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 an