Int J Antimicrob Agents, 2000 Oct, 16(2), 93 - 5 Unusual presentations of infection in neutropenic patients; Bodey GP; Neutropenic patients may have unusual presentations of infection because of their inability to mount an adequate inflammatory response and their susceptibility to infection caused by less virulent organisms . About 60% of febrile episodes are associated with no other signs and symptoms and no infecting organism can be identified, yet most respond to antibacterial therapy . If not treated promptly, infection in neutropenic patients can progress rapidly . Unusual sites of infection include typhlitis, perirectal infections and atypical forms of cellulitis. J Biol Chem, 2000 Nov 3, 275(44), 34780 - 6 DNA gyrase-mediated wrapping of the DNA strand is required for the replication fork arrest by the DNA gyrase-quinolone-DNA ternary complex; Hiasa H et al.; The ability of DNA gyrase (Gyr) to wrap the DNA strand around itself allows Gyr to introduce negative supercoils into DNA molecules . It has been demonstrated that the deletion of the C-terminal DNA-binding domain of the GyrA subunit abolishes the ability of Gyr to wrap the DNA strand and catalyze the supercoiling reaction (Kampranis, S . C., and Maxwell, A . (1996) Proc . Natl . Acad . Sci . U . S . A . 93, 14416-14421) . By using this mutant Gyr, Gyr (A59), we have studied effects of Gyr-mediated wrapping of the DNA strand on its replicative function and its interaction with the quinolone antibacterial drugs . We find that Gyr (A59) can support oriC DNA replication in vitro . However, Gyr (A59)-catalyzed decatenation activity is not efficient enough to complete the decatenation of replicating daughter DNA molecules . As is the case with topoisomerase IV, the active cleavage and reunion activity of Gyr is required for the formation of the ternary complex that can arrest replication fork progression in vitro . Although the quinolone drugs stimulate the covalent Gyr (A59)-DNA complex formation, the Gyr (A59)-quinolone-DNA ternary complexes do not arrest the progression of replication forks . Thus, the quinolone-induced covalent topoisomerase-DNA complex formation is necessary but not sufficient to cause the inhibition of DNA replication . We also assess the stability of ternary complexes formed with Gyr (A59), the wild type Gyr, or topoisomerase IV . The ternary complexes formed with Gyr (A59) are more sensitive to salt than those formed with either the wild type Gyr or topoisomerase IV . Furthermore, a competition experiment demonstrates that the ternary complexes formed with Gyr (A59) readily disassociate from the DNA, whereas the ternary complexes formed with either the wild type Gyr or topoisomerase IV remain stably bound . Thus, Gyr-mediated wrapping of the DNA strand is required for the formation of the stable Gyr-quinolone-DNA ternary complex that can arrest replication fork progression. Pediatr Infect Dis J, 2000 Oct, 19(10 Suppl), S120 - 2 Antibiotic and antiseptic resistance: impact on public health; Levy SB; More and more we are moving patients from hospitals to homes for continued treatment . Vancomycin and triclosan were used for 30 years before any resistance emerged, because their applications were strictly limited . Today, after greatly increased use, resistance to both antibiotics and antibacterials has appeared . Of importance there are genetic links between resistance to antibiotics and to antibacterials . Health professionals and the public need to be educated about the rational use of drugs that affect the microbial world . The Alliance for the Prudent Use of Antibiotics, an international organization established in 1981 with members in more than 100 countries, has adopted education as its prime mission . Via its web site and linked information on reservoirs of antibiotic resistance (ROAR) among nonpathogenic bacteria, it reaches both providers and consumers . The message is simple: bacteria are needed for our survival . The vast majority of bacteria perform important functions that are crucial for our lives . Prudent use of both antibiotics and antibacterials must be championed to achieve and maintain the balanced microbial environment in which we have entered and evolved. Klin Med (Mosk), 2000, 78(9), 44 - 7 {Upgrading efficiency and safety of combined antihelicobacterial treatment of ulcer patients using modern clinicopharmacological approaches}; Bezborodnyi SD; Therapeutic monitoring of ranitidine and omeprasol using automatic analyser REMEDi HS Drug Profiling System (Bio-Rad, USA) was performed in 120 patients with morphologically verified ulcer associated with Helicobacter pylori . The addition of antibacterial drugs elevated concentration of blood ranitidine, omeprasol being stable . The highest therapeutic effectiveness was achieved with combination of ranitidine plus metronidasol and jozamycin as well as omeprasol plus metronidasol and claritromycin . Ulcer patients with concomitant hepatobiliary diseases significantly more frequently developed side effects of antihelicobacterial therapy and the rise of ranitide and omeprasol concentrations in blood can serve a prognostic criterium of their appearance . As the highest tolerance was observed in the treatment with combination ranitidine + metronidasol + oletetrin, this regimen is recommended as the safest antihelicobacterial therapy. Drug Saf, 2000 Oct, 23(4), 333 - 49 Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data; Lawrenson RA et al.; OBJECTIVE: Minocycline is an antibacterial drug used in the treatment of acne . Concern has been expressed over the possibility of severe adverse reactions to minocycline, including hepatitis . This study set out to identify and characterise reported cases of hepatotoxicity associated with the use of minocycline . METHODS: A systematic review of the literature including a search of computerised databases and analysis of data from the Uppsala Monitoring Centre (WHO Collaborating Centre for International Drug Monitoring) was conducted . The review involved a search for original case reports involving liver damage in people using minocycline . Patients taking minocycline for reasons other than acne or those given intravenous minocycline were excluded . The search strategy involved an enquiry of computerised databases and a search for secondary references . Cases were then classified appropriately . RESULTS: 65 reported cases of hepatitis or liver damage in association with minocycline from either case reports or case series were identified from the literature review . 58% of cases occurred in females and 94% were aged under 40 years . For 20 case reports there was insufficient information to classify the type of event, but for the remaining 45, 2 types of hepatic reaction were recognised: autoimmune hepatitis associated with lupus-like symptoms occurring after a median duration of exposure to minocycline of 365 days in females (n = 20) and 730 days in males (n = 9), hypersensitivity reaction associated with eosinophilia and exfoliative dermatitis occurring within 35 days of therapy (n = 16) . Reports to the WHO of hepatic adverse drug reactions associated with minocycline accounted for 6% (493) of all minocycline-related adverse drug reactions (8025) . The pattern of distribution in relation to exposure demonstrated 2 groups, similar to that described by the case reports . CONCLUSIONS: Severe cases of minocycline-associated hepatotoxicity appear to be a hypersensitivity reaction and occur within a few weeks of commencing therapy . An autoimmune hepatitis usually presents after exposure to minocycline of a year or more, is more common in women and is sometimes associated with lupus-like symptoms. Clin Infect Dis, 2000 Oct, 31(4), 910 - 3 Epub 2000 Oct 11. Cluster of pulmonary infections caused by Cunninghamella bertholletiae in immunocompromised patients; Rickerts V et al.; Cunninghamella bertholletiae is a rare cause of pulmonary mucormycosis . We describe a cluster of invasive pulmonary infections caused by C . bertholletiae in 4 immunocompromised patients that occurred during a 2-year period at 1 center . Three of the patients were receiving antifungal prophylaxis with itraconazole . Presenting symptoms were fever unresponsive to antibacterial chemotherapy, hemoptysis, and infiltrates on chest radiograms . Three patients were treated with liposomal amphotericin B . Only 1 patient survived. Anticancer Drug Des, 2000 Jun, 15(3), 191 - 201 DNA intercalation, topoisomerase II inhibition and cytotoxic activity of the plant alkaloid neocryptolepine; Bailly C et al.; Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta . Both drugs have revealed antibacterial and antiparasitic activities and are strongly cytotoxic to tumour cells . We have recently shown that cryptolepine can intercalate into DNA and stimulates DNA cleavage by human topoisomerase II . In this study, we have investigated the mechanism of action and cytotoxicity of neocryptolepine, which differs from the parent isomer only by the orientation of the indole unit with respect to the quinoline moiety . The biochemical and physicochemical results presented here indicate that neocryptolepine also intercalates into DNA, preferentially at GC-rich sequences, but exhibits a reduced affinity for DNA compared with cryptolepine . The two alkaloids interfere with the catalytic activity of human topoisomerase II but the poisoning activity is slightly more pronounced with cryptolepine than with its isomer . The data provide a molecular basis to account for the reduced cytotoxicity of neocryptolepine compared with the parent drug. Arch Latinoam Nutr, 2000 Jun, 50(2), 113 - 20 {Cariogenicity and cariostatic properties of different types of milk-review}; Duarte PM et al.; The purpose of this study is to introduce some information about local and systemic effects of different kinds of milk in oral health, through the explicitness of its cariogenicity and cariostatic properties . Different kinds of milk and milk products are consumed most commonly by the worldwide population, raising the interest of researchers in its influence in the oral health for some decades . Several studies have been conducted to associate the consumption of bovine-, human- and infant formula-milk with caries development and other dental defect, but controversial results have not been able to define the cariogenic and cariostatic potential of different kinds of milk . Bovine milk has some cariostatic components as casein, lipids and antibacterial enzyme, though it has 4% lactose, supposedly cariogenic sugar . Human milk has been related to a sort of caries which is like bottle caries, even though some studies have demonstrated its non cariogenicity . The infant formula milk, which is elaborated for specific period in the childhood, has received low control on its potential for developing caries . It could be of great value to elucidate the controversy surrounding the cariogenicity and cariostatic properties of different kinds of milk, concerning caries prevention during infant and adult life. Bioorg Khim, 2000 Aug, 26(8), 631 - 40 {Study of dimerization of polysynthetic derivatives of the antibiotic eremomycin by ESI MS and its role in elucidating antibacterial activity}; Mirgorodskaia OA et al.; The dimerization constants for glycopeptide antibiotics vancomycin, ristocetin, and eremomycin and nine semisynthetic eremomycin derivatives were determined by the electrospray ionization mass spectrometry; the constants for natural antibiotics turned out to be close to those previously determined by NMR . No correlation between these dimerization constants and antibacterial activities of all the compounds toward the clinical strains of Gram-positive bacteria was found. Zhongguo Zhong Yao Za Zhi, 1997 Oct, 22(10), 613 - 5, 640 {Phenylethanoid glucosides from flos Buddlejae}; Li J et al.; Four phenylethanoid glucosides were isolated from the flower of Buddleja officinalis . On the basis of specteral data, they were identified as salidroside(1), verbascoside(2), isoverbascoside(3) and echinacoside(4) . Compounds 1, 3 and 4 were obtained from the plant for the first time . Compound 2 showed antibacterial and anticancer activities. Klin Khir, 2000 Aug, (8), 5 - 8 {Antibacterial therapy of patients with inflammatory necrotic pancreatitis}; Saenko VF et al.; The infectionized necrotic pancreatitis (NP) course, complicated by localized and diffusive peritonitis, abscess and retroperitoneal phlegmon in 86 patients, was analyzed . Severity of state of patients according to the APACHE II scale was estimated . Recommendations for application of empirical and purposeful antibacterial therapy was elaborated . Total mortality for infectionized NP with complicated course was 25.5%. J Immunol, 2000 Oct 15, 165(8), 4697 - 703 The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18; Kurosawa S et al.; The protein C pathway is a primary regulator of blood coagulation and a critical component of the host response to inflammatory stimuli . The most recent member of this pathway is the endothelial protein C receptor (EPCR), a type I transmembrane protein with homology to CD1d/MHC class I proteins . EPCR accelerates formation of activated protein C, a potent anticoagulant and antiinflammatory agent . The current study demonstrates that soluble EPCR binds to PMA-activated neutrophils . Using affinity chromatography, binding studies with purified components, and/or blockade with specific Abs, it was found that soluble EPCR binds to proteinase-3 (PR3), a neutrophil granule proteinase . Furthermore, soluble EPCR binding to neutrophils was partially dependent on Mac-1 (CD11b/CD18), a beta(2) integrin involved in neutrophil signaling, and cell-cell adhesion events . PR3 is involved in multiple diverse processes, including hemopoietic proliferation, antibacterial activity, and autoimmune-mediated vasculitis . The observation that soluble EPCR binds to activated neutrophils via PR3 and a beta(2) integrin suggests that there may be a link between the protein C anticoagulant pathway and neutrophil functions. Ann Surg Oncol, 2000 Oct, 7(9), 685 - 91 Taurolidine inhibits tumor cell growth in vitro and in vivo; McCourt M et al.; BACKGROUND: Taurolidine, a derivative of the amino acid taurine, exhibits antiendotoxin, antibacterial, and antiadherence activity . We hypothesized that Taurolidine may inhibit tumor cell growth, both in an in vitro and in vivo setting . Our aim was to examine the effect of Taurolidine on the growth of a rat metastatic colorectal tumor cell line (DHD/K12/TRb) in vitro and in vivo . METHODS: In the in vitro experiments, DHD/K12/TRb cells were incubated with 5, 10, 15, 25, microg/ml of Taurolidine . Cells incubated in culture medium alone were used as controls . Cell proliferation, cell viability, cell death, and cell apoptosis were measured using commercially available techniques . In the in vivo experiment, BD IX rats were randomized into two groups (n = 10/group) . Group A (control) underwent laparotomy and instillation of DHD/K12/TRb tumor cells intraperitoneally followed by phosphate buffered saline (PBS) . Group B received Taurolidine (100 mg/kg) instead of PBS . Animals were killed after 24 days and tumor burden assessed by counting the number of tumor nodules in the peritoneal cavity . RESULTS: Incubation of the tumor cells with Taurolidine resulted in a 4-fold decrease in proliferation rates (25+/-4% vs . 100+/-28% for controls) and a 4-fold increase in cell necrosis as demonstrated by the increase in LDH release (403+/-28% vs . 100+/-26% for controls), at a Taurolidine concentration of 25 microg/ml . A dose-dependent decrease in cell viability was also observed . In the in vivo study, local Taurolidine administration resulted in significant decreases in tumor burden (3+/-1 nodules in Group B animals vs . 649+/-101 nodules in Group A animals) . CONCLUSIONS: Taurolidine inhibits the growth of a rat metastatic colorectal tumor cell line in vitro and in vivo and thus may have potential in the prevention of peritoneal metastases. J Clin Periodontol, 2000 Oct, 27(10), 733 - 7 Effect of triclosan on interferon-gamma production and major histocompatibility complex class II expression in human gingival fibroblasts; Mustafa M et al.; BACKGROUND, AIMS: The effect of triclosan (2,4,4'-trichloro-2'-hydroxyl-diphenyl ether) on the production of interferon-gamma (IFN-gamma) and the expression of major histocompatibility complex (MHC) class II antigen was studied in human gingival fibroblasts isolated from 4 individuals . METHODS/RESULTS: All cell lines demonstrated high IFN-gamma production in 24-h cultures of human gingival fibroblasts stimulated by phytohemagglutinin (PHA) (5 microg/ml) . Human gingival fibroblasts showed a high expression of MHC class II when stimulated with 500 and 1,000 pg/ml rIFN-gamma in 7-day cultures . Treatment of the cells with triclosan (0.5 microg/ml) reduced both IFN-gamma production and MHC class II expression in human gingival fibroblast cultures . Similar inhibitory effects on IFN-gamma production and MHC class II expression were observed when the anti-inflammatory agent dexamethazone (1 microM) was used . CONCLUSION: The present study further supports the view that the agent has an anti-inflammatory effect in addition to its antibacterial capacity. Lik Sprava, 2000 Jul-Aug, (5), 77 - 80 {Seasonal fluctuations in the exocrine function of the pancreas, the state of the antioxidant system of protection and the efficacy of ethonium in chronic pancreatitis}; Khrystych TM; A differentiated approach is substantiated toward treatment with aethonium (antibacterial, antiinflammatory, antioxidant drug preparation) of chronic pancreatitis with special reference to the status of lipid peroxidation, glutathionic link of antioxidant defence, and exocrine function of the pancreas (season-related rhythm of its activity), in different forms and degrees of severity included. Biochim Biophys Acta, 2000 Aug 25, 1467(2), 271 - 80 Isolation and characterization of novel glycoproteins from fish epidermal mucus: correlation between their pore-forming properties and their antibacterial activities; Ebran N et al.; In fish, a layer of mucus covers the external body surface contributing therefore, among other important biological functions, to the defense system of fish . The prevention of colonization by aquatic parasites, bacteria and fungi is mediated both by immune system compounds (IgM, lysozyme, etc.) and by antibacterial peptides and polypeptides . We have recently shown that only the hydrophobic components of crude epidermal mucus of fresh water and sea water fish exhibit strong pore-forming properties, which were well correlated with antibacterial activity {N . Ebran, S . Julien, N . Orange, P . Saglio, C . Lemaitre, G . Molle, Comp . Biochem . Physiol . 122 (1999)} . Here, we have isolated novel glycosylated proteins from the hydrophobic supernatant of tench (Tinca tinca), eel (Anguilla anguilla) and rainbow trout (Oncorhynchus mykiss) mucus . The study of their secondary structure was performed by circular dichroism and revealed structures in random coil and alpha-helix in the same proportions . When reconstituted in planar lipid bilayer, they induced the formation of ion channels . This pore-forming activity was well correlated with a strong antibacterial activity (minimal inhibitory concentration < 1 microM for the three proteins) against both gram-negative and gram-positive bacteria . Our results suggest that fish secrete antibacterial glycoproteins able to kill bacteria by forming large pores (several hundreds to thousands of pS) in the target membrane. J Comb Chem, 2000 Sep-Oct, 2(5), 467 - 74 Solution-phase synthesis of a 1,5-dialkylamino-2,4-dinitrobenzene library and the identification of novel antibacterial compounds from this library; Liu G et al.; In this report we demonstrate that a 1,5-dialkylamino-2,4-dinitrobenzene small molecule library can be generated by a highly efficient solution-phase synthesis method . From this 2485-member library, a series of novel compounds with antibacterial activity were isolated . The significance of this report is that the synthetic scheme is extremely simple, with minimal number of liquid handling steps, and the solvents and reagents left in the final library preparation are fully compatible with cell-based assays. J Cardiovasc Pharmacol, 2000 Oct, 36(4), 510 - 5 QT-prolonging effects of sparfloxacin, a fluoroquinolone antibiotic, assessed in the in vivo canine model with monophasic action potential monitoring; Satoh Y et al.; Sparfloxacin, a fluoroquinolone antibacterial agent, prolongs cardiac repolarization, which may predispose to torsades de pointes . This study was designed to assess simultaneously the hemodynamic and electrophysiologic effects of sparfloxacin using the halothane-anesthetized, closed-chest in vivo canine model (n = 6) . Sparfloxacin was intravenously administered in the following two doses with a pause of 20 min, a clinically relevant dose of 3.0 mg/kg/10 min and a 10 times higher dose of 30 mg/kg/10 min . After the low dose of sparfloxacin, cardiac output increased, heart rate decreased, and ventricular repolarization and refractory periods were prolonged . After the high dose, cardiac output increased, whereas heart rate and mean blood pressure decreased, and ventricular repolarization and effective refractory periods were prolonged . The increment was greater in repolarization than in refractoriness, indicating an increase of electrical vulnerability . Because sparfloxacin prolonged repolarization in a reverse use-dependent manner, its negative chronotropic effect may have potentiated the QT prolongation . Left ventricle preload, left ventricular contraction, and AV nodal as well as intraventricular conduction were minimally affected . These results suggest that caution should be used when administering sparfloxacin to patients having risk factors for QT prolongation. Toxicol Pathol, 2000 Sep-Oct, 28(5), 643 - 8 Cecal torsion in rodents associated with chronic administration of clinafloxacin; Courtney CL; The chronic toxicity of clinafloxacin, a fluoroquinolone antibacterial agent, was evaluated in multiple strains of mice and rats . In 5 separate studies, mice and rats that were orally administered up to 1,000 mg/kg of clinafloxacin from 9 to 104 weeks developed dose-related cecal dilatation and deaths that were attributable to cecal torsion . Cecal rupture was observed in association with torsion . Although cecal dilatation is commonly observed in rodents given antibacterials such as fluoroquinolones, cecal torsion has not been a reported sequelae to dilatation. IEEE Trans Inf Technol Biomed, 2000 Sep, 4(3), 225 - 37 A family competition evolutionary algorithm for automated docking of flexible ligands to proteins; Yang JM et al.; In this paper, we study an evolutionary algorithm for flexible ligand docking . Based on family competition and adaptive rules, the proposed approach consists of global and local strategies by integrating decreasing mutations and self-adaptive mutations . To demonstrate the robustness of the proposed approach, we apply it to the problems of the first international contests on evolutionary optimization . Following the description of function optimization, our approach is applied to a dihydrofolate reductase enzyme with the anti-cancer drug methotrexate and with two analogs of the antibacterial drug trimethoprim . Our numerical results indicate that the proposed approach is robust . The docked lowest energy structures have rms derivations ranging from 0.72 A to 1.98 A with respect to the corresponding crystal structure. Clin Microbiol Rev, 2000 Oct, 13(4), 615 - 50 Interference of antibacterial agents with phagocyte functions: immunomodulation or "immuno-fairy tales"? Labro MT. Professional phagocytes (polymorphonuclear neutrophils and monocytes/macrophages) are a main component of the immune system . These cells are involved in both host defenses and various pathological settings characterized by excessive inflammation . Accordingly, they are key targets for immunomodulatory drugs, among which antibacterial agents are promising candidates . The basic and historical concepts of immunomodulation will first be briefly reviewed . Phagocyte complexity will then be unravelled (at least in terms of what we know about the origin, subsets, ambivalent roles, functional capacities, and transductional pathways of this cell and how to explore them) . The core subject of this review will be the many possible interactions between antibacterial agents and phagocytes, classified according to demonstrated or potential clinical relevance (e.g., neutropenia, intracellular accumulation, and modulation of bacterial virulence) . A detailed review of direct in vitro effects will be provided for the various antibacterial drug families, followed by a discussion of the clinical relevance of these effects in two particular settings: immune deficiency and inflammatory diseases . The prophylactic and therapeutic use of immunomodulatory antibiotics will be considered before conclusions are drawn about the emerging (optimistic) vision of future therapeutic prospects to deal with largely unknown new diseases and new pathogens by using new agents, new techniques, and a better understanding of the phagocyte in particular and the immune system in general. Microbiology, 2000 Oct, 146 ( Pt 10), 2375 - 84 Phylogeny of the replication regions of pPT23A-like plasmids from Pseudomonas syringae; Sesma A et al.; It was previously shown that most Pseudomonas syringae strains contain one or more plasmids with cross-hybridizing replication regions and other areas of homology, and these plasmids were designated the pPT23A-like family . The majority of these plasmids encode genes conferring epiphytic fitness or resistance to antibacterial compounds and those investigated in this study are essential for pathogenicity or increased virulence . The phylogeny of 14 pPT23A-like plasmids from five P . syringae pathovars was studied by comparing a fragment of the sequence of their repA genes (encoding a replicase essential for replication) . In the phylogenetic tree obtained, four groups (< or =88.8% identity between their members) could be identified . The first group contained the plasmids from three P . syringae pv . tomato strains, a P . syringae pv . apii strain and five out of the seven P . syringae pv . syringae strains, with identity ranging between 88.8 and 100% . The clustering of the pv . syringae strains did not reflect host specialization or previously reported phylogenetic relationships . The second group contained the plasmids from two strains of pv . glycinea and pv . tomato (95.5% identity), and it also included the previously sequenced replicon of a pathogenicity plasmid from P . syringae pv . phaseolicola . The plasmids from the remaining two pv . syringae strains were distantly related to the other plasmid sequences . Hybridization experiments using different genes or transposable elements previously described as plasmid-borne in P . syringae, showed that the gene content of highly related plasmids could be dissimilar, suggesting the occurrence of major plasmid reorganizations . Additionally, the phylogeny of the different native plasmids did not always correlate with the phylogeny of their harbouring strains, as determined by the analysis of extragenic repetitive consensus (ERIC) and arbitrarily primed PCR (AP-PCR) products . Collectively, these results suggest that pPT23A-like plasmids were, in most cases, acquired early during evolution. Scand J Plast Reconstr Surg Hand Surg, 2000 Sep, 34(3), 257 - 8 Repeated digital nerve block for pain control after tenolysis; Kirchhoff R et al.; We describe a way of achieving immediate painfree mobilisation after tenolysis or tenosynovectomy in Zone II . Bupivacaine is instilled along the flexor tendon sheath through a thin percutaneous catheter with an antibacterial filter. Free Radic Biol Med, 2000 Sep 1, 29(5), 425 - 33 Relative reactivity of lysine and other peptide-bound amino acids to oxidation by hypochlorite; Nightingale ZD et al.; Antibacterial and inflammatory responses of neutrophils and macrophages produce hypochlorite as a major oxidant . Numerous side chains of amino acids found in extracellular proteins can be modified by hypochlorite, including His, Arg, Tyr, Lys, Trp, and Met . We studied the relative reactivity of each of these amino acid residues in short N-blocked peptides, where other residues in the peptide were highly resistant to hypochlorite attack . Hypochlorite treatment led to modified peptides in each case, which were detected by changes in retention on reversed-phase HPLC . A distinct single product, consuming two equivalents of hypochlorite per equivalent of peptide, was obtained from the Lys-containing peptides . UV spectroscopy, nuclear magnetic resonance (NMR), and electrospray/mass spectroscopy identified this product as the dichloramine at the epsilon-amino group of the Lys side chain . The dichloramine at Lys did not decompose to form a detectable amount of carbonyl reactive with dinitrophenylhydrazine . The dichloramine at Lys did however quantitatively revert back to Lys during HCl digestion of the tetrapeptide for amino acid analysis, with simultaneous modification of the adjacent Phe residue . The formation of the dichloramine at Lys was not blocked by peptides or acetylated amino acids that contained Tyr, His, or Arg . In contrast, the presence of equimolar Met-containing peptide, or N-Acetyl-Trp, both inhibited the formation of the dichloramine at Lys . Thus, Met and Trp side chains of proteins might be able to protect Lys from chloramine formation under some circumstances, but this interpretation must consider that Met and Trp are typically found in relatively inaccessible hydrophobic sites, whereas lysine is typically exposed on the protein surface . The hierarchy of amino acid reactivities examined here will aid in the prediction of residues in biological samples most likely to be modified by hypochlorite. Clin Pharmacokinet, 2000 Sep, 39(3), 215 - 31 Effects of obesity on pharmacokinetics implications for drug therapy; Cheymol G; Obesity is a worldwide problem, with major health, social and economic implications . The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index . The main factors that affect the tissue distribution of drugs are body composition, regional blood flow and the affinity of the drug for plasma proteins and/or tissue components . Obese people have larger absolute lean body masses as well as fat masses than non-obese individuals of the same age, gender and height . However, the percentage of fat per kg of total bodyweight (TBW) is markedly increased, whereas that chrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available . Pharmacokinetic studies provide differing data on renal function in obese patients . This review analyses recent publications on several classes of drugs: antibacterials, anticancer drugs, psychotropic drugs, anticonvulsants, general anaesthetics, opioid analgesics, neuromuscular blockers, beta-blockers and drugs commonly used in the management of obesity . Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity (e.g . lithium and vecuronium) is generally rather predictable, as these drugs are distributed mainly in lean tissues . The dosage of these drugs should be based on the ideal bodyweight (IBW) . However, some of these drugs (e.g . antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient's excess bodyweight . There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g . remifentanil and some beta-blockers) and their distribution in obese individuals . The distribution of a drug between fat and lean tissues may influence its pharmacokinetics in obese patients . Thus, the loading dose should be adjusted to the TBW or IBW, according to data from studies carried out in obese individuals . Adjustment of the maintenance dosage depends on the observed modifications in clearance . Our present knowledge of the influence of obesity on drug pharmacokinetics is limited . Drugs with a small therapeutic index should be used prudently and the dosage adjusted with the help of drug plasma concentrations. Klin Med (Mosk), 2000, 78(8), 65 - 9 {Current aspects of differentiated therapy of infectious endocarditis}; Tatarchenko IP et al.; 150 patients (90 males and 60 females, mean age 41.9 +/- 3.3 years) with infectious endocarditis (IE) were treated . 26.7 and 71.3% of the patients had primary and secondary IE, respectively . Clinical and laboratory manifestations of the variants indicate that each variant is associated with a certain clinicolaboratory syndrome: acute IE is associated with toxicoseptic syndrome, subacute--with immune unbalance, and thromboembolic complications, chronic--with immunocomplex visceral lesions . Different variants of the course predetermine different therapy . It is recommended to combined active antibacterial therapy with UV radiation of autoblood and hemosorption, hyperbaric oxygenation . Immunocorrective and efferent therapy hold promise in IE treatment . Glucocorticosteroids are effective in immunocomplex disorders. Hinyokika Kiyo, 2000 Aug, 46(8), 561 - 4 {Torsion of the spermatic cord in undescended testis: report of two cases}; Miwa S et al.; We report two cases of torsion of the spermatic cord in undescended testis . Case 1: A 23-year-old man was admitted to our hospital with the complaints of fever and left inguinal pain . He had cerebral palsy in his past history . Tentative diagnosis of acute epididymitis of left undescended testis was made, and antibacterial drugs were given . Response was poor, and torsion of the spermatic cord was suspected strongly . Torsion of the spermatic cord in undescended testis and severe testicular infarction were seen in surgery after 13-day conservative treatment . Orchiectomy was performed . Case 2: A 6-year-old boy was admitted to our hospital with the chief complaints of left inguinal mass and pain . He had felt abdominal pain for 3 days . Scrotal contents were impalpable and the diagnosis of torsion of the spermatic cord was made . Orchiectomy was performed due to severe testicular infarction. Genes Dev, 2000 Oct 1, 14(19), 2461 - 71 A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity; Silverman N et al.; Here we report the identification of a Drosophila IkappaB kinase complex containing DmIKKbeta and DmIKKgamma, homologs of the human IKKbeta and IKKgamma proteins . We show that this complex is required for the signal-dependent cleavage of Relish, a member of the Rel family of transcriptional activator proteins, and for the activation of antibacterial immune response genes . In addition, we find that the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro . Thus, we propose that the Drosophila IkappaB kinase complex functions, at least in part, by inducing the proteolytic cleavage of Relish . The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes . Remarkably, this Drosophila IkappaB kinase complex is not required for the activation of the Rel proteins Dif and Dorsal through the Toll signaling pathway, which is essential for antifungal immunity and dorsoventral patterning during early development . Thus, a yet to be identified IkappaB kinase complex must be required for Rel protein activation via the Toll signaling pathway. J Pharm Sci, 2000 Nov, 89(11), 1395 - 403 Intrinsic absolute bioavailability prediction in rats based on in situ absorption rate constants and/or in vitro partition coefficients: 6-fluoroquinolones; Sanchez-Castano G et al.; A preliminary study attempting to predict the intrinsic absolute bioavailability of a group of antibacterial 6-fluoroquinolones-including true and imperfect homologues as well as heterologues-was carried out . The intrinsic absolute bioavailability of the test compounds, F, was assessed on permanently cannulated conscious rats by comparing the trapezoidal normalized areas under the plasma concentration-time curves obtained by intravenous and oral routes (n = 8-12) . The high-performance liquid chromatography analytical methods used for plasma samples are described . Prediction of the absolute bioavailability of the compounds was based on their intrinsic rat gut in situ absorption rate constant, k(a) . The working equation was: where T represents the mean absorbing time . A T value of 0.93 (+/-0.06) h provides the best correlation between predicted and experimentally obtained bioavailabilities (F' and F, respectively) when k(a) values are used (slope a = 1.10; intercept b = -0.05; r = 0.991) . The k(a) values can also be expressed in function of the in vitro partition coefficients, P, between n-octanol and a phosphate buffer . In this case, theoretical k(a) values can be determined with the parameters of a standard k(a)/P correlation previously established for a group of model compounds . When P values are taken instead of k(a) values, reliable bioavailability predictions can also be made . These and other relevant features of the method are discussed . Am J Med, 2000 Mar, 108(4), 282 - 9 A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer; Winston DJ et al.; PURPOSE: To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer . PATIENTS AND METHODS: A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily) . Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values . A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death . RESULTS: A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients) . Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi) . Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 {81%} of 159 patients) than patients treated with fluconazole (20 {13%} of 158 patients, P = 0.001) . Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005) . Overall mortality (27 {17%} patients treated with fluconazole versus 34 {21%} patients treated with amphotericin B) and mortality from fungal infection (7 {4%} patients treated with fluconazole versus 5 {3%} patients treated with amphotericin B) were similar in each study group . CONCLUSIONS: Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients . However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy. JPEN J Parenter Enteral Nutr, 2000 Sep-Oct, 24(5), 270 - 4; discussion 274-5 Glutamine-enriched total parenteral nutrition maintains intestinal interleukin-4 and mucosal immunoglobulin A levels; Kudsk KA et al.; BACKGROUND: Total parenteral nutrition (TPN) prevents progressive malnutrition but fails to maintain intestinal gut-associated lymphoid tissue (GALT) or established respiratory antiviral or antibacterial mucosal immunity . Our previous work demonstrated that decreases in intestinal immunoglobulin A (IgA) were associated with decreases in Th2-type IgA-stimulating cytokines, interleukin (IL)-4 and IL-10 . Because glutamine supplementation of TPN partially preserves respiratory defenses and normalizes GALT, we investigated the ability of parenteral glutamine to normalize respiratory and intestinal IgA levels and measured Th2 cytokines in intestinal homogenates . METHODS: Animals were cannulated and randomly assigned to receive chow (n = 17), TPN (n = 18), or an isonitrogenous, isocaloric TPN solution formulated by removing the appropriate amount of amino acids and replacing them with 2% glutamine (n = 18) for 5 days . Respiratory tract and intestinal washings were obtained for IgA and the intestine homogenized and analyzed for IL-4 and IL-10 . RESULTS: TPN decreased intestinal and respiratory IgA in association with decreases in intestinal IL-4 and IL-10 compared with chow-fed animals . Glutamine significantly improved respiratory and intestinal IgA levels, significantly improved IL-4 compared with TPN animals, and maintained IL-10 levels midway between chow-fed and TPN animals . CONCLUSIONS: Glutamine-enriched TPN preserved both extraintestinal and intestinal IgA levels and had a normalizing effect on Th2-type IgA-stimulating cytokines. JPEN J Parenter Enteral Nutr, 2000 Sep-Oct, 24(5), 261 - 8; discussion 268-9 Individual neuropeptides regulate gut-associated lymphoid tissue integrity, intestinal immunoglobulin A levels, and respiratory antibacterial immunity; Keith Hanna M et al.; BACKGROUND: Total parenteral nutrition (TPN) leads to atrophy of the gut-associated lymphoid tissue (GALT) and a significant decrease in intestinal immunoglobulin A (IgA) levels, a major constituent of mucosal immunity . Bombesin (BBS) prevents TPN-induced GALT atrophy and maintains intestinal IgA levels . BBS, a neuropeptide analogous to gastrin-releasing peptide in humans, stimulates the release of other gut neuropeptides including cholecystokinin (CCK), gastrin, and neurotensin (NT) . This study investigates the ability of CCK, gastrin, or NT to individually prevent TPN-induced GALT atrophy and preserve respiratory immunity . METHODS: Experiment 1: Male mice were randomly assigned to receive chow, TPN, TPN plus CCK, TPN plus gastrin, or TPN plus NT . After 5 days of feeding, Peyer's patches (PP) from the proximal and distal small bowel were harvested and analyzed for cell yields . PP cells were also analyzed for GALT cell type . Small bowel IgA levels were measured by enzyme-linked immunosorbent assay (ELISA) . Experiment 2: Mice were randomly assigned to receive either liposomes containing Pseudomonas antigen or liposomes without antigen . After 10 days, mice were randomly assigned to the same five treatment groups, fed for 5 days, and then given intratracheal Pseudomonas . Mortality was assessed after 48 hours . RESULTS: Experiment 1: GALT cell reductions due to IV-TPN were greater in the distal than proximal small bowel . All three neuropeptides prevented most TPN-induced GALT atrophy due mainly to the maintenance of the B-cell and T-cell populations in the PP of the distal bowel . Intestinal IgA levels were significantly higher in the animals treated with neuropeptides than animals treated with TPN only; however, these IgA levels were not maintained at levels observed in chow-fed animals . Experiment 2: Immunization resulted in significantly lower mortality in animals fed chow, TPN plus CCK, and TPN plus gastrin . TPN alone and TPN plus NT resulted in loss of immunity and mortality rate at comparable levels to unimmunized animals . CONCLUSIONS: Supplementation of IV-TPN with CCK, gastrin, and NT prevents GALT atrophy, primarily in the distal bowel . Intestinal IgA levels improve but not to normal levels . CCK and gastrin reversed IV-TPN-induced effects on antibacterial pneumonia in immunized animals while NT did not. Appl Environ Microbiol, 2000 Oct, 66(10), 4595 - 7 Antibacterial activity evaluation of microcin J25 against diarrheagenic Escherichia coli; Sable S et al.; The inhibitory activities of known microcins were evaluated against some diarrheagenic Escherichia coli strains . Some antibacterial properties of microcin J25, the most active one, were studied . A rapid two-step purification was performed . The MIC and the minimum bactericidal concentration of J25 against E . coli O157:H7 were 1 and 100 microg ml(-1), respectively . A 10(4)-CFU ml(-1) contamination by this strain was destroyed in milk and meat extract by 6.25 microg of J25 ml(-1) and in half-diluted egg yolk by 50 microg of J25 ml(-1). J Comput Aided Mol Des, 2000 Oct, 14(7), 679 - 87 Indices of differences of path lengths: novel topological descriptors derived from electronic interferences in graphs; Galvez J et al.; Novel topological descriptors, namely indices of differences of path lengths (DPs), are deduced from the physical model of wave interferences . Two electrons, moving through a circuit graph within a diffraction experiment, interfere in a given vertex of the graph . It is demonstrated that the overall sum of the inverse of the squares of the differences of topological distances between all pairs of vertices of the graph is a measure of the mean global kinetic energy of the electrons which are able to produce a constructive interference . New topological indices, namely indices of differences of path lengths are thus introduced as derived from such a diffraction pattern . These indices, according to the above expressed, should be a measure of the electron mobility within the molecule . As a consequence, a good prediction is to be expected for properties related to such mobility, such as resonance energy in aromatic hydrocarbons . Our results confirm that in fact, the resonance energies are well predicted by this means . Moreover, the new indices demonstrate to be very useful in the evaluation of biological properties such as antibacterial activities of a wide set of heterogeneous compounds. Biochim Biophys Acta, 2000 Jun 15, 1479(1-2), 275 - 85 Conformational study of a custom antibacterial peptide cecropin B1: implications of the lytic activity; Srisailam S et al.; Cecropin B1 (CB1) with two amphipathic alpha-helical segments is a derivative of the natural antibacterial peptide, cecropin B . The assays of cell lysis show that, compared with cecropin A (CA), CB1 has a similar ability to lyse bacteria with a higher potency (two- to six-fold higher) in killing cancer cells . The difference may be due to the fact that the peptides possess different structures and sequences . In this study, the solution structure of CB1 in 20% hexafluoroisopropanol was determined by two-dimensional nuclear magnetic resonance (NMR) spectroscopy . The (1)H NMR resonances were assigned . A total of 350 inter-proton distances were used to calculate the solution structure of CB1 . The final ensemble structures were well converged, showing the minimum root mean square deviation . The results indicate that CB1 has two stretches of helices spanning from residues 3 to 22 and from residues 26 to 33, which are connected by a hinge section formed by Gly-23 and Pro-24 . Lys-25 is partially incorporated in the hinge region . The bent angle between two helical segments located in two planes was between 100 and 110 degrees . With comparisons of the known NMR structure of CA and its activities on bacteria and cancer cells, the structure-function relationship of the peptides is discussed. J Nat Prod, 2000 Sep, 63(9), 1283 - 5 New antibacterial metabolites from the cyanobacterium Nostoc commune(EAWAG 122b); Jaki B et al.; Two new compounds, a diterpenoid and an anthraquinone, as well as an indane derivative, which is reported as a natural product for the first time, have been isolated from the cells of the cultured cyanobacterium Nostoc commune (EAWAG 122b) by means of bioguided isolation . The structures were determined by spectroscopic methods, mainly NMR, infrared spectroscopy, and mass spectrometry . All isolates exhibit antibacterial activity. Eur J Biochem, 2000 Oct, 267(19), 6018 - 24 Amine group of guanine enhances the binding of norfloxacin antibiotics to DNA; Lee EJ et al.; The binding mode of norfloxacin, a quinolone antibacterial agent, in the synthetic polynucleotides poly{d(G-C)2}, poly{d(I-C)2} and poly{d(A-T)2} was studied using polarized light spectroscopy, fluorescence spectroscopy and melting profiles . The absorption, circular and linear dichroism properties of norfloxacin are essentially the same for all the complexes, and the angle of electric transition dipole moment I and II of norfloxacin relative to the DNA helix axis is measured as 68-75 degrees for all complexes . These similarities indicate that the binding mode of norfloxacin is similar for all the polynucleotides . The decrease in the linear dichroism (LD) magnitude at 260 nm upon binding norfloxacin, which is strongest for the norfloxacin-poly{d(G-C)2} complex, and the identical melting temperature of poly{d(A-T)2} and poly{d(I-C)2} in the presence and absence of norfloxacin rule out the possibility of classic intercalation and minor groove binding . However, the characteristics of the fluorescence emission spectra of norfloxacin bound to poly{d(A-T)2} and to poly{d(I-C)2} are similar but are different to that of norfloxacin bound to poly{d(G-C)2} . As the amine group of the guanine base protrudes to the minor groove, this result strongly suggests that norfloxacin binds in the minor groove of B-form DNA in a nonclassic manner. J Ethnopharmacol, 2000 Oct, 72(3), 345 - 93 Eleutherococcus senticosus (Rupr . & Maxim.) Maxim . (Araliaceae) as an adaptogen: a closer look; Davydov M et al.; The adaptogen concept is examined from an historical, biological, chemical, pharmacological and medical perspective using a wide variety of primary and secondary literature . The definition of an adaptogen first proposed by Soviet scientists in the late 1950s, namely that an adaptogen is any substance that exerts effects on both sick and healthy individuals by 'correcting' any dysfunction(s) without producing unwanted side effects, was used as a point of departure . We attempted to identify critically what an adaptogen supposedly does and to determine whether the word embodies in and of itself any concept(s) acceptable to western conventional (allopathic) medicine . Special attention was paid to the reported pharmacological effects of the 'adaptogen-containing plant' Eleutherococcus senticosus (Rupr . & Maxim.) Maxim . (Araliaceae), referred to by some as 'Siberian ginseng', and to its secondary chemical composition . We conclude that so far as specific pharmacological activities are concerned there are a number of valid arguments for equating the action of so-called adaptogens with those of medicinal agents that have activities as anti-oxidants, and/or anti-cancerogenic, immunomodulatory and hypocholesteroletic as well as hypoglycemic and choleretic action . However, 'adaptogens' and 'anti-oxidants' etc . also show significant dissimilarities and these are discussed . Significantly, the classical definition of an adaptogen has much in common with views currently being invoked to describe and explain the 'placebo effect' . Nevertheless, the chemistry of the secondary compounds of Eleutherococcus isolated thus far and their pharmacological effects support our hypothesis that the reported beneficial effects of adaptogens derive from their capacity to exert protective and/or inhibitory action against free radicals . An inventory of the secondary substances contained in Eleutherococcus discloses a potential for a wide range of activities reported from work on cultured cell lines, small laboratory animals and human subjects . Much of the cited work (although not all) has been published in peer-reviewed journals . Six compounds show various levels of activity as anti-oxidants, four show anti-cancer action, three show hypocholesterolemic activity, two show immunostimulatory effects, one has choleretic activity and one has the ability to decrease/moderate insulin levels, one has activity as a radioprotectant, one shows anti-inflammatory and anti-pyretic activities and yet another has shown activity as an antibacterial agent . Some of the compounds show more than one pharmacological effect and some show similar effects although they belong to different chemical classes . Clearly, Eleutherococcus contains pharmacologically active compounds but one wishes that the term adaptogen could be dropped from the literature because it is vague and conveys no insights into the mechanism(s) of action . If a precise action can be attributed to it, then the exact term for said action should obviously be used; if not, we strongly urge that generalities be avoided . Also, comparison of Eleutherococcus with the more familiar Panax ginseng C.A . Meyer (Araliaceae), 'true ginseng' has underscored that they differ considerably chemically and pharmacologically and cannot be justifiably considered as mutually interchangeable . Accordingly, we recommend that the designation 'Siberian ginseng' be dropped and be replaced with 'Eleutherococcus' . In the case of both Eleutherococcus and true ginseng, problems inherent in herbal preparation use include inconsistencies not only in terms of indications for use, but in the nomenclature of constituent chemical compounds, standardization, dosage and product labeling . (ABSTRACT TRUNCATED) J Neuroimmunol, 2000 Sep 22, 109(2), 228 - 35 The presence of antibacterial and opioid peptides in human plasma during coronary artery bypass surgery; Tasiemski A et al.; Antibacterial peptides, found in both invertebrates and vertebrates, represent a potential innate defense mechanism against microbial infections . However, it is unknown whether this process occurs in humans during surgery . We looked for evidence of release of antibacterial peptides during coronary artery bypass grafting (CABG) . We used immunological techniques and antibacterial assays combined with high-performance gel-permeation chromatography, reverse-phase HPLC, N-terminal sequencing and comparison with synthetic standards to characterize the peptide B/enkelytin . We show the presence of anionic antibacterial peptide, the peptide B/enkelytin which correspond to the C-terminal part of proenkephalin A, from the plasma of patients undergoing CABG . Our studies show that peptide B/enkelytin is initially present at low levels in plasma and is then released in increased amounts just after skin incision . Antibacterial assays confirmed that the peptides specifically target gram-positive bacteria . We also demonstrate that peptide B/enkelytin is metabolized in vivo to the opioid peptides methionine-enkephalin-Arg-Phe and methionine-enkephalin, peptides that we show have granulocyte chemotactic activity . These findings suggest that in humans, surgical incision leads to the release of antibacterial peptides . Furthermore, these antibacterial peptides can be metabolized into compounds that have immune-activating properties. J Agric Food Chem, 2000 Sep, 48(9), 3801 - 5 Inhibition of oxidation of human low-density lipoproteins by phenolic substances in different essential oils varieties; Teissedre PL et al.; Phenolics antioxidant phytochemicals have been recently implicated for the lower rates of cardiac disease mortality among people consuming a Mediterranean diet . Essential oils are natural products extracted from vegetable materials, which can be used as antibacterial, antifungal, antioxidants, and anti-carcinogenic agents or to preserve and give specific flavors to foods . The activities of 23 selected essential oils in inhibiting the copper-catalyzed oxidation of human-low-density lipoproteins (LDL) were determined in vitro . LDL oxidation was inhibited between 6, 2, and 83% by 2 microM (GAE) total phenolics . The relative inhibition of LDL oxidation was used to categorize the essential oils into four groups below 2% when they contained methylchavicol, anethol, p-cymen, apiole, cinnamic ether; 6-10% if they possessed a majority of carvacrol, thymol, p-cymene, or vanillin; 10-50% for moderate amounts of thymol, carvacrol, cuminol, or eugenol; and 50-100% when eugenol is the major component . Total phenol content of essential oils gave a correlation with LDL antioxidant activity of r = 0.75 . The Activity of each phenolics compound could play a role in protecting LDL against oxidation if the substance is absorbed by the body. Arzneimittelforschung, 2000 Aug, 50(8), 752 - 7 8-Acyloxy-1,3-benzoxazine-2,4-diones as siderophore components for antibiotics; Wittmann S et al.; 8-Acyloxy-1,3-benzoxazine-2,4-diones as masked catechol derivatives represent a novel type of siderophore components, whose growth promoting activity is low or not existing if tested alone . But after conjugation with beta-lactam antibiotics the resulting conjugates show a significantly increased antibacterial activity against Gram-negative bacteria compared with their parent antibiotics . Investigations using a set of penetration and iron transport mutants demonstrated that the conjugates use iron transport systems to penetrate the bacterial outer membrane . Title compounds were synthesized from (2,3-dimethoxycarbonyloxy)-benzoic acid and different amino compounds . Conjugates with penicillins and cephalosporins were prepared. J Chromatogr B Biomed Sci Appl, 2000 Jul 21, 744(2), 359 - 65 Simple and reliable method of doxycycline determination in human plasma and biological tissues; Axisa B et al.; Over recent years there has been a resurgence in the use of doxycycline in clinical practice, which does not depend on its antibacterial properties . This paper describes a method of determination of doxycycline in human plasma and atheromatous tissue using high-performance liquid chromatography (HPLC), and a cheap commercially available extraction system . Doxycycline is extracted in the mobile phase and injected directly into the HPLC system, avoiding time consuming drying up steps . A limit of detection of 0.125 microg/ml of plasma, and a relative standard deviation of 3% was achieved, making the method very reliable and useful for assays within the usual therapeutic range . The method has also been applied to the extraction of a mixture of tetracyclines from plasma and atherma with equal efficacy, making it useful for assays of this class of drugs in veterinary practice and assays of food contaminants. J Pharmacol Exp Ther, 2000 Oct, 295(1), 146 - 52 Limited distribution of new quinolone antibacterial agents into brain caused by multiple efflux transporters at the blood-brain barrier; Tamai I et al.; Transport of new quinolone antibacterial agents (quinolones) at the blood-brain barrier (BBB) was studied in vitro by using immortalized rat brain capillary endothelial cells RBEC1, and in vivo by using the brain perfusion method in rats and multidrug-resistant mdr1a/1b gene-deficient mice . The permeability coefficient of grepafloxacin measured by brain perfusion was increased by an excess of unlabeled grepafloxacin, suggesting a participation of a saturable BBB efflux system . Uptake coefficients of {(14)C}grepafloxacin, {(14)C}sparfloxacin, and {(14)C}levofloxacin by RBEC1 cells at the steady state were increased in the presence of the unlabeled quinolones . The steady-state uptake of {(14)C}grepafloxacin was increased in the presence of various quinolones . Brain distributions of {(14)C}grepafloxacin and {(14)C}sparfloxacin evaluated in terms of the brain-to-plasma free concentration ratio in mdr1a/1b gene-deficient mice were significantly higher than those in wild-type mice, demonstrating an involvement of P-glycoprotein as the efflux transporter . Anionic compounds, including 4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and genistein, increased the steady-state uptake of {(14)C}grepafloxacin by RBEC1 cells . Because {(14)C}grepafloxacin was transported by multidrug resistance-associated protein (MRP), in MRP1-overexpressing cells and because RBEC1 and primary cultured brain capillary endothelial cells expressed MRP1, this protein may be an additional efflux transporter for quinolones . Furthermore, the permeability coefficient of {(14)C}grepafloxacin across the BBB was increased by DIDS or in the absence of bicarbonate ions in the brain perfusion method . DIDS or bicarbonate ion did not affect MRP1 function . Accordingly, the brain distribution of quinolones is restricted by the action of multiple efflux transporters, including P-glycoprotein, MRP1, and an unknown anion exchange transporter. Pharmazie, 2000 Aug, 55(8), 568 - 71 Synthesis and antibacterial activity of new cephalosporines containing a pyrrole ring in the N-acyl chain; Bijev A et al.; Nine new cephalosporines containing a pyrrole ring in the N-acyl chain have been synthesized by the N-acylation of 7-ACA or of its 3-analogues via the acid chlorides of substituted 2-pyrrole-carboxylic, -acetic or -propionic acids . H1 NMR and IR data confirming the structure are presented . Preliminary microbiological tests in vitro show significant antibacterial activity, compared with that of cefalexin . Some common structure-activity relationships have been observed. J Biol Chem, 2000 Dec 8, 275(49), 38355 - 62 Processing of proenkephalin-A in bovine chromaffin cells . Identification of natural derived fragments by N-terminal sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry; Goumon Y et al.; A large variety of proenkephalin-A-derived peptides (PEAPs) are present in bovine adrenal medulla secretory granules that are cosecreted with catecholamines upon stimulation of chromaffin cells . In the present paper, after reverse phase high performance liquid chromatography of intragranular soluble material, PEAPs were immunodetected with antisera raised against specific proenkephalin-A (PEA) sequences (PEA63-70 and PEA224-237) and analyzed by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry . Thirty PEAPs were characterized in addition to enkephalins and whole PEA, indicating that preferential proteolytic attacks occurred at both N- and C-terminal regions . A similar approach was used to characterize PEA-derived fragments exocytotically released into the extracellular space that showed five additional minor PEAPs . Among all these naturally generated peptides, enkelytin, the antibacterial bisphos- phorylated C-terminal peptide (PEA209-237), was predominantly generated, as shown by MALDI-TOF mass spectrometry analysis, which constituted an efficient method for its identification . Finally, the data on PEA intragranular and extracellular processing in adrenal medulla are discussed in regard to the known enzymatic processing mechanisms . We note the high conservation of the cleavage points in evolutionarily diverse organisms, highlighting an important biological function for the released PEAPs. Bioorg Med Chem Lett, 2000 Sep 4, 10(17), 2033 - 6 Molecular topology: a useful tool for the search of new antibacterials; de Gregorio Alapont C et al.; Molecular topology has been applied to find new lead antibacterial compounds . Among the selected compounds, hesperidin, neohesperidin and Mordant Brown 24 stand out, with minimum inhibitory concentrations 90, MIC90 < 0.3 mg/mL. Structure Fold Des, 2000 Sep 15, 8(9), 993 - 1004 Structure of nicotinamide mononucleotide adenylyltransferase: a key enzyme in NAD(+) biosynthesis; D'Angelo I et al.; BACKGROUND: Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor involved in fundamental processes in cell metabolism . The enzyme nicotinamide mononucleotide adenylyltransferase (NMN AT) plays a key role in NAD(+) biosynthesis, catalysing the condensation of nicotinamide mononucleotide and ATP, and yielding NAD(+) and pyrophosphate . Given its vital role in cell life, the enzyme represents a possible target for the development of new antibacterial agents . RESULTS: The structure of NMN AT from Methanococcus jannaschii in complex with ATP has been solved by X-ray crystallography at 2.0 A resolution, using a combination of single isomorphous replacement and density modification techniques . The structure reveals a hexamer with 32 point group symmetry composed of alpha/beta topology subunits . The catalytic site is located in a deep cleft on the surface of each subunit, where one ATP molecule and one Mg(2+) are observed . A strictly conserved HXGH motif (in single-letter amino acid code) is involved in ATP binding and recognition . CONCLUSIONS: The structure of NMN AT closely resembles that of phosphopantetheine adenylyltransferase . Remarkably, in spite of the fact that the two enzymes share the same fold and hexameric assembly, a striking difference in their quaternary structure is observed . Moreover, on the basis of structural similarity including the HXGH motif, we identify NMN AT as a novel member of the newly proposed superfamily of nucleotidyltransferase alpha/beta phosphodiesterases . Our structural data suggest that the catalytic mechanism does not rely on the direct involvement of any protein residues and is likely to be carried out through optimal positioning of substrates and transition-state stabilisation, as is proposed for other members of the nucleotidyltransferase alpha/beta phosphodiesterase superfamily. Org Lett, 2000 Sep 21, 2(19), 2951 - 4 Synthesis of 2-fluoro-6-O-propargyl-11,12-carbamate ketolides . A novel class of antibiotics; Phan LT et al.; A novel class of 2-fluoro-6-O-propargyl-11,12-carbamate ketolide derivatives of erythromycin has been synthesized for antibacterial SAR studies . Replacement of the C2-hydrogen by a fluorine atom allows the synthesis of 6-O-propargylic ketones and electron-deficient 6-O-propargylic aromatic derivatives by preventing intramolecular C2-enolate Michael cyclization. Biochemistry, 2000 Sep 19, 39(37), 11425 - 33 Interaction of the lantibiotic nisin with mixed lipid bilayers: a 31P and 2H NMR study; Bonev BB et al.; Nisin is a positively charged antibacterial peptide which binds to the negatively charged membranes of Gram-positive bacteria . The initial interaction of the peptide with model membranes of neutral (phosphatidylcholine) and negatively charged (phosphatidylcholine/phosphatidylglycerol) model lipid membranes was studied using nonperturbing solid state magic angle spinning (MAS) (31)P NMR and (2)H wide-line NMR . In the presence of nisin, the coexistence of two bilayer lipid environments was observed both in charged and in neutral membranes . One lipid environment was found to be associated with lipid directly interacting with nisin and one with noninteracting lipid . Solid state (31)P MAS NMR results show that the acidic membrane lipid component partitions preferentially into the nisin-associated environment . Deuterium NMR ((2)H NMR) of the selectively headgroup-labeled acidic lipid provides further evidence of a strong interaction between the charged lipid component and the peptide . The segregation of acidic lipid into the nisin-bound environment was quantified from (2)H NMR measurements of selectively headgroup-deuterated neutral lipid . It is suggested that the observed lipid partitioning in the presence of nisin is driven, at least initially, by electrostatic interactions . (2)H NMR measurements from chain-perdeuterated neutral lipids indicate that nisin perturbs the hydrophobic region of both charged and neutral bilayers. J Colloid Interface Sci, 2000 Sep 15, 229(2), 365 - 374 Nonionic Cellulose Ethers as Potential Drug Delivery Systems for Periodontal Anesthesia; Scherlund M et al.; Nonionic cellulose ethers displaying a lower consolute temperature, or cloud-point, close to body temperature were investigated as potential carrier systems for the delivery of local anesthetic agents to the periodontal pocket . The interaction between the polymers, i.e., ethyl(hydroxyethyl)cellulose (EHEC) and hydrophobically modified EHEC (HM-EHEC), and ionic surfactants was determined in the absence and in the presence of the local anesthetic agents lidocaine and prilocaine . The cloud-point and rheology data indicate interactions between the polymer and both anionic and cationic surfactants . More precisely, a number of ionic surfactants were found to result in an increase in cloud-point at higher surfactant concentrations, a surfactant-concentration-dependent thickening, and a temperature-induced gelation upon heating . Upon addition of the local anesthetic agents lidocaine and prilocaine in their uncharged form to EHEC and HM-EHEC, in the absence of surfactants, only minor interaction with the polymer could be inferred . However, these substances were found to affect the polymer-surfactant interaction . In particular, the drug release rate in vitro as well as the stability and temperature-dependent viscosity were followed for an EHEC/SDS system and EHEC/myristoylcholine bromide system upon addition of lidocaine and prilocaine . The data indicate a possibility of formulating a local anesthetic drug delivery system suitable for administration into the periodontal pocket where at least small amounts of active ingredients can be incorporated into the system without severely affecting the gelation behavior . The results found for the cationic myristoylcholine bromide system are particularly interesting for the application in focus here since this surfactant is antibacterial and readily biodegradable . Genome, 2000 Aug, 43(4), 707 - 11 Ceratotoxins: female-specific X-linked genes from the medfly, Ceratitis capitata; Rosetto M et al.; In this paper, we report the chromosomal localization of ceratotoxins, a gene family encoding antibacterial female-specific peptides from the mediterranean fruit fly Ceratitis capitata . The analysis of both polytene and mitotic chromosomes by in situ hybridization shows that ceratotoxins are the first case of female-specific X-linked genes from the medfly C . capitata . Southern blot analysis reveals that the ceratotoxin gene family is not specifically amplified in the female reproductive accessory glands of C . capitata. Farmaco, 2000 May, 55(5), 338 - 44 Studies on arylfuran derivatives . Part XI . Synthesis, characterisation and biological studies on some Mannich bases carrying 2,4-dichlorophenylfurfural moiety; Holla BS et al.; A series of 3-substituted-4-{5-(2,4-dichlorophenyl)-2-furfurylidine}amino-5-me rcapto-1, 2,4-triazoles (3) are synthesised . Aminomethylation of 3 with formaldehyde and a primary/secondary amine furnished Mannich bases 4 and 5 . Both Schiff bases 3 and Mannich bases 4 and 5 are characterised on the basis of IR, 1H NMR, mass spectral data and elemental analysis . All the newly synthesised compounds are tested for their antibacterial activities . Some of the selected compounds are also tested for their fungicidal and herbicidal properties. J Antimicrob Chemother, 2000 Sep, 46(3), 411 - 22 Regional variation in ampicillin and trimethoprim resistance in Escherichia coli in England from 1990 to 1997, in relation to antibacterial prescribing; Livermore DM et al.; Over 200 hospitals in England report resistance data for bacteraemia and meningitis isolates to the Public Health Laboratory Service . We reviewed ampicillin and trimethoprim resistance rates from 1990 to 1997 for Escherichia coli, which is the species reported most frequently from these bacteraemias . Ampicillin resistance was relatively stable over time, but varied between Health Regions . The proportion of ampicillin-resistant E . coli in the East Anglia region remained </=42% in all years except one and that in the South Western region always remained <50% . At the other extreme, the proportions of ampicillin-resistant isolates in the Northern and Trent regions never fell below 59% . The prevalence of resistance to trimethoprim rose over time in most regions; again, however, the prevalence of resistant isolates was lowest in the East Anglia and South Western regions, whereas the highest resistance rates were reported from Mersey, NW Thames, NE Thames and North Western regions . These observations were related to data for community prescribing, which accounts for most ampicillin and trimethoprim use . Prescribing data for ampicillin and trimethoprim from 1987 to 1997 were obtained from the IMS-HEALTH Medical Data Index, and data for all antibacterial drugs between 1995 and 1997 from the Prescription Pricing Authority . Correlations between resistance rates and prescribing of specific antibiotics were weak, although there was some trend for regions with high total prescribing to have higher rates of ampicillin resistance . The South Western region was conspicuous both for low rates of resistance and low prescribing . Several factors may determine the lack of wider and more obvious relationships between resistance and prescribing . In particular, regions may be inappropriately large areas to test the relationship, isolates from bacteraemias may not be representative of those experiencing selection pressure in the community and the resistance data may have been distorted by nosocomial strains, although this seems unlikely with E . coli. Int J Hematol, 2000 Jul, 72(1), 1 - 11 Advances in the management of hemophagocytic lymphohistiocytosis; Imashuku S; Hemophagocytic lymphohistiocytosis (HLH) is a prototype of the hemophagocytic syndrome and occurs most often in children . Progress in cytokine research has now made it possible to show that HLH occurs as a consequence of uncontrolled, dysregulated cellular immune reactivity caused by a number of different underlying diseases . Three major risk groups of HLH can be identified: (1) familial HLH (FHL), (2) Epstein-Barr virus-associated HLH (EBV-HLH), and (3) life-threatening infection-associated or underlying disease-unknown HLH in infancy . Diagnostic criteria now exist that allow the differential diagnosis of these groups, which is important because distinct therapeutic measures are advised for each group . FHL patients require immediate application of immunochemotherapy with a core combination of corticosteroids and etoposide together with monitoring of central nervous system disease by early and repeated magnetic resonance imaging of the brain, followed by timely stem cell transplantation (SCT) . EBV-HLH should also be treated with a combination of corticosteroids and etoposide . Aggressive or relapsed cases should be treated with cyclosporin A and, if necessary, with more intensive chemotherapy, such as that used for non-Hodgkin's lymphoma . SCT may also be needed in these refractory cases . In cases of herpes simplex virus, adenovirus 7, and other pathogen-undetermined HLH in early infancy, it is of great importance to administer appropriate antiviral or antibacterial agents . The most important point to make regarding HLH treatment is that the underlying cause of HLH must be promptly established to enable the rapid application of the appropriate therapy . Currently, 30% to 40% of HLH cases have a poor outcome . It is necessary for hematologists to cooperate with specialists in other fields so that early diagnosis, which is critical for improvements in outcome, can be made. Am J Manag Care, 2000 Mar, 6(5 Suppl), S265 - 75 Clinical and laboratory diagnosis of influenza virus infections; Newton DW et al.; Influenza epidemics account for more than 20,000 deaths in the United States each year, as well as substantial morbidity, medical costs, and time away from work and school . Since the 1950s, the principal weapon against these seasonal epidemics has been killed virus vaccine formulations . Despite massive efforts to immunize at-risk individuals against influenza, not everyone receives the vaccine . In addition, use of some drugs, such as amantadine and rimantadine, can lead to the development of drug resistant viruses in infected individuals and to transmission of these viruses to susceptible individuals . The many factors that contribute to the high annual incidence of influenza virus infections mandate prompt clinical recognition and appropriate patient management . Rapid diagnostic tests have been developed that may make it possible to avoid the use of antibacterial drugs, quickly decide whether isolation of infected patients is needed, and discharge hospitalized patients sooner. Bioorg Med Chem, 2000 Jul, 8(7), 1629 - 36 Acyloxymethyl as a drug protecting group . Part 7: Tertiary sulfonamidomethyl ester prodrugs of benzylpenicillin: chemical hydrolysis and anti-bacterial activity; Iley J et al.; Tertiary sulfonamidomethyl esters of benzylpenicillin (4) were synthesised and evaluated as a new class of potential prodrugs for beta-lactam antibiotics . Their hydrolysis in aqueous buffers was studied by HPLC and reveal a U-shaped pH rate profile with a pH-independent process extending from ca . pH 2 to ca . pH 10 . This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion . Benzylpenicillin and the corresponding sulfonamide are the ultimate products detected and isolated, indicating that beta-lactam ring opening is much slower than ester hydrolysis . As expected from the high reactivity, benzylpenicillin esters (4) displayed similar in vitro antibacterial activity to benzylpenicillin itself . Compared to the benzylpenicillin derivatives, sulfonamidomethyl esters of benzoic, clofibric and valproic acids display a much higher stability, giving rise to a Bronsted beta1g value of -0.96 and suggesting that tertiary sulfonamidomethyl esters may be useful prodrugs for carboxylic acid drugs with pKa > 4. Bioorg Med Chem, 2000 Jul, 8(7), 1579 - 97 Conformations in solution and bound to bacterial ribosomes of ketolides, HMR 3647 (telithromycin) and RU 72366: a new class of highly potent antibacterials; Evrard-Todeschi N et al.; The new class of antibiotics called ketolides is endowed with remarkable antibacterial activity against macrolide-resistant strains . Further modifications of the 3 keto-macrolactone backbone led to 11,12-hydrazonocarbamate ketolides with an imidazolyl pyridine chain: the file-leader of ketolide class, HMR 3647 (telithromycin), and its N-bis-demethyl-derivative, RU 72366 . The potency of HMR 3647 is higher than that of RU 72366 . Stereospecific 1H and 13C resonance assignments of HMR 3647 and RU 72366 have been determined and have allowed a detailed quantitative conformational analysis of the uncomplexed form of the molecules . The comparative conformation of HMR 3647 in solution and its N-bis-demethyl-derivative in D2O has been carried out using different heteronuclear correlation experiments in conjunction with nuclear Overhauser effect experiments and in particular long-range 3J(CH) coupling constants and using molecular dynamics (MD) methods . The study of ketolide ribosome interaction has been investigated using two-dimensional transferred nuclear Overhauser effect spectroscopy (TRNOESY) . The database of ribosome-bound ketolide structures has been used to compare the structure(s) of ketolide in ribosome-ketolide complexes with the conformational preferences of free ketolides and to highlight the significant differences between HMR 3647 and RU 72366 . A comparison of the conformations bound to ribosome was made with those of other previously studied ketolide (RU 004) and macrolides and would explain the remarkable potencies of HMR 3647 in inhibiting protein synthesis. Mol Microbiol, 2000 Aug, 37(4), 752 - 62 Biosynthesis of the anti-parasitic agent megalomicin: transformation of erythromycin to megalomicin in Saccharopolyspora erythraea; Volchegursky Y et al.; Megalomicin is a therapeutically diverse compound which possesses antiparasitic, antiviral and antibacterial properties . It is produced by Micromonospora megalomicea and differs from the well-known macrolide antibiotic erythromycin by the addition of a unique deoxyamino sugar, megosamine, to the C-6 hydroxyl . We have cloned and sequenced a 48 kb segment of the megalomicin (meg) biosynthetic gene cluster which contains the modular polyketide synthase (PKS) and the complete pathway for megosamine biosynthesis . The similarities and distinctions between the related megalomicin and erythromycin gene clusters are discussed . Heterologous expression of the megalomicin PKS in Streptomyces lividans led to production of 6-deoxyerythronolide B, the same macrolactone intermediate for erythromycin . A 12 kb fragment harbouring the putative megosamine pathway was expressed in Saccharopolyspora erythraea, resulting in the conversion of erythromycin to megalomicin . Considering the extensive knowledge surrounding the genetic engineering of the erythromycin PKS and the familiarity with genetic manipulation and fermentation of S . erythraea, the ability to produce megalomicin in this strain should allow the engineering of novel megalomicin analogues with potentially improved therapeutic activities. Mol Med, 2000 Jun, 6(6), 527 - 41 Luteolin, an abundant dietary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated kinetoplast DNA cleavage leading to apoptosis; Mittra B et al.; BACKGROUND: Plant-derived flavonoids, which occur abundantly in our daily dietary intake, possess antitumor, antibacterial, and free radical scavenging properties . They form active constituents of a number of herbal and traditional medicines . Several flavonoids have been shown to exert their action by interacting with DNA topoisomerases and promoting site-specific DNA cleavage . Therefore, flavonoids are potential candidates in drug design . We report here that, although the flavonoids luteolin and quercetin are potent antileishmanial agents, luteolin has great promise for acting as a lead compound in the chemotherapy of leishmaniasis, a major concern in developing countries . MATERIALS AND METHODS: Kinetoplast DNA (kDNA) minicircle cleavage in drug-treated parasites was measured by electrophoresis of the total cellular DNA, followed by Southern hybridization using 32P labeled kDNA as a probe . Cell cycle progression and apoptosis were measured by flow cytometry using propidium iodide and fluorescein isothiocyanate (FITC)-labeled Annexin V . RESULTS: Luteolin and quercetin inhibited the growth of Leishmania donovani promastigotes and amastigotes in vitro, inhibited DNA synthesis in promastigotes, and promoted topoisomerase-II-mediated linearization of kDNA minicircles . The IC50 values of luteolin and quercetin were 12.5 microM and 45.5 microM, respectively . These compounds arrest cell cycle progression in L . donovani promastigotes, leading to apoptosis . Luteolin has no effect on normal human T-cell blasts . Both luteolin and quercetin reduced splenic parasite burden in animal models . CONCLUSION: Luteolin and quercetin are effective antileishmanial agents . Quercetin has nonspecific effects on normal human T cells, but luteolin appears nontoxic . So, luteolin can be a strong candidate for antileishmanial drug design. Rev Prat, 2000 Jun 15, 50(12), 1310 - 3 {Drug-induced exanthemas}; Chosidow O; Drug-induced exanthemas are probably the most frequent cutaneous adverse drug reaction . Outcome of the isolated forms are usually favourable . However, exanthemas may be part of a more severe form, as hypersensitivity syndrome, Lyell syndrome, Stevens-Johnson syndrome or acute generalized exanthematic pustulosis . The mechanism is essentially immunologic . Antibiotics (aminopenicillins, antibacterial sulfamides, antituberculosis drugs) must be considered high risk drugs . Treatment is only symptomatic . Corticosteroids must be avoided. Nephron, 2000 Sep, 86(1), 79 - 83 Intracerebral abscess caused by Nocardia otitidiscaviarum in a renal transplant patient--cured by evacuation plus antibiotic therapy; Hartmann A et al.; We present a 50-year-old female who experienced generalized convulsion 3 months after a successful cadaveric renal transplantation . The first cerebral CT scan indicated cerebral frontal infarction . Repeat CT some days later revealed progressive lesions, and a highly malignant tumor or abscess was suspected . Antifungal and broad-spectrum antibacterial therapy was initiated . Cerebral MRI could not differentiate between these conditions, but a neutrophil granulocyte scan strongly suggested an infectious process . A stereotactic puncture of the frontal lobe was followed by temporary improvement . A severe progressive left-sided hemiparalysis gave indication for a craniotomy with evacuation of the abscess 9 days later . Culture of aspirated pus yielded growth of a gram-positive, rod-shaped bacterium, later identified as Nocardia otitidiscaviarum by sequencing the 16S rRNA . The patient was treated with meropenem plus rifampicin intravenously for 6 weeks followed by oral ciprofloxacin and rifampicin for 2 months . Due to pharmacokinetic interaction with rifampicin, the prednisolone dose was doubled, and the dose of tacrolimus had to be tripled for maintenance of adequate trough concentrations . Five months following cessation of antibiotic treatment, the patient has regained normal strength and function in her left-sided extremities and has a serum creatinine level of about 160 micromol/l (1.8 mg/dl) . Am J Respir Cell Mol Biol, 2000 Sep, 23(3), 364 - 70 Secretory leukoprotease inhibitor augments hepatocyte growth factor production in human lung fibroblasts; Kikuchi T et al.; Secretory leukoprotease inhibitor (SLPI), an 11.7-kD nonglycosylated serine protease inhibitor, is produced and released into the fluids of mucosal surfaces including human lung . It comprises two domains with homologous amino acid sequences: the N-terminal domain possessing antibacterial activity, and the C-terminal domain with antiprotease activity . Here we report the positive regulation of hepatocyte growth factor (HGF) production in human lung fibroblasts exerted by SLPI or its C-terminal domain under physiologic concentrations (1 to 10 microM) . This HGF production by SLPI was unaffected by the addition of interleukin (IL)-1 receptor antagonist . In contrast, human skin fibroblasts exerted no SLPI-stimulated increase in HGF production, despite the fact that IL-1beta increased HGF production with an intensity similar to that of human lung fibroblasts . Both the time-course and dose-response studies in human lung fibroblasts revealed that the induction of HGF messenger RNA (mRNA) and protein occurred in parallel, indicating that the mechanism existed at the steady-state mRNA level . A synthetic elastase inhibitor failed to induce HGF, but alpha(1)-antitrypsin also stimulated HGF production in lung fibroblasts . Inactivation of the antiprotease activity of SLPI or its C-terminal domain by an oxidizing agent (N-chlorosuccinimide) abolished their stimulatory effect on HGF production . These findings demonstrate that SLPI exerts a novel HGF induction and functions as an anti-inflammatory and regenerative factor in addition to its role in protease inhibition. Bioorg Med Chem Lett, 2000 Aug 21, 10(16), 1799 - 801 The total synthesis of piclavines A1-4 and their biological evaluation; Takahata H et al.; The total synthesis of piclavines A1, A2, A3, and A4 has been achieved starting from compound 10 with enantiomeric enhancement . Their biological activities (antibacterial, antimicrobacterial, and antiviral activities and inhibition of cell growth) were evaluated. Bioorg Med Chem, 2000 Jan, 8(1), 157 - 62 Synthesis, spectroscopic characterization and biological properties of new natural aldehydes thiosemicarbazones; Tarasconi P et al.; As part of a research programme aimed at the synthesis of compounds with antiviral, antibacterial and antitumor properties and their spectroscopic characterization, new thiosemicarbazones deriving from natural aldehydes have been investigated . These substances contain in the same molecule both a chain with nucleophilic centres N, S with tubercolostatic activity, and a glycosidic or alkyl moiety (modified glycosides and nucleosides have recently received a great deal of attention in the fields of neoplastic diseases and viral infections) . In this paper the synthesis and the characterization of these compounds by means of 1H NMR, IR, and MS techniques is reported . Biological studies have involved both inhibition of cell proliferation and apoptosis tests on human leukemia cell line U937. Bioorg Med Chem, 2000 Jan, 8(1), 69 - 72 Alumina-supported synthesis of antibacterial quinolines using microwaves; Kidwai M et al.; 7-(5'-Alkyl-1',3',4'-thiadiazol/oxadiazol-2'-ylthio)-6 -fluoro-2,4-dimethylquinolines and 3-formyl-2-(2'-hydroxy- 1',4'-naphthoquinon-3'-yl)-4-methyl/6-methyl/7-quinolines have been synthesised by the reaction of 5-alkyl-1,3,4-thiadiazol/oxadiazol-2-thiols with 7-chloro-6-fluoro-2,4-dimethylquinoline and by the reaction of 2-hydroxy-1,4-naphthoquinone with 2-chloro-3-formyl-4-methyl/6-methyl/7-methyl/8-methylquinolines respectively on basic alumina using microwaves, the reaction time has been brought down from hours to seconds with improved yield as compared to conventional heating . The compounds were tested for their in vitro antibacterial activity . All compounds showed promising antibacterial activity . The best activity was observed by compounds 3a and 3f. Bioorg Med Chem, 2000 Jan, 8(1), 27 - 36 Chemical investigation of Mycale mytilorum and a study on toxicity and antidiabetic activity of 5-octadecylpyrrole-2-carboxaldehyde; Reddy GB et al.; Chemical investigation of Mycale mytilorum afforded four new and two known compounds, of which 5-octadecylpyrrole-2-carboxaldehyde (1) and (6'Z)-5-(6'-heneicosenyl) pyrrole-2-carboxaldehyde (2, congeners of alkylpyrrole carboxadehyde), (2S,3R,4E)-1,3-dihydroxy-2-{(heneicosanoyl) amino}-4-heneicosene (5, sphingolipid) and 2-methyl-3-(4,5,7-trihydroxy-8-hydroxy-methyltetrahydro-6H-4-py ranyl)-2-propenoic acid (6, tetrahydropyran derivative) are new, and batylalcohol (3) and p-hydroxyphenylacetic acid (4) are known . The toxicity and antidiabetic activity of 5-octadecylpyrrole-2-carboxaldehyde were evaluated for the first time . Also, compounds 1, 2, 5 and 6 were studied for the antibacterial, antifungal and antiviral activity. J Ethnopharmacol, 2000 Sep, 72(1-2), 247 - 63 Antibacterial, anthelmintic and anti-amoebic activity in South African medicinal plants; McGaw LJ et al.; Hexane, ethanol and water extracts of plants used by South African traditional healers for treating stomach ailments were screened for antibacterial, anthelmintic and anti-amoebic activities . To evaluate antibacterial activity, the disc-diffusion assay was used against several Gram-positive and Gram-negative species . Minimal inhibitory concentration values were determined with a microdilution assay . Ethanolic extracts showed the greatest activity, and Gram-positive bacteria were the most susceptible microorganisms . The free-living nematode Caenorhabditis elegans was used in two different assays to evaluate anthelmintic activity . A microdilution technique was employed to investigate anti-amoebic activity against the enteropathogenic Entamoeba histolytica . These assays were suitable for the screening of a large number of extracts at one time . Several plants exhibited significant activity against these test organisms. Dent Mater, 2000 Nov, 16(6), 452 - 5 Antibacterial effect of silver-zeolite on oral bacteria under anaerobic conditions; Kawahara K et al.; OBJECTIVES: The purpose of this study was to evaluate the antibacterial effect of silver-zeolite (SZ) against oral bacteria under anaerobic conditions . METHODS: The antibacterial activity of SZ was evaluated by determining the minimum inhibitory concentrations (MICs) using two-fold serial dilutions of SZ in Brain Heart Infusion broth . Release of Ag+ into the broth was measured by an atomic absorption technique . RESULTS: SZ inhibited the growth of the bacteria tested under anaerobic conditions . The MIC of SZ ranged between 256 and 2048 micrograms/ml, which corresponded to a range of 4.8-38.4 micrograms/ml of Ag+ . All strains grew in broth containing 16,384 micrograms/ml of type-A zeolite . SIGNIFICANCE: These results suggested that SZ may be a useful vehicle to provide antibacterial activity to dental materials used even under anaerobic conditions such as deep in the periodontal pocket. Farmaco, 2000 Apr, 55(4), 256 - 63 Studies on arylfuran derivatives: part X . Synthesis and antibacterial properties of arylfuryl-delta2-pyrazolines; Holla BS et al.; Arylfurylpropenones 3 were synthesized by Claisen-Schmidt condensation of arylfurfurals 1 with various substituted acetophenones 2 . Cyclocondensation of these arylfurylpropenones 3 with hydrazine hydrate and phenylhydrazine furnished 1H-pyrazolines 4 and N-phenylpyrazolines 6, respectively . In order to study the structure-activity relationships, pyrazolines 4 were converted into their N-acetyl derivatives 5 . The antibacterial properties of the new pyrazoline derivatives were studied. Nature, 2000 Aug 17, 406(6797), 775 - 81 Molecular mechanisms that confer antibacterial drug resistance; Walsh C; Antibiotics--compounds that are literally 'against life'--are typically antibacterial drugs, interfering with some structure or process that is essential to bacterial growth or survival without harm to the eukaryotic host harbouring the infecting bacteria . We live in an era when antibiotic resistance has spread at an alarming rate and when dire predictions concerning the lack of effective antibacterial drugs occur with increasing frequency . In this context it is apposite to ask a few simple questions about these life-saving molecules . What are antibiotics? Where do they come from? How do they work? Why do they stop being effective? How do we find new antibiotics? And can we slow down the development of antibiotic-resistant superbugs? Biophys Chem, 2000 Jul 15, 85(2-3), 187 - 98 Binding of the antibacterial peptide magainin 2 amide to small and large unilamellar vesicles Wieprecht T, Apostolov O, Seelig J. The thermodynamics of binding of the antibacterial peptide magainin 2 amide (M2a) to negatively charged small (SUVs) and large (LUVs) unilamellar vesicles has been studied with isothermal titration calorimetry (ITC) and CD spectroscopy at 45 degrees C . The binding isotherms as well as the ability of the peptide to permeabilize membranes were found to be qualitatively and quantitatively similar for both model membranes . The binding isotherms could be described with a surface partition equilibrium where the surface concentration of the peptide immediately above the plane of binding was calculated with the Gouy-Chapman theory . The standard free energy of binding was deltaG0 approximately -22 kJ/mol and was almost identical for LUVs and SUVs . However, the standard enthalpy and entropy of binding were distinctly higher for LUVs (deltaH0 = -15.1 kJ/mol, deltaS0 = 24.7 J/molK) than for SUVs (deltaH0 = -38.5 kJ/mol, deltaS0 = -55.3 J/molK) . This enthalpy-entropy compensation mechanism is explained by differences in the lipid packing . The cohesive forces between lipid molecules are larger in well-packed LUVs and incorporation of M2a leads to a stronger disruption of cohesive forces and to a larger increase in the lipid flexibility than peptide incorporation into the more disordered SUVs . At 45 degrees C the peptide easily translocates from the outer to the inner monolayer as judged from the simulation of the ITC curves. J Bacteriol, 2000 Sep, 182(18), 5262 - 6 Lantibiotic biosynthesis: interactions between prelacticin 481 and its putative modification enzyme, LctM; Uguen P et al.; Class AII and AIII lantibiotics and mersacidin are antibacterial peptides containing unusual residues obtained by posttranslational modifications of prepeptides, presumably catalyzed by LanM . LctM, the LanM for lacticin 481, is essential for the production of this class AII lantibiotic . Using the yeast two-hybrid system, we showed direct contact between the prelacticin 481 and LctM, supporting the proposed LctM function . Sixteen domains are conserved between the 10 known LanM proteins, whereas three additional domains were found only in class AII LanM proteins and in MrsM, the LanM for mersacidin . All the truncated LctM proteins that we tested presented impaired LctA-binding activity. Biochemistry, 2000 Aug 22, 39(33), 10236 - 46 Efficient, Mg(2+)-dependent photochemical DNA cleavage by the antitumor quinobenzoxazine (S)-A-62176; Yu H et al.; The quinobenzoxazines, a group of structural analogues of the antibacterial fluoroquinolones, are topoisomerase II inhibitors that have demonstrated promising anticancer activity in mice . It has been proposed that the quinobenzoxazines form a 2:2 drug-Mg(2+) self-assembly complex on DNA . The quinobenzoxazine (S)-A-62176 is photochemically unstable and undergoes a DNA-accelerated photochemical reaction to afford a highly fluorescent photoproduct . Here we report that the irradiation of both supercoiled DNA and DNA oligonucleotides in the presence of (S)-A-62176 results in photochemical cleavage of the DNA . The (S)-A-62176-mediated DNA photocleavage reaction requires Mg(2+) . Photochemical cleavage of supercoiled DNA by (S)-A-62176 is much more efficient that the DNA photocleavage reactions of the fluoroquinolones norfloxacin, ciprofloxacin, and enoxacin . The photocleavage of supercoiled DNA by (S)-A-62176 is unaffected by the presence of SOD, catalase, or other reactive oxygen scavengers, but is inhibited by deoxygenation . The photochemical cleavage of supercoiled DNA is also inhibited by 1 mM KI . Photochemical cleavage of DNA oligonucleotides by (S)-A-62176 occurs most extensively at DNA sites bound by drug, as determined by DNase I footprinting, and especially at certain G and T residues . The nature of the DNA photoproducts, and inhibition studies, indicate that the photocleavage reaction occurs by a free radical mechanism initiated by abstraction of the 4'- and 1'-hydrogens from the DNA minor groove . These results lend further support for the proposed DNA binding model for the quinobenzoxazine 2:2 drug-Mg(2+) complex and serve to define the position of this complex on the minor groove of DNA. Ceska Slov Farm, 2000 Jan, 49(1), 32 - 6 {Antibacterial and antineoplastic activity of 2,4-disubstituted 6H-5,1,3-benzothiadiazocines}; Jantova S et al.; Nine 2,4-disubstituted 6H-5,1,3-benzothiadiazocines have been tested for antibacterial and cytotoxic efficacy . None of the tested compounds showed any significant antibacterial activity in comparison with ampicillin . The most cytotoxic effect was manifested by those derivatives which have morpholine or phenyl in position 2 and benzimidazole, imidazole or 1,2,4-triazole in position 4 . The highest concentrations of derivatives I, VII, IX induced an acute cytotoxic effect which was manifested by cell lysis after 24 h of culturing . Derivative VII, concentration 30.5 mumol/L, and derivative IX, concentration 13.3 mumol/L, exhibited a delayed cytotoxic effect on L1210 cells . While during the first 24 and 48 h a certain part of cell population proliferated, during further 24 h a total inhibition of cell division was found . The cytotoxic concentration of derivative IX induced damage to the integrity of the cytoplasmic membrane . Benzothiadiazocines I, VII and IX induced a two-phase unbalanced growth . Based on these results, benzothiodiazocines I, VII and IX could be considered new potential anticancer drugs which are appropriate for further research. Eur J Biochem, 2000 Sep, 267(17), 5330 - 41 The antibiotic and anticancer active aurein peptides from the Australian Bell Frogs Litoria aurea and Litoria raniformis the solution structure of aurein 1.2; Rozek T et al.; Seventeen aurein peptides are present in the secretion from the granular dorsal glands of the Green and Golden Bell Frog Litoria aurea, and 16 from the corresponding secretion of the related Southern Bell Frog L . raniformis . Ten of these peptides are common to both species . Thirteen of the aurein peptides show wide-spectrum antibiotic and anticancer activity . These peptides are named in three groups (aureins 1-3) according to their sequences . Amongst the more active peptides are aurein 1.2 (GLFDIIKKIAESF-NH2), aurein 2.2 (GLFDIVKKVVGALGSL-NH2) and aurein 3.1 (GLFDIVKKIAGHIAGSI-NH2) . Both L . aurea and L . raniformis have endoproteases that deactivate the major membrane-active aurein peptides by removing residues from both the N- and C-termini of the peptides . The most abundant degradation products have two residues missing from the N-terminal end of the peptide . The solution structure of the basic peptide, aurein 1.2, has been determined by NMR spectroscopy to be an amphipathic alpha-helix with well-defined hydrophilic and hydrophobic regions . Certain of the aurein peptides (e.g . aureins 1.2 and 3.1) show anticancer activity in the NCI test regime, with LC50 values in the 10-5-10-4 M range . The aurein 1 peptides have only 13 amino-acid residues: these are the smallest antibiotic and anticancer active peptides yet reported from an anuran . The longer aurein 4 and 5 peptides, e.g . aurein 4.1 (GLIQTIKEKLKELAGGLVTGIQS-OH) and aurein 5 . 1 (GLLDIVTGLLGNLIVDVLKPKTPAS-OH) show neither antibacterial nor anticancer activity. Microbiol Res, 2000 Jul, 155(2), 133 - 5 Physiological and antagonistic potential of actinomycetes from loquat rhizosphere; Gesheva V et al.; The microflora of Eriobotrya japonica (loquat) was studied by the serial dilutions-spread plate method . A variety of bacteria, fungi and actinomycetes was detected . The genus Steptomyces dominated in the population (83%) . A great species diversity was found among Streptomycetes . Some of the actinomycetes possessed antibacterial activity (47%), others produced different exo-enzymes. Microbiol Res, 2000 Jul, 155(2), 129 - 31 Studies on Alternaria sesami pathogenic to sesame; Rao NR et al.; Influence of pH on the growth of Alternaria sesami, its nutritional requirements and its ability to produce phytotoxic and antibacterial metabolites were tested . The isolate was cultured on Czapek-Dox broth and the culture filtrates were screened for phytotoxicity against seeds and seedlings of sesame . Chloroform extracts of the fungus exhibited antibacterial activity . Analysis of the culture filtrates for identifying toxins using chromatographic techniques revealed the presence of tenuazonic acid. J Chemother, 2000 Aug, 12(4), 274 - 9 A synthetic gamma-lactone group with beta-lactamase inhibitory and sporulation initiation effects; Gal Z et al.; Previous studies showed that some lactones have beta-lactamase inhibitory or antibacterial effects, others--like A-factor (a gamma-butyrolactone) and its derivatives--stimulate sporulation in Streptomyces griseus strains . Our experiments were aimed at exploring whether synthetic gamma-lactones had such effects . None of the seven gamma-lactones studied showed antibacterial activity, but two of them inhibited beta-lactamases isolated from various bacteria . These two gamma-lactones did not reduce colony formation of murine bone marrow cells in vitro, indicating that they were not toxic to proliferating mammalian cells . Four gamma-lactones, including the two inhibiting beta-lactamase, stimulated sporulation in the non-sporulating S . griseus bald 7 mutant . Further studies of gamma-lactones as potential inhibitors of beta-lactamase seem to be warranted. Clin Ther, 2000 Jul, 22(7), 798 - 817; discussion 797 The safety profile of the fluoroquinolones; Bertino J Jr et al.; BACKGROUND: Premarketing trials showed the fluoroquinolone agents to have a favorable side-effect profile, with treatment-related adverse events comprising gastrointestinal, central nervous system, and dermatologic effects that were generally mild and reversible on cessation of treatment . However, postmarketing surveillance studies have identified severe adverse events, including severe anaphylaxis, QTc-interval prolongation, and potential cardiotoxicity, associated with 3 quinolone agents that either resulted in the removal of the agent from the market (temafloxacin and grepafloxacin) or significantly restricted its use due to substantial mortality and morbidity associated with liver toxicity (trovafloxacin) . To date, there have been no such significant adverse events associated with the older fluoroquinolone agents, including ciprofloxacin, ofloxacin, norfloxacin, and levofloxacin . However, there are fewer data from postmarketing surveillance studies on the most recently approved agents, such as moxifloxacin and gatifloxacin, or agents awaiting approval, such as gemifloxacin . OBJECTIVE: This paper examines safety data from the premarketing trials and postmarketing surveillance studies of fluoroquinolones available in the United States . METHODS: A MEDLINE search was performed to identify all English-language studies published since 1980 concerning the safety profiles of the fluoroquinolones . CONCLUSIONS: The fluoroquinolone antibacterial agents offer broad-spectrum therapy in patients with a variety of infections . Given similar spectra of activity, the choice between quinolones may be based on differences in efficacy and safety or tolerability profiles . Most drug reactions involving these agents are minor and reversible on discontinuing treatment, but adverse effects can be associated with significant mortality and morbidity, as was seen in the case of trovafloxacin and temafloxacin. Drug Saf, 2000 Aug, 23(2), 143 - 64 Drug-induced respiratory disorders: incidence, prevention and management; Ben-Noun L; Various drugs are associated with adverse respiratory disorders (ARDs) ranging in severity from mild, moderate to severe and even fatal . Cardioselective and nonselective beta-blockers, calcium antagonists and dipyridamole can induce asthma . ACE inhibitors are mainly associated with cough . Amiodarone is related to a form of interstitial pneumonitis (IP) which can be fatal, tocainidine and flecainidine to a form of IP, and hydrochlorothiazide to a form of IP and pulmonary oedema . Antiasthmatic drugs can be associated with a paradoxical bronchospasm, while leukotriene antagonists are linked to the development of Churg-Strauss syndrome . Nonsteroidal anti-inflammatory drugs including aspirin (acetylsalicylic acid) may induce asthma . Gold is mainly related to IP, penicillamine to IP, systemic lupus erythematosus, bronchiolitis obliterans, and Goodpasture's syndrome . Acute respiratory reactions to nitrofurantoin include dyspnoea, cough, IP, and pleural effusion while IP and fibrosis are common in chronic reactions . Other antibacterials mainly evoke pneumonitis, pulmonary infiltrates and eosinophilia, and bronchiolitis obliterans . ARDs are similar for most categories of cytotoxic agents, with chronic pneumonitis and fibrosis being the most common . Noncardiogenic pulmonary oedema occurs as the most common respiratory complication in opioid agonist addiction . Psychotropic drugs such as phenothiazides, butyrophenones and tricyclic antidepressants can also induce pulmonary oedema . Oral contraceptives may produce asthma exacerbation, while long term use and/or high doses of postmenopausal hormone replacement therapy increase the risk of asthma . Bromocriptine is mainly associated with pleural effusion, while methysergide is usually associated with pleural effusion and fibrosis . Some anorectic agents have been linked to the development of primary pulmonary hypertension . The possibility of the occurrence of ARDs should be taken into account in each individual patient . Although in most cases the adverse effects are unpredictable, they can be reduced to a minimum or prevented if some drugs are avoided or stopped in time. Biosci Biotechnol Biochem, 2000 Jul, 64(7), 1410 - 5 Synthesis and absolute configuration of hongoquercin B, a sesquiterpene-substituted orsellinic acid isolated as a fungal metabolite; Tsujimori H et al.; (+)-Hongoquercin B (1), a weakly antibacterial fungal metabolite, was synthesized by starting from (S)-3-hydroxy-2,2-dimethylcyclohexanone, and its absolute configuration was determined as depicted by structure 1. Clin Transplant, 2000 Aug, 14(4 Pt 1), 269 - 81 Assistance programs available for medications commonly used in transplant patients; Chisholm MA et al.; Pharmaceutical manufacturers have programs available to supply medications to indigent patients at little or no cost . Enrolling needy patients into these programs should increase patient compliance to medications, minimize patient and institution financial burdens, and decrease adverse events associated with medication noncompliance . However, access to assistance programs by patients in need is limited if physicians and other health care providers are unaware of the existence of such programs or not informed of each program's enrollment process . The literature is void of a manuscript describing assistance programs available for commonly prescribed medications used in transplant patients . This article offers a concise summary of medication assistance programs available through the pharmaceutical industry to assist in the procurement of medications that are commonly prescribed for the transplant population, including immunosuppressants, antibacterials, gastrointestinal, cardiovascular, and hypoglycemic agents . This article should be used by health care professionals as a guide to the availability and requirements of medication assistance programs. J Mol Microbiol Biotechnol, 1999 Nov, 1(2), 309 - 17 A reporter gene assay for inhibitors of the bacterial phosphoenolpyruvate: sugar phosphotransferase system; Hesterkamp T et al.; The phosphoenolpyruvate:sugar phosphotransferase system (PTS) plays a key role in sugar uptake and metabolic regulation in bacteria . PTS proteins form a divergent phosphorylation cascade . Enzyme I (EI) is at the top of the cascade and mediates phosphoryl-transfer from phosphoenolpyruvate to the phosphoryl-carrier protein HPr, which then distributes the phosphoryl-groups to the different carbohydrate transporters . In addition, some PTS proteins have a regulatory function in catabolite repression, inducer exclusion and chemotaxis which is modulated by their degree of phosphorylation in response to the availability of substrates . Using as a reporter the IacZ gene under control of the bgl t2 transcriptional terminator and as an effector the transcriptional antiterminator LicT from B . subtilis, a two-plasmid reporter gene system was constructed in order to monitor PTS activity . LicT, when present at low concentration in E . coli, is inactivated by EI/HPr-dependent phosphorylation and conversely is active in a ptsl- mutant lacking El . Active LicT allows for transcriptional readthrough at bgl t2, resulting in a full-length lacZ transcript . Beta-galactosidase activities are increased 4-8-fold in a ptsl+ strain growing on PTS substrates relative to growth on non-PTS substrates and approximately 30-fold in a ptsl- mutant . This gain-of-function in response to dephosphorylation of El or lack of active El can be used to monitor changes of El activity caused by mutations and environmental factors and for screening and validation of inhibitors of the PTS as potentially novel antibacterial compounds. Skin Pharmacol Appl Skin Physiol, 2000 Sep-Oct, 13(5), 292 - 6 Synergistic activity of benzoyl peroxide and erythromycin; Burkhart CN et al.; BACKGROUND: Benzoyl peroxide (BP) i