J Nat Prod, 1999 Jul, 62(7), 954 - 8 Biological evaluation of proanthocyanidin dimers and related polyphenols; De Bruyne T et al.; A series of dimeric procyanidins (1-9) and some related polyphenols (10-15) were chosen as model compounds in a comparative investigation for various biological activities in order to obtain structure-activity relationships . Antiviral {herpes simplex virus (HSV) and human immunodeficiency virus (HIV)}, antibacterial, superoxide radical-scavenging, and complement-modulating properties were assessed . In general, more pronounced activities were seen with epicatechin-containing dimers for anti-HSV, anti-HIV, and radical-scavenging effects, while the presence of ortho-trihydroxyl groups in the B-ring was important in compounds exhibiting anti-HSV and radical-scavenging effects and complement classical pathway inhibition . Double interflavan linkages gave rise to interesting antiviral effects (HSV and HIV) and complement inhibition . The influence of the degree of polymerization or the type of interflavan linkage (4-->6 or 4-->8) differed in the different biological systems evaluated . Only minor or moderate antibacterial effects were observed for the compounds under investigation. Graefes Arch Clin Exp Ophthalmol, 1999 Jul, 237(7), 546 - 53 Quality of salivary tears following autologous submandibular gland transplantation for severe dry eye; Geerling G et al.; BACKGROUND: This study aimed to characterise the composition of the pre-ocular fluid after transplantation of the autologous submandibular gland (SMG) for patients with severe dry eye . METHODS: Stimulated and unstimulated pre-ocular fluid from 15 patients (17 eyes) with a viable SMG graft ("SMG-salivary tears"), as well as normal tears and SMG saliva (20 normal subjects/20 eyes), was sampled . As global tear parameters, fern pattern analysis and SDS gel electrophoresis were performed . As specific quality parameters, total protein content, secretory immunoglobulin A (SIgA), lysozyme, amylase, sodium, potassium and osmolality were measured using routine laboratory methods . The flow rate of SMG-salivary tears was determined in 5 patients by means of sequential scintillography . RESULTS: The fern pattern of SMG-salivary tears was coarse and thus more similar to normal SMG saliva than tears . SDS gel electrophoresis of the SMG-salivary tears showed albumin and two unidentified proteins in addition to the normal tear pattern . Osmolality and total protein content of SMG-salivary tears were higher than in normal SMG saliva, but still lower than in normal tears . High activities of normal tear antibacterial proteins (SIgA, lysozyme and amylase) were detected in the salivary tears . Stimulation of the secretion did not alter the composition of SMG-salivary tears . The flow rate of SMG-salivary tears was closer to that of normal tears than normal SMG saliva . CONCLUSION: Salivary tears resulting from SMG-transplantation represent condensed SMG saliva . Thus their quality is intermediate between normal tears and normal SMG saliva . High levels of secretory proteins demonstrate that the gland maintains an active function . Surgical denervation and residual tear components from the ocular surface are the most likely factors to cause the complex differences between normal SMG saliva and SMG-salivary tears . The effects of this secretion on the ocular surface are currently being evaluated in a clinical and laboratory study. Lik Sprava, 1999 Mar, (2), 80 - 2 {The rational antibacterial therapy of patients with infectious prostatitis}; Martynenko AV; The paper is concerned with the problem of treatment of chronic infectious prostatitis . It is really a problem of today taking into account that it is most prevalent and difficult to deal with . Groups of drugs to be used for treatment are offered together with rational treatment schemes and drug routes . A treatment scheme is described for the most prevalent complication dysbacteriosis. Antibiot Khimioter, 1999, 44(6), 27 - 32 {Prevention and treatment of postoperative pyoinflammatory complications and cefuroxime}; Bogomolova NS et al.; Antibacterial activity and efficacy of cefuroxime (ketocef, Pliva, Zagreb) in the treatment and prophylaxis of surgical infections in a general hospital and particularly in the unit of vessel and aorta surgery, the unit of lung surgery and the unit of microsurgery were estimated . The study included 57 patients (43 males and 14 females) at the age of 21 to 70 years . Cefuroxime was administered intravenously in a dose of 1.5 g followed by its intramuscular administration in a dose of 750 mg with an interval of 8 hours . The results showed that cefuroxime was effective in the treatment (80 per cent) and prophylaxis (93.6 per cent) of the pyo-inflammatory complications and was active against the majority of the surgical infection pathogens. Boll Chim Farm, 1999 Apr, 138(4), 186 - 90 Antibacterials: spontaneous report analysis for a six years period in Bulgaria; Getov I et al.; The pharmacovigilance started in Bulgaria in 1975 . The doctors had to send the filled so called "yellow cards" for the suspected Adverse Drug Reactions to the Centre for Drug Safety at the National Drug Institute . In Bulgaria a spontaneous reporting on the adverse drug reactions has been studied during the period 1991-1996 for Antibacterials . The total number of the reports was 2409 and 18% of this number related to the Antibacterials . The reporting rate varied from 0.3 to 1.8 per 100,000 inhabitancy . As a whole 29% of the adverse drug reaction reports concerned the patients in the age groups of 0-5 year old . Amoxicillin is a drug with a majority of reports for the period . This article reveals the limits of the operating spontaneous reporting system in Bulgaria and suggests some possible measures to improve and refine it in a connection to the WHO and EMEA requirements. Arch Insect Biochem Physiol, 1999, 41(4), 178 - 85 Cecropin D-like antibacterial peptides from the sphingid moth, Agrius convolvuli; Lee IH et al.; Two major antibacterial peptides were isolated and purified from immunized larval hemolymph of Agrius convolvuli . Acid extraction, gel filtration, ultrafiltration, and reversed-phase FPLC were used for purification of peptides . These peptides had similar molecular mass and amino acid composition . Moreover, 21 of the first 23 N terminal residues were identical . The peptides were highly homologous with cecropin D in size and primary sequence, and named Agrius cecropin D1 and D2 . The molecular masses of Agrius cecropin D1 and D2 were 3,879.39 and 3,839.27, respectively . In antibacterial and hemolytic assays, Agrius cecropin D showed potent antibacterial activities against a panel of Gram positive and negative bacteria without hemolytic activity against human red blood cells . Notably, our antibacterial assay revealed Agrius cecropin D possessed stronger or at least equivalent activities against B . megaterium than cecropin A . It suggests that Agrius cecropin D, which has an alternative structure from cecropin D, could be the model for the development of peptide antibiotics . Arch . J Food Prot, 1999 Jul, 62(7), 747 - 50 Antibacterial effect of lactoferricin B on Escherichia coli O157:H7 in ground beef; Venkitanarayanan KS et al.; The antibacterial activity of lactoferricin B on enterohemorrhagic Escherichia coli O157:H7 in 1% peptone medium and ground beef was studied at 4 and 10 degrees C . In 1% peptone medium, 50 and 100 microg of lactoferricin B per ml reduced E . coli O157:H7 populations by approximately 0.7 and 2.0 log CFU/ml, respectively . Studies comparing the antibacterial effect of lactoferricin B on E . coli O157:H7 in 1% peptone at pH 5.5 and 7.2 did not reveal any significant difference (P > 0.5) at the two pH values . Lactoferricin B (100 microg/g) reduced E . coli O157:H7 population in ground beef by about 0.8 log CFU/g (P < 0.05) . No significant difference (P > 0.5) was observed in the total plate count between treatment and control ground beef samples stored at 4 and 10 degrees C . The antibacterial effect of lactoferricin B on E . coli O157:H7 observed in this study is not of sufficient magnitude to merit its use in ground beef for controlling the pathogen. Lab Invest, 1999 Jul, 79(7), 807 - 13 Salicylate attenuates gentamicin-induced ototoxicity; Sha SH et al.; Aminoglycosides, primarily gentamicin, are the most commonly used antibiotics worldwide despite their toxicity to the kidney and the inner ear . A preventive therapy against these side effects should combine safety and efficacy with low cost because aminoglycoside-induced deafness is most prevalent in developing countries . We have previously shown that aminoglycosides catalyze the formation of free radicals in an iron-dependent reaction and have delineated the structure of an iron-gentamicin complex . Here we demonstrate that 2-hydroxybenzoate (salicylate), which can act as an iron chelator and antioxidant, effectively protects against gentamicin-induced hearing loss in guinea pigs . Co-therapy with salicylate reduced a profound gentamicin-induced auditory threshold shift of more than 60 dB to less than 20 dB . Morphological assessment of the inner ear confirmed protection of auditory sensory cells . Salicylate altered neither serum levels of gentamicin nor its antibacterial efficacy . Because the required salicylate levels correspond to anti-inflammatory levels in humans, this treatment holds promise for clinical application. Chirurg, 1999 May, 70(5), 566 - 70 {Use of pedicled greater omentum-plasty as thoraco-abdominal defect repair following extensive tumor resection}; Maiwald G et al.; Patients suffering from long-untreated malignomas of the chest or abdominal wall may require plastic surgery due to extensive defects after tumor resection . Despite a variety of pedicled or free myocutaneous flaps, there are defects in which these reconstructional options may not be indicated . In these patients, the omental flaps are a valid alternative . Since a secondary split skin graft is mandatory with the omentum flap, antibacterial and granulation-enhancing xerodressings are required for wound bed conditioning . We report one patient in whom the omentum flap was used for coverage of an extensive defect after resection of a widespread basal cell carcinoma at the lateral thorax and abdominal wall . After wound conditioning with silver-impregnated activated charcoal xerodressing (Actisorb) in combination with a hydroactive polymer dressing (Allevyn), secondary skin grafting was performed . In this patient fibrosis and calcification of the omentum led to stable abdominal wall coverage even without the application of a synthetic mesh. An Acad Bras Cienc, 1999, 71(2), 207 - 13 Pharmacological effects of essential oils of plants of the northeast of Brazil; Leal-Cardoso JH et al.; The authors have reviewed the pharmacological studies done with essential oils obtained in the state of Ceara, in Northeast of Brazil, from 15 species of aromatic plants, some of which are native to the phytogeographic semiarid region characteristic of the Northeast, the "caatingas" . These studies have dealt with the effect of these oils on muscle contraction and with their antispasmodic, analgesic, antiinflammatory, anticonvulsant and antibacterial activity . The essential oils of the medicinal species have shown activity coherent with the use of these plants in folk medicine . The review is aimed primarily at summarizing the information relevant for a critical evaluation of the perspectives and potential of these oils as pharmacological and therapeutic agents. RNA, 1999 Jul, 5(7), 939 - 46 Ribosomal RNA is the target for oxazolidinones, a novel class of translational inhibitors; Matassova NB et al.; Oxazolidinones are antibacterial agents that act primarily against gram-positive bacteria by inhibiting protein synthesis . The binding of oxazolidinones to 70S ribosomes from Escherichia coli was studied by both UV-induced cross-linking using an azido derivative of oxazolidinone and chemical footprinting using dimethyl sulphate . Oxazolidinone binding sites were found on both 30S and 50S subunits, rRNA being the only target . On 16S rRNA, an oxazolidinone footprint was found at A864 in the central domain . 23S rRNA residues involved in oxazolidinone binding were U2113, A2114, U2118, A2119, and C2153, all in domain V . This region is close to the binding site of protein L1 and of the 3' end of tRNA in the E site . The mechanism of action of oxazolidinones in vitro was examined in a purified translation system from E . coli using natural mRNA . The rate of elongation reaction of translation was decreased, most probably because of an inhibition of tRNA translocation, and the length of nascent peptide chains was strongly reduced . Both binding sites and mode of action of oxazolidinones are unique among the antibiotics known to act on the ribosome. Pol Arch Med Wewn, 1998 Nov, 100(5), 437 - 41 {Antibacterial treatment in patients after extended bowel resection with ileo-cecal valve removal--personal experience}; Paluszkiewicz P et al.; Small bowel infection in patients that underwent extensional bowel resection is one of causal mechanisms of massive diarrhoea in postoperative period . The aim of this study was to investigate clinical importance of ciprofloxacin efficacy in treatment of massive diarrhoea in patients after extensional bowel resection with removing of ileo-coecal valve (EBR + ICVR) . From group of 21 patients that underwent EBR + ICVR the postoperative period survived only 11 . In 9 cases massive diarrhoea and sepsis was observed . Routinely applied three-drugs antibacterial therapy based on penicillin or first-generation cephalosporin, aminoglycoside and metronidazole was efficient in 18% of patients only . The ciprofloxacin was used as a second-shot therapy in patients which did not realt on routine three-drugs antibacterial management . In all cases the clinical efficacy was observed as recessing of diarrhoea and septic symptoms . On the basis of our experience we suggest that in patients with massive diarrhea due to ascending contamination of small bowel after extensive resection with removal of ileo-coecal valve, ciprofloxacine is the treatment of choice. Khirurgiia (Mosk), 1999, (6), 4 - 9 {Infection in burn patients: the problems of pathogenesis, prevention and treatment}; Alekseev AA et al.; Urgent issues of pathogenesis, prophylaxis and treatment of infection in patients with thermal injuries are considered . Analysis of the results of multifactorial dynamic examinations of immunological reactivity and nonspecific resistance of 198 burnet patients is presented . For the first time a substantial decrease of B-lymphocytes count in normal or elevated level of immunoglobulins of the main classes is shown as well as a decrease in plasma fibronectin content . Lowering of T-lymphocytes content and polymorphonuclear leucocytes function disturbances, dominant role of St . aureus and P . aeruginosa in etiology of infections in burnt patients and high antibiotic resistance of these microorganisms are demonstrated . Pathogenetic substantiation of combined therapeutic usage of thymus and interferon preparations and when indicated--immunoglobulines is recorded . Positive experience in application of recombinant interleukine-2 (Ronkoleukine) is outlined . The data are provided on advisability of application of new cephalosporines and fluorine-quinolones for antibiotic therapy and prophylaxis in the burnet . In complicated forms of gram-negative infections the combination of aminoglycosides with ureidopenicillines or cyprofloxacine is recommended, in infections provoked by polyresistant strains of S . aureus vancomycin is indicated . With prophylactic aim in case of early surgical treatment it is recommended to apply modern antibacterial preparations with broad spectrum of action . Prophylaxis of hospital infections inpatients of specialised clinics for the burnt is discussed. Eur J Biochem, 1999 Jul, 263(2), 447 - 54 Biosynthesis of bitter acids in hops . A (13)C-NMR and (2)H-NMR study on the building blocks of humulone; Goese M et al.; The biosynthesis of humulone, an antibacterial bitter acid from hops, was studied by isotope-incorporation experiments using (13)C-labelled glucose or (2)H(2)O . (13)C enrichments, (2)H enrichments and (13)C(13)C coupling patterns identify isovaleryl-CoA, malonyl-CoA and dimethylallyl pyrophosphate as precursors for humulone . Dimethylallyl pyrophosphate, which serves as a building block for the bitter acid, is generated via the deoxyxylulose pathway of terpenoid biosynthesis . The data confirm that a symmetrical intermediate is involved in humulone formation. Bioorg Med Chem Lett, 1999 Jul 5, 9(13), 1847 - 52 Synthesis and antibacterial properties of beta-diketone acrylate bioisosteres of pseudomonic acid A; Bennett I et al.; A series of beta-diketone acrylate bioisosteres 4 of pseudomonic acid A 1 have been synthesized and evaluated for their ability to inhibit bacterial isoleucyl-tRNA synthetase and act as antibacterial agents . A number of analogues have excellent antibacterial activity . Selected examples were shown to afford good blood levels and to be effective in a murine infection model. Lepr Rev, 1999 Mar, 70(1), 78 - 84 Disease and disease control . International Leprosy Congress, Beijing, 7-12 September 1998 . Workshop report; Smith WC; Four workshops were conducted during the congress under the disease control theme . The workshops were on the issues of defining disease and antibacterial therapy, early case detection, sustaining leprosy control in low endemic situations, and the prevention of disability . These workshops spanned the spectrum of disease and its consequences through from early detection, the definition of disease to the prevention of disability . All of these topics being important contemporary issues challenging leprosy control programmes world wide . Despite the broad spectrum of the topics it was interesting to see that a number of important themes emerged which were common to all topics . It is possible to identify five major themes arising from the output of the workshops which are now described below . Each of the workshops adopted broad and comprehensive approaches to their topic . In the past, there has been narrowness in defining disease in terms of the need for chemotherapy . The approach taken in the workshop now is for a much more comprehensive approach looking at all the consequences of the disease process rather than the requirement for antibacterial chemotherapy . Similarly broad approaches were taken to low endemic situations, considering comprehensive approaches which are inclusive rather than exclusive . Disability prevention also continues this same theme of comprehensive approaches based on multidisciplinary involvement in prevention of the consequences of the disease process . The second major theme to be identified in the output of the workshops was the importance of relevance to patients and people affected by leprosy . It is no longer adequate to view programmes in terms of their acceptance to those running the programmes . Control programmes must be acceptable to the people they are designed to benefit . This even impacts on definitions of disease in terms of what matters to patients rather than only restricting this to disease pathology . Similarly, approaches to disability prevention are not merely about measurement of impairments due to nerve function deficit but rather consider the abilities and functions which are most important to the individuals affected . The third theme which spans all of the workshops is the need to develop partnerships with others in addressing the challenges of leprosy today . Each workshop identified important groups with which partnerships need to be developed included local patient groups, voluntary associations and primary health care services . All of these have a role to play, from early case detection right through to the prevention of disability and the sustaining of control under low endemic situations . The fourth important theme is sustainability of programmes which need to be developed for the long term benefit of those affected by disease rather than short term goals . Again, this impacts an area such as case detection methods which need to be sustained in the long term . Approaches such as intensive case detection through mass survey are not sustainable given changes to the patterns of disease, whereas involvement of communities and community participation in the process of early case detection is a much more sustainable approach . This is important, as programmes attain low endemic status and is also important in preventing disabilities where the progressive nature of secondary impairments following primary impairments may be lifelong . The final theme is that of the importance of training, as each area is recommending new approaches to be taken and for new people to be involved in leprosy programmes . The implications are that those to be involved need to be trained and that the training requirements will be different from those of the last ten years . Training programmes will need to adapt to a wider range of individuals and groups being involved in programmes and to much more comprehensive approaches . These implications for training are profound and training centres and training programmes rapidly J Antimicrob Chemother, 1999 Jun, 43(6), 837 - 9 Antibacterial effect of garlic and omeprazole on Helicobacter pylori; Jonkers D et al.; The antibacterial effect of a home-made raw garlic extract and commercial garlic tablets alone and in combination with antibiotics or omeprazole was determined against clinical isolates of Helicobacter pylori . MIC values of raw garlic extract and three types of commercial garlic tablets ranged from 10,000 to 17,500 mg/L . When MIC values of the commercial tablets were based on the allicin content, no differences between the three types were observed . The combination of garlic and omeprazole, studied with killing curves, showed a synergic effect which was concentration dependent . Further clinical evaluation of garlic in combination with the conventional agents for H . pylori treatment seems warranted. Voen Med Zh, 1999 May, 320(5), 51 - 7, 96 {Treatment efficacy in acute intestinal infections, chronic diseases of the gastrointestinal tract and viral hepatitis B using large doses of Russian Bifidumbacterin-forte}; Gracheva NM et al.; Until now viral and bacterial acute intestinal infections have a high percent in the whole structure of modern intestinal disorders morbidity . Taking into consideration inefficacy of antibacterial treatment in a number of cases, probiotics with antagonist effect on a wide range of bacteria have found a wide usage . This study proves clinic and morphological efficacy of large doses Bifidumbacterinum forte for the treatment of the diseases mentioned . The patients of the test group demonstrated a relation dyspeptic disturbances, improvement of total state in a shorter period than the patients of control group. J Biomed Mater Res, 1999 Oct, 47(1), 18 - 27 Biological activities of sustained polymyxin B release from calcium phosphate biomaterial prepared by dynamic compaction: an in vitro study; Kimakhe S et al.; Calcium phosphate ceramics (CaP) have recently been proposed as a potential matrix for a bioactive drug delivery system (DDS) in which the effect in situ of a released therapeutic agent is favored by the biocompatibility, osteoconductivity, and bioresorption of the ceramic material . Polymyxin B (PMB) is a polypeptidic antibiotic which undergoes thermodamage above 60 degrees C . The dynamic compaction method was developed to consolidate the drug load on CaP powder without external heating . Two projectile velocities (50 and 25 m/s) were used here to achieve powder consolidation . Among the different techniques used to associate therapeutic agents with CaP, wet adsorption was performed before the dynamic compaction process . The PMB release profile was measured by a capillary electrophoresis technique, CaP crystallography was studied by x-ray diffraction, and CaP physicochemical analysis was performed by infrared spectroscopy . The biological activities of PMB-loaded compacted CaP were determined by the effect of the antibiotic and monocyte/macrophage degradation on compact surfaces . PMB release began after 2-3 days of incubation for blocks compacted at 25 m/s velocity and on day 5 for those compacted at 50 m/s velocity . A discrepancy was noted between the amounts of PMB released (0.5-2.1 mg) and the amounts initially compacted (2-8 mg) with CaP powder . The biological activities (antibacterial activity and inhibited lipopolysaccharide effects on monocyte/macrophage CaP degradation) of PMB released from compacted calcium-deficient apatite were unaltered . Thus, dynamic compaction allows PMB to be used with CaP ceramics without any loss in its integrity and biological effects . Ann Allergy Asthma Immunol, 1999 Jun, 82(6), 554 - 8 Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin disorders; Asero R; BACKGROUND: Previous studies show skin reactions after exposure to acetaminophen and/or nimesulide to occur in about 10% of patients with a history of urticaria induced by aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) . This fact is surprising since cross-reactivity among different NSAIDs should not occur among subjects without a history of chronic urticaria . OBJECTIVE: To detect risk factors for intolerance to alternative drugs such as acetaminophen and nimesulide in different groups of patients with a history of adverse skin reactions (urticaria/angioedema, or anaphylaxis) after the ingestion of aspirin and other NSAIDs . METHODS: Two hundred fifty-six patients with a history of recent pseudoallergic skin reactions caused by NSAIDs underwent elective oral challenges with increasing doses of both acetaminophen and nimesulide . Patients were divided into three groups: A = 69 subjects with chronic urticaria, B = 163 otherwise normal subjects with a history of urticaria after the ingestion of aspirin, and C = 24 otherwise normal subjects with a history of urticaria after the ingestion of pyrazolones but aspirin-tolerant . RESULTS: Forty-eight (19%) patients reacted to acetaminophen and/or nimesulide . Similar numbers of patients with chronic urticaria (23%) and of normal subjects with a history of aspirin-induced urticaria (19%) did not tolerate one of the alternative drugs challenged . Pyrazolones-intolerant patients showed the lowest number of reactors (4%) . Aspirin intolerance represented a risk factor for acetaminophen- and/or nimesulide-induced urticaria (RR = 5.4) . A history of anaphylactoid reactions induced by NSAID represented a risk factor for urticaria after the ingestion of the alternative study drugs (RR = 5.7) . Atopic status was associated with a higher risk of reactivity to nimesulide: this drug induced urticaria in 11/47 (23%) atopics versus 18/209 (9%) non-atopics (P < .005; RR = 3.2) . A history of intolerance to antibacterial drugs was not associated with a higher prevalence of reactivity against acetaminophen and/or nimesulide . CONCLUSIONS: In at least 20% of patients with a history of urticaria/angioedema or anaphylaxis induced by aspirin or other NSAIDs, but without a history of chronic urticaria, cross-reactivity with other NSAIDs occurs . Atopy as well as a history of aspirin-induced anapylactoid reactions seem to represent relevant risk factors for intolerance to alternative NSAIDs . In view of these findings, aspirin-intolerant patients with such clinical features should be submitted to peroral tolerance tests with at least two alternative substances in order to avoid potentially severe reactions. Chem Pharm Bull (Tokyo), 1999 Jun, 47(6), 777 - 82 Inhibition effects of 5-S-glutathionyl-N-beta-alanyl-L-dopa analogues against Src protein tyrosine kinase; Zheng ZB et al.; Twelve analogues of the antibacterial phenolic peptide 5-S-glutathionyl-N-beta-alanyl-L-dopa (5-S-GA-L-D, 1) were synthesized via orthoquinone using tyrosinase . Several synthesized compounds inhibited the v-Src autophosphorylation tyrosine kinase reaction with an IC50 value comparable to that of herbimycin A . The inhibition of c-Src substrate phosphorylation was much less active than v-Src autophosphorylation inhibition . 5-S-GA-L-D (1) and its analogous competed with peptide substrate and non-compared with ATP . The analogues showed no effects on substrate phosphorylation by epidermal growth factor receptor (EGFR), and this selectivity is the most characteristic feature of the 5-S-GA-L-D and its analogues (1-12). J Mol Biol, 1999 Jul 23, 290(4), 859 - 65 Structural basis and mechanism of enoyl reductase inhibition by triclosan; Stewart MJ et al.; The enoyl-acyl carrier protein reductase (ENR) is involved in bacterial fatty acid biosynthesis and is the target of the antibacterial diazaborine compounds and the front-line antituberculosis drug isoniazid . Recent studies suggest that ENR is also the target for the broad-spectrum biocide triclosan . The 1.75 A crystal structure of EnvM, the ENR from Escherichia coli, in complex with triclosan and NADH reveals that triclosan binds specifically to EnvM . These data provide a molecular mechanism for the antibacterial activity of triclosan and substantiate the hypothesis that its activity results from inhibition of a specific cellular target rather than non-specific disruption of the bacterial cell membrane . This has important implications for the emergence of drug-resistant bacteria, since triclosan is an additive in many personal care products such as toothpastes, mouthwashes and soaps . Based on this structure, rational design of triclosan derivatives is possible which might be effective against recently identified triclosan-resistant bacterial strains . J Antibiot (Tokyo), 1999 Apr, 52(4), 374 - 82 Feglymycin, a novel inhibitor of the replication of the human immunodeficiency virus . Fermentation, isolation and structure elucidation; Vertesy L et al.; The novel peptide feglymycin has been isolated from cultures of Streptomyces sp . DSM 11171 by solid phase extraction, size exclusion chromatography and repeated reversed-phase chromatography . The molecular weight was found to be 1900.90 g/mol and the molecular formula is C95H97Nl3O30 . Feglymycin contains 13 amino acids of which four are 3-hydroxyphenylglycine and five are 3,5-dihydroxyphenylglycine residues . The structure of the linear peptide has been determined by 1H and 13C NMR spectroscopy . The sequence was confirmed by the observed mass spectroscopic fragmentation pattern . As well as having weak antibacterial activity, feglymycin inhibits the replication of the human immunodeficiency virus (HIV) in vitro. Klin Med (Mosk), 1999, 77(5), 49 - 52 {Diagnostic errors in the treatment of patients with pleural diseases}; Khanin AL et al.; As illustrated by analysis of 342 case histories, none of 280 patients admitted for two years to the Center for Diagnosis and Treatment of Pleural Diseases had the verified admission diagnosis . Missed diagnosis was possible because the physicians in charge had not prescribed pleural puncture, tomography of the lungs and mediastinum after maximal removal of the exudate . Other causes were inadequate investigation of the pleural fluid, administration of antibacterial therapy and glucocorticoids in obscure diagnosis . Poor diagnosis of pleural disease reflects the absence of clear-cut policy of management of such patients as a result of which in general practice pleural diseases are detected 2 weeks after visit to a doctor, on the average . To the specialized center the patients are sent only 47 days after the disease onset . Specialists of the center make differential diagnosis with early use of needle biopsy of the pleura which enables to reduce the time of making diagnosis to 10-12 days. Comp Biochem Physiol B Biochem Mol Biol, 1999 Apr, 122(4), 409 - 14 cDNA cloning and gene expression of cecropin D, an antibacterial protein in the silkworm, Bombyx mori; Yang J et al.; We have isolated a cDNA clone encoding a cecropin D precursor from the fat body of Bombyx mori larvae immunized with bacteria by means of differential display . The cDNA contains 298 bp with a coding region of 183 bp for 61 amino acids plus a termination codon (TAG), a 5'-untranslated region of 36 bp, and a 3'-untranslated region of 79 bp including the poly(A) tail . There is a polyadenylation signal sequence of AATAAA at position 266, 43 nucleotides downstream from the termination codon TAG . The homology of the deduced amino acids is greater to the cecropin D precursor from Hyalophora cecropia (67% identity) than to the precursors of cecropins A and B from B . mori (49% to both) . Northern blotting analyses reveal that the gene expression of cecropin D is detectable by 4 h after the bacterial injection and reaches the maximal level at 24 h . That high level is maintained up to 48 h post-immunization . Additionally, the gene is expressed mainly in the fat body and slightly in hemocytes, but it is undetectable in other tissues such as the midgut, the Malpighian tubule and silk gland. Am J Respir Crit Care Med, 1999 Jul, 160(1), 283 - 90 Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients; Agerberth B et al.; Antibacterial peptides and proteins are an integral part of the epithelial defense barrier that provides immediate protection against bacterial invasion . In humans, alpha-defensins are mainly bactericidal effectors in circulating granulocytes, beta-defensin-1 is synthesized in epithelial cells, and LL-37 is produced in granulocytes but is also induced in skin epithelia during inflammation . To investigate the importance of these defense effectors in disease, we analyzed bronchoalveolar lavage fluid (BALF) for bactericidal activity . Antibacterial activity was found in BALF material from healthy individuals and sarcoidosis patients, with enhanced activity in BALF from the patients . The activity was present as several antibacterial components, of which we have so far characterized LL-37, lysozyme, alpha-defensins, and antileukoprotease . In addition, the antibacterial peptide LL-37 was located in alveolar macrophages, bronchial epithelial cells, and bronchial glands, suggesting that it has a defensive role in airway mucosa . In conclusion, the airway epithelium is protected by a complex antibacterial defense system . This is activated in sarcoidosis, and may explain why these patients seldom develop severe respiratory tract infections. Antimicrob Agents Chemother, 1999 Jul, 43(7), 1693 - 9 Multiple mechanisms of action for inhibitors of histidine protein kinases from bacterial two-component systems; Hilliard JJ et al.; Many pathogenic bacteria utilize two-component systems consisting of a histidine protein kinase (HPK) and a response regulator (RR) for signal transduction . During the search for novel inhibitors, several chemical series, including benzoxazines, benzimidazoles, bis-phenols, cyclohexenes, trityls, and salicylanilides, were identified that inhibited the purified HPK-RR pairs KinA-Spo0F and NRII-NRI, with 50% inhibitory concentrations (IC50s) ranging from 1.9 to >500 microM and MICs ranging from 0.5 to >16 microg/ml for gram-positive bacteria . However, additional observations suggested that mechanisms other than HPK inhibition might contribute to antibacterial activity . In the present work, representative compounds from the six different series of inhibitors were analyzed for their effects on membrane integrity and macromolecular synthesis . At 4x MIC, 17 of 24 compounds compromised the integrity of the bacterial cell membrane within 10 min, as measured by uptake of propidium iodide . In this set, compounds with lower IC50s tended to cause greater membrane disruption . Eleven of 12 compounds inhibited cellular incorporation of radiolabeled thymidine and uridine >97% in 5 min and amino acids >80% in 15 min . The HPK inhibitor that allowed >25% precursor incorporation had no measurable MIC (>16 microg/ml) . Fifteen of 24 compounds also caused hemolysis of equine erythrocytes . Thus, the antibacterial HPK inhibitors caused a rapid decrease in cellular incorporation of RNA, DNA, and protein precursors, possibly as a result of the concomitant disruption of the cytoplasmic membrane . Bacterial killing by these HPK inhibitors may therefore be due to multiple mechanisms, independent of HPK inhibition. Anesth Analg, 1999 Jul, 89(1), 218 - 24 The effects of cimetidine, ranitidine, and famotidine on human neutrophil functions; Mikawa K et al.; Neutrophil functions, which play an important role in the antibacterial host defense system, are inhibited by various anesthetics and surgical procedures . Histamine H2-receptor antagonists are perioperatively used as a prophylaxis against acid aspiration syndrome or stress ulceration . We examined the effect of cimetidine, ranitidine, and famotidine, at clinically relevant concentrations and at 10 and 100 times this concentration, on several aspects of human neutrophil function using an in vitro system . The three H2-receptor antagonists did not impair neutrophils' chemotaxis or phagocytosis . Cimetidine and famotidine inhibited superoxide (O2-) and hydrogen peroxide (H2O2) production of the neutrophils in a dose-dependent manner, although the inhibitory effects were minimal . In contrast, ranitidine failed to change O2- or H2O2 production of neutrophils . The three H2-receptor antagonists did not scavenge these reactive oxygen species generated by the xanthine-xanthine oxidase system . The increase in intracellular calcium concentrations in neutrophils by a stimulant were dose-dependently attenuated with cimetidine or famotidine . This decreasing effect of the drugs on {Ca2+}i in neutrophils may represent one of mechanisms responsible for inhibition of reactive oxygen species generation . IMPLICATIONS: Neutrophils play a pivotal role in the antibacterial host defense system and tissue injury . We found that cimetidine and famotidine slightly reduced the O2- or H2O2 production of neutrophils in a dose-dependent manner, although ranitidine failed to do so . At least ranitidine does not seem to have any deleterious effect on neutrophil function, which is clearly an important consideration in its use in severely ill patients. Phytochemistry, 1999 Jun, 51(4), 529 - 41 Bioactive sesquiterpenes from Santolina rosmarinifolia subsp . Canescens . A conformational analysis of the germacrane ring; Barrero AF et al.; The hexane extract of aerial parts of Santolina rosmarinifolia subsp . canescens afforded eight new sesquiterpenes in addition to known compounds . Their structures were determined by spectroscopic methods and chemical transformations . The conformational analysis of the germacrane constituents was carried out by spectroscopic methods, including NMR at varying temperature and by molecular mechanics calculations . The antifeedant, antibacterial and antitumoral activity of selected compounds has been tested. Biochemistry, 1999 Jun 22, 38(25), 7989 - 98 Mechanistic insights into the inhibition of serine proteases by monocyclic lactams; Wilmouth RC et al.; Although originally discovered as inhibitors of pencillin-binding proteins, beta-lactams have more recently found utility as serine protease inhibitors . Indeed through their ability to react irreversibly with nucleophilic serine residues they have proved extraordinarily successful as enzyme inhibitors . Consequently there has been much speculation as to the reason for the general effectiveness of beta-lactams as antibacterials or inhibitors of hydrolytic enzymes . The interaction of analogous beta- and gamma-lactams with a serine protease was investigated . Three series of gamma-lactams based upon monocyclic beta-lactam inhibitors of elastase {Firestone, R . A . et al . (1990) Tetrahedron 46, 2255-2262.} but with an extra methylene group inserted between three of the bonds in the ring were synthesized . Their interaction with porcine pancreatic elastase and their efficacy as inhibitors were evaluated through the use of kinetic, NMR, mass spectrometric, and X-ray crystallographic analyses . The first series, with the methylene group inserted between C-3 and C-4 of the beta-lactam template, were readily hydrolyzed but were inactive or very weakly active as inhibitors . The second series, with the methylene group between C-4 and the nitrogen of the beta-lactam template, were inhibitory and reacted reversibly with PPE to form acyl-enzyme complexes, which were stable with respect to hydrolysis . The third series, with the methylene group inserted between C-2 and C-3, were not hydrolyzed and were not inhibitors consistent with lack of binding to PPE . Comparison of the crystal structure of the acyl-enzyme complex formed between PPE and a second series gamma-lactam and that formed between PPE and a peptide {Wilmouth, R . C., et al . (1997) Nat . Struct . Biol . 4, 456-462.} reveals why the complexes formed with this series were resistant to hydrolysis and suggests ways in which stable acyl-enzyme complexes might be obtained from monocyclic gamma-lactam-based inhibitors. Arch Intern Med, 1999 Jun 28, 159(12), 1301 - 9 Pulmonary mucormycosis: the last 30 years; Lee FY et al.; Pulmonary mucormycosis is relatively uncommon but an important opportunistic fungal infection in immunocompromised persons . The literature on the subject is sparse . We describe a recent case and review the literature to delineate the clinical characteristics of this infection . We searched the MEDLINE database for articles published in the English-language literature since 1970 and carefully analyzed 87 cases . The main risk factors were diabetes mellitus, hematologic cancers, renal insufficiency, and organ transplantation . Several patients had no apparent immune compromise . There was a predilection for involvement of the upper lobes . Air crescent signs on chest x-ray films were predictors of pulmonary hemorrhage and death from hemoptysis . Fiberoptic bronchoscopy was a useful diagnostic method, and histopathologic examination was more sensitive than fungal cultures . The overall survival rate was 44% . Patients treated with a combined medical-surgical approach had a better outcome than patients who did not undergo surgery . Thus, this relatively rare but often fatal disease should be suspected in immunocompromised patients who fail to respond to antibacterial therapy . Early recognition and aggressive management are warranted to maximize chances for cure . Optimal therapy requires systemic antifungal therapy, surgical resection, and, when possible, control of the patient's underlying disease. Microbiol Immunol, 1999, 43(4), 311 - 6 Antibacterial activities of new synthetic divalent cation chelators; Ashoori M et al.; A series of new synthetic ligand compounds which chelate divalent cations was examined for the antibacterial activities of the compounds . Only 2 of 14 synthetic chelators, 9-trans-anthryl-1, 4, 8, 11-tetraaza-tetradecane (No . 6) and bis(2-pyridyl)methylamine (No . 13) showed antibacterial activities, whereas none of the diamines, hydrophilic triamines nor tetramines showed antibacterial activities . Chelators No . 6 and No . 13 inhibited the growth of both Gram-negative and -positive bacteria at doses of 25-200 microg/ml, comparable to those of common antibiotics such as polymixin B, fosfomycin and macrolides . Ethylenediaminetetraacetate (EDTA) potentiated these antibacterial activities, whereas an inhibitory effect of Mg2+ on the MICs of these chelators was observed . Moreover, these chelators enhanced the leakage of periplasmic beta-lactamase . It is therefore suggested that chelators No . 6 and No . 13 disrupt both the membranes and cytoplasmic functions of bacteria, resulting in cell death. Eur J Immunol, 1999 Jun, 29(6), 1901 - 11 Molecular mimicry between bacterial and self antigen in a patient with systemic lupus erythematosus; Kowal C et al.; The importance of microbial infection as a trigger for the induction of systemic lupus erythematosus is frequently debated . Clinical observations indicate that anti-viral and antibacterial responses are often accompanied by self reactivity, and anti-pneumococcal antibodies elicited in non-autoimmune individuals by pneumococcal vaccine express lupus-associated anti-DNA idiotypes . To explore the relationship between protective and pathogenic antibodies in humans, we have used the phage display immunoglobulin expression system to generate a combinatorial library from spleen cells of a lupus patient immunized with a polyvalent pneumococcal polysaccharide vaccine prior to splenectomy . From this library, monovalent antigen-binding fragments expressing the 3I Vkappa1-associated idiotype were isolated . This idiotype is expressed on up to 90% of anti-DNA antibodies in the serum of lupus patients and on anti-pneumococcal antibodies in the serum of non-autoimmune individuals . Eight 3I+ monovalent antigen-binding fragments reacting with pneumococcal polysaccharide, DNA or both were analyzed . Four of these fragments were cross-reactive with both foreign and self antigen, demonstrating that a high percentage of anti-bacterial antibodies produced in a patient with lupus bind double-stranded DNA . These studies provide support at the molecular level for a potential role of molecular mimicry in the generation of anti-DNA antibodies . In addition, this is, to our knowledge, the first panel of fully sequenced human anti-pneumococcal antibodies. Aliment Pharmacol Ther, 1999 Jul, 13(7), 851 - 6 Helicobacter pylori infection and gastric cancer: systematic review of the epidemiological studies; Danesh J; BACKGROUND: The published epidemiological studies of chronic Helicobacter pylori infection and gastric cancer yield conflicting results, so there is uncertainty as to whether any material association exists and, if so, how strong it is . AIM: To review these studies quantitatively . METHODS: A systematic review of sero-epidemiological studies published before 1998 of H . pylori and gastric cancer, as identified by computer-assisted literature searches of relevant journals, reference lists and discussions with authors . All relevant studies identified were included, subdivided by study design . The following was abstracted from published reports: adjusted odds ratio (or, in prospective studies, the risk ratio) and confidence interval, study design, type of controls, mean age, mean duration of follow-up, assay methods, location of study, and degree of adjustment for confounders . RESULTS: The 34 retrospective studies included in total 3300 gastric cancers, but their controls were of uncertain validity . The 10 'nested' case-control comparisons in prospective studies included in total only 800 gastric cancers, and combined analysis of them yielded a risk ratio of 2.5 (95% CI: 1.9-3.4; 2P < 0.00001) for gastric cancer in people seropositive for H . pylori antibodies . CONCLUSIONS: The prospective studies suggest that gastric cancer is 2 or 3 times as common in those chronically infected by H . pylori, but to help investigate causality, further observational studies are still needed, as are large-scale randomized trials of whether antibacterial regimens reduce the eventual incidence of gastric cancer. J Antimicrob Chemother, 1999 May, 43 Suppl B, 91 - 100 Preclinical safety evaluation of moxifloxacin, a novel fluoroquinolone; von Keutz E et al.; The toxicity of moxifloxacin (BAY 12-8039), a novel fluoroquinolone with a broad spectrum of antibacterial activity, was evaluated in a comprehensive programme of toxicological studies that included single and multiple dose toxicity studies in rats, mice, dogs and monkeys, reproductive system toxicity studies in rats and monkeys and in-vitro and in-vivo mutagenicity assays . Although moxifloxacin is not intended for long-term clinical use, an accelerated bioassay in target organs to assess carcinogenesis was performed in rats . In addition to the routine toxicological programme required for the development of a drug intended for short-term administration, a major part of the preclinical programme for moxifloxacin comprised studies designed specifically to address the safety issues known to be features of fluoroquinolones, i.e . adverse effects on the central nervous and cardiovascular systems, phototoxicity, arthrotoxicity and oculotoxicity . The results of the toxicological investigations confirmed that the safety profile of moxifloxacin is comparable to those of other fluoroquinolones. Helicobacter, 1999 Jun, 4(2), 113 - 20 Combined activity of azithromycin and lansoprazole against Helicobacter pylori; Trautmann M et al.; BACKGROUND: Due to its unique pharmacokinetic properties, azithromycin may be an attractive combination partner for H . pylori eradication regimens . However, up to 15% of clinical isolates are primarily resistant to azithromycin as well as to other macrolide antibiotics . Combination therapy with lansoprazole, a proton pump inhibitor known to have intrinsic antibacterial activity against H . pylori, may be useful to counteract such resistance . We therefore evaluated the combined effects of azithromycin and lansoprazole in vitro . MATERIALS AND METHODS: Minimal inhibitory concentrations (MICs) of azithromycin and lansoprazole alone and in combination were determined for 106 clinical H . pylori isolates by means of an agar dilution technique . Killing kinetics of seven isolates were also studied in fluid medium . RESULTS: MIC values for 50 and 90% of the isolates (MIC50, MIC90) were 0.19 and 0.5 mg/l for azithromycin, and 44.5 and 104 mg/l for lansoprazole . Nine strains (8.5%) had an MIC of azithromycin > or = 16 mg/l and were regarded as resistant . An additive interaction between the two drugs was found in 72 (68%), and indifferent effects in 24 strains (23%) . Three of 9 azithromycin-resistant strains regained sensitivity in the presence of lansoprazole . In fluid culture, synergism between the two drugs occurred in 6 out of 7 strains tested . CONCLUSION: In the majority of strains, lansoprazole and azithromycin interacted in an additive or synergistic manner depending on the test method employed . Addition of lansoprazole restored in vitro sensitivity to azithromycin in 3 out of 9 azithromycin-resistant strains . Such effects may enhance the elimination of H . pylori during clinical eradication therapy. J Pharmacol Exp Ther, 1999 Jul, 290(1), 51 - 7 Efflux transport of a new quinolone antibacterial agent, HSR-903, across the blood-brain barrier; Murata M et al.; The distribution of HSR-903, a new quinolone antibacterial agent, to the brain after i.v . administration to rats was low compared with that to other tissues . The blood-brain barrier permeability to HSR-903 determined by the brain perfusion method was low, and increased nonlinearly with increasing concentration of HSR-903 in the perfusate . When the brain-to-plasma concentration ratio (Kp, brain) was measured in mdr1a gene-knockout mice, the value was 8 times higher than that in normal mice . The uptake of {14C}HSR-903 by multidrug-resistant K562/ADM cells, which express P-glycoprotein (P-gp), was significantly lower than that by the drug-sensitive parent K562 cells . In addition, the uptake of {14C}HSR-903 by K562/ADM cells was significantly increased in the presence of cyclosporin A and ATP-depleting agents . These observations support the idea that P-gp participates in HSR-903 efflux from the brain . The steady-state uptake of HSR-903 by a monolayer of primary cultured bovine brain capillary endothelial cells was increased in the presence of several quinolone antibacterial agents or anionic compounds, such as 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, and in bicarbonate ion-free medium, as well as by P-gp inhibitors (cyclosporin A and quinidine) . These results suggested that the efflux of HSR-903 proceeds at least partly via an anion-sensitive efflux transport mechanism as well as via P-gp . In conclusion, the low brain distribution of the new quinolone antibacterial agent HSR-903 can be ascribed to multiple efflux mechanisms including P-gp and an unidentified anion-sensitive transporter operating in the brain capillary endothelial cells that constitute the blood-brain barrier. Infection, 1999, 27 Suppl 1, S46 - 8 Determination of the silver ion release from polyurethanes enriched with silver; Joyce-Wohrmann RM et al.; The Erlanger silver catheter was developed in order to reduce the risk of infection from long-term catheters by means of silver ions, which are known to have antibacterial properties . This is achieved by incorporating silver into polyurethane catheters by means of a special procedure . The aim of this materials science study was to verify the release of silver ions from the polyurethanes . Static experiments were carried out following the usual norms . Clinically relevant dynamic experiments, which were designed and constructed at this institute, were also performed . The eluates from both experiments were analyzed by anodic stripping voltammetry . Polyurethanes filled with silver, as used in the Erlanger silver catheter, release silver in static as well as in dynamic experiments . If the experimentally determined releases are converted to the usual catheter length of 30 cm, the release is about 0.1 microgram/l . This lies in the order of concentrations that have been reported in the literature to be antibacterial. Pharmacol Res, 1999 Jul, 40(1), 47 - 52 Prescribing habits of general practitioners in choosing an empirical antibiotic regimen for lower respiratory tract infections in adults in Sicily; Mazzaglia G et al.; The survey was carried out, between September 1995 and May 1996, in order to describe the prescriptive behaviour among Sicilian general practitioners (GPs) in choosing an empirical antibiotic regimen for LRTIs in adult patients and begin an educational process which involves the same GPs in decisions regarding their prescriptions and in performing local guidelines . Each practitioner filled out a questionnaire for each therapeutic intervention which ended with an antibiotic prescription . The questionnaire also enquired into the patient's characteristics, diseases to be treated and drug prescription . Doctors were asked to give an opinion about the severity assessment of the infectious disease before choosing the antibiotic treatment, in order to evaluate the prescriptive behaviour of physicians related to the patient's symptoms . Of all Sicilian GPs approached, 76 physicians from 25 Sicilian towns, with a patient population of 96,630, agreed to participate . The GPs used 49 different molecules and six different associations of two antibiotics . The most frequently used antibacterial agents were cephalosporins (55.0%) . Penicillins (11.7%), fluoroquinolones (11 . 4%), macrolides (10.1%) and combinations of penicillins with beta-lactamase inhibitors (7.9%), together, represented 41.1% of the remaining antibiotic prescriptions . The choice of the route of administration was significantly influenced by age of the patients, by symptoms and signs of the disease and by the presence of concurrent diseases rather than by bacteria suspected of causing the disease . The rather marked variation in antibiotic prescribing pattern for LRTIs among Sicilian GPs reflects lack of availability or knowledge of any local or national guidelines about the management of these diseases . Vestn Ross Akad Med Nauk, 1999, (4), 56 - 61 {Imunofan: new-generation synthetic peptide agent}; Lebedev VV et al.; The paper reviews the development, mode of action and field of application of synthetic regulatory peptides in the pathogenetic and immunocorrective therapy of infectious and noninfectious diseases . Great progress has been made in designing new-generation small regulatory peptides by modifying the sequence of amino acid residues in the active fragments of natural hormones to change their biological activity and therapeutic properties . The original hexapeptide Arg-alpha-Asp-Lys-Val-Tyr-Arg has been designed by chemically modifying the thymic hormone Thymopoietin in positions 32-37 . The agent has been called Immunofan . It is manufactured in ampoules containing 1 ml of 0.005% sterile solution for subcutaneous and intramuscular injections . The trials of Immunofan have demonstrated that it is able to restore cell immunity, the oxygen-dependent neutrophilic bactericidal system and antiviral antibody production . It decreases the levels of inflammatory mediators, such as TNF and IL-6, and activates the redox system . Included into the complex therapy of patients with cancer diseases, Immunofan enhances the body's reserve capacity to inactivate free radicals and oxidants, substantially shortens radiation and toxic reactions . Its use ensures the continuum of chemoradiotherapy . Used in the complex therapy for chronic infections (brucellosis, hepatitis B and C, opportunistic infections), Immunofan enhances antiviral and antibacterial immunity, shortens the manifestation of clinical symptoms and major syndromes of diseases. J Med Chem, 1999 Jun 17, 42(12), 2136 - 44 Design and synthesis of modified quinolones as antitumoral acridones; Tabarrini O et al.; The bacterial topoisomerase II (DNA gyrase) and the mammalian topoisomerase II represent the cellular targets for quinolone antibacterials and a wide variety of anticancer drugs, respectively . In view of the mechanistic similarities and sequence homologies exhibited by the two enzymes, tentative efforts to selectively shift from an antibacterial to an antitumoral activity was made by synthesizing a series of modified tricyclic quinolones, in which the essential 3-carboxylic function is surrogated by phenolic OH and the classic C-6 fluorine atom is replaced by a NH2 group . The resulting 7-amino-9-acridone derivatives were assayed for their antibacterial as well as cytotoxic activities . No antibacterial activity was found . On the other hand, many derivatives showed significant cytotoxic activity against both HL-60 and P388 leukemias and a wide panel of human and rodent solid tumor cells, derivatives 25 and 26 displaying the best overall antiproliferative activity . Against the LoVo cell line, derivative 25 exhibited higher cytotoxic effects than etoposide. Infect Immun, 1999 Jul, 67(7), 3571 - 9 Fatal granuloma necrosis without exacerbated mycobacterial growth in tumor necrosis factor receptor p55 gene-deficient mice intravenously infected with Mycobacterium avium; Ehlers S et al.; The pathogenesis of mycobacterial infections is associated with the formation of granulomas in which both antibacterial protection and tissue damage take place concomitantly . We used murine Mycobacterium avium infection to compare the development of granulomatous lesions in intravenously infected tumor necrosis factor receptor p55 (TNFRp55) gene-deficient (p55(-/-)) mice to the development of granulomatous lesions in M . avium-infected syngeneic C57BL/6 (p55(+/+)) mice . Up to 5 weeks after infection with either the highly virulent M . avium strain TMC724 or the intermediately virulent M . avium strain SE01, bacterial counts in the liver, spleen, and lung of p55(-/-) mice were identical to or lower than those in infected p55(+/+) mice . However, the formation of mononuclear cell foci in the liver was delayed by approximately 2 to 3 weeks in p55(-/-) mice compared to the results obtained for infected p55(+/+) mice . Despite comparable bacterial loads, granulomas in p55(-/-) mice underwent progressive necrosis, causing damage to the surrounding liver tissue . The appearance of necrotizing granulomas was associated with the death of all infected p55(-/-) mice, regardless of the virulence of the M . avium strain used for infection . Granulomatous lesions in the liver contained three times as many CD3(+) cells in p55(-/-) mice yet appeared more diffuse than in p55(+/+) mice . Semiquantitative reverse transcription-PCR studies revealed that prior to mouse death, interleukin-12 (IL-12) and gamma interferon mRNA levels were up regulated in the livers of infected p55(-/-) mice, while mRNA levels for tumor necrosis factor, the inducible isoform of nitric-oxide synthase (iNOS), and IL-10 were similar to those found in infected p55(+/+) mice . In response to persistent mycobacterial infection, the absence of TNFRp55 causes the disregulation of T-cell-macrophage interactions and results in fatal granuloma necrosis even when adequate antibacterial functions are maintained. Mol Biochem Parasitol, 1999 May 15, 100(1), 53 - 9 Inhibition of succinyl CoA synthetase histidine-phosphorylation in Trypanosoma brucei by an inhibitor of bacterial two-component systems; Hunger-Glaser I et al.; Recent drug screenings for new antibacterial drugs directed against histidine phospho-relay signalling pathways in bacteria have resulted in compounds which potently inhibit the histidine kinase activity of bacterial two-component systems . The present study demonstrates that one of these compounds, LY266500, is also a potent inhibitor of histidine phosphorylation in the unicellular eukaryotic parasite Trypanosoma brucei, both in vitro and in whole cells . In vitro, it inhibits histidine phosphorylation of mitochondrial succinyl CoA synthetase . LY26650 does not interfere with the phosphotransfer from the histidine-phosphorylated protein to ADP . In standardized cell culture tests, LY266500 potently inhibits the proliferation of the human pathogens T . brucei rhodesiense and Leishmania donovani . Since the inhibitory activity in vivo is life-cycle stage specific and correlates well with the mitochondrial activity in the different stages, the effect of LY266500 is most likely due to its specific inhibition of the mitochondrial succinyl CoA synthetase. Zhonghua Nei Ke Za Zhi, 1997 Jun, 36(6), 406 - 10 {Antibacterial activity in vitro and clinical use of sulperazon}; Wang X et al.; In order to approach antibacterial activity in vitro and the efficacy of Sulperazon (SPZ) (sulbactam/cefoperazone), the sensitivity tests of 1,372 strains from clinical isolated bacteria to 17 antibiotics including SPZ were determined . The Gram negative bacteria occupied 1,035 strains (75.4) and Gram positive 337 strains (24.6%) . 50 episodes of infections of major respiratory system in 43 patients were treated by SPZ . 58% of bacterial infections occurred in hematologic malignant diseases and solid tumors patients . 24% of 50 episodes were in neutropenia status . The positive rate of bac-terial cluteres was 56% in the series . 1.0-2.0 g SPZ was administered twice a day for 5-18 days, 56% of them was more than seven days (28/50 episodes) . The results of susceptibility tests showed that sensitive rates were most high and the nesistant rates of SPZ were lower than these of to common Gram negative and Gram positive bacteria in third-generation cephalosporins . The efficacy rate of SPZ in clinical use was 84% (42/50 episodes), bacterial clearance rate was 89% (25/28 episodes) . Three cases (6%) had temporary elevation and other adverse reactions of SPZ were not seen. Mar Biotechnol (NY), 1999 Jan, 1(1), 44 - 51 Callinectin, an Antibacterial Peptide from Blue Crab, Callinectes sapidus, Hemocytes; Khoo L et al.; This paper describes the isolation of an approximately 3.7 kDa, basic, antibacterial peptide (designated callinectin), which represents the major antibiotic activity in blue crab, Callinectes sapidus, hemocytes . A single-step purification using low-pressure cation-exchange chromatology yielded a highly purified (>95%) peptide . Purity was confirmed by C4 reverse-phase high-performance liquid chromatography (RP-HPLC), native gel electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary electophoresis, and mass spectral analysis . The partial amino acid sequence obtained via Edman degradation revealed no significant homology to other reported peptides in the Basic Local Alignment Search Tool (BLAST) program database. FEBS Lett, 1999 May 28, 451(3), 249 - 52 The origin of cecropins; implications from synthetic peptides derived from ribosomal protein L1; Putsep K et al.; We recently showed that Helicobacter pylori grown on plates produce cecropin-like antibacterial peptides to which H . pylori is resistant . This antibacterial activity was traced to fragments from the N-terminus of ribosomal protein L1 (Putsep et al., Nature, April 22, 1999) . The evolutionary suggestion from this finding has now been extended by the synthesis of eight peptides with sequences taken from the N-terminus of ribosomal protein L1 (RpL1) of five different species . Two peptides of different length derived from H . pylori RpL1 showed a potent antibacterial activity, while a peptide with the sequence from Escherichia coli was 20 times less active . Like cecropins the H . pylori peptides were not cytolytic . We suggest that the cecropins have evolved from ribosomal protein L1 of an ancestral intracellular pathogen that developed to a symbiont ending as an organelle . When the R1 gene moved into the host nucleus, a duplication provided a copy from which today cecropins could have evolved. Farmaco, 1999 Mar 31, 54(3), 191 - 4 Synthesis and antibacterial activity of 2-aryl-2,5-dihydro-3(3H)-oxo-pyridazino{4,3-b}indole-4-carboxylic acids; Palluotto F et al.; The in vitro antibacterial and antifungal activities of a series of pyridazinoindolonic acids II against some selected representative of Gram-positive, Gram-negative bacteria and fungi have been investigated . Some interesting observations among the structural features necessary for high antibacterial activity are presented and discussed. Farmaco, 1999 Mar 31, 54(3), 169 - 77 Preparation and biological evaluation of 6/7-trifluoromethyl(nitro)-, 6,7-difluoro-3-alkyl (aryl)-substituted-quinoxalin-2-ones . Part 3; Sanna P et al.; A new series of quinoxalinones 6/7-trifluoromethyl or nitro- and 6,7-difluoro substituted bearing various side-chains (alkyl, halogenoalkyl, benzyl and phenyl groups) at C-3 of the ring system was synthesized and submitted to preliminary in vitro evaluation for antibacterial, antifungal, antimycobacterial, anticancer and anti-HIV activities . Results of these screenings showed that compounds 23-28 exhibited a good inhibition activity against various strains of Candida . Compound 24 showed also an interesting in vitro anticancer activity. Klin Khir, 1999, (3), 16 - 9 {Causes of unsatisfactory outcome in patients with diabetes mellitus complicated by necrotic inflammation of the foot}; Fedorenko VP; Retrospective analysis of the conservative and surgical treatment results of 222 patients with diabetes mellitus, complicated by necrotic-inflammatory affection of foot, was performed for the 1991-1996 period . In 25.2% of observations the extremity amputation was done on the hip level, 13 (5.8%) of patients died . The unsatisfactory result causes were the reoperation performance on foot in a critical ischemia zone, the decrease of the first operation volume, nonadequate correction of metabolic, haemorheologic disturbances, antibacterial therapy. J Mol Biol, 1999 Jun 18, 289(4), 991 - 1002 Structure of aspartate-beta-semialdehyde dehydrogenase from Escherichia coli, a key enzyme in the aspartate family of amino acid biosynthesis; Hadfield A et al.; Aspartate beta-semialdehyde dehydrogenase (ASADH) lies at the first branch point in an essential aspartic biosynthetic pathway found in bacteria, fungi and the higher plants . Mutations in the asd gene encoding for ASADH that produce an inactive enzyme are lethal, which suggests that ASADH may be an effective target for antibacterial, herbicidal and fungicidal agents.We have solved the crystal structure of the Escherichia coli enzyme to 2.5 A resolution using single isomorphous replacement and 3-fold non-crystallographic symmetry . Each monomer has an N-terminal nucleotide-binding domain and a dimerisation domain . The presence of an essential cysteine locates the active site in a cleft between the two domains . The functional dimer has the appearance of a butterfly, with the NADP-binding domains forming the wings and the dimerisation domain forming the body.A histidine residue is identified as a likely acid/base catalyst in the enzymic reaction . Other amino acids implicated in the enzymic activity by mutagenesis are found in the active site region and define the substrate binding pocket . Trends Microbiol, 1999 Jun, 7(6), 242 - 7 Protective mechanisms against toxic electrophiles in Escherischia coli; Ferguson GP; Escherichia coli are exposed to toxic electrophiles from both endogenous and exogenous sources . To survive, E . coli have developed novel protective mechanisms that appear unique to bacteria . In the absence of one of these mechanisms, electrophiles induce rapid killing . Hence it appears that electrophile-protective mechanisms represent novel targets for antibacterial drug research. Pathol Int, 1999 Apr, 49(4), 332 - 7 An evaluative system for the response of antibacterial therapy: based on the morphological change of Helicobacter pylori and mucosal inflammation; Wen M et al.; The diagnostic standard is an important factor in the evaluation of the antibacterial effect to Helicobacter pylori (H . pylori) . Few studies have evaluated the bacterial morphological change . In the present study, H . pylori was examined by means of electron microscopy (EM), light microscopy (LM) and immunohistochemical staining . Patients were followed up from 6 weeks to more than 1 year after treatment for H . pylori, and the results of the 13C-urea breath test (UBT) were compared . A '4-L' evaluative system was used for histological diagnosis; that is, complete, significant, partial and negative response for H . pylori treatment . Complete response showed no H . pylori in histology, and positive 13C-UBT and negative response showed positive in both diagnoses . A significant response showed the morphology of H . pylori was thick walled by EM, that there was no obvious active inflammation, and was negative for C-UBT . These H . pylori showed a coccoid form and possibly static bacteria, which was resistant to further antibacterial therapy . The '4-L' system could evaluate the antibacterial effect, suggesting the necessity for a second line of therapy for H . pylori . It is suggested that this sensitive evaluative system is suitable for clinical applications for antibacterial therapy. Bioorg Med Chem Lett, 1999 May 17, 9(10), 1459 - 62 Synthesis and structure-activity relationship of novel glycylcycline derivatives leading to the discovery of GAR-936; Sum PE et al.; A number of new glycylcyclines were synthesized for structure-activity relationship study . Many of the derivatives exhibit potent, broad spectrum antibacterial activity against both tetracycline susceptible and resistant organisms . GAR-936 (TBG-MINO) shows better activity than the previously reported DMG-MINO and DMG-DMDOT. Bioorg Med Chem Lett, 1999 May 17, 9(10), 1347 - 50 A highly stereoselective synthesis of plaunotol and its thiourea derivatives as potent antibacterial agents against Helicobacter pylori; Kogen H et al.; Practical and highly stereoselective synthesis of diterpene alcohol, plaunotol (1) and its thiourea derivatives 2a, 3a and 4a, via Z-selective Wittig reaction between alpha-acetal ketone 5 and phosphonium salt 6 and their antibacterial activity against Helicobacter pylori are described. FEBS Lett, 1999 May 7, 450(3), 227 - 30 Mutation of the N-terminal proline 9 of BLMA from Streptomyces verticillus abolishes the binding affinity for bleomycin; Kumagai T et al.; A gene, blmA, from bleomycin (Bm)-producing Streptomyces verticillus, encodes a Bm-binding protein, designated BLMA . The expression of BLMA conferred resistance to Bm in the Escherichia coli host, whereas a mutant protein, designated Pro-9/Leu, with the N-terminal proline 9 residue in BLMA replaced by leucine, did not . We created a fusion protein between the maltose-binding protein (MBP) and a mutant protein Pro-9/Leu/Leu with Met-94 in Pro-9/Leu replaced by leucine . Pro-9/Leu/Leu from the fusion protein, obtained by digestion with CNBr digestion, did not inhibit DNA-cleaving and antibacterial activities of Bm . Native-polyacrylamide gel electrophoresis (PAGE) and gel filtration column chromatographic analysis showed that the molecular size of Pro-9/Leu/Leu is roughly half of that of BLMA, suggesting that the mutant protein cannot form dimeric structure . Furthermore, Far-UV circular dichroism (CD) spectrum of Pro-9/Leu/Leu was quite different from that of BLMA and similar to the spectra obtained from unordered proteins {Venyaminov, S.Y . and Vassilenko, K.S . (1994) Anal . Biochem . 222, 176184}, suggesting that the secondary structure of Pro-9/Leu/Leu is disrupted . These results indicate that the mutation abolishes not only dimer formation but also the secondary structure of BLMA, which results in the loss of its function as a Bm-resistance determinant. Vopr Kurortol Fizioter Lech Fiz Kult, 1999 Mar-Apr, (2), 23 - 5 {The staged medical rehabilitation of patients with secondary chronic pyelonephritis in infravesical obstructions}; Nesterov NI et al.; The authors believe that chronic pyelonephritis patients operated for infravesical obstructions need staged postoperative rehabilitation . In antibacterial postoperative treatment, a significant response was seen in 7.9%, a partial response in 18.4% and no response in 73.7% of patients . After combined physiotherapy--in 38%, 41.7% and 20.3% of patients, respectively. Khirurgiia (Mosk), 1999, (5), 18 - 20 {Extended lymphadenectomy in stomach cancer}; Arutiunian GA et al.; The results of surgical treatment in 120 patients with cancer of the stomach have been analyzed . Metastatic involvement in all groups of lymphatic nodes was revealed in 68.3% cases, retroperitoneal metastases were detected in 46 patients (38.3%) . 38 subtotal resections of the stomach and 82 gastrectomies with retroperitoneal lymphadenectomy R2 and R3 were performed . Esophagojejunoanastomosis end-to-end with a loop excluded by Roux was applied in 110 patients and esophagoduodenoanastomosis--in 10 patients . Insufficiency of esophagointestinal anastomosis was revealed in 3 patients . The rate of complications was 29.2%, lethality--8.3% . High rate of postoperative complications and lethality were explained by initially severe conditions of the patients (61%) and by complicated forms of gastric cancer in 6 patients . Improvement of early results of surgical interventions lies in the usage of antibacterial prophylaxis, preventive intravenous introductions of 5-fluorouracil, adequate drainage of the abdominal cavity, careful preparation and ligation in the course of the operation. Ter Arkh, 1999, 71(4), 44 - 7 {Infectious endocarditis: immune disorders, differentiated therapy}; Tatarchenko IP et al.; AIM: Immunological assessment of variants of infectious endocarditis (IE) and design of differentiated approach to the disease therapy . MATERIALS AND METHODS: Of 150 patients treated (90 males and 60 females, mean age 41.9 +/- 3.3 years) 28.7% and 71.3% had primary and secondary endocarditis, respectively . With chronization of the process, there was a trend to growing immune unbalance (IU) . RESULTS: The IU in IE patients manifested with leukocytosis changing for leukopenia, reduced absolute and relative number of lymphocytes, complement, T- and B-lymphocytes, growing content of CIC, IgM, rheumatoid factor and cryoproteins . CONCLUSION: Besides antibacterial therapy, IE patients need immunocorrective and efferent therapy. J Biol Chem, 1999 Jun 11, 274(24), 17226 - 35 Structural insight into a quinolone-topoisomerase II-DNA complex . Further evidence for a 2:2 quinobenzoxazine-mg2+ self-assembly model formed in the presence of topoisomerase ii; Kwok Y et al.; Quinobenzoxazine A-62176, developed from the antibacterial fluoroquinolones, is active in vitro and in vivo against murine and human tumors . It has been previously claimed that A-62176 is a catalytic inhibitor of mammalian topoisomerase II that does not stabilize the cleaved complex . However, at low drug concentrations and pH 6-7, we have found that A-62176 can enhance the formation of the cleaved complex at certain sites . Using a photocleavage assay, mismatched sequences, and competition experiments between psorospermin and A-62176, we pinpointed the drug binding site on the DNA base pairs between positions +1 and +2 relative to the cleaved phosphodiester bonds . A 2:2 quinobenzoxazine-Mg2+ self-assembly model was previously proposed, in which one drug molecule intercalates into the DNA helix and the second drug molecule is externally bound, held to the first molecule and DNA by two Mg2+ bridges . The results of competition experiments between psorospermin and A-62176, as well as between psorospermin and A-62176 and norfloxacin, are consistent with this model and provide the first evidence that this 2:2 quinobenzoxazine-Mg2+ complex is assembled in the presence of topoisomerase II . These results also have parallel implications for the mode of binding of the quinolone antibiotics to the bacterial gyrase-DNA complex. Zh Mikrobiol Epidemiol Immunobiol, 1999 Mar-Apr, (2), 65 - 8 {The characteristics of the humoral antibacterial immunity of young children with respiratory organ diseases}; Zinkevich OD et al.; The state of antibacterial humoral immunity in young children with acute bronchitis, acute obstructive bronchitis and bronchial asthma at the period of exacerbation has been shown with the use of the enzyme immunoassay . The concentration of antibodies to endotoxin positively correlates with the severity of clinical manifestations of the endogenic intoxication of the body . As the inflammatory process in the bronchial tree increases, the spectrum bacterial agents to which elevated concentrations of specific antibodies can be detected becomes wider, and this finds its maximum reflection in bronchial asthma. Phytother Res, 1999 May, 13(3), 236 - 8 Studies on in vitro metabolism of shikonin; Li H et al.; Shikonin is one of the active components isolated from the root of Arnebia euchrona (Royle) Johnst . It has been shown to possess significant antibacterial, antiinflammatory and antitumour activities and has been used clinically . In this paper, rat liver microsomes were incubated in vitro to study the metabolism of shikonin and a reverse-phase high performance liquid chromatography/photodiode array detector (DAD) method was used to separate and detect the metabolites . The effects of several factors on the metabolism were investigated and the metabolic system was optimized . The main metabolites were purified by RP-HPLC and their structures were determined by UV, 1H-NMR and MS . S-1 was dihydroxylated shikonin, S-2 was 2-OH shikonin and S-3 was 6-OH or 7-OH shikonin. Pharmacology, 1999 Jul, 59(1), 34 - 44 Effects of green tea catechins on membrane fluidity; Tsuchiya H; Catechins originating from green tea have been used in plaque inhibition for caries prevention and treatment for liver damage because of their antibacterial activity against cariogenic bacteria and protective activity on hepatic cells . The effects of catechins on membrane fluidity were studied by a fluorescence polarization method using liposomes prepared with dipalmitoylphosphatidylcholine and dioleoylphosphatidylcholine to assess their pharmacological mechanism at micromol/l levels found in human body fluids after clinical application . All eight catechins tested, ranging from 1 to 1,000 micromol/l, significantly reduced membrane fluidity in both hydrophilic and hydrophobic regions of lipid bilayers . Catechin gallate esters were superior in fluidity reduction to the corresponding nonesters . The fluidity-reducing degree was different between the cis and trans forms, suggesting the stereospecific activity of catechins . A reference antiplaque agent, chlorhexidine, similarly reduced membrane fluidity at the antibacterial concentration . (+)-Catechin (250 micromol/l) and (-)-epigallocatechin gallate (2.5 micromol/l) significantly prevented the membrane fluidization induced by hepatotoxic chloroform . These results indicate that the reduction in membrane fluidity is responsible for the antiplaque and hepatoprotective effects of green tea catechins. J Biol Chem, 1999 Jun 4, 274(23), 16107 - 14 Porins OmpC and PhoE of Escherichia coli as specific cell-surface targets of human lactoferrin . Binding characteristics and biological effects; Sallmann FR et al.; The binding of lactoferrin, an iron-binding glycoprotein found in secretions and leukocytes, to the outer membrane of Gram-negative bacteria is a prerequisite to exert its bactericidal activity . It was proposed that porins, in addition to lipopolysaccharides, are responsible for this binding . We studied the interactions of human lactoferrin with the three major porins of Escherichia coli OmpC, OmpF, and PhoE . Binding experiments were performed on both purified porins and porin-deficient E . coli K12 isogenic mutants . We determined that lactoferrin binds to the purified native OmpC or PhoE trimer with molar ratios of 1.9 +/- 0.4 and 1.8 +/- 0.3 and Kd values of 39 +/- 18 and 103 +/- 15 nM, respectively, but not to OmpF . Furthermore, preferential binding of lactoferrin was observed on strains that express either OmpC or PhoE . It was also demonstrated that residues 1-5, 28-34, and 39-42 of lactoferrin interact with porins . Based on sequence comparisons, the involvement of lactoferrin amino acid residues and porin loops in the interactions is discussed . The relationships between binding and antibacterial activity of the protein were studied using E . coli mutants and planar lipid bilayers . Electrophysiological studies revealed that lactoferrin can act as a blocking agent for OmpC but not for PhoE or OmpF . However, a total inhibition of the growth was only observed for the PhoE-expressing strain (minimal inhibitory concentration of lactoferrin was 2.4 mg/ml) . These data support the proposal that the antibacterial activity of lactoferrin may depend, at least in part, on its ability to bind to porins, thus modifying the stability and/or the permeability of the bacterial outer membrane. Appl Environ Microbiol, 1999 Jun, 65(6), 2534 - 9 Use of antibacterial agents To elucidate the etiology of juvenile oyster disease (JOD) in Crassostrea virginica and numerical dominance of an alpha-proteobacterium in JOD-affected animals; Boettcher KJ et al.; Since 1988, juvenile oyster disease (JOD) has resulted in high seasonal losses of cultured Eastern oysters (Crassostrea virginica) in the Northeast . Although the cause of JOD remains unknown, most evidence is consistent with either a bacterial or a protistan etiology . For the purpose of discerning between these hypotheses, the antibacterial antibiotics norfloxacin and sulfadimethoxine-ormetoprim (Romet-B) were tested for the ability to delay the onset of JOD mortality and/or reduce the JOD mortality of cultured juvenile C . virginica . Hatchery-produced C . virginica seed were exposed in triplicate groups of 3,000 animals each to either norfloxacin, sulfadimethoxine-ormetoprim, or filter-sterilized seawater (FSSW) and deployed in floating trays on the Damariscotta River of Maine on 17 July 1997 . Each week thereafter, a subset of animals from each group was reexposed to the assigned treatment . Repeated immersion in either a sulfadimethoxine-ormetoprim or a norfloxacin solution resulted in a delay in the onset of JOD mortality in treated animals and reduced weekly mortality rates . Weekly treatments with either norfloxacin or sulfadimethoxine-ormetoprim also resulted in a statistically significant reduction in cumulative mortality (55 and 67% respectively) compared to animals treated weekly with FSSW (81%) or those that had received only a single treatment with either norfloxacin, sulfadimethoxine-ormetoprim, or FSSW (77, 84, and 82%, respectively) . Bacteriological analyses revealed a numerically dominant bacterium in those animals with obvious signs of JOD . Sequence analysis of the 16S rRNA gene from these bacteria indicates that they are a previously undescribed species of marine alpha-proteobacteria. Manag Care Interface, 1999 Feb, 12(2), 92 - 4 Antibacterial management of acute and chronic sinusitis; Gooch WM 3rd; Sinusitis is a common disorder in both children and adults . It is responsible for significant absenteeism from school and work . Up to 10% of upper respiratory infections in children are complicated by acute sinusitis . Since antibacterial therapy is most often empirically chosen to treat the disorder, knowledge of the typical etiologic agents as well as awareness of the antibacterial susceptibility profiles in a given community are of paramount importance . The need for consistently bactericidal antibacterials, the recognition of the importance of nontypable Hemophilus influenzae unresponsive to first-generation cephalosporins, tetracyline-resistant Gram-positive cocci, and the increasing emergence of beta-lactamase-positive respiratory pathogens such as H . influenzae and Moraxella catarrhalis, now mandate the use of newer therapeutic agents for acute and chronic sinusitis. Pharmacoeconomics, 1999 Jan, 15(1), 97 - 113 Economic evaluation of antibacterials in the treatment of acute sinusitis; Laurier C et al.; OBJECTIVE: The objective of this study was to compare costs, efficacy and cost efficacy of alternate oral antibacterial regimens for the ambulatory treatment of acute sinusitis . A public third-party perspective was adopted . DESIGN: The analysis was based on a decision tree and considered the episode of care from the decision to initiate an antibacterial until the end of the first course of treatment or the end of a subsequent course of treatment when needed . Efficacy data were retrieved from published clinical trials . Direct medical costs included the costs of physician visits, diagnostic tests and medications . SETTING: The study pertained to adults treated in a primary-care setting in the Canadian province of Quebec . INTERVENTIONS: The antibacterials studied were amoxicillin, amoxicillin/clavulanate, azithromycin, cefaclor, cefuroxime axetil and clarithromycin . MAIN OUTCOME MEASURES AND RESULTS: The main outcome measured was the proportion of patients showing resolution or improvement of their symptoms . Initiating a treatment with amoxicillin was associated with similar efficacy and lower overall costs when compared with the other antibacterials . Low dosages of clarithromycin and azithromycin followed amoxicillin in terms of cost-efficacy ratio . CONCLUSIONS: This study confirms the place of amoxicillin as a first choice agent for acute sinusitis, with low dose clarithromycin and azithromycin as second choices. Pharmacoeconomics, 1999 Jan, 15(1), 85 - 95 Cost analysis of 2 empiric antibacterial regimens containing glycopeptides for the treatment of febrile neutropenia in patients with acute leukaemia; Bucaneve G et al.; OBJECTIVE: Patients with cancer-associated neutropenia are at high risk of developing severe infections which can be fatal if treatment is not promptly administered . For this reason, fever is treated as soon as possible with broad spectrum antibacterial therapy . The objective of this study was to conduct a cost analysis in Italy comparing 2 empiric glycoprotein-containing antibacterial regimens for the treatment of febrile neutropenia in patients with acute leukaemia . DESIGN AND SETTING: A retrospective cost analysis was conducted, using the records of 527 febrile neutropenic patients with acute leukaemia who participated in an 18-month multicentre (29 Italian haematological units) randomised trial during 1991 . All patients received either of the following 2 empiric intravenous regimens, each containing 3 antibacterial agents: ceftazidime (2 g, 3 times daily) and amikacin (15 mg/kg/day, in 3 separate doses) plus teicoplanin (6 mg/kg, in a single dose) or vancomycin (30 mg/kg/day, in 2 separate doses) . Economic analyses were carried out from a hospital perspective . Only the direct costs per patient, i.e . mean antibacterial treatment and management cost, mean overall treatment failure cost and mean cost of adverse effects, were included . MAIN OUTCOME MEASURES AND RESULTS: No differences were found in the clinical response, defined as the improvement in the rate of fever or infection (if documented), between the 2 regimens . However, tolerability, defined as the incidence of adverse effects probably or definitely related to the assigned treatment, was reported to be better with the teicoplanin-rather than the vancomycin-containing regimen . CONCLUSIONS: Thus retrospective cost analysis showed that despite the higher acquisition cost of teicoplanin relative to vancomycin, the lower incidence of adverse effects associated with teicoplanin and its ease of administration (single daily dose) resulted in equivalent overall treatment costs between teicoplanin- and vancomycin containing regimens. Pharmacoeconomics, 1998 Oct, 14(4), 423 - 32 Threshold analysis of Helicobacter pylori therapy; Sonnenberg A; OBJECTIVE: Conflicting recommendations have been made on whom to treat with antibacterials to eradicate Helicobacter pylori . The present analysis aims to explain the basis of such discrepancies . DESIGN AND SETTING: The decision in favour of or against antibacterial therapy in patients with upper gastrointestinal symptoms is modelled as a threshold analysis . The threshold is the lowest probability for a given diagnosis at which the decision in favour of antibacterial therapy yields a higher expected outcome than the decision against it . A strong indication for antibacterial therapy is shown by a low threshold value . MAIN OUTCOME MEASURES AND RESULTS: In patients with suspected peptic ulcer disease, both the high success rate of antibacterial therapy and its low cost make it the most favourable treatment option, its threshold being less than 35% . In ulcer patients receiving nonsteroidal anti-inflammatory drugs, the threshold is 73% if based on success rates of different treatment modalities, but only 7% if treatment costs are considered . The relatively poor success rate of antibacterial therapy in non-ulcer dyspepsia raises the diagnostic threshold for antibacterial therapy to 76% if based on therapeutic success rates . The small marginal cost of antibacterial therapy lowers the diagnostic threshold to 16% . CONCLUSION: If therapeutic success is the primary concern, patients with vague abdominal symptoms should not be given antibacterial therapy, unless H . pylori has been established as a probable cause of their symptoms . If healthcare costs are the driving force for choosing one type of therapy over another, a trial of antibacterials appears indicated irrespective of any firm validation of H . pylori playing a role in the patient's disease. Pharmacoeconomics, 1998 Oct, 14(4), 385 - 94 Economic impact of aminoglycoside toxicity and its prevention through therapeutic drug monitoring; Slaughter RL et al.; Therapeutic drug monitoring (TDM) of aminoglycoside antibacterials with the goal of minimising toxicity and maximising effectiveness has become routine . Successful management of serious infections requires the ability to achieve therapeutic peak concentrations, while maintaining low trough concentrations will assist in avoiding nephrotoxicity . Reported nephrotoxicity rates range from 1.7 to 58% and depend on the definition used, the patient group studied, concomitant drug therapy used and whether TDM services have been provided . TDM services have been shown to reduce aminoglycoside nephrotoxicity . The costs of providing TDM averages $US301.87 (1997 values) per patient and the cost for each use of nephrotoxicity is estimated at $US4583 (1997 values) . In order for the costs of providing a TDM service to 100 patients ($US30,187) to be offset by cost savings due to decreasing nephrotoxicity, the service would need to be able to reduce nephrotoxicity by 6.6%, resulting in a saving of $US30,248 . The ability to achieve this saving is dependent on the characteristics of the population in which aminoglycoside therapy is used . In populations where high rates of nephrotoxicity (e.g . > 15%) would be expected, TDM services are cost justified . In populations where nephrotoxicity is low (e.g . < 5%), TDM service is not justified for this purpose . In order to provide a cost-efficient approach to TDM, resources should be focused on providing service to high risk patient groups. CLAO J, 1999 Apr, 25(2), 109 - 13 Effects of eyelid scrubbing on the lid margin; Greiner JV et al.; PURPOSE: To compare the effects of eyelid scrubbing with an eyelid cleansing solution (ECS) to eyelid scrubbing with ECS and the addition of antibacterial or anti-inflammatory pharmaceuticals on the clinical appearance, microbial status, tissue histology, and the inflammatory cell profile of the normal eyelid margin . METHODS: Eyelid scrubbing was performed twice daily using ECS; ECS with the antibacterial sulfacetamide (ECS+); and ECS with sulfacetamide and prednisolone acetate (ECS++) over a 21 day period on three groups of 16 rabbits with clinically normal eyelids . RESULTS: Significant hyperemia of the margin occurred in all three groups over the 3 week period; however, the degree of hyperemia was less with ECS+ (P<0.05) and ECS++ (P<0.05) . Chemosis, tearing, mucus discharge, and the microbial status were not significantly different than controls . There were no marked histologic differences in the tissues, except for increased red blood cell packing in the small vessels near the lid margins in scrubbed eyelids, consistent with hyperemia . The inflammatory cell profile showed minimal changes that were not statistically significant in any of the three groups, except that >50% of mast cells showed evidence of degranulation . CONCLUSIONS: Use of ECS with an antibiotic, or an antibiotic and steroid solution, resulted in less inflammation than scrubbing with ECS alone. Eur J Emerg Med, 1999 Mar, 6(1), 41 - 7 Comparison of four drugs for local treatment of burn wounds; Hadjiiski OG et al.; Effective local treatment is very important in preventing wound infection and its generalization and ensuring successful skin grafting . The aim of our study is to compare the activity of four topical agents {deflamol (20 patients), polyvidone-iodine (21 patients), flammazine (silver sulphadiazine--SSD) (28 patients) and flammacerium (SSD with cerium nitrate) (five patients)} for treatment of patients with burns by confirming our clinical observations of their efficacy with comparative bacteriological investigations . The final estimation of our results showed the undoubted priority of flammazine and flammacerium over deflamol and polyvidone-iodine, as the treatment of all the patients with these two drugs gave very good and good results, respectively . In contrast, the results in 70% of the patients from the deflamol group and in 52.4% of those from the polyvidone-iodine group were unsatisfactory . At this stage we cannot find any significant differences in the antibacterial activity between flammazine and flammacerium . However, the excision of the firm eschars formed by flammacerium is easier and it gives the opportunity to postpone operation for a month or more . In conclusion we found suitable indications for preference of each of the topical agents included in our study. Neuropharmacology, 1999 May, 38(5), 717 - 23 Characterization of quinolone antibacterial-induced convulsions and increases in nuclear AP-1 DNA- and CRE-binding activities in mouse brain; Ito Y et al.; The quinolone antibacterials enoxacin and norfloxacin (2.5 mg/kg, i.v.) provoked clonic convulsions in mice treated concomitantly with biphenylacetic acid (BPAA, 100 mg/kg, i.p.), a major metabolite of the nonsteroidal anti-inflammatory drug fenbufen . Gel-shift assays showed that enoxacin-induced convulsions resulted in increases in nuclear activator protein 1 (AP-1) DNA- and cyclic AMP responsive element (CRE)-binding activities in the cerebral cortex and hippocampus, but not in other regions, such as the cerebellum and thalamus . In contrast, ofloxacin and levofloxacin, at the same doses, in the presence of BPAA did not evoke convulsions or increase these DNA-binding activities . Administration of these quinolones and BPAA alone elicited neither convulsions nor increases in these DNA-binding activities . These results suggest that the increased nuclear AP-1 DNA- and CRE-binding activities in the cerebral cortex and hippocampus induced by quinolones with BPAA correlated with seizure activities and that these brain regions play pivotal roles in quinolone-induced convulsions. J Small Anim Pract, 1999 Apr, 40(4), 158 - 62 Compliance with short-term oral antibacterial drug treatment in dogs; Grave K et al.; Compliance with a 10-day course of oral antibacterial drugs in dogs being treated as outpatients at a veterinary clinic was assessed by use of pill count data obtained by telephone interview . The association between compliance and several possible determinants of compliance was investigated . Ninety-five animal owners were included in the study, with 44 per cent reporting 100 per cent compliance with the treatment regimen and as many as 88 per cent reporting a compliance level of 80 per cent or more . The compliance level was significantly higher (P < 0.002) when the animal owners felt that the veterinarians spent enough time on the consultation . Moreover, compliance was significantly higher (P < 0.05) for dogs being treated for gastrointestinal infections compared with those being treated for other diseases. Pharmacotherapy, 1999 May, 19(5), 641 - 7 Experience with ceftazidime parenteral-to-parenteral dosage stepdown in the empiric treatment of febrile neutropenia; Schwagly N et al.; We assessed the clinical and economic impact of a new parenteral-toparenteral stepdown program involving ceftazidime for the treatment of febrile neutropenia . This was a two-phase (before and after), 12-month, single-center, prospective study with a historical control . Ninety-eight ceftazidime treatment courses (47 preintervention, 51 postintervention) were administered for management of febrile neutropenia in 85 adults with hematologic malignancies . Multidisciplinary creation and promotion of parenteral-to-parenteral ceftazidime stepdown criteria were applied at the discretion of the health care team . Patient demographics between phases were similar . Only 2 (4%) treatment courses before the intervention involved parenteral-to-parenteral dosage stepdown, compared with 34 (67%) after the intervention (p<0.00001) . Mean number of total ceftazidime doses/treatment course and mean duration of therapy did not change between phases . Clinical cure or improvement was identified in 74% and 80% of treatment courses before and after the intervention, respectively . The two main reasons for discontinuing the drug before the intervention were recovery of neutrophil count (60%) and adverse reactions (19%) . Neutrophil count recovery (59%) and hospital discharge (14%) were the two most common reasons for discontinuation after the intervention . Of 34 stepdown treatment courses after the intervention, 3 (9%) failed to meet established stepdown criteria, and 2 of these required stepdown reversal . Ancillary antibacterial drugs and treatment course outcomes were similar between phases . Total ceftazidime acquisition cost for 704 treatment days in the preintervention phase was $52,473 CAN compared with $54,778 CAN for 907 days of therapy in the postintervention phase . The mean acquisition cost/ceftazidime treatment course was $1100 CAN and did not differ between phases . The mean daily cost of ceftazidime therapy was lower after the intervention ($60.39 vs $74.54 CAN) as a result of a greater frequency of stepdown (p<0.001) . Assuming an equivalent number of treatment days, the projected annual acquisition cost avoidance associated with this stepdown program was $19,900 CAN. Arch Pharm (Weinheim), 1999 Apr, 332(4), 111 - 4 Synthesis and antibacterial activity of 1 beta-methylcarbapenem having a 1,3-diazabicyclo{3.3.0}octan-4-one moiety, Part II; Oh CH et al.; The synthesis of a new series of 1 beta-methylcarbapenems having a 1,3-diazabicyclo{3.3.0}octan-4-one moiety is described . Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria are tested and the effect of substituent on the bicyclic ring was investigated . A particular compound (11 h) having aminoethyl group showed the most potent antibacterial activity. J Chromatogr A, 1999 Apr 16, 839(1-2), 183 - 92 Electrophoretic behaviour of quinolones in capillary electrophoresis . Effect of pH and evaluation of ionization constants; Barbosa J et al.; Quinolones are a family of antibacterial agents that are used extensively in both human and veterinary clinics . Their antibacterial activity is pH-dependent, and therefore an examination of protonation equilibria in quinolone solution is essential . In this work, dissociation constants of quinolones in water were obtained using capillary electrophoresis (CE) . The method is based on measuring the electrophoretic mobility of the solute as a function of pH . Mobility and pH data are fitted using different models . These developed equations have two advantages . They permit the determination of pKa of analytes with the advantages of CE and also permit the prediction of the effect of pH on the electrophoretic behaviour of substances and then the prediction of the pH optimum for the separation methods, using the minimum of experimental measurements. Comp Biochem Physiol A Mol Integr Physiol, 1999 Feb, 122(2), 181 - 9 Pore-forming properties and antibacterial activity of proteins extracted from epidermal mucus of fish; Ebran N et al.; Among several biological functions, the epidermal mucus of fish may play an important role in host defense, particularly in the prevention of colonization by parasites, bacteria and fungi . In previous work, two hydrophobic proteins of 27 and 31 kDa were isolated from carp mucus . This study identified a strong antibacterial activity (0.16-0.18 microM) well correlated with pore-forming properties . Here this work was extended to other fish species, four fresh water fish and one sea water fish . After a first step of purification, water-soluble and hydrophobic material were separated, and both fractions were analyzed by SDS-PAGE and capillary electrophoresis . Only the hydrophobic component induced pore-forming activity, when reconstituted in planar lipid bilayers . This pore-forming activity was well correlated to a strong antibacterial activity against several bacteria strains . These results suggest that fish secrete antibacterial proteins able to permeabilize the membrane of the target cell and thus act as a defense barrier. J Capillary Electrophor, 1998 Jan-Apr, 5(1-2), 45 - 50 Capillary electrophoresis and liquid chromatography in the analysis of some quaternary ammonium salts used in lozenges as antibacterial agents; Taylor RB et al.; A comparison is made of the relative merits of high-performance liquid chromatography and capillary electrophoresis, both using direct UV detection, for the determination of three quaternary ammonium compounds used as the active antibacterial ingredient in lozenge formulations . While both techniques are capable of separating the compounds cetylpyridinium chloride, dequalinium chloride, and benzalkonium chlorides, the liquid chromatographic method involving ion pairing and using a 5-micron cyanopropyl stationary phase, was unable to resolve the benzalkonium chlorides from the lozenge excipients and quantitation was not possible . The capillary electrophoresis method using a 205-mm 50-micron-i.d . capillary with a running buffer of 50% vol/vol 50 mM phosphate buffer at pH 3 provided superior resolution of the three antibacterials in all lozenge formulations . This system was also capable of resolving impurities in the dequalinium chloride both in the standard and in lozenges containing this compound . On the basis of quantitative results previously published, both methods have adequate validation parameters since the relative insensitivity of capillary electrophoresis compared with liquid chromatography is not important at the concentration required to be determined following a single simple sample pretreatment. Burns, 1999 May, 25(3), 250 - 5 Development in the treatment of burns in South America during the last decades; Benaim F et al.; The scientific approach toward the problems of burn treatment in South America started in the 1930's and was emphasized in the 1940's as a result of the positive influence of the Latin American Congresses of Plastic Surgery initiated in 1941 . During the 1950's, as an appropriate answer to the problem, specialized burns facilities started to spread over the Latin American countries . Consequently, there was a progressive incorporation of very important advances such as a more adequate fluid replacement, early excision and grafting, enteral feeding, new topical antibacterial agents, a more appropriate approach for the prevention and treatment of infections, a better understanding of the smoke inhalation injury and better management of physical and psychological rehabilitation . Thus, during the past 25 years, burn care has dramatically evolved toward excellence . The Latin American Committee for Prevention and Care of Burns, created in 1964 was one important land-mark in the development of burn treatment in South America . The creation of Burn Associations in many South American countries was initiated in 1990, and culminated in 1991 when the Latin American Federation of Burn Associations was founded . These developments illustrate how the specialists in the South American countries have followed the tune of international progress . They constitute at this time, an important group of committed workers, not only to the treatment of burned patients but also to the scientific and academic side of this specialty. Arch Pharm Res, 1994 Apr, 17(2), 87 - 92 Synthesis and antibacterial activity of new cephalosporins with lactonyloxyimino moiety; Suh KH et al.; A series of 7- inverted question mark2-(2-aminothiazol-4-yl)-2-Z-(gamma-lacton-3-yl)oxyimin oacetamido inverted question mark cephalosporins with various substituents at the 3-position in cephem nucleus were synthesized and evaluated microbiologically . The tested compounds showed potent activities but were somewhat less active than cefotaxime or cefixime against a wide variety of Gram-positive and Gram-negative bacteria. Arch Pharm Res, 1991 Mar, 14(1), 48 - 51 Nalidixic acid prodrugs: amides from amino acid ester and nalidixic acid; Taori A et al.; Amides from amino acid ester and nalidixic acid were synthesized . The solubility characteristics and partition coefficient of the compounds were studied . The hydrolysis of the compounds was studied in the simulated gastric fluid and simulated intestinal fluid . Some compounds showed better antibacterial activity than nalidixic acid. Ann Surg, 1999 May, 229(5), 662 - 7; discussion 667-8 Route and type of nutrition influence IgA-mediating intestinal cytokines; Wu Y et al.; OBJECTIVE: To examine the levels of a Th1 IgA-inhibiting cytokine (interferon gamma) and the Th2 IgA-stimulating cytokines (interleukin {IL}-4, IL-5, IL-6, and IL-10) within the intestine of animals manipulated with enteral or parenteral nutrition, and to correlate these cytokine alterations with intestinal IgA levels . SUMMARY BACKGROUND DATA: Enteral feeding significantly reduces the incidence of pneumonia in critically injured patients compared with intravenous total parenteral nutrition (IV TPN) or no nutritional support . Experimentally, complex diets prevent impairments in mucosal immunity induced by IV TPN . These impairments include decreases in intestinal and respiratory tract IgA levels, impaired IgA-mediated antiviral defenses, and increases in the mortality rate against established immunity to Pseudomonas pneumonia . Intragastric (IG) TPN maintains antiviral defenses but only partially preserves protection against Pseudomonas pneumonia . Because IgA levels depend on interactions between Th1 IgA-inhibiting and Th2 IgA-stimulating cytokines, the authors postulated differences in gut cytokine balance in enterally and parenterally fed mice . METHODS: Sixty-one mice were randomized to receive chow, IV TPN, IG TPN, or an isocaloric, complex enteral diet . After 5 days of feeding, animals were killed and supernatants from samples of intestine were harvested, homogenized, and assayed for Th1 and Th2 cytokines by enzyme-linked immunosorbent assay . RESULTS: The Th2 cytokines, IL-5 and IL-6, and the Th1 cytokine, interferon gamma, remained unchanged by diet . IL-4 levels decreased significantly in both IV and IG TPN groups versus the chow or complex enteral diet groups, whereas IL-10 decreased only in IV TPN mice . Decreases in Th2 cytokines correlated with intestinal IgA levels . CONCLUSION: Chow and complex enteral diets maintain a normal balance between IgA-stimulating and IgA-inhibiting cytokines while preserving normal antibacterial and antiviral immunity . The IgA-stimulating cytokine IL-4 drops significantly in mice receiving IG and IV TPN in association with reduced IgA levels, whereas IL-10 decreases significantly only in mice receiving IV TPN . These data are consistent with severely impaired mucosal immunity with IV TPN and partial impairment with IG TPN and provide a cytokine-mediated explanation for reduction in diet-induced mucosal immunity. Klin Lab Diagn, 1999 Mar, (3), 34 - 7 {Comparative study of results of serological diagnosis of Lyme borreliosis by indirect immunofluorescence and immunoenzyme analysis}; Kufko IT et al.; A total of 176 sera from 73 patients with verified Lyme borreliosis at different stages of the disease are examined . Serological diagnosis was carried out by 2 methods: indirect immunofluorescence (IIF) with corpuscular B . burgdorferi antigen and enzyme immunoassay (EIA) with purified flagellar B . burgdorferi antigen (Dako) . EIA with Dako antigen is more sensitive for the diagnosis of Lyme borreliosis at any period of the disease than IIF . Analysis of correlations between the results of IIF and EIA showed correlation in the levels of IgG but not IgM antibodies . The findings confirmed a previous hypothesis that inadequate antibacterial therapy before investigation decreases the leve