical success rates were similar for the 2 treatment groups . The median number of days of in-hospital antibacterial treatment was 11 for standard i.v . therapy and 10 for switch therapy . Adverse events occurred in 33% of the standard i.v . therapy group and in 50% of the switch therapy group . Sensitivity analysis of drug price and hospital bed cost showed that switch therapy was consistently more cost effective than standard i.v . therapy . Standard i.v . therapy would have to be 10% more effective than switch therapy to change the economic decision . In this analysis, switch therapy was a cost-effective treatment with no demonstrated change in efficacy compared with standard i.v . therapy.

Biochem Biophys Res Commun, 1996 Dec 4, 229(1), 243 - 8
Chemically modified tetracyclines inhibit inducible nitric oxide synthase expression and nitric oxide production in cultured rat mesangial cells; Trachtman H et al.; Tetracyclines inhibit matrix metalloproteinases (MMP) and attenuate connective tissue degradation in a wide variety of human and animal disorders . Chemically modified tetracyclines (CMT) have been synthesized in which the antibacterial potency has been eliminated but in which the anti-MMP efficacy is retained . Nitric oxide (NO) modulates MMP synthesis and activity in mesangial cells in vitro . Therefore, we examined whether CMT inhibit iNOS gene and protein expression and NO production in cultured rat mesangial cells . Mesangial cells were maintained in media containing IFN-gamma and LPS for 24-72 h . Test media contained either no further additives or CMT-1, 3, 5, or 8 at concentrations of 1, 2.5, 5, and 10 micrograms/ml . iNOS gene and protein expression were assessed and NO production was determined by the Griess reaction . Incubation of mesangial cells with CMT-3 and CMT-8 resulted in time- and dose-dependent inhibition of NO production that was maximal at 48 h (< 20% of control) and at a drug concentration of 5 micrograms/ml (P < 0.05) . Addition of CMT-1 had a modest (40%) inhibitory effect and CMT-5 did not alter NO production . The impact of CMT on NO production was directly related to their potency as collagenase inhibitors . Moreover, CMT-induced changes in NO synthesis were associated with parallel alterations in steady-state iNOS mRNA abundance and protein expression . These agents may be useful to ameliorate NO-dependent glomerular inflammation.

J Endod, 1996 Dec, 22(12), 668 - 73
Effects of a combination of an antibacterial agent (ofloxacin) and a collagenase inhibitor (FN-439) on the healing of rat periapical lesions; Anan H et al.; To investigate the effects of a combination of an antibacterial agent (ofloxacin) and a collagenase inhibitor (FN-439) in the root canal treatment of apical periodontitis, we studied the healing process of experimentally induced periapical lesions in rats by using immunohistochemical methods . With a topical application of a combination of ofloxacin and FN-439 following experimentally induced periapical lesions, both neutrophils and macrophages became significantly decreased in number, while active cementogenesis and extensive bone formation were seen in the periapical region . However, the use of ofloxacin alone also demonstrated a beneficial effect on periapical inflammation and healing . Therefore, it is suggested that ofloxacin is powerful against bacterial infection whether FN-439 is added . The only observed effect of a combination of ofloxacin and FN-439 is that it may more effectively inhibit osteoclastic bone resorption and activate the remodeling of the apical periodontal tissue if this combined medicament is used in a stage of active bone destruction characterized by high production of tissue collagenase.

Voen Med Zh, 1996 Dec, 317(12), 21 - 2, 80
{The intra-aortic antibacterial therapy of wounded patients with gunshot meningoencephalitis}; Murashkin SV et al.; The original decision of permanent introduction of antibacterial means to tissues of brain at gunshot meningoencephalitis is offered . For antibacterial therapy the intra-aortal catheter with diameter of 2,5 mm (through a.femoralis) was introduced . After washing the catheter by solution of crystalloid with heparin the various combinations of preparations in 5% solution of glucose were introduced: cephalosporin--8 g/day; hentamicin and brumacilin--240 mg/day accordingly, amicacin--1500 mg/day . Speed of introduction--20-50 mg/h, total volume--500 ml . The catheter was in aorta not more than 10 days, maximum--14 days . A described technique was applied in Burdenko Main Military Clinical Hospital on 34 wounded in head . At computer tomography of brain of all wounded intracranially the splinters and bullets were revealed, clinically--meningoencephalitis . Foreign bodies have been extracted after cupping of clinical and laboratory signs of meningoencephalitis . The authors consider, that the technique is effective not only at wounds of brain, but also at suppurative meningoencephalitis of other etiology.

Med Oncol, 1996 Dec, 13(4), 223 - 31
Clinical and laboratory diagnosis of invasive candida infection in neutropenic patients; Kalin M et al.; Cancer patients, especially those with acute leukaemia, represent a group that has the greatest risk for deep fungal infection . Almost no cases were seen before the advent of modern chemotherapy, and prior to the availability of antibacterial agents, less than 5% of patients with acute leukaemia died of fungal infection . These infections are now responsible for 40% or more of the deaths at some institutions . Candida species continues to be the most common fungal pathogen . Rapid and specific diagnosis of invasive candiosis enabling early effective therapy is therefore an important measure for reducing mortality in patients . Here the current status of clinical and laboratory diagnosis of invasive candida infection in neutropenic patients is discussed and recommendations made as to future development programmes.

Boll Chim Farm, 1996 Dec, 135(11), 638 - 42
Studies on the synthesis and biological activity of 3-(substituted anilinomethyl)-4-(5-substituted-2-furfurylidene)amino-1,2,4 -triazole-5- thiones and their Mannich bases; Kalluraya B et al.; A series of 3-(substituted anilinomethyl)-4-(5-substituted-2- furfurylidene)amino-1,2,4-triazole-5-thiones were synthesized as potential biologically active agents . They were converted to Mannich bases, by treating with suitable amine in the presence of formaldehyde in alcohol medium . The newly synthesized compounds were screened for their antibacterial and antifungal activities.

Farmaco, 1996 Dec, 51(12), 801 - 8
Synthesis and biological activity of platinum group metal complexes of o-vanillin thiosemicarbazones; Offiong OE et al.; o-Vanillin-(4-methylthiosemicarbazone), o-Vanillin-(4-phenylthiosemicarbazone) and some of their metal complexes of the platinum group have been synthesized, characterized by chemical and spectral methods and studied for their antibacterial, antifungal and amoebicidal activity in vitro . The platinum group metal chelates exibited significant activity against a wide spectrum of microorganisms at different concentrations . The Pt(II) and Ru(III) chelates derived from o-vanillin-(4-phenylthiosemicarbazone) seem to be the most efficient inhibitors . Evaluation of the antimalarial activity of the compounds in mice infected with Plasmodium berghei indicated that cures were attainable at dose levels of 40-160 mg/kg but with toxic death prevalence at higher dose levels.

Farmaco, 1996 Dec, 51(12), 785 - 92
Studies on arylfuran derivatives-Part VI . Synthesis, characterization and antibacterial activities of some 6-(5-aryl-2-furyl)-1,2,4-triazolo {3,4-b}-1,3,4-thiadiazoles and 6-(5-nitro-2-furyl)-1,2,4-triazolo{3,4-b}-1,3,4-thiadiazoles; Holla BS et al.; A series of 4-{5-aryl-2-furfurylidene}amino-3-mercapto-5-substituted-1,2,4-tri azoles and 4-{5-Nitro-2-furfurylidene}amino-3-mercapto-5-substituted-1,2,4-tr iazoles have been synthesized and were converted into 1,2,4-triazolo {3,4-b}-1,3,4-thiadiazoles . These triazolothiadiazoles are also synthesized by an alternative method in better yields employing arylfuroic acids and s-triazoles in the presence of phosphorus oxychloride . The newly synthesized compounds are screened for their antibacterial properties.

Nippon Geka Gakkai Zasshi, 1996 Dec, 97(12), 1072 - 8
{Recent advances and treatment of sepsis}; Hirata K; This article introduces recent advances in experimental or clinical pathophysiology and in treatment of sepsis . Both the concept of systemic inflammatory response syndrome (SIRS) and the definition of sepsis, as the systemic response to infection, have actually been overwhelming and its generalization is contributing on the better prognosis after treatment for the patients with sepsis and also on the pioneer researches in this field, using molecular biology techniques . In the mediator network and the immune cell network, cytokines released from polymorphonuclear cells, macrophages, monocytes and vascular endothelial cells have important roles in initiation of the immune cells activations or priminings . On the other hand, free radicals, supecroxides, proteolytic enzymes directly involved the pathophysiology, and occasionally impaired the cellular or the organ function . The patient with one or more organ dysfunctions should be cared intensively by multidisciplinary control, i . e . antibacterial therapies, nutritional control, immunomodulation, removal of toxic substances, etc . Our attentions should be concentrated to prevent from septic MODF, especially for a patient primed by infection, because rapid response at the second at tack is important for care . Anyhow, fine observation and strict investigation is required for the treatment of the primed patient by infection.

J Antibiot (Tokyo), 1996 Dec, 49(12), 1266 - 74
Novel C-2 substituted carbapenem derivatives . Part II . Synthesis and structure-activity relationships of isoxazolin-2-yl, isoxazolidin-2-yl and 2-pyrazolin-2-yl carbapenems generated using 1,3-dipolar cycloaddition chemistry; Burton G et al.; A series of carbapenems containing novel C-2 semisaturated heterocyclic substituents were synthesised by 1,3 dipolar cycloaddition reactions of nitrile oxides, nitrile imines and a nitrone to 2-vinylcarbapenem . The isoxazoline and isoxazolidine compounds showed potent antibacterial activity but moderate stability to human dehydropeptidase 1 (DHP-1) . Stability to DHP-1 was improved by methyl substitution in the isoxazoline ring, but at the expense of antibacterial activity . The pyrazolines exhibited excellent stability to DHP-1, but reduced potency against Gram-negative organisms.

J Antibiot (Tokyo), 1996 Dec, 49(12), 1258 - 65
Novel C-2 substituted carbapenem derivatives . Part I . Synthesis and biological activity of non-aromatic heterocyclic derivatives; Burton G et al.; A new series of carbapenems, having a saturated or partially unsaturated heterocycle at C-2, has been synthesised . The in vitro antibacterial activity of these compounds and their stability to human dehydropeptidase-1 (DHP-1) are described . The stereochemistry of the C-2 side-chain and the presence of a double bond in the heterocycle were shown to have significant effects on the stabilities of the compounds to DHP-1.

J Clin Periodontol, 1996 Dec, 23(12), 1100 - 3
The effect of toothpaste containing triclosan on oral mucosal desquamation . A model study; Skaare A et al.; SLS-containing toothpaste has previously been shown to cause oral mucosal desquamations when used in an experimental cap splint model . The aim of the present study was to examine the effect of toothpastes containing SLS in combination with triclosan on oral mucosal desquamation in a similar cap splint model system . It has previously been shown that the antibacterial agent triclosan also may have anti-inflammatory properties . The concentration of triclosan in the experimental toothpastes was 0.3%, while SLS varied from 1.5% to 3% . No oral mucosal desquamations were observed after use of a 1.5% SLS 0.3% triclosan containing toothpaste, contrary to the positive control toothpaste that contained 1.5% SLS without triclosan . Furthermore, a statistically significant reduction in severe desquamations was observed after use of a toothpaste containing 3% SLS-0.3% triclosan compared with the positive control . It may thus be suggested that triclosan exerts a moderating effect on desquamative reactions caused by SLS and that the effect is dependent on the relative amount of triclosan and SLS in the toothpastes.

Chem Pharm Bull (Tokyo), 1996 Dec, 44(12), 2335 - 7
Effects of the structures of polyoxyethylene alkyl ethers on uptake of butyl p-hydroxybenzoate by Escherichia coli and its antibacterial activity; Fukahori M et al.; The effects of the structures of non-ionic surfactants on the uptake of butyl p-hydroxybenzoate (BP) into Escherichia coli cells and its antibacterial activity were systematically studied using polyoxyethylene alkyl ethers (PAEs) possessing various oxyethylene and hydrocarbon chain lengths . The uptake of BP into bacterial cells in an aqueous PAE solution was proportional to free BP in an aqueous phase, depending on the structures of PAEs . The antibacterial activity of BP decreased in the presence of PAEs, whereas it was greater than that anticipated from free BP . However, only PAE with 12 carbons in the hydrophobic group caused unusual increases in the uptake and antibacterial activity of BP, and the surfactant was more extensively incorporated into bacterial cells, differing from other PAEs, which were much less incorporated . The PAEs were thus concluded to increase the susceptibility of bacteria against BP due to direct interactions with the cells . Particularly, the PAE with 12 carbons in the hydrophobic group, which penetrated abundantly into the cells, might result in an increase in the fluidity of the cellular lipid matrix and a decrease in the resistance of drug permeation.

Chem Pharm Bull (Tokyo), 1996 Dec, 44(12), 2326 - 30
Studies on the synthesis and structure-activity relationships of 2-(2-functionalized pyrrolidin-4-ylthio)-1 beta-methylcarbapenems; Lee HW et al.; A series of new carbapenem derivatives, which have a pyrrolidin-4-ylthio group substituted with a hydroxyalkyl or carbamoyl group at the 2' position as the C-2 side chain, have been prepared . The antibacterial activity and the stability to renal dehydropeptidase-I of these compounds were investigated, and the structure-activity relationships were studied . Among these new carbapenems, (1R,5S,6S)-2-{(2S,4S)-2- inverted question mark(2-hydroxy)ethylmercaptomethyl inverted question markpyrroli din-4 -ylthio}-6-{(1R)-I-hydroxyethyl}-1-methyl-1-carbapen-2-em-3- carboxylic acid (1a) showed the most potent and well balanced activity and was selected as a candidate for further evaluation.

Graefes Arch Clin Exp Ophthalmol, 1996 Dec, 234(12), 731 - 8
Predictive factors for response to medical therapy in bacterial ulcerative keratitis; Kim RY et al.; BACKGROUND: Fifty-four consecutive cases of culture-positive bacterial ulcerative keratitis presenting at a major university hospital were reviewed to identify factors predictive of response to medical therapy for bacterial ulcerative keratitis (BUK) . METHODS: Eleven patients (20%) failed medical therapy (defined as the need for surgical intervention or cyanoacrylate gluing) . Using multivariate logistic regression, the following variables were evaluated: (1) predisposing ocular factors (e.g., contact lens wear), (2) pre-existing ocular diseases, (3) ulcer size, and (4) the number of topical ocular medications used at the time of presentation . RESULTS: We noted certain factors to be potentially predictive of medical therapy outcome . The average size of the ulcer at the time of presentation was 4.4 +/- 2.4 mm in the failure group but only 2.5 +/- 1.9 mm for the success group (P = 0.027) . In addition, patients in the medical failure group used more topical ocular medications at the time of presentation (P = 0.0075) . Further analysis of the individual topical ocular medications revealed that the use of corticosteroids was higher in the failure group (56% vs 12%, P = 0.0005 by Fisher's exact test) . Other factors such as patient age, the type of organism(s), and the time elapsed between the onset of symptoms and the beginning of definitive therapy were not statistically significant . CONCLUSION: In this population, ulcer size at the onset of antibacterial treatment and the use of certain ocular medications, specifically corticosteroids, were significant predictive factors for failure of medical therapy for BUK.

Eur J Epidemiol, 1996 Dec, 12(6), 631 - 6
Periodontal disease, oral microbial flora and salivary antibacterial factors in diabetes mellitus type 1 patients; Pinducciu G et al.; One hundred and thirty-one patients with diabetes mellitus type 1 (IDDM) and 20 healthy controls were checked for the presence of periodontal diseases and for some oral microbiological parameters . Results demonstrated that IDDM patients, who were well compensated from both the metabolic and clinical point of view, showed a prevalence for periodontopathies, which only differed slightly from controls . Only the presence of gingivitis was significantly higher in IDDM patients than in healthy subjects . Both anaerobic and aerobic microbial flora did not show substantial differences for either group . Among the salivary antibacterial factors studied, lysozyme was significantly decreased in diabetic patients compared to controls . It is concluded that IDDM patients undergo periodontal complications with a frequency quite close to that of non-diabetic healthy subjects, when the disease is under strict metabolic and clinical control.

J Vet Pharmacol Ther, 1996 Dec, 19(6), 423 - 30
A study of the pharmacokinetics and tissue residues of an oral trimethoprim/sulphadiazine formulation in healthy pigs; Garwacki S et al.; Twenty-six healthy female pigs weighing 19.5-33 kg were used in three separate experiments . The animals were fed individually twice a day . Trimethoprim/sulphadiazine (TMP/SDZ) formulation was added to feed in the amount of 6 mg/kg bw (TMP) and 30 mg/kg bw (SDZ) . TMP and SDZ concentrations in blood plasma, muscles, liver and kidneys were measured . Pharmacokinetic parameters show that the absorption of TMP from the alimentary tract in pigs is faster than the absorption of SDZ, and the elimination of TMP is slower than that of SDZ . The absorption half-lives were 0.96 (TMP) and 2.24 h (SDZ), whereas elimination half-lives were 5.49 (TMP) and 4.19 h (SDZ) . The observed TMP:SDZ ratios in blood plasma after multiple dose administration ranged from 1:11.4 to 1:23.2 . One day after administration of the last dose of TMP/SDZ the plasma concentration ratio was 1:15.5, but in muscles, liver and kidneys it was much lower: 1:0.79, 1:0.14 and 1:1.53 respectively . The absolute TMP and SDZ tissue concentrations 1 day after the last multiple dose administration were very low (maximum TMP: 0.29 micrograms/g in liver; maximum SDZ: 0.23 micrograms/g in kidneys) . Neither drug was detected in any tissue 8 days after the last administration of TMP/SDZ . Based on our results, it was concluded that there is no support for the TMP:SDZ pharmaceutical ratio 1:5 in oral formulations of these compounds for pigs . The administration oral TMP/SDZ formulations once a day may result in the absolute tissue concentrations of these drugs being too low for antibacterial activity . The withdrawal period for such an oral TMP/SDZ formulation for pigs (according to accepted guidelines in Europe for MRL of TMP < 0.05 mg/kg of tissue) should not be less than 5 days.

Aliment Pharmacol Ther, 1996 Dec, 10(6), 905 - 12
Effects of ranitidine bismuth citrate on gastric acid secretion and gastrin release in subjects with and without Helicobacter pylori infection; Ciociola AA et al.; BACKGROUND: Ranitidine bismuth citrate is a novel antiulcerant that provides the antisecretory activity of ranitidine and the gastric mucosal protection and antibacterial properties of bismuth . METHODS: This randomized, double-blind, placebo-controlled study evaluated the effects of single doses of ranitidine bismuth citrate 200 mg, 400 mg and 800 mg and ranitidine hydrochloride 150 mg on gastrin release and suppression of gastric acid secretion, and compared acid secretory profiles and gastrin release between Helicobacter pylori-negative and -positive patients . Plasma gastrin concentrations were determined by radioimmunoassay under basal conditions and in response to peptone meal stimulation . Acid secretion was measured under basal conditions and in response to peptone meal stimulation . Presence of H . pylori was determined by both 14C-urea breath test and ELISA serology . RESULTS: Inhibition of gastric acid output by ranitidine bismuth citrate was both time- and dose-dependent over the 9-h post-dose study period . Doses of ranitidine bismuth citrate 400 mg and ranitidine hydrochloride 150 mg, which are equimolar, produced similar suppression of acid output regardless of H . pylori status . Ranitidine bismuth citrate had no effect on plasma gastrin concentrations regardless of H . pylori status . All doses of ranitidine bismuth citrate were well tolerated . CONCLUSIONS: Ranitidine bismuth citrate caused time- and dose-dependent reductions in meal-stimulated and between-meal gastric acid output regardless of H . pylori status . The magnitude of decreased acid secretion was similar with ranitidine bismuth citrate 400 mg and ranitidine hydrochloride 150 mg . Ranitidine bismuth citrate had no effect on plasma gastrin concentrations.

Appl Environ Microbiol, 1996 Dec, 62(12), 4652 - 5
Functional mapping of amino acid residues responsible for the antibacterial action of apidaecin; Taguchi S et al.; Functional mapping was carried out to address the amino acid residues responsible for the activity of the antibacterial peptide apidaecin from the honeybee by an in vivo assay system developed previously . The C-terminal region and many of the proline and arginine residues which are present at high frequency in apidaecin were found to play an important role in its antibacterial activity.

J Biol Chem, 1996 Nov 29, 271(48), 30493 - 8
ASABF, a novel cysteine-rich antibacterial peptide isolated from the nematode Ascaris suum . Purification, primary structure, and molecular cloning of cDNA; Kato Y et al.; Previously, we reported antibacterial activity in the body fluid of the nematode Ascaris suum (Kato, Y . (1995) Zool . Sci . 12, 225-230) . The antibacterial activity is due to a heat-stable and trypsin-sensitive molecule that was designated as ASABF (A . suum antibacterial factor) . In the present study, the purification, determination of primary structure, and cDNA cloning of ASABF were carried out . The mature peptide of ASABF is a basic peptide consisting of 71 residues and containing four intramolecular disulfide bridges . The amino acid sequence of a precursor for ASABF, deduced from a cDNA clone, indicates that flanking peptides both at the N terminus and at the C terminus are eliminated by processing . ASABF exhibits potent antibacterial activity particularly against Gram-positive bacteria . ASABF has several features that resemble those of insect/arthropod defensins, whereas the statistical significance of the similarity is not observed on comparison of amino acid sequences . A search of data bases revealed ASABF homologues in Caenorhabditis elegans.

J Biol Chem, 1996 Nov 8, 271(45), 28533 - 40
Antibacterial activity of glycosylated and phosphorylated chromogranin A-derived peptide 173-194 from bovine adrenal medullary chromaffin granules; Strub JM et al.; Recently, we have isolated from bovine chromaffin granules and identified two natural peptides possessing antibacterial activity: secretolytin (chromogranin B 614-626) and enkelytin (proenkephalin-A 209-237) . Here, we characterize a large natural fragment, corresponding to chromogranin A 79-431, that inhibits growth of both Gram-positive and Gram-negative bacteria . The aim of the present work was to determine the shortest active peptide located in the 79-431 chromogranin A region . Three peptides, which shared the same 173-194 chromogranin A sequence (YPGPQAKEDSEGPSQGPASREK) but differed in post-translational modifications, including O-glycosylation and tyrosine phosphorylation, were isolated . A detailed study using microsequencing and mass spectrometry allowed us to correlate their antibacterial activity with these post-translational modifications . The chromogranin A precursor fragment (79-431) and the active glycosylated and phosphorylated peptides were, respectively, named prochromacin and chromacin (P, G, and PG for phosphorylated, glycosylated, and phosphorylated-glycosylated form).

J Biol Chem, 1996 Nov 8, 271(45), 28031 - 7
Redesigning the quaternary structure of R67 dihydrofolate reductase . Creation of an active monomer from a tetrameric protein by quadruplication of the gene; Bradrick TD et al.; R67 dihydrofolate reductase (DHFR) provides resistance to the antibacterial drug trimethoprim . This R-plasmid-encoded enzyme does not share any homology with chromosomal DHFR . A recent crystal structure of active, homotetrameric R67 DHFR (Narayana, N., Matthews, D . A., Howell, E . E., and Xuong, N.-H . (1995) Nat . Struct . Biol . 2, 1018-1025) indicates that a single active site pore traverses the length of the molecule . Since the center of the pore possesses exact 222 symmetry, site-directed mutagenesis of residues in the pore will produce four mutations/active site . To break this inevitable symmetry, four copies of the gene have been linked in frame to create an active monomer possessing the essential tertiary structure of native tetrameric R67 DHFR . The protein product, quadruple R67 DHFR, is 4 times the molecular mass of native R67 DHFR in SDS-polyacrylamide gel electrophoresis and is monomeric under nondenaturing conditions as measured by sedimentation equilibrium experiments . The catalytic activity of quadruple R67 DHFR is decreased only slightly when compared with native R67 DHFR . Folding of quadruple R67 DHFR is completely reversible at pH 5 . However, at pH 8, folding is not fully reversible; this is likely due to a competition between productive intramolecular versus nonproductive intermolecular domain association . The production of a fully active, monomeric R67 DHFR variant will enable the design of more meaningful site-directed mutants where single substitutions per active site pore can be generated.

Science, 1996 Nov 8, 274(5289), 980 - 2
Antibacterial agents that inhibit lipid A biosynthesis; Onishi HR et al.; Lipid A constitutes the outer monolayer of the outer membrane of Gram-negative bacteria and is essential for bacterial growth . Synthetic antibacterials were identified that inhibit the second enzyme (a unique deacetylase) of lipid A biosynthesis . The inhibitors are chiral hydroxamic acids bearing certain hydrophobic aromatic moieties . They may bind to a metal in the active site of the deacetylase . The most potent analog (with an inhibition constant of about 50 nM) displayed a minimal inhibitory concentration of about 1 microgram per milliliter against Escherichia coli, caused three logs of bacterial killing in 4 hours, and cured mice infected with a lethal intraperitoneal dose of E . coli.

Pharmacoeconomics, 1996 Dec, 10(6), 630 - 43
Prescribing practice and cost of antibacterial prophylaxis for surgery at a US Veteran Affairs hospital; Ryono RA et al.; This study retrospectively compared the actual drug-related cost of antibacterial prophylaxis for specific operative procedures with the theoretical costs based on recommendations published in Medical Letter on Drugs and Therapeutics, the Surgical Infection Society, and those of the chiefs of each surgical subspecialty at our institution . We identified all patients who received in intravenous bacterial for prophylaxis before a clean or clean-contaminated operation between 1st January and 30th September 1993, using the medical centre's computerised information system . The information included comprehensive surgical case histories, and pharmacy and microbiology records . Only those operations in which recommendations for surgical prophylaxis were present in all 3 guidelines were included . The outcome measures were antibacterial-related costs (drug acquisition and administration costs), the number of antibacterial doses dispensed, and choice of antibacterial agents . During the study period, 3,322 operations were performed, 2,993 of which were excluded . Thus, 329 patients undergoing operations in 6 subspecialties were included in the analysis . The actual mean cost per patient significantly exceeded the projected costs using Medical Letter Consultants' and Surgical Infection Society guidelines for all 6 subspecialties {mean excess cost per patient: $US49.04 and $US34.95, respectively (1994 values)} and institutional guidelines for 4 of the 6 subspecialties (mean excess cost per patient: $US24.36) . The actual mean number of doses per patient significantly exceeded those projected using Medical Letter Consultants' and Surgical Infection Society guidelines for all 6 subspecialties (mean excess number of doses per patient: 6.0 and 4.0, respectively) and institutional guidelines for 4 of the 6 subspecialties (mean excess number of doses per patient: 2.9) . The choice of antibacterial was appropriate in approximately 90% of cases . We conclude that the practice of antibacterial prophylaxis for specific operative procedures performed by 6 subspecialties is not in accordance with institutional or published guidelines, and the excess cost is primarily a result of prolonged duration of antibacterial prophylaxis.

Pharmacoeconomics, 1996 Dec, 10(6), 539 - 45
The economic potential of dual individualisation methodologies; Paladino JA et al.; Cost-effective treatment of patients with bacterial infections can best be accomplished by facilitating a rapid response . Achieving a more rapid cure of the infection should result in reduced utilisation of healthcare resources . An innovative means of achieving a more rapid response to antibacterial therapy has been termed dual individualisation . Dual individualisation allows for the simultaneous consideration of the pharmacokinetic interaction between an antibacterial agent and a patient, with the pharmacodynamic interaction between the antibacterial agent and the bacterial pathogen . Integrating the pharmacokinetic parameter of area under the curve (AUC), with the pharmacodynamic measure of minimum inhibitory concentration (MIC) yields a ratio called the area under the inhibitory curve (AUIC) . Clinical studies using dual individualisation to achieve a target AUIC24h of 125-250 have been performed with cephalosporins and fluoroquinalones . Economic evaluation of the results demonstrate that dual individualisation is cost-effective . Dual individualisation can be implemented in most practice setting using existing clinical data . Use of a computer model allows for cost-effective calculation of AUIC24h without having to measure serum drug concentrations of bacterial MIC . By adjusting antibacterial regimens to achieve a target AUIC, optimisation of antibacterial therapy can be achieved with resultant economic benefits.

Oper Dent, 1996 Nov-Dec, 21(6), 257 - 64
Antibacterial activity of dentin bonding systems, resin-modified glass ionomers, and polyacid-modified composite resins; Meiers JC et al.; The antibacterial effects of the dentin bonding systems Syntac, ProBOND, Gluma 3-Step, the resin-modified glass ionomers Photac-Fil, Fuji Lining LC, Fuji II LC, and the polyacid-modified composite resins VariGlass, Geristore, and Infinity were evaluated using the cariogenic bacteria S mutans, L salivarius, S sobrinus, and A viscosus in vitro with a modified cylinder drop plate agar diffusion assay . All glass ionomers, the polyacid-modified composites, and the primers and adhesives of the dentin bonding systems exhibited various degrees of antibacterial activity against most of the test bacteria . The antibacterial activity of the adhesives of dentin bonding systems was anticipated because of the glutaraldehyde used in their formulations . However, the antibacterial activity of the various primers was unexpected and indicates a dual antibacterial action of these systems.

Vestn Otorinolaringol . 1996 Nov-Dec;(6):41.
{The use of superior and inferior skin trapeziform flaps in treating cicatricial stenoses of the larynx and trachea occurring after extensive laryngeal cancer operations}; Karimova FS et al.; Partial laryngeal resections and extended laryngectomies for advanced laryngeal cancer bring scarry stenoses in 22-33% of cases . To correct scarry laryngostenoses and stenosed cervical trachea, the authors propose reconstructive surgery using anterior and inferior skin trapeziform flaps stimulating formation of wide stroma . The frequency of laryngostenoses and stenosis of cervical part of the trachea after operations for laryngeal cancer decreased 2-fold due to application of trapeziform flaps, antibacterial powder iodopor and suturing material kaproiod.

Mikrobiol Z, 1996 Nov-Dec, 58(6), 45 - 9
{The antibacterial activity of preparations with highly dispersed iron}; Hvozdiak RI et al.; High-dispersed magnetized iron preparations of various coercive force and its preparations with Ag, Au, Pt obtained by thermochemical method have been studied for their effect on plants and bacteria pathogenic for animals . It is established that magnetized iron intensifies antibacterial effect of certain metals . Of the studied preparations only high-dispersed Fe-Ag had distinctly expressed bactericidal effect . Other preparations had weak antibacterial effect or had not it at all . All the preparations have strong adsorption capacity.

Urol Nefrol (Mosk), 1996 Nov-Dec, (6), 19 - 23
{The surgical treatment of suppurative destructive forms of acute pyelonephritis in pregnant women}; Dovlatian AA et al.; The paper presents the results of surgical treatment of pyodestructive pyelonephritis diagnosed in 111 puerperae and gravidae . Suppurative nephritis, carbuncle and abscess of the kidney ran as unilateral (94 patients, 84.7%) or bilateral (16 patients, 14.4%) process . The diagnosis of pyodestructive pyelonephritis of the solitary kidney was made in 1 gravida . The outcomes of pyodestructive pyelonephritis in puerperae and gravidae depend primarily on individual approach to therapy . Different operative interventions warranted a complete response in 97.3% of the gravidae . 96 of 108 gravidae operated on the kidneys delivered viable neonates . Early operative interventions in many cases preserved the kidney and prevented septic complications . Pyodestructive changes restricted to 1-2 segments of the kidney were effectively treated by nephrostomy . Bilateral pyodestructive pyelonephritis should be managed step-by-step starting at the side of the most evident symptoms . Two-stage bilateral lumbotomy with nephrostomy in combination with antibacterial therapy and plasmapheresis eliminated septic complications thus allowing normal development of the fetus . Nephrectomy is the best treatment in advanced pyodestructive lesion with severe life-threatening septic intoxication.

Urol Nefrol (Mosk), 1996 Nov-Dec, (6), 12 - 4
{The use of laser therapy in correcting hemostatic system disorders in patients with chronic pyelonephritis}; Neimark AI et al.; The paper analyzes treatment outcomes in 72 patients with chronic pyelonephritis in the phase of active inflammation . The patients have received combined therapy including laser blood radiation to correct hemostatic defects . The latter manifested as DIC syndrome resistant to antibacterial treatment . Attempts to apply transcutaneous laser radiation (TLR) and intravascular laser radiation (ILR) showed that DIC syndrome may be cured only in the combined use of the above modalities.

Pharmazie, 1996 Nov, 51(11), 805 - 10
Pyrrolidino enaminones structural related to gyrase inhibitors: synthesis, cyclization and pharmacological activity; Dannhardt G et al.; The synthesis and stereochemical characteristics of pyrrolidino enaminones with structural analogy to quinolone antibacterial agents are reported . Retro-aldol reaction of the esters 7 is observed under all conditions of hydrolysis, the enzyme catalyzed reaction also does not yield the corresponding acids . In contrast to clinically used quinolones exemplary tests with monocyclic esters of type 7 and the tricyclic derivative 10 indicate low or no antibacterial activity . Additionally to the lack of the carboxylic acid function the enaminones 7 differ from quinolones in stereochemical demands and the electronic situation of the phenyl substituents of 10, respectively possibly preventing the formation of a co-operative tetrametric system between compounds and DNA bases.

J Gastroenterol Hepatol, 1996 Nov, 11(11), 1006 - 11
Effects of combination therapy with interferon and ofloxacin on chronic type C hepatitis: a pilot study; Tsutsumi M et al.; Interferon is effective in only a limited number of patients with the 1b type of hepatitis C virus (HCV), indicating that a combination therapy with other antiviral drugs may be essential to obtain better results . In the present pilot study, the effects of a combination therapy with interferon (IFN) and an antibacterial drug, ofloxacin, were analysed . Ten patients with chronic type C hepatitis received the combination therapy (combination group) . Six million units of natural IFN-alpha were administered daily for 3 weeks and then three times a week for 21 weeks . The combination therapy was initiated at the beginning of the eighth week of IFN treatment and 600 mg ofloxacin per day was administered for 12 weeks . As a control, changes in HCV-RNA were also analysed in patients who were treated with only IFN for the same period (IFN-alone group) . In the combination group, serum transaminase levels and the titres of HCV decreased significantly with ofloxacin administration . Such changes were not observed in the IFN-alone group . The incidence of HCV-negativity at the end of ofloxacin administration of the combination group was significantly higher than in the IFN-alone group . The complete response rate was twice as high in the combination group as in the IFN-alone group . In two patients who did not respond well to the IFN-alone treatment, ofloxacin administration was commenced after the 24th week . Serum transaminase levels were normalized and HCV-RNA became negative in these two patients after the administration of ofloxacin . These results suggest that combination therapy with IFN and ofloxacin may be an effective treatment for chronic type C hepatitis.

J Antibiot (Tokyo), 1996 Nov, 49(11), 1157 - 61
A modification of the N-terminal amino acid in the eremomycin aglycone; Miroshnikova OV et al.; An Edman degradation of the antibiotic eremomycin aglycone produced the corresponding hexapeptide, which was aminoacylated with D-lysine, D-histidine or D-tryptophan derivatives to give new heptapeptide analogs of the eremomycin aglycone . The aminoacylation of the eremomycin aglycone produced an octapeptide analog . The substitution of D-lysine for the N-terminal N-methyl-D-leucine does not seriously affect the in vitro antibacterial properties of the eremomycin aglycone whereas the heptapeptides with the N-terminal D-tryptophan or D-histidine moieties and the octapeptide with the N-terminal D-lysine are practically devoid of the antibacterial properties.

J Gastroenterol, 1996 Nov, 31 Suppl 9, 56 - 8
Sofalcone for treatment of Helicobacter pylori infection; Fujioka T et al.; It is difficult to regard sofalcone as a single drug for the treatment of Helicobacter pylori infection . However, sofalcone exerts multiple effects against H . pylori: it has antibacterial activity, induces morphological changes, inhibits adhesion to gastric mucin and inhibits lipolytic activity . The safety profile of sofalcone even on long-term administration is well established . Therefore, it may be possible to establish a new triple therapy for H . pylori infection using sofalcone combined with antibacterial drugs and proton pump inhibitors.

J Gastroenterol, 1996 Nov, 31 Suppl 9, 41 - 3
Effect of lansoprazole in mono-, dual-, or triple therapy on Helicobacter pylori eradication; Kawano S et al.; The effect of lansoprazole, in mono, dual, or triple therapy, on the eradication of Helicobacter pylori was reviewed . Lansoprazole has a cytotoxic action against this organism, the MIC being 2.56-5.25 micrograms/ml . In in vitro experiments, lansoprazole exerts direct action, i.e., antibacterial activity of lansoprazole against H . pylori and also inhibits urease activity . With antibiotics, this drug has a synergistic effect against H . pylori . In clinical studies, the eradication rate of H . pylori with lansoprazole is 0%-25% with monotherapy, 22%-33% with dual therapy (of AMPC), and 75%-82.4% with triple therapy with metronidazole and antibiotics . We inves-tigated the effect of lansoprazole on the eradication of H . pylori with dual therapy, the other agent being amoxicillin (AMPC) . The eradication rate was 0% when 30 mg lansoprazole was employed as monotherapy, 33% for dual therapy with 30 mg lansoprazole and 1 g AMPC, and 71% for dual therapy with 60 mg lansoprazole and 1 g AMPC, the eradication rate with 60 mg lansoprazole and 1 g AMPC being significantly higher than that with the lower dose of lansoprazole . This result suggested that the greater acid suppression brought about by lansoprazole 60 mg enhances the action of AMPC, indicating that lansoprazole, when used with AMPC, is effective for eradication of H . pylori.

Biol Pharm Bull, 1996 Nov, 19(11), 1457 - 62
Structure-antibacterial activity and cytotoxicity relationships of thiazolo and thiazetoquinolone derivatives; Ozaki M et al.; In the course of our search for derivatives with potent antibacterial activity and low cytotoxicity, we have studied the relationships among the structure, antibacterial activity and cytotoxicity of thiazoloquinolone and thiazetoquinolone derivatives (the term quinolone as used in this paper includes the quinolone, 1,8-naphthyridine and pyridopyrimidine nuclei) . The antibacterial activities and cytotoxicity of these derivatives were compared with those of norfloxacin, ofloxacin, enoxacin and ciprofloxacin . The antibacterial activities of the thiazoloquinolone derivatives were more potent than those of the dihyrothiazoloquinolone derivatives, and comparable to that of ciprofloxacin . All of the thiazoloquinolone derivatives were highly cytotoxic against mammalian cells, but some of the dihyrothiazoloquinolone derivatives were less cytotoxic, being comparable in cytotoxicity to the reference drugs . The thiazetoquinolone derivatives were less cytotoxic than the thiazoloquinolone derivatives, and one of them, 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-{1,3}thiazeto{3,2-a} quinoline-3-carboxylic acid, showed the most potent antibacterial activity of all compounds tested in this study, as well as a very low cytotoxicity . The antibacterial activity and cytotoxicity of this compound were similar to that of ciprofloxacin.

Am J Med, 1996 Nov, 101(5), 550 - 61
Bacterial osteomyelitis in adults: evolving considerations in diagnosis and treatment; Haas DW et al.; Bacterial osteomyelitis causes substantial morbidity worldwide, despite continued progress toward understanding its pathophysiology and optimal management . The approach to osteomyelitis depends upon the route by which bacteria gained access to bone, bacterial virulence, local and systemic host immune factors, and patient age . While imaging studies and nonspecific blood tests may suggest the diagnosis, an invasive technique is generally required to identify the causative pathogens . Given the paucity of comparative clinical trials, antibacterial regimen selection has been largely guided by knowledge of the relative activities and pharmacokinetics of individual drugs, supported by data from animal models . Definitive therapy often requires a combined medical and surgical approach . Newer microvascular and distraction osteogenesis techniques and the use of laser doppler allow more complete surgical resection of infected material while maintaining function . Despite recent advances, many patients with osteomyelitis fail aggressive medical and surgical therapy . More accurate diagnostic methods, better ways to assess and monitor the effectiveness of therapy, and novel approaches to eradicate sequestered bacteria are needed.

J AOAC Int, 1996 Nov-Dec, 79(6), 1263 - 8
Microbiological method for determining macrolides in animal feeds in the presence of other drugs by thin-layer chromatography detection; Markakis PK; A method was developed to separate, detect, and quantitate erythromycin (ERY) and tylosin (TYL) in animal feeds in the presence of 11 other drugs: 3 nitrofurans, 2 tetracycline antibiotics, 3 sulfonamides, 2 coccidiostats, and 1 antibacterial growth promoter . ERY and TYL were separated from coexisting drugs, detected by thin-layer chromatography, and quantitated microbiologically by an agar diffusion method . Analysis of 125 experimental animal feed samples fortified at 5 levels (7.5-400 ppm) with ERY and TYL and at 1 level (50 ppm) with the rest of the drugs gave limits of quantitation of 2 and 5 ppm, recoveries of 90.3 and 92.4%, and relative standard deviations of 4.3-7.3% and 3.6-6.1%, respectively.

Eur J Biochem, 1996 Nov 1, 241(3), 699 - 706
Cloning of the gene encoding the antibacterial peptide drosocin involved in Drosophila immunity . Expression studies during the immune response; Charlet M et al.; A potent inducible antibacterial peptide carrying an O-glycosylated substitution has recently been isolated from Drosophila {Bulet, P., Dimarcq, J . L., Hetru, C., Lagueux, M., Charlet, M., Hegy, G., Van Dorsselaer, A . and Hoffmann, J . A . (1993) J . Biol . Chem . 268, 14893-14897} . Here we report cloning studies that show that Drosophila contains a single, intronless gene, located at position 51C1-6, which encodes the precursor protein from which drosocin is processed . The upstream and the downstream sequences of the drosocin gene contain putative cis-regulatory elements similar to mammalian regulatory motifs, namely three kappa B-related decameric sequences . The drosocin gene is silent in naive animals, and is strongly induced with acute phase kinetics after immune challenge in larvae and in adults . We have established several transgenic fly lines in which reporter genes were placed under the control of various drosocin promoter sequences . Our results indicate that 2.5 kb of upstream sequences confer inducibility and tissue specificity to the transgene, but that the level of its expression in the fat body after immune challenge is low . Addition of genomic regions downstream of the drosocin transcribed sequences results in increased transcription levels, which are similar for the fusion and the resident drosocin genes upon infection . Analysis of transgenic fly lines showed that the drosocin reporter gene is constitutively expressed in the oviducts of egg-laying females.

Bone Marrow Transplant, 1996 Nov, 18 Suppl 2, 97 - 106
Fungal infections in patients undergoing bone marrow transplantation: an approach to a rational management protocol; Castagnola E et al.; Candida sp . and Aspergillus sp . are the most common fungal pathogens causing infection in bone marrow transplant recipients and represent an increasing cause of morbidity and mortality . At this time there is no generally accepted rule for the antifungal management of these complications . Antifungal drugs in immunocompromised patients are usually administered for prophylaxis, for therapy of specific infections or for empirical or preemptive therapy . The present article reports schedules of administrations and pediatric and adult dosages of the main antifungal drugs presently available, (fluconazole, itraconazole, amphotericin B deoxycholate, lipid formulations of amphotericin B and flucytosine), together with their spectrum of action and main toxicities . Thereafter, the available information about prevention and treatment of fungal infections in bone marrow transplant recipients is summarized . Briefly, fluconazole remains the drug of choice for prevention of Candida infections in bone marrow transplant recipients, while itraconazole has been seldomly used for this indication, due to erratic oral absorption . However, new itraconazole formulations are being studied, that might disclose new clinical perspectives, due to improved bioavailability . The duration of prophylaxis is still an open issue . Resistance to the new azoles may become a problem in the near future . For this reason, it is likely that the approach to the use of these new drugs should be similar to the one commonly used for antibacterial drugs, i.e . based on pathogen-related, drug-related and host-related factors . Mainly due to lack of diagnostic tools, very little studies have been performed for prevention of aspergillosis . Available data seem to show that there might be a role for low-dose intravenous amphotericin B, which has shown to be effective for secondary prophylaxis . Itraconazole and intranasal amphotericin B have been studied, as well . Although fluconazole and itraconazole (in the rare instances in which the oral route is reliable) can also have therapeutic indications, both for empirical and for specific therapy, amphotericin B (with or without flucytosine) remains the main therapeutic option . New antifungal drugs and new supportive strategies (i.e . role of hematopoietic growth factors) are in the research pipeline and will hopefully disclose new perspectives in the near future.

Am J Gastroenterol, 1996 Nov, 91(11), 2347 - 54
Relevance of the ferret model of Helicobacter-induced gastritis to evaluation of antibacterial therapies; Alder JD et al.; OBJECTIVES: The goals of the study were 1) to evaluate the efficacy of clinically relevant antibacterial therapies in the ferret model of Helicobacter-induced gastritis and 2) to compare these results to the efficacy achieved clinically in humans . METHODS: Ferrets were inoculated with H . mustelae, and gastritis was allowed to develop . The double therapy of clarithromycin and omeprazole and the triple therapies of clarithromycin or amoxicillin with metronidazole and omeprazole were administered . Efficacy was evaluated by Helicobacter burden cultured from biopsy samples and by histopathological evaluation of Helicobacter burden and gastric inflammation with pylorus and fundus samples obtained 4 wk after the end of antibacterial therapy . RESULTS: Clarithromycin-based double and triple therapies significantly reduced Helicobacter burden and decreased gastric inflammation . Clarithromycin-based double therapy was more effective than amoxicillin-based triple therapy . Reduction of the length of clarithromycin therapy from 14 to 7 days decreased efficacy . Antibacterial therapies in the ferret did not produce eradication rates comparable to clinical results, even though the serum concentrations of clarithromycin in ferret were in excess of concentrations used in humans . Relapse of Helicobacter infection after the end of therapy occurred in some cases . CONCLUSIONS: Although the ferret model of Helicobacter gastric infection underestimated the clinical efficacy of antibacterial treatments in humans, the model was valuable for comparing the relative efficacy of antibacterial therapies.

Photochem Photobiol, 1996 Nov, 64(5), 838 - 44
Photohaptenic properties of fluoroquinolones; Tokura Y et al.; Although quinolone antibacterial agents have both phototoxicity and photoallergenicity, the latter's potency has been poorly investigated compared with the former's . Some of the photoallergic chemicals serve as photohaptens, which lead to T-cell-mediated immune reactions after photobinding to protein by UVA radiation . We examined the photohaptenic potential of fluoroquinolones, including lomefloxacin (LFLX), ciplofloxacin, norfloxacin, ofloxacin, levofloxacin, fleroxacin, enoxacin and sparfloxacin (SPFX) . The absorption spectra of the quinolones were altered by UVA irradiation, with an exception of SPFX that seems to be photostable toward UVA . Bovine serum albumin and murine epidermal cells were coupled with these fluoroquinolones other than SPFX by exposure to UVA . Subcutaneous inoculation of fluoroquinolone-photomodified epidermal cells induced and elicited a delayed-type hypersensitivity reaction in mice . However, epidermal cells incubated with LFLX without UVA exposure also induced and elicited a significant hypersensitivity reaction to a lesser degree than LFLX-photomodified epidermal cells . Furthermore, there was cross-reactivity between LFLX-photomodified epidermal cells and simply LFLX-incubated cells . This suggests that cells can be weakly modified with LFLX even in the dark and that UVA irradiation promotes this modification . Our study demonstrated that fluoroquinolones have photohaptenic properties to which their photoallergenicity is probably ascribed.

Am J Vet Res, 1996 Nov, 57(11), 1627 - 30
Bacterial killing by use of once daily gentamicin dosage in guinea pigs with Escherichia coli infection; Campbell BG et al.; OBJECTIVE: To determine whether the antibacterial activity of 6 mg of gentamicin/kg of body weight given SC once daily, is equivalent to the standard gentamicin dose of 2 mg/kg given SC every 8 hours . ANIMALS: Guinea pigs with infected thigh wound: 5 in an untreated control group and 12 in 6 and 2 mg/kg gentamicin treatment groups . PROCEDURE: Guinea pigs were inoculated with 10(9) Escherichia coli in the thigh muscle . Gentamicin treatment (2 mg/kg, SC, q 8 h or 6 mg/kg, SC, q 24 h) was begun 4 hours after E coli inoculation and continued for 72 hours . Four hours after the last gentamicin treatment, all guinea pigs were euthanatized and the cranial thigh muscle containing the entire inoculum was removed . Colony-forming units were counted to determine the E coli concentration in each thigh . RESULTS: Mean +/- SD log10 colony-forming units was 9.293 +/- 0.074 in the control group, 8.161 +/- 0.478 in the 2 mg/kg treatment group, and 7.796 +/- 0.182 in the 6 mg/kg treatment group . One-way ANOVA revealed a significant (P < 0.05) difference between the control group and both treatment groups, and between both treatment groups . CONCLUSION: Bacterial killing did not differ between gentamicin given at a dosage of 6 mg/kg once daily, compared with 2 mg/kg every 8 hours in guinea pigs infected with E coli . CLINICAL RELEVANCE: Gentamicin dosage regimens with high peak concentration and long dosing interval are as efficacious as divided dosage regimens . These data support the concept that once daily administration of gentamicin for treatment of E coli infection should be investigated clinically.

Antimicrob Agents Chemother, 1996 Nov, 40(11), 2545 - 9
Enhanced intramacrophage activity of resorcinomycin A against Mycobacterium avium-Mycobacterium intracellulare complex after liposome encapsulation; Gomez-Flores R et al.; The activities of free and liposomal resorcinomycin A against Mycobacterium avium-Mycobacterium intracellulare complex (MAC) grown in broth and in murine peritoneal macrophages were evaluated . Liposomal resorcinomycin A was composed of dimyristoyl phosphatidylcholine and phosphatidylinositol at a molar ratio of 9:1 . Both free resorcinomycin A and liposomal resorcinomycin A showed no toxicity to macrophages at concentrations up to 50 micrograms/ml, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay . Minimal inhibitory concentrations of free resorcinomycin A and liposomal resorcinomycin A in broth were 6 and 12 micrograms/ml, respectively, as determined by the MTT colorimetric microassay . In macrophages, liposomal resorcinomycin A caused significantly higher intramacrophage antimycobacterial activity than the free form of the drug . At doses ranging from 6 to 50 micrograms/ml, liposomal resorcinomycin A caused 50 to 93% MAC growth inhibition, respectively (as determined by CFU), while free resorcinomycin A was associated with 33 to 62% MAC growth inhibition, respectively, 3 days after drug treatment . In addition, antimycobacterial activity of liposomal resorcinomycin A in macrophages was maintained 7 days after treatment, whereas the activity of free resorcinomycin A was reduced to negligible 3 days after treatment . In summary, liposome encapsulation of resorcinomycin A resulted in significant enhancement of antibacterial activity against intramacrophagic MAC infection.

Antimicrob Agents Chemother, 1996 Nov, 40(11), 2468 - 77
Efficacy of ampicillin-sulbactam is not dependent upon maintenance of a critical ratio between components: sulbactam pharmacokinetics in pharmacodynamic interactions; Alexov M et al.; An in vitro pharmacokinetic model (IVPM) and a mouse model of lethal bacteremia were used to compare the pharmacodynamics of ampicillin-sulbactam when the two components were dosed simultaneously and in sequence against TEM-1-producing Escherichia coli . The challenge isolates included three strains of E . coli producing various levels of beta-lactamase . Human pharmacokinetics of ampicillin-sulbactam (1.5- and 3.0-g intravenous doses) were simulated in each model, and pharmacodynamic interactions were evaluated over one 6-h dosing interval . Against all three strains, the sequential dosing of sulbactam prior to ampicillin did not alter the pharmacodynamics of these combinations from comparison with results obtained with the simultaneous administration of the two components . Similar pharmacodynamics were observed for the two dosing regimens regardless of the ampicillin-sulbactam dose used or whether the bacteria were treated in an immunocompetent mouse or in the absence of immune defenses in the IVPM . When antibacterial activity was lost and regrowth of the inoculum was observed, viable bacterial counts increased in both the simultaneous and sequential regimens at a point when sulbactam levels fell below a critical concentration . These data suggest that the efficacy of ampicillin-sulbactam is not dependent upon the maintenance of a constant 2:1 ratio for the two components . Rather, the efficacy of ampicillin-sulbactam appears to be dependent upon the maintenance of one or both components above a critical concentration . Furthermore, the pharmacokinetics of sulbactam, specifically, how long sulbactam levels remain above a minimum critical concentration, appears to dictate how long antibacterial activity is maintained with the combination.

J Infect Dis, 1996 Nov, 174(5), 1127 - 30
Fluoroquinolone resistance associated with specific gyrase mutations in clinical isolates of multidrug-resistant Mycobacterium tuberculosis; Xu C et al.; Fluoroquinolones are potent antibacterial agents being used clinically against multidrug-resistant tuberculosis . Treatment failure is thought to arise from acquisition of fluoroquinolone resistance by Mycobacterium tuberculosis . A collection of 13 resistant clinical isolates of M . tuberculosis was examined for ciprofloxacin sensitivity relative to controls exhibiting the same IS6110 DNA type . Specific alleles were associated with distinct levels of drug susceptibility for 11 isolates that contained nucleotide changes expected to alter the amino acid sequence of the A subunit of DNA gyrase . Five different gyrA (ciprofloxacin resistance) alleles were present among 7 isolates having the W DNA subtype . These isolates, which are representative of an outbreak strain, constitute a panel of organisms that can be used to evaluate contributions of gyrase and DNA topoisomerase IV to resistance.

Eur J Biochem, 1996 Oct 15, 241(2), 330 - 7
Molecular characterization of ceratotoxin C, a novel antibacterial female-specific peptide of the ceratotoxin family from the medfly Ceratitis capitata; Rosetto M et al.; Ceratotoxins A and B are antibacterial peptides produced by the sexually mature females of Ceratitis capitata . The gene expression is restricted to the female reproductive accessory glands, and is not affected by bacterial infection, but is enhanced by mating . We report here the purification and the amino acid sequence of ceratotoxin C, a novel member of the ceratotoxin family, the cloning of its cDNA and the analysis of its expression . Ceratotoxin C is coordinately expressed with the other members of the ceratotoxin family . Its antibacterial activity is directed against both Gram-negative and Gram-positive bacterial strains but it is lower than that of ceratotoxin A . We demonstrate in the genome of C . capitata the presence of at least three ceratotoxin genes which express, in the female accessory glands, a set of peptides presumably involved in the protection of the genital tract during fertilization.

J Biol Chem, 1996 Oct 11, 271(41), 25338 - 44
Mechanisms for the transport of alpha,omega-dicarboxylates through the mitochondrial inner membrane; Liu G et al.; alpha,omega-Dicarboxylates have antibacterial properties, have been used in the treatment of hyperpigmentary disorders, are active against various melanoma cell lines, and can also undergo beta-oxidation . Little, however, is known about their transport . In this paper, we examine the mitochondrial transport of alpha, omega-dicarboxylates ranging from oxalate (DC2) to sebacate (DC10) . DC2-DC10 are transported by the inner membrane anion channel (IMAC) . DC6-DC10 are also transported by an electroneutral mechanism that appears to reflect transport of the acid through the lipid bilayer . At 37 degrees C and pH 7.0, DC10 is transported very rapidly at 3 micromol/min.mg, and respiring mitochondria swell in the K+ salts of these acids . This transport mechanism is probably the major pathway by which the longer dicarboxylates enter cells, bacteria, and mitochondria . We also demonstrate that DC5-DC10 can also be transported by an electroneutral mechanism mediated by tributyltin, a potent inhibitor of IMAC . The mechanism appears to involve electroneutral exchange of a TBT-dicarboxylate-H complex for TBT-OH . Finally, we present evidence that of all the dicarboxylates tested only DC2-DC4 can be transported by the classical dicarboxylate carrier.

J Biol Chem, 1996 Oct 11, 271(41), 25261 - 8
Modulation of structure and antibacterial and hemolytic activity by ring size in cyclic gramicidin S analogs; Kondejewski LH et al.; We have evaluated the effect of ring size of gramicidin S analogs on secondary structure, lipid binding, lipid disruption, antibacterial and hemolytic activity . Cyclic analogs with ring sizes ranging from 4 to 14 residues were designed to maintain the amphipathic character as found in gramicidin S and synthesized by solid phase peptide synthesis . The secondary structure of these peptides showed a definite periodicity in beta-sheet content, with rings containing 6, 10, and 14 residues exhibiting beta-sheet structure, and rings containing 8 or 12 residues being largely disordered . Peptides containing 4 or 6 residues did not bind lipopolysaccharide, whereas longer peptides showed a trend of increasing binding affinity for lipopolysaccharide with increasing length . Destabilization of Escherichia coli outer membranes was only observed in peptides containing 10 or more residues . Peptides containing fewer than 10 residues were completely inactive and exhibited no hemolytic activity . The 10-residue peptide showed an activity profile similar to that of gramicidin S itself, with activity against Gram-positive and Gram-negative microorganisms as well as yeast, but also showed high hemolytic activity . Differential activities were obtained by increasing the size of the ring to either 12 or 14 residues . The 14-residue peptide showed no antibiotic activity but exhibited increased hemolytic activity . The 12-residue peptide lost activity against Gram-positive bacteria, retained activity against Gram-negative microorganisms and yeast, but displayed decreased hemolytic activity . Biological activities in the 12-residue peptide were optimized by a series of substitutions in residues comprising both hydrophobic and basic sites resulting in a peptide that exhibited activities comparable with gramicidin S against Gram-negative microorganisms and yeast but with substantially lower hemolytic activity . Compared with gramicidin S, the best analog showed a 10-fold improvement in antibiotic specificity for Gram-negative microorganisms and a 7-fold improvement in specificity for yeast over human erythrocytes as determined by a therapeutic index . These results indicate that it is possible to modulate structure and activities of cyclic gramicidin S analogs by varying ring sizes and further show the potential for developing clinically useful antibiotics based on gramicidin S.

Pharmacoeconomics, 1996 Nov, 10(5), 494 - 503
The economic impact of once-daily versus conventional administration of gentamicin and tobramycin; Mithani H et al.; This retrospective, observational study was designed to compare once-daily with conventional aminoglycoside administration for costs while determining equivalency in efficacy and toxicity . 100 consecutive patients who had been treated with once-daily aminoglycosides after 1st August 1993, were evaluated via retrospective chart review . For comparison, 100 consecutive patients who were treated with conventional regimens of aminoglycosides, over the same calender period 1 year earlier (beginning on 1st August 1992), were evaluated in a similar manner . Aminoglycoside antibacterials, excluding amikacin, were administered as a single daily dose of 6 mg/kg . 89 patients were cured or improved with once-daily administration versus 90 patients with conventional administration . One patient in each group developed definite aminoglycoside-induced renal toxicity . The total cost {in 1993 Canadian dollars ($Can)} per patient for once-daily and conventionally administered aminoglycosides was $Can97.62 and $ Can199.43, respectively . Thus, once-daily administration of aminoglycosides is as effective and well tolerated, while considerably less expensive than, aminoglycoside treatment utilising conventional regimens.

Gene, 1996 Oct 3, 174(2), 245 - 9
Trichoplusia ni attacin A, a differentially displayed insect gene coding for an antibacterial protein; Kang D et al.; The mRNA differential display method was used to isolate antibacterial defense genes from Trichoplusia ni . The mRNA population in last-instar T . ni larvae injected with bacteria was compared to that of untreated larvae . Using a PCR amplified probe corresponding to an induced mRNA, we were able to clone an attacin homolog from a lambda cDNA library from vaccinated larvae . The corresponding protein showed 63% identity to Hyalophora cecropia acidic attacin . The induction kinetics of T . ni attacin A gave optimal mRNA levels at 20 h post-infection . Genomic analysis showed this to be a single-copy gene with two introns.

Quintessence Int, 1996 Oct, 27(10), 673 - 8
Reducing the risk of sensitivity and pulpal complications after the placement of crowns and fixed partial dentures; Brannstrom M; Sensitivity after cementation of a crown with glass-ionomer cement is often attributed to an adverse effect on the pulp by the luting agent . Most permanent restorative materials in common use today do not tend to irritate the pulp; the main cause of pulpal damage is infection, the bacteria originating in the smear layer or deep in the dental tubules, inaccessible to caries-excavating procedures . A poorly fitting provisional crown may expose cut dentin to the oral fluids, and mechanical trauma caused by frictional heat during preparation may also damage the pulp . The following precautions are recommended during precementation procedures to reduce the risk of an inflammatory response in the pulp: (1) The provisional crown should be well fitting, covering cervical dentin but not impinging on the periodontal tissues . The permanent crown should be cemented as soon as possible . (2) The superficial smear layer should be removed and the dentinal surface should be treated with an antibacterial solution before the provisional crown is placed . (3) To decrease dentinal permeability under the provisional crown, the dentinal surface should be covered with a liner that can be easily removed before final cementation . (4) to ensure optimal mircomechanical bonding, the dentinal surface should be thoroughly cleaned, and the dentin should be kept moist until cementation . (5) The occlusion should be carefully checked before cementation of the crown.

Eur J Oral Sci, 1996 Oct-Dec, 104(5-6), 529 - 34
Antiplaque, antibacterial, and anti-inflammatory properties of triclosan mouthrinses in combination with zinc citrate or polyvinylmethylether maleic acid (PVM-MA) copolymer; Kjaerheim V et al.; The antibacterial agent triclosan has demonstrated antiplaque and antigingivitis activity in several clinical studies . Retention of antiplaque agents is of significance for their clinical effect . Triclosan has a relatively rapid clearance from the oral cavity, and attempts have been made to increase its oral retention . In the present clinical antiplaque study, it was found that 0.5% copolymer polyvinyl-methylether maleic acid (PVM-MA) or 0.5% zinc citrate, which are both added to commercial products, inhibited plaque formation to a similar degree when used in combination with 0.3% triclosan, 1.5% sodium lauryl sulfate (SL.S) and diluted propylene glycol (PG) in water (1:8) . Plaque inhibition was significantly improved compared to a placebo solution . It was shown that these results could not be explained by an increase in antibacterial activity or by a change in the critical micellar concentration . The effect of the same solutions on SLS-induced inflammation on skin was also tested . It was seen that the triclosan/ zinc citrate solution and the control (triclosan/ethanol) decreased the inflammatory response, whereas the solutions containing triclosan in either propylene glycol (PG) or copolymer/PG did not exhibit any anti-inflammatory capacity.

Vet Immunol Immunopathol, 1996 Oct, 53(3-4), 277 - 83
Effect of antibacterial growth promoters on the immune system of broiler chicks; al-Ankari AS et al.; Administration of either 0.001 g/kg ampicillin (A), 0.05 g/kg oxytetracycline (O) or 0.05 g/kg sulphadimidine (S) in feed to broiler chicks for 50 days caused an increased serum concentration of the drug compared to the control birds that were given no drugs . O and S but not A resulted in a significant decrease of the total number of leukocytes, lymphocytes and the size of bursa of Fabricius and thymus but not spleen or body weight . The antibacterials significantly reduced the macrophage phagocytic activity compared to controls . It is suggested that the prolonged administration of O and S to chickens may induce an immunosuppressant effect.

J Chemother, 1996 Oct, 8(5), 375 - 81
Empiric antibiotic monotherapy with carbapenems in febrile neutropenia: a review; Cometta A et al.; Early empiric antibiotic therapy can significantly decrease the risk of mortality and infectious morbidity in patients with hematologic malignancies . Broad-spectrum antibiotics, usually a combination regimen of a beta-lactam and an aminoglycoside, have traditionally been employed against the wide variety of organisms that cause febrile episodes . However, since the 1970's, there has been a shift in epidemiology from Gram-negative to Gram-positive infections, against which traditional combination regimens have only limited efficacy . The carbapenems offer a suitable monotherapeutic alternative as they have a very broad spectrum of antibacterial activity, and equivalent efficacy and safety compared with combination regimes . Trials using imipenem/cilastatin have shown equal efficacy to ceftazidime but neurologic and gastrointestinal toxicity were observed at high doses (1 g 6-hourly) . In the largest study to date, meropenem (1 g 8-hourly) provided effective, well tolerated monotherapy for patients with febrile neuropenia, equivalent to a regimen of ceftazidime plus amikacin . It is concluded that meropenem appears to be a realistic option for initial monotherapy in febrile neutropenic patients, providing therapy that is equivalent to a standard regimen of ceftazidime and amikacin.

J Antimicrob Chemother, 1996 Oct, 38(4), 605 - 14
The mode of antibacterial action of the novel agent ZM240304 (D-arabino-2,3,4-tris(4-chlorobenzyl) pentane-1,5-diamine); Barrett-Bee K et al.; ZM240304 is an example of a new class of antibacterial agents that is active against experimental infections in animals . The compound was demonstrated to be a membrane-active compound that disrupted the outer membrane of Gram-negative organisms and allowed the leakage of periplasmic enzymes . Respiration was inhibited and cellular ATP levels were reduced, leading to cell death . The ability of the bacteria to take up small molecules such as amino acids and sugars was inhibited, probably by interference with inner membrane function.

Arch Histol Cytol, 1996 Oct, 59(4), 369 - 73
An immunohistochemical localization of transferrin binding protein in the chicken respiratory tract; Cho SS et al.; Transferrin binding protein (TfBP), a glycoprotein, is originally purified from the chicken oviduct . Recently, TfBP has been revealed as a novel transferrin binding protein, structurally related to the chicken heat shock protein 108 . The physiological function of this protein, however, has not yet been established . Antiserum to TfBP was found to stain selectively transferrin- and iron-rich oligodendrocytes of the normal chicken brain, suggesting a role for this protein in connection with transferrin and iron storage in these cells . In this study, we further demonstrate a TfBP-immunoreactivity in the chicken respiratory tract mucosa, where transferrin is known to be present and have antioxidant and antibacterial properties . A strong TfBP immunoreactivity was revealed in certain regions of the respiratory tract . In the trachea and bronchi, TfBP-immunoreactive product was localized specifically to the mucous gland cells, whereas ciliated epithelial cells were negative . In the lung, TfBP immunoreactivity was mostly confined to the parabronchi and atria . The immunoreactive products were found in the cytoplasm of the epithelial cells lining the parabronchial and atrial walls . These findings suggest that the presence of TfBP in the airway mucosa may be a necessary condition for transferrin concentration in the extracellular milieu of the respiratory tract.

Arch Pharm (Weinheim), 1996 Oct, 329(10), 443 - 6
Synthesis and antibacterial activity of 1-beta-methylcarbapenem having a 1,3-diazabicyclo{3.3.0}octan-4-one moiety; Nam KH et al.; The synthesis of new series of 1-beta-methylcarbapenems having a 1,3-diazabicyclo{3,3,0}octan-4-one moiety is described . Their in vitro antibacterial activities against both Gram-positive and Gram negative bacteria are reported and the effect of the substituent on the bicyclic ring was investigated and was in agreement with findings from our previous studies.

J Paediatr Child Health, 1996 Oct, 32(5), 463 - 5
Bilateral chronic conjunctivitis and corneal scarring in a boy with X-linked hypogammaglobulinaemia; al Ghonaium A et al.; We report an unusual case of bilateral chronic conjunctivitis and corneal scarring in a boy with X-linked hypogammaglobulinaemia (XLH) who did not respond to the usual antibacterial and antiviral therapy . An immunofluorescence test for Chlamydia trachomatis from an eye swab was strongly positive . Within days of commencement of local and systemic tetracycline therapy, he showed marked improvement . Since conjunctival follicle formation, which depends on the presence of a B-cell population, may not occur in XLH, clinical examination in chlamydia conjunctivitis may be misleading and lead to a delay in diagnosis and treatment with resulting corneal complications, unless laboratory evidence of chlamydia infection is specifically sought.

J Clin Periodontol, 1996 Oct, 23(10), 927 - 33
Triclosan reduces prostaglandin biosynthesis in human gingival fibroblasts challenged with interleukin-1 in vitro; Modeer T et al.; The effect of the toothpaste ingredient triclosan (2,4,4'-trichloro-2'-hydroxyldiphenyl ether) on the prostaglandins biosynthesis in human gingival fibroblasts challenged with interleukin-1beta (IL-1beta) or tumor necrosis factor alpha (TNFalpha) was studied in vitro . When gingival fibroblasts were treated simultaneously with triclosan and IL-1beta, the stimulatory effect of IL-1beta on prostaglandin E2 (PGE2) and PGI2 formation was reduced in a dose-dependent manner by triclosan . Triclosan also reduced the PGE2 formation induced by TNFalpha . Furthermore, the capacity of IL-1beta to induce release of {3H} arachidonic acid from prelabelled gingival fibroblasts was reduced in the presence of triclosan . Addition of exogenous unlabelled arachidonic acid (AA) to the cells resulted in enhanced PGE2 formation which was reduced by triclosan . The upregulation of the metabolism of AA to PGE2 induced by IL-1beta, was markedly reduced in the presence of triclosan . The study indicates that the stimulatory effect of IL-1beta on prostanoid formation (PGE2, PGI2) in human gingival fibroblasts was diminished in the presence of triclosan partly at the level of phospholipase A2 and partly at the level of cyclooxygenase . The present data that triclosan, in vitro, inhibits the production of inflammatory mediators such as prostaglandins suggests that this can be an aspect of its clinical effect on gingivitis, in addition to its antibacterial effect.

Clin Exp Allergy, 1996 Oct, 26(10), 1155 - 60
Fine structural specificity differences of trimethoprim allergenic determinants; Pham NH et al.; BACKGROUND: Adverse reactions, including immediate hypersensitivity, to the widely used antibacterial agent trimethoprim occur quite frequently . In recent years some progress has been made in developing an immunoassay to aid diagnosis of type 1 allergic reactions to trimethoprim and to define the basis of IgE antibody recognition of the drug . OBJECTIVES: The molecular basis of IgE binding to trimethoprim was examined more closely with a view to defining the fine structural recognition differences between patient's sera . Utilization of such information may lead to immunoassays that are more specific and sensitive and of greater diagnostic value . METHODS: Immunoassays for specific IgE antibodies and quantitative hapten inhibition studies with trimethoprim and selected structural analogues were employed, together with sera from eight subjects clearly defined clinically as allergic to trimethoprim . RESULTS: Three different allergenic determinant structures have been identified on the trimethoprim molecule . Identification of the 3,4-dimethoxybenzyl group as a determinant was achieved on the basis of inhibitory activities of diaveridine, 3,4-dimethoxyphenylethylamine, 3,4-dimethoxybenzoic acid and 3,4,5-trimethoxycinnamic acid . Evidence that the opposite end of the trimethoprim molecule was not being recognized was obtained from results with some pyrimidine derivatives, each of which showed no activity . Identification of the second determinant, the 2,4-diamino-5-(3',4'-dimethoxybenzyl) pyrimidine group, rested mainly on the superior inhibitory potency of diaveridine, which differs from trimethoprim by just one methoxy group . With sera from some trimethoprim-allergic subjects, only trimethoprim was active, suggesting that the entire molecule was a third IgE-binding determinant structure . CONCLUSION: As with other drug allergenic determinants defined so far, heterogeneity of trimethoprim IgE-binding determinants exists, and fine structural differences between determinants may be as small as a single methoxy group . Identification of the 2,4-diamino-5-(3',4'-dimethoxybenzyl) pyrimidine group as an allergenic determinant increases the number of known trimethoprim determinants to three, and suggests that the number and heterogeneity of determinants will be a reflection of the number of allergic subjects studied.

J Periodontol, 1996 Oct, 67(10 Suppl), 1055 - 9
Medications as risk factors for periodontal disease; Ciancio SG; As the United States population ages, people will be taking more medications which may benefit their general health but not necessarily their periodontal health . The effects of medications have been grouped into six categories as follows: behavioral alteration of oral hygiene methods, alteration of plaque composition, effect on gingival tissues, effect on alveolar bone, effect on gingival crevicular fluid, and effect on salivary flow . Although most medications discussed in this paper increase the risk for periodontal disease, a few may actually decrease the risk . These include the effect of phenytoin on alveolar bone, the antibacterial effect of antibiotics, the anticollagenolytic effects of tetracyclines, and the effect of non-steroidal anti-inflammatory drugs on decreasing alveolar bone resorption.

FEMS Immunol Med Microbiol, 1996 Oct, 15(4), 181 - 7
Interleukin-10 inhibits neutrophil phagocytic and bactericidal activity; Laichalk LL et al.; Effective host defense against bacterial invasion is characterized by the vigorous recruitment and activation of inflammatory cells, which is dependent upon the coordinated expression of both pro- and anti-inflammatory cytokines . Interleukin-10 (IL-10) is a recently described cytokine with potent anti-inflammatory properties in vivo and in vitro . In this study we investigated whether IL-10 could directly regulate the ability of neutrophils (PMN) to phagocytose and kill bacteria . Initial studies demonstrated that human recombinant IL-10 (hrIL-10) inhibited the ability of PMN to phagocytose Escherichia coli in vitro . Inhibition of phagocytosis occurred in the absence of changes in CR1 (C3b) or Fc receptor expression, as treatment of PMN with IL-10 failed to induce significant changes in Fc gamma IIR, Fc gamma IIIR or CR1 cell surface expression . However, incubation of PMN with IL-10 resulted in a dose-dependent decrease in CDIIb (Mac-1) expression . In addition to effects on PMN phagocytosis, hrIL-10 significantly attenuated PMN microbicidal activity, as bactericidal assays revealed that co-incubation of PMN with hrIL-10 resulted in a marked decrease in killing of phagocytosed bacteria . Furthermore, IL-10 inhibited the production of superoxide from PMA-stimulated PMN, suggesting that the detrimental effects of IL-10 on PMN microbicidal activity were due, in part, to suppression of respiratory burst . In summary, our studies indicate that IL-10 inhibits PMN-dependent phagocytosis and killing of E . coli in vitro, and suggest that this cytokine may impair effective antibacterial host defense in vivo.

Drug Saf, 1996 Oct, 15(4), 261 - 73
Drug interactions with neuromuscular blockers; Feldman S et al.; Drugs administered to patients undergoing anaesthesia may complicate the use of the neuromuscular blockers that are given to provide good surgical conditions . The various sites of interaction include actions on motor nerve conduction and spinal reflexes, acetylcholine (ACh) synthesis, mobilisation and release, sensitivity of the motor end plate to ACh and the ease of propagation of the motor action potential . In addition, many drugs affect the pharmacokinetics of neuromuscular blockers, especially as most drugs depend to a greater or lesser extent upon renal excretion . The clinically significant interaction between nondepolarisers and depolarisers may be due to blockade of the pre-synaptic nicotinic receptors by the depolarisers, leading to decreased ACh mobilisation and release . Synergism between nondepolarisers probably results from post-synaptic receptor mechanisms . Volatile anaesthetic agents affect the sensitivity of the motor end-plate (post-synaptic receptor blockade) in addition to having effects on pre-synaptic nicotinic function . The effects of nondepolarisers are likely to be potentiated and their action prolonged by large doses of local anaesthetics due to depression of nerve conduction, depression of ACh formation, mobilisation and release, decreases in post-synaptic receptor channel opening times and reductions in muscular contraction . Most antibacterials have effects on pre-synaptic mechanisms . Procainamide and quinidine principally block nicotinic receptor channels . Magnesium has a marked inhibitory effect on ACh release . Calcium antagonists could theoretically interfere with neurotransmitter release and muscle contractility . Phenytoin and lithium decrease ACh release, whilst corticosteroids and furosemide (frusemide) tend to increase the release of the transmitter . Ecothiopate, tacrine, organophosphates, propanidid, metoclopramide and bambuterol depress cholinesterase activity and prolong the duration of the neuromuscular block . The probability of clinically significant interactions increases in patients receiving several drugs with possible effects on neuromuscular transmission and muscle contraction.

Drug Metab Dispos, 1996 Oct, 24(10), 1134 - 8
Fluoroquinolone antibiotics inhibit cytochrome P450-mediated microsomal drug metabolism in rat and human; McLellan RA et al.; The fluoroquinolone antibacterial agents have gained widespread use in the treatment of a broad range of bacterial infections . We recently described a possible interaction concerning the concomitant use of cyclosporine A and norfloxacin in pediatric renal transplant patients . We examined the effect of two common fluoroquinolone antibiotics on cytochrome P450-mediated drug biotransformations in human and rat liver microsomes . Rats were pretreated with inducers, which increased the levels of the P450 isozymes CYP3A2, CYP1A, CYP2E1, and CYP4A1 . Ciprofloxacin and norfloxacin significantly depressed the N-demethylation of erythromycin by CYP3A4 in human microsomes and by CYP3A2 in rat microsomes . The inhibition was determined to be competitive in nature in rat microsomes, with ciprofloxacin and norfloxacin both exhibiting similar Ki values of 2.0 and 2.3 mM, respectively . Ciprofloxacin and norfloxacin also inhibited ethoxyresorufin-O-dealkylase (CYP1A) . In contrast, ciprofloxacin and norfloxacin did not inhibit the metabolism of substrates that are specific for the P450 isozymes CYP2E1 and CYP4A1 . Rats treated chronically with norfloxacin revealed no alterations in hepatic CYP3A2 protein levels or activity . These studies in hepatic microsomes demonstrate that fluoroquinolones can decrease CYP3A- and CYP1A-mediated biotransformation by competitive inhibition and that they have the potential to cause drug interactions with agents metabolized by these enzymes.

Biochem Biophys Res Commun, 1996 Sep 24, 226(3), 783 - 90
Elicitors triggering the simultaneous gene expression of antibacterial proteins of the silkworm, Bombyx mori; Taniai K et al.; Various elicitors were examined by Northern blot analysis to investigate the simultaneous induction of gene expression of antibacterial proteins such as cecropin B, attacin and lebocin from the silkworm, Bombyx mori . Lipopolysaccharide (LPS), lipid A, 2-keto-3-deoxyoctonate (KDO) and peptidoglycan (PG) triggered efficiently and simultaneously the gene expression of antibacterial proteins . Effects of inhibitors for signal transduction on the gene expression of Bombyx mori (Bm) cecropin B triggered by lipid A were observed using isolated adherent hemocytes consisting of granular cells and plasma cells . H-7, H-89 but not W-7 inhibited gene expression, suggesting that protein kinase C and A but not myosine light chain kinase may participate in signal transduction.

Biochemistry, 1996 Sep 24, 35(38), 12612 - 22
Peptide helicity and membrane surface charge modulate the balance of electrostatic and hydrophobic interactions with lipid bilayers and biological membranes; Dathe M et al.; An amphipathic model peptide, KLALKLALKALKAAKLA-NH2, and its complete double D-amino acid replacement set was used to analyze the process of peptide binding at lipid vesicles of different surface charge and to determine the structure of the lipid-bound peptides using CD spectroscopy . The relationship between peptide helicity, model membrane permeability, and biological activity has been studied by dye release from liposomes and investigation of antibacterial and hemolytic activity . The accumulation of cationic KLAL peptides at and the membrane-disturbing effect on bilayers of high negative surface charge were found to be dominated by charge interactions . Independent of any structural propensity, the cationic peptide side chains bind to the anionic phosphatidylglycerol moieties . The charge interactions hold the peptides at the bilayer surface, where they may disturb preferentially lipid headgroup organization by formation of peptide-lipid clusters . In contrast, KLAL peptide interaction with bilayers of low negative surface charge is highly dependent on peptide helicity . With decreasing amounts of anionic phosphatidylglycerol in the bilayer the membrane-disturbing effect of KLAL and other helical analogs substantially increases despite drastically reduced binding affinity . Less helical peptides exhibit reduced bilayer-disturbing activity, showing that the hydrophobic helix domain is decisive for binding at and inducing permeability in membranes of low negative surface charge . It is suggested that hydrophobic interactions drive the penetration of the amphipathic peptide structure into the inner membrane region, thus disturbing the arrangement of the lipid acyl chains and causing local disruption . On the basis of the proposed model for membrane disturbance, interactions modulating antibacterial and hemolytic activity are discussed.

Vet Rec, 1996 Sep 21, 139(12), 282 - 6
Usage of antibacterial and antiparasitic drugs in animals in Sweden between 1988 and 1993; Bjornerot L et al.; The total usage of antibacterial and antiparasitic drugs in animals in Sweden between 1988 and 1993 was assessed . The data for the antibacterial drugs were divided among the different classes of drug used each year . Special attention was paid to the use of antibacterial drugs in feeding stuffs and to their use in pigs and fish . During the period studied, the total usage of antibacterial drugs remained stable at approximately 35 tonnes of active substance annually . The use of antibacterial drugs for growth-promoting purposes was prohibited in Sweden in 1986 and became available by veterinary prescription only . As a result the total amount used annually has decreased and stabilised at a level about 35 per cent lower than before the ban . Important changes during 1988 to 1993 were a doubled usage of tetracyclines and a 50 per cent decrease in the use of olaquindox . The five major classes of antibacterial drugs used in 1993 were benzyl penicillin (13.2 tonnes), tetracyclines (8.8 tonnes), olaquindox (3.5 tonnes), sulphonamides (2.0 tonnes) and aminoglycosides (1.9 tonnes) . The total annual usage of coccidiostatic drugs, mainly used in the poultry industry, was stable at approximately 10 tonnes, while the usage of other antiparasitic drugs increased slightly to 7.7 tonnes.

Br Dent J, 1996 Sep 21, 181(6), 226 - 7
Centenary year of scientific papers in the British Dental Journal; McGowan D; In this paper Professor Fleming describes several aspects of antiseptics . He begins by considering the influence of the medium on the antiseptic, and of far more relevance, the speed of disappearance of the antiseptic . He then describes the ineffectiveness of an antiseptic in sterilising and treating a septic wound, backing up his remarks with experimental evidence . His lecture then looks at the effect of chemical antiseptics on the body's normal protective mechanism, specifically how some antiseptics inhibit the antibacterial effect of protective fluids (such as saliva and tears) as well as the antibacterial action of leucocytes . At the conclusion of the lecture he mentions specificity, and prophetically remarks on how penicillin may be used in the future in the treatment of septic wounds.

Cell, 1996 Sep 20, 86(6), 973 - 83
The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults; Lemaitre B et al.; The cytokine-induced activation cascade of NF-kappaB in mammals and the activation of the morphogen dorsal in Drosophila embryos show striking structural and functional similarities (Toll/IL-1, Cactus/I-kappaB, and dorsal/NF-kappaB) . Here we demonstrate that these parallels extend to the immune response of Drosophila . In particular, the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spatzle, control expression of the antifungal peptide gene drosomycin in adults . We also show that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection . Antibacterial genes are induced either by a distinct pathway involving the immune deficiency gene (imd) or by combined activation of both imd and dorsoventral pathways.

Proc Natl Acad Sci U S A, 1996 Sep 17, 93(19), 10343 - 7
Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila; Dushay MS et al.; NF-kappa B/Rel transcription factors are central regulators of mammalian immunity and are also implicated in the induction of cecropins and other antibacterial peptides in insects . We identified the gene for Relish, a compound Drosophila protein that, like mammalian p105 and p100, contains both a Rel homology domain and an I kappa B-like domain . Relish is strongly induced in infected flies, and it can activate transcription from the Cecropin A1 promoter . A Relish transcript is also detected in early embryos, suggesting that it acts in both immunity and embryogenesis . The presence of a compound Rel protein in Drosophila indicates that similar proteins were likely present in primordial immune systems and may serve unique signaling functions.

Acta Crystallogr C, 1996 Sep 15, 52 ( Pt 9), 2377 - 9
Biological activity of 4-(4-bromophenyl)-thiosemicarbazide; Seth S et al.; The two molecules (A and B) in the asymmetric unit of the title compound, C7H8BrN3S, display different conformation . In both molecules, the S atom is trans to the NH2 group . The Br atoms of the two molecules approach each other at a distance of 3.573(2) A . The crystal structure of the bromine compound is isomorphous with that of its chlorine analogue . In the crystal structure, intramolecular N-H...N and intermolecular N-H...S hydrogen bonds help stabilize the molecular packing . The increased antibacterial activity of the title compound compared to that of its chlorine analogue may be attributed to the increase in electron density on the hydrazinic end of the thiosemicarbazide chain.

Structure, 1996 Sep 15, 4(9), 1065 - 75
Crystal structure of UDP-N-acetylglucosamine enolpyruvyltransferase, the target of the antibiotic fosfomycin; Schonbrunn E et al.; BACKGROUND . The ever increasing number of antibiotic resistant bacteria has fuelled interest in the development of new antibiotics and other antibacterial agents . The major structural element of the bacterial cell wall is the heteropolymer peptidoglycan and the enzymes of peptidoglycan biosynthesis are potential targets for antibacterial agents . One such enzyme is UDP-N-acetylglucosamine enolpyruvyltransferase (EPT) which catalyzes the first committed step in peptidoglycan biosynthesis: the transfer of the enolpyruvyl moiety of phosphoenolpyruvate (PEP) to the 3-hydroxyl of UDP-N-acetylglucosamine (UDPGlcNAc) . EPT is of potential pharmaceutical interest because it is inhibited by the broad spectrum antibiotic fosfomycin . RESULTS . The crystal structure of substrate-free EPT has been determined at 2.0 A resolution . The structure reveals a two-domain protein with an unusual fold (inside out alpha/beta barrel) which is built up from the sixfold repetition of one folding unit . The only repetitive element in the amino acid sequence is a short motif, Leu-X3-Gly(Ala), which is responsible for the formation of hydrogen-bond interactions between the folding units . An enzyme which catalyzes a similar reaction to EPT, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), has a very similar structure despite an amino acid sequence identity of only 25% . To date, only these two enzymes appear to display this characteristic fold . CONCLUSIONS . The present structure reflects the open conformation of the enzyme which is probably stabilized through two residues, a lysine and an arginine, located in the cleft between the domains . Binding of the negatively charged UDPGlcNAc to these residues could neutralize the repulsive force between the two domains, thereby allowing the movement of a catalytically active cysteine residue towards the cleft.

Cas Lek Cesk, 1996 Sep 11, 135(17), 552 - 4
{Primary immunodeficiencies . II . Current therapeutic possibilities}; Litzman J; The possibilities of the influence of the immune system in patients with primary immunodeficiencies are nowadays limited . Bone marrow transplantation is the only causal treatment at present, but it is used only in patients with the most severe diseases . Gene transplantation is a possible approach in diseases with known genetic defects, but the experience is still very limited . As a replacement therapy, immunoglobulin is the most frequently used, while enzyme replacement therapy has only a restricted applicability . Adequate antibiotic therapy is an essential part of the treatment of the patients with primary immunodeficiencies, both as an adequate and rasant antibiotic treatment of acute infections and also as a long-term antibacterial, and in some cases also anti-viral and anti-fungal prophylaxis.

Anal Biochem, 1996 Sep 5, 240(2), 185 - 96
Scintillation proximity assay for human DNA topoisomerase I using recombinant biotinyl-fusion protein produced in baculovirus-infected insect cells; Lerner CG et al.; DNA topoisomerases are well-established targets of important therapeutic agents which include the antibacterial quinolones and anticancer camptothecins . Screens for new classes of topoisomerase inhibitors generally employ methods, such as gel electrophoresis, which are not readily amenable to a rapid high-throughput format . We describe here a high-throughput assay to screen for inhibitors of human DNA topoisomerase I based on the scintillation proximity assay . The assay employs recombinant biotinyl-topoisomerase I fusion protein, a hybrid protein which contains a domain that is biotinylated during in vivo expression . The hybrid topoisomerase I fusion protein is found to be biotinylated, active, and nuclear-localized when produced in insect cells using a baculovirus expression system . The biotinyl-topoisomerase I fusion protein can be captured from crude nuclear extracts by immobilization on streptavidin-coated scintillation proximity assay beads . The assay detects binding of 3H-labeled DNA to the bead-immobilized enzyme by scintillation counting . The method is also able to detect stabilization of covalent protein-DNA complexes by camptothecin, an inhibitor previously shown to stabilize covalent intermediates that form during catalysis.

Biochemistry, 1996 Sep 3, 35(35), 11414 - 24
Unusual binding stoichiometries and cooperativity are observed during binary and ternary complex formation in the single active pore of R67 dihydrofolate reductase, a D2 symmetric protein; Bradrick TD et al.; R67 dihydrofolate reductase (DHFR) is an R-plasmid-encoded enzyme that confers resistance to the antibacterial drug, trimethoprim . This DHFR variant is not homologous in either sequence or structure to chromosomal DHFRs . A recent crystal structure of the active tetrameric species describes a single active site pore that traverses the length of the protein (Narayana et al., 1995) . Related sites (due to a 222 symmetry element at the center of the active site pore) are used for binding of ligands, i.e., each half-pore can accommodate either the substrate, dihydrofolate, or the cofactor, NADPH, although dihydrofolate and NADPH are bound differently . Ligand binding in R67 DHFR was evaluated using time-resolved fluorescence anisotropy and isothermal titration calorimetry techniques . Under binary complex conditions, two molecules of either NADPH, folate, dihydrofolate, or N10 propargyl-5,8-dideazafolate (CB3717) can be bound . Binding of NADPH displays negative cooperativity, binding of either folate or dihydrofolate shows positive cooperativity, and binding of CB3717 shows two identical sites . Any asymmetry introduced by binding of one ligand is proposed to induce the cooperativity associated with binding of the second ligand . Evaluation of ternary complex formation demonstrates that one molecule of folate binds to a 1:1 mixture of R67 DHFR+NADPH . These binding results indicate a maximum of two ligands bind in the pore . A mechanism describing catalysis is proposed that is consistent with the binding results.

Pol Merkuriusz Lek, 1996 Sep, 1(3), 165 - 8
{Morphologic changes of gastric mucosa in Helicobacter pylori infection in patients with peptic ulcer disease and chronic gastritis}; Raczynska A et al.; The present study was carried out to value the histological method of detection of Helicobacter pylori in gastric mucosa and to analyse the pathological changes of the Helicobacter pylori-positive patients with duodenal and gastric ulcer and with chronic gastritis . The studies population consisted of 150 patients, 76 F and 74 M . The samples were taken during gastroscopy from the prepyloric region and gastric body . After routine histological procedure they were stained HE and by Giemsa method for detection of H.pylori . The latter was identified in 56.6% of of the patients with duodenal ulcer, in 54.8% of those with gastric ulcer, in 17.6% of the patients after partial gastrectomy and in 46.9% of patients suffering from chronic gastritis . The increased density of H.pylori (third grade) was detected in the cases with clinical diagnosis of duodenal and gastric ulcer and erythematous endoscopic gastritis and was correlated with the histological picture of chronic active gastritis, which was characterized by diffuse mixed cellular exudation, lesion of the superficial epithelial, mucosal erosions and by foveolar hyperplasia . We suggest that this morphological picture corresponded to the active phase of Helicobacter infection . We conclude, that the histological method by Giemsas staining is effective especially in the acute phase of H.pylori infection and represents high diagnostic value and may be used in monitoring during the antibacterial (anti H.pylori) treatment . There is the correlation between massive density of H.pylori observed in gastric mucosa and chronic active gastritis.

Crit Care Nurs Clin North Am, 1996 Sep, 8(3), 253 - 71
Transplant medications; O'Donnell M et al.; This article discusses the medications used most commonly to keep the lung transplant patient free of rejection and infection . Medications used in the treatment of rejection are categorized by their use; therefore, the most common three- and four-drug regimens used for induction, maintenance, and treatment of rejection are discussed . The most commonly used antibacterial, antiviral, and antifungal drugs also are identified . Tables listing the characteristics of the medications are included to make it easier for the reader to quickly identify the indications, mechanisms of action, major adverse reactions, and nursing implications of these medications.

J Exp Med, 1996 Sep 1, 184(3), 945 - 54
Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes; Sinnis P et al.; Remnants of lipoproteins, intestinal chylomicrons, and very low density lipoprotein (VLDL), are rapidly cleared from plasma and enter hepatocytes . It has been suggested that remnant lipoproteins are initially captured in the space of Disse by heparan sulfate proteoglycans (HSPGs), and that their subsequent internalization into hepatocytes is mediated by members of the LDL-receptor gene family . Similarly to lipoprotein remnants, malaria sporozoites are removed from the blood circulation by the liver within minutes after injection by Anopheles mosquitoes . The sporozoite's surface is covered by the circumsporozoite protein (CS), and its region II-plus has been implicated in the binding of the parasites to glycosaminoglycan chains of hepatocyte HSPGs . Lactoferrin, a protein with antibacterial properties found in breast milk and neutrophil granules, is also rapidly cleared from the circulation by hepatocytes, and can inhibit the hepatic uptake of lipoprotein remnants . Here we provide evidence that sporozoites, lactoferrin, and remnant lipoproteins are cleared from the blood by similar mechanisms . CS, lactoferrin, and remnant lipoproteins compete in vitro and in vivo for binding sites on liver cells . The relevance of this binding event for sporozoite infectivity is highlighted by our demonstration that apoliprotein E-enriched beta-VLDI and lactoferrin inhibit sporozoite invasion of HepG2 cells . In addition, malaria sporozoites are less infective in LDL-receptor knockout (LDLR -/-) mice maintained on a high fat diet, as compared with littermates maintained on a normal diet . We conclude that the clearance of lipoprotein remnants and sporozoites from the blood is mediated by the same set of highly sulfated HSPGs on the hepatocyte plasma membrane.

Clin Infect Dis, 1996 Sep, 23(3), 515 - 21
Risk factors for fungemia in children infected with human immunodeficiency virus: a case-control study; Gonzalez CE et al.; To define the risk factors related to the occurrence of fungemia in children infected with human immunodeficiency virus (HIV), we performed a matched case-control study . During a 6-year period (1987-1993), fungemia developed in 22 (6.3%) of 347 HIV-infected children observed at the Pediatric Branch of the National Cancer Institute . Each of these 22 cases was matched by age and gender with three controls . Multiple logistic regression indicated that the best predictor of fungemia in this population was the presence of a central venous catheter placed for > 90 days (P < .00001), followed by a group of risk factors composed of 10 independent variables adjusted for a CD4 cell count of < 100/MicroL (P < .045) . Those variables included treatment with more than three antibiotics, treatment with more than three parenteral antibiotics, > 30 days of antibiotic treatment, bacterial infections, > 30 days in the hospital, hypoalbuminemia, C3 (Centers for Disease Control and Prevention) classification of HIV infection, and malnourishment . We conclude that prolonged placement of central venous catheters is the most important risk factors for fungemia in HIV-infected children and that the risk of fungemia is further influenced by antibacterial therapy, catheter manipulation, and host response.

Comp Biochem Physiol C Pharmacol Toxicol Endocrinol, 1996 Sep, 115(1), 1 - 9
Pharmacokinetic considerations in the camel (Camelus dromedarius): a review; Ali BH et al.; In this article the pharmacokinetic profile of several antibacterial, antiparasitic and antiinflammatory agents in camels has been reviewed . The effect of dehydration on the kinetics of these drugs has also been discussed.

Technol Health Care, 1996 Sep, 4(3), 311 - 6
New therapeutic uses for an old family of drugs: travels of a dental researcher from the lab to the university's office of technology transfer and beyond; Golub LM et al.; The authors, including an academic-inventor, the director of the University's tech-transfer office, and the CEO of a "start-up" pharmaceutical company based on the professor's (and his colleague's) inventions, relate the history and current status of their interactions . To start, the basic research leading to the "eureka" experiment (such things really do happen) is summarized: namely, the discovery of (i) the surprising ability of the tetracycline antibiotics to inhibit mammalian tissue-destructive proteinases (collagenase, gelatinase) during a variety of disease processes, e.g., periodontitis, the arthritides, osteopenia/osteoporosis, sterile corneal ulcers, tumor invasion/metastasis/angiogenesis, and (ii) a series of chemically-modified, non-antibacterial analogs of tetracyclines to inhibit these enzymes without producing typical antibiotic side effects . The role of the University in obtaining the services of patent attorneys, and its assistance in developing the strategy to deal with an industrial partner, is addressed . Above all, the authors stress the need for close cooperation and collegial interactions between all three groups in this high-risk (but potentially high-benefit-to-the-public) enterprise.

J Antimicrob Chemother, 1996 Sep, 38(3), 443 - 55
gyrA mutations in high-level fluoroquinolone-resistant clinical isolates of Escherichia coli; Conrad S et al.; Double mutations in the quinolone resistance determining region of the gyrase A gene (gyrA) have recently been reported to be associated with high-level resistance to fluoroquinolones in clinical isolates of Escherichia coli . We examined the type and frequency of such mutations in a large number of clinical isolates that were obtained from ten different geographical locations and had been genotypically characterized by pulsed field gel electrophoresis (PFGE) of chromosomal DNA digests . Of 36 isolates with ofloxacin MICs > or = 4 mg/L that represented at least 24 distinct genotypes, 35 had double mutations at amino acid codons 83 and 87 of gyrA, while two isolates with ofloxacin MICs of 0.5 and 4 mg/L, respectively, each had a single mutation at codon 83 . Mutations at codon Ser-83 were uniform, resulting in substitution by Leu . The additional mutations at amino acid codon 87 in the 35 double-mutants were diverse, resulting in Asp-87 substitutions by residues Asn (23 isolates), Gly (7 isolates), Tyr (4 isolates), or His (1 isolate) without a discernable correlation with fluoroquinolone MICs or with phenotypic resistance to chemically unrelated antibacterial agents . Maximal differences between MICs of double-mutants with the same amino acid substitution were eight-fold . The changes of amino acid residues at codon Asp-87 differed between individual patient isolates with the same genotype (and similar MICs), suggesting that the amino acid codon 87 mutations (and possibly the development of high-level fluoroquinolone resistance) might have occurred after the transmission and sharing of a precursor strain carrying the Ser-83-->Leu mutation.

Scand J Gastroenterol, 1996 Sep, 31(9), 856 - 62
Severity of Helicobacter pylori gastritis predicts duodenal ulcer recurrence; Miehlke S et al.; BACKGROUND: Helicobacter pylori gastritis is suggested to be the underlying condition leading to duodenal ulcer disease . The aim of the study was to investigate the relationship between chronic active H . pylori gastritis and the risk of duodenal ulcer (DU) recurrence . METHODS: One hundred and eighty-eight patients were followed up with regard to the evolution of their H . pylori gastritis after they had received antibacterial or acid-suppressing treatment for their DU . Four weeks, 1 year, and 2 years after treatment and in the case of DU recurrence several morphologic indicators of gastritis were studied histologically in the antrum and corpus . RESULTS: In patients who were cured of H . pylori infection a significant and long-lasting regression of all gastritis variables were observed . patients with persistent H . pylori infection after antibacterial treatment showed only a temporary regression of all gastritis variables . In the overall group of patients who received acid-suppressive therapy there was no change in gastritis . However, in the subgroup of patients who received omeprazole monotherapy, no change in the antrum but a statistically significant increase of gastritis in the corpus was observed . The grade of antral gastritis at the end of treatment was significantly and positively correlated with the risk of DU recurrence and was independent of the kind of pretreatment (18.5% recurrences in grade-2 versus 86% in grade-4 gastritis) . CONCLUSIONS: The data show that the grade of gastritis is an important risk factor for duodenal ulcer recurrence . Cure of H . pylori infection is associated with healing of chronic H . pylori-associated gastritis . These data lend considerable support to the hypothesis that H . pylori gastritis is the most important factor among those leading to duodenal ulcer disease.

J Ethnopharmacol, 1996 Sep, 53(3), 149 - 56
An ethnobotanical study of the traditional medicine of the Mestizo people of Suni Miraño, Loreto, Peru; Jovel EM et al.; Research on the ethnobotany of Mestizos in Suni Mirano in 1994 documented 60 plant species used for medicinal purposes . Some cultural data on traditional healing and etiology were also collected . Of these 60 species, 31 were submitted to antibacterial and antifungal assays in the presence and absence of UV light and a number of species were shown to be active.

Drug Saf, 1996 Sep, 15(3), 167 - 75
Cisapride . Drug interactions of clinical significance; Bedford TA et al.; Cisapride is a prokinetic agent which restores motility of the gastrointestinal tract in conditions of decreased bowel transit . It may also alter the absorption of coadministered drugs . The absorption of morphine, diazepam, cyclosporin, alcohol (ethanol) and levodopa are increased . Initial absorption of cimetidine and raniditine is also increased, but overall absorption is lower due to increased bowel transit . The absorption of digoxin, propranolol and the anticoagulants warfarin and phenprocoumon appears unaffected by cisapride, although increase thrombotest values were seen with acenocoumarol (nicoumalone) . Drug interactions leading to increased plasma concentrations of cisapride may produce an increase in adverse effects . The most important of these is QT interval prolongation and ventricular arrhythmias . Phenytoin does not appear to affect protein binding of cisapride . Cisapride metabolism is inhibited by the antifungals ketoconazole, fluconazole, itraconazole and miconazole, and by the antibacterials erythromycin, troleandomycin and clarithromycin . Cisapride should not be coadministered with these drugs . Cimetidine produces a small increase in cisapride plasma concentrations, which may be due to inhibition of metabolism . Cisapride absorption is unaffected by other antacids . Atropine may reverse the cisapride-induced increase in peristalsis . Prescribers should remain vigilant to the presence of these and other, as yet unreported, reactions.

Drugs, 1996 Sep, 52(3), 344 - 70
Aminoglycoside administration as a single daily dose . An improvement to current practice or a repeat of previous errors?
Marra F, Partovi N, Jewesson P.
Despite the availability of newer and safer antibacterials, aminoglycosides continue to play a major role in the management of infections in hospitalised patients . The concept of single daily dose (SDD) regimens was introduced many years ago and is now receiving much attention as an alternative regimen for this class of drugs . To evaluate the rationale and clinical support for SDD schemes, we conducted a 'MEDLINE' search to locate relevant preclinical and clinical literature pertaining to this issue . The results of animal model and noncomparative clinical data tended to be variable and inconclusive . We were able to identify 28 prospective comparative clinical trials; however, only one was randomised, double-blind and of sufficient sample size to detect differences in efficacy between treatment arms, should any exist . Despite these flaws, our review suggests that SDD schemes appear to be no more efficacious and no less toxic, but may be less costly, than traditional multiple daily dose schemes . We also assessed the predicted disposition of tobramycin/gentamicin in 415 patients with known pharmacokinetic parameters . With doses of 7 mg/kg at intervals of between 24 and 60 hours (depending upon renal function), the maximum serum concentration at steady-state (Cmaxss) varied from 8.5 to 55.6 mg/L, while the Cminss was < 2.0 mg/L in the majority of patients . Mid-interval serum aminoglycoside concentrations were < 0.5 mg/L in up to 23% of patients, suggesting possible underdosage in certain patients with this scheme . More conclusive clinical evidence is necessary before SDD schemes should be adopted as standard clinical practice . Empirical weight-based dosage schemes appear to yield widely variable serum aminoglycoside concentrations which could be considered therapeutically inadequate or toxic.

J Nat Prod, 1996 Sep, 59(9), 823 - 7
Macrocarpals H, I, and J from the Leaves of Eucalyptus globulus; Osawa K et al.; A 50% EtOH extract of Eucalyptus globulus leaves yielded eight phloroglucinol--sesquiterpene-coupled constituents, including three novel compounds named macrocarpals, H, I, and J . Some of these compounds possessed antibacterial activity against oral pathogenic microorganisms with MIC values ranging from 0.20 micrograms/mL to 6.25 micrograms/mL . Inhibition of glucosyltransferase activity by these compounds was also noted.

J Chromatogr A, 1996 Aug 2, 740(2), 273 - 8
Determination of peptidoglycan-associated protein in Escherichia coli NCIB 8545 by capillary zone electrophoresis; Xing JZ et al.; An efficient reliable and sensitive capillary zone electrophoresis assay for the six major bacterial peptidoglycan-associated proteins of Escherichia coli NCIB 8545 is described . The method provides the facility to determine quantitatively the effect of antibacterials on bacterial peptidoglycan-associated protein synthesis and thus to further elucidate the mechanism of antibacterial action of such drugs as the antifolates which recently have been shown to adversely affect peptidoglycan synthesis.

Tierarztl Prax, 1996 Aug, 24(4), 368 - 72
{The plasma level of kanamycin after intravenous and intramuscular injections in horses}; Klee S et al.; A therapeutical dose of kanamycin was tested intravenously and intramuscularly in four normal standardbreds and plasma concentrations were measured over a 12 hour period . Plasma levels exceeded a minimum inhibitory concentration of 4 micrograms/ml within only 15 minutes for 8 hours both after i.v . and i.m . injection . Kanamycin revealed a mean plasma half life of 2.3 hours . Bioavailability of an intramuscular dose was about 76% . The pharmacokinetic parameters demonstrate the rapid onset of antibacterial plasma levels of the test compound . A dose regimen for horses of two times daily 5 mg/kg body weight ensures therapeutically effective plasma levels . The risk of accumulation as well as nephro- or ototoxic side effects are negligible at short-term treatment.

Lett Appl Microbiol, 1996 Aug, 23(2), 75 - 8
Replicate plating: does it increase reliability?
Wille KK, Vowels BR, Foglia AN, Berge CA, Schnell BM, Briese FW.
As a part of a clinical study to evaluate the antibacterial effect of a topically applied erythromycin gel, microbiological specimens were taken from two groups of patients: one group using 2% erythromycin gel and the other group using a placebo gel . These specimens were plated in triplicate using a common source on bacteriological media using standard procedures . After the appropriate incubation times, the numbers of aerobic and anaerobic organisms were counted separately from each of three plates . A comparison of the bacterial colony counts from the replicate plates showed a high degree of similarity for each type of organism . Tests for treatment differences in organism counts were performed based on single, double and triplicate plating . The results obtained were almost identical, suggesting that replicate plating from a common source is no more accurate than single plating . The only apparent advantage of this type of replicate plating is heightened confidence in the reliability of bacterial counts from single plates.

Nihon Kyobu Shikkan Gakkai Zasshi, 1996 Aug, 34(8), 937 - 42
{Computed tomographic findings in septic pulmonary emboli secondary to renal abscess}; Matsumoto H et al.; A 73-year-old woman with diabetes mellitus and hypothyroidism had been well until 4 days before she presented with fever, productive coughing, and general malaise . Dyspnea gradually worsened, and she was admitted to Kobe City General Hospital . She appeared toxic and was in moderate respiratory distress on admission . There were scattered rales in both lung fields . The abdomen was soft with no tenderness . A chest roentgenogram showed peripheral infiltrates in both lung fields . Arterial blood gas analysis showed a Po2 of 48.6 Torr and Pco2 of 27.2 Torr . A blood culture on admission showed Escherichia coli . Computerized tomography of the chest showed multiple nodules of various sizes in the peripheral lung fields . Some nodules had necrotic centers and feeding vessels . Wedge-shaped lesions abutting the pleura were also seen . These findings strongly suggested septic pulmonary emboli . An abscess in the left kidney, which was considered to be the source of the septic pulmonary emboli, was found with Ga scintigraphy, ultrasonography, and computerized tomography of the abdomen . Treatment with antibacterial drugs was effective against the lung lesions but not the renal abscess . A left nephrectomy was done . In the proper clinical setting, characteristic CT features of septic emboli can contribute to early diagnosis of this disease.

Br J Ophthalmol, 1996 Aug, 80(8), 685 - 8
Comparative intraocular penetration of topical and injected cefuroxime; Jenkins CD et al.; AIMS: The choice of a prophylactic antibiotic for cataract surgery is dependent on its antibacterial activity and tissue penetration . The influence of the route and timing of administration of cefuroxime on its intraocular concentrations was examined . METHODS: 120 patients were recruited before cataract surgery into a prospective trial to compare the anterior chamber concentration of cefuroxime at a fixed time after administration by three routes . In a further 110 patients, the interval before sampling was varied in order to permit an examination of the kinetics of penetration . In another 10 patients, cefuroxime was given topically at the completion of surgery to assess the effect of a corneal wound on aqueous penetration . Cefuroxime concentrations were measured by high performance liquid chromatography on 0.2 ml samples of aqueous aspirated from the anterior chamber . Mean aqueous concentrations of cefuroxime for each group were compared using Student's t test . RESULTS: After 25 mg cefuroxime, mean aqueous concentrations increased in the order forniceal (< 0.1 microgram/ml) < topical (0.18 microgram/ml) < subconjunctival (2.31 microgram/ml) when sampled 12-24 minutes after administration . Aqueous concentrations of cefuroxime reached a peak between 80 and 110 minutes after both forniceal and peribulbar injection but were still rising at this time after subconjunctival injection . Topical application of 12.5 mg cefuroxime to eyes with a 10 mm corneal wound resulted in a mean aqueous concentration of 9.34 micrograms/ml . CONCLUSION: In the intact eye, only sub-conjunctival injection resulted in clinically significant aqueous concentrations of cefuroxime (> 1 microgram/ml) between 12 and 24 minutes after administration . For all routes, maximal aqueous concentrations were delayed by at least 80 minutes from administration . In the presence of a corneal wound, high aqueous levels of cefuroxime were rapidly attained after topical application.

J Pharm Pharmacol, 1996 Aug, 48(8), 801 - 5
The preparation of norfloxacin-loaded liposomes and their in-vitro evaluation in pig's eye; Lin HH et al.; The effectiveness of norfloxacin as an antibacterial agent in ophthalmology is limited by poor drug delivery and limited ocular bioavailability . Liposomes containing norfloxacin have been prepared from different phospholipids using a novel technique with an encapsulation efficiency sixteen times greater than that of a conventional film method . The in-vitro release of the norfloxacin and the transcorneal characteristics of the liposomes have been evaluated . Differential scanning calorimetry was used to determine the interaction occurring between liposomes and cornea . The release of liposome-entrapped norfloxacin was affected by the pH of the environment . In the in-vitro corneal perfusion studies, norfloxacin-loaded liposome was transferred through the cornea at a slower rate than was the free drug . Norfloxacin-loaded liposomes were accumulated primarily in the cornea . The drug corneal retention of the lipids increased in the order dimyristoyl-L-alpha-phosphatidylcholine < dipalmitoyl-L-alpha -phosphatidylcholine < distearoyl-L-alpha-phosphatidylcholine . In the corneal drug-elimination study, liposomal norfloxacin increased the loading of the drug in cornea; the maximum value of the loading occurred 5 h after dosing . The drainage of liposomes from the cornea was somewhat slower than the solution form . Accumulation of norfloxacin in the cornea was greater for the liposome-entrapped drug . The results suggest that norfloxacin-loaded liposomes are absorbed by the cornea via endocytosis.

Drug Saf, 1996 Aug, 15(2), 87 - 90
Neurotoxicity of carbapenem antibacterials; Norrby SR; Similar to other beta-lactam antibacterials, carbapenems have a neurotoxic potential that seems to be higher than that of the penicillins and cephalosporins . Seizures have been reported in several large studies of patients treated with imipenem/cilastatin . However, it seems clear that the main factor increasing the risk of neurotoxicity with imipenem/cilastatin is administration of excessive dosages relative to bodyweight and/or renal function . If the manufacturer's dosage recommendations are followed, the risk of seizures in patients receiving this combination is minimal . With meropenem, a newly registered carbapenem, the safety margin with respect to neurotoxic reactions has been increased compared with imipenem and meropenem can be used at higher doses than imipenem/cilastatin . Since the neurotoxicity of beta-lactam antibacterials seems to be caused by an interaction with gamma-aminobutyric acid (GABA) receptors, other drugs with a similar mechanism of action, such as fluoroquinolone antibacterials, should be used with caution when combined with carbapenems.

Bioorg Med Chem, 1996 Aug, 4(8), 1307 - 15
The synthesis and in vitro antibacterial activity of conformationally restricted quinolone antibacterial agents; Cooper CS et al.; Two series of conformationally restricted quinolone antibacterials were synthesized . One series was restricted by formation of a tetrahydrofuran ring between the C-6 position and the C-7 position of the quinolone ring skeleton . The second series achieved conformational rigidity by formation of a tetrahydrofuran ring between the C-7 and the C-8 positions . These compounds were evaluated for their in vitro antibacterial activity . Compounds 19 and 20 were the most active compounds in either series and were about equipotent.

J Clin Periodontol, 1996 Aug, 23(8), 778 - 81
Mouthrinses containing triclosan reduce the incidence of recurrent aphthous ulcers (RAU); Skaare AB et al.; Triclosan, an antibacterial agent introduced in toothpastes and mouthrinses, has recently been shown to have anti-inflammatory and analgesic properties . The aim of the present double-blind cross-over study was to examine the effect of triclosan on the incidence of recurrent aphthous ulceration (RAU) when administered in mouthrinses . The study included 30 patients with a history of multiple recurrent aphthous ulcers . Three different triclosan-containing mouthrinses, differing only in their solubilizing agents were used and compared with a control rinse . The number of new ulcers, ulcer-free days and the severity of pain were recorded . The results showed that the patients experienced a significant decrease in the number of oral ulcers during the experimental period when the mouthrinses contained triclosan . It may thus be concluded that triclosan has the potential to reduce the number of aphthous ulcers presumably due to its anti-inflammatory properties.

J Antimicrob Chemother, 1996 Aug, 38(2), 167 - 82
Issues in the adjunct therapy of severe sepsis; Verhoef J et al.; Until recently the concept of immunomodulation in patients with severe sepsis (formerly called sepsis syndrome or septic shock) appeared very promising . Research has focused on the possible therapeutic potential of interfering with cytokine pathways, either by preventing the induction of cytokines, such as TNF-alpha, by neutralization of lipopolysaccharide (LPS), or through the use of agents that attenuate cytokine action . Nowadays research on protein or protein constructs with antibacterial activities such as bacterial/permeability increasing protein (BPI), platelet activating factor receptor antagonists, nitric oxide and cyclo-oxygenase inhibitors, are still being followed . In large clinical trials monoclonal antibodies against core glycolipid (E5, HAIA) were shown to be at best of only marginal benefit, and in some trials results were indecisive . Also, the results with IL-lra, although initially heralded with high expectation, were at the end disappointing and the trials discontinued . Two large trials with monoclonal antibodies against TNF showed some effect in subcategories of patients: a third trial is on its way . Other phase I; II studies include those of soluble TNF receptors and BPI . The area of immunomodulation has now become an area of more realism and the results of early trials has forced investigators to go back the drawing board and to re-investigate the whole concept of immunotherapy and immunoprophylaxis.

New Horiz, 1996 Aug, 4(3), 338 - 44
Resistance to antifungal agents in the critical care setting: problems and perspectives; Martins MD et al.; As is the case with antibacterial agents, the increasing use of antifungal agents has led to development of antifungal resistance, the most clinically important of which is the resistance of Candida to fluconazole . While mutation to high-level fluconazole resistance is possible, the most important aspect of fluconazole resistance for patients in the ICU is the possibility of an epidemiologic shift away from such susceptible species as C . albicans and C . parapsilosis toward the most resistant species, such as C . glabrata and C . krusei . Resistance to amphotericin B by Candida is also possible, but less frequent . Strategies for treating invasive Candida infections must consider the relative rates of non-C . albicans Candida infection and the likelihood of antifungal resistance . The agents that cause invasive mold infections in the ICU are intrinsically moderately resistant to the available antifungal agents, and therapy depends less on the choice of antifungal therapy than on the correction of predisposing factors . The role of susceptibility testing as a guide in selecting appropriate therapy for all of these infections is as yet incompletely defined, but testing for resistance to fluconazole may soon be ready for clinical use.

Mol Biochem Parasitol, 1996 Aug, 79(2), 153 - 65
Potential antifolate resistance determinants and genotypic variation in the bifunctional dihydrofolate reductase-thymidylate synthase gene from human and bovine isolates of Cryptosporidium parvum; Vasquez JR et al.; We have determined the nucleic acid sequences of a gene encoding the bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) from bovine and human AIDS isolates of Cryptosporidium parvum . THe DHFR-TS gene was isolated from genomic DNA libraries by hybridization with a probe amplified from C . parvum genomic DNA using generic TS primers in the polymerase chain reaction . Genomic Southern and electrophoretic karyotype analyses reveal C . parvum DHFR-TS is a single-copy gene on a 1200-kb chromosome . The DHFR-TS nucleic acid sequence contains no introns and the single 1563-bp open reading frame encodes a 179 residue N-terminal DHFR domain connected by a 55 amino acid junction peptide to a 287 residue C-terminal TS domain . The sequences of the DHFR-TS gene from the bovine and human C . parvum isolates differ at two positions in the 5'-flanking sequence and at 38 positions in the encoding sequence . These DNA sequence polymorphisms will provide a powerful probe to examine the genotypic diversity and genetic population structure of C . parvum . The two sequences encode identical TS domains which share all except one of the phylogenetically conserved amino acid residues identified among reported TS sequences . The predicted DHFR domain sequences contain nine amino acid differences; these polymorphisms all map to non-active site, surface locations in known DHFR structures . The C . parvum DHFR active site contains novel residues at several positions analogous to those at which point mutations have been shown to produce antifolate resistance in other DHFRs . Thus C . parvum DHFR may be intrinsically resistant ti inhibition by some antifolate DHFR inhibitors which may explain why cryptosporidiosis is refractory to treatment with the clinically common antibacterial and antiprotozoal antifolates.

Antimicrob Agents Chemother, 1996 Aug, 40(8), 1775 - 84
Mechanism of differential activities of ofloxacin enantiomers; Morrissey I et al.; Ofloxacin, a potent quinolone antibacterial agent, has a tricyclic ring structure with a methyl group attached to the asymmetric carbon at the C-3 position on the oxazine ring . The S isomer (DR-3355) of ofloxacin has antibacterial activity up to 2 orders of magnitude greater than that of the R isomer (DR-3354) . This differential antibacterial activity was not due to different drug transport mechanisms of the two isomers but was found to be derived from the inhibitory activity against the target enzyme, DNA gyrase . Previous mechanistic studies have suggested that the bactericidal effect of the drug is mediated through the stabilization of a cleavable complex via a cooperative drug binding process to a partially denatured DNA pocket created by DNA gyrase . The drug binds to supercoiled DNA in a manner similar to that to which it binds to the enzyme-DNA complex . In the present studies, we first examined the binding of the two radiolabeled ofloxacin enantiomers to supercoiled pUC9 plasmid DNA . Surprisingly, the two enantiomers possessed similar apparent binding affinities and binding cooperatives . The major difference in binding between the two stereoisomers was the molar binding ratio: 4 for the more active S isomer versus 2 for the less active R isomer . We next examined the relative binding potencies of the stereoisomers to the DNA-DNA gyrase complex . The results of a competition assay showed that (S)-ofloxacin binds 12-fold better to the complex than (R)-ofloxacin . The binding potencies of the two enantiomers and two other quinolones correlated well with their respective concentrations causing 50% inhibition against DNA gyrase . The results are interpreted by a stacking model by using the concept of the cooperative drug-DNA binding mechanism, indicating that the potencies of quinolones cannot be determined solely by the DNA binding affinity and cooperativity but can also be determined by their capability in maximally saturating the binding site . The capability of the drug in saturating the binding pocket manifests itself in an increased efficacy at inhibiting the enzyme through a direct interaction between the drug and the enzyme . The results augment the previous suggestion that the binding pocket in the enzyme-DNA complex involves multiple receptor groups including not only DNA bases but also a gyrase subunit . The higher level of potency of (S)-ofloxacin is proposed to derive from the fact that a greater number of molecules are assembled in the pocket . This greater number of molecules optimizes the interaction between the drug and the enzyme, possibly through a contact between the C-7 substituent and the quinolone pocket on the B subunit of DNA gyrase.

Insect Mol Biol, 1996 Aug, 5(3), 203 - 10
Inducible immune factors of the vector mosquito Anopheles gambiae: biochemical purification of a defensin antibacterial peptide and molecular cloning of preprodefensin cDNA; Richman AM et al.; Larvae of the mosquito vector of human malaria, Anopheles gambiae, were inoculated with bacteria and extracts were biochemically fractionated by reverse-phase HPLC . Multiple induced polypeptides and antibacterial activities were observed following bacterial infection, including a member of the insect defensin family of antibacterial proteins . A cDNA encoding An . gambiae preprodefensin was isolated using PCR primers based on phylogenetically conserved sequences . The mature peptide is highly conserved, but the signal and propeptide segments are not, relative to corresponding defensin sequences of other insects . Defensin expression is induced in response to bacterial infection, in both adult and larval stages . In contrast, pupae express defensin mRNA constitutively . Defensin expression may prove a valuable molecular marker to monitor the An . gambiae host response to infection by parasitic protozoa of medical importance.

Insect Mol Biol, 1996 Aug, 5(3), 167 - 72
Differential induction of antibacterial transcripts in Drosophila susceptible and resistant to parasitism by Leptopilina boulardi; Coustau C et al.; Two well-described elements of the immune response of insects include encapsulation of metazoan parasites (blood-cell-mediated) and the production of antibacterial peptides (humoral and/or cellular) . However, the possible functional interrelationship between cellular encapsulation and antibacterial responses, and the extent to which the two components may be co-regulated, are poorly understood . We used a novel approach involving strains of Drosophila resistant (R) or susceptible (S) to the wasp parasitoid Leptopilina boulardi to study the expression of three genes involved in the antibacterial response: Dorsal-related immunity factor (Dif), Cecropin (CecA1) and Diptericin (Dip) . Both S and R strains produced high levels of all antibacterial transcripts upon bacterial injection . However, when parasitized the R strain showed no induction whilst the S strain did . This lack of antibacterial transcript induction in the parasitized R strain not only clarifies the separation of these two types of immune response but also raises the fascinating possibility of a link in their genetic regulation.

Planta Med, 1996 Aug, 62(4), 377 - 9
Chemical and biological studies on two Helichrysum species of Greek origin; Chinou IB et al.; The chemical composition of the essential oils obtained from the aerial parts of Helichrysum amorginum and H.italicum were analysed with GC and GC/MS . From the twenty-five identified constituents representing the 89.98% and 82.06% of the two oils respectively, geraniol, geranyl acetate, neryl acetate, and nerolidol were the major components . Furthermore, it was found that the oils exhibited definite antibacterial activity against the six tested Gram (+/-) bacteria.

Planta Med, 1996 Aug, 62(4), 352 - 3
Antibacterial and antifungal compounds from Kigelia pinnata; Binutu OA et al.; A biologically monitored fractionation of the methanolic extracts of the root and fruits of Kigelia pinnata D.C . led to the isolation of the naphthoquinones kigelinone (1), isopinnatal (2), dehydro-alpha-lapachone (3), and lapachol (4) and the phenylpropanoids p-coumaric acid (5) and ferulic acid (6) as the compounds responsible for the observed antibacterial and antifungal activity of the root and kigelinone (1) and caffeic acid (7) from the fruits of this plant.

Dig Dis Sci, 1996 Aug, 41(8), 1589 - 94
Eradication of Helicobacter pylori and long-term outcome of functional dyspepsia . A clinical endoscopic study; Lazzaroni M et al.; The aim of this study was to assess the effect of colloidal bismuth subcitrate (CBS) and metronidazole on Helicobacter pylori eradication and on the course of symptoms due to functional dyspepsia . Forty-one patients with functional dyspepsia were entered into the study and randomized to treatment with CBS (120 mg four times a day) for four weeks combined with metronidazole (250 mg four times a day) for one week (group A, N = 21) or matching placebo (group B, N = 20) . The severity of gastritis and of bacterial colonization and the symptom score was assessed by endoscopy and clinical evaluation at baseline and after four, eight, and 24 weeks from the start of the treatment . With intent-to-treat analysis eradication was achieved in 16/25 (64%) patients in group A and in 6/24 (25%) in group B . At eight and 24 weeks the gastritis score was significantly lower only in those patients with eradication . No change was seen in patients in whom the bacteria was not eradicated . The symptom score at eight weeks was considerably lower both in patients with eradication and in those with infection . However, at 24 weeks a gradual decrease in the symptom score in patients with eradication and a worsening of symptoms in controls was observed . No differences were observed between patients with ulcerlike and those with dysmotility-like dyspepsia . The study confirms the need for a long observation period after antibacterial treatment in patients with functional dyspepsia and suggests that Helicobacter pylori-eradicating treatment improves the course of this functional syndrome.

J Trauma, 1996 Aug, 41(2), 356 - 64
Iron and infection: new developments and their implications; Ward CG et al.; Unsaturated transferrin in plasma ensures that the amount of free ferric iron available to bacteria is about 10(-18) mol/L . This low iron environment is essential for the bacteriostatic and bactericidal systems in blood, lymph, and exudates . Antibacterial systems are abolished when iron becomes freely available . This results in rapid extracellular bacterial growth and greatly increased bacterial virulence . In human plasma, a fall in Eh (oxidation-reduction potential) or pH results in the abolition or marked reduction of its bactericidal properties . This is highly relevant to infection after trauma, where a fall in Eh and pH frequently accompanies tissue damage . Bacterial resistance to antibiotics has put the treatment of serious infections in jeopardy . Reinforcement of natural means of resistance needs to be explored, as well as examining new antibacterials that interfere with bacterial iron metabolism.

Invest Ophthalmol Vis Sci, 1996 Aug, 37(9), 1826 - 32
Synthesis of group II phospholipase A2 and lysozyme in lacrimal glands; Aho HJ et al.; PURPOSE . The aim of this study was to demonstrate the synthesis and cellular distribution of group II phospholipase A2 and lysozyme in the main and accessory lacrimal glands . METHODS . The authors studied samples of normal main lacrimal glands of seven autopsied subjects and accessory lacrimal glands of eight patients who underwent ptosis surgery . The specimens were immunostained with a rabbit antiserum against group II phospholipase A2 and a monoclonal antibody against lysozyme . Expression of group II phospholipase A2 gene was shown using Northern hybridization and in situ hybridization . RESULTS . Lysozyme was present in the secretory granules of most acini, whereas group II phospholipase A2 was seen in a minority of acinar cells, primarily in the central parts of lobules in the main and accessory lacrimal glands . Synthesis of group II phospholipase A2 in the glandular cells was confirmed by Northern hybridization and by in situ hybridization . CONCLUSIONS . There are two specialized cell types in the main and accessory lacrimal glands, one synthesizing group II phospholipase A2 and the other synthesizing lysozyme . These enzymes are important nonspecific antibacterial factors in tears.

Biochemistry, 1996 Jul 30, 35(30), 9892 - 9
Release of lipid vesicle contents by an antibacterial cecropin A-melittin hybrid peptide; Mancheno JM et al.; A synthetic cecropin A(1-8)-melittin(1-18) hybrid peptide, with antimalarial and antibacterial properties, promotes leakage of aqueous contents of phospholipid vesicles, as determined by measuring the induced release of vesicle-entrapped fluorescence probes . The release of vesicle contents corresponds to an all-or-none mechanism . High molecular weight entrapped solutes (fluorescence-labeled dextrans, 20 and 4 kDa molecular mass) are also released by the peptide . This fact and the high peptide stoichiometry required for the release of vesicle contents suggest a detergent-like disruption of the bilayer . The leakage process is not related to any membrane event requiring lipid-mixing between bilayers . The peptide destabilizes both negatively and neutrally charged phospholipid vesicles . The thermal variation of the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene-labeled vesicles is modified by the peptide . Circular dichroism and tryptophan fluorescence emission spectra reveal conformational changes in the peptide molecule upon interaction with the lipid vesicles . These changes are consistent with an increased alpha-helical content and a less polar environment for the single tryptophan residue of the peptide . The leakage induced in phosphatidylserine vesicles is a faster process than in phosphatidylcholine vesicles, while the peptide is more effective in releasing the contents of the latter type of vesicles . This suggests that acidic phospholipids may modulate the effect of the peptide on membranes.

J Ethnopharmacol, 1996 Jul 26, 53(1), 11 - 4
Antibacterial activity of the phenolic acids fractions of Scrophularia frutescens and Scrophularia sambucifolia; Fernandez MA et al.; The phenolic fractions of aerial part of Scrophularia frutescens and S . sambucifolia (Scrophulariaceae) showed a potent antibacterial activity . Ferulic, isovanillic, p-hydroxycinnamic, p-hydroxybenzoic, syringic, caffeic, gentisic and protocatechuic acids were isolated from S . frutescens and ferulic, p-coumaric, vanillic, p-hydroxibenzoic and syringic acids were isolated from S . sambucifolia . Since phenolic acids have been shown in the literature to exert an antibacterial effect, the presence of these compounds in the two plants explains their antibacterial activity.

Am J Health Syst Pharm, 1996 Jul 15, 53(14), 1691 - 3
Pharmaceutical services in an Army field hospital in Haiti during Operation Uphold Democracy; Frank KJ; The pharmaceutical services provided by an Army field hospital in Haiti during Operation Uphold Democracy are described . In January 1995, 155 soldiers of the 47th Field Hospital from Ft . Sill, Oklahoma, were deployed to Haiti to provide medical care for 2400 U.S . troops and 7000 multinational troops and police officers . The pharmacy staff (one pharmacist and two technicians) provided patient counseling, drug information, staff consultation, and clinical support to the intensive and intermediate care wards and emergency medical tent of the field hospital . Other responsibilities were providing nonprescription drugs to outpatients, interpreting and evaluating drug orders, participating in drug selection, and ordering supplies . A 30- to 60-day drug supply was maintained . The formulary was designed by the pharmacist and an internist and was based on the mission requirements and conditions in Haiti . Of the 10 oral medications most commonly dispensed to outpatients, 6 were antibacterials and 1 was an antimalarial . An average of two patients were admitted to the hospital daily . Some 240 inpatients were recorded in the pharmacy computer during the hospital's six-month deployment, and more than 5000 were treated in the emergency tent . The pharmacy service of the 47th Field Hospital met the challenge of supporting U.S . and multinational troops in Haiti during Operation Uphold Democracy.

Pharmacoeconomics, 1996 Aug, 10(2), 129 - 40
Cost-effective prophylaxis of surgical infections; Norrby SR; There are few formal pharmacoeconomic studies of antibacterial prophylaxis in surgery . An important reason for this is that such prophylaxis is difficult to study, because extremely large patient samples are needed to demonstrate differences or equalities with reasonable statistical power . When the cost effectiveness of various regimens is evaluated, indirect methods must often be used . Clearly, the ideal prophylactic regimen, both clinically and economically, is one that is easy to administer, has a low acquisition cost, can be given as a single dose and provides maximal protection against postoperative infections . However, if and when such a regimen is identified, its universal acceptance and use might have negative ecological consequences (e.g . the selection of resistant organisms in the hospital environment) . Thus, the search for the ideal prophylactic regimen must be a continuous process.

Boll Chim Farm, 1996 Jul-Aug, 135(7), 447 - 51
Studies on arylfuran derivatives--Part V . Synthesis and antibacterial properties of 7H,6-{5-(4-nitrophenyl)-2-furyl}-1,2,4-triazolo {3,4-b}-1,3,4-thiadiazines; Holla BS et al.; The preparation of fifteen new 7H, 6-{5-(4-nitrophenyl)-2-furyl}-1,2,4-triazolo{3,4-b}-1,3,4-thiadiazine is described . The structural elucidation of all the compounds is carried out on the basis of analytical and spectral data . The newly synthesized compounds are evaluated for their antibacterial activity against both Gram-positive and Gram-negative bacteria.

Indian J Exp Biol, 1996 Jul, 34(7), 712 - 5
A novel approach to study antibacterial properties of volatile components of selected Indian medicinal herbs; Agnihotri S et al.; The aromatic substances of natural origin are used medicinally in Ayurveda, and can have diverse bio-dynamic actions . The existing methods like agar-cup method or disc diffusion method are not adequate to study the exclusive antibacterial effects of the volatile components of aromatic oils due to lack of ideal diffusion and evaporation from the surface . Hence an attempt is made to develop a novel approach to assess the antibacterial activity of few aromatic herbs like Eugenia caryophyllus, Thymus vulgaris, Cinnamonum zeylanium, Cuminum cyminum; these were extracted with hexane filled in tiny sterile tubes and the volatile components were tested for their antibacterial properties using standard strains of gram +ve and gram -ve bacteria grown on agar slants . The results are expressed as a percent of inhibition of the area on the slants, from the top of the extract tube . Of the four herbs selected, volatile components of Thymus vulgaris were most effective againsts all the seven test organisms.

Diagn Microbiol Infect Dis, 1996 Jul, 25(3), 123 - 6
In vitro activity of macrolides against intracellular Legionella pneumophila; Segreti J et al.; The antibacterial effects of clarithromycin, azithromycin, and erythromycin were determined against five strains of Legionella pneumophila including L . pneumophila ATCC 33823 and four clinical isolates . Extracellular minimum inhibitory concentrations (MICs) and MBCs were determined by a microdilution method . Clarithromycin was the most active drug (MIC < or = 0.015-0.06), followed by azithromycin (MIC 0.03-0.12) and erythromycin (MIC 0.06-0.25) . The antibacterial effect of these macrolides was then determined against L . pneumophila grown intracellularly in MRC-5 human fetal lung fibroblast cells . At two and eight times the extracellular MBC, erythromycin, azithromycin, and clarithromycin were equally effective in inhibiting growth of these five strains of intracellular L . pneumophila.

Hepatogastroenterology, 1996 Jul-Aug, 43(10), 792 - 5
Quantitative assessment of severity of biliary tract infection; Krastev Z et al.; BACKGROUND/AIMS: It is very important for physicians to evaluate the severity of the biliary infection . At the moment, there is no useful quantitative system . In this study, we propose a scoring system for assessing the severity of biliary infections and evaluation of the efficacy of antibacterial and endoscopic treatments . MATERIALS AND METHODS: We created a biliary tract infection score (BTIS) including local physical and ultrasound findings, signs of inflammation and hepatobiliary involvement . The BTIS was calculated in 317 patients: group I-155 pts with cholecystitis and cholangitis, treated only by antibiotics and group II-162 pts with acute cholangitis treated by endoscopic procedures . RESULTS: The BTIS allowed the differentiation of the severity of biliary infections: 15.50 +/- 0.52 in acute cholangitis group and 5.77 +/- 2.79 in group I (p < 0.001) . The BTIS significantly decreased after antibacterial therapy (excluding only the cefotiam subgroup) and in endoscopicaly treated patients . CONCLUSIONS: The BTIS is a combination of simple, reliable, acceptable and low cost parameters, reflecting the principal pathological processes and degree of abnormalities . A BTIS facilitated the assessment of severity of biliary infection and comparison of the results of various methods of treatment.

J Dairy Sci, 1996 Jul, 79(7), 1198 - 208
Elevation of lactoferrin gene expression in developing, ductal, resting, and regressing parenchymal epithelium of the ruminant mammary gland; Molenaar AJ et al.; Accumulation of lactoferrin mRNA in mammary tissue from virgin, pregnant, lactating, and involuting ewes and cows was localized using 35S-labeled cRNA probes . Expression of lactoferrin was low in the glands of virgin animals . In the glands of animals in early pregnancy, very high expression occurred in the ducts and immature alveoli, but expression tended to decrease as the alveoli matured . In the lactating and involuting gland, expression was generally low or absent in actively secreting alveoli and high in alveoli that had an accumulation of vesicles in the lumen and secretory epithelium, which was indicative of stasis . Occasionally, expression of lactoferrin was seen in cells that appeared to be secretory, particularly in involuting glands . Lactoferrin mRNA was expressed not only at different sites from other milk protein genes, such as alpha-lactalbumin and alpha s1-casein, but also during different stages of mammary development, supporting the view that the expression of lactoferrin is regulated differently from that of other milk proteins . For all ewes and cows, lactoferrin mRNA was detected in the epithelial ducts of the mammary parenchyma and the teat in a gradient that increased in ducts nearer the teats . The expression of lactoferrin in the ductal epithelium close to the teat was consistent with the antibacterial role of lactoferrin.

Drug Saf, 1996 Jul, 15(1), 79 - 85
Antibacterial-induced hepatotoxicity . Incidence, prevention and management; George DK et al.; Hepatotoxic reactions to antibacterials are rare, occurring with an estimated frequency of between 1 and 10 per 100,000 drug prescriptions for most antibacterials . Although many antibacterial-induced hepatotoxic reactions have a characteristic clinical and biochemical pattern e.g . cholestatic hepatitis (flucloxacillin) or fatty liver (tetracycline), many can also present with a variety of clinicopathological patterns e.g . nitrofurantoin is associated with the development of acute hepatitis, granulomatous hepatitis and chronic active hepatitis . Almost all reactions are idiosyncratic, with no diagnostic laboratory tests to aid the diagnosis . Early diagnosis is essential and requires a vigilant physician to elicit a detailed drug history . Although the outcome is usually good when the offending antibacterial is withdrawn, morbidity may persist for years and fatalities have occurred, particularly when there is a delay in recognising the hepatotoxic antibacterial . There is no specific treatment for antibacterial-induced hepatotoxicity other than withdrawing the implicated drug . For severe disease, however, liver transplantation should be considered.

J Small Anim Pract, 1996 Jul, 37(7), 327 - 32
Resolution of dysrhythmias and conduction abnormalities following treatment for bacterial endocarditis in a dog; Boswood A; A four-year-old boxer presented with a recent history of intermittent collapse . The dog was found to have dysrhythmias and conduction abnormalities which were attributed to the presence of aortic bacterial endocarditis . These dysrhythmias and conduction abnormalities resolved following antibacterial treatment of the endocarditis . Specific antiarrhythmic therapy was not required . The short term response to therapy was good . The long term prognosis remains guarded in view of the damage the aortic valve has undergone.

Support Care Cancer, 1996 Jul, 4(4), 294 - 7
High incidence of infectious gastrointestinal complications observed in patients with acute myeloid leukemia receiving intensive chemotherapy for first induction of remission; Micozzi A et al.; An increased incidence of severe infections, in particular gastrointestinal complications, was observed in our institution among 35 consecutive patients with acute myelogenous leukemia submitted to their first intensive pilot protocol for induction of remission containing idarubicin, etoposide and cytosine arabinoside . Ten patients presented fever and severe diarrhea (4 or more loose stools/day for at least 4 consecutive days); 3 of these developed ileothyphlitis, which proved fatal in 2 cases, 7 needed amphotericin B addition to antibacterial treatment and, in 6 cases, a fungal infection was documented . We have compared these 10 patients with the other 25 submitted to the same chemotherapeutic protocol and the incidence of candidemias (5/10 compared to 0/25), the early use of systemic fluconazole from the onset of fever (0/10 compared to 9/25) and the pre-emptive use of total parenteral nutrition (0/10 compared to 8/25) differed in the two groups . We conclude that during this chemotherapeutic protocol the incidence of severe gastrointestinal infectious complications was particularly high (28.5%) and, even though only a small number of patients were studied, our results suggest an important role for Candida spp . in the pathogenesis of this disease.

Artif Organs, 1996 Jul, 20(7), 752 - 60
Changes in polyurethane calcification due to antibiotics; Chandy T et al.; To develop artificial materials for prolonged use in the vascular system, the complicated process of surface-induced calcification must be better understood . Calcification was examined on porous polyurethane incubated in metastable solutions of calcium phosphate, and the role of certain antibiotics in the medium was evaluated . It seems that certain aminoglycoside antibiotics can modify polyurethane surfaces and, subsequently, their mineralization process . In addition, these antibiotics may alter the calcium transport through polyurethanes . Therefore, it is conceivable that certain antibiotics can, in addition to producing their antibacterial effect, modulate surface calcium binding by changing the calcium mobilization and crystallization . Additional studies are needed to develop applications.

Ann Pharmacother, 1996 Jul-Aug, 30(7-8), 768 - 75
Phenytoin in wound healing; Anstead GM et al.; OBJECTIVE: To describe a patient with a massive Grade IV pressure ulcer that responded rapidly to treatment with topical phenytoin and to review the literature supporting the use of this therapy . CASE SUMMARY: A 55-year-old morbidly obese white man (266 kg), with respiratory failure secondary to obesity-hypoventilation syndrome and heart failure, developed pressure ulcers on his lower back and sacrum with the first 2 weeks of hospitalization . Traditional methods of treatment were unsuccessful, and by day 79, the wound involved the entire lumbosacral area and buttocks, and had extensive undermining and sinus tract formation . Within 2 days of applying topical phenytoin, fresh granulation was apparent . After 54 days of treatment, nearly all the sinus tracts were healed . Four months after treatment with topical phenytoin had facilitated the healing of the wounds, even though the patient's multiple underlying medical problems had not resolved . DISCUSSION: Phenytoin has been used in the healing of pressure sores, venous stasis and diabetic ulcers, traumatic wounds, and burns . Many of the existing clinical studies have methodologic flaws, such as inappropriate statistical analysis, inadequate control groups, and the absence of randomization and double-blinding . Nevertheless, all the studies have reported enhancement of wound healing, with insignificant adverse effects . Phenytoin may promote wound healing by a number of mechanisms, including stimulation of fibroblast proliferation, facilitation of collagen deposition, glucocorticoid antagonism, and antibacterial activity . CONCLUSIONS: Phenytoin promoted the healing of a massive necrotizing soft tissue wound that was unresponsive to conventional treatment . Clinical success in this difficult case and the other reports in the literature suggest that phenytoin is effective in would healing and deserves further investigation.

Z Naturforsch {C}, 1996 Jul-Aug, 51(7-8), 487 - 91
(+)-10 alpha-Hydroxy-4-muurolen-3-one, a new inhibitor of leukotriene biosynthesis from a Favolaschia species . Comparison with other sesquiterpenes; Zapf S et al.; A new inhibitor of leukotriene biosynthesis, (+)-10 alpha-hydroxy-4-muurolen-3-one (1), was isolated from fermentations of Favolaschia sp . 87129 . Its structure was established by spectroscopic methods . The compound exhibited no antifungal or antibacterial activities . The effects of 1 on leukotriene biosynthesis were compared with (+)-T-cadinol, (-)-3-oxo-T-cadinol, and (+)-3 alpha-hydroxy-T-cadinol, three related sesquiterpenes.

Antimicrob Agents Chemother, 1996 Jul, 40(7), 1649 - 52
Accumulation of trimethoprim, sulfamethoxazole, and N-acetylsulfamethoxazole in fish and shrimp fed medicated Artemia franciscana; Chair M et al.; In a previous paper (H.J . Nelis, P . Leger, P . Sorgeloos, and A . P . De Leenheer, Antimicrob . Agents Chemother . 35:2486-2489, 1991) it was reported that two selected antibacterial agents, i.e., trimethoprim and sulfamethoxazole, can be efficiently bioencapsulated in nauplii of the brine shrimp Artemia franciscana for administration to fish . This follow-up study showed that larvae of the sea bass and the turbot as well as postlarvae of the white shrimp accumulate the therapeutic agents in high quantities when fed medicated A . franciscana . To monitor their levels as a function of time, the liquid chromatographic method originally developed for the analysis of A . franciscana was modified with respect to chromatography, internal standardization, and sample pretreatment . The levels of trimethoprim ranged from 1 to 7 micrograms/g (sea bass), 1 to 13 micrograms/g (turbot), and 4 to 38 micrograms/g (white shrimp) . The corresponding values for sulfamethoxazole were 0.3 to 4 micrograms/g (sea bass), 1 to 42 micrograms/g (turbot), and 4 to 35 micrograms/g (white shrimp) . Only the two fish species, unlike the shrimp, metabolized the latter to N-acetylsulfamethoxazole (concentration range, 1 to 10 micrograms/g) . These data suggest the potential of the bioencapsulation of therapeutic agents in live food as a tool to control infectious diseases in aquaculture . A preliminary challenge test also confirmed the in vivo efficacy of this approach.

Antimicrob Agents Chemother, 1996 Jul, 40(7), 1640 - 4
Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli; Brandish PE et al.; Using a continuous fluorescence-based enzyme assay, we have characterized the antibacterial agents tumicamycin and liposidomycin B as inhibitors of solubilized Escherichia coli phospho-N-acetylmuramyl-pentapeptide translocase . Tunicamycin exhibited reversible inhibition (Ki = 0.55 +/- 0.1 microM) which was noncompetitive with respect to the lipid acceptor substrate and competitive with respect to the fluorescent substrate analog, dansyl-UDPMurNAc-pentapeptide . Liposidomycin B exhibited slow-binding inhibition (Ki = 80 +/- 15 nM) which was competitive with respect to the lipid acceptor substrate and noncompetitive with respect to dansyl-UDPMurNAc-pentapeptide . These results provide insight into the molecular mechanisms of action of these two classes of nucleoside antibiotics.

Antimicrob Agents Chemother, 1996 Jul, 40(7), 1594 - 9
Fluoroquinolone action in mycobacteria: similarity with effects in Escherichia coli and detection by cell lysate viscosity; Drlica K et al.; Fluoroquinolones are potent antibacterial agents that are being used as therapeutic agents for the treatment of multidrug-resistant tuberculosis . To better understand fluoroquinolone action in mycobacteria, the effects of ciprofloxacin were examined . DNA synthesis was inhibited rapidly in Mycobacterium smegmatis, DNA cleavage was readily observed by an empirical assay of cell lysate viscosity, and cell growth was blocked . These data are explained by the formation of gyrase-DNA-ciprofloxacin complexes that block replication fork movement . The bactericidal action of ciprofloxacin against M . smegmatis, Mycobacterium bovis BCG, and Escherichia coli occurred more slowly in cells with longer doubling times . The bactericidal effect against M . bovis BCG was partially blocked by pretreatment with chloramphenicol, an inhibitor of protein synthesis, and by very high concentrations of ciprofloxacin itself . Similar responses occur when E . coli is treated with ciprofloxacin . These similarities between E . coli and mycobacteria indicate that results from extensive fluoroquinolone studies with E . coli can be applied to mycobacteria . A simple viscometric assay of DNA cleavage is described . The assay is expected to be useful for screening new fluoroquinolone derivatives for increased effectiveness against clinically important bacteria.

J Clin Microbiol, 1996 Jul, 34(7), 1628 - 32
Brain abscess caused by Schizophyllum commune: an emerging basidiomycete pathogen; Rihs JD et al.; Despite the worldwide distribution and prevalence of Schizophyllum commune, an emerging basidiomycetous pathogen, human infections occur only rarely . We describe the first well-documented pulmonary infection caused by S . commune which disseminated to the brain of a 58-year-old patient undergoing empiric corticosteroid therapy . Magnetic resonance imaging scans revealed ring-enhancing masses . Histologic examination of biopsy tissue from lungs and brain showed hyaline, septate, branched hyphae with clamp connections . Cultures of the lung tissue grew S . commune, which produced numerous, characteristic flabelliform and medusoid fruiting bodies on Czapek's agar . The isolate was susceptible to amphotericin B (MIC, < 0.03 microgram/ml) and fluconazole (MIC, 8 micrograms/ml) . Despite treatment with antifungal and antibacterial agents, the patient developed progressive pulmonary failure and bacterial sepsis and died.

Chem Pharm Bull (Tokyo), 1996 Jul, 44(7), 1376 - 86
Studies on quinolone antibacterials . V . Synthesis and antibacterial activity of chiral 5-amino-7-(4-substituted-3-amino-1-pyrrolidinyl)-6- fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acids and derivatives; Yoshida T et al.; We previously demonstrated that 5-amino-7-(3-amino-1-pyrrolidinyl) -1-cyclopropyl-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (7) has strong in vitro antibacterial activity even against quinolone-resistant bacteria . We examined optimization of the 3-aminopyrrolidine moiety of 7 by introduction of C-alkyl (Me, Et, Pr, di-Me, cyclopropyl) and N-alkyl groups (Me, di-Me) . C-Alkylation at the 4-position of the 3-aminopyrrolidine moiety enhanced in vitro and in vivo antibacterial activity . (S)-5-Amino-7-(7-amino-5-azaspiro{2.4}hept-5-yl)-1-cyclopropyl-pyr rolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (15b) showed strong antibacterial activity (in vitro antibacterial activity including quinolone-resistant bacteria is 4 times more potent than that of ciprofloxacin (CPFX) (1); in vivo antibacterial activity is 1.5 to 20 times more potent than that of CPFX (1)) and reduced quinolone toxicity (free from both phototoxicity at a dosage of 30 mg/kg in guinea pigs (i.v.) and convulsion when coadministered with 4-biphenylacetic acid at a dosage of 20 micrograms in rats (i.c.v.)) . Their selectivity between DNA topoisomerase II (derived from eukaryotic cells) and DNA gyrase (derived from bacterial cells) was about 3000-fold.

Exp Parasitol, 1996 Jul, 83(2), 191 - 201
Aedes aegypti: induced antibacterial proteins reduce the establishment and development of Brugia malayi; Lowenberger CA et al.; The effect of host immune activation on the development of Brugia malayi in one susceptible and four refractory strains of Aedes aegypti and in Armigeres subalbatus was assessed . A . aegypti that were immune activated by the injection of saline or bacteria 24 hr before feeding on a B . malayi-infected gerbil had significantly reduced prevalences and mean intensities of infection from those of naive controls when exposed to bloodmeals with low (105 mf/20 microliters) and medium (160 mf/20 microliters) microfilaremias . At a higher microfilaremia (237 mf/20 microliters) there were no significant differences in mean intensities, suggesting that the number of parasites ingested may affect the host's ability to mount an effective defense response . Because the major immune proteins in A . aegypti are defensins, we did Northern analyses of fat body RNA 8 hr after immune activation or bloodfeeding . All mosquitoes demonstrated rapid transcriptional activity for defensins following immune activation by intrathoracic inoculation with either saline or bacteria . However, no strain of A . aegypti, susceptible or refractory to B . malayi, nor Ar . subalbatus produced defensin transcripts after bloodfeeding on an uninfected or a B . malayi-infected gerbil . These data suggest that inducible immune proteins of mosquitoes can reduce the prevalence and mean intensity of infections with ingested parasites, but these proteins are not expressed routinely after parasite ingestion and midgut penetration and probably do not contribute to existing refractory mechanisms . Immune proteins such as defensins, however, represent potential candidates to genetically engineer mosquitoes for resistance to filarial worms.

Am J Respir Crit Care Med, 1996 Jul, 154(1), 18 - 23
Trimethoprim and tetracycline inhibit airway epithelial sodium absorption; Middleton PG et al.; Despite their frequent use in the treatment of chronic lung disease, the effect of antibiotics on the airway mucosa has not been defined . We have assessed the effect of a number of antibiotics on the ion transport processes of airway epithelia . Initial evaluation performed on sheep tracheal epithelium in vitro demonstrated that trimethoprim and tetracycline induced a rapid decrease in electrogenic ion transport . These responses were fully reversible, mediated through the mucosal surface, and reduced by amiloride pretreatment, suggesting inhibition of Na+ absorption . Serosal application of erythromycin produced a gradual decrease in short-circuit current, whereas other antibiotics (ampicillin, ceftazidime, colistin, chloramphenicol, gentamicin, and sulfamethoxazole) caused no significant change within 30 min of addition . In healthy human volunteers, trimethoprim and tetracycline induced a rapid decrease in nasal potential difference, which was attenuated by amiloride pretreatment . In subjects with cystic fibrosis, who exhibit increased Na+ absorption across respiratory epithelia, the responses to trimethoprim and tetracycline were enhanced, providing further evidence that these drugs inhibit Na+ absorption . In conclusion, this study has identified two antibacterial agents that also reduce the Na+ absorption found in CF . These drugs may offer combined effects for the treatment of CF.

Curr Microbiol, 1996 Jul, 33(1), 40 - 3
The novel antibacterial peptide ceratotoxin A alters permeability of the inner and outer membrane of Escherichia coli K-12; Marri L et al.; Ceratotoxins are antibacterial 3-kDa amphiphilic peptides isolated from the female reproductive apparatus of the medfly Ceratitis capitata . The antibacterial activity of a chemically synthesized ceratotoxin A (ctx A) has been investigated . Ctx A was mainly active against Gram-negative organisms, and it had a lytic effect on nongrowing Escherichia coli K-12 . Data showed that ctx A alters both the outer and the inner membrane of E.coli K-12 cells.

Am J Med, 1996 Jun 24, 100(6A), 83S - 89S
Clinical experience with single agent and combination regimens in the management of infection in the febrile neutropenic patient; Ramphal R et al.; Choice of antibiotic therapy for the management of infection in the neutropenic patient continues to challenge the clinician . The shift toward gram-positive organisms and the continuing need to provide gram-negative coverage demands the use of an agent or agents that provide coverage for the spectrum of potential infecting organisms . Cefepime is an extended-spectrum fourth-generation cephalosporin that has good activity against gram-positive and gram-negative organisms; in addition, it resists degradation by Bush group 1 beta-lactamases . These properties make this agent a promising candidate for empiric therapy with febrile neutropenic patients . Data presented in this article are from febrile neutropenic cancer patients enrolled into two randomized, prospective, nonblinded comparative U.S . clinical trials . Patients were randomized to receive cefepime (2 g thrice daily) or a comparator regimen of either ceftazidime (2 g thrice daily) or piperacillin + gentamicin (3 g every 4 hours + 1.5 mg/kg every 8 hours) . When indicated, vancomycin was added to the regimen . A total of 109 febrile episodes were treated with cefepime and 107 episodes were treated with the comparator regimens . Neutropenia (< or = 500 PMNs/mm3) persisted for > or = 10 days in >40% of episodes and severe neutropenia (< or = 100 PMNs/mm3) in >25% . More than 40% of the total number of episodes were documented bacterial infections . These characteristics did not differ among treatment groups . Duration of therapy was similar in both groups (median: cefepime, 9 days; comparators, 11 days) . In >40% of episodes, patients received study therapy without addition of other antibacterials (cefepime, 46%; comparators, 41%) . Vancomycin was added in almost half of all the episodes (cefepime, 45%; comparators, 53%) . Patients became afebrile by the fourth day of study therapy in approximately 60% of episodes (cefepime, 58%; comparators, 60%) . In approximately 75% of the episodes, patients had a satisfactory response at the end of therapy (cefepime, 74%; comparators, 76%); and following approximately 90% of episodes, patients survived for >30 days (cefepime, 90%; comparators, 92%) . Eradication rates were similar for all pathogens for cefepime and comparator agents . There were similar numbers of superinfecting organisms in each treatment arm; most involved gram-positive organisms . These multiple measures of efficacy suggest that initial empiric cefepime monotherapy is comparable to the pooled experience with standard therapies and that antibacterial modifications occur with similar frequency for cefepime compared with standard empiric regimens.

Vet Immunol Immunopathol, 1996 Jun 15, 52(1-2), 127 - 34
Influence of flumequine and oxytetracycline on the resistance of the European eel against the parasitic swimbladder nematode Anguillicola crassus; van der Heijden MH et al.; The effect of the antibacterial drugs flumequine (FQ) and oxytetracycline (OTC) on the defence system of the European eel (Anguilla anguilla L., 1758) was investigated using an experimentally induced infection with the parasitic swimbladder nematode Anguillicola crassus . Eight weeks after oral administration of infective larvae, the mean recovery of the parasites in FQ-treated eels was lower than in non-medicated control animals, and significantly lower than in OTC-treated eels . Mean numbers of peripheral blood granulocytes and B-lymphocytes, as well as the total number of circulating lymphoid cells, showed a significant increase as a result of the infection, while drug treatment merely affected the quantity of the lymphoid cells . The difference in protection against the parasite after FQ or OTC administration points to a modulation of the fish resistance as a result of the drug treatment . The results favour a modulation of the cellular rather than the humoral response, as no specific antibodies were found.

J Immunol, 1996 Jun 15, 156(12), 4789 - 96
Both N- and C-terminal regions of the bioactive N-terminal fragment of the neutrophil granule bactericidal/permeability-increasing protein are required for stability and function; Capodici C et al.; An N-terminal fragment (residues 1-199) of the 456-residue human bactericidal/permeability-increasing protein (BPI), isolated after limited proteolysis, exhibits antibacterial and LPS-neutralizing activities equal to or greater than those of holo-BPI . To assess minimal structural requirements for bioactivity, mutant species of BPI were expressed in vivo by transient transfection and in vitro by cellfree transcription/translation . BPI1-456 and BPI1-193 demonstrated the expected antibacterial and LPS-binding activities . Deletion of the N-terminal 12 residues did not diminish BPI function . However, further truncation either from the C-terminus to residue 169 (BPI1-169) or from the N-terminus (BPIdelta15-56) yielded in vitro products with little or no LPS-binding activity and in vivo products that could not be recovered from the culture medium or cellular acid extracts . The possible role of cysteine-175 (the three cysteines in human BPI are at residues 132, 135, and 175) in BPI stability/function was examined by substitution of Cys(175) with serine . Recovery of C175S BPI from extracellular medium was reduced 10-fold, and C175S BPI produced in vitro had little LPS-binding activity . Compared with wild-type holo-BPI and BPI1-193, BPI1-169, BPIdelta15-56, and C175S BPI showed increased susceptibility to cleavage by elastase in the region 1-193 (but not in the region 200-456), indicating conformational changes that may account for the loss of function . These findings suggest that the proteolytic N-terminal fragment of BPI corresponds closely to the minimum functional (antibacterial/anti-LPS) domain of BPI and that residues near both ends of this fragment are essential for structural stability and functional integrity.

Gene, 1996 Jun 12, 172(1), 87 - 91
Characterization of Streptomyces argillaceus genes encoding a polyketide synthase involved in the biosynthesis of the antitumor mithramycin; Lombo F et al.; Mithramycin (Mtm) is an aromatic polyketide which shows antibacterial and antitumor activity . From a chromosomal cosmid library of Streptomyces argillaceus, a Mtm producer, a clone (cosAR7) was isolated by homology to the actI/III region of S . coelicolor and the strDEM genes of S . griseus . From this clone, a 5.3-kb DNA region was sequenced and found to encode six open reading frames (designated as mtmQXPKST1), five of them transcribed in the same direction . The deduced products of five of these genes resembled components of type-II polyketide synthases . The mtm genes would code for an aromatase (mtmQ), a polypeptide of unknown function (mtmX), a beta-ketoacylsynthase (mtmP) and a related 'chain length factor' (mtmK), an acyl carrier protein (mtmS) and a beta-ketoreductase (mtmT1) . The involvement of this gene cluster in Mtm biosynthesis was demonstrated by the Mtm non-producing phenotype of mutants generated in two independent insertional inactivation experiments.

Biochemistry, 1996 Jun 11, 35(23), 7387 - 93
DNA cleavage is not required for the binding of quinolone drugs to the DNA gyrase-DNA complex; Critchlow SE et al.; The primary target for the quinolone group of antibacterial agents is DNA gyrase . One model for the interaction of quinolone drugs with gyrase and DNA suggests that the drugs bind to the single-stranded regions revealed following DNA cleavage by the enzyme . We have tested this hypothesis by using mutants which have the active-site tyrosine in the gyrase A subunit altered to phenylalanine or serine . We have found that proteins bearing these mutations are still able to bind drug, suggesting that DNA cleavage is not a prerequisite for drug binding . We have also found that the blocking of transcription by RNA polymerase in vitro by the gyrase-quinolone complex on DNA does not occur when the active-site tyrosine is mutated to serine; i.e., polymerase blocking requires DNA cleavage.

J Chromatogr A, 1996 Jun 7, 736(1-2), 303 - 11
Investigation of enantioselective separation of quinolonecarboxylic acids by capillary zone electrophoresis using vancomycin as a chiral selector; Arai T et al.; When a chiral selector that is a pharmaceutical compound is added to the separation buffer in capillary electrophoresis, the enantioselectivity and the mobility of analytes which interact with that chiral selector may be altered . The changes in enantioselectivity and mobility of the analyte are a function of the strength of the affinity interaction, which depends on the structure of each . The macrocyclic antibiotic vancomycin contains a variety of functionalities that are known to be useful for enantioselective interactions (e.g., hydrogen bonding groups, hydrophobic pockets, aromatic groups, amide linkages) . Capillary electrophoresis with vancomycin as a buffer additive was used to separate the enantiomers of different compounds . In this study, the chiral separation of quinolonecarboxylic acids that exhibit marked antibacterial activity and of related compounds was achieved by capillary electrophoresis using vancomycin . The correlations between the separation parameters and analyte structures were investigated . The molecular interaction, which is based on the differences of structure, and the effect of experimental parameters on the enantioselective separation between the quinolonecarboxylic acids and vancomycin are discussed.

J Biol Chem, 1996 Jun 7, 271(23), 13573 - 7
Purification and characterization of N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine, a novel antibacterial substance of Sarcophaga peregrina (flesh fly); Leem JY et al.; We purified a novel antibacterial substance from immunized adult Sarcophaga and determined its molecular structure to be N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine (5-S-GAD) . We synthesized 5-S-GAD enzymatically from N-beta-alanyl-3, 4-dihydroxyphenylalanine (beta-Ala-Dopa) and reduced glutathione (GSH) . The antibacterial activity of 5-S-GAD was found to be due to its production of H2O2 . This is a novel antibacterial mechanism as it differs from the mechanisms of known antibacterial peptides . Two possible roles of 5-S-GAD in insect immunity, suppression of bacterial growth and activation of a Rel family transcription factor, are proposed.

Adv Contracept, 1996 Jun, 12(2), 101 - 9
Risk for ovulation in women taking a low-dose oral contraceptive (Microgynon) when receiving antibacterial treatment with a fluoroquinolone (ofloxacin); Csemiczky G et al.; The possibility of escape ovulation in women using a fluoroquinolone ofloxacin for antibacterial treatment at a dose of 200 mg twice daily for 7 days when taking a combined oral contraceptive (Microgynon, 150 micrograms levonorgestrel and 30 micrograms ethinyl estradiol) was studied in 20 women . By using a placebo-controlled, randomized, cross-over design 6 contraceptive pill cycles were followed . Follicle-stimulating hormone and estradiol concentrations were measured on tablet days 5-8, 19-21; progesterone was assayed on days 19-21 during treatment with ofloxacin or placebo . Ultrasonographical investigations for measurements of the number and diameter of ovarian follicles were performed on one of days 5-10, 11-17, 18-24, 25-28 . No indications of ovulation during ofloxacin medication were detected . It is concluded that alternative contraceptive precautions should not be needed when ofloxacin is prescribed for patients taking oral contraceptives.

J Antimicrob Chemother, 1996 Jun, 37(6), 1063 - 75
Rapid flow cytometric assessment of mecillinam and ampicillin bacterial susceptibility; Walberg M et al.; The effects of antibiotics on Escherichia coli during exponential growth in liquid medium were monitored by flow cytometry measuring cellular DNA content and cell size of individual cells in large numbers as well as cell counts . A statistically significant increase in cellular DNA as well as size was recorded after 20 and 40 min of incubation with the MIC of ampicillin and mecillinam, respectively . The optical density (OD600nm) of treated cultures continued to increase for at least 80 minutes, showing that the increase in cellular DNA and size reflected continued growth and elongation of cells coupled with inhibition of cell division, the latter being confirmed by the cell counting . Since fixation, staining and flow-cytometric analysis can be carried out within a few minutes, the present results suggest that flow cytometry may have potential as a rapid and quantitative technique that can be automated for clinical and experimental susceptibility testing of antibacterial drugs.

Int J Pept Protein Res, 1996 Jun, 47(6), 460 - 6
Gramicidin S is active against both gram-positive and gram-negative bacteria; Kondejewski LH et al.; Four linear and four cyclic analogs of gramicidin S (GS) in which D-Phe was replaced with either D-His, D-Ser, D-Tyr or D-Asn have been prepared by solid-phase peptide synthesis and characterized with respect to antibacterial, antifungal and hemolytic activity . Unlike previous reports, GS and a number of cyclic analogs were found to be active against gram-positive as well as gram-negative bacteria . GS showed MICs ranging from 3 to 12.5 micrograms/mL for gram-negative bacteria, compared to MICs of 3 micrograms/mL for gram-positive bacteria . Furthermore, these analogs were also found to exhibit antifungal activity . Unlike the cyclic analogs, all linear analogs were found to be inactive against a wide range of microorganisms tested, and showed low levels of hemolytic activity . The antibacterial activity was found to be highly dependent on the type of assay used, with solution-based assays showing greater activity against gram-negative bacteria than agar-based assays . The GS cyclic analogs were all less toxic than GS itself, with the analog containing the D-Phe to D-Tyr substitution showing the greatest activity of the synthetic analogs . Hemolytic activity in solution against human and sheep red blood cells paralleled antibiotic activity, with those peptides exhibiting greater antibiotic activity generally showing greater hemolytic activity . Membrane destabilization as monitored using the hydrophobic probe N-phenyl-1-naphthylamine was also found to parallel antibacterial and hemolytic activity of cyclic and linear analogs . These results indicate that GS and certain related analogs may have applications as broad-spectrum antibiotics and should be reevaluated for such purposes.

Anticancer Drugs, 1996 Jun, 7(4), 461 - 8
Inhibitory effect of six green tea catechins and caffeine on the growth of four selected human tumor cell lines; Valcic S et al.; Green tea is an aqueous infusion of dried unfermented leaves of Camellia sinensis (family Theaceae) from which numerous biological activities have been reported including antimutagenic, antibacterial, hypocholesterolemic, antioxidant, antitumor and cancer preventive activities . From the aqueous-alcoholic extract of green tea leaves, six compounds (+)-gallocatechin (GC), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG) and caffeine, were isolated and purified . Together with (+)-catechin, these compounds were tested against each of four human tumor cells lines (MCF-7 breast carcinoma, HT-29 colon carcinoma, A-427 lung carcinoma and UACC-375 melanoma) . The three most potent green tea components against all four tumor cell lines were EGCG, GC and EGC . EGCG was the most potent of the seven green tea components against three out of the four cell lines (i.e . MCF-7 breast cancer, HT-29 colon cancer and UACC-375 melanoma) . On the basis of these extensive in vitro studies, it would be of considerable interest to evaluate all three of these components in comparative preclinical in vivo animal tumor model systems before final decisions are made concerning which of these potential chemopreventive drugs should be taken into broad clinical trials.

Acta Paediatr, 1996 Jun, 85(6), 719 - 23
Chemiluminescence activity of phagocytes from tracheal aspirates of premature infants after surfactant therapy; Schrod L et al.; The effect of surfactant on the respiratory burst of phagocytic cells was studied in the tracheobronchial tract of 40 mechanically ventilated neonates (gestational age 24-37 weeks) over the first week of life . We measured the luminol-dependent chemiluminescence (CL) activity of granulocytes and macrophages isolated from tracheal aspirates in 23 preterm infants 1-6 days after administration of bovine surfactant and in 17 untreated controls . Following stimulation by the chemotactic peptide N-formylmethionylleucylphenylalanine, CL activity was not or only slightly impaired in the surfactant group . In contrast, treatment with exogenous surfactant significantly reduced CL response to opsonized zymosan (OPZ), which involves phagocytosis, for up to 6 days (p < 0.05) . The impairment of CL activity seemed to be dose dependent, as repeated surfactant applications (cumulative phospholipid dose of 200 mg/kg) reduced OPZ-elicited CL activity to a greater extent than application of a single dose of 100 mg/kg . In agreement with in vitro studies, our data suggest that high-dose application of exogenous surfactant may affect the antibacterial function of phagocytic cells in the lung.

J Vet Pharmacol Ther, 1996 Jun, 19(3), 184 - 91
Comparison in prescribing patterns of antibacterial drugs in salmonid farming in Norway during the periods 1980-1988 and 1989-1994; Grave K et al.; The choice of antibacterial drugs for the treatment of bacterial diseases in farmed salmonids changed dramatically during the period 1980-1994 . In terms of treatment doses, oxytetracycline chloride was the most frequently prescribed antibacterial drug during the periods 1980-1983 and 1985-1986 . In 1984, prescriptions changed in favour of furazolidone and trimethoprim/ sulphadiazine (1:5) . Oxolinic acid was introduced for use in farmed fish in Norway in 1987, and immediately became the drug of choice, comprising 36% and 50% of the prescribed treatment doses in 1987 and 1988, respectively . In 1989, flumequine was temporarily approved for use in farmed salmonids, and during the period 1989-1994 antibacterial drug therapy in farmed salmonids acquired the character of "mono-therapy' with the quinolones flumequine and oxolinic acid . This rapid change-over in the choice of drug may partly be explained by the development of bacterial drug resistance in farmed salmonids, both to oxytetracycline and trimethoprim/sulphadiazine . The prescribing of furazolidone declined to zero during the study period . The morbidity caused by bacterial infections was defined as the number of treatment doses of antibacterial drugs per kg biomass of farmed salmonids per year . It was estimated that during the period 1988-1995, an average of 39% (mean value) of farmed salmon received, in theory, an antibacterial cure once each year . In comparison, the corresponding figure for the period 1981-1988 was 60% . However, in 1993 this figure fell to 13%, and declined even further in 1994 to 2.3% . The practice of on-farm mixing of medicated feed, using prescribed raw materials (pure drug substances) or premix formulations, declined significantly during the period 1992-1994 . This was due to the introduction, in 1992, of new regulations on the prescribing of drugs to farmed fish.

Aliment Pharmacol Ther, 1996 Jun, 10(3), 367 - 72
The effects of omeprazole 20 and 40 mg twice daily on intragastric acidity in duodenal ulcer patients; Savarino V et al.; BACKGROUND: The combination of omeprazole with amoxycillin or clarithromycin is used as treatment against Helicobacter pylori . It seems likely that the antibacterial activity of the antibiotic may be improved by increasing gastric pH towards neutrality, and a twice daily regimen of omeprazole is probably needed . AIM: To assess the effects of twice daily administration of omeprazole 20 and 40 mg . METHODS: Twelve duodenal ulcer patients in remission were randomized to receive in single-blind fashion either placebo, omeprazole 20 mg or omeprazole 40 mg twice daily (08.00 and 20.00 h) . On the sixth day of dosing they underwent 24-h gastric pH-metry . RESULTS: Omeprazole 20 and 40 mg b.d . produced marked decreases (P < 0.001) of 24-h gastric acidity (pH 5.4 +/- 0.9 and pH 5.7 +/- 0.6, respectively, vs . a basal pH of 1.4 +/- 0.2) and kept gastric pH at levels higher than 3.0 for almost 24 h . Gastric pH was kept above 5.0 for about 18 h and above 6.0 for about 10 h, while the time spent above 7.0 did not exceed 3 h . There were no significant differences between the two omeprazole dosages at any pH threshold . CONCLUSION: Omeprazole 20 mg b.d . is sufficient to render the gastric milieu as anacidic as possible in duodenal patients.

Aliment Pharmacol Ther, 1996 Jun, 10(3), 295 - 301
Pharmacokinetic and pharmacodynamic interactions between omeprazole and amoxycillin in Helicobacter pylori-positive healthy subjects; Pommerien W et al.; BACKGROUND: Omeprazole with amoxycillin has been used to treat Helicobacter pylori infection . It was speculated that omeprazole-induced hypoacidity enhances the antibacterial activity of amoxycillin . Limited information exists about intragastric pH and bioavailability of amoxycillin during combination therapy . No data are available about possible effects of the antibiotic on the pharmacokinetics and pharmacodynamics of omeprazole . METHODS: The study was performed in a three-way cross-over double-blind design . After a run-in period on placebo with a baseline intragastric pH-metry, 24 H . pylori-positive healthy subjects were randomly dosed with amoxycillin 750 mg b.d . + placebo, amoxycillin 750 mg b.d . + omeprazole 40 mg b.d . and omeprazole 40 mg b.d . + placebo for 5 days . On the last day of each regimen intragastric pH-metries were performed, and blood samples taken for omeprazole and amoxycillin serum profiles . RESULTS: Amoxycillin monotherapy had no acid-inhibiting effect . Median pH during combined dosing was significantly lower, compared to omeprazole monotherapy (P < 0.01) . Mean serum concentrations of omeprazole and amoxycillin given alone or in combination were not different . CONCLUSIONS: High-dose omeprazole does not alter the pharmacokinetics of amoxycillin . The significantly lower intragastric pH during combination therapy might be due to the H . pylori-suppressive effect of this treatment.

Microbiologia, 1996 Jun, 12(2), 197 - 206
Interactions between professional phagocytes and Brucella spp; Liautard JP et al.; Induced pathogenicity in animals and humans differs considerably . This review is devoted to the relations between Brucella spp . and professional phagocytes, particularly macrophages and macrophagic cell lines in vitro . Although numerous studies have been reported, the type of ingestion by macrophages, the receptor involved, and the molecular mechanisms, are poorly understood . The ability of most Brucella species to actively inhibit their ingestion by neutrophils or macrophages has been proposed as an explanation for the poor rate of in vitro phagocytosis and in vivo alteration of the phagocytic cells . Oxidative burst plays a significant role in the antibacterial processes of phagocytic cells . The effects of whole or fractioned B . abortus on the ability of neutrophils to induce an oxidative burst in response to stimulation with opsonized zymosan particles were examined . Besides oxygen-based killing, the phagocytic cells have developed other types of defence, including hydrolytic enzymes and reactive halides . Inside the cell, the bacteria encounter new environmental conditions . Their survival is conditioned by an adaptation to this new situation . Pathogens that have acquired the ability to multiply within macrophages should synthesize products specifically interacting with the host cell defence system . Survival of intracellular pathogens is closely linked to the mechanisms of evasion from cellular defences . Brucellae stay in membrane bound vacuoles called phagosomes, but the exact nature and the maturation pathway of this compartment have not yet been understood . Macrophages play a central role in the evolution of brucellosis; this first interaction between the pathogens and the cell will determine the course of the disease . There are natural differences between brucellae species regarding macrophage response to the bacteria.

Arzneimittelforschung, 1996 Jun, 46(6), 625 - 8
LD50 value, phototoxicity and convulsion induction test of the new quinolone antibacterial agent (S)-10-{(S)-(8-amino-6-azaspiro{3,4}octan-6-yl)}-9-fluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido{1,2,3-de}{1,4}benzoxazine-6-carboxyl ic acid hemihydrate in laboratory animals; Shimoda K et al.; (S)-10-{(S)-(8-Amino-6-azaspiro{3,4}octan-6-yl)}-9-fluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido{1,2,3-de}{1,4}benzoxazine-6-carboxyli c acid hemihydrate (CAS 151390-79-3, DV-7751a) a new quinolone antibacterial agent, was examined for LD50 value, phototoxicity and convulsion inducing potential in laboratory animals . A single oral administration of DV-7751a induced soft stool in rats at 1000 and 2000 mg/ kg and in monkeys at 250 mg/kg and vomiting in monkeys at 500 mg/kg or more . A single intravenous administration caused a decrease in locomotor activity, respiratory depression, convulsion, pulmonary edema and death in rats and mice . The LD50 values with oral administration were more than 2000 mg/ kg for rats and mice and more than 250 mg/kg for monkeys, and those with intravenous administration were 164.3 mg/kg for rats of both sexes at an injection rate of 2 ml/min, 118.8 mg/kg for male rats and 104 to 125 mg/kg for female rats at 0.5 ml/min, and 184.7 mg/kg for male mice and 187.4 mg/kg for female mice . DV-7751a showed very weak phototoxicity in mice after single oral administration of 600 mg/kg, followed by UVA irradiation, but no convulsion after oral administration of 200 or 1000 mg/kg in combination with 4-biphenylacetic acid at 400 mg/kg.

Tierarztl Prax, 1996 Jun, 24(3), 261 - 9
{Demonstration of activity of two potentiated sulfonamides in feces of horses after oral or intravenous administration}; Fey K et al.; Both, the oral and intravenous application of two trimethoprim-potentiated sulfonamides induced measurable antibacterial activities in the feces of horses . With regard to the risk of antibiotic-induced alterations of the gastrointestinal flora, the route of application of potentiated sulfonamides seems to be of minor importance . The antibiotics used were Sulfadimethoxine/Trimethoprim (Trafigal 30% ad us . vet.) for oral and Sulfadoxine/Trimethoprim (Borgal 24% ad us . vet., both Hoechst AG, Frankfurt) for intravenous application . As recommended, both drugs were given in a dose of 20 mg per kg bodyweight . The detection method is based on a procedure layed down in German laws for sulfonamide residues in meat-samples and has undergone some modifications for the examination of feces.

Hinyokika Kiyo, 1996 Jun, 42(6), 451 - 5
{Squamous cell carcinoma of the renal pelvis associated with renal stones in a patient with chronic renal failure: a case report and a review of the Japanese literature}; Nakamura Y et al.; A case of squamous cell carcinoma of the left renal pelvis associated with chronic renal failure on hemodialysis is reported . The patient, a 59-year-old man, had undergone bilateral nephrolithotomy, in 1966, followed by right ureterolithotomy and bilateral percutaneous nephrolithotripsy, but residual stones existed . He suffered from left flak pain and fever, and computed tomography (CT) and magnetic resonance imaging (MRI) revealed left perirenal abscess in July 1994 . Percutaneous drainage and antibacterial chemotherapy were performed, but his symptoms did not improve . Three months later, CT and MRI revealed a mass in the left perirenal space and destruction of the 12th thoracic vertebra, which were considered to be infectious changes . On November 9, 1994, left nephrectomy was performed . Histopathological diagnosis was moderately differentiated squamous cell carcinoma, grade 2, INF-gamma, pT4, pR1, pL0 and pV1 . In spite of irradiation therapy, he died on January 19, 1995.

Drugs, 1996 Jun, 51(6), 974 - 80; discussion 981
Ebrotidine; Patel SS et al.; Ebrotidine is the first of a new generation of H2 receptor antagonists with gastroprotective activity It stimulates epithelial cell proliferative activity and produces beneficial physicochemical changes in the gastric mucus that contribute to its gastro-protective action against ethanol-, aspirin- or stress-induced gastric mucosal damage The antisecretory properties of ebrotidine are similar to those of ranitidine and approximately 10-fold greater than those of cimetidine This drug exhibits anti-Helicobacter pylori activity that is synergistic with a number of antibacterial agents; it inhibits the urease enzyme and the proteolytic and mucolytic activities of H . pylori, and counteracts the inhibitory effects of H . pylori lipo-polysaccharide Ebrotidine is as effective as ranitidine for the treatment of patients with gastric or duodenal ulcers or erosive reflux oesophagitis Ebrotidine therapy results in significantly better ulcer healing rates than ranitidine treatment in patients who smoke.

J Biomed Mater Res, 1996 Jun, 31(2), 219 - 26
A study of the influence of biphase calcium phosphate ceramics on bacterial strains: in vitro approach; Opalchenova G et al.; An in vitro study of the influence of Biphase Calcium Phosphate Ceramics (BCPCs) on bacterial strains is presented . The test procedures were carried out in saline test solution to which different quantities (2,4,50,100, and 200 mg) of BCPCs(samples A and B) were added . The influence of BCPCs on standard bacterial strains has been determined by measuring bacterial contamination using the plate count method . The testing method was validated with membrane filtration and direct inoculation in culture media of sediment and supernatant . The test demonstrated reduction of the bacterial cell population in from 1 to 24 h in all experiments . The antibacterial effect revealed the specific inherent properties of the BCPCs under investigation.

Antimicrob Agents Chemother, 1996 Jun, 40(6), 1426 - 31
Identification, cloning, and expression of the Escherichia coli pyrazinamidase and nicotinamidase gene, pncA; Frothingham R et al.; Pyrazinamide (PZA) is one of the three most important drugs for treatment of Mycobacterium tuberculosis infections . The antibacterial activity of PZA requires a bacterial enzyme, pyrazinamidase (PZAase), which hydrolyzes PZA to form pyrazinoic acid and ammonia . Most PZA-resistant clinical M . tuberculosis isolates lack PZAase activity . With the goal of eventually identifying and characterizing the M.tuberculosis PZAase gene, we began with the more tractable organism, Escherichia coli, which also has PZAase activity . We screened a transposon-generated E . coli insertion mutant library, using a qualitative PZAase assay . Two PZAase-negative mutants out of 4,000 colonies screened were identified . In each mutant, the transposon interrupted the same 639-bp open reading frame (ORF), ORF1 . The expression of ORF1 on a multicopy plasmid complemented a PZAase-negative mutant, leading to PZAase activity levels approximately 10-fold greater than those of the wild type . PZA has a structure similar to that of nicotinamide, a pyridine nucleotide cycle intermediate, so we tested our strains for nicotinamidase activity (EC 3.5.1.19) (genetic locus pncA) . The construct with multiple plasmid copies of ORF1 had an approximately 10-fold increase in levels of nicotinamidase activity . This overexpressing strain could utilize nicotinamide as a sole nitrogen source, through wild-type E . coli cannot . We conclude that a single E . coli enzyme accounts for both PZAase and nicotinamidase activities and that ORF1 is the E.coli PZAase and nicotinamidase gene, pncA.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 33 - 44
{Single-dose toxicity studies of prulifloxacin (NM441) in mice, rats and dogs and the active metabolite (NM394) in rats}; Shimazu H et al.; Single-dose toxicity studies of prulifloxacin, a new antibacterial agent, were conducted in mice, rats and dogs . In addition, a single-dose toxicity study of (+/-)-6-fluoro-1-methyl-4-oxo-7- (1-piperazinyl)-4H-{1,3}thiazeto{3,2-a}quinoline- 3-carboxylic acid (NM394), an active metabolite of prulifloxacin, was performed in rats . Prulifloxacin was administered orally, intraperitoneally (i.p.) or subcutaneously (s.c.) to mice and rats, and orally to dogs . NM394 was administered intravenously (i.v.) to rats . When prulifloxacin was administered orally or s.c., LD50 values were more than 5000 mg/kg in both sexes of mice and rats; when it was administered i.p., LD50 values were 1757 mg/kg in male mice, 1652 mg/kg in female mice, 915 mg/kg in male rats, and 1076 mg/kg in female rats . The lethal doses of this drug were more than 5000 mg/kg in both sexes of dogs by the oral route . The LD50 values of NM394 were 226 mg/kg in male rats and 238 mg/kg in female rats by the i.v . route . In mice, the major clinical signs observed following the administration of prulifloxacin were sedation, oligopnea, abnormal gait, piloerection, closed eye and tremor by the i.p . route and a scab at the site of injection by the s.c . route; in rats, decreased spontaneous locomotor activity by any of the three routes, oligopnea, lacrimation, hypothermia, piloerection and abnormal gait by the i.p . route, and a scab at the site of injection by the s.c . route; and in dogs, vomiting, reddening of the skin, and loose stool by the oral route . When NM394 was administered i.v., rats showed clonic convulsion and dyspnea . The site of injection was hyperemic, swollen and necrotic . Mice showed a decrease in body weight or an inhibition in weight gain when prulifloxacin was administered i.p . and rats showed the same effects when prulifloxacin or NM394 was administered by any of the above-mentioned routes . Macroscopic findings detected following the i.p . administration of prulifloxacin in mice were pale color of the liver and spleen, thickening of the liver, and adhesion of intra-abdominal organs; and in rats, hydrothorax, congestion and edema of the lung, adhesion of intra-abdominal organs, swelling of the kidney accompanied by fine yellowish-white foci, and atrophy of the testis . When NM394 was administered i.v . to rats, congestion of the lung was macroscopically observed.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 259 - 65
{A photoallergenicity study of prulifloxacin (NM441) in guinea pigs}; Kamata K et al.; Photoallergenicity of prulifloxacin, a new antibacterial agent, was examined using guinea pigs compared with those of the other quinolone antibacterial drugs, ofloxacin (OFLX), lomefloxacin (LFLX), ciprofloxacin (CPFX), enoxacin (ENX) and nalidixic acid (NA) . Prulifloxacin and other drugs were orally administered at minimal phototoxic doses 1 hr before UVA (18 J/cm2) irradiation . This photosensitization procedure was daily repeated for 5 days . On 16 days after the final sensitization, the animals were challenged with UVA (18 J/cm2) after the administration of correspondent substances at maximal non-phototoxic doses . Photoallergic reactions were induced by OFLX (40 mg/kg), LFLX (3 mg/kg), CPFX (170 mg/kg) and ENX (80 mg/kg), but were not observed in prulifloxacin (170 mg/kg) and NA (30 mg/kg) . These results show that photoallergenicity of prulifloxacin were less severe than those of the other quinolone antibacterial drugs under the conditions of this study.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 231 - 9
{Antigenicity studies of prulifloxacin (NM441)}; Tateda C et al.; Antigenicity of prulifloxacin, a new antibacterial agent, and that of its active metabolite (NM394) were investigated using guinea pigs and mice in this study . In the study with guinea pigs, the animals were immunized with prulifloxacin by oral administration, the predetermined clinical route, and with prulifloxacin alone or emulsified with Freund's complete adjuvant (FCA) by s.c . When active systemic anaphylaxis (ASA) test and passive cutaneous anaphylaxis (PCA) test of these animals were conducted by eliciting with NM394 alone or protein conjugate (NM394-GPSA) of NM394 and guinea pig serum albumin (GPSA), no ASA and PCA reactions were observed . When guinea pigs were immunized subcutaneously with protein conjugate (NM394-BSA) of NM394 and bovine serum albumin (BSA) together with FCA, ASA and PCA reactions were positive by eliciting with NM394-GPSA or NM394-BSA, but were negative by eliciting with NM394 alone . In the study with mice, the animals were immunized orally with prulifloxacin and intraperitoneally with prulifloxacin alone or suspended with aluminum hydroxide gel (alum) . When rat PCA test of sera from these mice was conducted by eliciting with NM394 or NM394-GPSA, no positive PCA reaction was observed . When mice were immunized intraperiotneally with NM394-BSA together with alum, PCA reactions were positive by eliciting with NM394-GPSA or NM394-BSA, but were negative by eliciting with NM394 alone . These results show that prulifloxacin has no immunogenicity to guinea pigs and mice, and NM394 as its active form has no eliciting potential to anti-NM394-BSA antibody.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 219 - 30
{Reproductive and developmental toxicity studies of prulifloxacin (NM441)(4)--A perinatal and postnatal study in rats by oral administration}; Morinaga T et al.; A peri- and postnatal study of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats . Female rats were given prulifloxacin orally at dose levels of 0 (control), 30, 100 and 300 mg/kg from day 17 of pregnancy to day 21 after delivery . All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring . Food consumption in the period of pregnancy decreased in the dams given 100 and 300 mg/kg, and food and water consumption during lactational period increased in the dams given 300 mg/kg . The weight of the cecum of the dams increased in 100 and 300 mg/kg groups, and these doses caused enlargement of the cecum . Prulifloxacin had no effects on general sign, delivery, nursing, body weight gain, and kidney . Prulifloxacin also did not affect the number of live newborns and birth index, and have any adverse effects on the postnatal development of the first generation offspring (F1) such as differentiation, functional development, emotionality, motor ability, learning ability and reproductive performance . Prulifloxacin also had no adverse effects on the second generation offspring (F2) . These results show that the NOAEL of prulifloxacin are 30 mg/kg for general toxicity in mother animals, 300 mg/kg for pregnancy and delivery of mother animals and development of their offspring.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 207 - 17
{Reproductive and developmental toxicity studies of prulifloxacin (NM441)(3)--A teratogenicity study in rabbits by oral administration}; Morinaga T et al.; A study of the effect of prulifloxacin, a new antibacterial agent, during the period of organogenesis was conducted in New Zealand White rabbits . Female rabbits were given prulifloxacin orally at dose levels of 0 (control), 10, 30 and 100 mg/kg from day 6 to 18 of pregnancy . Female rabbits were sacrificed on day 29 of pregnancy for examination of their fetuses . In the 30 mg/kg group, food and water consumption decreased . In the 100 mg/kg group, soft stool was observed and body weight gain, food consumption and water consumption decreased . Premature delivery (2/16) occurred and enlargement of cecum and increased weight of cecum were observed . The number of fetal death increased in the 100 mg/kg group . However, prulifloxacin had no effects on the number of corpora lutea, implantations and live fetuses, and on body weight, placental weight, sex ratio, and external, visceral and skeletal development of live fetuses . These results show that the NOAEL of prulifloxacin are 10 mg/kg for general toxicity in mother animals, 30 mg/kg for pregnancy of mother animals and for development of fetuses.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 187 - 206
{Reproductive and developmental toxicity studies of prulifloxacin (NM441)(2)--A teratogenicity study in rats by oral administration}; Morinaga T et al.; A study of the effect of prulifloxacin, a new antibacterial agent, during the period of organogenesis was conducted in Sprague-Dawley rats . Female rats were given prulifloxacin orally at dose levels of 0 (control), 30, 300, and 3000 mg/kg from day 7 to day 17 of pregnancy . Twenty-four or twenty-five female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the pregnant rats (12-15 per dose levels) were allowed to deliver naturally for postnatal examination of their offspring . In the 300 or 3000 mg/kg groups, the food consumption decreased and water consumption increased in the dams . In the 3000 mg/kg group, the body weight gain was suppressed in the dams . In the 300 and 3000 mg/kg groups, the weights of cecum increased and the enlargement of cecum was observed . In the 3000 mg/kg group, white spots and rough surface of the kidney and renal tubular nephrosis with crystalline substance were observed and the weight of the kidney increased in the dams, and the body weight decreased and retarded ossifications in the fetuses . Prulifloxacin had no effect on the number of corpora lutea and implantations, or on fetal mortality, sex ratio, or external and visceral development of the fetuses . Prulifloxacin also did not affect delivery and the number of live newborns and birth index, or have any adverse effects on the postnatal development of the first generation offspring (F1) such as differentiation, functional development, emotionality, motor ability, learning ability or reproductive performance . Prulifloxacin also had no adverse effects of the second generation offspring (F2) . These results show that the NOAEL of prulifloxacin are 30 mg/kg for general toxicity in mother animals, 3000 mg/kg for pregnancy and delivery of mother animals and 300 mg/kg for development of their offspring.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 171 - 85
{Reproductive and developmental toxicity studies of prulifloxacin (NM441)(1)--A fertility study in rats by oral administration}; Morinaga T et al.; A study of fertility and fetal development of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats . Male rats were given the drug orally from 63 days before mating to the end of the mating period . Female rats were given from 14 days before mating to day 7 of pregnancy . The dose levels for both males and females were 0 (control), 30, 170 and 1000 mg/kg . The females were sacrificed on day 20 of pregnancy for examination of their fetuses . In the 170 mg/kg group, water consumption increased in the female rats, and food consumption decreased and the cecum increased in weight and was enlarged in the males and the females . In the 1000 mg/kg group, body weight gain was suppressed in the males, and food consumption decreased, water consumption increased and cecum increased in weight and enlarged in the males and the females . Moreover, this dose caused white spots and rough surface of the kidney in the males . Prulifloxacin had no adverse effects on reproductive function of the parent animals, and also on development of the fetuses . These results show that the NOAEL of prulifloxacin are 30 mg/kg for general toxicity in parent animals, 1000 mg/kg for reproductive function of parent animals and for development of fetuses.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 149 - 69
{Single and 4-week oral toxicity studies of prulifloxacin (NM441) in aged dogs}; Ihara T et al.; Single-dose and repeated dose toxicity studies of prulifloxacin, a new antibacterial agent, were conducted in aged beagle dogs . I . A single-dose toxicity study Prulifloxacin was administered orally to aged female dogs at a single dose of 2500 and 5000 mg/kg . No death occurred in any group . Vomiting was observed in one of two animals at 2500 mg/kg and in both animals at 5000 mg/kg 3-4 hr after dosing . At 5000 mg/kg, vomiting was observed in both animals after feeding on the day after dosing . One animal also showed soft stool . Thereafter, no abnormalities were observed in any animal . No test article related changes were noted in food consumption, water consumption, body weight or pathological examination in any group . The results show that the lethal dose of prulifloxacin is judged to be greater than 5000 mg/kg in aged female dogs . II . A repeated dose toxicity study Aged male and female dogs were given the test article orally for 4 weeks at doses of 0 (control), 20, 100 and 500 mg/kg . No death occurred in any group . At 500 mg/kg, vomiting was observed every day or intermittently throughout the dosing period and salivation was observed almost every day from day 6 to the end of the dosing onward . Decreases or lack of food and water consumption, and decrease of body weight were noted at 500 mg/kg . At 100 mg/kg, slight decreases in food consumption and body weight were noted in the females . No abnormalities were noted in ophthalmoscopic or electrocardio-graphic examination . In urinalysis, decreases in Na+, K+ and Cl- concentrations and the total excretion amount were noted mostly at 500 mg/kg . A low specific gravity was noted in males at 500 mg/kg . In hematology and serum biochemistry, high GPT, BUN and creatinine, and decreases in WBC were noted in both sexes at 500 mg/kg . A high GOT was noted in males, and low Cl- in females at 500 mg/kg . At 100 mg/kg, a high GPT was noted . Rough surface in the kidney and chronic interstitial nephritis (basophilic change of tubule, atrophy of tubule, thickening of tubular basement membrane, interstitial mononuclear cell infiltration, interstitial focal fibrosis) were increased at 500 mg/kg . No toxicological findings were seen in the 20 mg/kg group . The results show that the NOAEL of prulifloxacin is 20 mg/kg for 4-week repeated dose toxicity in aged dogs.

J Toxicol Sci, 1996 Jun, 21 Suppl 1, 113 - 29
{A 13-week oral toxicity study of prulifloxacin (NM441) in dogs followed by a 5-week recovery test}; Yoshida M et al.; A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in beagle dogs . Male and female dogs were given the test material orally for 13 weeks at doses of 0 (control), 20, 100 and 500 mg/kg . After discontinuation of the treatment, a 5-week recovery test was also conducted . Vomiting, salivation and decreased body weight gain or reduced body weight were seen in the 100 and 500 mg/kg groups . In the 500 mg/kg group, tremor, paresis of posterior limb associated with prone or sitting position and decreased food consumption were also observed . There were no treatment-related effects on survival and water consumption . Ophthalmoscopic, electrocardiographic and hematologic examinations, and urinalysis failed to show any abnormalities attributable to the treatment . Blood chemical examination showed increased GPT and decreased beta- and gamma-globulins in the 100 and 500 mg/kg groups, and increased GOT in the 500 mg/kg group . In pathological examination, cavitations and erosions were seen in the humeral and femoral articular cartilages in the 100 and 500 mg/kg groups . The above-mentioned changes were satisfactorily reversible except for erosions in the humeral and femoral articular cartilages in the 100 and 500 mg/kg groups . No toxicological findings were seen in the 20 mg/kg group . The results show that the NOAEL of prulifloxacin is 20 mg/kg for 13-week repeated dose toxicity in dogs.

Nord Med, 1996 Jun, 111(6), 176 - 9
{Man's own antibiotics--an innate immune system}; Boman HG; In 1981, Steiner and co-workers of Stockholm described a newly discovered type of potent antibacterial peptides which lack cysteine, so called cecropins, which are spiral-formed molecules of 30-40 amino acids found to kill bacteria within a few minutes by disintegration of the bacterial cell wall, but to do no damage to the membrane of insect or mammalian cells . To date, descriptions have been published of about a hundred peptide antibiotics from various mammals (including man), birds, frogs, many types of insects . Peptide antibiotics exert a bacteriostatic effect on the normal flora of the skin and of the oral cavity and other orifices . It is also possible that peptide antibiotics protect us against many pathogenic organisms.

J Appl Bacteriol, 1996 Jun, 80(6), 667 - 72
In vitro inhibition of Helicobacter pylori by extracts of thyme; Tabak M et al.; Extracts of several plants were tested for inhibitory activity against Helicobacter pylori . Among these plants thyme (aqueous extract) and cinnamon (alcoholic extract) were the most effective . Since aqueous extract of thyme is easier to produce and consume, it was further investigated . Compared with several antibacterials, the thyme extract had a significant inhibitory effect on H . pylori, reducing both its growth and potent urease activity . From the results of this study, the aqueous extract of thyme possesses a therapeutic potential which merits validation by clinical studies.

J Antibiot (Tokyo), 1996 Jun, 49(6), 582 - 92
Cladinose analogues of sixteen-membered macrolide antibiotics . I . Synthesis of 4-O-alkyl-L-cladinose analogues via glycosylation; Kurihara K et al.; The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as the neutral sugar are described . The nine novel derivatives have been synthesized by glycosylation with 1-thio sugars . The most active derivative of them showed prolonged antibacterial activity in rat plasma in vitro and improved pharmacokinetics.

Planta Med, 1996 Jun, 62(3), 256 - 9
Antibacterial and antifungal polyine compounds from Glehnia littoralis ssp . leiocarpa; Matsuura H et al.; Glehnia littoralis F . Schmidt ssp . leiocarpa (Mathias) Hult . (Apiaceae), a species of ethnopharmacological interest in British Columbia, has antibacterial and antifungal properties . Antibacterial and antifungal compounds include two hitherto unreported polyine compounds, (9Z)1,9-heptadecadiene-4,6-diyne-3,8,11-triol and (10E)1,10-heptadecadiene-4,6-diyne-3,8,9-triol.

Eur J Biochem, 1996 Jun 1, 238(2), 325 - 32
The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes; Gudmundsson GH et al.; The peptide FA-LL-37, previously termed FALL-39, was originally predicted from on ORF of a cDNA clone isolated from a human bone marrow library . This peptide was synthesized and found to have antibacterial activity . We have now characterized and sequenced the complete gene for FA-LL-37, termed FALL39 . It is a compact gene of 1963 bp with four exons . Exons 1-3 code for a signal sequence and the cathelin region . Exon 4 contains the information for the mature antibacterial peptide . Our results indicate that FALL39 is the only member of the cathelin gene family present in the human genome . Potential binding sites for acute-phase-response factors are identified in the promoter and in intron 2 . A possible role for the cytokine interleukin-6 in the regulation of FALL 39 is discussed . Anti-(FA-LL-37) IgG located the peptide in granulocytes and we isolated the mature peptide from these cells after degranulation . Structural analysis determined the mature peptide to be LL-37 . To obtain LL-37 for antibacterial assays, synthetic FA-LL-37 was degraded with dipeptidyl-peptidase I . This analysis showed that mature LL-37 is a potent antibacterial peptide.

Am J Gastroenterol, 1996 Jun, 91(6), 1248 - 50
Invasive candidiasis complicating spontaneous esophageal perforation (Boerhaave syndrome); Bauer TM et al.; Spontaneous esophageal perforation is a rare condition that frequently results in infectious complications . Empirical broad-spectrum antibacterial therapy is therefore part of the standard management . We describe two patients suffering from spontaneous esophageal perforation who developed invasive candidiasis with hematogenous dissemination . One patient died of multiple organ failure due to Candida sepsis . Preexistent Candida colonization, incomplete mediastinal drainage, broad-spectrum antibacterial therapy, and prolonged intensive care therapy place patients with esophageal perforation at high risk for secondary fungal infection . Intense microbiological searching is mandatory, but the distinction between colonization and infection may be impossible . Empirical antifungal treatment with imidazole derivatives, particularly in patients with potential risk factors, should be considered.

J Med Microbiol, 1996 Jun, 44(6), 425 - 33
Factors affecting growth and antibiotic susceptibility of Helicobacter pylori: effect of pH and urea on the survival of a wild-type strain and a urease-deficient mutant; Sjostrom JE et al.; This study investigated how pH and the presence of urea affect the survival and growth of Helicobacter pylori and whether these factors affect susceptibility to antibiotics in vitro . The viability of a wild-type strain and a urease-deficient mutant of H . pylori was studied after incubation for 1 h in buffers at different pH values at 37 degrees C under microaerophilic conditions . Viable counts were not affected at pH 5 and pH 7 . In buffer at pH 3, there were no viable organisms, but urea (6.25 mM) protected the wild-type strain, which survived well . At pH 9, urea further reduced the viability of H . pylori and flurofamide almost abolished the effect of urea on the wild-type strain . Neither urea nor flurofamide affected the viability of the urease-deficient mutant under the same conditions . Growth was also pH dependent and was enhanced in shake-cultures . At pH 5, urea supported growth of the wild-type strain, but at pH 7 a toxic effect on the bacteria was observed . Growth of H . pylori at pH 5.9 was poor, and susceptibility to amoxycillin, erythromycin and clarithromycin was markedly less than at pH 7.2 and 7.9 . The bactericidal activities of metronidazole and tetracycline were similar at the different pH values studied . At neutral pH the killing rates of amoxycillin and clarithromycin were growth rate dependent . Susceptibility to metronidazole was enhanced in stationary cultures . The interaction obtained between the proton pump inhibitor, omeprazole, and amoxycillin at pH 7 was of additive type . These results suggest that pH and growth conditions may be important in the antibacterial efficacy of different antibiotics in vivo and also provide a possible explanation for the potentiating effect of omeprazole with antibiotics in the treatment of H . pylori infections.

J Biol Chem, 1996 May 31, 271(22), 12790 - 4
Cooperative interactions between the amino- and carboxyl-terminal lobes contribute to the unique iron-binding stability of lactoferrin; Ward PP et al.; Lactoferrin is a member of the transferrin family of iron-binding proteins . Several functions have been ascribed to lactoferrin, including regulation of iron homeostasis, antibacterial properties, and regulation of myelopoiesis . However, the structural features of lactoferrin that are required for most of these functions are unknown . Previously, we reported the development of an efficient fungal expression system to produce recombinant human lactoferrin . The availability of this production system demonstrated the feasibility of producing mutant lactoferrins to address the structure/function relationship of the protein . In the present study, we used a site-directed mutagenesis approach to address the contribution of the bilobal structure of lactoferrin to its unique iron-binding stability . Like transferrin, lactoferrin consists of two repeated iron-binding lobes that bind one iron atom each . However, unlike transferrin, lactoferrin retains iron over a broad pH range, a key property that contributes to the unique iron-binding functions of the protein . Using mutants that selectively ablate the iron-binding function in either lobe, we demonstrate differential iron-binding stability of the amino- and carboxyl-terminal iron-binding lobes of lactoferrin . Further, we show that the unique iron-binding stability of the protein is imparted primarily by the carboxyl-terminal domain which functions cooperatively to stabilize iron-binding to the amino-terminal domain of lactoferrin.

J Biol Chem, 1996 May 31, 271(22), 12708 - 15
Helix pomatia lectin, an inducer of Drosophila immune response, binds to hemomucin, a novel surface mucin; Theopold U et al.; We describe the isolation and initial characterization of hemomucin, a novel Drosophila surface mucin that is likely to be involved in the induction of antibacterial effector molecules after binding a snail lectin (Helix pomatia A hemagglutinin) . Two proteins of 100 and 220 kDa were purified from the membrane fraction of a Drosophila blood cell line using lectin columns . The two proteins are products of the same gene, as demonstrated by peptide sequencing . The corresponding cDNAs code for a product that contains an amino-terminal putative transmembrane domain, a domain related to the plant enzyme strictosidine synthase, and a mucin-like domain in the carboxyl-terminal part of the protein . The gene is expressed throughout development . In adult flies, high expression is found in hemocytes, in specialized regions of the gut, and in the ovary, where the protein is deposited onto the egg surface . In the gut, the mucin co-localizes with the peritrophic membrane . The cytogenetic location of the gene is on the third chromosome in the region 97F-98A.

J Mol Biol, 1996 May 24, 258(5), 860 - 70
Structure and orientation of the mammalian antibacterial peptide cecropin P1 within phospholipid membranes; Gazit E et al.; Cecropins are positively charged antibacterial peptides that act by permeating the membrane of susceptible bacteria . To gain insight into the mechanism of membrane permeation, the secondary structure and the orientation within phospholipid membranes of the mammalian cecropin P1 (CecP) was studied using attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and molecular dynamics simulations . The shape and frequency of the amide I and II absorption peaks of CecP within acidic PE/PG multibilayers (phosphatidylethanolamine/phosphatidylglycerol) in a 7:3 (w/w) ratio (a phospholipid composition similar to that of many bacterial membranes), indicated that the peptide is predominantly alpha-helical . Polarized ATR-FTIR spectroscopy was used to determine the orientation of the peptide relative to the bilayer normal of phospholipid multibilayers . The ATR dichroic ratio of the amide I band of CecP peptide reconstituted into oriented PE/PG phospholipid membranes indicated that the peptide is preferentially oriented nearly parallel to the surface of the lipid membranes . A similar secondary structure and orientation were found when zwitterionic phosphatidylcholine phospholipids were used . The incorporation of CecP did not significantly change the order parameters of the acyl chains of the multibilayer, further suggesting that CecP does not penetrate the hydrocarbon core of the membranes . Molecular dynamics simulations were used to gain insight into possible effects of transmembrane potential on the orientation of CecP relative to the membrane . The simulations appear to confirm that CecP adopts an orientation parallel to the membrane surface and does not insert into the bilayer in response to a cis positive transmembrane voltage difference . Taken together, the results further support a "carpet-like" mechanism, rather than the formation of transmembrane pores, as the mode of action of CecP . According to this model, formation of a layer of peptide monomers on the membrane surface destablizes the phospholipid packing of the membrane leading to its eventual disintegration.

Am J Med, 1996 May 20, 100(5A), 42S - 50S; discussion 50S-51S
Eradication of Helicobacter pylori infection; Hunt RH; Helicobacter pylori is probably the most common bacterial infection worldwide and the accepted cause of chronic active gastritis . It has a critical role in duodenal ulcer, where the prevalence of infection is 90-95% . There is a dramatic reduction in the rate of ulcer recurrence after successful eradication of the organism to about 4% per annum compared with up to 80% when the infection persists . What is true for duodenal ulcers is also true for patients with gastric ulcer who are infected with H . pylori . The risk of recurrent ulcer complications with bleeding is virtually abolished following successful eradication of H . pylori; in contrast, the risk of rebleeding is about 33% in patients still harboring the organism . The treatment of H . pylori infection in patients with confirmed peptic ulcer on first presentation or recurrence has been advocated by a Consensus Conference of the National Institutes of Health . The most evaluated regimens include dual therapy with a proton pump inhibitor and either amoxicillin or clarithromycin, and bismuth-based triple therapy with metronidazole and tetracycline . The use of a proton pump inhibitor-containing regimen offers the advantage of rapid symptom relief and the highest rates of duodenal ulcer healing . Moreover, combinations of a proton pump inhibitor and clarithromycin show more predictable and higher eradication rates than amoxicillin combinations . Newer triple therapies with a proton pump inhibitor plus two antibacterial agents given for 7-1O days are being increasingly described and may become the treatment of choice if initial results are confirmed . However, the optimum dosage regimen needs to be established . A new combination of ranitidine bismuth citrate and clarithromycin has also recently been shown to be effective . At this time it is reasonable to consider all patients with confirmed duodenal or gastric ulcer for eradication of H . pylori, and no patient should be considered for elective surgery without first being offered eradication therapy.

Vet Rec, 1996 May 18, 138(20), 489 - 92
Clinical evaluation of in-feed zinc bacitracin for the control of porcine intestinal adenomatosis in growing/fattening pigs; Kyriakis SC et al.; This field trial was designed to investigate whether the incorporation of zinc bacitracin into pig feed would prevent porcine intestinal adenomatosis . Two hundred-and-eighty-eight weaned pigs on a farm with a previous history of the disease were divided into 16 pens of 18 pigs . Two dietary regimens of zinc bacitracin were tested: from weaning up to 100 days of age, either 300 or 200 ppm zinc bacitracin were incorporated; from 100 to 125 days of age, either 200 or 100 ppm zinc bacitracin were added; and from 125 to 156 days of age (slaughter), either 100 or 50 ppm zinc bacitracin were added . The results were compared with a positive control group which received 60, 60 and 30 ppm salinomycin during the same periods, and with a negative control group which received no antibacterial and/or performance enhancer . The mortality, diarrhoea scores, average daily weight gains, average daily feed intakes and feed conversion ratios of the pigs were assessed . At slaughter, samples of ileum were taken from eight randomly selected pigs per group for bacteriological and histopathological examinations . The three treated groups all performed better than the control group, and the group receiving the high dose regimen of zinc bacitracin performed significantly better than the groups receiving the low dose of zinc bacitracin or salinomycin.

Eur J Cancer, 1996 May, 32A(5), 814 - 20
Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial; Viscoli C et al.; Amphotericin B, despite its intrinsic servere toxicity, is the most commonly used empirical antifungal therapy in cancer patients with unexplained fever not responding to empirical antibacterial therapy . The aim of this study was to show whether fluconazole was as effective as, and less toxic than, amphotericin, with no effort made to compare the antifungal activity of the two drugs . A group of 112 persistently febrile (> 38 degrees C) and granulocytopenic (< 1000 cells/mm3) cancer patients, not receiving any absorbable antifungal antibiotic for prophylaxis, with a mean age of 27 years (range 1-73 years), undergoing chemotherapy for a variety of malignancies and with a diagnosis of unexplained fever after at least 96 h of empirical antibacterial therapy, were randomised to receive either fluconazole (6 mg/kg/day up to 400 mg/day) or amphotericin B (0.8 mg/kg/day) as empirical antifungal treatment . Patients were required to have normal chest X-rays at randomisation, no previous history of aspergillosis and negative surveillance cultures for Aspergillus . The intention-to-treat analysis showed defervescence and survival without treatment modification in 42 of 56 patients (75%) in the fluconazole group and in 37 of 56 (66%) in the amphotericin B group (P = 0.4) . Duration of therapy was 6 days (95% CI = 4-8 days) in both groups . Death occurred in 3 patients (5%) in the fluconazole and in 2 (4%) in the amphotericin B group . No fungal death was documented in either group . Adverse events developed in 18 of 56 patients (32%) in the fluconazole group and in 46 of 56 (82%) in the amphotericin B group (P < 0.001) . In the amphotericin B group, 5 patients had treatment discontinued because of toxicity, versus none in the fluconazole group, a difference which approached statistical significance (P = 0.06) . This study shows that fluconazole is by far less toxic than amphotericin B and suggests that it might be as effective as amphotericin B, in pragmatical terms and for this specific indication . However, numbers are too small to allow definitive conclusions about efficacy, and the use of fluconazole for this indication remains experimental . Future studies should try to identify patients more at risk of fungal infections, with the aim of individualising antifungal approaches.

Antibiot Khimioter, 1996 May, 41(5), 30 - 4
{Recovery rate in chemotherapy of glanders}; Batmanov VP et al.; It was shown that out of all the studied methods for the estimation of the recovery rate in animals with experimental malleus the solid-phase enzyme immunoassay with parallel growing of the test material and subsequent isolation of the antigens and L-forms proved to be the most efficient . In addition to the routine criteria of the recovery the malleinic test was a valuable diagnostic means for the estimation of the recovery rate and the efficacy of the antibacterial drugs in a model of guinea pigs . The immunological investigations revealed a dependence of the host sanation on the term of the animal chemotherapy . There was detected no L-transformation of Pseudomonas mallei during the treatment of the animals with experimental malleus with combinations of sulfanilamides with trimethoprim (biseptol and sulfaton) or rifampicin which was evident of their high sanation activity and safety in comparison to sulfamonomethoxin used alone.

Fiziol Zh Im I M Sechenova, 1996 May-Jun, 82(5-6), 18 - 25
{The role of glycosaminoglycans and proteoglycans in hemopoiesis and the physiological functions of the blood cells}; Kharchenko MF et al.; Literature review as well as own data on the role of glycosaminoglycans and proteoglycans of leukocytes, platelets and hemopoietic microenvironment are presented . These compounds are involved in the storage of lysosomal enzymes, cationic antibacterial polypeptides and other granular constituents of blood cells, take part in mediating of cellular interactions, occurring in hematopoiesis, phagocytosis, immunity and other processes . Due to the capacity to react with many substances, including enzymes, cell growth factors, cytokines, receptors, changing their conformation and biological activity glycosaminoglycans and proteoglycans can take part in regulation of cell adhesion, migration, proliferation differentiation and special functions of various types of hematopoietic and lymphoid cells.

FEMS Microbiol Lett, 1996 May 1, 138(2-3), 201 - 6
Is the CvaA protein, encoded within the colicin V export gene cvaA, required for colicin V transport?
Skvirsky RC, Shen X, Reginald S.
The antibacterial peptide toxin colicin V is exported from Escherichia coli cells by a signal sequence-independent, ABC export system . Export requires at least three proteins-membrane fusion protein CvaA, ABC export protein CvaB, and outer membrane protein TolC . The cvaA gene also encodes a second protein, CvaA, initiated from an in-frame translational re-start within the cvaA coding sequence . To determine whether the internally encoded CvaA protein also functions in the export pathway, the putative start codons for CvaA were mutagenized, while maintaining CvaA function . Elimination of CvaA translation caused no change in colicin V export levels, indicating that the CvaA protein is not required in the secretion pathway.

Fundam Appl Toxicol, 1996 May, 31(1), 133 - 40
Effect of antioxidants, anti-inflammatory drugs, and histamine antagonists on sparfloxacin-induced phototoxicity in mice; Shimoda K et al.; We examined the effects of antioxidants, anti-inflammatory drugs, and histamine antagonists on auricular inflammation and retinal degeneration induced by the phototoxicity of sparfloxacin (SPFX), a quinolone antibacterial agent . Catalase (CAT), dimethyl sulfoxide (DMS0), dexamethasone (DM), indomethacin (IM), phenidone (PD), AA-861 (AA), pyrilamine maleate (PY), or cimetidine (CM) was continuously administered to female Balb/c mice using microosmotic pumps for 72 hr and intraperitoneally once before SPFX administration . The mice were given a single oral administration of 50 or 100 mg/kg SPFX and irradiated with ultraviolet-A (UVA) light at 1.5 mW/cm(2) for 4 hr . SPFX administration plus UVA irradiation induced thickening and inflammation of the auricular skin and retinal degeneration in the eye . CAT and DMS0 significantly inhibited the auricular thickening only 4 hr after SPFX administration . DM, IM, and PD also inhibited this toxicity from 4 to 48 or 72 hr . On the other hand, PY and CM showed no effect on this change . With regard to the eye, CAT and DMSO completely inhibited the occurrence of retinal degeneration and IM and PD tended to decrease its incidence, whereas DM, AA, PY, and CM showed no or an exacerbating effect . These results suggest that reactive oxygen species contribute to the initiation of auricular inflammation and retinal degeneration and that cyclooxygenase products are also involved in the initiation and later progression of auricular inflammation . They also show that histamine and 5-lipoxygenase products are not involved in either phototoxic lesion.

Anesteziol Reanimatol, 1996 May-Jun, (3), 18 - 21
{The factors in local protection of the lungs and the status of cellular immunity in patients before and after thoracic operations}; Vinnitskii LI et al.; Twenty-seven patients operated on the lungs and heart (aortocoronary bypass surgery) were examined . Cellular immunity parameters were studied in venous blood, and the function of immunocompetent cells, status of the surfactant system, and albumin level were assessed in the bronchoalveolar washings off . An impairment of the T-component of cellular immunity (T-suppressors), reduced level of alveolar macrophages and of their phagocytic activity, reduced activity of the surfactant system, and increased albumin content in the bronchoalveolar lavage fluid were revealed in patients with a complicated course of the postoperative period . In patients with a smooth course of the postoperative period these shifts were less expressed . The data indicate the necessity of antibacterial and immunomodulated therapy in such patients before and after surgery.

Boll Chim Farm, 1996 May, 135(5), 351 - 4
Studies on arylfuran derivatives--Part IV . Synthesis and antibacterial properties of arylfurylvinylquinazolinones; Holla BS et al.; A number of arylfurylvinylquinazolinones were prepared as possible antibacterial agents . The structural elucidations of all the compounds were carried out on the basis of analytical and spectral data . The newly synthesised compounds were screened for their antibacterial properties against both Gram-positive and Gram-negative bacteria.

Boll Chim Farm, 1996 May, 135(5), 297 - 300
Synthesis and antibacterial testing of some new quinolines, pyridazinoquinolines and spiroindoloquinolines; el-Ahl AA et al.; 3-Dicyanomethylideneindole derivatives were involved in (i) ring expansion reactions in alcoholic piperidine to form new quinolines from which a new pyridazinoquinoline was synthesised; and (ii) formation of new spiroindoloquinolines by reactions with cyclohexanone and beta-tetralone . The suggested structures of the new products were confirmed by IR, 1H-NMR, 13C-NMR and mass spectral analyses . Some of the new derivatives were active against the bacteria Escherichia cell.

Urol Nefrol (Mosk), 1996 May-Jun, (3), 17 - 20
{The immune status of patients with primary and secondary chronic pyelonephritis}; al-Shukri SKh et al.; Immunological examination (T- and B-cell immunity, metabolic activity of phagocytes) was conducted in 10 patients with primary and 21 patients with secondary chronic pyelonephritis in the phase of latent inflammation resistant to conventional antibacterial therapy versus 12 patients free of this disease . It was found that immunoreactivity in the above patients was compromised as shown by quantitative and qualitative deficiency of T-cell immunity (a fall in the absolute number of CD3+, absolute and relative content of CD2+DR+, changed proportion of T-lymphocyte subpopulations, low activity of oxygen-dependent anti-infection systems of phagocytes) . B-system immunity did not much change for the worse . In primary chronic pyelonephritis immunoreactivity was affected more seriously.

J Pharm Biomed Anal, 1996 May, 14(7), 807 - 14
Separation of diastereoisomers of DuP 105, a novel oxazolidinone antibacterial agent, by supercritical fluid chromatography on a Chiralcel OD column; Alasandro M; Oxazolidinones are a novel class of synthetic, orally-active antibacterial agents . DuP 105, which is representative of this class of compounds, is synthesized as a racemic mixture of two diastereoisomers . To ensure lot-to-lot consistency, separation and quantitation of these diastereoisomers is essential . Separation by reverse phase LC has not been achieved . This paper presents a supercritical fluid chromatography method using a Chiralcel OD column to resolve these diastereoisomers . A retention mechanism is briefly elaborated, based on the effects of temperature, pressure, percent modifier and type of modifier on resolution.

Arzneimittelforschung, 1996 May, 46(5), 534 - 8
{Antibacterial action of clindamycin in chronic, recurrent tonsillitis}; Muller R et al.; After oral administration of 300 mg Sobelin, the efficacy and pharmacological kinetics of clindamycin (CAS 18323-44-9) were analysed in 35 patients with recurrent tonsillitis . Minimal inhibitor concentration (MIC) and minimal bactericidal concentration (MBC) have been evaluated for 120 strains . MIC and MBC for 91.7% of the strains amounted to 0.25 micrograms/ml . Concentrations of antibiotics in the serum were higher than 0.25 micrograms/ml after 12 h, i.e . higher than the minimal inhibitory concentration . The established free and efficient portion of clindamycin in the serum which is not bound to plasma proteins shows that a clear bacteriostatic effect is achieved up to 6 h after application of the antibiotic . The concentration in the tissue of the tonsils was 0.6-0.8 micrograms/g after 7-9 h indicating that sufficient MIC values were achieved . The free portion of the antibiotic in the tissues after 9 h also reached the MIC of germs . Hence clindamycin is considered to be an efficient antibiotic in the management of acute exacerbation of recurrent tonsillitis . Due to serum- and tissue levels of the tonsils administration of 300 mg of the test drug is indicated three times daily.

J Antimicrob Chemother, 1996 May, 37(5), 919 - 29
In-vitro and in-vivo antibacterial activity of plaunotol, a cytoprotective antiulcer agent, against Helicobacter pylori; Koga T et al.; Recently, some antiulcer agents have been reported to have antibacterial activity against Helicobacter pylori, which is highly associated with gastritis and peptic ulcers . In-vitro and in-vivo activity of plaunotol, a cytoprotective antiulcer agent, against H . pylori was investigated . Antibacterial activity of plaunotol against a standard strain (NCTC 11637) and 14 clinical isolates was compared with those of other cytoprotective antiulcer agents: benexate, sofalcone, teprenone, cetraxate, and gefarnate, by an agar dilution method . The MIC50 and MIC90 of plaunotol against 15 strains were 6.25 and 12.5 mg/L, respectively, making it the most potent of the cytoprotective antiulcer agents . The bactericidal effect of plaunotol was investigated using an in-vitro killing assay . Plaunotol at concentrations of more than 6 mg/L induced a rapid reduction of culture turbidity, with an extensive loss of viability, within 30 min . Observation by scanning electron microscopy revealed that plaunotol caused autolysis and treated cells were deformed . In-vivo activity of plaunotol against H . pylori was examined in a nude mouse gastritis model . Plaunotol significantly decreased the number of H . pylori in the stomach of nude mice . In addition, the antiulcer agent enhanced the antibacterial activity of amoxycillin or clarithromycin in the infection model.

J Antimicrob Chemother, 1996 May, 37 Suppl A, 145 - 60
Safety profile of sparfloxacin in the treatment of respiratory tract infections; Rubinstein E; A total of 2081 adult patients with community-acquired lower respiratory tract infections participated in Phase III clinical trials of sparfloxacin . A total of 1040 patients were randomised to sparfloxacin and 1041 patients received a comparator regimen . Sparfloxacin was administered as a 400 mg loading dose on day 1 followed by 200 mg once daily to patients with community-acquired pneumonia and as a 200 mg loading dose on day 1 followed by 100 mg daily to patients with acute exacerbations of chronic obstructive pulmonary disease . Comparator regimens were amoxycillin/clavulanic acid 500/125 mg tid, amoxycillin 1000 mg tid, a combination of amoxycillin 1000 mg tid plus ofloxacin 200 mg bid or erythromycin 1000 mg bid . The incidence of adverse events, the incidence and severity of antibacterial-related adverse events and the incidence of antibacterial discontinuation due to adverse events were no different among patients treated with sparfloxacin compared with those who received a comparator antibacterial agent . Sparfloxacin appears to be as well tolerated as other oral antibacterial regimens commonly used to treat lower respiratory tract infections.

J Antimicrob Chemother, 1996 May, 37 Suppl A, 83 - 91
Comparative efficacy of sparfloxacin in comparison with amoxycillin plus ofloxacin in the treatment of community-acquired pneumonia . French Study Group; Portier H et al.; A prospective, placebo controlled double-blind, randomised study comparing oral sparfloxacin 200 mg once daily following a 400 mg loading dose on day 1 with an oral combination of amoxycillin 1 g tid plus ofloxacin 200 mg bid was conducted in 211 hospitalised patients with community-acquired pneumonia . Patients were included in the study if they were aged > 65 years or had failed a previous course of antibacterial therapy . The duration of treatment was 10 days . The overall efficacy rates for the sparfloxacin and amoxycillin plus ofloxacin treatment groups were 91.9% and 81.5%, respectively, in evaluable patients at the end of treatment . Age or prior failure of antibacterial therapy did not affect the overall success rate of sparfloxacin . The safety profile of sparfloxacin was similar to that of the antibacterial combination . This study demonstrated that sparfloxacin given once daily is a suitable therapy for the treatment of community-acquired pneumonia in the elderly or in patients with failure of previous antibiotic therapy.

J Antimicrob Chemother, 1996 May, 37 Suppl A, 73 - 82
Sparfloxacin for the treatment of community-acquired pneumonia: a pooled data analysis of two studies; Aubier M et al.; A pooled data analysis of two double-blind studies encompassing 1137 episodes of community-acquired pneumonia in hospitalised adults, of which 560 were treated with sparfloxacin and 577 were randomised to comparator antibacterial agents (amoxycillin/clavulanic acid, erythromycin or amoxycillin administered at reference dosages), was performed . The global efficacy rate at the end of treatment in evaluable patients treated with sparfloxacin was 88.3% compared with 84.1% in those who received comparator antibacterial agents . This analysis verified the efficacy of this new aminofluoroquinolone, given orally once daily, in the treatment of community acquired pneumonia . The overall outcome favoured sparfloxacin for use in the empirical treatment of community-acquired pneumonia.

J Antimicrob Chemother, 1996 May, 37 Suppl A, 65 - 72
Study design, methodology and statistical analyses in the clinical development of sparfloxacin; Genevois E et al.; Many publications in the past 10 years have emphasised the difficulties of evaluating anti-infective drugs and the need for well-designed clinical trials in this therapeutic field . The clinical development of sparfloxacin in Europe, involving more than 4000 patients in ten countries, provided the opportunity to implement a methodology for evaluation and statistical analyses which would take into account actual requirements and past insufficiencies . This methodology focused on a rigorous and accurate patient classification for evaluability, subgroups of particular interest, efficacy assessment based on automation (algorithm) and individual case review by expert panel committees . In addition, the statistical analyses did not use significance testing but rather confidence intervals to determine whether sparfloxacin was therapeutically equivalent to the reference comparator antibacterial agents.

J Ethnopharmacol, 1996 May, 52(1), 41 - 3
Inhibition of herpes simplex virus type 1 by aqueous extracts from shoots of Helichrysum aureonitens (Asteraceae); Meyer JJ et al.; Helichrysum aureonitens, a southern African medicinal plant reported to have antibacterial properties, was evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro . The crude aqueous extract from shoots of H . aureonitens at a concentration of 1.35 mg/ml (w/v) showed significant antiviral activity on HSV-1 in human lung fibroblasts as demonstrated by the absence of a cytopathic effect.

Antimicrob Agents Chemother, 1996 May, 40(5), 1266 - 9
Multiple antibiotic resistance (mar) locus protects Escherichia coli from rapid cell killing by fluoroquinolones; Goldman JD et al.; The multiple antibiotic resistance (mar) locus in Escherichia coli consists of two divergently expressed operons (marC and marRAB), both of which contribute to the Mar phenotype . Overexpression of the marRAB operon protected E . coli against rapid cell killing by fluoroquinolones . Inactivation of the operon in mar mutants restored a wild-type bactericidal susceptibility . Both operons of the locus were required for protection from the quinolone-mediated bactericidal activity in mar locus deletion mutants . The effect was lost at high concentrations of fluoroquinolones, unlike the case for the previously described genes hipA and hipQ . The inducible mar locus appears to specify a novel antibactericidal mechanism which may play a role in the emergence of fluoroquinolone-resistant clinical E . coli isolates.

Radiats Biol Radioecol, 1996 May-Jun, 36(3), 394 - 9
{Chemiluminescence, blood lipid peroxidation and neutrophil activity during the hypoxic training of persons subjected to ionizing radiation exposure}; Serebrovskaia ZA et al.; Free radical processes and some indices of antibacterial defense system have been examined in 29 male residents of Chernobyl area during adaptation to periods of intermittent hypoxia . 18 men (the experimental group) were exposed to normobaric isocapnic progressive hypoxia during 10 days of three daily 5-7 min sessions with 15 min breaks, and 11 men (control group) were exposed to air breathing . All subjects were divided into two subgroups with initial high (1) and low (2) level of blood chemiluminescence (ChL) . Patients of the 1 subgroup were characterized with high oxygen-generated activity of neutrophils (OGA) and high malondialdehyde (MDA) concentration . After hypoxic training (HT) there was a decrease of spontaneous and initiated ChL and MDA . Patients of the 2 subgroup were characterised with low level both spontaneous and initiated ChL, low MDA concentration and low phagocytosing activity of neutrophils . After HT there was significant rise of initiated ChL and MDA concentration up to normal level with the increasing of neutrophil phagocytosing activity . We suggest that HT causes the normalizing effect on free radical processes in subjects who were exposed to radiation influences.

Chem Pharm Bull (Tokyo), 1996 May, 44(5), 987 - 90
5-Alkoxyimidazoquinolones as potential antibacterial agents . Synthesis and structure-activity relationships; Fujita M et al.; 4-Substituted 6-cyclopropyl-6, 9-dihydro-5-methoxy-9-oxo-1H-imidazo{4,5-f} quinoline-8-carboxylic acids (6) and 8-substituted 1,5,6,11-tetrahydro-5-methyl-1-oxo-imidazo{4,5-g}pyrido{1,2,3-de}{1,4} benzoxazine-2-carboxylic acids (7) were prepared as potential antibacterial quinolone derivatives . The appendages at C-4 of -6 and at C-8 of -7 were selected from 1-piperazinyl, 4-methylpiperazinyl, 3-aminomethylpyrrolidinyl, and 3-aminomethylpyrrolidinyl groups . The 5-methoxyimidazoquinolones 6 were superior to the corresponding ofloxacin type analogues 7 in in vitro antibacterial activity . The activity of 6 was equipotent against S . aureus, but 2 to 16 times less potent against E . coli and P . aeruginosa compared to that of the 5-fluoro analogue 3.

Chem Pharm Bull (Tokyo), 1996 May, 44(5), 1074 - 85
Studies on quinolone antibacterials . IV . Structure-activity relationships of antibacterial activity and side effects for 5- or 8-substituted and 5,8-disubstituted-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acids; Yoshida T et al.; A series of 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-1,4-dihydro-4- oxoquinoline-3-carboxylic acids bearing various substituents (H, F, C1, Me, OH, OMe, OEt, OCH2F, OCHF2, OCF3, SMe) at the C-8 position was prepared and evaluated for in vitro antibacterial activity against both standard laboratory strains and bacteria resistant to quinolones such as ciprofloxacin (CPFX, 1) and ofloxacin (OFLX, 2) from clinical isolates . The 8-methyl (8a), 8-fluoro (9a), 8-chloro (10a) and 8-methoxy (12a) compounds were 4 times more potent than CPFX (1) against both gram-positive and gram-negative bacteria . But these four compounds caused injury to the chromosomes of mammalian cells at a concentration of 100 micrograms/ml . Next, a series of quinolones having various substituents (H, C1, Me, NH2, NHMe, NMe2) at the C-5 position was prepared and evaluated for antibacterial activity and injurious effect on the chromosome . We found that the 5-amino-8-methyl compound (8d) showed strong antibacterial activity (in vitro antibacterial activity of 8d is 4 times more potent than that of CPFX (1) against both gram-positive and gram-negative bacteria), reduced injury to the chromosome, and reduced quinolone-type toxicity (free from both phototoxicity at a dosage of 30 mg/kg in guinea pigs (i.v.) and convulsion-inducing activity when coadministered with fenbufen at dosage of 100 mg/kg in mice (i.p.)).

Phytochemistry, 1996 May, 42(2), 427 - 30
Phaeophytins from a cell suspension culture of the liverwort Plagiochila ovalifolia; Matsuo A et al.; A suspension culture of the liverwort Plagiochila ovalifolia was established from callus tissue induced by culturing spores . From the cultured cells, four phaeophytins were isolated as major components and their structures determined by spectroscopic methods . The phaeophytin derivatives showed antibacterial activity . A major sesquiterpenoid, ovalifoliene, found in the mother plant, was detected in the cultures by GC-mass spectrometry.

J Antibiot (Tokyo), 1996 May, 49(5), 465 - 77
3-Keto-11,12-carbazate derivatives of 6-O-methylerythromycin A synthesis and in vitro activity; Griesgraber G et al.; The 11,12-cyclic carbazate of 3-keto-6-O-methylerythromycin A (4) was prepared . This compound shows in vitro antibacterial activity comparable to erythromycin A (1) against erythromycin-susceptible organisms and increased activity against some erythromycin-resistant organisms . Using 4 as a lead, a series of analogues was prepared by acylation or alkylation of the carbazate nitrogen . Several of the N-alkylated derivatives showed dramatically improved antibacterial activity against both susceptible and resistant organisms as compared to erythromycin A.

J Antibiot (Tokyo), 1996 May, 49(5), 458 - 64
Enzymatic 2'-N-acetylation of arbekacin and antibiotic activity of its product; Hotta K et al.; Aminoglycoside antibiotics (AGs) with a free 2'-amino group were subjected to enzymatic N-acetylation using a cell free extract that contained an aminoglycoside 2'-N-acetyltransferase, AAC (2'), derived from a kasugamycin-producing strain of Streptomyces kasugaensis . TLC and antibiotic assay of the incubated reaction mixtures revealed that a modified compound retaining substantial antibiotic activity was formed from arbekacin (ABK), while modification of the other AGs resulted in the marked decrease in antibiotic activity . Structure determination following isolation from a large scale reaction mixture showed the modified ABK to be 2'-N-acetyl ABK . In addition, 2',6'-di-N-acetyl ABK was formed as a minor product . The same conversion also occurred with dibekacin (DKB) resulting in the formation of 2'-N-acetyl DKB and 2',6'-di-N-acetyl DKB . MIC determination showed antibacterial activity (1.56 approximately 3.13 micrograms/ml) of 2'-N-acetyl ABK against a variety of organisms . By contrast, 2'-N-acetyl DKB showed no substantial antibiotic activity . We believe 2'-N-acetyl ABK has the highest and broadest antibacterial activity, compared with known N-acetylated AGs.

Cancer Immunol Immunother, 1996 May, 42(4), 251 - 4
Effects of ifosfamide on immunocompetent effector cells; Multhoff G et al.; We analyzed the effects of ifosfamide, a chemotherapeutic agent that is broadly used within anticancer therapy, on immunocompetent effector cell subpopulations . For our in vitro studies we used 4-hydroperoxyifosfamide (4-OOH-IF), which rapidly gives rise to 4-OH-IF, the activated form of ifosfamide . Activated cytotoxic T lymphocytes and natural killer (NK) cells were used because of their antitumor activity and their antiviral or antibacterial activity . Our study demonstrated three major findings . (1) The capacity of cytotoxic T cells to lyse their specific target cells was substantially reduced by 4-OH-IF treatment . This inhibition of the lytic activity could be correlated with a substantial depletion of the intracellular glutathione (GSH) levels . A rapid reconstitution of the depleted GSH levels and of the cytotoxic activity was achieved by incubation of the T cells with thiols such as mercaptoethanesulfonate (mesna) . (2) In contrast to T cells the lytic activity of NK cells was not substantially affected by 4-OH-IF treatment; this increased resistance of NK cells against 4-OH-IF treatment could be explained by their higher initial GSH levels and by their higher rate of GSH synthesis . Furthermore, we demonstrated that (3) NK cells, but not T cells, have the capacity to take up cystine, the oxidized form of cysteine, from the medium . In conclusion we can state that NK cells are much more resistant to ifosfamide treatment compared to T cells with respect to intracellular GSH levels and cytotoxic activity.

Z Naturforsch {C}, 1996 May-Jun, 51(5-6), 277 - 80
Antibacterial diterpenic acids from Brazilian propolis; Bankova V et al.; Four labdane-type diterpenic acids and syringaldehyde were isolated and identified from Brazilian propolis . All the compounds exhibit antibacterial activity . The diterpenes, found for the first time in propolis, are typical for some Araucaria species and thus indicate a possible plant source of Brazilian propolis.

J Med Microbiol, 1996 May, 44(5), 320 - 4
Quinolones: structure-activity relationships and future predictions; Tillotson GS; Development of the first clinically useful quinolone--nalidixic acid-- occurred in 1962, but the significant breakthrough with this class of agents occurred almost 20 years after the original discovery when the addition of a fluorine molecule at position C6 of the pharmacore created the 'fluoroquinolones' . It has been estimated that over 10000 analogues of nalidixic acid or the fluoroquinolones have now been synthesised . The benefits of some of these new compounds include: oral and parenteral dosing, a much broader spectrum of antibacterial activity, good tissue distribution, improved pharmacokinetic profiles, stability and a comparatively low incidence of adverse effects . This review considers the structure of the core fluoroquinolone molecule, some of the changes that feature on current class members under development, and the effects that these chemical modifications may have on the interaction of these compounds with man.

J Cell Physiol, 1996 May, 167(2), 359 - 68
Minocycline impairment of both osteoid tissue removal and osteoclastic resorption in a synchronized model of remodeling in the rat; Klapisz-Wolikow M et al.; In addition to their antibacterial effects, tetracyclines may inhibit interstitial collagenase activity and bone resorption . These properties were assessed morphometrically using minocycline (25 and 50 mg/kg/day given by the IM route) in a rat model of synchronized remodeling in which osteoclastic resorption peaks 4 days after the activating event (the extractions of the upper molars) along the antagonist mandibular cortex, a zone undergoing physiologically active formation . During the first 2 days of activation, minocycline at the two doses impaired very significantly the disorganization of both the osteoid seam and the layer of osteoblasts, a prerequisite to give osteoclasts access to the mineralized bone surface . The number of readily identifiable osteoblasts decreased slightly during this period, suggesting that minocycline prevented their transformation into lining cells . Their synthetic activity, as estimated by the size of the cells and their nucleus, appeared relatively preserved too, mostly with the higher dose . AT the peak of osteoclasia, the bone surfaces undergoing remodeling were significantly decreased in the minocycline-treated groups . The resorption surface was reduced (P < 0.0003) as well as the number of osteoclasts (P < 0.0007), which were also significantly smaller . Their resorbing activity was dramatically affected as well: they excavated lacunae whose area was significantly reduced by over 70% . In addition, formation was still a prominent activity in the treated animals . These data are compatible with the inhibition at the early stages of activation of an osteoblast-secreted collagenase whose action may be the elimination of the osteoid seam . The inhibition of an osteoclast collagenase and/or of a bone matrix bound-collagenase may be responsible for the reduction in lacunar size . A direct effect of minocycline on osteoclast resorptive activity may also participate in the low resorption profile, as tetracyclines are known to interfere with the intracellular {Ca2+}.

FEBS Lett, 1996 Apr 29, 385(1-2), 96 - 100
Shortened amoebapore analogs with enhanced antibacterial and cytolytic activity; Andra J et al.; Amoebapores are cytolytic peptides of Entamoeba histolytica which function by the formation of ion channels in target cell membranes . Three isoforms (amoebapore A, B, and C) exist in amoebic cytoplasmic granules . They are composed of 77 amino acid residues arranged in four alpha-helical domains . In order to analyze the structure-function relationships, 15 synthetic peptides of 24-25 residues were constructed based on the assumption that the third helix is the membrane-penetrating domain and on the previous finding that positively charged residues are significant for activity . Activity of these short versions of amoebapores was determined towards artificial and natural targets, such as liposomes, bacteria, erythrocytes and a human tumor cell line . It was found that some of the novel peptides were highly active and showed a broader activity spectrum compared to the parent molecules.

J Biol Chem, 1996 Apr 26, 271(17), 10116 - 20
NK-lysin, a disulfide-containing effector peptide of T-lymphocytes, is reduced and inactivated by human thioredoxin reductase . Implication for a protective mechanism against NK-lysin cytotoxicity; Andersson M et al.; The cytotoxic and antibacterial polypeptide NK-lysin has a molecular mass of approximately 9 kDa and contains three disulfide bonds . The activity was highly dependent on intact disulfides, because the bactericidal effect on Escherichia coli and the cytolytic effect on human 3B6 lymphocytes was inhibited when NK-lysin was treated with dithiothreitol prior to incubation with the cells . NK-lysin was a direct substrate for human or calf thymus thioredoxin reductase and preincubation of the peptide with mammalian thioredoxin reductase, and NADPH abolished its antibacterial and cytolytic activities . The addition of human thioredoxin further enhanced the inhibitory effect of thioredoxin reductase and NADPH . In contrast, e . coli thioredoxin reductase showed no direct disulfide reductase activity with NK-lysin in agreement with previous data showing large differences in structure and substrate specificity between the mammalian and E . coli enzymes . NK-lysin is the first identified macromolecular disulfide substrate for human thioredoxin reductase apart from human thioredoxin . When 3B6 cells were incubated with NADPH, thioredoxin, and thioredoxin reductase prior to addition of NK-lysin, cytotoxicity was markedly reduced . These data suggest that thioredoxin reductase inactivates NK-lysin and provides a mechanism by which the cytotoxic activity of NK-lysin is regulated.

Biochemistry, 1996 Apr 16, 35(15), 5083 - 92
The interaction of coumarin antibiotics with fragments of DNA gyrase B protein; Gormley NA et al.; DNA gyrase is the target of the coumarin group of antibacterial agents . The drugs are known to inhibit the ATPase activity of gyrase and bind to the 24-kDa N-terminal subdomain of gyrase B protein . Supercoiling assays with intact DNA gyrase and ATPase assays with a 43-kDa N-terminal fragment of the B protein suggest that the drugs bind tightly, with Kd values <10(-7) M . In addition, the ATPase data suggest that 1 coumermycin molecule interacts with 2 molecules of the 43-kDa protein while the other coumarins form a 1:1 complex . This result is confirmed by cross-linking experiments . Rapid gel-filtration experiments show that the binding of ADPNP(5'-adneylyl beta,gamm-imidodiphosphate) and coumarins to the 43-kDa protein is mutally exclusive, consistent with a competitive mode of action for the drugs . Rapid gel-filtration binding experiments using both the 24-and 43-kDa proteins also show that the drugs bind with association rate constants of >10(5) M-1.s-1, and dissociation rate constants of approximately 3x10(-3)s-1 and approximately 4x10(-3)s-1 for the 43-and 24-kDa proteins, respectively . Titration calorimetry shows that the Kd values for coumarins binding to both proteins are approximately 10-8M and that binding is enthalpy driven.

Vet Rec, 1996 Apr 6, 138(14), 320 - 3
Assessment of the effect of three treatments to remove intrauterine fluid on pregnancy rate in the mare; Pycock JF et al.; The effects on pregnancy rate of three different treatments to remove intrauterine fluid were assessed in 1267 mares . The mares were mated and allocated, in strict rotation, to four treatment groups: 1) untreated controls, 2) intrauterine infusion of broad spectrum antibiotics, 3) intravenous injection of oxytocin, 4) intravenous injection of oxytocin followed by intrauterine antibiotics . The pregnancy status of the mares was determined 13 to 15 days and 27 to 30 days after ovulation by transrectal ultrasonography . The pregnancy rate of group 4 (72 per cent) was higher than that of group 2 (64 per cent, P < 0.01) or group 3 (63 per cent, P < 0.01) . The pregnancy rates of groups 2 and 3 were higher than that of group 1 (56 per cent, P < 0.01) . The treatment with antibiotics and oxytocin appeared to have an additive beneficial effect which suggested two different modes of action of the combination treatment, namely antibacterial activity and fluid drainage . In the untreated mares more fluid accumulated in the uterine lumen after mating, and this was the most likely reason for their lower pregnancy rate.

Antibiot Khimioter, 1996 Apr, 41(4), 30 - 5
{Erysipelothrix rhusiopathiae: plasmids, resistance to antibacterial drugs}; Pomerantsev AP et al.; The plasmid profile, virulence and antibacterial drug susceptibility of various strains of E . rhusiopathiae were determined . No correlations between the virulence of the strains, their antibiotic resistance and the plasmid content were detected . Structural and functional analysis of one of the isolated plasmids was carried out to use the plasmid as a vector in the genetic study of E . rhusiopathiae.

Spinal Cord, 1996 Apr, 34(4), 243 - 6
T-cell predominant balanitis in a traumatic tetraplegic patient: a case report; Van Velzen D et al.; T-cell predominant balanitis is described in a 38 year old uncircumcised tetraplegic man whose presenting feature was non-progressive red lesions over the inner prepuce and the glans penis without signs of infection, phimosis, or meatal stenosis . There was no regional lymphadenopathy . He was not exposed to any of the high risk factors for human immunodeficiency virus infection . As the lesion did not respond to topical antibacterial, antifungal, and corticosteroid medications applied in that order, circumcision was performed . Following circumcision, the remaining lesion over the glans penis regressed completely over a period of 1 month . Histopathology of the excised prepuce revealed that both areas of normal nonkeratinizing squamous epithelium as well as areas with hyperplasia . No atypia was noted and Bowenoid changes were not seen . Immunohistochemical studies on the inflammatory infiltrate in the excised prepucial lesion using tissue proliferation markers (PCNA and MIB-1) revealed active proliferation of the band-like infiltrate shown by immunophenotyping (anti-human T cell, CD45RO, clone UCHL1 and L26, pan-B marker) to consist predominantly of T-cells, further supporting the hypothesis of a local immune-mediated inflammatory process as the final pathogenic mechanism of the penile lesion.

Trends Biotechnol, 1996 Apr, 14(4), 134 - 40
New targets and strategies for the development of antibacterial agents; Desnottes JF; The increasing incidence of bacterial drug-resistance is stimulating the development of strategies targeting previously unexploited mechanisms of antibiotic action . Combinatorial chemistry, which generates molecularly diverse compounds, target-directed strategies, and high-throughput screens are being used to detect potential antibacterial agents . Bacterial DNA replication and cell division are the targets of new screening methods, as are membrane proteins, particularly those constituting efflux pumps; two-component signalling systems are also being targeted . Secondary-screening methods are being developed to find antibiotics that destroy slowly growing or resting bacteria, and to evaluate whether new antibiotics will be active against intracellular bacteria.

Med Parazitol (Mosk), 1996 Apr-Jun, (2), 3 - 8
{Antibacterial therapy as a means of preventing ixodid tick-borne borreliosis}; Korenberg EI et al.; A special epidemiological experiment to prevent borreliosis in persons bitten by infected ticks was performed in 1992-1994 in the Russia's Perm region where Borrelia garinii and B.afzelii circulate, and Ixodes persulcatus tick is the sole vector transmitting these pathogens to human beings . Adult ticks were removed from the bodies of persons who had referred to health facilities for first aid . Vital preparations were made from the material obtained from the gut of each tick and examined microscopically (up to 250 microscopic fields per preparation) . The patients bitten by infected ticks were divided into experimental and control groups and kept under special medical and serological control for 4-5 months . The patients of the experimental group received doxycycline (100 mg twice daily) for 3-5 days after ticks had bitten . Borreliosis was diagnosed by a combination of clinical and serological data . The control group consisted of 97 patients who took no antibiotics after ticks biting and 12 of them contracted borreliosis . In 823 cases Borrelia were not revealed while microscopically analyzing the ticks removed from the patients' bodies; in this group six patients contracted borreliosis . The morbidity rate (per 100 patients) in the experimental group was 1.1, i.e . 11 times lower than that in control group . Among the patients bitten by infected ticks and untreated with antibiotics, this index was 17.6 times higher than in the group bitten by ticks in which Borrelia were not found . There is no absolute probability of detecting the pathogen during a direct microscopic analysis of the preparation made from the tick removed from the body of a bitten patient . However, this rapid identification of Borrelia, followed by short-term antibiotic treatment for microbiological evidence is an effective tool for preventing patients from contracting borrelioses.

Insect Biochem Mol Biol, 1996 Apr, 26(4), 395 - 402
Cloning and characterization of cDNAs encoding the antibacterial peptide, defensin A, from the mosquito, Aedes aegypti; Cho WL et al.; Insect defensins are cationic, inducible antibacterial peptides . Four full-length cDNAs encoding defensin A from the mosquito Aedes aegypti were cloned using polymerase chain reaction (PCR) and sequenced . All four cDNAs are 473 base pairs long, bearing an open reading frame of 98 amino acids with a few substitutions in the signal peptide domain . The deduced amino acid sequence of Aedes aegypti defensin (AaDef) contains a signal peptide sequence of 18 amino acids followed by a 40-amino acid putative propeptide domain and a 40-amino acid mature peptide domain . The mature peptide, with a predicted M(r) of 4148, shows 80% identity and 93% similarity to Phormia defensin A, and is identical to the peptide sequencing data for mosquito defensin A of Lowenberger et al . (1995) and B of Chalk et al . (1995) . There are three potential phosphorylation sites but no glycosylation sites detected in AaDef . Three putative disulfide linkages between cysteines, characteristic of insect defensins, are conserved in AaDef . Aedes aegypti defensin mRNA is produced in response to a bacterial challenge; it is dramatically enhanced 6 h after bacterial injection, continues to increase through 24 h, and is maintained at high levels until at least 30 h post-bacterial injection.

Insect Biochem Mol Biol, 1996 Apr, 26(4), 389 - 94
L-homoarginine studies provide insight into the antimetabolic properties of L-canavanine; Rosenthal GA et al.; A method for the chemical synthesis of L-homoarginine, based on the guanidination of L-lysine with O-methylisourea, has been developed; this procedure provides radiochemically pure L-{guanidino-14C}homoarginine in high yield . Radiolabeled homoarginine is incorporated readily into the newly synthesized hemolymphic proteins of larvae of the tobacco hornworm, Manduca sexta without adversely affecting larval growth and development . This finding stands in sharp contrast to the effect of L-canavanine, another L-arginine analog, which is markedly deleterious to these larvae . Homoarginine is incorporated into M . sexta lysozyme, and the antibacterial proteins of the fly, Phormia terranovae with impunity . In contrast, the comparable canavanine-containing enzymes are inhibited severely . Experimental evidence is presented that the innocuous nature of homoarginine results from the elevated pKa value of its guanidino group which arguably exceeds even that of arginine . As a result, homoarginine does not disrupt essential residue interactions . In contrast canavanine, which is much less basic than arginine, does adversely affect R group interactions forming the requisite three-dimensional conformation of the protein.

J Comput Aided Mol Des, 1996 Apr, 10(2), 107 - 22
On the electrostatic and steric similarity of lactam compounds and the natural substrate for bacterial cell-wall biosynthesis; Frau J et al.; Electrostatic and structural properties of a set of beta-lactam, gamma-lactam and nonlactam compounds have been analyzed and compared with those of a model of the natural substrate D-alanyl-D-alanine for the carboxy- and transpeptidase enzymes . This first comparison of the electrostatic properties has been based on a distributed multipole analysis of high-quality ab initio wave functions of the substrate and potential antibiotics . The electrostatic similarity of the substrate and active compounds is apparent, and contrasts with the electrostatic properties of the noninhibitors . This has been quantified to give a reasonable correlation with the MIC (Minimum Concentration for Inhibition) and with kinetic data (k2/K) in accordance with the model for interaction of the lactam compounds with DD-peptidase . These correlations provide a better prediction of antibacterial activity than purely structural criteria.

FEMS Immunol Med Microbiol, 1996 Apr, 13(4), 273 - 7
Inhibition of Helicobacter pylori by garlic extract (Allium sativum); Cellini L et al.; The antibacterial effect of aqueous garlic extract (AGE) was investigated against Helicobacter pylori . Sixteen clinical isolates and three reference strains of H . pylori were studied . Two different varieties of garlic were used . The concentration of AGE required to inhibit the bacterial growth was between 2-5 mg ml-1 . The concentration, for both AGE types, to inhibit 90% (MIC90) of isolates was 5 mg ml-1 . The minimum bactericidal concentration (MBC) was usually equal to, or two-fold higher than, minimum inhibitory concentration (MIC) . Heat treatment of extracts reduced the inhibitory or bactericidal activity against H . pylori; the boiled garlic extract showed a loss of efficacy from two- to four-fold the values of MIC and the MBC obtained with fresh AGE . The antibacterial activity of garlic was also studied after combination with a proton pump-inhibitor (omeprazole) in a ratio of 250:1 . A synergistic effect was found in 47% of strains studied; an antagonistic effect was not observed.

Soc Sci Med, 1996 Apr, 42(8), 1133 - 9
Drug prescribing practices of general practitioners and paediatricians for childhood diarrhoea in Karachi, Pakistan; Nizami SQ et al.; Observations were made of 996 encounters between children with diarrhoea and practitioners (28 paediatricians, 62 general practitioners) in Karachi, Pakistan . Oral rehydration salt (ORS) was prescribed in more than 50% of encounters by 53% of general practitioners (GPs) and 61% of paediatricians . Sixty-six percent of GPs and 50% of paediatricians prescribed antibacterials, 60% of GPs and 28% of paediatricians prescribed antidiarrhoeals and 39% of GPs and 32% of paediatricians prescribed antiamoebics in more than 30% of their encounters . Looking at all the encounters, we observed that ORS was prescribed in 52 and 51%, antibacterials in 41 and 36%, antidiarrhoeals in 48 and 29%, and antiamoebics in 26 and 22% of encounters by GPs and paediatricians, respectively, Cotrimoxazole was the most frequently prescribed antibacterial by both types of practitioners . Antidiarrhoeals were prescribed more often by GPs than by paediatricians . In 77% of their encounters, GPs dispensed drug formulations known as "mixtures' made in their own dispensing corners . The mean duration of encounters between patients and GPs was 3 +/- 2 minutes and between patients and paediatricians was 9 +/- 4 minutes . These results indicate inadequate prescription of ORS and excessive prescription of antibacterials, antidiarrhoeals and antiamoebics . Intervention strategies need to be planned to improve the prescribing practices of both groups.

Bioorg Med Chem, 1996 Apr, 4(4), 593 - 602
Pyrrolo{2,3-d}pyrimidines and pyrido{2,3-d}pyrimidines as conformationally restricted analogues of the antibacterial agent trimethoprim; Kuyper LF et al.; Conformationally restricted analogues of the antibacterial agent trimethoprim (TMP) were designed to mimic the conformation of drug observed in its complex with bacterial dihydrofolate reductase (DHFR) . This conformation of TMP was achieved by linking the 4-amino function to the methylene group by one- and two-carbon bridges . A pyrrolo{2,3-d}pyrimidine, a dihydro analogue, and a tetrahydropyrido{2,3-d}pyrimidine were synthesized and tested as inhibitors of DHFR . One analogue showed activity equivalent to that of TMP against DHFR from three species of bacteria . An X-ray crystal structure of this inhibitor bound to Escherichia coli DHFR was determined to evaluate the structural consequences of the conformational restriction.

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