Antimicrobials

Biol Chem, 2004 Dec, 385(12), 1197 - 202
St . John's wort (Hypericum perforatum) counteracts cytokine-induced tryptophan catabolism in vitro; Winkler C et al.; St . John's wort (Hypericum perforatum) is an ancient folk remedy that has antiviral and antibacterial properties . Anti-inflammatory effects of the plant have been described and the application of H . perforatum extract as an effective antidepressant is well established . In this study we assayed the effect of H . perforatum extract on cytokine-induced tryptophan degradation in human peripheral blood mononuclear cells . Simultaneously, changes in the production of the immune activation marker neopterin were monitored . Both these biochemical pathways are triggered by interferon-gamma . Our results show that extracts of H . perforatum strongly down-regulate mitogen-mediated tryptophan degradation in a dose-dependent manner . This effect seems to be based on a suppressive activity of H . perforatum on activated immunocompetent cells, resulting in a diminished production of interferon-gamma . In line with this finding, neopterin synthesis was strongly down-regulated by the plant extract . Our results suggest that the reduction of tryptophan degradation by H . perforatum might be important in the action of the plant as an antidepressant.

Curr Opin Immunol, 2005 Feb, 17(1), 79 - 87
Antigen presentation and recognition in bacterial infections; Kaufmann SH et al.; Antigen processing and recognition is a key feature of antibacterial immune responses to intracellular bacteria . In contrast to viruses, which are primarily controlled by conventional MHC II- and MHC I-restricted CD4(+) or CD8(+) T cells, respectively, unconventional T cells participate additionally in antibacterial protection . These unconventional T cells include glycolipid-specific CD1-restricted T cells and phospholigand-specific gammadelta T cells . We are just beginning to understand the broad spectrum of antigen recognition and stimulation of distinct T-cell populations by bacterial pathogens . From the host perspective, a broad spectrum of different T-cell populations that recognize proteins, lipids and carbohydrates strengthens protective immunity . From the perspective of the pathogen, antigen presentation represents a bottleneck that should be exploited for evasion from, or devastation of, acquired immunity . Although several such mechanisms have been described in viral systems, few have thus far been elucidated in bacterial infections.

J Ethnopharmacol, 2005 Feb 10, 97(1), 107 - 15 Epub 2004 Dec 13.
Effect of storage on the chemical composition and biological activity of several popular South African medicinal plants; Stafford GI et al.; The in vitro biological activity of nine frequently used medicinal plants in South Africa was assessed and re-assessed after various lengths of storage . The plants investigated were Alepidea amatymbica, Leonotis leonurus, Drimia robusta, Vernonia colorata, Merwilla natalensis, Eucomis autumnalis, Bowiea volubilis, Helichrysum cymosum and Siphonochilus aethiopicus . Water, ethanol and hexane extracts of fresh, 90-day-old and 1-year-old material were assayed for antibacterial activity against four strains of bacteria and for COX-1 inhibition activity . TLC-fingerprints of the fresh and stored extracts were produce to document chemical changes . Alepidea amatymbica, Eucomis autumnalis, Helichrysum cymosum, Leonotis leonurus, Siphonochilus aethiopicus and Vernonia colorata were investigated further as to the effect of 1 year's storage . Elevated temperature and humidity (55 degrees C and 100% relative humidity) were used to accelerate the ageing process of Alepidea amatymbica, Leonotis leonurus and Vernonia colorata plant material for further investigation . The TLC-fingerprints indicated that there was chemical breakdown during storage in certain species . The degree of changes in biological activity and chemistry due to storage were species-specific . In general, antibacterial activity was retained in most species while COX-1 inhibition activity was lost rapidly.

Vestn Khir Im I I Grek, 2004, 163(5), 111 - 5
{Improvement of curative measures for peritonites of obstetric and gynecologic etiology}; Hydrogen peroxide produced by two amino acid oxidases mediates antibacterial actions; Key Laboratory of Structural Biology, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, The People's Republic of China . zhanghm77@yahoo.com

The antibacterial actions of two amino acid oxidases, a D-amino acid oxidase from hog kidney and a L-amino acid oxidase from the venom of Agkistrodon halys, were investigated, demonstrating that both enzymes were able to inhibit the growth of both Gram-positive and Gram-negative bacteria, and that hydrogen peroxide, a product of their enzymatic reactions, was the antibacterial factor . However, hydrogen peroxide generated in the enzymatic reactions was not sufficient to explain the degree to which bacterial growth was inhibited . A fluorescence labeling assay showed that both of these two enzymes could bind to the surfaces of bacteria . To the best of our knowledge, this is the first report regarding the antibacterial activity of the D-amino acid oxidases.

Phytochemistry, 2005 Jan, 66(1), 5 - 29
Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae); Heitzman ME et al.; The Uncaria genus is an important source of medicinal natural products, particularly alkaloids and triterpenes . The collected information is an attempt to cover the more recent developments in the ethnobotany, pharmacology and phytochemistry of this genus . During the past 20 years, alkaloids, terpenes, quinovic acid glycosides, flavonoids and coumarins have been isolated from Uncaria . Fifty-three novel structures are reported in this review . The species in which the largest number of compounds has been identified is the Peruvian Uncaria tomentosa or 'cat's claw.' Pharmacological studies are described according to cytotoxicity, anti-inflammatory, antiviral, immunostimulation, antioxidant, CNS-related response, vascular, hypotensive, mutagenicity and antibacterial properties . The potential for development of leads from Uncaria continues to grow, particularly in the area of immunomodulatory, anti-inflammatory and vascular-related conditions . The information summarized here is intended to serve as a reference tool to practitioners in the fields of ethnopharmacology and natural products chemistry.

Dis Aquat Organ, 2004 Nov 23, 62(1-2), 97 - 102
In vitro efficacy of new antiprotozoals against Philasterides dicentrarchi (Ciliophora, Scuticociliatida); Parama A et al.; Philasterides dicentrarchi is a histiophagous ciliate that causes severe losses in turbot and sea bass farming . This study investigated the in vitro efficacy against P . dicentrarchi of 85 newly synthesized compounds and 12 commercial compounds, of which 2 are fluoroquinolones (norfloxacine and lomefloxacine) with known antibacterial activity . Seventeen of the newly synthesized compounds (2 naphthyridines, 2 pyridothienodiazines and 13 pyridothienotriazines) and the fluoroquinolone norfloxacin showed good activity . The most promising compound was the pyridothienotriazine 12k, with activity similar to that of the salicylanilides niclosamide and oxiclozanide (MLC 0.8 mg l(-1) in PBS, 1.5 mg l(-1) in seawater; MLC = minimum 24 h lethal concentration).

Appl Microbiol Biotechnol . 2005 Jan 13; {Epub ahead of print}
Mycobacterium sp . mutant strain producing 9alpha-hydroxyandrostenedione from sitosterol; Donova MV et al.; Mycobacterium sp . VKM Ac-1815D and its derivatives with altered resistance to antibacterial agents were able to produce androst-4-ene-3,17-dione (AD) as a major product from sitosterol . In this study, those strains were subjected to subsequent mutagenization by chemical agents and UV irradiation in combination with sitosterol selection pressure . The mutant Mycobacterium sp . 2-4 M was selected, being capable of producing 9alpha-hydroxyandrost-4-ene-3,17-dione (9-OH-AD) as a major product from sitosterol, with a 50% molar yield . Along with 9-OH-AD, both AD and 9alpha-hydroxylated metabolites with a partially degraded side-chain were formed from sitosterol by the mutant strain . The strain was unable to degrade 9-OH-AD, but degraded androsta-1,4-diene-3,17-dione (ADD), thus indicating a deficiency in steroid 1(2)-dehydrogenase and the presence of 9alpha-hydroxylase activity.

Theor Biol Med Model . 2005 Jan 12;2(1):2 {Epub ahead of print}
Construction of predictive promoter models on the example of antibacterial response of human epithelial cells; Shelest E et al.; BACKGROUND: Binding of a bacteria to a eukaryotic cell triggers a complex network of interactions in and between both cells . P . aeruginosa is a pathogen that causes acute and chronic lung infections by interacting with the pulmonary epithelial cells . We use this example for examining the ways of triggering the response of the eukaryotic cell(s), leading us to a better understanding of the details of the inflammatory process in general . RESULTS: Considering a set of genes co-expressed during the antibacterial response of human lung epithelial cells, we constructed a promoter model for the search of additional target genes potentially involved in the same cell response . The model construction is based on the consideration of pairwise combinations of transcription factor binding sites (TFBS) . It has been shown that the antibacterial response of human epithelial cells is triggered by at least two distinct pathways . We therefore supposed that there are two subsets of promoters activated by each of them . Optimally, they should be "complementary" in the sense of appearing in complementary subsets of the (+)-training set . We developed the concept of complementary pairs, i.e., two mutually exclusive pairs of TFBS, each of which should be found in one of the two complementary subsets . CONCLUSIONS: We suggest a simple, but exhaustive method for searching for TFBS pairs which characterize the whole (+)-training set, as well as for complementary pairs . Applying this method, we came up with a promoter model of antibacterial response genes that consists of one TFBS pair which should be found in the whole training set and four complementary pairs . We applied this model to screening of 13,000 upstream regions of human genes and identified 430 new target genes which are potentially involved in antibacterial defense mechanisms.

J Am Dent Assoc, 2004 Dec, 135(12), 1728 - 32
Serum and gingival crevicular fluid levels of ciprofloxacin in patients with periodontitis; Tozum TF et al.; BACKGROUND: The use of antibiotics as an adjunctive therapy in the treatment of periodontal diseases is of special interest to dental practitioners . In addition to using an appropriate antibacterial agent, clinicians may find it useful to determine the local and systemic concentrations of antibiotics in infected periodontal sites to reduce the levels of bacteria . The purpose of this study was to determine the serum and gingival crevicular fluid, or GCF, concentrations of systemic ciprofloxacin in patients with periodontitis . METHODS: Ten subjects with chronic periodontitis received ciprofloxacin (500 milligrams) twice daily for five days . The authors collected GCF and serum samples immediately after administering the first dose (baseline = 0 hours) and at consecutive time points . The orifice method was used for GCF sampling, and 5 milliliters of venous blood was drawn for serum analysis . The authors used high-performance liquid chromatography to determine ciprofloxacin concentrations in GCF and serum . RESULTS: The authors found that ciprofloxacin concentrations in GCF were significantly higher than concentrations in serum at two, four, seven, 24 and 120 hours . Ciprofloxacin reached the maximum concentration, or Cmax (3.72 micrograms/ mL), in GCF two hours after the initial dose was administered . The concentration decreased to 2.06 microg/mL 24 hours after the initial administration of the drug . Serum Cmax was 2.58 microg/mL at 1.5 hours, and the concentration decreased to 0.26 microg/mL at 24 hours . CONCLUSION: The results of this clinical study show that ciprofloxacin is found in GCF and its concentration in GCF is significantly higher than that in serum . CLINICAL IMPLICATIONS: Ciprofloxacin may be useful in treating patients with periodontitis because it reaches higher concentrations in GCF than in serum.

Oral Health Prev Dent, 2004, 2 Suppl 1, 301 - 6
Lesion orientated caries treatment--a classification of carious dentin treatment procedures; Noack MJ et al.; PURPOSE: To review experimental and marketed techniques for the treatment of infected dentin as a potential substitute for conventional rotary excavation . MATERIALS AND METHODS: A hand and systematic search of Medline (via DIMDI) was performed . Additionally, manufacturers' data about relevant clinical studies were checked . After classification of the identified techniques described, relevant studies are cited to allow an overview of the different treatment options . RESULTS: Excavation, disinfection and sealing techniques for the treatment of infected dentin can be differentiated . Besides several mechanical approaches, chemo-mechanical excavation, enzymatic digestion and photo ablation are discussed . Disinfection techniques can be undertaken with even less invasive approaches like gasiform ozone application, photodynamic therapy or local application of antibacterial materials . Additionally, or alternatively, the sealing of carious dentin is discussed using fluoride-releasing cements, dentin adhesives or antibacterial resin materials . CONCLUSION: Although some of the techniques are still experimental and much clinical research has to be done, many different approaches are so promising, or already established, that hopefully the days of radical excavation with rotary instruments are numbered.

New Microbiol, 2004 Oct, 27(4), 369 - 74
Beneficial effects of antibacterial peptide PR-39 in a neonatal murine model of endotoxic shock; Delfino D et al.; The lethal effects occurring in neonatal (< 24-h old) BALB/c mice after challenge with E . coli lipopolysaccharide (LPS) were significantly counteracted by pretreatment with antibacterial peptide PR-39 . Neonatal mice protection was probably related to the depressive effect of PR-39 on production of TNF-alpha known to be the major mediator of the lethal effects of neonatal endotoxic shock . Indeed, TNF-alpha plasmatic levels were consistently lower in pups pretreated with PR-39 compared with controls . Administration 24 h after challenge was no longer effective . Although PR-39 and anti-TNF-alpha doses were ineffective alone, when combined at different ratios protected neonatal mice . The present experiments show the potential use of peptide PR-39 in preventing neonatal endotoxic shock.

Pediatr Surg Int, 2005 Jan, 21(1), 20 - 4
Effect of antibacterial cathelicidin peptide CAP18/LL-37 on sepsis in neonatal rats; Fukumoto K et al.; Cathelicidins are a family of antibacterial peptides . Human cathelicidin LL-37 inhibits the binding of endotoxin lipopolysaccharide (LPS) to CD14-positive cells and could ameliorate sepsis . The aim of this study was to observe the effect of LL-37 on sepsis in neonatal rats . Intraperitoneal injection (IPI) of LPS was used to create sepsis in suckling rats . Group 1 rats were given LPS with LL-37, group 2 rats were given LL-37 2 h after LPS, and group 3 rats were given LPS without LL-37 . Control group rats were given isovolemic normal saline by IPI . Rats given LL-37 IPI were divided into seven subgroups . Following IPI, an overall assessment score (OAS) and rectal temperature (RT) were assessed hourly . Serum C-reactive protein (CRP) was also assessed at death or at sacrifice 10 h after IPI . All rats in group 3 died . For rats receiving lower doses of LL-37 in groups 1 and 2, mortality was decreased . No deaths occurred among those receiving higher doses of LL-37 in group 1; however, mortality increased in group 2 . In group 1, OAS and RT deteriorated initially for those receiving lower doses of LL-37, then improved . OAS and RT did not deteriorate throughout the study in rats given higher doses of LL-37 . In group 2 rats given higher doses of LL-37, OAS and RT were not significantly different from rats in group 3 . CRP was significantly decreased in group 1 compared with group 3, and decreased in group 2 for lower doses only . We conclude that LL-37 may prevent sepsis and be useful in lower doses for treating sepsis . However, LL-37 appears to have adverse effects when used at higher doses for treating sepsis.

Genome, 2004 Dec, 47(6), 1082 - 90
Evolution of cow nonstomach lysozyme genes; Irwin DM; Expansion of the lysozyme gene family is associated with the evolution of the ruminant lifestyle in ruminant artiodactyls such as the cow . Gene duplications allowed recombination between stomach lysozyme genes that may have assisted in the evolution of an enzyme adapted to survive and function in the stomach environment . Despite amplification of lysozyme genes, cow tears, milk, and blood are considered to be lysozyme deficient . Here we have identified 2 new cow lysozyme cDNA sequences and show that at least 4 different lysozymes are expressed in cows in nonstomach tissues and probably function as antibacterial defence enzymes . These 4 lysozyme genes are in addition to the 4 digestive lysozyme genes expressed in the stomach, yielding a number of expressed lysozyme genes in the cow larger than that found in most nonlysozyme-deficient mammals . In contrast to expectations, evidence for recombination between stomach and nonstomach lysozyme genes was found . Recombination, through concerted evolution, may have allowed some lysozymes to acquire the ability to survive in occasional acidic environments.

Bosn J Basic Med Sci, 2004 Feb, 4(1), 73 - 8
Endodontic-periodontal locally delivered antibiotics; Lacevic A et al.; Endodontic pathology is a bacterial disease . It is well established that periapical disease is the result of bacteria, their product, and the host response to them . Periradicular disease will occur after microorganisms and their metabolic products affect the periradicular tissue . Aim of using antibiotics as part of a treatment regimen is to achieve, within the periodontal environment, a concentration of the drug that is sufficient either to kill (bactericidal) or arrest the growth (bacteriostatic) of pathogenic microorganisms . There are two possible approaches to improve the drug action: sustained and controlled drug release to reduce or eliminate side effects by improving the therapeutic index and site-specific drug delivery to minimize systemic effects . These two strategies have been explored by the association of drugs with different vehicles, either naturals or synthetics . A wide variety of specialized local delivery systems (i.e.intrapocket devices) have been designed to maintain the antibiotic in the GCF (gingival crevicular fluid) at a concentration higher than the MIC (minimum inhibitory concentration) . Fibres, films, strips and microparticles made of biodegradable or non-biodegradable polymers have been reported as effective methods to administer antibacterial agents for periodontal therapy . Together with these solid devices, semisolid adhesive or non-adhesive formulations have also been proposed.

Neoplasma, 2004, 51(6), 436 - 41
Cytotoxic and genotoxic effects of some substituted tetrazolo{1,5-c}quinazolines; Jantova S et al.; Nine substituted tetrazolo{1,5-c}quinazolines have been tested for cytotoxic effects and structure activity relationship on the murine cancer cell line B16 and four bacterial strains . The most cytotoxic activity had non-substituted in the aromatic ring or substituted by bromo- or chloro-group, and in the pyrimidine ring of quinazoline skeleton by phenyl or morpholine group, respectively . In the bacterium all tested quinazolines had a lower antibacterial effect than ampicillin . 9-bromo-5-morpholino-tetrazolo{1,5-c}quinazoline (BMTQ) at the highest concentration tested (30.0 mumol/l) had an acute cytostatic effect manifested by the total inhibition of the cell proliferation . Other concentrations caused a cytotoxicity proportional to the concentation used . The IC50 values were found to be less than 4 mug/ml, a limit put forward by the National Cancer Institute (NCI) for clasification of the compound as a potential anticancer drug . BMTQ induced mutations in a dose-related manner, starting from 10 mug/plate in strains TA100 and TA102 . Lesser but significant increases in revertant colonies were also obtained in strain TA98 . The mutagenity was slighly enhanced by metabolic activation.

Nat Immunol . 2005 Jan 09; {Epub ahead of print}
Downregulation of lipopolysaccharide response in drosophila by negative crosstalk between the AP1 and NF-kappaB signaling modules; Kim T et al.; IkappaB kinase (IKK) and Jun N-terminal kinase (Jnk) signaling modules are important in the synthesis of immune effector molecules during innate immune responses against lipopolysaccharide and peptidoglycan . However, the regulatory mechanisms required for specificity and termination of these immune responses are unclear . We show here that crosstalk occurred between the drosophila Jnk and IKK pathways, which led to downregulation of each other's activity . The inhibitory action of Jnk was mediated by binding of drosophila activator protein 1 (AP1) to promoters activated by the transcription factor NF-kappaB . This binding led to recruitment of the histone deacetylase dHDAC1 to the promoter of the gene encoding the antibacterial protein Attacin-A and to local modification of histone acetylation content . Thus, AP1 acts as a repressor by recruiting the deacetylase complex to terminate activation of a group of NF-kappaB target genes.

Biomacromolecules, 2005 Jan-Feb, 6(1), 392 - 9
Dual properties of the deacetylated sites in chitosan for molecular immobilization and biofunctional effects; Liao JD et al.; Polypropylene nonwoven fabric was surface-activated by high-density oxygen microwave plasma, followed by graft copolymerization with acrylic acid (AAc) and then coupling with chitosan molecules . The pAAc-grafted surface containing C=O in carboxylic acid exhibited a hydrophilic character capable of promoting water absorbency . A larger portion of minimum 85% deacetylated sites in chitosan molecules was then coupled with the grafted pAAc (around 149 mug.cm(-2)) by forming amide bonds at their interface . The covalently bonded chitosan was weighted around 44 mug.cm(-2) . The smaller portion of the deacetylated sites demonstrated a distinctive structure as polycations, i.e., NH(3)(+), on the immobilized chitosan . The respective structures following sequential reactions were identified using Fourier transform infrared-attenuated total reflection and X-ray photoelectron spectroscopy with peaks deconvolution . The NH(3)(+) sites on the immobilized chitosan exhibited biofunctional in anticoagulation and in antibacterial property . Blood cells agglutination or agglomeration upon the chitosan-immobilized surface, in particular for red blood cells and platelets, resulted from hydrophilic effect derived from the grafted pAAc and the chitosan itself, and ionic attractions between polycations and blood cells . In addition, the agglutinated cells retained their original morphologies . It is therefore very promising to apply this durable chitosan-immobilized surface for making an antibacterial support, at the same time, for retaining blood cell affinity.

J Pept Sci . 2004 Sep 15; {Epub ahead of print}
Structure-activity relationship study of anoplin; Ifrah D et al.; Anoplin is a decapeptide amide, GLLKRIKTLL-NH(2) derived from the venom sac of the solitary spider wasp, Anoplius samariensis . It is active against Gram-positive and Gram-negative bacteria and is not hemolytic towards human erythrocytes . The present paper reports a structure-activity study of anoplin based on 37 analogues including an Ala-scan, C- and N-truncations, and single and multiple residue substitutions with various amino acids . The analogues were tested for antibacterial activity against both S . aureus ATCC 25923 and E . coli ATCC 25922, and several potent antibacterial analogues were identified . The cytotoxicity of the analogues against human erythrocytes was assessed in a hemolytic activity assay . The antibacterial activity and selectivity of the analogues against S . aureus and E . coli varied considerably, depending on the hydrophobicity and position of the various substituted amino acids . In certain cases the selectivity for Gram-positive and Gram-negative bacteria was either reversed or altogether eliminated . In addition, it was generally found that antibacterial activity coincided with hemolytic activity . Copyright (c) 2004 European Peptide Society and John Wiley & Sons, Ltd.

J Pept Sci, 2004 Dec, 10(12), 714 - 8
Arthropod defensins illuminate the divergence of scorpion neurotoxins; Froy O et al.; Defensins are phylogenetically ancient antibacterial polypeptides found in plants and animals . Isolation of the cDNA and genomic sequences encoding the scorpion (Leiurus quinquestriatus hebraeus) defensin revealed similarity to scorpion neurotoxins in gene organization (two exons and a phase I intron) and intron characteristics (conserved acceptor, donor and putative branch sites) . This commonality, alongside a similar core structure, protein sequence and bioactivity suggest that arthropod defensins and scorpion neurotoxins share a common ancestor . Interestingly, phylogenetic analysis of defensins and scorpion neurotoxins illuminates for the first time a putative evolutionary trajectory for scorpion sodium and potassium channel neurotoxins.

J Zhejiang Univ Sci, 2005 Feb, 6(2), 91 - 5
Volatile constituents in the flowers of Elsholtzia argyi and their variation: a possible utilization of plant resources after phytoremediation; Peng HY et al.; Phytoremediation effectiveness and remediation costs are driving factors of this project . Full utilization of plant resources after their being used for phytoremediation is an unsolved problem . GC/MS technique was used to investigate the volatiles of the flowers from Elsholtzia argyi (PFE1: Purple Flower Elsholtzia) and their variation (WFE: White Flower Elsholtzia), naturally growing in Pb/Zn mined area, and Elsholtzia argyi (PFE2: Purple Flower Elsholtzia), naturally growing in Jiuxi uncontaminated agriculture soil . Seventeen compounds constituting 86.88% of total essential oils were identified in PFE1, with 2,6-octadienoic acid,3,7-dimethyl-methyl ester being the main constituent (63.30%) . Sixteen compounds accounting for 95.32% of total essential oils were identified in WFE, with caryophyllene being the main component (55.02%) . Compared to PFE1, PFE2 contains lower level of 2,6-octadienoic acid,3,7-dimethyl-methyl ester (31.76%), which is the main constituent in the total essential oils of PFE2 . Caryophyllene is the main ingredient of flavor . Elsholtzia ketone was identified in all the three Elsholtzia plants . It can be concluded that the selected Elsholtzia argyi plants can be exploited on their versatile uses as fragrances and antiseptics due to the perfume ingredient and antibacterial components existing in their essential oils.

Bosn J Basic Med Sci, 2004 Oct, 4(4), 73 - 8
Endodontic-periodontal locally delivered antibiotics; Lacevic A et al.; Endodontic pathology is a bacterial disease . It is well established that periapical disease is the result of bacteria, their product, and the host response to them . Periradicular disease will occur after microorganisms and their metabolic products affect the periradicular tissue . Aim of using antibiotics as part of a treatment regimen is to achieve, within the periodontal environment, a concentration of the drug that is sufficient either to kill (bactericidal) or arrest the growth (bacteriostatic) of pathogenic microorganisms . There are two possible approaches to improve the drug action: sustained and controlled drug release to reduce or eliminate side effects by improving the therapeutic index and site-specific drug delivery to minimize systemic effects . These two strategies have been explored by the association of drugs with different vehicles, either naturals or synthetics . A wide variety of specialized local delivery systems (i.e . intrapocket devices) have been designed to maintain the antibiotic in the GCF (gingival crevicular fluid) at a concentration higher than the MIC (minimum inhibitory concentration) . Fibres, films, strips and microparticles made of biodegradable or non-biodegradable polymers have been reported as effective methods to administer antibacterial agents for periodontal therapy . Together with these solid devices, semisolid adhesive or non-adhesive formulations have also been proposed.

Medicina (B Aires), 2004, 64(2), 146 - 8
{Endogenous Nocardia asteroides endophthalmitis in a patient with systemic lupus erythematosus}; Pelayes DE et al.; We report a case of endogenous nocardial endophthalmitis in a 32-year-old man with systemic lupus erythematosus . The patient developed pulmonary and ocular disease while on systemic corticosteroid and cyclophosphamide treatment . The intraocular infection progressed to a scleral fistula, and was treated with pars plana vitrectomy, lensectomy, intravitreous and intravenous antibacterial therapy . The diagnosis of Nocardia asteroides was made by isolation and growth of colonies from samples of a vitreous specimen and bronchioloalveolar aspirates . The eye became phthisical, it was eviscerated, and histopathogical examination was carried out.

J Chromatogr A, 2004 Dec 3, 1059(1-2), 25 - 31
Continuous microwave-assisted extraction coupled with derivatization and fluorimetric monitoring for the determination of fluoroquinolone antibacterial agents from soil samples; Morales-Munoz S et al.; An automated screening approach for fluoroquinolone (FQ) antibiotics (norfloxacin and ciprofloxacin) in soil samples has been developed . The proposed approach consists on dynamic microwave-assisted extraction and subsequent real-time on-line monitoring of the analytes extracted; thus, the extraction is halted when complete leaching of the analytes has been reached (independently of the sample matrix), avoiding extraction times in excess . The end of the extraction allowed quantifying the total content of the analytes . The extraction was carried out using pure water as extractant and consisted of a number of extraction cycles (depending on the sample matrix) in which the sample was subjected to microwave irradiation while the direction of the extractant was changed in an iterative manner . The target analytes were fluorometrically monitored after derivatization with a terbium (Tb3+)/tri-n-octylphosphine oxide (TOPO)/cetylpyridinium chloride (CPCl)/acetate buffer solution . Optimum conditions for analytes extraction and formation of FQ-Tb3+-TOPO ternary complexes have been obtained using the experimental design methodology . The mean recoveries from soil samples spiked with 5 and 0.5 microg/g of each analyte were (95.2+/-4.16%) and (98+/-5.21%), respectively . The within-laboratory reproducibility and repeatability, expressed as relative standard deviation, were 7.29 and 5.80%, respectively . The approach only allows monitoring of the overall content of the species that yield fluorescent complexes with the derivatizing reagent, so the use of chromatography is mandatory for individual separation/quantification of the target compounds.

J Nutr, 2005 Jan, 135(1), 48 - 52
Flavonoid glucosides are hydrolyzed and thus activated in the oral cavity in humans; Walle T et al.; Increasing epidemiological evidence supports the view that dietary flavonoids have protective roles in oral diseases, including cancer . However, the dietary forms of flavonoids, the flavonoid glycosides, must first be hydrolyzed to the aglycones, which is thought to occur mainly in the intestine . In the present study we tested whether this hydrolytic activity occurs in the oral cavity . Saliva was collected from human subjects, incubated with flavonoid glycosides, and analyzed for aglycone formation by HPLC . When quercetin 4'-glucoside or genistein 7-glucoside was incubated with human saliva, hydrolysis to quercetin and genistein, respectively, was detected within minutes . Studies of additional flavonoid glycosides demonstrated that glucose conjugates were rapidly hydrolyzed, but not conjugates with other sugars, i.e., rutin, quercitrin, and naringin . In a limited study of 17 subjects, the interindividual variability in the hydrolysis of genistein 7-glucoside was >20-fold . This supports the contention that salivary hydrolysis of certain flavonoid glucosides may be important in some individuals but not in others . Support for a bacterial contribution to this hydrolysis was obtained from the inhibitory effect of antibacterials in vivo and in vitro and from experiments with subcultured oral bacterial colonies . However, cytosol isolated from oral epithelial cells was also capable of effective hydrolysis . Dietary flavonoid glucosides may thus be hydrolyzed in the oral cavity by both bacteria and shedded epithelial cells to deliver the biologically active aglycones at the surface of the epithelial cells . The aglycones quercetin and genistein both potently inhibited proliferation of oral cancer cells . The large interindividual variability in this hydrolytic activity may be a factor that should be taken into consideration in future studies.

Comp Biochem Physiol B Biochem Mol Biol, 2005 Jan, 140(1), 127 - 31
A novel lebocin-like gene from eri-silkworm, Samia cynthia ricini, that does not encode the antibacterial peptide lebocin; Bao Y et al.; A cDNA clone with homology to lebocin gene was isolated from fat body of immunized Samia cynthia ricini larvae . The cDNA has an open reading frame encoding 162 amino acid residues . The deduced amino acid sequence shows significant homology to lebocin precursor proteins from Bombyx mori and Trichoplusia ni only in the "prosegment" region, but no homology to mature lebocin, a proline-rich antibacterial peptide, indicating the protein is not a precursor for lebocin antibacterial peptide . Northern analysis indicates that transcript of the lebocin-like gene is not detected in any tissues of naive larvae, but induced mainly in fat body after injection of the larvae with bacterial cells or cell wall components, such as peptidoglycan.

J Inorg Biochem, 2005 Feb, 99(2), 432 - 42
Mixed-valence Cu(II)/Cu(I) complex of quinolone ciprofloxacin isolated by a hydrothermal reaction in the presence of l-histidine: comparison of biological activities of various copper-ciprofloxacin compounds; Drevensek P et al.; A new quinolone-metal complex was prepared by a hydrothermal reaction in the presence of l-histidine that served as a reducing agent for a metal . The title compound {Cu(II)(cfH)(2)(Cu(I)Cl(2))(2)} (1) is a mixed-valence Cu(II)-Cu(I) complex, which contains two ciprofloxacin (cfH) molecules bonded to the central copper(II) atom and two almost planar {Cu(I)Cl(2)}(-) moieties . Both metal centers are connected through two bridging atoms (chloride and quinolone oxygen) . The electrochemical methods (differential-pulse polarography and cyclovoltammetric measurements) confirmed the presence of various copper-ciprofloxacin complex species in aqueous solution at low concentrations used in biological activity tests and also indicated that the equilibria in this system are very complex . The biological properties of the title compound and some previously isolated copper-ciprofloxacin complexes ({Cu(cfH)(2)Cl(2)}.6H(2)O (2) and {CuCl(cfH)(phen)}Cl.2H(2)O (3)) (phen=1, 10-phenantroline) were determined and compared . The DNA gyrase inhibition tests and antibacterial activity tests have shown that the effect of copper complexes is comparable to that of free quinolone . Additionally, an interesting DNA cleavage activity of the title compound was also discovered.

Int J Antimicrob Agents, 2005 Jan, 25(1), 62 - 7
Pharmacokinetics of piperacillin-tazobactam: intermittent dosing versus continuous infusion; Buck C et al.; In the present study 24 hospitalized patients requiring empirical antibiotic treatment were randomly assigned to receive the beta-lactam antibiotic/beta-lactamase inhibitor combination piperacillin-tazobactam either as an intermittent or as a continuous infusion . According to pharmacokinetic modelling, the daily dose was reduced by 33% in patients receiving continuous infusion compared with intermittent infusion . Dose reduction because of impaired renal function was required in the intermittent dosing group for 5 of 12 patients compared with 1 of 12 patients in the continuous infusion group . However, the mean daily dose in the continuous group was 15% less than the intermittent infusion group . Mean serum concentrations of piperacillin were to 39.0mug/ml after the end of bolus distribution, exceeding by far the minimal inhibitory concentration of the most clinically relevant pathogens . The corresponding mean value for tazobactam was 6.3mug/ml . Pharmacokinetic/pharmacodynamic modelling suggests that both treatment schemes should produce virtually identical anti-infective responses to sensitive, intermediate and resistant strains . In the present study the continuous infusion of piperacillin/tazobactam provided adequate antibacterial activity over the 24-h dosing period and offers the potential for a substantial reduction in the total daily dose.

J Nat Prod, 2004 Dec 28, 67(12), 2108 - 2110
Antimycobacterial Coumarins from the Sardinian Giant Fennel (Ferula communis); Appendino G et al.; The structure of a new prenylated coumarin (E-omega-benzoyloxyferulenol, 1b) from the Sardinian giant fennel (Ferula communis) has been confirmed by synthesis . The parent compound ferulenol (1a) showed sub-micromolar antimycobacterial activity, which was partly retained in 1b and in the simplified synthetic analogue 3, but diminished in its omega-hydroxy and omega-acetoxy derivatives (1c and 1d, respectively) . The outstanding activity of 1a, its low toxicity, and the evidence for definite structure-activity relationships make this prenylated 4-hydroxycoumarin an interesting antibacterial chemotype worth further investigation.

Pest Manag Sci, 2005 Feb, 61(2), 186 - 90
Antifungal activity of limonoids from Khaya ivorensis; Abdelgaleil SA et al.; Chemical investigation of the diethyl ether extract of the stem bark of Khaya ivorensis A Chev (Meliaceae) afforded ten limonoids of angolensates, ring D-opened limonoids and mexicanolides . The structures of the limonoids isolated were determined by comparison of their (1)H and (13)C NMR data with those reported in the literature . These compounds were evaluated for their antifungal activity against the plant pathogenic fungus Botrytis cinerea Pers . Methyl 6-hydroxyangolensate and 3,7-dideacetylkhivorin were also tested for their antifungal and antibacterial activities on several fungal and bacterial species . Methyl angolensate and 1,3,7-trideacetylkhivorin displayed the highest antifungal activity against B cinerea, with respectively 62.8 and 64.0% mycelial growth inhibition at 1000 mg litre(-1), and 73.3 and 68.6% mycelial growth inhibition at 1500 mg litre(-1) . 3,7-Dideacetylkhivorin showed stronger antifungal and antibacterial activities than methyl 6-hydroxyangolensate against all of the test fungi and bacteria except Penicillium expansum Link . This is the first report on the antifungal and antibacterial effects of these limonoids . Structure-antifungal activity relationships of the limonoids isolated are discussed . Copyright (c) 2004 Society of Chemical Industry.

J Ethnopharmacol, 2005 Jan 15, 96(3), 551 - 4
Composition and antibacterial activity of essential oil of Lantana achyranthifolia Desf . (Verbenaceae); Hernandez T et al.; The essential oil of the aerial parts of Lantana achyranthifolia Desf . (Verbenaceae) was examined by GC and GC-MS . Eighteen constituents were identified . Carvacrol, 1,8-cineole, isocaryophyllene, beta-bisabolene and alpha-bisabolol were found to be the major components . The oil exhibited antibacterial activity against fourteen Gram-positive and Gram-negative bacteria.

Drug Metab Pharmacokinet, 2002, 17(5), 379 - 94
Safety Evaluation and Drug Development based on Biological Fate of Drugs -Efforts Made to Overcome Drug Interaction in Drug Development-; Matsubara T; 1 . Assay methods to detect drug interaction in toxicological samples were established by determining cytochrome P450 content and its activity in liver samples . The O-dealkylation reaction of 7-alkoxycoumarin was indicated to reflect changes in the molecular forms of P450s, and the enzyme induction or inhibition in the toxicological samples was easily detected by using the established methods . 2 . During toxicological studies of 450191-S or the sleep inducer rilmazafone, a phenobarbital type-induction of hepatic drug metabolizing enzymes was observed in animals, and the doses required for the induction differed markedly between rats and dogs . Enzyme induction was caused by some specific metabolites of 450191-S, and the plasma concentrations of these metabolites were comparable when the enzyme induction was developed in both animals . 3 . A nonsteroidal antiinflammatory compound 480156-S showed a slight or no effect on microsomal drug metabolizing activity in rats . On the other hand, repeated administration of this compound to humans resulted in a marked decrease in the oxidative metabolism of 480156-S, followed by a marked increase in the plasma concentrations of the compound . When volunteers were given 480156-S followed by several drugs, such as tolubutamide, the plasma clearance was delayed remarkably, indicating a severe drug interaction . 4 . Cytochrome P450 belonging to the CYP2C family was indicated to participate in the oxidative metabolism of 480156-S in both rat and human liver microsomes . The preincubation of microsomes with 480156-S caused a concentration-dependent inhibition of CYP2C-dependent tolubutamide hydroxylation reaction in both rats and humans . There was a marked species difference in the susceptibility to the inhibitory effect of 480156-S, and the concentration required to inhibit rat CYP2C was almost 10 times higher than that required in humans . 5 . The cephem antibiotics having N-methyltetrazolethiol (NMTT) at the 3'-position substituent were demonstrated to inhibit mitochondrial low K(m) aldehyde dehydrogenase (ALDH), and produced disulfiram-like (Antabuse) reaction during alcohol metabolism . Pharmacokinetic studies indicated that NMTT released from the antibiotics in bile duct or intestine cause the inhibitory action followed by the development of disulfiram-like reaction . 6 . Attempts had been made to develop new cephem antibiotics lacking the disulfiram-like reaction by changing the chemical structure of 3'-position substituents, and a hydroxyethyltetrazolethiol was found not to inhibit the enzyme . Based on this result, together with the antibacterial activity, we have developed a new oxacephem antibiotic flomoxef (6315-S) . Flomoxef showed no disulfiram-like reaction both in rats and human.

J Med Chem, 2004 Dec 30, 47(27), 6669 - 72
A Novel Class of Inhibitors of Peptide Deformylase Discovered through High-Throughput Screening and Virtual Ligand Screening; Howard MH et al.; Peptide deformylase (PDF) has been identified as a promising antibacterial and herbicide target . A structurally novel class of inhibitors containing a 2-thioxo-thiazolidin-4-one heterocycle substituted by an arylidene group at the 5-position and a hexanoic acid side chain at the 3-position was discovered independently via high-throughput screening and virtual ligand screening . Data mining and analogue synthesis established a structure-activity relationship for the side chain region that is consistent with the docked structure.

Zhongguo Zhong Yao Za Zhi, 2003 Nov, 28(11), 1034 - 7
{Relationship between antibacterial activity of aloe and its anthaquinone compounds}; Tian B et al.; OBJECTIVE: To investigate the relationship between the antibacterial activity of aloe and its contents of anthaquinone compounds, measure and compale antibacterial activities of aloin and aloe-emodin, and analyse the effect of glycoside on the antibacterial activity of aloin . METHOD: The antibacterial activities of the extracts from the outer leaf of Aloe saponaria Haw, aloin and aloe-emodin against three Gram-negative and two Gram-positive bacteria were investigated with the method of agar diffusion . The antibacterial effect of aloin on E . coli was further studied with scanning electron microscopy . RESULT: The antibacterial activities of aloe showed to be dependent on the dose of anthraquinone, aloin (1 g x L(-1)) exhibited higher antibacterial activity {inhibition diameter > (7 . 1 +/- 0.15) mm} than Aloe-emodin (inhibition diameter < 5.0 mm), and aloin changed the morphology of E . coli and damaged the outer cell structrue . CONCLUSION: Anthraquinone compounds are the active antibacterial components in aloe and aloin is the main active compound . The glycoside makes it easy for aloin to invade cells and enhances its activity.

J Physiol Pharmacol, 2004 Dec, 55(4), 811 - 21
Extract of grapefruit-seed reduces acute pancreatitis induced by ischemia/reperfusion in rats: possible implication of tissue antioxidants; Dembinski A et al.; Grapefruit seed extract (GSE) has been shown to exert antibacterial, antifungal and antioxidant activity possibly due to the presence of naringenin, the flavonoid with cytoprotective action on the gastric mucosa . No study so far has been undertaken to determine whether this GSE is also capable of preventing acute pancreatic damage induced by ischemia/reperfusion (I/R), which is known to result from reduction of anti-oxidative capability of pancreatic tissue, and whether its possible preventive effect involves an antioxidative action of this biocomponent . In this study carried out on rats with acute hemorrhagic pancreatitis induced by 30 min partial pancreatic ischemia followed by 6 h of reperfusion, the GSE or vehicle (vegetable glycerin) was applied intragastrically in gradually increasing amounts (50-500 microl) 30 min before I/R . Pretreatment with GSE decreased the extent of pancreatitis with maximal protective effect of GSE at the dose 250 microl . GSE reduced the pancreatitis-evoked increase in serum lipase and poly-C specific ribonuclease activity, and attenuated the marked fall in pancreatic blood flow and pancreatic DNA synthesis . GSE administered alone increased significantly pancreatic tissue content of lipid peroxidation products, malondialdehyde and 4-hydroxyalkens, and when administered before I/R, GSE reduced the pancreatitis-induced lipid peroxidation . We conclude that GSE exerts protective activity against I/R-induced pancreatitis probably due to the activation of antioxidative mechanisms in the pancreas and the improvement of pancreatic blood flow.

Chem Biol, 2004 Dec, 11(12), 1701 - 7
The use of carbohydrate microarrays to study carbohydrate-cell interactions and to detect pathogens; Disney MD et al.; The use of carbohydrate microarrays to investigate the carbohydrate binding specificities of bacteria, to detect pathogens, and to screen antiadhesion therapeutics is reported . This system is ideal for whole-cell applications because microarrays present carbohydrate ligands in a manner that mimics interactions at cell-cell interfaces . Other advantages include assay miniaturization, since minimal amounts ( approximately picomoles) of a ligand are required to observe binding, and high throughput, since thousands of compounds can be placed on an array and analyzed in parallel . Pathogen detection experiments can be completed in complex mixtures of cells or protein using the known carbohydrate binding epitopes of the pathogens in question . The nondestructive nature of the arrays allows the pathogen to be harvested and tested for antibacterial susceptibility . These investigations allow microarray-based screening of biological samples for contaminants and combinatorial libraries for antiadhesion therapeutics.

Helicobacter, 2004 Dec, 9(6), 632 - 42
Protective Mechanism of Epigallocatechin-3-Gallate against Helicobacter pylori-Induced Gastric Epithelial Cytotoxicity via the Blockage of TLR-4 Signaling; Lee KM et al.; ABSTRACT Background . Helicobacter pylori infection leads to gastric mucosal damage by several mechanisms including the direct effect of virulence factors produced by H . pylori, propagation of inflammation, oxidative stress, DNA damage, and induction of apoptosis . (-)-Epigallocatechin-3-gallate (EGCG), one of the green tea catechins, is known to suppress H . pylori-induced gastritis through its antioxidative and antibacterial actions . In this study, we evaluated the protective mechanism of EGCG against H . pylori-induced cytotoxicity in gastric epithelial cells . Materials and Methods . MTT assays and dye exclusion assays were performed to analyze the effect of EGCG on the viability of gastric epithelial cells . The degree of DNA damage was evaluated by Comet assay and apoptotic DNA fragmentation assay . To investigate the effect of EGCG on H . pylori-induced toll-like receptor 4 (TLR-4) signaling, reverse transcription-polymerase chain reaction and Western blot analysis corresponding to glycosylated TLR-4 were carried out . Lipoxygenase metabolites were measured with reverse-phase, high-performance liquid chromatography . Results . EGCG pretreatment effectively rescued gastric mucosal cells from the H . pylori-induced apoptotic cell death and DNA damage, and administration of this catechin enhanced gastric epithelial cell proliferation . Helicobacter pylori infection stimulated the glycosylation of TLR-4, which initiates intracellular signaling in the infected host cell, but the pretreatment with EGCG completely blocked the TLR-4 glycosylation . The blockage of TLR-4 activation by EGCG resulted in inactivation of extracellular signal response kinase 1/2 and of nuclear factor-kappaB, the downstream molecules of TLR-4 signaling induced by H . pylori . This disturbance of H . pylori-induced host cell signaling by EGCG attenuated the synthesis of the proinflammatory mediator, hydroxyeicosatetraenoic acid . Conclusions . EGCG pretreatment showed significant cytoprotective effects against H . pylori-induced gastric cytotoxicity via interference of the TLR-4 signaling induced by H . pylori . Thus, our result implies that continuous intakes of green tea could prevent the deleterious consequences of H . pylori infection.

Biotechnol Bioeng . 2004 Dec 17; {Epub ahead of print}
Antibacterial and antifungal efficacy of surface functionalized polymeric beads in repeated applications; Hu FX et al.; A simple method was developed to prepare polymeric microbeads with antibacterial and antifungal properties . The microbeads of approximately spherical shape and narrow size distribution were prepared from a mixture of poly (4-vinyl pyridine) (P4VP) and poly (vinylidene fluoride) (PVDF) by a phase inversion technique and subsequently derivatized with alkyl bromides having 4-10 carbon atoms . The quaternization of the pyridine groups into pyridinium groups confers the surface with highly effective and long-lasting antibacterial and antifungal properties, as shown by the effect on Escherichia coli and Aspergillus niger . Upon contact with the N-alkylated beads, the bacteria and fungal spores are lysed and intracellular constituents leach out into the medium . The efficacy of the alkyl chains in disrupting the cell membrane was investigated . The stability of the functional group and microbiocidal effectiveness of the microbeads in repeated applications was also assessed . (c) 2004 Wiley Periodicals, Inc.

Eur J Health Econ, 2002 Dec, 3(4), 261 - 6
Pharmacoeconomic analysis of prescriptions in Italian pediatric general practice; Campi R et al.; Most drugs used by children are prescribed by general pediatric practitioners (GPPs) in ambulatory settings . Prescription profiles are affected by GPPs' attitudes while the cost is related to the reimbursement modality . This study evaluated the Italian National Health Service (INHS) and family expenditures associated with prescribing practices to children younger than 12 years . Forty-two GPPs from southern Italy participated in the study.All visits recorded by GPPs during a 13-week period (February-April 1998), including telephone contacts and office and home visits were analyzed . The cost analysis of prescriptions is based on a sample of randomly selected consultations . INHS and family expenditures were evaluated according to reimbursement modalities for drug prescriptions . Total expenditure induced by all prescriptions during the study period was about 148 million Italian lire (7650 euros); 54% of this was borne by the INHS and the rest remaining by families . When corrections according to prescription modalities - following appropriate reimbursement form - were applied, only 49% of total expenditure were covered by INHS and 51% by families.Analysis of expenditures showed that drugs for symptomatic therapies (e.g., cough and cold preparations, analgesics, antipyretics) and vitamins accounted for most of the families' expenditure, while antibacterial and antiasthmatic drugs did so for the INHS.Of the ten most prescribed drugs the cost of three fell entirely on the family: paracetamol (the most commonly prescribed drug),morniflumate, and ambroxol . Therapeutic indications causing greatest expenditures for families were all the common,trivial childhood symptoms such as cough, fever, rhinitis, flu, and pharyngitis . Despite the universal coverage for pharmaceutical care more than onehalf of drug therapy expenditures for children was covered directly by the parents . Prescription attitudes by GPPs remain the crucial factor for an equal cost distribution between families and the INHS.

Chemotherapy, 2004 Dec, 50(6), 302 - 7 Epub 2004 Dec 08.
In vitro measurement of the time-related efficacy of gentamicin sulfate release from bone cements; Balint L et al.; BACKGROUND: The aim of the present study was to establish an in vitro microbiologic monitoring system which measures the dynamics of antibiotic release from acrylic bone cement and its antibacterial efficacy . METHODS: Palacos R and Orthofix R cements containing gentamicin sulfate were tested . The in vitro elution dynamics was analyzed by plate diffusion method during a 1-year period after mixing . High but rapidly decreasing antibiotic levels were detected within the 1st week, resulting in an almost steadily low concentration by the end of the 1st month . After 1 year, it was still possible to demonstrate the inhibitory effect of the drug from both cements . Comparison of the time-related release between the antibiotics failed to find any statistically significant differences . CONCLUSION: The method described is a useful and reproducible technique for the in vitro measurement of the inhibitory activity of antibiotic released from bone cements . 2004 S . Karger AG, Basel.

Treat Respir Med, 2004, 3(5), 291 - 4
Use of antibacterials in infancy: clinical implications for childhood asthma and allergies; Celedon JC et al.; Evidence from experimental studies in rodents and results from epidemiologic studies with a retrospective design suggest a possible causal association between antibacterial use in early childhood and asthma . Such an association is thought to be mediated by antibacterial-induced alterations in the intestinal flora, leading to a skewing of the immune system of young children toward an atopic phenotype . However, results from recently conducted prospective studies suggest that the previously observed association between antibacterial use in early childhood and asthma is not one of 'cause and effect' but rather that frequent antibacterial use in early childhood may be a marker of an increased risk of being diagnosed with asthma later in childhood . Although antibacterials should not be used excessively in young children, their use in early childhood is not likely to explain the increased prevalence of asthma and allergies in children in industrialized countries.

Lik Sprava, 2004 Jul-Sep, (5-6), 74 - 7
{Prostatilin polypeptide medication in treating a complicated prostatitis}; Investigations of the motivation underlying Norwegian dairy farmers' use of homoeopathy; Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, PB 8146 Dep, 0033 Oslo, NorwayEighteen Norwegian dairy farmers were interviewed to examine their reasons for using homoeopathic treatments in managing their herds' health . Overall, they chose the treatments on the basis of factors related to their personal experience, considerations of individual animals and the framework for dairy production . For individual animals homoeopathy was used as an alternative to conventional veterinary treatment, but at the herd level it was used to complement it . The farmers' use of homoeopathic treatment for personal health problems and the experience of their colleagues with its use in dairy production were important factors motivating their initial use of homoeopathy . Other factors included a desire to decrease the use of antibacterial drugs, reduce costs and find alternatives when conventional veterinary medicine provided no effective treatment . In individual cases, the severity of disease, previous experience and the farmers' personal knowledge and resources were important . These factors parallel those found to influence the use of complementary and alternative therapies in human medicine . The lack of understanding and documentation of the effects of homoeopathic remedies was not important to the farmers, and they valued personal experience more highly than scientific evidence or the opposition to homoeopathy encountered within the veterinary profession.

Bioorg Med Chem Lett, 2005 Jan 17, 15(2), 405 - 11
QSAR study on the antibacterial activity of some sulfa drugs: building blockers of Mannich bases; Mandloi D et al.; Sulfa drugs are building blockers of several types of Mannich bases . Consequently, the antibacterial activities of sulfa drugs are reported in this paper, which will help in explaining and understanding antibacterial activities of Mannich bases . Reported QSAR is carried out using distance-based topological indices and discussed critically on the basis of statistical parameters.

Bioorg Med Chem Lett, 2005 Jan 17, 15(2), 337 - 343
Effects of positional and geometrical isomerism on the biological activity of some novel oxazolidinones; Das J et al.; Some novel oxazolidinone derivatives with benzotriazole as pendant have been synthesized and tested for antibacterial activity . Linearly attached benzotriazole derivative showed more potency compared to angular one in vitro . Out of E/Z-isomers of angularly attached derivatives E-isomer was found to be more potent than Z-isomer . Either less active or inactive molecules were obtained, when benzotriazole was replaced with benzimidazole, benzthiazole, or benzoxazole . Finally, thioacetamide analogue of linear compound gave a lead having activity similar to linezolid in vitro.

Pol Merkuriusz Lek, 2004, 17 Suppl 1, 139 - 41
{Clinical analysis of unsuccessful Helicobacter pylori eradication}; Szadkowski A et al.; Numerous medical reports claim that the effectiveness of H . pylori therapy decreases . The aim of the study was the analysis of the reasons of this phenomenon on own material . The study included 437 subjects, aged 19-64 years with chronic gastritis with H . pylori infection . All patients were subjected to: endoscopy, fast urease test, breath test (UBT-13C) and antibody titer in IgG class was determined . In the case of ineffective therapy bacteriological examination was performed . In the first stage of the therapy pantoprazol (2 x 40 mg) and amoxicillin (2 x 1000 mg) with metronidazol (2 x 500 mg) were applied in 282 subjects for 7 days (group I), amoxicillin with clarithromycin (2 x 500 mg) in 182 subjects (group II) and clarithromycin with metronidazol in 43 subjects (group III) . After 6 weeks negative breath test was observed on average in 65.68% without significant differences between the groups . Ineffective therapy was more frequent in subjects over 45 years of age with high intensity of H . pylori colonization and earlier treated with antibiotics due to other reasons; such differences were not observed dependently on the antibody titer . In the second stage of the therapy pantoprazol was still administered but antibacterial drugs were changed among the groups . From among 150 subjects eradication was obtained in 117 (78.0%) . In 33 subjects with ineffective therapy bacteriological examination of gastric bioptates confirmed antibiotic resistance in 75.76% . It results from the study that the applied therapy, consistent with current recommendations of the experts, does not ensure H . pylori eradication in part of the patients, what points to the necessity of searching for other effective antibiotics.

Pol Merkuriusz Lek, 2004, 17 Suppl 1, 136 - 8
{The influence of Helicobacter pylori eradication on oesophageal pH-metry and bilimetry results in patients with nonulcer dyspepsia}; Piotrowski W et al.; Substernal, fasting and night pains with no endoscopic findings in the upper gastrointestinal tract are the leading symptoms of nonulcer dyspepsia (NUD) . Our study aimed at determining whether there is duodenogastroesophageal reflux in patients with NUD and to evaluate what role Helicobacter pylori plays in NUD pathophysiology . The study comprised 40 patients, in whom endoscopy, breath test (UBT-13C), 24-hour pH-metry (Digitrapper III) and bilimetry (Bilitec 2000) of the esophagus were performed before and after 7-day antibacterial treatment (pantoprazole 2 x 40 mg, amoxicillin 2 x 1000 mg, clarithromycin 2 x 500 mg) . Eradication was achieved in 29 patients, in whom total index of acid reflux (t% pH < 4.0) decreased from 23.1+/-10.4% to 13.1+/-6.2% (p<0.05) and alkaline reflux index (t% abs > 0.14) from 12.9+/-6.3 to 8.1+/-5.7% (p>0.05) . Positive correlations between urea breath test results and the indexes of acid (r=0.692) and alkaline refluxes (r=0.246) were observed . In patients with nonulcer dyspepsia infected with Helicobacter pylori complex functional disorders are present . They are expressed as duodenogastroesophageal reflux . The refluxes intensity depends on the extent of Helicobacter pylori infection, which should be remembered when planning antibacterial treatment.

Org Biomol Chem, 2005 Jan 7, 3(1), 123 - 9 Epub 2004 Nov 29.
Aspergillazines A-E: novel heterocyclic dipeptides from an Australian strain of Aspergillus unilateralis; Capon RJ et al.; Biological and chemical profiling of an Australian strain of the fungus Aspergillus unilateralis(MST-F8675), isolated from a soil sample collected near Mount Isa, Queensland, revealed a complex array of metabolites displaying broad chemotherapeutic properties . Noteworthy among these metabolites were a unique series of highly modified dipeptides aspergillazines A-E, incorporating a selection of unprecedented and yet biosynthetically related heterocyclic systems . Co-occurring with the aspergillazines was the recently described marine-derived fungal metabolite trichodermamide A (cf . penicillazine), whereas re-fermentation of A . unilateralis in NaCl (1%) enriched media resulted in co-production of the only other known example of this structure class, the marine-derived fungal metabolite trichodermamide B . Further investigation of A . unilateralis returned the known terrestrial fungal metabolite viridicatumtoxin as the cytotoxic and antibacterial principle, together with E-2-decenedioic acid, ferulic acid, (7E,7{prime or minute}E)-5,5{prime or minute}-diferulic acid and (7E,7{prime or minute}E)-8,5{prime or minute}-diferulic acid . The aromatic diacids have previously been reported from the chemical and enzymatic (esterase) treatment of plant cell wall material, with their isolation from A . unilateralis being their first apparent reported occurrence as natural products . Structures for all metabolites were determined by detailed spectroscopic analysis and, where appropriate, comparison to literature data and/or authentic samples.

Curr Opin Investig Drugs, 2004 Aug, 5(8), 809 - 22
Structure-activity relationship analysis and therapeutic potential of peptide deformylase inhibitors; Boularot A et al.; Peptide deformylase inhibitors (PDFIs) appear to be one of the most exciting classes of antibacterial agents discovered to date . Rapid progress in the development of PDFIs has been possible because peptide deformylase is a metalloprotease, and this class of enzymes shows a high degree of structure-function conservation, and because the most potent PDFIs are hydroxamate derivatives, a well known category of pharmacophores . The current challenge in structure-activity relationship analysis is obtaining molecules with potent in vivo antibacterial activity against a range of drug-resistant pathogens . The PDFIs currently in clinical trials target community-based bacterial infections, with a potential major pharmaceutical market.

Curr Opin Investig Drugs, 2004 Aug, 5(8), 799 - 808
Antibacterial agents: patent highlights January to June 2004; Phillips OA; This review presents highlights of 32 patents, published between January and June 2004, detailing different classes of antibacterial agents . Disclosures on novel oxazolidinone derivatives with antibacterial activity continue to dominate patent publications in recent years . Novel oxazolidinone derivatives active against linezolid-resistant cocci are reviewed . Patents on beta-lactam antibiotics focused mainly on developing new processes and formulations to improve cost, purity and pharmacokinetic parameters of existing clinical agents . Disclosures on novel potential dual-acting macrolide-quinolone hybrids designed to overcome erythromycin resistance, and new macrolide derivatives with antimycobacterial activity are described . Also presented are novel antibacterial agents, including peptide deformylase and cell-wall inhibitors, and those with undefined mechanisms of action as potential lead compounds, as well as quinolone and quinoline derivatives.

Crit Care Med, 2004 Dec, 32(12), 2524 - 36
Management of the critically ill patient with severe acute pancreatitis; Nathens AB et al.; OBJECTIVE: Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course requiring only brief hospitalization to a rapidly progressive, fulminant illness resulting in the multiple organ dysfunction syndrome (MODS), with or without accompanying sepsis . The goal of this consensus statement is to provide recommendations regarding the management of the critically ill patient with severe acute pancreatitis (SAP) . DATA SOURCES AND METHODS: An international consensus conference was held in April 2004 to develop recommendations for the management of the critically ill patient with SAP . Evidence-based recommendations were developed by a jury of ten persons representing surgery, internal medicine, and critical care after conferring with experts and reviewing the pertinent literature to address specific questions concerning the management of patients with severe acute pancreatitis . DATA SYNTHESIS: There were a total of 23 recommendations developed to provide guidance to critical care clinicians caring for the patient with SAP . Topics addressed were as follows . 1) When should the patient admitted with acute pancreatitis be monitored in an ICU or stepdown unit? 2) Should patients with severe acute pancreatitis receive prophylactic antibiotics? 3) What is the optimal mode and timing of nutritional support for the patient with SAP? 4) What are the indications for surgery in acute pancreatitis, what is the optimal timing for intervention, and what are the roles for less invasive approaches including percutaneous drainage and laparoscopy? 5) Under what circumstances should patients with gallstone pancreatitis undergo interventions for clearance of the bile duct? 6) Is there a role for therapy targeting the inflammatory response in the patient with SAP? Some of the recommendations included a recommendation against the routine use of prophylactic systemic antibacterial or antifungal agents in patients with necrotizing pancreatitis . The jury also recommended against pancreatic debridement or drainage for sterile necrosis, limiting debridement or drainage to those with infected pancreatic necrosis and/or abscess confirmed by radiologic evidence of gas or results or fine needle aspirate . Furthermore, the jury recommended that whenever possible, operative necrosectomy and/or drainage be delayed at least 2-3 wk to allow for demarcation of the necrotic pancreas . CONCLUSIONS: This consensus statement provides 23 different recommendations concerning the management of patients with SAP . These recommendations differ in several ways from previous recommendations because of the release of recent data concerning the management of these patients and also because of the focus on the critically ill patient . There are a number of important questions that could not be answered using an evidence-based approach, and areas in need of further research were identified.

Phytother Res, 2004 Nov, 18(11), 865 - 72
Studies on the bioactivity and elementology of marine algae from the coast of Karachi, Pakistan; Rizvi MA et al.; Some species of marine benthic algae belonging to the Chlorophyta, Phaeophyta and Rhodophyta collected from different coastal areas of Karachi (Pakistan) were investigated for their antibacterial, antifungal, phytotoxic and insecticidal activities . Brown seaweeds showed greater antibacterial activity than the green and red ones . Botryocladia leptopoda (J . Ag.) Kylin exhibited the greatest antifungal activity and Codium shameelii Nizam . the least . The highest phytotoxic activity (95%) was displayed by Enteromorpha intestinalis (L.) Nees at 100 microg/mL concentration, while Osmundea pinnatifida (Huds.) Stack . showed the low insecticidal activity as compared to the other investigated species . Many elements e.g . Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Na, Pb, Zn were determined quantitatively . Among them Ca, Cr and Pb were found to occur in largest amount in green seaweeds, Co, Cu, Fe and Zn in greatest quantity in brown seaweeds, while Cd, K, Mg and Na in highest proportion in the investigated red seaweeds .

Langmuir, 2004 Dec 21, 20(26), 11557 - 68
Using wavelets to analyze AFM images of thin films: surface micelles and supported lipid bilayers; Carmichael M et al.; This paper presents micro- and nanoanalysis of thin films based on images obtained by atomic force microscopy (AFM) . The analysis exploits the discrete wavelet transform and the resulting wavelet spectrum to study surface features . It is demonstrated that the wavelet technique can characterize micro- and nanosurface features and distinguish between similar surface structures . The use of a feature extraction method is shown . The method involves the separation of certain frequency content from the original AFM images and analyzing the data independently to gain quantitative information about the images . By using the feature extraction method, soft surfaces in water are analyzed and nanofeatures are measured . The packing of surface micelles of sodium dodecyl sulfate on a self-assembled monolayer is analyzed . The characteristics of pore formation, due to penetration of the antibacterial peptide protegrin, into a solid-supported lipid bilayer are quantified . The sizes of the pores are obtained, and it is observed that the line tension of the pores reduces the fluctuations of the lipid bilayer.

Nat Prod Res, 2004 Dec, 18(6), 537 - 42
A novel bioactive flavonol glycoside from Teramnus labialis spreng; Yadava RN et al.; A novel biologically active flavonol glycoside (1), C26H28O17, m.p . 216-217 degrees C, was isolated from the chloroform soluble fraction of the ethanol extract of the stems of Teramnus labialis . Its structure was characterized as 3,5,7,3',4',5'-hexahydroxyflavone-3-O-beta-D-glucopyranosyl(1-->3)-O-alpha-L-arabinopyranoside by spectral analysis . The chloroform extract of compound (1) showed antibacterial and antifungal activities.

Chembiochem, 2005 Jan 7, 6(1), 171 - 177
Aristoforin, a Novel Stable Derivative of Hyperforin, Is a Potent Anticancer Agent; Gartner M et al.; Hyperforin, a natural product of St . John's wort (Hypericum perforatum L.), has a number of pharmacological activities, including antidepressive and antibacterial properties . Furthermore, hyperforin has pronounced antitumor properties against different tumor cell lines, both in vitro and in vivo . Despite being a promising novel anticancer agent, the poor solubility and stability of hyperforin in aqueous solution limits its potential clinical application . In this study, we present the synthesis of hyperforin derivatives with improved pharmacological activity . The synthesized compounds were tested for their solubility and stability properties . They were also investigated for their antitumor properties, both in vitro and in vivo . One of these hyperforin derivatives, Aristoforin, is more soluble in aqueous solution than hyperforin and is additionally highly stable . Importantly, it retains the antitumor properties of the parental compound without inducing toxicity in experimental animals . These data strongly suggest that Aristoforin has potential as an anticancer drug.

J Leukoc Biol . 2004 Dec 8; {Epub ahead of print}
A murine antibacterial orthologue to human bactericidal/permeability-increasing protein (BPI) is expressed in testis, epididymis, and bone marrow; Lennartsson A et al.; The bactericidal/permeability-increasing protein (BPI), stored in human neutrophil granulocytes, is cytotoxic against Gram-negative bacteria . Several genes related to BPI cluster on human chromosome 20 and on mouse chromosome 2, but expression and characterization of a BPI ortholog in the mouse have not been reported . We asked whether BPI is structurally and functionally conserved between humans and mice and whether murine BPI might be synthesized in neutrophils as well as in other tissues . We report the isolation of a murine full-length cDNA encoding a 54-kDa protein, showing 53% amino acid identity and 71% similarity, to human BPI . The murine BPI and human BPI genes show a similar exon-intron organization . Murine BPI mRNA was detected in testis, epididymis, and bone marrow, as well as in Sertoli and promyelocytic cell lines . Although levels of BPI mRNA in human and murine testis were comparable, expression in murine bone marrow cells was low as compared with that in human bone marrow . BPI protein showed a cytoplasmic, granular localization in mature neutrophils . BPI gene expression in Sertoli and promyelocytic cells was enhanced several-fold by all-trans retinoic acid . Overexpression of murine BPI in human embryonic kidney 293 cells resulted in antibacterial activity against Escherichia coli, comparable with that obtained with human BPI . In conclusion, it was demonstrated that mouse neutrophils store BPI with antibacterial activity and that murine BPI is also expressed in testis and epididymis.

J Ethnopharmacol, 2005 Jan 4, 96(1-2), 325 - 30
Variation in antibacterial and anti-inflammatory activity of different growth forms of Malva parviflora and evidence for synergism of the anti-inflammatory compounds; Shale TL et al.; Malva parviflora leaves and roots were collected from five sites within the Qacha's Nek District in Lesotho . These plants had two distinct growth forms--upright and prostrate . Hexane, methanol and water extracts were made from the plant material and tested for antibacterial and anti-inflammatory activity using the disc diffusion and cyclooxygenase-1 (Cox-1) bioassays, respectively . Hexane, methanol and water extracts made from Malva parviflora with a prostrate growth form inhibited the growth of Gram-positive and Gram-negative bacteria, while extracts made from plants with an upright growth form inhibited the growth of Gram-positive bacteria only . Cox-1 anti-inflammatory activity of hexane, methanol and water extracts did not show any variation between the two growth forms . The hexane extracts of both the leaves and roots were the most inhibitory . The water extracts had the least inhibitory activity . Bioassay-guided fractionation of the root dichloromethane extract showed that Cox-1 anti-inflammatory activity was caused by at least two compounds that acted synergistically to produce the biological effect.

J Ethnopharmacol, 2005 Jan 4, 96(1-2), 227 - 32
Hepatoprotective and antibacterial effects of extracts from Trichilia emetica Vahl . (Meliaceae); Germano MP et al.; Trichilia emetica Vahl . (Meliaceae) is a tree widely distributed in Tropical Africa . It has been used in Mali folk medicine for the treatment of various illnesses . The aim of this work was to study the hepatoprotective and antibacterial effects of a crude aqueous extract from Trichilia emetica root . An ethyl ether fraction from the aqueous extract was also prepared and studied . We have examined the hepatoprotective activity of the extracts on CCl4-induced damage in rat hepatocytes, their toxicity using the brine shrimp bioassay and their antibacterial activity against clinical isolated bacterial strains, which are commonly responsible for respiratory infections . A preliminary phytochemical analysis showed a high polyphenolic content in the aqueous extract and the presence of limonoids in the ethyl ether fraction . These latter compounds may be considered responsible for the good activity against the bacterial strains tested . Trichilia emetica extracts exerted also a significant (P<0.05) hepatoprotective effect at a dose of 1000 microg/ml both on plasma membrane and mitochondrial function as compared to silymarin used as a positive control . These activities may be a result of the presence of either polyphenols or limonoids . Finally, both the aqueous extract and its ethyl ether fraction did not show toxicity (LC50>1000 microg/ml) in the brine shrimp bioassay.

World Health Organ Tech Rep Ser, 2004, 925, 1 - 72
Evaluation of certain veterinary drug residues in food . Sixty-second report of the Joint FAO/WHO Expert Committee on food additives; Applying lessons learned in the treatment of diffuse panbronchiolitis to other chronic inflammatory diseases; Nippon Medical School, Tokyo, JapanIn addition to having antibacterial effects, macrolides modulate inflammatory responses . Their effectiveness in treating chronic inflammatory airway disease is well documented in patients with diffuse panbronchiolitis (DPB), a chronic condition characterized by inflammation of the airways that, if left untreated, progressively leads to respiratory failure and death . Long-term treatment with certain macrolides has dramatically improved the survival of patients with DPB . The mechanisms of action for the anti-inflammatory properties of macrolides are still being studied . The effects of macrolides on inflammation include decreasing chemotaxis of neutrophils to the respiratory tract and inhibiting the expression of adhesion molecules, with decreased infiltration of neutrophils into the respiratory epithelium . Macrolides also inhibit expression of transcription factors and formation of proinflammatory cytokines, and directly and indirectly block mucus secretion . Even with long-term use, macrolides are safe and well tolerated . The effectiveness of macrolides for treating DPB has led to interest in their use in treating other chronic inflammatory airway diseases . As discussed in this article, because of the similarities between the clinical presentation of cystic fibrosis and chronic bronchitis and DPB, the effects of macrolides in patients with these diseases are currently being studied with particular interest.

Klin Med (Mosk), 2004, 82(10), 66 - 9
{Complex treatment of patients with the diabetic foot}; Crystallization and preliminary X-ray crystallographic analysis of a non-specific lipid-transfer protein with antipathogenic activity from Phaseolus mungo; Institute of Biotechnology, Fuzhou University, Fujian 350002, People's Republic of ChinaA 9 kDa non-specific lipid-transfer protein (nsLTP) from mung bean (Phaseolus mungo) seeds, displaying antifungal activity, antibacterial activity and lipid-transfer activity, was crystallized at 297 K using ammonium sulfate as a precipitant by means of the hanging-drop vapour-diffusion method . Native X-ray diffraction data were collected to a resolution of 2.4 A . The crystals are rhombohedral, belonging to space group P2(1)2(1)2(1), with unit-cell parameters a = 38.671, b = 51.785, c = 55.925 A . Assuming the presence of one molecule in the crystallographic asymmetric unit results in a Matthews coefficient (V(M)) of approximately 3.0 A(3) Da(-1), corresponding to a solvent content of about 58%.

Bioorg Med Chem Lett, 2005 Jan 3, 15(1), 231 - 4
Novel 1beta-methylcarbapenems with isoxazoloethenyl moieties containing carboxylic acid sodium salt; Lee KS et al.; The synthesis of novel 1beta-methylcarbapenems 1a,b having sodium 5-(3- and 5-carboxylic acid)isoxazoloethenyl moieties at C-5 position of pyrrolidine ring and their biological evaluation are described . Both compounds showed potent and well-balanced antibacterial activity as well as high stability to DHP-I . The selected sodium 3-carboxylic acid derivative 1a possessed excellent DHP-I stability and advanced pharmacokinetic parameters in comparison with 2 and meropenem.

Bioorg Med Chem Lett, 2005 Jan 3, 15(1), 221 - 6
Synthesis and in vitro study of novel Mannich bases as antibacterial agents; Joshi S et al.; A series of novel Mannich bases derived from 5-chloro-2-methoxybenzamide and sulfonamides/amines have been synthesised and the antibacterial activities were evaluated against various Gram positive and Gram negative strains of bacteria . Some of the synthesized compounds showed superior in vitro activities as compared to their parent sulfonamides.

Biochim Biophys Acta, 2004 Dec 15, 1667(2), 148 - 56
Antibacterial activity and pore-forming properties of ceratotoxins: a mechanism of action based on the barrel stave model; Bessin Y et al.; Ceratotoxins are alpha-helical cationic peptides isolated from the medfly Ceratitis capitata . These amphipathic peptides were found to display strong antibacterial activity and weak hemolytic activity . When reconstituted into planar lipid bilayers, ceratotoxins developed highly asymmetric I/V curves under voltage ramps and formed, in single-channel experiments, well-defined voltage-dependent ion channels according to the barrel stave model . The antibacterial activity and pore-forming properties of these molecules were well correlated . Similar experiments performed with synthesized truncated fragments showed that the C-terminal domain of ceratotoxins is strongly implicated in the formation of helical bundles in the membrane whereas the largely cationic N-terminal region is likely to anchor ceratotoxins on the lipid surface.

Vet Rec, 2004 Nov 20, 155(21), 672 - 4
Serum activity/concentration profiles of a sustained-released formulation of sulphathiazole-trimethoprim (2.5:1) in calves; Sumano H et al.; Thirty-six two-week-old healthy Holstein-Friesian calves weighing between 52 and 58 kg were divided at random into three groups of 12; group A calves were given a single oral bolus containing 2.5 g sulphathiazole and 1 g trimethoprim in a sustained-release formulation; group B received the same doses of the drugs but the trimethoprim was not in a sustained-release formulation; group C received a bolus containing 2.5 g sulphathiazole and 0.5 g conventional trimethoprim . Blood samples were collected at intervals for two days, the serum was separated and the composite antibacterial activity profiles of the mixture were analysed by an agar-diffusion microbiological method . The mean maximum activities in the serum of the three groups were 23.4 microg/ml in group A, 9.25 microg/ml in group B and 8.01 microg/ml in group C . The mean areas under the curves of the serum activity time curves were 838 microg/ml/hour in group A, 216 microg/ml/hour in group B and 182 microg/ml/hour in group C.

J Antibiot (Tokyo), 2004 Sep, 57(9), 559 - 63
Phomol, a new antiinflammatory metabolite from an endophyte of the medicinal plant Erythrina crista-galli; Weber D et al.; Phomol (1), a novel antibiotic, was isolated from fermentations of a Phomopsis species in the course of a screening of endophytic fungi from the medicinal plant Erythrina crista-galli . For this Argentinean leguminosa antiinflammatory and neuroleptic activities have been described . The compound exhibits antifungal, antibacterial and weak cytotoxic acticity . The antiinflammatory activity was tested in different reporter gene assays (TNF-alpha, STAT1/STAT2 and NF-kappaB) and in an ear edema model in mice . In the reporter gene assays 1 exhibited no activity, whereas 1 showed interesting antiinflammatory activity in the mouse ear assay . The compound is a polyketide lactone and its structure was elucidated by spectroscopic methods.

Med Oncol, 2004, 21(4), 297 - 304
Monoclonal antibodies in the treatment of chronic lymphocytic leukemia; Liu NS et al.; Traditional therapy for chronic lymphocytic leukemia (CLL) has consisted of alkylating agents, purine analogs, or a combination of these drugs . These agents are effective at producing remissions but are not curative.Thus, new drugs are still needed to improve the outcome of patients with CLL . The introduction of monoclonal antibodies, such as rituximab and alemtuzumab, provides a novel therapeutic modality.Rituximab is an active agent in CLL . Standard doses of rituximab result in higher response rates in previously untreated than in relapsed patients but low complete response (CR) rates . Rituximab is most effective in combination with chemotherapy, especially fludarabine-based regimens in the first-line and salvage setting . Rituximab is also useful in the treatment of complications of CLL, such as pure red cell aplasia, autoimmune thrombocytopenia, and autoimmune hemolytic anemia.Alemtuzumab has impressive activity in patients with refractory CLL and may play an important role in the consolidation treatment of CLL . Alemtuzumab is most efficacious at clearing disease in the peripheral blood and bone marrow . Bulky lymphadenopathy is less sensitive to therapy . Because of the significant lymphopenia associated with alemtuzumab, antibacterial and antiviral prophylaxis should always be used.

Curr Drug Targets Infect Disord, 2004 Dec, 4(4), 261 - 72
New aminoacyl-tRNA synthetase inhibitors as antibacterial agents; Pohlmann J et al.; Increasing rates of bacterial resistance to known classes of antibiotics present a severe global challenge . As a consequence, the search for new chemical entities that address novel bacterial targets remains ongoing . Aminoacyl-tRNA synthetases (aa-RS) are essential enzymes for protein biosynthesis and emerged as an interesting target class in antibacterial research . These enzymes are present in all living organisms, and they are indispensable for the highly specific translation of the messenger-RNA (mRNA) template into protein via specific transfer-RNAs (tRNAs) as adapter molecules . When one aa-RS is inhibited, the corresponding tRNA is not charged and is therefore unavailable for translation . This leads to protein synthesis inhibition, which, in turn, causes cell growth arrest . Consequently, each compound that inhibits any of the aa-RS is a potential antibacterial agent . The clinical utility of this principle is proven by the natural product Ile-RS inhibitor pseudomonic acid, which is currently marketed as an antibacterial agent for topical application . Various chemical structures that inhibit aa-RS have been identified . These inhibitors have either been isolated from natural sources or have been generated synthetically . The synthetic inhibitors are modifications of natural inhibitors, derivatives of the natural synthetase substrates and reaction intermediates, or have been identified by screening of compound libraries . The recent progress achieved with these different classes of aa-RS inhibitors and their antibacterial potential in vitro and in vivo is discussed in this review.

J Allergy Clin Immunol, 2004 Dec, 114(6), 1395 - 7
Risk of severe allergic reactions from the use of potassium iodide for radiation emergencies; Sicherer SH; Potassium iodide (KI) may be prescribed for widespread use in the event of a radiation emergency to prevent the uptake of radioactive iodide by the thyroid gland . The available literature was reviewed and expert opinion sought among members of the Adverse Reactions to Foods and the Adverse Reactions to Drugs and Biologicals Committees of the Academy to assemble evidenced-based conclusions regarding the risks of an allergic reaction to this therapy . This article describes the information leading to the following conclusions: (1) anaphylactoid reactions to radiocontrast media should not be considered evidence of KI allergy, (2) allergic contact dermatitis from iodine-containing antibacterial preparations should not be considered evidence of IgE antibody-mediated KI allergy or sensitivity, (3) IgE antibody-mediated allergy to seafood should not be considered evidence of KI allergy or sensitivity, and (4) physicians should ensure that persons are not allergic to inactive ingredients or components of the KI formulation prescribed.

Chem Pharm Bull (Tokyo), 2004 Dec, 52(12), 1487 - 8
A new cytotoxic naphthoquinone from Paepalanthus latipes; Kitagawa RR et al.; Quinones constitute an important class of naturally occurring compounds . They are found in plants, fungi and bacteria . Large number of quinones has been associated with antitumor, antibacterial, antimalarial and antifungal activities . In this work we describe the isolation, structure determination and the cytotoxic index of a new 1,4-naphthoquinone isolated from the capitula of Paepalanthus latipes.

FASEB J, 2004 Dec, 18(15), 1862 - 9
Targeting extracellular pyrophosphates underpins the high selectivity of nisin; Bonev BB et al.; The spread of infectious diseases and the increase in antibiotic resistance represent a life-threatening global development that calls for new approaches to control microorganisms . Of all potential targets, the essential and unique pathway of bacterial cell wall synthesis, targeted by the first known antibiotic penicillin, remains a perfect candidate for the development of new antibiotics . Here we show that the lantibiotic nisin exercises its antibacterial action by targeting peptidoglycan intermediates' extracellular pyrophosphate, unique to bacterial cell wall precursors . We show that nisin sequesters cell wall precursors found in the outer leaflet of bacterial plasma membranes, Lipid II and undecaprenyl pyrophosphate, into stable complexes . We propose a model of antibacterial action for nisin in which the terminal amino group of Ile1 targets the pyrophosphate groups of the bacterial cell wall precursors, where it docks via a hydrogen bond . The pyrophosphate moiety, a highly conserved chemical group different from the L-Lys-D-Ala-D-Ala docking motif for vancomycin, has no biochemical analogs with comparable properties and is unlikely to be susceptible to bacterial adaptations akin to those responsible for resistance to penicillins and vancomycin.

Orv Hetil, 2004 Oct 24, 145(43), 2177 - 81
{Clinical and pharmacological aspects of rifaximin, local antibiotic therapy in intestinal disorders}; Gasztonyi B et al.; The authors report pharmacokinetics and indications of rifaximin and the results of clinical studies . Rifaximin has a large antibacterial spectrum with a good therapeutic effect on both gram positive and gram negative aerob and anaerob bacteria . Practically there is no absorption (< 1%) following oral administration with a high concentration in gastrointestinal mucosa (8000 microg/g) . No increase in absorption can be detected in intestinal damage caused by inflammatory bowel disease . The remarkable safety profile of rifaximin is due to its negligible quality of absorption . According to the clinical studies rifaximin could be an adequate therapeutic approach in all gastrointestinal diseases and interventions when antibacterial therapy is needed.

Environ Sci Technol, 2004 Nov 1, 38(21), 5607 - 15
Transformation of the antibacterial agent sulfamethoxazole in reactions with chlorine: kinetics, mechanisms, and pathways; Dodd MC et al.; Sulfamethoxazole (SMX)--a member of the sulfonamide antibacterial class--has been frequently detected in municipal wastewater and surface water bodies in recent years . Kinetics, mechanisms, and products of SMX in reactions with free chlorine (HOCl/OCl-) were studied in detail to evaluate the effect of chlorination processes on the fate of sulfonamides in municipal wastewaters and affected drinking waters . Direct reactions of free available chlorine (FAC) with SMX were quite rapid . A half-life of 23 s was measured under pseudo-first-order conditions ({FAC}0 = 20 microM (1.4 mg/L) and {SMX}0 = 2 microM) at pH 7 and 25 degrees C in buffered reagent water . In contrast, a half-life of 38 h was determined for reactions with combined chlorine (NH2Cl, NHCl2) under similar conditions . Free chlorine reaction rates were first-order in both substrate and oxidant, with specific second-order rate constants of 1.1 x 10(3) and 2.4 x 10(3) M(-1) s(-1) for SMX neutral and anionic species, respectively . Investigations with substructure model compounds and identification of reaction products verified that chlorine directly attacks the SMX aniline-nitrogen, resulting in (i) halogenation of the SMX aniline moiety to yield a ring-chlorinated product at sub-stoichiometric FAC concentrations (i.e., {FAC}0:{SMX}0 < or = 1) or (ii) rupture of the SMX sulfonamide moiety in the presence of stoichiometric excess of FAC to yield 3-amino-5-methylisoxazole, SO4(2-) (via SO2), and N-chloro-p-benzoquinoneimine . Reaction ii represents an unexpected aromatic amine chlorination mechanism that has not previously been evaluated in great detail . Experiments conducted in wastewater and drinking water matrixes appeared to validate measured reaction kinetics for SMX, indicating that SMX and likely other sulfonamide antibacterials should generally undergo substantial transformation during disinfection of such waters with free chlorine residuals.

Med Clin (Barc), 2004 Nov 27, 123(19), 749 - 57
{Secreted phospholipases A<sub>2</sub> (sPLA<sub>2</sub>): friends or foes? Actors of the antibacterial and anti-HIV resistance?}; Villarrubia VG et al.; In this paper the authors update on the deletereous or beneficial roles of human and animal secretory phospholipases A2 (sPLA2) . Although human sPLA2-IIA (inflammatory) was initially thought as a foe because its pathogenic implication in sepsis, multiorganic failure or other related syndromes, recent data indicates its role in in the antiinfectious host resistance . Thus, sPLA2-IIA exhibits potent bactericidal activities against gram-negative and gram-positive (in this case, together with other endogenous inflammtory factors) bacteria . Surprisingly, human sPLA-IIA does not show in vitro anti-human immunodeficiency virus (HIV) activity, whilst several sPLA2-IA isolated from bee and serpent venons do it: this is the case for crotoxin, a sPLA2-IA isolated from the venon of Crotalus durissus terrificus (sPLA2-Cdt) . The mechanism for the in vitro anti-HIV activity of sPLA2-Cdt (inhibition of Gag p24) appears to be related to the ability of the drug to desestabilize ancorage (heparans) and fusion (cholesterol) receptors on HIV target cells.

J Am Chem Soc, 2004 Dec 8, 126(48), 15870 - 5
Tuning the hemolytic and antibacterial activities of amphiphilic polynorbornene derivatives; Ilker MF et al.; Amphiphilic cationic polynorbornene derivatives, soluble in water, were prepared from modular norbornene monomers, with a wide range of molecular weights (M(n) = 1600-137 500 g/mol) and narrow polydispersities (PDI = 1.1-1.3) . The antibacterial activity determined by growth inhibition assays and the hemolytic activity against human red blood cells were measured and compared to determine the selectivity of the polymers for bacterial over mammalian cells . The effects of monomer repeat unit hydrophobicity and polymer molecular weight on antibacterial and hemolytic activities were determined . The hydrophobicity of the repeat unit was observed to have dramatic effects on antibacterial and hemolytic activities . Lipid membrane disruption activities of the polymers was confirmed by measuring polymer-induced dye leakage from large unilamellar vesicles . By tuning the overall hydrophobicity of the polymer through random copolymerizations of modular norbornene derivatives, highly selective, nonhemolytic antibacterial activities were obtained . For appropriate monomer composition, selectivity against bacteria versus human red blood cells was determined to be over 100.

J Coll Physicians Surg Pak, 2003 Dec, 13(12), 708 - 10
Changing trend in emergency surgery for perforated duodenal ulcer; Gurleyik E; OBJECTIVE: To evaluate changes in the emergency surgery of the duodenal ulcer . DESIGN: Descriptive and analytical study . PLACE AND DURATION OF STUDY: Department of Surgery, Haydarpasa Numune Teaching and Research Hospital . Data of peptic ulcer patients, operated on between January 1975 and the end of 1999, were collected between 1990 and 2000, and analysed retrospectively in the first half of 2003 . SUBJECTS AND METHODS: Hospital records of 523 surgically treated patients, with duodenal ulcer perforation, during the period of 25 years (1975-1999) in the same surgical department, was retrospectively analysed . Changing aspects of emergency surgery of peptic ulcer disease, in the recent period, were determined in respect to number of operations per year and in the choice of operative methods . RESULTS: The average number of patients and emergency operations per year was 21 . No significant change was observed during the study period . Elective operations gradually decreased in the last ten years, and none was performed in the last 4 years . On the other hand, 226 emergency interventions for duodenal ulcer perforation were performed in the last ten years and 84 interventions in the last 4 years . Definitive anti-ulcer surgery was performed in 42% of patients between 1985 and 1994 . Simple closure of the perforation plus treatment with proton pump inhibitors and with anti-Helicobacter pylori medication was the method in 80% during the last year . CONCLUSION: Emergency surgery for perforated duodenal ulcer preserves its steady rate despite disappearance of elective operations after tremendous progress in medical control of peptic ulcer disease . There is an obvious return from definitive anti-ulcer surgery to simple closure of the perforation followed by antisecretory and antibacterial medication in the recent years.

J Nat Prod, 2004 Nov, 67(11), 1936 - 8
Antibacterial activity of naphthoquinones and triterpenoids from Euclea natalensis root bark; Weigenand O et al.; Phytochemical studies of an ethanolic extract of Euclea natalensis root bark afforded two new compounds, octahydroeuclein (1) and 20(29)-lupene-3 beta-isoferulate (2), in addition to three known compounds, shinanolone (3), lupeol, and betulin . The chemical structures of 1 and 2 were determined by spectroscopic means . Shinanolone (3) showed inhibitory activity against Gram-positive bacterial strains and a drug-sensitive strain of Mycobacterium tuberculosis at a concentration of 0.1 mg/mL.

Dtsch Tierarztl Wochenschr, 2004 Oct, 111(10), 408 - 14
Topical tea tree oil effective in canine localised pruritic dermatitis--a multi-centre randomised double-blind controlled clinical trial in the veterinary practice; Reichling J et al.; Tea tree oil, a volatile oil, is well known for its broad antibacterial and antifungal activity . A standardised and stabilised 10% tea tree oil cream was tested against a commercial skin care cream (control cream) in the management of canine localised acute and chronic dermatitis . Fifty-seven dogs with clinical manifestations of mostly pruritic skin lesions or alterations, skin fold pyodermas and other forms of dermatitis, corroborated by predominantly positive fungal and bacterial skin isolates, were enrolled by seven practising veterinarians and randomly allocated to two study groups (28:29) and were treated twice daily with a blinded topical preparation . After 10 days of treatment, success rates of 71% for the tea tree oil cream and 41% for the control cream (over-all efficacy documented by the veterinary investigator) differed significantly (p = 0.04), favouring tea tree oil cream treatment . Accordingly on day 10, the tea tree oil cream caused significantly faster relief than the control cream (p = 0.04) for two common clinical dermatitis signs, pruritus (occurring in 84 % of dogs) and alopecia . Only one adverse event was reported in the tea tree oil group (suspected not to be causally related to the study drug) and none in the control cream group . The tested herbal cream appears to be a fast-acting safe alternative to conventional therapy for symptomatic treatment of canine localised dermatitis with pruritis.

J Reprod Med, 2004 Oct, 49(10), 817 - 24
Mutagenicity of vaginal spermicides containing nonoxynol-9 in a bacterial assay; Lambert PC et al.; OBJECTIVE: To evaluate the potential mutagenicity of 3 commonly used over-the-counter spermicidal gels containing nonoxynol-9 as the active ingredient . STUDY DESIGN: The gels were examined for their ability to produce mutations in a bacterial assay (Ames test) . The results were compared with those from testing a series of nonantibacterial and antibacterial personal prwhen there is antibacterial personal products that come into contact with mucous membranes as well as some caustic, nonpersonal home products and a known mutagen . RESULTS: All 3 spermicidal gels were as mutagenic or more mutagenic than the other products tested in each category . Although activation by liver extract was required for 2 of the gels to show mutagenicity in this assay, the third was mutagenic without liver activation . CONCLUSION: Because of the intimate contact of spermicidal gels with human gametes and the possibility that components of the gels may be absorbed systemically and reach the unfertilized or fertilized ovum, the fact that these gels have mutagenic potential raises concern in cases in which conception occurs.

J Mol Biol, 2005 Jan 7, 345(1), 115 - 27
The crystal structure of E.coli 1-deoxy-D-xylulose-5-phosphate reductoisomerase in a ternary complex with the antimalarial compound fosmidomycin and NADPH reveals a tight-binding closed enzyme conformation; Mac Sweeney A et al.; The key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) has been shown to be the target enzyme of fosmidomycin, an antimalarial, antibacterial and herbicidal compound . Here we report the crystal structure of selenomethionine-labelled Escherichia coli DXR in a ternary complex with NADPH and fosmidomycin at 2.2 A resolution . The structure reveals a considerable conformational rearrangement upon fosmidomycin binding and provides insights into the slow, tight binding inhibition mode of the inhibitor . Although the inhibitor displays an unusual non-metal mediated mode of inhibition, which is an artefact most likely due to the low metal affinity of DXR at the pH used for crystallization, the structural data add valuable information for the rational design of novel DXR inhibitors . Using this structure together with the published structural data and the 1.9 A crystal structure of DXR in a ternary complex with NADPH and the substrate 1-deoxy-D-xylulose 5-phosphate, a model for the physiologically relevant tight-binding mode of inhibition is proposed . The structure of the substrate complex must be interpreted with caution due to the presence of a second diastereomer in the active site.

Fitoterapia, 2004 Dec, 75(7-8), 683 - 9
New polyisoprenylated benzophenones from Venezuelan propolis; Trusheva B et al.; Two new polyisoprenylated benzophenones, 18-ethyloxy-17-hydroxy-17,18-dihydroscrobiculatone A and 18-ethyloxy-17-hydroxy-17,18-dihydroscrobiculatone B, together with the known scrobiculatones A and B, were isolated from Venezuelan propolis . The scrobiculatones A and B showed significant antibacterial activity and moderate toxicity to Artemia salina nauplii.

Nitric Oxide, 2004 Nov, 11(3), 247 - 55
Nitric oxide formation in the oropharyngeal tract: possible influence of cigarette smoking; Marteus H et al.; Cigarette smoking reduces the level of nitric oxide (NO) in exhaled air by an unknown mechanism . The view that part of the effect of cigarette smoking on NO production should occur in the oropharyngeal tract is supported by several studies . We have therefore compared smokers and non-smokers regarding non-enzymatic formation of NO from nitrite in the oral cavity since this is a primary candidate target for cigarette smoke . We have also looked at NO synthase-dependent NO formation in the mucosa of the oropharyngeal tract as an alternative target for the inhibitory effect induced by cigarette smoke . Smokers exhaled 67% lower levels of NO than controls (p<0.01, n=15 each group) . We could not detect any significant difference in salivary nitrite, nitrate or ascorbate between smokers and non-smokers . Mouthwash with the antibacterial agent chlorhexidine reduced salivary nitrite (-65%) and exhaled NO levels (-10%) similarly in the two groups . Immunohistochemical techniques revealed dense expression of inducible (but not endothelial or neuronal) NO synthase in the squamous epithelium of non-inflamed tonsillar and gingival tissue biopsies . In the same biopsies, significant Ca2+ -independent citrulline-forming activity was detected . We found no difference between smoking and non-smoking subjects regarding NO-synthase expression and in vitro activity . In another group of non-smoking subjects (n=10), spraying the oropharyngeal tract with the NO-synthase inhibitor NG-monomethyl-L-arginine (250 mg) significantly reduced exhaled NO levels for at least 30 min (-18%, p<0.01) . Our data suggest that cigarette smoking does not affect non-enzymatic NO formation from nitrite in saliva . However, NO is also formed by inducible NO synthase in the squamous epithelium of the normal oropharyngeal tract . We suggest that cigarette smoking may down-regulate enzymatic NO formation in the oropharyngeal compartment as well as in the bronchial compartment.

J Exp Zoolog A Comp Exp Biol . 2004 Aug 16;301A(9):745-755 {Epub ahead of print}
Seminal vesicle secretion of African catfish, its composition, its behaviour in water and saline solutions and its influence on gamete fertilizability; Mansour N et al.; The seminal vesicle secretion (SVS) of the African catfish, Clarias gariepinus, was investigated by analytical and experimental methods . SVS consists mainly of proteins and glycoproteins which are responsible for its viscous and sticky nature . The secretion contains also high activities of acid phosphatase, alkaline phosphatase, and proteases . These catabolic enzymes do not have functions in autolysis or liquefaction of SVS but are considered to eliminate aging spermatozoa from the proximal portions of seminal vesicle and from the spermatic duct . SVS of the African catfish is unstable in the environment relevant for natural spawning . When SVS was mixed with water, seminal plasma or different types of saline solutions its protein coagulated forming fibrous or granular particles of variable size within a few seconds . Pure SVS completely inhibited the motility as the sticky secretion hindered spermatozoa in free swimming . SVS had also a negative effect on sperm fertility, egg fertility, and sperm egg contact, as the fertilization was drastically suppressed in the presence of SVS . Basing on our analytical and experimental results we exclude that SVS has functions in stabilizing the viability of spermatozoa stored in the spermatic ducts or is an energy resource of spermatozoa . It also does not improve or stabilize the fertilization process and has no functions in adhering the eggs to substrates or in covering the eggs for mechanical protection or antibacterial defense . A function of SVS in the male and female communication during the prenuptial spawning behaviour is discussed . J . Exp . Zool . 301A:745-755, 2004 . (c) 2004 Wiley Liss, Inc.

Biosci Biotechnol Biochem, 2004 Nov, 68(11), 2265 - 9
Structure-activity relationship of S-benzylisothiourea derivatives to induce spherical cells in Escherichia coli; Iwai N et al.; We have previously reported that a novel S-benzylisothiourea derivative, S-(3,4-dichlorobenzyl)isothiourea, tentatively named A22, induced spherical cells in Escherichia coli . To elucidate the structural element(s) required for inducing these spherical cells, the biological activity of S-benzylisothiourea derivatives and related compounds toward E . coli cells was investigated . S-(4-Chlorobenzyl)isothiourea revealed spherical cell-inducing activity, although being slightly less potent than A22, and S-benzylisothiourea itself showed much less activity . S-Cyclohexylmethylisothiourea did not show antibacterial activity and had little effect on the cell shape . S-Heptylisothiourea showed antibacterial activity and induced elongated cells rather than spherical cells . Benzylisothiocyanate inhibited cell growth but did not induce spherical cells . S-Ethylisothiourea, benzylthiocyanate, benzylisocyanate, and N-phenylthiourea did not show any activity under the present experimental conditions . These results indicate that the S-benzylisothiourea structure was necessary and sufficient for inducing spherical cells and that 3- and/or 4-chloro-substitution of the S-benzyl group enhanced this activity.

Bioorg Khim, 2004 Sep-Oct, 30(5), 458 - 65
{Structure-function relationship between analogues of the antibacterial peptide indolicidin . I . Synthesis and biological activity of analogues with increased amphipathicity and elevated net positive charge of the molecule}; Genetic correlation between melanization and antibacterial immune responses in a natural population of the malaria vector Anopheles gambiae; Laboratoire de Parasitologie Evolutive, CNRS UMR 7103, Universite Pierre and Marie Curie, CC237, 7 quai St Bernard, 75252 Paris Cedex 05, France . Louis.Lambrechts@snv.jussieu.fr

The immune system of invertebrates can mount different responses, including melanotic encapsulation and several antibacterial defense mechanisms . Variation of the efficacies of these responses is generally considered to be a product of the evolutionary pressure on each response due to infection by parasites . However, potential interactions and trade-offs among the different responses of the immune system could constrain the evolutionary potential of each response . In a natural population of the mosquito Anopheles gambiae, we measured the genetic association between the melanization response and an antibacterial response in two environmental qualities (well-fed and undernourished larvae) . In both environments the two immune responses were positively genetically correlated: in full-sib families that were most likely to melanize a bead, injected bacteria were most likely to be cleared . Thus, our data do not support the idea of a trade-off among different outcomes of the invertebrate immune system, but rather that some families are overall immunologically superior to others.

Magn Reson Chem . 2004 Nov 23;43(2):184-185 {Epub ahead of print}
NMR spectroscopic analysis of lotusine; Yang J; Lotusine, a soluble alkaloid, is one of the major constituents of the Chinese medicine Lotus Plumule, and has antihypertension and antibacterial activity . In order to confirm the structures reported in the literature by explicit (1)H and (13)C assignments, we applied a series of NMR experiments including (1)H-(1)H COSY, HSQC and HMBC . Copyright (c) 2004 John Wiley & Sons, Ltd.

Antimicrob Agents Chemother, 2004 Dec, 48(12), 4835 - 42
Pharmacokinetics in animals and humans of a first-in-class peptide deformylase inhibitor; Ramanathan-Girish S et al.; BB-83698, a potent and selective inhibitor of peptide deformylase, was the first compound of this novel antibacterial class to progress to clinical trials . Single- and/or multiple-dose studies with doses ranging from 10 to 50 mg of BB-83698/kg of body weight were done with mice, rats, and dogs . Intravenous pharmacokinetics were characterized by low to moderate clearances and moderate volumes of distribution for all species . In dogs, but not in rodents, central nervous system (CNS) effects were dose limiting for intravenously administered BB-83698 and were suspected to be related to a high maximum concentration of the agent in plasma (Cmax) rather than to total systemic exposure . Controlled infusion studies with dogs demonstrated that CNS effects could be avoided without compromising systemic exposure by reducing the Cmax . A randomized, double-blind, placebo-controlled, five-way-crossover, single-dose-escalation, phase I study to explore the safety, tolerability, and pharmacokinetics of intravenous BB-83698 at doses ranging from 10 to 475 mg was performed with healthy male volunteers . Systemic exposures were generally in linear relationships with administered doses in animals and humans . Pharmacokinetics were consistent, predictable, and exhibited good allometric scaling among all species (r2 >0.98) . Moreover, BB-83698 dosing in humans proceeded to a predicted efficacious exposure (the area under the concentration-time curve/MIC ratio, up to 184) without any clinically significant adverse effects.

J Biochem Biophys Methods, 2004 Oct 29, 61(1-2), 215 - 27
Earthworm leukocytes kill HeLa, HEp-2, PC-12 and PA317 cells in vitro; Engelmann P et al.; Earthworm coelomic fluid contains biologically active molecules and leukocytes that participate in phagocytosis, encapsulation . Presumably they synthesize and secrete several effector modulators of innate immune responses such as antibacterial molecules, cytotoxic proteins and cytokines . Several lytic molecules have been detected in coelomic fluid previously but it is not yet clear which are actually released from the coelomocytes . Our aim was to analyze the cytotoxic effects of coelomocytes on mammalian target cells and to provide evidence that the lytic factors originate from coelomocytes . Cell-free coelomic fluid, supernatants of short-term cultured coelomocytes, and lysates from coelomocytes--derived by mechanical and detergent extraction--were used in cytotoxicity assays performed on different mammalian standard tumor cell lines and mouse fibroblasts . We used native and denaturized (using proteinase K, and trypsin digestions, or heat-inactivation) coelomocyte lysates (CCL) . The viability controls of targeted cells were made by measuring photometrically and analyzing by inverted microscopy . According to our results the coelomic fluid, the supernatant of cultured coelomocytes, and the CCL significantly decreased ratios of living cells compared to controls in a dose-dependent manner . Our experiments performed with CCLs suggest that coelomocytes are responsible for the productions of cytotoxic components presumably proteins.

Klin Khir, 2004 Aug, (8), 16 - 8
{Drainage operation for the infectious pancreonecrosis}; Kostyrnoi AV et al.; The prospective investigation a was conduct in 218 patients and retrospective ones--in 253 patients . The results of drainage operations in infectious forms of pancreonecrosis were studied basic task in preoperative period was adequate antibacterial therapy, directed on all microorganisms.

J Exp Zoolog A Comp Exp Biol, 2004 Sep 1, 301(9), 745 - 55
Seminal vesicle secretion of African catfish, its composition, its behaviour in water and saline solutions and its influence on gamete fertilizability; Mansour N et al.; The seminal vesicle secretion (SVS) of the African catfish, Clarias gariepinus, was investigated by analytical and experimental methods . SVS consists mainly of proteins and glycoproteins which are responsible for its viscous and sticky nature . The secretion contains also high activities of acid phosphatase, alkaline phosphatase, and proteases . These catabolic enzymes do not have functions in autolysis or liquefaction of SVS but are considered to eliminate aging spermatozoa from the proximal portions of seminal vesicle and from the spermatic duct . SVS of the African catfish is unstable in the environment relevant for natural spawning . When SVS was mixed with water, seminal plasma or different types of saline solutions its protein coagulated forming fibrous or granular particles of variable size within a few seconds . Pure SVS completely inhibited the motility as the sticky secretion hindered spermatozoa in free swimming . SVS had also a negative effect on sperm fertility, egg fertility, and sperm egg contact, as the fertilization was drastically suppressed in the presence of SVS . Basing on our analytical and experimental results we exclude that SVS has functions in stabilizing the viability of spermatozoa stored in the spermatic ducts or is an energy resource of spermatozoa . It also does not improve or stabilize the fertilization process and has no functions in adhering the eggs to substrates or in covering the eggs for mechanical protection or antibacterial defense . A function of SVS in the male and female communication during the prenuptial spawning behaviour is discussed.

Am J Kidney Dis, 2004 Dec, 44(6), 1097 - 102
Linezolid disposition after standard dosages in critically ill patients undergoing continuous venovenous hemofiltration: a report of 2 cases; Pea F et al.; Linezolid is a new oxazolidinone antibiotic active against most Gram-positive microorganisms the renal elimination of which accounts for about 30% to 35% of all the clearance . Its pharmacokinetic ability was assessed during continuous venovenous hemofiltration (CVVH) in 2 anuric patients with severe postsurgical intraabdominal infections who were receiving standard dosages (600 mg intravenously twice a day) . Blood samples for quantification of linezolid in plasma and in filtrate were collected after more than 4 days of therapy before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9, and 11 hours after the morning 1-hour intravenous infusion, and concentrations were determined by means of high-performance liquid chromatography . Linezolid was partially cleared by CVVH in both the patients (hemofiltration clearance {CL CVVH } = 0.38 and 0.35 mL/min/kg), with high sieving coefficient values (0.76 to 0.92) . Efficacious plasma exposure for time-dependent antibacterial activity of linezolid, either in terms of trough levels above minimum inhibitory concentration (MIC) at which 90% of the isolates are inhibited (Cmin >MIC90 ) or of area under the plasma concentration time curve to MIC90 ratio (AUC/MIC90 ) >100 hours, was ensured during CVVH in both patients . However, despite similar CL CVVH , significant interindividual pharmacokinetic variability was found in the 2 patients (AUC during the observational period {AUC 0-tau } 334.71 versus 109.34 mg/L x h), mainly owing to substantial differences in non-CVVH-related clearance of linezolid (total CL, 0.55 versus 1.21 mL/min/kg) . Our findings indicate that linezolid, although partially removed, does not warrant dosage modification during the first 48 hours when CVVH (with polysulfide hemofilter) at standard 2,000 mL/h substitution flow rate in predilution is applied to anuric patients . Thereafter, this choice is a reasonable one with the exception of those patients who have other features of linezolid toxicity and in which non-CVVH-related clearance might be impaired, although further evaluations are warranted.

J Immunol, 2004 Dec 1, 173(11), 6938 - 48
CCR1 and CC chemokine ligand 5 interactions exacerbate innate immune responses during sepsis; Ness TL et al.; CCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis . In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1(-/-)) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls . The peritoneal and systemic cytokine profile in CCR1(-/-) mice was characterized by a robust, but short-lived and regulated antibacterial response . CCR1 expression was not required for leukocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1(-/-) resident or recruited peritoneal cells during sepsis . Peritoneal macrophages isolated from naive CCR1(-/-) mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages . CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro . Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival . CCL5 acted in a CCR1-dependent manner to augment production of IFN-gamma and MIP-2 to damaging levels . These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention.

Bioorg Med Chem, 2004 Dec 15, 12(24), 6389 - 95
Synthesis and microbial inhibition study of novel 5-imidazolyl substituted isoxazolidines; Sadashiva MP et al.; Cycloaddition of C-imidazolyl-N-phenylnitrones with monosubstituted alkenes afforded 5-imidazolyl substituted isoxazolidines with high regioselectivity . Novel isoxazolidines were screened for their antibacterial activities against S . aureus, E . coli and B . subtilis by using streptomycin as a positive control . They were also tested for their antifungal activities against F . moniliforme, A . niger and C . acremonium by using nystatin as a positive control . Isoxazolidines, 4a and 4f exhibited more potent inhibition towards antifungal activity than the other isoxazolidines prepared.

Bioorg Med Chem, 2004 Dec 15, 12(24), 6351 - 69
Total and local (atom and atom type) molecular quadratic indices: significance interpretation, comparison to other molecular descriptors, and QSPR/QSAR applications; Ponce YM; This paper describes the significance interpretation, comparison to other molecular descriptors, and QSPR/QSAR applications of a new set of molecular descriptors: atom, atom type, and total molecular quadratic indices . The features of the kth total and local quadratic indices are illustrated by examples of various types of molecular structures, including chain lengthening, branching, heteroatoms content, and multiple bonds . The linear independence of the local (atom type) quadratic indices to others 0D, 1D, 2D, and 3D molecular descriptors is demonstrated by using principal component analysis for 42 heterogeneous molecules . It is concluded that the local quadratic indices are independent indices containing important structural information to be used in QSPR/QSAR and drug design studies . In this sense, molecular quadratic indices were used to the description and prediction of the boiling point of 28 alkyl alcohols and to the modeling of the partition coefficient (logP), specific rate constant (logk), and antibacterial activity of 2-furylethylene derivatives . These models were statistically significant and showed very good stability to data variation in leave-one-out (LOO) cross-validation experiment . The comparison with the other approaches also revealed good behaviors of our method in this QSAR study.

J Chromatogr B Analyt Technol Biomed Life Sci, 2004 Dec 5, 812(1-2), 277 - 90
Separation methods used for Scutellaria baicalensis active components; Li HB et al.; Scutellaria baicalensis Georgi is one of the most widely used traditional Chinese herbal medicines . Its roots have been used for anti-inflammation, anticancer, antiviral and antibacterial infections of the respiratory and the gastrointestinal tract, cleaning away heat, moistening aridity, purging fire, detoxifying toxicosis, reducing the total cholesterol level and decreasing blood pressures . Baicalin, baicalein, wogonin and oroxylin A are its main active components . This review provides an overview of various separation, detection, and identification techniques employed for the quantitative and qualitative determination of these active components . Applications of high-performance liquid chromatography, high-speed counter-current chromatography, thin layer chromatography, capillary electrophoresis, and micellar electrokinetic capillary chromatography to the separation and determination of these active components are described . Examples of identification of these active components and their metabolites in complex matrices by high-performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry are also presented . The advantages and limitations of these separation and identification methods are assessed and discussed.

J Chromatogr B Analyt Technol Biomed Life Sci, 2004 Dec 5, 812(1-2), 101 - 17
Separation methods for antibacterial and antirheumatism agents in plant medicines; Wen D et al.; Traditional oriental medicines (TOM), with a very long history and many remarkable features, are very popular in Asian countries, especially in China, Japan and Korea . With the development of advanced analytical techniques, the modernization of traditional medicine has become a hot area in recent years and some herbal medicines have been increasingly accepted in western countries . Separation and determination of active components in various herbal medicines are considered to be critical for the modernization process . Antibacterial and antirheumatism agents are widely distributed in many medical plants and commonly used in clinical treatment . Therefore, the development of effective separation methods for the quality control of herbal medicines is absolutely important . In this article, the separation methods for the analysis of antibacterial and antirheumatism compounds in TOM were reviewed, including thin layer chromatography (TLC), gas chromatography (GC), supercritical fluid chromatography (SFC), high-performance liquid chromatography (HPLC), capillary electrophoresis (CE) and related hyphenation techniques . Sample preparation procedures and further development of these methods were also discussed.

Infect Dis Clin North Am, 2004 Dec, 18(4), 777 - 90
Antibacterial drug resistance: implications for the treatment of patients with community-acquired pneumonia; Metlay JP; In contrast to the tremendous number of articles and meetings devoted to elucidating the mechanisms of antibacterial drug resistance and describing the emergence of drug resistance patterns, little research has been completed on the impact of bacterial drug resistance on clinical outcomes . Moreover.among the studies that have been completed, the better-designed studies generally have failed to detect an effect of most current levels of antibacterial drug resistance on clinical outcomes for patients who have CAP . Yet, practice patterns are shifting in response to the perception that current levels of drug resistance necessitate changes in treatment patterns . This is unfortunate because it severely limits one's ability to continue to monitor the effectiveness of available therapies in light of changing patterns of antibacterial drug resistance . If levels of drug resistance continue to rise, it is likely that outcomes from those drug treatments will be affected adversely . In this regard, the recent licensing of a 7-valent pneumococcal conjugate vaccine for infants and young children may have an important effect on future trends in antibacterial drug resistance . The vaccine reduces childhood carriage of vaccine serotypes,which are among the most common serotypes found among drug-resistant isolates, and may reduce transmission of these serotypes to adults {65}.In conclusion, antibacterial drug resistance has not reduced substantially the effectiveness of first-line treatments for CAP . Whether levels of drug resistance will continue to increase or decline is unknown . Therefore,carefully designed outcomes studies likely will continue to be essential to help define optimal therapy for patients who have CAP.

Immunology, 2004 Dec, 113(4), 427 - 37
Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzle; Kolios G et al.; In recent years, nitric oxide (NO), a gas previously considered to be a potentially toxic chemical, has been established as a diffusible universal messenger that mediates cell-cell communication throughout the body . Constitutive and inducible NO production regulate numerous essential functions of the gastrointestinal mucosa, such as maintenance of adequate perfusion, regulation of microvascular and epithelial permeability, and regulation of the immune response . Up-regulation of the production of NO via expression of inducible nitric oxide synthase (iNOS) represents part of a prompt intestinal antibacterial response; however, NO has also been associated with the initiation and maintenance of inflammation in human inflammatory bowel disease (IBD) . Recent studies on animal models of experimental IBD have shown that constitutive and inducible NO production seems to be beneficial during acute colitis, but sustained up-regulation of NO is detrimental . This fact is also supported by studies on mice genetically deficient in various NOS isoforms . However, the mechanism by which NO proceeds from being an indispensable homeostatic regulator to a harmful destructor remains unknown . Furthermore, extrapolation of data from animal colitis models to human IBD is questionable . The purpose of this review is to update our knowledge about the role of this universal mediator and the enzymes that generate it in the pathogenesis of IBD.

Zh Mikrobiol Epidemiol Immunobiol, 2004 Sep-Oct, (5), 76 - 80
{Specific features of humoral immunity in cryptogenic fibrosing alveolitis patients}; Laser-mediated photodynamic therapy of actinic cheilitis; Yale University School of Medicine, Department of Dermatology, New Haven, CT, USA . dralexiades@nyderm.org

Actinic cheilitis (AC) is a common precancerous condition for which a safe, effective, rapid, and cosmetically favorable treatment is needed . The objective of this study was to assess the safety and efficacy of the long-pulsed pulsed dye laser (LP PDL) (595 nm) with photodynamic therapy (PDT) for the treatment of AC . This study was designed to be a prospective, proof-of concept pilot study to assess safety and efficacy of LP PDL in conjunction with topical 20% 5-aminolevulinic acid solution PDT for the treatment of AC . Control patients received LP PDL alone . The setting was an outpatient clinical research center . A volunteer sample of 21 patients with biopsy-proven AC was enrolled (age range, 42-86 years; skin types I-III) . All patients were refractory to prior therapies . Patients with a history of herpes labialis were pre-treated with famcyclovir . Nineteen patients received one-to-three treatments of topical 20% 5-aminolevulinic acid for 2-3 hours, followed by LP PDL (595 nm) at monthly intervals . Two control patients received one treatment with LP PDL alone . Patients in the ALA-LP PDL group were followed at 1, 2, 3, 6, 9, and 12 months . Clearance of AC was assessed by clinical evaluation . Control patients were followed to the one month interval . We observed none-to-mild pain; slight-to-moderate erythema; no crusting, purpura, or scarring; treatment time of less than one minute; and complete resolution of post-operative erythema by day three . Complete clearance was achieved in 13/19 (68%) of patients following a mean of 1.8 treatments (7/13 (37%) after one, 2/13 (11%) after two, and 1/13 (21%) after three treatments) . Patients were followed for a mean of 4.1 (range 1-12) months . Among the remaining cases, partial clearing was achieved in two patients, recurrence during the follow-up interval was observed in one patient, and failure to follow-up occurred in three patients . Post-operative impetiginization occurred in three patients with erosive AC, which resolved with dicloxacillin therapy . Among the control patients, no clearing was observed . Treatment of AC using LP PDL (595 nm) at nonpurpuric parameters following topical application of 5-aminolevulinic acid at short incubation times is safe and effective . It may offer the advantages of rapid incubation, treatment, and recovery times, minimal discomfort, excellent cosmetic outcome, and good efficacy rates . Patients with erosive AC should receive antibacterial prophylaxis . Multiple treatments may be required for complete clearing.

Planta Med, 2004 Nov, 70(11), 1058 - 63
Effect of 13-epi-sclareol on the bacterial respiratory chain; Tapia L et al.; 13-epi-sclareol is a labdane-type diterpene isolated from the resinous exudates of the medicinal plant species Pseudognaphalium cheiranthifolium (Lam.) Hilliard et Burtt . and P . heterotrichium (Phil.) A . Anderb . This compound has antibacterial activity only against Gram-positive bacteria, showing a bactericidal and lytic action . The interaction of 13- epi-sclareol with the bacterial respiratory chain was analyzed . The compound inhibited oxygen consumption of intact Gram-positive cells, but not with Gram-negative bacteria . The compound inhibited NADH oxidase and cytochrome c reductase activities, while coenzyme Q reductase and the cytochrome c oxidase activities were not affected . These results suggest that the target site of 13-epi-sclareol is located between coenzyme Q and cytochrome c . Using cytoplasmic membrane fractions, the results of the analysis of the enzyme activities associated with the respiratory chain complexes were the same for both Gram-positive and Gram-negative bacteria, indicating that the compound has no access to the cytoplasmic membrane of intact Gram-negative bacteria . Thus, the Gram-negative envelope may act as a physical barrier that prevents the access of this compound to the site of action.

Ann Hematol . 2004 Nov 10; {Epub ahead of print}
Reduction of catheter-related infections in neutropenic patients: a prospective controlled randomized trial using a chlorhexidine and silver sulfadiazine-impregnated central venous catheter; Jaeger K et al.; Antiseptic coating of intravascular catheters may be an effective means of decreasing catheter-related colonization and subsequent infection . The purpose of this study was to assess the efficacy of chlorhexidine and silver sulfadiazine (CH-SS)-impregnated central venous catheters (CVCs) to prevent catheter-related colonization and infection in patients with hematological malignancies who were subjected to intensive chemotherapy and suffered from severe and sustained neutropenia . Proven CVC-related bloodstream infection (BSI) was defined as the isolation of the same species from peripheral blood culture and CVC tip (Maki technique) . This randomized, prospective clinical trial was carried out in 106 patients and compared catheter-related colonization and BSI using a CH-SS-impregnated CVC (n=51) to a control arm using a standard uncoated triple-lumen CVC (n=55) . Patients were treated for acute leukemia (n=89), non-Hodgkin's lymphoma (n=10), and multiple myeloma (n=7) . Study groups were balanced regarding to age, sex, underlying diseases, insertion site, and duration of neutropenia . The CVCs were in situ a mean of 14.3+/-8.2 days (mean+/-SD) in the study group versus 16.6+/-9.7 days in the control arm . Catheter-related colonization was observed less frequently in the study group (five vs nine patients; p=0.035) . CVC-related BSI were significantly less frequent in the study group (one vs eight patients; p=0.02) . In summary, in patients with severe neutropenia, CH-SS-impregnated CVCs yield a significant antibacterial effect resulting in a significantly lower rate of catheter-related colonization as well as CVC-related BSI.

Org Lett, 2004 Nov 25, 6(24), 4455 - 8
Synthesis of novel 6,11-O-bridged bicyclic ketolides via a palladium-catalyzed bis-allylation; Wang G et al.; A bridging chemistry process was developed to form an ether bridge between 6-O and 11-O of erythromycin A via a tandem or stepwise palladium-catalyzed bis-pi-allylation . By applying this bridging process, new 6,11-O-bridged bicyclic ketolides (BBKs) were synthesized . These BBKs showed good antibacterial activities against the macrolide-susceptible strains as well as mef-resistant strains and served as a good core for further modifications to study the structure-activity relationship (SAR) and to overcome bacterial resistance . {reaction: see text}

Bioorg Med Chem Lett, 2004 Dec 20, 14(24), 5997 - 6000
Isoxazole-3-hydroxamic acid derivatives as peptide deformylase inhibitors and potential antibacterial agents; Cali P et al.; A series of isoxazole-3-hydroxamic acid derivatives has been identified as a new class of small, nonpeptidic inhibitors of peptide deformylase (PDF) . The synthesis, enzyme inhibition and preliminary investigation of the binding mode of this potential antibacterial compounds are reported.

Mediators Inflamm, 2004 Aug, 13(4), 263 - 8
Effects of 'casoparan', a peptide isolated from casein hydrolysates with mastoparan-like properties; Lebrun I et al.; Casein, a protein found in milk of several species, is divided into different chains from 19 to 25 kDa . Casein is also considered as a source of amino acids and generating peptides with biological activities such as opiate, immunostimulating, antibacterial, peptidase inhibitors, among others . In this work, Sephadex G-10 chromatography followed by high-performance liquid chromatography isolation purified NZCase TT, an industrial culture media for tetanus toxin production . In the first step, four pools were isolated and tested in different assays: isolated smooth muscle assay (guinea pig ileum, rat uterus), phagocytosis in vitro of opsonized sheep red blood cells, and hydrogen peroxide (H2O2) release from mouse peritoneal macrophages . Pool III was the main active pool being able to potentiate bradykinin action in guinea pig ileum, stimulating phagocitic activity by resident macrophages and increasing H2O2 release from macrophages previously activated with bacille Calmette Guerin . Using mass spectra the primary structure of the main peptide from pool III was obtained--INKKI, which corresponds to beta-casein fragment 26-30 . The immunostimulating action is probably related to a direct action in macrophage cells.

Curr Pharm Des, 2004, 10(25), 3095 - 110
Clinical implications of macrolide therapy in chronic sinopulmonary diseases; Martinez FJ et al.; Macrolides have broad antibacterial spectrum and proven efficacy in the management of respiratory tract infections . Over the past decade there has been progressive interest in these agents for their potential role as tissue modifying, anti-inflammatory agents . Increasingly, the effect of macrolides on numerous cell types has been documented . Preliminary data have suggested a beneficial clinical role of chronic macrolide therapy in selected patients with chronic rhinosinusitis, chronic obstructive pulmonary disease, cystic fibrosis, non-cystic fibrosis bronchiectasis and asthma . This review presents the biological rationale and the available clinical data of chronic macrolide therapy in chronic respiratory tract diseases . When available, the data addressing the presumed mechanisms underlying clinical benefits are presented.

Curr Pharm Des, 2004, 10(25), 3081 - 93
Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and in-vivo models; Tsai WC et al.; Macrolide antibiotics appear to play a role in the management of diseases of chronic airway inflammation, distinctly separate from their antibactericidal activity . In the last fifteen years, their success in human clinical trials has prompted both in-vitro and in-vivo investigations to determine the mechanisms by which this family of antibiotics modulate the immune response . A large body of evidence suggests that macrolides directly target multiple components of the inflammatory cascade that occur independent of bactericidal/bacteriostatic effects . We will review the existing data in support of immunomodulatory effects of macrolides on activated leukocytes at the site of lung inflammation, on pulmonary host cells, and in animal models of lung disease.

Langmuir, 2004 Nov 23, 20(24), 10718 - 26
Synthesis of copolymer brushes endowed with adhesion to stainless steel surfaces and antibacterial properties by controlled nitroxide-mediated radical polymerization; Ignatova M et al.; Novel copolymer brushes have been synthesized by a two-step "grafting from" method that consists of the electrografting of poly(2-phenyl-2-(2,2,6,6-tetramethyl-piperidin-1-yloxy)-ethylacrylate) onto stainless steel, followed by the nitroxide-mediated radical polymerization of 2-(dimethylamino ethyl)acrylate and styrene or n-butyl acrylate, initiated from the electrografted polyacrylate chains . The grafted copolymers were quaternized in order to endow them with antibacterial properties . Peeling tests have confirmed the strong adhesion of the grafted copolymer onto the stainless steel substrate . Quartz crystal microbalance experiments have proven that fibrinogen adhesion is lower on the hydrophilic quaternized films compared to the nonionic counterpart . Such quaternized copolymers exhibit significant antibacterial activity against the Gram-positive bacteria S . aureus and the Gram-negative bacteria E . coli.

Pharmazie, 2004 Oct, 59(10), 756 - 62
Improved synthesis, antibacterial activity and potential carcinogenicity of 5-amino-1 ,2,4-thiadiazol-3(2H)-one; Piskala A et al.; This paper reports on the preparation of 5-amino-1,2,4-thiadiazol-3(2H)-one, a sulfur-containing analogue of cytosine with the -CH=CH- group between the positions 5 and 6 of the pyrimidine ring replaced by the divalent sulfur (-S-) . Improved procedures for the preparation of thiobiuret, some of its methyl derivatives and 5-amino-1,2,4-thiadiazol-3(2H)-one are documented . Thiobiuret and its N-methyl derivatives were obtained by addition of hydrogen sulfide to the respective 1-cyanoureas . Subsequent oxidation of thiobiuret with hydrogen peroxide in alkaline medium produced 5-amino-1,2,4-thiadiazol-3(2H)-one . This substance was traced back converted to the starting thiobiuret by reaction with cysteine hydrochloride . Alkaline degradation of thiadiazol led to the formation of 1-cyanourea isolated as its silver salt . An investigation of the thiadiazol biological activities has shown that it inhibits the growth of E . coil by 10% at 8.5 microM concentrations, but exhibited no cytostatic activity in L1210, HeLa S3 and HL-60 cell lines . Potential carcinogenicity of the prepared compounds was determined by a DC polarographic method . While the values of the parameter of carcinogenicity for all intermediates indicate only marginal carcinogenic potential, the value of the parameter of carcinogenicity for the thiadiazole indicates possible carcinogenicity of this compound.

J Hand Surg {Br}, 2004 Dec, 29(6), 634 - 5
The use of chloramphenicol ointment as an adhesive for replacement of the nail plate after simple nail bed repairs; Pasapula C et al.; Fingertip injuries are common and are often repaired . The nail plate is replaced to protect the repair and maintain the alignment of the nail bed edges after repair . Once replaced, this can be secured by any means and often a suture is used . We advocate that a small bleb of chloramphenicol provides a simple method of securing the nail plate . It is fast, easy and secure . In addition it provides an antibacterial effect, which may be of some benefit.

Vaccine, 2004 Dec 16, 23(5), 585 - 94
Targeting of Porphyromonas gingivalis with a bispecific antibody directed to FcalphaRI (CD89) improves in vitro clearance by gingival crevicular neutrophils; Kobayashi T et al.; Phagocytosis and killing of pathogens by polymorphonuclear neutrophils (PMN) from gingival crevicular fluid (GCF) is diminished in chronic periodontitis patients . As an approach to improve targeting of PMN toward a periodontopathogen, Porphyromonas gingivalis, the efficacy of a bispecific antibody (BsAb) directed against both recombinant 130 kDa hemagglutinin domain (r130k-HMGD) of P . gingivalis, and PMN Fc receptor (FcR) was evaluated . GCF PMN exhibited higher IgA FcR (FcalphaRI) levels, and lower IgG FcR (FcgammaRIIa and FcgammaRIIIb) levels than PB PMN . Functional studies revealed that GCF PMN exhibited a higher capacity to phagocytose and kill P . gingivalis opsonized with a BsAb targeting P . gingivalis r130k-HMGD to FcalphaRI as compared to an anti-r130k-HMGD antibody . However, phagocytosis and killing activity of PB PMN that were incubated with the two antibodies proved comparable . These data support targeting of pathogens toward FcalphaRI as an option to improve antibacterial immunity in chronic periodontitis patients.

J Inorg Biochem, 2004 Dec, 98(12), 2131 - 40
Synthesis, characterization, EXAFS investigation and antibacterial activities of new ruthenium(III) complexes containing tetradentate Schiff base; Prabhakaran R et al.; A series of new hexa-coordinated ruthenium(III) complexes of the type {Ru(X)(2-atmp-ba)(EPh3)} (where H2-2-atmp-ba=N,N'-bis(2-aminothiophenol)benzoylacetone; X=Cl or Br; E=P or As) have been prepared by reacting {RuX3(EPh3)3} (where X=Cl or Br; E=P or As) with tetradentate Schiff base ligand (H2-2-atmp-ba) in 1:1 molar ratio . The complexes have been characterized by elemental analyses, Infra red, electronic, electron paramagnetic resonance spectroscopy and cyclic voltammetry . In order to confirm the coordination and structure of the complexes extended X-ray absorption fine structure spectroscopy (EXAFS) studies have been carried out . Based on the above data, an octahedral structure has been confirmed for the complexes . The new complexes were also screened for their antibacterial properties.

Z Naturforsch {C}, 2004 Sep-Oct, 59(9-10), 663 - 72
Biological evaluation of some selected cyclic imides: mitochondrial effects and in vitro cytotoxicity; Prado SR et al.; Cyclic imides such as succinimides, maleimides, glutarimides, phthalimides and their derivatives contain an imide ring and a general structure -CO-N(R)-CO- that confers hydrophobicity and neutral characteristic . A diversity of biological activities and pharmaceutical uses have been attributed to them, such as antibacterial, antifungal, antinociceptive, anticonvulsant, antitumor . In spite of these activities, much of their action mechanisms at molecular and cellular levels remain to be elucidated . We now show the effects of several related cyclic imides: maleimides (S2, S2.1, S2.2, S3), glutarimides (S4, S5, S6), 4-aminoantipyrine derivatives (L1, F1, AL1, F1.14, F1.2) and sulfonated succinimides (RO1, FA, FE, FD, MC, DMC) on isolated rat liver mitochondria, B16-F10 melanoma cell line, peritoneal macrophages and different bacterial streams . The effects on mitochondrial respiratory parameters, cell viability and antibacterial activity were also evaluated . The results indicated that S3, S5 and S6 caused an increased oxygen consumption in the presence of ADP (state III) or its absence (state IV), while all other compounds decreased those parameters at different degrees of inhibition . All the compounds decreased the respiratory control coefficient (RCC) . Loss of cell viability of peritoneal macrophages and the B16-F10 cell line was observed, L1 and S2.1 being more effective . S1, S2, S3, L1 and F1 compounds showed antibacterial activity at experimental concentrations.

Curr Med Res Opin, 2004 Nov, 20(11), 1769 - 76
How to improve current therapeutic standards in upper respiratory infections: value of fusafungine; German-Fattal M et al.; Despite guidelines and educational programs, systemic antibiotics and anti-inflammatory drugs are often inappropriately prescribed in upper respiratory tract infections (URTIs), although they are most often of viral origin, generally benign, and self-limiting with spontaneous recovery in more than 80% of cases . Reduced use of systemic antibiotics is crucial in the current context of concern about emerging antibiotic resistance and reducing unnecessary costs associated both with drug over-consumption and with the management of the consequences of antibiotic resistance . Local bacterial or viral infection of the airways induces an early inflammatory reaction . Although this inflammatory reaction has a beneficial effect in the capture and destruction of the pathogens, it can be responsible for deleterious tissue damage and vascular alterations leading to a self-perpetuating cycle of events . A wide array of medicines is available for symptomatic relief of URTIs: many of them are partially effective in reducing symptoms, but none is curative . Local administration of antibiotics and anti-inflammatory drugs allows drug delivery directly to the target site of infection and inflammation, i.e., the respiratory mucosa, thus enabling a higher concentration of the drug, which results in smaller doses to be given, decreased potential for systemic toxicity, fewer side effects, protection of other flora, and rapid relief . Fusafungine is a naturally occurring peptide antibiotic with anti-inflammatory properties, which selectively targets the tissue reaction and preserves the natural antibacterial and antiviral defences . It is indicated for topical use in nose and throat infections . A recent analysis of French general practitioners' (GPs) prescribing pattern in the field of URTIs has demonstrated that prescription of fusafungine has achieved what many educational programs have failed to do: a significant reduction in the 'real life' prescription of systemic antibiotics and antiinflammatory drugs, without the side effects of corticosteroids and vasoconstrictive agents, and without impact on microbial ecology.

J Eukaryot Microbiol, 2004 Sep-Oct, 51(5), 516 - 21
Ancient weapons for attack and defense: the pore-forming polypeptides of pathogenic enteric and free-living amoeboid protozoa; Leippe M et al.; Pore-forming polypeptides have been purified from several amoeboid protozoans that are well-known human pathogens . Obligate enteric parasites, such as Entamoeba histolytica, and free-living but potentially highly pathogenic species, such as Naegleria fowleri, contain these cytolytic molecules inside cytoplasmic granules . Comprehensive functional and structural studies have been conducted that include isolation of the proteins from their natural sources, monitoring of their biological activity towards different targets, and molecular cloning of the genes of their precursors . In the case of the most prominent member of the protein family, with respect to protozoans, the three-dimensional structure of amoebapore A was solved recently . The amoebic pore-forming polypeptides can rapidly perforate human cells . The antibacterial activity of amoebapores and of related polypetides from free-living protozoa points to a more vital function of these molecules: inside the digestive vacuoles they combat growth of phagocytosed bacteria which are killed when their cytoplasmic membranes are permeabilized . The concommitant activity of these proteins towards host cells may be due to a coincidental selection for an efficient effector molecule . Nonetheless, several lines of evidence indicate that these factors are involved in pathogenesis of fatal diseases induced by amoeboid protozoa.

Biochim Biophys Acta, 2004 Nov 18, 1675 1-3, 54 - 61
Structural and serological characterization of the major glycolipid from Rothia mucilaginosa; Pasciak M et al.; Structural studies on the major glycolipid isolated from Rothia mucilaginosa were carried out utilising specific chemical degradation, NMR spectroscopy and matrix-assisted laser-desorption/ionization time of flight mass spectrometry (MALDI TOF-MS) . The glycolipid was found to be a dimannosylacylmonoglyceride in which the carbohydrate part was the glycerol-linked dimannoside alpha-D-Manp-(1-->3)-alpha-D-Manp-(1-->3)-sn-Gro (Man A-Man B-Gro), of which Man B was esterified at O-6 by a fatty acid residue . A second fatty acid substituted the secondary methylene position of the glycerol residue, in contrast to the glycolipid previously found in R . dentocariosa and Saccharopolyspora strains, in which the second fatty acid esterified the primary methylene position of glycerol . Results of the ELISA experiment with rabbit specific antibacterial sera indicate that these two major glycolipids are antigenic, and the patterns of serological reactivity are similar but not identical.

Jpn J Antibiot, 2004 Aug, 57(4), 404 - 12
{Effect of pazufloxacin mesilate, a new quinolone antibacterial agent, for intravenous use on QT interval}; Fukuda H et al.; The potential for QT interval prolongation of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, was investigated by in vitro and in vivo electrophysiology studies . Following results were obtained . In vitro electrophysiology study using guinea pig papillary muscles: PZFX mesilate (30-300 microM) had no effects on resting membrane potential (RMP), action potential amplitude (APA) and action potential duration (APD) . Reference quinolones, sparfloxacin (3-30 microM) and moxifloxacin (10-100 microM), had no effects on RMP and APA, but significantly prolonged APD at more than 3 and 10 microM, respectively, while ciprofloxacin (10-100 microM) had no effect on each parameter . In vivo electrophysiology study using anesthetized dogs: PZFX mesilate had no effects on electrocardiograph parameter (PR interval, QRS interval, QT interval and QTc) after intravenous administration of 3-30 mg/kg . These results suggest that PZFX mesilate has low potential for QT interval prolongation.

Ir Med J, 2004 Sep, 97(8), 234 - 6
Prescription patterns in the elderly population--"new" versus "old" medical card holders; Usher C et al.; INTRODUCTION: In July 2001, the GMS Scheme was extended to the whole elderly population aged 70 and over, permitting access to medical care services free of charge . We undertook a study to compare prescribing patterns between those relatively affluent people referred to as "new" over 70s with those relatively deprived people referred to as "old" over 70's, over the 18 months since the introduction of the scheme . Patients who had received a prescription for antibacterials, diuretics, psycholeptics, psychoanaleptics, statins, b-blockers, antithrombolytics, antianaemic drugs and drugs for obstructive airway diseases, were identified over the 18 month period using the GMS database . We also compared the average defined daily dose (DDD) received per month for each of the therapies above . RESULTS: All therapies directed at treatment were significantly more likely to be prescribed to the old over 70's, such as the vasodilators (OR=1.59, 1.51-1.67), peptic ulcer drugs (OR=1.37, 1.33-1.43) and the antibacterials (OR=1.37, 1.33-1.41) with the exception of those associated with cardiovascular prevention; statins (OR=0.88, 0.85-0.92), beta-blockers (OR=0.95, 0.92-0.98) and antithrombolytics (OR=0.96, 0.93-0.99) . The old over 70's received more prescriptions with a higher than the average DDD per month for vasodilators, diuretics, and drugs for obstructive airway disease . This study highlights a potential inequality in prescribing in primary care, evident following a change in the health policy in Ireland . These results suggest that differences in socio-economic status (such as income) and morbidity may be associated with differences in prescribing by GPs.

Bioorg Chem, 2004 Dec, 32(6), 483 - 93
1-Deoxy-D-xylulose 5-phosphate reductoisomerase: an overview; Proteau PJ; The methylerythritol phosphate pathway to isoprenoids, an alternate biosynthetic route present in many bacteria, algae, plants, and the malarial parasite Plasmodium falciparum, has become an attractive target for the development of new antimalarial and antibacterial compounds . The second enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR; EC 1.1.1.267), has been shown to be the molecular target for fosmidomycin, a promising antimalarial drug . This enzyme converts 1-deoxy-D-xylulose 5-phosphate (DXP) into the branched compound 2-C-methyl-D-erythritol 4-phosphate (MEP) . The transformation of DXP into MEP requires an isomerization, followed by a NADPH-dependent reduction . The discovery of DXR, its subsequent characterization, and the identification of inhibitors will be presented.

Clin Chim Acta, 2004 Dec, 350(1-2), 195 - 200
Association of interleukin-8 with inflammatory and innate immune components in bronchoalveolar lavage of children with chronic respiratory diseases; Babu PB et al.; BACKGROUND: The host inflammatory response and innate immunity play a complex role in respiratory diseases . METHODS: We evaluated the levels of inflammatory mediators and antibacterial proteins in children who required bronchoscopy and bronchoalveolar lavage fluid (BALF) for clinical indications such as chronic tracheostomy (n=15) and chronic suppurative lung disease (n=8) . RESULTS: Our results suggested the presence of interleukin-1beta (IL-1beta) and IL-8 as major inflammatory mediators in BALF samples . The level of the antibacterial protein sIgA was higher than lactoferrin and lysozyme . BALF IL-8 levels significantly correlated with the presence of IL-1beta, IL-6, IL-10, IL-16, sIgA and lysozyme . BALF IL-8 levels did not correlate with the levels of immunomodulatory and anti-inflammatory clara cell 10 kDa protein (CC10) or lactoferrin . CONCLUSION: This study suggests that patients with high levels of BALF IL-8 could potentially have high levels of IL-6, IL-10, IL-16, lysozyme and sIgA . Evaluating the inflammatory mediators (IL-8) in relation to other BALF protein components provides insight into understanding the role of inflammatory mediators in the regulation of host defense and the response to lung inflammation and injury.

Biochemistry (Mosc), 2004 Oct, 69(10), 1082 - 91
Antibacterial proline-rich oligopeptides and their target proteins; Markossian KA et al.; This review presents findings on a new family of antibacterial proline-rich oligopeptides--pyrrhocoricin, drosocin, apidaecin, and formaecin--isolated from insects . The functional and physicochemical properties of proline-rich oligopeptides are considered, a role of proline in their antibacterial activity is discussed, and experimental evidence is given in favor of the ability of these oligopeptides to suppress metabolism of bacteria by means of stereospecific interaction with heat shock protein DnaK and inhibition of DnaK-dependent protein folding . Binding of the peptides under investigation with DnaK correlates with their antibacterial activity . Evidence that pyrrhocoricin, drosocin, apidaecin, and formaecin are nontoxic for human and animal cells serves as a prerequisite for their use as novel antibiotic drugs.

Chemotherapy, 2004 Nov, 50(5), 211 - 3 Epub 2004 Nov.
Action of fluoroquinolones and Linezolid on logarithmic- and stationary-phase culture of Mycobacterium tuberculosis; Garcia-Tapia A et al.; BACKGROUND: The new challenges involved in the chemotherapy of tuberculosis make it necessary to find novel drugs, especially ones that are useful in the latent phase of the disease . METHODS: We evaluated the activity of linezolid and fluoroquinolones against logarithmic- and stationary-phase Mycobacterium tuberculosis . RESULTS: We observed that linezolid exhibits antibacterial action, although slowly, in both situations . Quinolones with an 8-methoxy group exhibit greater activity than levofloxacin in logarithmic growth phases, whereas levofloxacin exhibits greater activity in stationary-phase growth . CONCLUSION: The study of the activity of drugs against the M . tuberculosis microorganism in the latent phase is one of the most important tools available in the fight against the tuberculosis epidemic, and both linezolid and the new fluoroquinolones appear to be promising drugs.

Clin Microbiol Infect, 2004 Nov, 10 Suppl 4, 32 - 6
Antibacterial drug discovery: is small pharma the solution?
Boggs AF, Miller GH.
Although antibacterial research has declined in many larger pharmaceutical companies, small companies have begun to fill in the gap . Antibacterial discovery research is currently being conducted in at least 35 small companies . One successful approach taken by small pharma has been to continue clinical programmes that were abandoned by large companies . Issues surrounding these activities, as well as proposed changes, are outlined.

Clin Microbiol Infect, 2004 Nov, 10 Suppl 4, 18 - 22
Antibacterial drug discovery: is it all downhill from here?
Projan SJ, Shlaes DM.
There has been a marked decline in the industrial research aimed at discovering novel antibacterial agents, including new drugs that target resistant organisms . While this decline may reflect past cyclical changes that often affect resource allocation at pharmaceutical companies, this decline is occurring at a time of increasing levels of antibacterial drug resistance and meagre pipelines of new agents that are active against them . There are multiple reasons for this decline, although few are unique to antibacterial drug discovery research . These include: lack of industry productivity, increasing size of clinical trials, increased generic competition and other pressures on drug pricing, a crowded and confused marketplace and industry consolidation . And while many (if not most) large companies and biotechs have exited the field or severely curtailed their research, others have made it a point to continue their efforts, citing both the unmet medical need and a large and apparently growing market . Despite the fact that some companies have remained engaged, the view here is that the current level of industrial effort is insufficient to sustain a healthy flow of new and better agents that are needed to counter the imminent threat of bacterial drug resistance . Therefore, a clear and urgent need for finding ways to improve the level and quality of industrial research in this area is apparent.

Clin Microbiol Infect, 2004 Nov, 10 Suppl 4, 10 - 7
Antibacterial drug discovery in the 21st century; Bush K; Antibacterial research over the past 50 years has been focused on meeting medical needs caused by infectious, life-threatening pathogens . In spite of the introduction of a variety of antibacterial agents in multiple unrelated drug classes, resistance continues to emerge . The pharmaceutical industry must respond to these clinical challenges by bringing forward a stream of new agents with antibacterial activity against resistant bacteria . Although the projected growth of the anti-infective area may not be as large as for some therapeutic areas, development advantages for these agents include their higher predictability for success, well-defined biomarkers, shorter clinical trials, and shorter duration of therapy leading to fewer long-term safety concerns . Anti-infectives are still attractive commercially, representing the third largest therapeutic area in terms of worldwide sales of 45 bn dollars, with growth predicted at least through 2010, particularly for the hospital-related products . Finally, companies that conduct anti-infective research demonstrate their social responsibility by developing agents to treat patients with acute and potentially fatal illnesses.

Clin Microbiol Infect, 2004 Nov, 10(11), 984 - 9
Assessing the residual antibacterial activity of clinical materials disinfected with glutaraldehyde, o-phthalaldehyde, hydrogen peroxide or 2-bromo-2-nitro-1,3-propanediol by means of a bacterial toxicity assay; Lerones C et al.; This study investigated the use of a rapid bacterial toxicity test for detecting disinfectant residues released by disinfected materials . The test substances included an environmental disinfectant used in hospitals in high-risk areas, such as critical care units or emergency services, and three disinfectants used on clinical devices when a high level of disinfection is required . The test materials were polyurethane, polypropylene, glass, latex and cotton from different instruments and utensils used in hospitals . Of the four test disinfectants, o-phthalaldehyde (OPA) and 2-bromo-2-nitro-1,3-propanediol (BNP) showed the greatest inhibitory activity (as much as 300-fold greater than hydrogen peroxide in the case of OPA) according to the toxicity text . However, with the exception of hydrogen peroxide on latex, it was the most porous test materials, namely latex and cotton, that accumulated the least residue . BNP was the disinfectant that left the least residue on the five test materials, while the greatest residual concentration was left by hydrogen peroxide on latex (as much as 5 microg/cm2) . The biotest used in this study permitted the detection of disinfectant residues released by different types of previously disinfected clinical materials, and can be adapted to simulate elution conditions similar to those existing in routine hospital practice.

Indian J Med Res, 2004 Oct, 120(4), 398 - 417
Current trends in chemotherapy of tuberculosis; Jawahar MS; After treptomycin, which heralded the era of antibacterial chemotherapy for tuberculosis (TB), many important advances have made available treatment regimens that are almost 100 per cent curative . Randomised clinical trials by the Tuberculosis Research Centre, in Chennai and British Medical Research Council in East Africa and in the Far East have helped to establish many of the principles of antituberculosis chemotherapy . With successes have also come fresh challenges . Mycobacterium tuberculosis becomes rapidly resistant to the drugs used against it and in the last decade, the HIV epidemic has had an adverse impact on the global epidemiology of tuberculosis, with many countries in Sub-Saharan Africa experiencing a 2-3 fold increase in their TB burden . While the currently recommended treatment regimens are very effective, they have failed to control the burden of TB in the developing countries due to less than satisfactory implementation of the control programmes . Faced with the dual threat of multidrug resistant TB and the HIV/facilitated increase in TB, the WHO has instituted a Global TB Control Programme based on the directly observed treatment shortcourse (DOTS) strategy . Much of the principles of this strategy have come out of research in India . As part of this strategy, the Government of India is implementing a Revised National Tuberculosis Control Programme (RNTCP) . Under the RNTCP standardized treatment regimens are prescribed for different treatment categories . Already more than 80 per cent of the population is covered by this Programme and full coverage is slated for 2005 . Meanwhile, fresh research is ongoing to shorten treatment duration, a measure that should greatly aid TB control.

Carbohydr Res, 2004 Nov 15, 339(16), 2693 - 700
Preparation and antibacterial activity of chitosan nanoparticles; Qi L et al.; Chitosan nanoparticles, such as those prepared in this study, may exhibit potential antibacterial activity as their unique character . The purpose of this study was to evaluate the in vitro antibacterial activity of chitosan nanoparticles and copper-loaded nanoparticles against various microorganisms . Chitosan nanoparticles were prepared based on the ionic gelation of chitosan with tripolyphosphate anions . Copper ions were adsorbed onto the chitosan nanoparticles mainly by ion-exchange resins and surface chelation to form copper-loaded nanoparticles . The physicochemical properties of the nanoparticles were determined by size and zeta potential analysis, atomic force microscopy (AFM), FTIR analysis, and XRD pattern . The antibacterial activity of chitosan nanoparticles and copper-loaded nanoparticles against E . coli, S . choleraesuis, S . typhimurium, and S . aureus was evaluated by calculation of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) . Results show that chitosan nanoparticles and copper-loaded nanoparticles could inhibit the growth of various bacteria tested . Their MIC values were less than 0.25 microg/mL, and the MBC values of nanoparticles reached 1 microg/mL . AFM revealed that the exposure of S . choleraesuis to the chitosan nanoparticles led to the disruption of cell membranes and the leakage of cytoplasm.

J Am Soc Mass Spectrom, 2004 Nov, 15(11), 1593 - 603
Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry; Oehlers L et al.; Electrospray ionization mass spectrometry is used to compare the metal ion binding and metal-mediated DNA binding of benzoxazole (1, 2, 3, 4) and benzimidazole (5) compounds and to elucidate the putative binding modes and stoichiometries . The observed metal versus non-metal-mediated DNA binding, as well as the specificity of DNA binding, is correlated with the biological activities of the analogs . The ESI-MS spectra for the antibacterial benzoxazole and benzimidazole analogs 4 and 5 demonstrated non-specific and non-metal-mediated binding to DNA, with the appearance of DNA complexes containing multiple ligands . The anticancer analog 2 demonstrates a clear preference for metal-mediated DNA interactions, with an apparent selectivity for Ni2+ -mediated binding over the more physiologically relevant Mg2+ or Zn2+ cations . Complexation between DNA and the biologically inactive analog 1 was not observed, either in the absence or presence of metal cations.

Eur Respir J, 2004 Nov, 24(5), 834 - 8
Azithromycin for cystic fibrosis; Southern KW et al.; During what is a relatively barren time for new therapies for cystic fibrosis (CF), azithromycin has received a lot of attention as a potential treatment for CF lung disease . Laboratory studies suggest that azithromycin may have indirect actions, including anti-inflammatory, in addition to the standard antibacterial properties . The unique pharmacokinetics of azithromycin sets it aside from other macrolide antibiotics, but may result in increased resistance patterns . Three well-designed randomised controlled trials have demonstrated a small but significant improvement in respiratory function (forced expiratory volume in one second) with azithromycin compared with placebo . These trial results are confirmed by a recent meta-analysis . Mild adverse events (wheeze, diarrhoea and nausea) were significantly increased in one trial . There is no clear consensus regarding the correct dose and length of treatment with azithromycin . The present review discusses the role of azithromycin in the management of cystic fibrosis and the need for close monitoring of patients started on this drug . In addition, clinics should liaise closely with their microbiology departments and monitor resistance patterns.

J Antibiot (Tokyo), 2004 Aug, 57(8), 496 - 501
Laschiatrion, a new antifungal agent from a Favolaschia species (Basidiomycetes) active against human pathogens; Anke T et al.; Laschiatrion (1), a new antifungal antibiotic, was isolated from fermentations of Favolaschia sp . 87129 . (1) exhibits broad in vitro activity against several human pathogens while no antibacterial and cytotoxic activities could be detected . The structure was elucidated by spectroscopic techniques . As to our knowledge laschiatrion possesses a new steroid skeleton.

Presse Med, 2004 Aug 28, 33(14 Pt 1), 930 - 3
{Maternal pancytopenia during antenatal treatment of congenital toxoplasmosis}; Mubiayi N et al.; INTRODUCTION: The treatment of reference of congenital toxoplasmosis combines two folate synthesis inhibitors, pyrimethamine and an antibacterial sulfamide (sulfadiazine or sulfadoxine) . Despite the efficacy of this combination, the possibility of eventually severe side effects must also be taken into account . OBSERVATION: A pancytopenia occurred at 37 weeks of amenorrhea during antenatal treatment for congenital toxoplasmosis in a tripara . The outcome was positive following administration of strong doses of parenteral folinic acid combined with platelet transfusion and broad-spectrum antibiotics . DISCUSSION: Each of the molecules (pyrimethamine and antibacterial sulfamide) used for the treatment of congenital toxoplasmosis can lead to acute haematological problems . The occurrence of maternal pancytopenia however remains exceptional . It is principally related to pyrimethamine and is usually observed in the presence of factors enhancing folate deficiency.

J Ethnopharmacol, 2004 Dec, 95(2-3), 113 - 21
Assessing African medicinal plants for efficacy and safety: agricultural and storage practices; Fennell CW et al.; The paper reviews an important but little researched area of ethnopharmacology, namely, the effect of cultivation and post-harvest storage practices on levels of biological activity in traditionally used medicinal plants . Changes in COX-1 inhibition and antibacterial activity, for example, occur at the onset of senescence and, in some species, are influenced by plant age . Plants in cultivation were also shown to have reduced anthelmintic and antibacterial activity while hypoxoside production was affected by nitrogen and phosphorous . Irrigation treatments, however, increased anthelmintic activity and, therefore, could be applied to medicinal plants cultivated in low rainfall areas . Pesticides have also been implicated in the regulation of plant growth and secondary metabolite production in cultivated medicinal plants, but residue levels have, so far, not been monitored . Post harvest storage of medicinal plants has been poorly researched in southern Africa . Available data indicates that antibacterial and anti-inflammatory activity changes following storage and is both species and temperature dependent . Similar trends were noted for materials that had been rapidly aged . Fatty acids with antibacterial activity are stable in dry specimens and, as such, may account for the fact that activity is unaffected by storage in certain instances.

J Am Chem Soc, 2004 Nov 3, 126(43), 13998 - 4003
A chemoenzymatic approach to glycopeptide antibiotics; Lin H et al.; Many biologically active natural products are constrained by macrocyclization and modified with carbohydrates . These two types of modifications are essential for their biological activities . Here we report a chemoenzymatic approach to make carbohydrate-modified cyclic peptide antibiotics . Using a thioesterase domain from the decapeptide tyrocidine synthetase, 13 head-to-tail cyclized tyrocidine derivatives were obtained with one to three propargylglycines incorporated at positions 3-8 . These cyclic peptides were then conjugated to 21 azido sugars via copper(I)-catalyzed cycloaddition . Antibacterial and hemolytic assays showed that the two best glycopeptides, Tyc4PG-14 and Tyc4PG-15, have a 6-fold better therapeutic index than the natural tyrocidine . We believe this method will also be useful for modifying other natural products to search for new therapeutics.

Invest Ophthalmol Vis Sci, 2004 Nov, 45(11), 3997 - 4003
Expression of phospholipases A2 and C in human corneal epithelial cells; Landreville S et al.; PURPOSE: To achieve a better understanding of the involvement of phospholipases in the inflammation and wound-healing processes in human corneal epithelial cells (HCECs), expression of phospholipase A2s (PLA2s) and phospholipase Cs (PLCs) was examined in the human corneal epithelium . METHODS: Specific primers were designed for RT-PCR amplification of the known secreted (s)PLA2, cytosolic (c)PLA2, and PLC mRNAs . Corresponding PCR products were cloned and the DNA sequenced . Immunofluorescence of flatmounted corneal sections and Western blot analyses were used to detect the PLA2s and PLCs expressed by HCECs . RESULTS: The mRNAs for the following phospholipases were detected by RT-PCR in the HCECs: sPLA2GIII, -GX, and -GXIIA; cPLA2alpha and -gamma; PLCbeta1, -beta2, -beta3, -beta4, -gamma1, -gamma2, -delta1, -delta3, -delta4, and -epsilon . Immunofluorescence analyses conducted on corneal epithelium cryosections and Western blot on freshly isolated HCECs demonstrated the presence of sPLA2GIII, -GX, and -GXIIA; cPLA2alpha and -gamma; and PLCbeta2, -beta3, -gamma1, -gamma2, and -delta3 . CONCLUSIONS: Many phospholipase isoforms are expressed by HCECs and may play a major role in signal transduction (PLCs) as well as in the release of precursors of potent mediators of inflammation, such as leukotrienes and prostaglandins (PLA2s) . Moreover, the sPLA2s expressed by the corneal epithelium could be involved in the normal antibacterial activity in the tears and in wound healing.

Int Dent J, 2004 Oct, 54(5), 269 - 72
Cariology in Japanese dental schools; Fukushima M et al.; AIM: The aim of this study was to evaluate the teaching of cariology in Japanese dental schools . DESIGN: Postal questionnaires were sent to all Japanese dental schools . PARTICIPANTS: Twenty-five of the 29 Japanese dental schools (response rate: 86%) . RESULTS: The results were in many areas similar to those reported from North America . The non-surgical approach to the management of primary caries predominated, but no schools used bacteriological tests in caries diagnosis and only one school recommended antibacterial treatment . Four of the 25 responding schools advocated the treatment of primary enamel lesions by surgical intervention while three awaited operative intervention until the lesions had reached the middle third of the dentine . Recommendation of fluoride treatment was less common than in North America . The use of electronic devices to diagnose occlusal caries lesions was more common than in North America, but 'explorer catch' was the most frequently used method to diagnose primary and secondary caries in dental schools in both regions . CONCLUSION: Research in cariology over the years has led to altered views on how and when to treat caries lesions . The interpretation of research findings and the transfer of knowledge by teachers in dental schools have an impact on the practice of operative dentistry, but the diversity in the teaching of cariology indicates that the interpretation and implementation of modern principles in the treatment of caries differ quite markedly in Japanese dental schools.

Presse Med, 2004 Aug, 33(14-C1), 930 - 933
{Maternal pancytopenia during antenatal treatment of congenital toxoplasmosis.}; Mubiayi N et al.; Introduction The treatment of reference of congenital toxoplasmosis combines two folate synthesis inhibitors, pyrimethamine and an antibacterial sulfamide (sulfadiazine or sulfadoxine) . Despite the efficacy of this combination, the possibility of eventually severe side effects must also be taken into account . Observation A pancytopenia occurred at 37 weeks of amenorrhea during antenatal treatment for congenital toxoplasmosis in a tripara . The outcome was positive following administration of strong doses of parenteral folinic acid combined with platelet transfusion and broad-spectrum antibiotics . DISCUSSION: Each of the molecules (pyrimethamine and antibacterial sulfamide used for the treatment of congenital toxoplasmosis) can lead to acute haematological problems . The occurrence of maternal pancytopenia however remains exceptional . It is principally related to pyrimethamine and is usually observed in the presence of factors enhancing folate deficiency.

Eur J Med Chem, 2004 Nov, 39(11), 993 - 1000
Synthesis of prenylated benzaldehydes and their use in the synthesis of analogues of licochalcone A; Kromann H et al.; In this paper, a general applicable synthesis of prenylated aromatic compounds exemplified by prenylated benzaldehydes starting from readily available acetophenones is described . The synthesized benzaldehydes are used to prepare a number of novel analogues of Licochalcone A, a known antibacterial compound, and for the exploration of the pharmacophoric elements that are essential for the antibacterial activity . It is shown that the hydroxyl group in the A ring is essential for the activity and that the hydroxyl group in the B ring has no influence on the antibacterial effect of Licochalcone A . Furthermore, it is shown that the prenyl group at the position 5 of the B ring also has a dominating influence on the activity . This aliphatic group can be replaced by other lipophilic long chained substituents in order to maintain the activity.

Peptides, 2004 Nov, 25(11), 1849 - 55
Mammalian thioredoxin reductase alters cytolytic activity of an antibacterial peptide; Bjorkhem-Bergman L et al.; Granulysin is a disulfide rich 9 kDa human tumoricidal protein produced by cytolytic cells . Here we show that thioredoxin reductase (TrxR) reduced a 23-residue peptide from granulysin (GranF2), and this markedly enhanced the killing of small cell lung cancer cells (SCLC) by GranF2 . Cells treated with reduced GranF2 showed rapid ATP deletion within 90 min and strong annexin V staining after 4 h incubation . SCLC with elevated TrxR levels was more sensitive to oxidized GranF2 than normal cells . The levels of TrxR are enhanced in many cancer cells, including SCLC, and it is possible that cytolytic activity of cytolytic cells on SCLC may in part be mediated by granulysin and modulated by TrxR.

Phytochemistry, 2004 Nov, 65(21), 2867 - 79
4-Alkyl- and 4-phenylcoumarins from Mesua ferrea as promising multidrug resistant antibacterials; Verotta L et al.; Supercritical CO2 selectively extracted a series of 4-alkyl and 4-phenyl 5,7-dihydroxycoumarins from Mesua ferrea blossoms . Chemical modifications of the isolated compounds allowed us to confirm the structures elucidated by spectroscopic means and to prepare new derivatives amenable to SAR studies and potential pharmaceutical development . Biological investigations towards the screening on a number of bacteria strains and Plasmodium falciparum, identified compounds 1-9 as weak antiprotozoal agents and potent antibacterials on resistant Gram-positive strains.

J Vet Pharmacol Ther, 2004 Oct, 27(5), 317 - 20
Clinical efficacy of carprofen as an adjunct to the antibacterial treatment of bovine respiratory disease; Elitok B et al.; A clinical trial was undertaken to investigate the efficacy of a single dose of carprofen (CPF) in the treatment of bovine respiratory disease in cattle . Tilmicosin was used as a basal treatment in all animals . Six hours after dosing, body temperature and respiratory rates in animals treated with CPF-tilmicosin had decreased and were significantly lower than in the animals treated with tilmicosin alone (P < 0.05) . Over the period of clinical observation, CPF-tilmicosin treatment produced a clinical resolution of the pneumonia similar to treatment with tilmicosin alone . However, it is significant from an animal welfare perspective that over the period of the study after treatment, CPF-tilmicosin therapy produced significantly greater symptomatic improvement than tilmicosin.

Bioorg Med Chem, 2004 Nov 15, 12(22), 5909 - 15
Synthesis and antibacterial activity of oxazolidinones containing pyridine substituted with heteroaromatic ring; Jo YW et al.; A series of oxazolidinone derivatives, which morpholino group of linezolid was replaced with heteroaromatic ring substituted pyridine moiety, were newly synthesized, and their substituted effects on in vitro and in vivo antibacterial activities were evaluated against four problematic gram-positive strains including drug resistant strains and two gram-negative strains . Most compounds exhibited the enhanced in vitro activities with 4-16-fold and three compounds exerted more than 2-fold increased in vivo efficacies than linezolid.

J Nat Prod, 2004 Oct, 67(10), 1736 - 9
Hyrtiosenolides A and B, two new sesquiterpene gamma-methoxybutenolides and a new sterol from a Red Sea sponge Hyrtios species; Youssef DT et al.; Two new sesquiterpene gamma-methoxybutenolides, hyrtiosenolides A (1) and B (2), together with a new 4alpha-methyl polyoxygenated steroid, hyrtiosterol (3), were isolated from a Red Sea sponge, Hyrtios species . Their structures were elucidated by analysis of their 1D and 2D NMR spectra and HRFABMS . Compounds 1 and 2 showed weak antibacterial activity against Escherichia coli.

DNA Seq, 2004 Jun, 15(3), 188 - 95
Cloning and characterization of a new polyketide synthase gene cluster in Streptomyces aureofaciens CCM 3239; Novakova R et al.; We cloned a new polyketide gene cluster, aur2, in Streptomyces aureofaciens CCM3239 . Sequence analysis of the 9531-bp DNA fragment revealed 10 open reading frames, majority of which showed high similarity to the previously characterized type II polyketide synthase (PKS) genes . An unusual feature of the aur2 cluster is a disconnected organization of minimal PKS genes; ACP is located apart from the genes for ketosynthases KSalpha and KSbeta . The aur2 gene cluster was disrupted in S . aureofaciens CCM3239 by a homologous recombination, replacing the four genes (aur2A, E, F, G) including ketosynthase KSalpha, with antibiotic resistance marker gene . The disruption did not affect growth and differentiation, and disrupted strain produced spores with wild-type grey-pink pigmentation . The biochromatographic analysis of the culture extracts from S . aureofaciens wild type and aur2-disrupted strains did not reveal any difference in the pattern of antibacterial compounds.

Mol Cell, 2004 Oct 22, 16(2), 301 - 7
Structure of EthR in a ligand bound conformation reveals therapeutic perspectives against tuberculosis; Frenois F et al.; Mycobacterium tuberculosis EthR is a repressor of ethA, a gene encoding a mono-oxygenase required for the activation of the prodrug ethionamide . Here we describe the X-ray crystal structure of EthR, a homodimer with an entirely helical structure showing similarities to TetR family members . Each monomer contained a fortuitous ligand identified as hexadecyl octanoate . The crystal structure of EthR purified in M . smegmatis revealed the presence of a comparable ligand . The binding of hexadecyl octanoate to EthR induces a conformational state incompatible with repressor function, which should lead to ethA derepression and consequently to an increased sensitivity to ethionamide and other thioamides . A related, more hydrophilic ketone was found to exhibit synergistic antimycobacterial effects when tested together with ethionamide, indicating that this strategy may help reduce the dosage of potent antibacterial compounds that otherwise are too toxic to be used as first-line drugs.

J Invertebr Pathol, 2004 Sep, 87(1), 59 - 66
In vivo dynamics of an immune response in the bumble bee Bombus terrestris; Korner P et al.; Concepts from evolutionary ecology have recently been applied to questions of immune defences . However, an important but often neglected aspect is the temporal dynamics of the simple immune measures used in ecological studies . Here, we present observations for workers of the bumble bee Bombus terrestris on the dynamics of the phenoloxidase (PO) system, antibacterial activity, and the total number of haemocytes following a challenge with immune elicitors (LPS, Laminarin), over a time-span ranging from 1min to 14 days . The dynamics of the PO measurement showed a complex pattern and was correlated with haemocyte counts . Antibacterial activity, on the other hand, increased sharply between 2 and 24h post-challenge followed by a slow decrease . Surprisingly, the effects of a challenge lasted up to 14 days.

Biochemistry, 2004 Oct 26, 43(42), 13380 - 9
Role of inhibitor aliphatic chain in the thermodynamics of inhibitor binding to Escherichia coli enoyl-ACP reductase and the Phe203Leu mutant: a proposed mechanism for drug resistance; Protasevich II et al.; The antibacterial target enoyl-acyl carrier protein (ACP) reductase is a homotetrameric enzyme that catalyzes the last reductive step of fatty acid biosynthesis . In the present paper, four 2-(2-hydroxyphenoxy)phenol inhibitors, wherein the 4-position substituent varied from H to n-propyl, were studied to determine the contribution of the aliphatic chain to the binding to the wild-type (wt) enoyl-ACP reductase from Escherichia coli (FabI) and a drug-resistant mutant, (F203L)FabI, in which phenylalanine 203 is mutated to leucine . Thermodynamic parameters of ternary complex formation (enzyme-NAD(+)-inhibitor) were determined by isothermal titration calorimetry . The inhibitor affinity to wt FabI and (F203L)FabI increases with increasing aliphatic chain length, although the corresponding affinity for (F203L)FabI is lower, and also, it shows no detectable binding to the 4-H inhibitor . A distinguishing feature of inhibitor binding to either binary enzyme-NAD(+) complex is the apparent negative cooperativity for binding to the tetramer with half-site occupancy . For both enzymes, binding is enthalpy, DeltaH, driven . However, binding DeltaH becomes less favorable with increasing aliphatic chain length . Increases in affinity are found to be exclusively due to favorable changes in solvation entropy . Incremental changes in thermodynamic parameters within the series of inhibitors binding to wt FabI and (F203L)FabI are approximately the same . However, absolute differences between the two enzymes for binding to a given inhibitor are significant, suggesting different binding modes . This finding, coupled with a binding site conformation that is likely to be more rigid in the mutant, appears to result in the drug resistance of (F203L)FabI.

Chem Biol, 2004 Oct, 11(10), 1423 - 30
Multicopy suppressors for novel antibacterial compounds reveal targets and drug efflux susceptibility; Li X et al.; Gene dosage has frequently been exploited to select for genetic interactions between a particular mutant and clones from a random genomic library at high copy . We report here the first use of multicopy suppression as a forward genetic method to determine cellular targets and potential resistance mechanisms for novel antibacterial compounds identified through high-throughput screening . A screen of 8640 small molecules for growth inhibition of a hyperpermeable strain of Escherichia coli led to the identification of 49 leads for suppressor selection from clones harboring an E . coli genomic library . The majority of suppressors were found to encode the multidrug efflux pump AcrB, indicating that those compounds were substrates for efflux . Two leads, which produced clones containing the gene folA, encoding dihydrofolate reductase (DHFR), proved to target DHFR in vivo and were competitive inhibitors in vitro.

J Photochem Photobiol B, 2004 Oct 25, 76(1-3), 33 - 40
Molecular organization of the antifungal and anticancer drug 2-(2,4-dihydroxyphenylo)-5,6-dichlorobenzothiazole (dHBBT) in solution and in lipid membranes studied by means of electronic absorption spectroscopy; Gagos M et al.; 2-(2,4-Dihydroxyphenylo)-5,6-dichlorobenzthiazole (dHBBT) is a new drug from the group of chemical compounds characterized by documented antifungal, antibacterial, cytostatic as well as antitumour activity . Despite general knowledge regarding pharmacological importance of dHBBT its interaction to biomembranes has not been investigated . In this work, we present the electronic absorption spectroscopic study on molecular organization of dHBBT in organic solvents and on its localization and molecular organization within model lipid membranes formed with dipalmitoylphosphatidylcholine (DPPC) . The spectroscopic measurements are interpreted within the framework of the exciton splitting theory . It is concluded that complex absorption spectrum of dHBBT both in the organic solvents and incorporated to DPPC represents superposition of two spectral forms: representing monomers and hypsochromically shifted spectrum representing molecular dimers . Analysis of the temperature dependencies of the absorption spectra of dHBBT incorporated to DPPC liposomes suggests localization of the drug in the polar head-group region of the membrane or in the region of the polar-nonpolar interface . Linear dichroism measurements of dHBBT incorporated to DPPC multibilayers reveal roughly vertical orientation of the drug molecules with respect to the plane of the membrane . A model is presented of molecular organization of dHBBT in lipid membranes . Potential effects of dHBBT on membrane physical properties is briefly discussed.

Int J Pharm, 2004 Nov 5, 285(1-2), 1 - 11
Spectroscopic features of radiolytic intermediates induced in gamma irradiated sulfatiazole: an ESR study; Colak S et al.; Sulfonamides are used as active ingredients in different drugs to treat infections caused by bacteria . Sulfatiazole (STZ) is one of the commonly used sulfonamides as antibacterial agent in drugs, which constitute potential candidates for radiosterilization . However, the crucial point in this respect is to monitor the amount and characteristic features of the radiolytic intermediates produced after irradiation . Electron spin resonance (ESR) spectroscopy is extensively used for this purpose due to its high sensitivity toward intermediates exhibiting radicalic nature . Thus, the aim of the present work is to investigate the spectroscopic and kinetic features of the species having unpaired electrons induced in gamma irradiated STZ at room and different temperatures in the dose range of 5-50kGy using ESR spectroscopy . Spectra of irradiated STZ consisted of many resonance peaks in the studied dose and temperature ranges . Heights of the peaks measured with respect to the base line were used to monitor microwave, temperature, time-dependent features of the radical species contributing to the experimental ESR spectra . Four tentative species of different spectroscopic and structural features assigned as A, B, C and D were found well explaining the experimental ESR spectra of gamma irradiated STZ . Comparison between the principal IR bands of unirradiated and gamma irradiated samples showed no detectable changes and appearance of new bands . copyright 2004 Elsevier B.V.

Environ Sci Technol, 2004 Sep 15, 38(18), 4849 - 55
Analysis of triclocarban in aquatic samples by liquid chromatography electrospray ionization mass spectrometry; Halden RU et al.; Triclocarban, N-(4-chlorophenyl)-N'-(3,4-dichlorophenyl)urea, is a polychlorinated phenyl urea pesticide, marketed under the trademark TCC and used primarily as an antibacterial additive in personal care products . Despite its extensive use over several decades, environmental occurrence data on TCC are scarce . This is due in part to a lack of analytical techniques offering the desired sensitivity, selectivity, affordability, and ease of use . This need is addressed here by introducing a liquid chromatography electrospray ionization mass spectrometry (LC/ESI/MS) method allowing for the determination of TCC concentrations in aquatic environments at the ng/L level . TCC was concentrated from aqueous samples by solid-phase extraction, separated from interferences on a C18 column by either isocratic or gradient elution, and detected and identified in negative ESI mode by selectively monitoring the (M - H)- base peak (m/z 313) and its 37Cl-containing isotopes (m/z 315, 317) that served as reference ions . Particulates contained in aquatic samples were extracted and analyzed separately . Accurate quantification was achieved using stable isotopes of TCC and triclosan as internal standards . Addition of 10 mM acetic acid to the mobile phase yielded acetic acid adducts ({M - H + 60}-) that were successfully exploited to boost method sensitivity and selectivity, especially when analyzing challenging environmental matrixes . Method detection limits were matrix dependent, ranging from 3 to 50 ng/L . In 36 grab samples obtained from the Greater Baltimore area, TCC was detected in river water and wastewater at concentrations of up to 5600 and 6750 ng/L, respectively . Raw and finished drinking water did not contain detectable quantities of the pesticide (<3 ng/L) . In conclusion, the new LC/ESI/MS method was applied successfully to collect environmental occurrence data on TCC in U.S . water resources . Study results suggest that the bacteriostat and pesticide is a frequent but currently underreported contaminant whose environmental fate and behavior deserve further scrutiny.

Bioorg Med Chem Lett, 2004 Nov 15, 14(22), 5667 - 72
Myxopyronin B analogs as inhibitors of RNA polymerase, synthesis and biological evaluation; Doundoulakis T et al.; A series of myxopyronin B analogs has been prepared via a convergent synthetic route and were tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against E . coli and S . aureus . The parent lead compound proved to be very sensitive to even small changes . Only the achiral desmethyl myxopyronin B (1a) provided enhanced potency.

Bioorg Med Chem Lett, 2004 Nov 15, 14(22), 5573 - 7
Nocathiacin I analogues: synthesis, in vitro and in vivo biological activity of novel semi-synthetic thiazolyl peptide antibiotics; Naidu BN et al.; Several nocathiacin I analogues (4-35) were synthesized and evaluated for their antibacterial activity . Most of these semi-synthetic analogues retained very good in vitro and in vivo antibacterial activity of 1.

Bioorg Med Chem Lett, 2004 Nov 15, 14(22), 5569 - 72
Aryl urea analogs with broad-spectrum antibacterial activity; Seth PP et al.; The preparation and evaluation of novel aryl urea analogs as broad-spectrum antibacterial agents is described . Numerous compounds showed low micromolar minimum inhibitory concentrations (MIC) against both Gram-positive and Gram-negative bacteria . Selected analogs also exhibited in vivo efficacy in a lethal murine model of bacterial septicemia.

Expert Rev Anti Infect Ther, 2004 Feb, 2(1), 61 - 72
Can virulence factors be viable antibacterial targets?
Marra A.
There is a real crisis in healthcare with the emergence of bacterial pathogens resistant to multiple drugs . The drug discovery industry is faced with the challenge of developing new classes of antibiotics that are effective against resistant organisms . Targeting bacterial virulence is one approach that has yet to be fully exploited, and the last decade or so has seen the development of reagents, screens and approaches that could make this possible . Several processes utilized by bacteria to cause infection are employed in a wide range of pathogens and as such may make attractive targets . Inhibitors of such targets would be unlikely to affect host cells, be cross-resistant to existing therapies and induce resistance themselves.

Zh Mikrobiol Epidemiol Immunobiol, 2004 Jul-Aug, (4), 46 - 50
{Risk factors of Pseudomonas infection in hemoblastosis patients}; Polygalae radix extract protects cultured rat granule cells against damage induced by NMDA; College of Veterinary Medicine and Research Institute of Veterinary Medicine Chungbuk National University, Cheongju, Chungbuk, 361-763, KoreaPolygalae Radix (PR) from Polygala tenuifolia (Polygalaceae) is traditionally used in China and Korea, as this herb has a sedative, anti-inflammatory and antibacterial agent . To extend our understanding of the pharmacological actions of PR in the CNS on the basis of its CNS inhibitory effect, the present study examined whether PR has the neuroprotective action against N-methyl-D-aspartate (NMDA)-induced cell death in primarily cultured rat cerebellar granule neurons . PR, over a concentration range of 0.05 to 5 microg/ml, inhibited NMDA (1 mM)-induced neuronal cell death, which was measured by a trypan blue exclusion test and a 3-{4,5-dimethylthiazol-2-yl}-2,5-diphenyl-tetrazolium bromide (MTT) assay . PR (0.5 microg/ml) inhibited glutamate release into medium induced by NMDA (1 mM), which was measured by HPLC . Pre-treatment of PR (0.5 microg/ml) inhibited NMDA (1 mM)-induced elevation of intracellular Ca2+ concentration ({Ca2+}i), which was measured by a fluorescent dye, Fura 2-AM, and generation of reactive oxygen species (ROS) . These results suggest that PR prevents NMDA-induced neuronal cell damage in vitro.

Evid Based Complement Alternat Med, 2004 Sep 1, 1(2), 133 - 144
Traditional and Modern Biomedical Prospecting: Part II-the Benefits: Approaches for a Sustainable Exploitation of Biodiversity (Secondary Metabolites and Biomaterials from Sponges); Muller WE et al.; The progress in molecular and cell biology has enabled a rational exploitation of the natural resources of the secondary metabolites and biomaterials from sponges (phylum Porifera) . It could be established that these natural substances are superior for biomedical application to those obtained by the traditional combinatorial chemical approach . It is now established that the basic structural and functional elements are highly conserved from sponges to the crown taxa within the Protostomia (Drosophila melanogaster and Caenorhabditis elegans) and Deuterostomia (human); therefore, it is obvious that the molecular etiology of diseases within the metazoan animals have a common basis . Hence, the major challenge for scientists studying natural product chemistry is to elucidate the target(s) of a given secondary metabolite, which is per se highly active and selective . After this step, the potential clinical application can be approached . The potential value of some selected secondary metabolites, all obtained from sponges and their associated microorganisms, is highlighted . Examples of compounds that are already in medical use (inhibition of tumor/virus growth {arabinofuranosyl cytosine and arabinofuranosyl adenine}), or are being considered as lead structures (acting as cytostatic and anti-inflammatory secondary metabolites {avarol/avarone}, causing induction of apoptosis {sorbicillactone}) or as prototypes for the interference with metabolic pathways common in organisms ranging from sponges to humans (modulation of pathways activated by fungal components {aeroplysinin}, inhibition of angiogenesis {2-methylthio-1,4-napthoquinone}, immune modulating activity {FK506}) are discussed in this study . In addition, bioactive proteins from sponges are listed (antibacterial activity {pore-forming protein and tachylectin}) . Finally, it is outlined that the skeletal elements-the spicules-serve as blueprints for new biomaterials, especially those based on biosilica, which might be applied in biomedicine . These compounds and biomaterials have been isolated/studied by members of the German Center of Excellence BIOTECmarin . The goal for the future is to successfully introduce some of these compounds in the treatment of human diseases in order to raise the public awareness on the richness and diversity of natural products, which should be sustainably exploited for human benefit.

Gut, 2004 Nov, 53(11), 1658 - 64
NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression; Wehkamp J et al.; BACKGROUND: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear . Human alpha defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum . Paneth cells also express NOD2 . To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease . METHODS: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied . Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor alpha, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene) . Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes . RESULTS: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations . In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients . In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status . Immunohistochemistry identified Paneth cells as the sole source of HD-5 . CONCLUSION: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.

J Appl Microbiol, 2004, 97(5), 1063 - 8
Induction of the mar operon by miscellaneous groceries; Rickard AH et al.; AIM: To investigate the potential of non-antibacterial consumer products to act as inducers of the multiple antibiotic resistance (mar) operon of Escherichia coli SPC105 . METHODS AND RESULTS: Wells were cut into chemically defined agar medium (CDM) contained within Petri dishes . Molten agar slurries were prepared by mixing known quantities of 35 consumer products with molten CDM and these were pipetted into each well . Plates were overlaid with molten CDM (5 ml), containing 40 microg ml(-1) X-gal and approx . 1000 CFU ml(-1) of an overnight culture of E . coli SPC105 containing a chromosomal marOII::lacZ fusion . After incubation (37 degrees C, 24 h), plates were examined for zones of growth inhibition and the presence of a blue coloration, indicative of mar (marOII::lacZ) induction . Of the 35 products tested (nine herbs and spices, 19 food and drinks and seven household products), 24 (69%) of the items produced inhibitory zones and 22 (63%) of the items induced mar expression . Apple puree was inhibitory but did not induce marOII::lacZ . Mustard, chilli and garlic were shown to be powerful inducers of marOII::lacZ . Overall six products were shown to be powerful marOII::lacZ inducers . None of these made hygiene claims . CONCLUSIONS: In addition to induction by specific biocides and antibiotics, mar is induced by the exposure of bacteria to natural substances, many of which are common to a domiciliary setting . SIGNIFICANCE AND IMPACT OF THE STUDY: Concern that the overuse of antibacterials within consumer products might select for mar-mediated resistance is shortsighted and fails to recognize the ubiquity of inducers in our environment.

Phytother Res, 2004 Sep, 18(9), 777 - 9
Antibacterial and antifungal activity of Senecio inaequidens DC . and Senecio vulgaris L; Loizzo MR et al.; The antibacterial and antifungal activities of methanol extract, ethyl acetate, dichloromethane, n-hexane, n-butanol and chloroform fractions of Senecio inaequidens DC . and Senecio vulgaris L . were assayed . The hexane extract of Senecio vulgaris L . (MIC 0.031 mg/ml) showed significant activity against Trichophyton tonsurans . Copyright (c) 2004 John Wiley & Sons, Ltd.

Khirurgiia (Mosk), 2004, (10), 54 - 8
{Prophylaxis of wound infection with immobilized antibacterial drugs}; Effect of lattice constant of zinc oxide on antibacterial characteristics; Research Institute of Materials and Resources, Faculty of Engineering and Resource Science, Akita University, 1-1 Tegata Gakuen, Akita 010-8502, Japan . yamamoto@rimr.akita-u.ac.jpZinc oxide powders were heated in different atmospheres at 800 and 1400 degrees C, of which the characterization and the antibacterial activity were studied by X-ray diffractometry and the measurement of the change in electrical conductivity with bacterial growth . The diffraction peaks corresponding to zinc oxide with hexagonal type structure were detected in all samples, which shifted in low-angle side with the increase in the oxidizability of atmosphere during heat-treatment . From the results of calculating lattice constants, a0 and c0, it was found that the value of c0 in hexagonal structure increased with the increase in the oxidizability of atmosphere . On the samples heated at 1400 degrees C, the changes of the c0 value were less than those at 800 degrees C . However, no change of the a0 value showed, irrespective of atmosphere and temperature . Hydrogen peroxide that contributes to the occurrence of antibacterial activity was found to generate from all samples, and the generation amount increased with the increase of c0 value; incidently the amount in the samples heated at 1400 degrees C was less than that at 800 degrees C . The antibacterial activity of zinc oxide increased with the increase of c0 value; that is, it was found that the value of c0 in crystal structure affected the antibacterial activity of zinc oxide.

Phytother Res, 2004 Aug, 18(8), 640 - 6
Oxygen activation by photoexcited protoberberinium alkaloids from Mahonia aquifolium; Brezova V et al.; Protoberberinium salts, i.e . berberine (I), palmatine (II) and jatrorrhizine (III) prepared from Mahonia aquifolium (Pursh) Nutt . belong to isoquinoline alkaloids possessing interesting biological activity (e.g . antibacterial, antimalarial, antitumor) . The characteristic UV/Vis absorption band maxima of I-III iodide salts were found in regions 350 and 425 nm in dimethylsulfoxide (DMSO) and ethanol solvents, and were only negligibly influenced by substitution changes on the C-2 and C-3 positions . The fluorescence intensity of protoberberinium salts monitored in ethanol solutions was significantly lowered by iodide counter-ions, and decreased in the order berberine > palmatine > jatrorrhizine . EPR spectroscopy supplied evidence of the formation of super-oxide anion radicals and singlet oxygen upon irradiation of berberine in oxygenated DMSO solvent . The photochemical generation of O(2) (.-) and (1)O(2) in DMSO solutions of palmatine and jatrorrhizine was substantially lower, and probably reflected the replacement of a photolabile methylenedioxy group at C-2 and C-3 positions in the berberine molecule by two methoxy groups in palmatine, and methoxyl (C-2) and hydroxyl (C-3) substitution in jatrorrhizine . Additionally, the powder EPR spectra of protoberberinium iodides I-III measured at 290 K revealed the presence of single-line EPR signals (g(eff) = 2.0044), which were attributed to hydroperoxidic structures produced by the autoxidation process . The photochemical reactions of protoberbenium salts producing reactive oxygen species after UVA excitation should be integrated in biological activity investigations, as well as in their applications in skin disorder treatment . Copyright (c) 2004 John Wiley & Sons, Ltd.

J Hosp Infect, 2004 Oct, 58(2), 115 - 21
Comparison of two in vivo and two ex vivo tests to assess the antibacterial activity of several antiseptics; Messager S et al.; An ex vivo test was adapted to mimic the in vivo conditions of testing antiseptic activity on human forearms and in the European Standard Hygienic Handwash Test (BSEN 1499) . The study was to validate the ex vivo protocols using 4.8% (w/v) para-chloro-meta-xylenol (PCMX, neat Dettol), 0.5% (w/v) triclosan in 70% (v/v) isopropanol, and 2% (v/v) povidone-iodine against a high bacterial inoculum (>10(8) cfu/mL) of Escherichia coli NCTC 10538 . Two ex vivo tests using human skin samples, including one introducing a mechanical rubbing effect, were compared with two corresponding in vivo tests (the forearm test and the BSEN handwashing test) . All antiseptics assessed in vivo (forearm and handwash tests) produced reductions in bacterial counts that were significantly greater than those for the non-medicated soft soap control . When assessed ex vivo without rubbing, only PCMX and povidone-iodine achieved reductions significantly greater than soft soap . When assessed ex vivo with mechanical rubbing, only PCMX and triclosan achieved reductions significantly greater than soft soap . Overall, the antiseptics at the concentrations tested were more active when tested in vivo than ex vivo . The addition of a mechanical effect, either in vivo by the volunteers washing their hands or ex vivo by a drill rubbing two skin samples against each other, produced a significantly greater reduction in bacterial concentrations . The ex vivo tests were easily adapted to mimic in vivo protocols . The value of such tests, particularly the one that includes a rubbing effect, may be significant as they avoid the need for human volunteers.

Biochem J . 2004 Oct 11; {Epub ahead of print}
Isoprenoid biosynthesis as target for antibacterial and antiparasitic drugs: phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto-isomerase; Kuntz L et al.; Isoprenoid biosynthesis via the methylerythritol phosphate pathway is a target against pathogenic bacteria and the malaria parasite Plasmodium falciparum . 4-(Hydroxyamino)-4-oxobutylphosphonic acid and 4-{hydroxy(methyl)amino}-4-oxobutyl phosphonic acid, two novel inhibitors of the deoxyxylulose phosphate reducto-isomerase (DXR), the second enzyme of the pathway, have been synthesized and compared to fosmidomycin, the best known inhibitor of this enzyme . The latter phosphonohydroxamic acid showed a high inhibitory activity toward DXR, much like fosmidomycin, as well as significant antibacterial activity against Escherichia coli in tests on Petri dishes.

J Pept Sci, 2004 Sep, 10(9), 566 - 77
A 4.2 kDa synthetic peptide as a potential probe to evaluate the antibacterial activity of coumarin drugs; Scatigno AC et al.; The coumarin antibiotics are potent inhibitors of DNA replication whose target is the enzyme DNA gyrase, an ATP-dependent bacterial type II topoisomerase . The coumarin drugs inhibit gyrase action by competitive binding to the ATP-binding site of DNA gyrase B protein . The production of new biologically active products has stimulated additional studies on coumarin-gyrase interactions . In this regard, a 4.2 kDa peptide mimic of DNA gyrase B protein from Escherichia coli has been designed and synthesized . The peptide sequence includes the natural fragment 131-146 (coumarin resistance-determining region) and a segment containing the gyrase-DNA interaction region (positions 753-770) . The peptide mimic binds to novobiocin (Ka = 1.4+/-0.3 x 10(5) M(-1)), plasmid (Ka = 1.6+/-0.5 x 10(6) M(-1)) and ATP (Ka = 1.9+/-50.4 x 10(3) M(-1)), results previously found with the intact B protein . On the other hand, the binding to novobiocin was reduced when a mutation of Arg-136 to Leu-136 was introduced, a change previously found in the DNA gyrase B protein from several coumarin-resistant clinical isolates of Escherichia coli In contrast, the binding to plasmid and to ATP was not altered . These results suggest that synthetic peptides designed in a similar way to that described here could be used as mimics of DNA gyrase in studies which seek a better understanding of the ATP, as well as coumarin, binding to the gyrase and also the mechanism of action of this class of antibacterial drugs.

J Clin Microbiol, 2004 Oct, 42(10), 4828 - 31
First case of Arthrographis kalrae ethmoid sinusitis and ophthalmitis in the People's Republic of China; Xi L et al.; We present here the first case in the People's Republic of China of human disease caused by the fungus Arthrographis kalrae . The male patient had fungal panophthalmitis and invasive sinusitis involving the maxillary and ethmoid sinuses . He was an apparently healthy man before receiving trauma to his left eye . He complained of pain and loss of visual acuity in the injured eye, which displayed redness and edema and eventually discharged pus . His symptoms became more severe after he was treated with steroids and several antibacterial agents . A computed tomography scan of the left eye revealed that the maxillary and ethmoid sinuses were involved . A smear of purulent material from the left eye orbit revealed fungal elements, and cultures of the material grew a fungus . The isolate was identified as A . kalrae based on gross and microscopic morphologies, biochemical assays, and DNA sequence analysis . The patient received amphotericin B intravenously, itraconazole orally, and atomized allitridum by nebulizing allitridum therapy . The patient's wound healed following surgical intervention, but the patient lost the use of his left eye . This case should remind ophthalmologists and other clinicians to consider the possibility of infections being fungal when antibacterial agents have no effect and the patient's condition worsens.

J Clin Microbiol, 2004 Oct, 42(10), 4744 - 8
Detection of galactomannan antigenemia in patients receiving piperacillin-tazobactam and correlations between in vitro, in vivo, and clinical properties of the drug-antigen interaction; Walsh TJ et al.; Recent case reports describe patients receiving piperacillin-tazobactam who were found to have circulating galactomannan detected by the double sandwich enzyme-linked immunosorbent assay (ELISA) system, leading to the false presumption of invasive aspergillosis . Since this property of piperacillin-tazobactam and galactomannan ELISA is not well understood, we investigated the in vitro, in vivo, and clinical properties of this interaction . Among the 12 reconstituted antibiotics representing four classes of antibacterial compounds that are commonly used in immunocompromised patients, piperacillin-tazobactam expressed a distinctively high level of galactomannan antigen in vitro (P = 0.001) . After intravenous infusion of piperacillin-tazobactam into rabbits, the serum galactomannan index (GMI) in vivo changed significantly (P = 0.0007) from a preinfusion mean baseline value of 0.27 to a mean GMI of 0.83 by 30 min to slowly decline to a mean GMI of 0.44 24 h later . Repeated administration of piperacillin-tazobactam over 7 days resulted in accumulation of circulating galactomannan to a mean peak GMI of 1.31 and a nadir of 0.53 . Further studies revealed that the antigen reached a steady state by the third day of administration of piperacillin-tazobactam . Twenty-six hospitalized patients with no evidence of invasive aspergillosis who were receiving antibiotics and ten healthy blood bank donors were studied for expression of circulating galactomannan . Patients (n = 13) receiving piperacillin-tazobactam had significantly greater mean serum GMI values (0.74 +/- 0.14) compared to patients (n = 13) receiving other antibiotics (0.14 +/- 0.08) and compared to healthy blood bank donors (0.14 +/- 0.06) (P < 0.001) . Five (38.5%) of thirteen patients receiving piperacillin-tazobactam had serum GMI values > 0.5 compared to none of thirteen subjects receiving other antibiotics (P = 0.039) and to none of ten healthy blood bank donors (P = 0.046) . These data demonstrate that among antibiotics that are commonly used in immunocompromised patients, only piperacillin-tazobactam contains significant amounts of galactomannan antigen in vitro, that in animals receiving piperacillin-tazobactam circulating galactomannan antigen accumulates in vivo to significantly increased and sustained levels, and that some but not all patients receiving this antibiotic will demonstrate circulating galactomannan above the threshold considered positive for invasive aspergillosis by the recently licensed double sandwich ELISA.

Respiration, 2004 Sep-Oct, 71(5), 469 - 76
Low incidence of paradoxical bronchoconstriction with bronchodilator drugs administered by Respimat Soft Mist inhaler: results of phase II single-dose crossover studies; Koehler D et al.; BACKGROUND AND OBJECTIVES: Respimat Soft Mist Inhaler (SMI) is an innovative device that offers improved lung deposition and is an environmentally friendly alternative to conventional, chlorofluorocarbon-containing metered-dose inhalers (CFC-MDIs) . The aqueous formulations of bronchodilator drugs administered from Respimat SMI contain low concentrations of ethylene diamine tetra-acetic acid (EDTA), a stabilising agent, and benzalkonium chloride (BAC), an antibacterial agent, both of which have been associated with bronchoconstriction when administered via nebulisers . The aim of this retrospective analysis was to compare the incidence of paradoxical bronchoconstriction with bronchodilator drugs administered via Respimat SMI or a CFC-MDI in patients with asthma or chronic obstructive pulmonary disease (COPD) . METHODS: Nine randomised, active- and/or placebo-controlled, double-blind, crossover studies, in which asthmatic and COPD patients (n = 444 and n = 216, respectively) received a beta(2)-agonist and/or anticholinergic or placebo via Respimat SMI or CFC-MDI, were included in the analysis . The incidence of conditions indicative of paradoxical bronchoconstriction were collated and divided into four categories: (1) 'bronchospasm'; (2) two or more of the following events: 'other respiratory adverse events', 'rescue medication use' or 'asymptomatic drop in forced expiratory volume in one second' (FEV(1)); (3) either 'rescue medication use' or 'other respiratory adverse event'; (4) 'asymptomatic drop in FEV(1)' . RESULTS: The incidence of adverse events indicative of paradoxical bronchoconstriction was low in those patients using the Respimat SMI device, and similar to that seen in the CFC-MDI group . In addition, the incidence of adverse events indicative of paradoxical bronchoconstriction observed in the Respimat SMI group was similar for BAC + EDTA and BAC-only drug formulations . CONCLUSIONS: These studies demonstrate that, due to the extremely low absolute amounts of BAC and EDTA delivered to the lungs by the device, Respimat SMI is safe with regard to paradoxical bronchoconstriction in patients with asthma or COPD.

Biol Pharm Bull, 2004 Oct, 27(10), 1666 - 9
Biological activity of beta-dolabrin, gamma-thujaplicin, and 4-acetyltropolone, hinokitiol-related compounds; Morita Y et al.; Beta-dolabrin, gamma-thujaplicin, and 4-acetyltropolone, the components of Aomori Hiba (Thujopsis dolabrata SIEB . et ZUCC . var . hondai MAKINO), showed antifungal activity on seven kinds of plant-pathogenic fungi, antibacterial activity against two kinds of Legionella sp., and in vitro cytotoxic effect on murine P388 lymphocytic leukemia cell line . Firstly, beta-dolabrin, gamma-thujaplicin and 4-acetyltropolone had clear antifungal activity against seven kinds of plant-pathogenic fungi tested . In particular, beta-dolabrin and 4-acetyltropolone showed strong antifungal activity against Pythium aphanidermatum IFO 32440, with minimum inhibitory concentration (MIC) values of 6.0 microg/ml . Secondly, beta-dolabrin, gamma-thujaplicin and 4-acetyltropolone had obvious growth-inhibitory effect on two kinds of Legionella sp . 4-Acetyltropolone especially had strong antibacterial activity toward Legionella pneumophila SG 1, and its MIC value was 3.1 microg/ml . These three compounds showed cytotoxic effects against murine P388 lymphocytic leukemia cell line in vitro . The cytotoxic effect of three compounds in the murine P388 lymphocytic leukemia cell line were clear when cell growth was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method . At 48 h after treatment, gamma-thujaplicin and 4-acetyltropolone at 0.63 microg/ml inhibited cell growth of murine P388 lymphocytic leukemia by 85% and 65%, respectively . At the same time after treatment, the growth of the murine P388 lymphocytic leukemia cell line was completely suppressed by the three compounds at concentrations higher than 5.0 microg/ml . Among these three compounds, gamma-thujaplicin had the strongest cytotoxic activity on the growth of this tumor cell line in vitro.

Bioorg Med Chem, 2004 Nov 1, 12(21), 5571 - 8
Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship; Murias M et al.; Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is found in grapes and various medical plants . Among cytotoxic, antifungal, antibacterial cardioprotective activity resveratrol also demonstrates non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition . In order to find more selective COX-2 inhibitors a series of methoxylated and hydroxylated resveratrol derivatives were synthesized and evaluated for their ability to inhibit both enzymes using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production . Hydroxylated but not methoxylated resveratrol derivatives showed a high rate of inhibition . The most potent resveratrol compounds were 3,3',4',5-tetra-trans-hydroxystilbene (COX-1: IC(50)=4.713, COX-2: IC(50)=0.0113 microM, selectivity index=417.08) and 3,3',4,4',5,5'-hexa-hydroxy-trans-stilbene (COX-1: IC(50)=0.748, COX-2: IC(50)=0.00104 microM, selectivity index=719.23) . Their selectivity index was in part higher than celecoxib, a selective COX-2 inhibitor already established on the market (COX-1: IC(50)=19.026, COX-2: IC(50)=0.03482 microM, selectivity index=546.41) . Effect of structural parameters on COX-2 inhibition was evaluated by quantitative structure-activity relationship (QSAR) analysis and a high correlation was found with the topological surface area TPSA (r=0.93) . Docking studies on both COX-1 and COX-2 protein structures also revealed that hydroxylated but not methoxylated resveratrol analogues are able to bind to the previously identified binding sites of the enzymes . Hydroxylated resveratrol analogues therefore represent a novel class of highly selective COX-2 inhibitors and promising candidates for in vivo studies.

Bioorg Med Chem, 2004 Nov 1, 12(21), 5515 - 24
Synthesis and antibacterial activity of novel and potent DNA gyrase inhibitors with azole ring; Tanitame A et al.; The 4-piperidyl moiety and the pyrazole ring in 1-(3-chlorophenyl)-5-(4-phenoxyphenyl)-3-(4-piperidyl)pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, were transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated . The selected pyrazole, oxazole and imidazole derivatives showed moderate inhibition against DNA gyrase and topoisomerase IV with similar IC(50) values (IC(50)=9.4-25 microg/mL) . In addition, many of the pyrazole, oxazole and imidazole derivatives synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates and coumarin-resistant laboratory isolates of Gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.

Am J Pharmacogenomics, 2004, 4(5), 299 - 312
Microarray expression profiling reveals candidate genes for human uterine receptivity; Giudice LC; The endometrium undergoes cyclic changes in response to circulating ovarian steroid hormones as it prepares for implantation . This dynamic tissue is well suited to microarray expression profiling for elucidation of molecular players participating in the maturation of the endometrium and during the process of implantation . Recent advances in sequencing the human and mouse genomes and the availability of microarray technology and bioinformatic analyses have made elucidating these molecular participants and dialogs a reality . Analysis of the window of implantation, a temporal and spatially unique period in which the endometrium is receptive to embryonic implantation, has revealed numerous processes to be occurring simultaneously or sequentially . These include cell cycle regulation, angiogenesis, immune modulation of implantation, defense mechanisms put into place by antibacterial agents and detoxicants, secretion of unique products, transport of ions and water, growth factor actions, steroid hormone action and metabolism, and production of extracellular matrix proteins, unique cell surface glycoproteins, and a variety of transcription factors, to name a few . Several groups have recently conducted studies with human endometrium, and remarkable similarities exist with mouse . Also, many genes and gene families involved in the unique differentiation process of stromal cell decidualization are conserved . In addition, infertility associated with endometriosis is partly implantation-based, and gene profiling of such tissue during the window of implantation has revealed additional insight into mechanisms underlying infertility in this disorder . Global profiling of genes in the endometrium, decidua, and at the interface between the trophoblast and the decidua, has provided remarkable in sight into endometrial maturation and implantation.

Eksp Klin Gastroenterol, 2004, (2), 48 - 52, 109
{Dynamics of markers of blood inflammation against the background of antibacterial therapy in children with mucoviscidosis, with the various regimens of intake of pancreatic enzymes}
{Detection of antibiotics in cerebrospinal fluid}
{No authors listed}

The suggested method provides for the semi-quantitative detection of antibiotics in liquor made for the purpose of prognosticating the possibility of cultural secretion of infectious agents of purulent bacterial meningitis (PBM); it is also a basis for the need in using the non-cultural diagnostic tools . The method can be used in detecting the pharmacokinetic specificity of antibacterial drugs now in use and of their combinations with the aim of making corrections in antibiotic therapy . It is based on inhibiting the surface growth of test-culture by a liquor-dissolved antibiotic with the growth-delay zone being shaped . The preparation concentration is estimated in U/ml of the penicillin equivalent (PE) . Examinations of 131 liquor samples (primary puncture) obtained from patients with meningitis showed clear-cut correlations between the antibiotics' concentrations, cultural verification of the PBM diagnosis and the efficiency of non-cultural examinations . 82.14% of cultures were derived from liquor samples with the negative antibacterial activity (range 1); 7.14% of cultures were derived from liquor samples containing the antibacterial preparation of up to 0.5 U/ml PE (range 2); culture of secondary PBM agents (S . aureus) were isolated from liquor samples containing up to 10 U/ml PE (range 3); and no microbe agents were isolated from liquor samples containing above 10 U/ml PE (range 4) . The designed method, when used, demonstrated a high efficiency and significance of laboratory PBM diagnosis in presence of the antibacterial liquor efficiency.

Anim Health Res Rev, 2004 Jun, 5(1), 35 - 47
Recent pre-harvest supplementation strategies to reduce carriage and shedding of zoonotic enteric bacterial pathogens in food animals; Callaway TR et al.; Food-borne bacterial illnesses strike more than 76 million North Americans each year . Many of these illnesses are caused by animal-derived foodstuffs . Slaughter and processing plants do an outstanding job in reducing bacterial contamination after slaughter and during further processing, yet food-borne illnesses still occur at an unacceptable frequency . Thus, it is imperative to widen the window of action against pathogenic bacteria . Attacking pathogens on the farm or in the feedlot will improve food safety all the way to the consumer's fork . Because of the potential improvement in overall food safety that pre-harvest intervention strategies can provide, a broad range of preslaughter intervention strategies are currently under investigation . Potential interventions include direct anti-pathogen strategies, competitive enhancement strategies and animal management strategies . Included in these strategies are competitive exclusion, probiotics, prebiotics, antibiotics, antibacterial proteins, vaccination, bacteriophage, diet, and water trough interventions . The parallel and simultaneous application of one or more preslaughter strategies has the potential to synergistically reduce the incidence of human food-borne illnesses by erecting multiple hurdles, thus preventing entry of pathogens into the food chain . This review emphasizes work with Escherichia coli O157:H7 to illustrate the various strategies.

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi, 2004 Sep, 18(5), 352 - 5
{Effect of anti-infective reconstituted bone xenograft as primary bone grafting on repair of contaminated radius defect in canine}; Yuan Z et al.; OBJECTIVE: To investigate the effect of anti-infective reconstituted bone xenograft (ARBX) as primary grafting on repair of a segmental contaminated defect in canine radius . METHODS: The contaminated segmental defects of 1.5 cm were made in both radius of 8 canine and 1 ml of staphylococal suspension was injected into the defect region at a concentration of 5 x 10(6) CFU/ml . ARBX(experimental side) or RBX(control side) was implanted into the two sides of the defects respectively as primary grafting followed by internal fixation . The results were compared between the two grafting materials in repairing the contaminated segmental defect . RESULTS: In ARBX side, the defects were repaired completely in 5 cases and partially in 1 case, and there existed no osteomyelitis in all cases; while in RBX side, the defects were repaired partially in 1 case and were not repaired in 5 cases after 6 months of operation, and there existed osteomyelitis in all cases . CONCLUSION: Besides its strong osteoinductive and osteoconductive activity, ARBX is highly antibacterial and can be used as primary grafting in repairing contaminated segmental defects.

J Biol Chem, 2004 Dec 3, 279(49), 50969 - 75 Epub 2004 Dec 3.
Acyl carrier protein is a cellular target for the antibacterial action of the pantothenamide class of pantothenate antimetabolites; Zhang YM et al.; Pantothenate is the precursor of the essential cofactor coenzyme A (CoA) . Pantothenate kinase (CoaA) catalyzes the first and regulatory step in the CoA biosynthetic pathway . The pantothenate analogs N-pentylpantothenamide and N-heptylpantothenamide possess antibiotic activity against Escherichia coli . Both compounds are substrates for E . coli CoaA and competitively inhibit the phosphorylation of pantothenate . The phosphorylated pantothenamides are further converted to CoA analogs, which were previously predicted to act as inhibitors of CoA-dependent enzymes . Here we show that the mechanism for the toxicity of the pantothenamides is due to the inhibition of fatty acid biosynthesis through the formation and accumulation of the inactive acyl carrier protein (ACP), which was easily observed as a faster migrating protein using conformationally sensitive gel electrophoresis . E . coli treated with the pantothenamides lost the ability to incorporate {1-(14)C}acetate to its membrane lipids, indicative of the inhibition of fatty acid synthesis . Cellular CoA was maintained at the level sufficient for bacterial protein synthesis . Electrospray ionization time-of-flight mass spectrometry confirmed that the inactive ACP was the product of the transfer of the inactive phosphopantothenamide moiety of the CoA analog to apo-ACP, forming the ACP analog that lacks the sulfhydryl group for the attachment of acyl chains for fatty acid synthesis . Inactive ACP accumulated in pantothenamide-treated cells because of the active hydrolysis of regular ACP and the slow turnover of the inactive prosthetic group . Thus, the pantothenamides are pro-antibiotics that inhibit fatty acid synthesis and bacterial growth because of the covalent modification of ACP.

Urologiia, 2004 Jul-Aug, (4), 32 - 4
{Dopplerographic assessment of therapeutic efficacy of incoherent quantum irradiation in combined therapy of acute pyelonephritis}; Efficacy of camphorated paramonochlorophenol to a mixture of honey and mustard oil as a root canal medicament; Department of Operative Dentistry, Armed Forces Institutes of Dentistry, RawalpindiOBJECTIVE: To compare the efficacy of camphorated paramonochlorophenol to a mixture of honey and mustard oil as a root canal medicament . DESIGN: An in vitro comparative study . PLACE AND DURATION OF STUDY: This study was carried out in collaboration with microbiology department of Armed Forces Institute of Pathology, Rawalpindi and was conducted from Aug-2001 to Nov-2001 . MATERIALS AND METHODS: A sample of 90 infected root canal contents of decayed teeth was collected from Operative Dentistry Department of Armed Forces Institute of Dentistry, Rawalpindi . Each sample was inoculated aerobically as well as an-aerobically . Organisms were identified and isolates were preserved and refrigerated for experiments . Medicaments were procured and prepared in comparable dilutions . Minimum inhibitory concentration of both medicaments was compared by susceptibility testing against already preserved isolates . RESULTS: The tested mixture (honey and mustard oil equal v/v ) demonstrated antibacterial activity against all isolates at concentration of 12.5%(mean of effective conc.17.11%) while that of camphorated paramonochlorophenol was comparably at higher concentration 3.1%(mean of effective conc . 3.35%) . However the mixture revealed better results than that of individual agents, which was 12.5% to 25% respectively . CONCLUSION: Mixture (honey and mustard oil) was effective, viable alternate endodontic medicament.

Drugs, 2004, 64(19), 2159 - 75
Management of invasive candidiasis in critically ill patients; Blot S et al.; Candida species have become predominant pathogens in critically ill patients . In this population, invasive candidiasis is associated with a poor prognosis but adequate management can limit the attributable mortality . Adequate management, however, is hampered by a problematic diagnosis as the clinical picture of invasive disease is non-specific and blood cultures have a low sensitivity . Moreover, it is often hard to differentiate colonisation from infection and many critically ill patients are heavily colonised with Candida species, especially when receiving broad-spectrum antibacterials . The question of which antifungal agent to choose has become more complex as the development of new drugs raises promising expectations . Until the 1980s therapy for invasive candidiasis was limited to amphotericin B, but with the advent of new antifungal agents, such as azoles and echinocandins, less toxic therapeutic options are possible and doors have opened towards prevention and optimised therapy in the case of documented candidiasis . Through the arrival of these new antifungal agents, a range of therapeutic strategies for the management of invasive candidiasis has been developed: antifungal prophylaxis, pre-emptive therapy, and empirical and definitive antifungal therapy . Each of these strategies has a specific target population, as defined by specific underlying conditions and/or individual risk factors . Antifungal prophylaxis, in order to prevent candidal infection, is based on the type of underlying diseases with a high risk for invasive candidiasis . Individual risk factors are not taken into account . Potential indications are bone marrow transplantation, liver transplantation, recurrent gastrointestinal perforations or leakages, and surgery for acute necrotising pancreatitis . Pre-emptive therapy is also a preventive strategy . It can be recommended on the basis of an individual risk profile including overt candidal colonisation . Empirical therapy is started in patients with a risk profile for invasive candidiasis . It is recommended in the presence of clinical signs of infection, deteriorating clinical parameters, or a clinical picture of infection not responding to antibacterials but in the absence of a clear causative pathogen . Definitive antifungal therapy is defined as therapy in patients with documented invasive infection . The main goal is to maintain a balance between optimal prevention and timely initiation of therapy on one hand, and to minimise selection pressure in order to avoid a shift towards less susceptible Candida species on the other hand.

Bioorg Med Chem Lett, 2004 Nov 1, 14(21), 5257 - 61
Optimizing the antibacterial activity of a lead structure discovered by "SAR by MS" technology; Jefferson EA et al.; We report on lead optimization of a compound that was originally discovered to bind bacterial 23S rRNA near the L11 binding site and inhibit translation in vitro, but lacked detectable antibacterial activity . In this study, we were able to generate compounds with antibacterial activity against Gram-negative and Gram-positive pathogens, including a methicillin-resistant S . aureus strain.

Curr Opin Microbiol, 2004 Oct, 7(5), 466 - 76
Taking inventory: antibacterial agents currently at or beyond phase 1; Bush K et al.; At least 18 antibacterial agents are currently undergoing clinical trials for the treatment of infections caused by susceptible and resistant bacteria . The beta-lactam class includes new parenteral carbapenems and cephalosporins with varying spectra of activities . The glycopeptides are antibiotics with in vitro activity primarily against Gram-positive bacteria, including multi-resistant strains . Three quinolones are being investigated for use against a variety of Gram-positive and respiratory Gram-negative organisms . Several other classes of antibacterial agents currently in clinical trials are represented by a glycolipodepsipeptide, a dihydrofolate reductase inhibitor, an oxazolidinone, two peptide antibiotics, a glycylcycline, and a peptide deformylase inhibitor, a member of a new antibacterial class.

Curr Opin Microbiol, 2004 Oct, 7(5), 451 - 9
The impact of transcriptome and proteome analyses on antibiotic drug discovery; Freiberg C et al.; Recent scientific publications demonstrate the increasing interest in measurement of genome-wide gene expression on transcript and protein level in response to treatment with antibacterial agents . Nevertheless, the number of large bacterial transcriptome and proteome datasets available so far is limited, although a high number and diversity of antibiotic-triggered expression profiles aid to optimally exploit these technologies . The first published examples substantiate the need to establish these so-called reference compendia of bacterial expression profiles, to discover the molecular mechanism-of-action of uncharacterized bioactive substances . In addition, such compendia open up ways for novel cell-based drug screening approaches.

Curr Opin Microbiol, 2004 Oct, 7(5), 445 - 50
Antibacterial research and development in the 21(st) Century--an industry perspective of the challenges; Thomson CJ et al.; The continued evolution of resistance to antibiotics has led to wide ranging consultation at National and International levels as to how to address this issue . In addition to attempting to limit the spread of resistance there is growing consensus that a cornerstone requirement is the development of new antibiotics to help redress the balance of resistance versus available antibiotics . The availability of new technologies such as genomics has opened up new approaches for antibacterial research . It would appear that from an industry perspective, the research and development of antibiotics should be an attractive option . However, this is not the current perception at the majority of large pharmaceutical companies . In addition, the perceived failure of new technologies to create another golden age of new antibacterial classes has led many companies to prioritise other areas of research and, in some cases, to exit antibacterial research . In response, a plethora of small biotech companies have emerged with an interest in antibacterial discovery and large pharmaceutical companies may look to these as a source of development candidates although, to date, these have contributed a very low number of truly novel antibiotic lead compounds . As a reaction to these changes several initiatives are ongoing to examine ways to incentivise antibacterial research and development and ensure a healthy pipeline of compounds in the 21st Century.

Phytochemistry, 2004 Sep, 65(18), 2539 - 43
Nor-ent-kaurane diterpenes and hydroxylactones from Antennaria geyeri and Anaphalis margaritacea; Ahmed AA et al.; In a study of Pacific Northwest plants of the Asteraceae family, a nor-ent-kaurane diterpene and a known diterpene, both displaying antibacterial activities, were isolated together with scopoletin and sitosterol-3-O-beta-glucopyranoside from the aerial parts of Antennaria geyeri . Anaphalis margaritacea afforded two hydroxylactones . The structures were established by one and two dimensional NMR techniques, IR and CIMS.

Theriogenology, 2004 Nov, 62(8), 1383 - 90
Isolation of E . coli from foam and effects of fluoroquinolones on E . coli and foam production in male Japanese quail; Mohan J et al.; Sexually active male Japanese quail (Coturnix coutrnix Japonica) produce a foamy substance from their cloacal gland . It was postulated that bacteria played an important role in production of foam . The primary objective of this study was to isolate and identify bacteria present in the cloacal foam . The secondary objective was to evaluate the effect of fluoroquinolone treatment on bacterial counts and foam production . Healthy adult Japanese quail were maintained in individual cages under uniform husbandry conditions and allocated arbitrarily into three groups (each group consisted of 12 male and 12 female birds) . Foam was collected from the cloacal gland of male birds of each group separately into sterile petri dishes and was cultured to isolate and identify bacteria and to determine their sensitivity to various antibiotics . Escherichia coli bacteria, sensitive to various antibacterials (including the fluoroquinolones ciprofloxacin and pefloxacin), were isolated . In the second part of the study, male quails of Group I (control) received I mL vehicle (normal saline 0.9% (w/v) NaCl) daily (via the intraperitoneal route) for 12 days . Male birds from groups II and III were treated intraperitoneally with ciprofloxacin or pefloxacin at the rate of 10 mg and 12 mg per/kg body weight respectively, for 12 days . In antibiotic-treated birds, there was a gradual reduction in foam production during treatment . At the end of treatment, the cloacal gland area was smaller (P < 0.05) in pefloxacin-treated birds compared to the other groups . Furthermore, a trend towards decreasing body weight and fertilizing ability was noted in the same group . A drastic reduction in bacterial counts of foam was recorded only in fluoroquinolone-treated groups during treatment period . After cessation of treatment, all end points were increasing back to pre-treatment levels . In conclusion, E . coli were present in the foam of the cloacal gland of Japanese quail and may have a role in foam production.

Curr Opin Chem Biol, 2004 Oct, 8(5), 492 - 7
Mechanism of action of S-ribosylhomocysteinase (LuxS); Pei D et al.; S-Ribosylhomocysteinase (LuxS) cleaves the thioether bond in S-ribosylhomocysteine to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione . This reaction serves the dual purposes of detoxification of S-adenosylhomocysteine and production of type 2 quorum sensing molecule . Recent research has shown that LuxS uses Fe(2+) to catalyze an internal redox reaction, shifting the ribose carbonyl group from its C1 to C3 position . Subsequent beta-elimination completes this highly unusual reaction . LuxS and other enzymes on the same pathway may provide a novel class of antibacterial drug targets.

Klin Med (Mosk), 2004, 82(7), 36 - 40
{Temporal organization of external respiratory function in elderly patients with chronic obstructive lung disease}; Zaslavskaia RM et al.; The clinical course and the circadian, circaseptan, and circasemiseptan chronostructure of external respiratory function (ERF) were studied in 26 elderly patients with chronic obstructive lung diseases before and after routine therapy (RT) . ERF was studied on a meta-test spirograph (Russia) and a Ferraris medical peak flowmeter (UK) . The values of ERF and bronchial patency were measured every 4 hours within 7 days before and after 10-day RT . The latter included euphylline, expectorants, and antibacterial drugs, if indicated . The patients also use "on-demand" dosage aerosol inhalators not more than 3-5 times a day . The chronobiological data were analyzed by the averaged group cosinor test described by F . Halberg . The results of the study made it possible to detect the impaired temporary organization of ERF and bronchial patency, the phenomena of external and internal desynchronism both prior to and following RT . It clinical effect occurred on day 5.5 after RT . Before RT, circadian variations were found in respiratory volume (RV), respiratory minute volume (RMV), vital capacity (VC), forced expiratory value per sec (FEV1), the Tiffeneau test, and peakflowmetry . After RT, they remained other than variations in RV . The average daily values of VC, FEV1, Tiffeneau test, PO2, and KIO2 statistically significantly increased . The increases of MESORs and other indices tended to be significant . Circasemiseptan variations were found in RV, VC, and FEV1 before RT . After treatment, these were detected in respiration rate (RR), RMV, VC, and KIO2 . The MESORs of RMV, VC, FEV1, and KIO2 statistically significantly increased . Prior to and following RT, there were virtually no 7-day (circaseptan) variations, other than those in RR before therapy . The MESORs of VC, FEV1, MVL, and RD statistically significantly increased . The MESORs of other parameters of ERF tended to be significant . Thus, RT led to the improved circadian and circasemiseptan organization of ERF and, to a lesser degree, to that of circaseptan chronostructure of the parameters of ERF.

J Enzyme Inhib Med Chem, 2004 Apr, 19(2), 185 - 92
Antineoplastic and antibacterial activity of some mononuclear Ru(II) complexes; Mazumder UK et al.; These ligands (L) show a bidentate behavior, forming octahedral ruthenium complexes . The title complexes were subjected to in-vivo anticancer activity tests against a transplantable murine tumor cell line, Ehrlich's Ascitic Carcinoma (EAC) and in-vitro antibacterial activity against several Gram positive and Gram negative bacterial strains . {Ru(bpy)2(ihqs)}Cl2 and {Ru(bpy)2 (hc)}Cl2 (where bpy = 2,2'-bipyridine, ihqs = 7-iodo-8hydroxy quinoline-5-sulphonic acid and hc = 3-hydroxy coumarin) showed promising antitumor activity . Treatment with these complexes prolonged the life span of EAC bearing mice as well as decreased their tumor volume and viable ascitic cell count . All the tested complexes exhibited mild to moderate antibacterial activity.

J Endod, 2004 Oct, 30(10), 689 - 94
An evidence-based analysis of the antibacterial effectiveness of intracanal medicaments; Law A et al.; The authors reviewed the literature evaluating the antibacterial effectiveness of intracanal medicaments used in the management of apical periodontitis . A PICO (problem, intervention, comparison, outcome) strategy was developed to identify studies dealing with calcium hydroxide, phenolic derivatives, iodine-potassium iodide, chlorhexidine, and formocresol . The final inclusion/exclusion criteria eliminated all papers except five that evaluated calcium hydroxide . The total sample size in the included studies was 164 teeth . Microbiologic sampling was performed before endodontic treatment (S1), after instrumentation and irrigation (S2), and after intracanal medication (S3) . At S2, 62% of canals were positive . After medication, 27% still showed detectable growth . Of cultures that were positive at S2, 45% were still positive at S3 . Most studies did not address issues of culture reversals or false positive and false negative cultures . The main component of antibacterial action appears to be associated with instrumentation and irrigation, although canals cannot be reliably rendered bacteria free . Calcium hydroxide remains the best medicament available to reduce residual microbial flora further.

Pharmacoepidemiol Drug Saf, 2005 Jan, 14(1), 31 - 40
Generating signals of drug-adverse effects from prescription databases and application to the risk of arrhythmia associated with antibacterials; Corrao G et al.; BACKGROUND: Although it is well known that a variety of antibacterials may incidentally cause malignant arrhythmia, the list of drugs causing arrhythmia and the impact of these adverse effects are still uncertain . We investigated on this topic by using a large prescription database with different observational designs . METHODS: Prescription data on all incident users of several antibacterial and antiarrhythmic drugs over the period July 1997 through December 1999 were retrieved from the Drug Prescription Database (DPD) of the Italian Province of Varese . The association between the use of antibacterial and antiarrhythmic drugs was investigated by applying prescription sequence symmetry, cohort and nested case-control designs . RESULTS: Lower proarrhythmic effects were on an average obtained from prescription sequence symmetry approach with respect to both cohort and nested case-control . Evidence of association between exposure to drugs (erythromycin and ciprofloxacin) and the risk of arrhythmia was consistently found by the three approaches . No other signals were generated from the prescription sequence symmetry analysis . Two drugs (clarithromycin and levofloxacin) showed patterns compatible with an arrhythmic effect according to both cohort and nested case-control designs . CONCLUSIONS: Prescription databases are useful tools to explore drug safety through both conventional and emerging observational designs . In spite of its appealing features, prescription sequence symmetry design shows lower sensitivity with respect to conventional designs . Evidence about the association between the use of certain macrolides and fluoroquinolones and the onset of arrhythmia is confirmed by this study . Copyright (c) 2004 John Wiley & Sons, Ltd.

Mass Spectrom Rev . 2004 Jul 29; {Epub ahead of print}
Bacterial proteomics and its role in antibacterial drug discovery; Brotz-Oesterhelt H et al.; I.Introduction000 II.The Role of Proteomics to Decipher the Bacterial Response Towards Changes in Environmental Conditions and Antibiotic Attack000A . Proteome Mapping000B . The Concept of Proteomic Signatures000C . Snapshots of Protein Biosynthesis: Metabolic Labeling and Dual-Channel Imaging000D . Protein Modifications000III.Proteomics and the Antibacterial Drug Discovery Process000A . Current Approaches in Antibacterial Drug Discovery000B . The Potential Roles of Proteomics in Antibacterial Drug Discovery000IV.Remarks on Technological Progress000A . Progress in Two-Dimensional Gel-Based Technologies000B . Progress in Non-Gel-Based Proteomics000 V.Outlook000References000Gene-expression profiling technologies in general, and proteomic technologies in particular have proven extremely useful to study the physiological response of bacterial cells to various environmental stress conditions . Complex protein toolkits coordinated by sophisticated regulatory networks have evolved to accommodate bacterial survival under ever-present stress conditions such as varying temperatures, nutrient availability, or antibiotics produced by other microorganisms that compete for habitat . In the last decades, application of man-made antibacterial agents resulted in additional bacterial exposure to antibiotic stress . Whereas the targeted use of antibiotics has remarkably reduced human suffering from infectious diseases, the ever-increasing emergence of bacteria that are resistant to antibiotics has led to an urgent need for novel antibiotic strategies . The intent of this review is to present an overview of the major achievements of proteomic approaches to study adaptation networks that are crucial for bacterial survival with a special emphasis on the stress induced by antibiotic treatment . A further focus will be the review of the, so far few, published efforts to exploit the knowledge derived from bacterial proteomic studies directly for the antibacterial drug-discovery process .

Sex Transm Dis, 2004 Oct, 31(10), 631 - 5
Treatment of sexually transmitted diseases in Estonia: consistency with the evidence-based medicine principles; Uuskula A et al.; BACKGROUND: Estonia is among those Eastern European countries that have witnessed an explosive intravenous drug use-driven HIV epidemic . Early sexually transmitted disease (STD) diagnosis and appropriate treatment is essential to prevent an STD-driven HIV epidemic . OBJECTIVES: The objectives of this study were to define the schedule of antibiotic treatment doctors in Estonia used to treat STDs, and to determine if the treatments used correspond to evidence-based medicine treatment principles . STUDY DESIGN: Using an administrative database of the Estonian Health Insurance Fund on pharmaceuticals reimbursement, we obtained information on: drug (ATC 1998) prescribed with an STD diagnosis (International Classification of Diseases and Related Health Problems, syphilis, gonorrhea, genital Chlamydia trachomatis and Trichomonas vaginalis infections, and genital herpes), prescribing physician specialty, and patient demographics (date of birth, gender) . To evaluate the correspondence of STD treatment to evidence-based medicine principles, the therapeutic regimens used were compared with recommendations from the European Sexually Transmitted Infections Management Guidelines . RESULTS: In 2001 and 2002, physicians ordered 17,077 prescriptions for systemic antibacterial medications to treat STDs in 12,823 different individuals: 2942 men (mean age, 31.8 years) and 9880 women (mean age, 29.5 years) . The majority of STD treatments were prescribed by gynecologists (60%) or dermatovenerologists (29%); general practitioners treated 8% of STDs . In 11% of treatment episodes, the drug prescribed was inconsistent with guideline recommendations; additionally, in 9% of episodes, the recommended drug was chosen but the prescribed dose was too low . At least 20% of treatment episodes could therefore be considered inappropriate . CONCLUSIONS: Educational efforts are needed to increase physician awareness of evidence-based approaches for STD management and treatment to assure effective STD care.

Antimicrob Agents Chemother, 2004 Oct, 48(10), 3912 - 7
Long depletion time of enrofloxacin in rainbow trout (Oncorhynchus mykiss); Lucchetti D et al.; The international production of farmed fish has been growing continuously over recent years . Until now few veterinary drugs have been approved by the European Union for use in aquaculture, and this has favored the off-label use of products authorized for use in food-producing animal species different from fishes among fish farmers . Adequate field studies are lacking, especially for those species called minor species which are consumed extensively only in some European countries . In the present investigation we studied the depletion of the fluoroquinolone antibacterial enrofloxacin over time in a minor species, the rainbow trout (Oncorhynchus mykiss), reared on a real fish farm and treated with medicated feed (10 mg kg of trout body weight(-1) day(-1)) . Edible tissue samples (muscle plus skin in natural proportions) and fish bone samples were analyzed for enrofloxacin and for its major metabolite, ciprofloxacin, by high-performance liquid chromatography with fluorescence detection at different times after the end of treatment . Our results show that at 500 degrees C-day (in which degree-days are calculated by multiplying the mean daily water temperature by the total number of days on which the temperature was measured), which is the minimum withdrawal period established by European Economic Commission Directive No . 82/2001 for any type of product administered off-label, edible trout tissues might still contain about 170 microg of enrofloxacin kg(-1), whereas the maximum residue level for enrofloxacin plus ciprofloxacin is set at 100 microg kg(-1) . To our knowledge, no studies of the depletion of enrofloxacin in rainbow trout have been performed . On the basis of the data obtained in the present study, we suggest a more appropriate withdrawal time of 816 degrees C-day for the sum of enrofloxacin plus ciprofloxacin levels in rainbow trout muscle plus skin tissues.

Org Lett, 2004 Sep 30, 6(20), 3433 - 6
Synthesis and characterization of peptide-cationic steroid antibiotic conjugates; Ding B et al.; {reaction: see text} New cationic steroid antibiotics have been prepared by conjugating tripeptides to a triamino analogue of cholic acid . These compounds were synthesized on a solid phase in an indexed library that was screened for antibacterial activity against Gram-negative and Gram-positive bacteria . Selected compounds were synthesized on a larger scale, and minimum inhibition concentrations were measured . These results correlated very well with the screening of the indexed library of antibiotics . The most active antibiotics demonstrate a marked improvement over a related and well characterized cationic steroid antibiotic.

J Surg Oncol, 2004 Oct 1, 88(1), 21 - 26
Invasive cutaneous fungal infections requiring radical resection in cancer patients undergoing chemotherapy; Radhakrishnan R et al.; Invasive fungal infections have emerged as a significant problem in patients with cancer with the development of better systemic therapies for malignancy and more effective antibacterial agents . The currently available world published medical literature was reviewed on invasive fungal infections in cancer patients with specific attention devoted to the multidisciplinary role of surgery in refractory cutaneous cases . Infections can develop on the forearm where peripheral intravenous catheters had been inserted in cancer patients undergoing cytotoxic chemotherapy . Curative intent begins with systemic contemporary anti-fungal therapy . Following resolution of neutropenia, patients may require radical surgical debridement with negative margins of resection for complete eradication of the fungal infection . Although invasive fungal infections refractory to antifungal systemic therapy in immunocompromised patients undergoing chemotherapy are a rare event, it is critical for surgeons and other multidisciplinary clinicians to recognize these potentially life-threatening infections that may necessitate radical surgical resection for cure.

Microb Drug Resist, 2004 Fall, 10(3), 255 - 63
Impact of ketolides on resistance selection and ecologic effects during treatment for respiratory tract infections; Nord CE et al.; Ketolides are a new class of antibacterials that have been specifically developed for the treatment of community-acquired respiratory tract infections in an era of increasing resistance among major etiologic pathogens . These agents possess several unique structural features, including a 3-keto function and a large aromatic side chain, that confer not only a mode of action that differentiates them from the macrolide class but also a reduced potential to induce--or select for--resistant strains . Studies also suggest that ketolides such as telithromycin have a lower ecologic impact on the body's microflora than agents such as clarithromycin and amoxicillin-clavulanate, potentially reducing the risk of emergence of resistant strains and the spread of such resistance to pathogenic species . Therefore, available evidence suggests that ketolides may not only provide important new treatment options in an era of increasing resistance but may also contribute to reducing the pressure for development of further resistance . Clearly, further studies are required to confirm this low resistance potential once the ketolide agents become more widely used in routine practice . Copyright Mary Ann Liebert, Inc.

Phytochemistry, 2004 Aug, 65(16), 2387 - 90
Deoxypreussomerins from Jatropha curcas: are they also plant metabolites?
Ravindranath N, Reddy MR, Mahender G, Ramu R, Kumar KR, Das B.
Three deoxypreussomerins, palmarumycins CP1, JC1 and JC2, have been isolated from a collection of the stems of Jatropha curcas . The second and third compounds are antibacterial constituents which were characterized from spectral evidence . The X-ray crystallographic structure of palmarumycin JC1 was also studied . Deoxypreussomerins have been obtained here from a plant source in appreciable quantities.

Regul Pept, 2004 Oct 15, 122(2), 99 - 107
Presence and release of the chromogranin B-derived secretolytin-like peptide KR-11 from the porcine spleen; Depreitere J et al.; Chromogranin B (CgB) is a major matrix protein in secretory granules/large dense-cored vesicles and a precursor for smaller peptides . In an earlier study, we have identified a secretolytin-like peptide (KR-11, pCgB(637-647)) from porcine chromaffin granules . Further evidence is presented here to show the processing of chromogranin B to this peptide during axonal transport in the splenic nerve and its release in the spleen upon various conditions of stimulation . Immunohistochemical staining showed that in the porcine spleen chromogranin B and NPY completely colocalize in nerve fibres and varicosities in blood vessel walls and trabeculae, and along the loose network of smooth muscle cells in the red pulp, as identified by their alpha-smooth muscle cell actin content . No antibacterial activity was found for the porcine secretolytin-like peptide, KR-11 . The change of one amino acid residue (Thr-->Asn) in the porcine homologous fragment of secretolytin appears to be responsible for its loss of antibacterial activity.

Bioorg Med Chem Lett, 2004 Oct 18, 14(20), 5211 - 3
Synthesis and biological activity of novel antibacterial quinazolines; Bedi PM et al.; Novel quinazolines, having interesting antibacterial activity have been prepared, characterized and tested against a panel of susceptible and resistant Gram positive and Gram negative organisms.

Bioorg Med Chem Lett, 2004 Oct 18, 14(20), 5193 - 8
Synthesis and antibacterial activity of novel 6-fluoro-1-{(1R,2S)-2-fluorocyclopropan-1-yl}-4-oxoquinoline-3-carboxylic acids bearing cyclopropane-fused 2-amino-8-azabicyclo{4.3.0}nonan-8-yl substituents at the C-7 position; Inagaki H et al.; A series of novel 6-fluoro-1-{(1R,2S)-2-fluorocyclopropan-1-yl}-4-oxoquinoline-3-carboxylic acids bearing cyclopropane-fused 2-amino-8-azabicyclo{4.3.0}nonan-8-yl substituents at the C-7 position were synthesized to obtain potent drugs for the treatment of Gram-positive infections . Some compounds exhibited excellent antibacterial activity, and potent inhibitory activity against bacterial DNA topoisomerase IV . In addition, some of the potent compounds showed reduced inhibitory activity against human DNA topoisomerase II compared with the corresponding noncyclopropane-fused compounds.

Curr Drug Targets Infect Disord, 2004 Sep, 4(3), 241 - 60
The macrolide-bacterium interaction and its biological basis; Goldman RC et al.; Erythromycin, the first antibacterial macrolide introduced into the clinical setting over 50 years ago, was used extensively not only for the treatment of respiratory tract infections in both adults and children, but also for bone and soft tissue infections, and specific sexually transmitted diseases . Macrolide antibiotics have undergone a dramatic chemical evolution over the past 50 years, culminating in the improved 14- and 16-membered macrolides, acylides and new ketolides . In all cases, improvements in antibacterial activity involved changes in the interplay between the chemical structure of the macrolide and the components of the bacterial cell that dictate ultimate antibacterial activity and efficacy . Target site modification by methylation of ribosomal RNA, the so-called Macrolide-Streptogramin-Lincosamide, (MLS0 resistance and active efflux are the two most common forms of resistance present in the clinic today; however, other resistance mechanisms are known . The first macrolide that bound to MLS-resistant ribosomes was reported in 1989, demonstrating that appropriate structural changes could regain access to the modified ribosome-binding site . In addition, macrolide analogs with reduced affinity for the active efflux pump were identified in 1990, demonstrating that features of pump recognition could be separated from ribosome binding site recognition . Progressive medicinal chemistry led to the synthesis and development of the more recent ketolide class, which combines attributes of both prototypes into one molecule, i.e . non-recognition by the efflux pump and regaining some access to the modified ribosome binding site . Ketolide also lack of induction of erm methylase as do 16-member macrolides.

Cell Mol Life Sci, 2004 Sep, 61(18), 2418 - 24
Polarization of immunity induced by direct injection of naked sequence-stabilized mRNA vaccines; Carralot JP et al.; In the context of developing a safe genetic vaccination strategy we tested and studied globin-stabilized mRNA-based vaccination in mice . This vaccination strategy has the advantages of genetic vaccination (easy production, adaptability to any disease and inexpensive storage when lyophilized), but not the drawbacks of DNA vaccination (long-term uncontrolled expression of a transgene, possibility of integration into the host genome and possible induction of anti-DNA antibodies) . We report here that injection of naked beta-globin untranslated region (UTR)-stabilized mRNA coding for beta-galactosidase is followed by detectable translation in vivo . In addition, we show that such a vaccination strategy primes a T helper 2 (Th2) type of response which can be enhanced and shifted to a Th1-type immune response by application of recombinant granulocyte/macrophage colony-stimulating factor 1 day after mRNA injection . Our data demonstrate that the administration of globin UTR-stabilized mRNA is a versatile vaccination strategy that can be manipulated to fit the requirement of antiviral, antibacterial or antitumor immunity.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz, 2004 Sep, 47(9), 834 - 40
{Influence of pharmacologically active substances on food safety}; Kietzmann M; In the European Community and in Germany drug residues are scarcely found in food of animal origin . Therefore, a high degree of safety is ensured for consumers . Problems may result from imported foods, because limitations of drug use in livestock of the European Community do not exist everywhere . Because antibacterial drugs are administered frequently, the problem of transferred multiple-drug resistance of bacteria has to be especially considered.

J Antimicrob Chemother, 2004 Oct, 54(4), 836 - 9 Epub 2004 Sep 16.
Tissue and serum levofloxacin concentrations in diabetic foot infection patients; Oberdorfer K et al.; OBJECTIVES: Levofloxacin has a high bioavailability and a broad antibacterial spectrum which covers the common pathogens found in acute and chronic diabetic foot infections . The purpose of our study was to determine the serum and tissue concentrations of levofloxacin when administered orally in patients with infected diabetic foot ulcers and to compare these values with microbiological findings . PATIENTS AND METHODS: Ten outpatients with diabetes and ulcerations of the lower extremity were included . All patients received oral levofloxacin therapy at a dose of 500 mg once daily . Wound tissue and serum samples were collected and levofloxacin concentrations determined by HPLC with fluorescence detection . Additionally, microbiological cultures were performed from swabs and debrided wound tissue, both before and after treatment . MICs of levofloxacin for all bacterial isolates were determined using the Etest . RESULTS: Following oral treatment with levofloxacin for an average of 10 +/- 3.8 days, all patients received debridement at the affected limbs . The levofloxacin concentrations in necrotic wound tissue were between 2.33-23.23 mg/kg and between 0.12-6.41 mg/L in serum . Tissue-to-serum ratios of levofloxacin concentrations for each patient were >1.0 . The MIC values for all 17 initially isolated bacteria were < or = 2 mg/L . In half of our patients, fluoroquinolones were one of the few oral monotherapy options where the spectrum covered all initially isolated pathogens . CONCLUSION: Our data showed good tissue penetration of levofloxacin in diabetic foot ulcers . In combination with adequate surgical debridement, levofloxacin seems well suited to the treatment of skin structure infections of diabetics caused by susceptible organisms.

Klin Khir, 2004 Jun, (6), 40 - 2
{Efficacy of application of conservative-anticipating tactics in the treatment of renal abscess}; Sarychev LP et al.; Conservative management of patients with renal abscess is indicated in destructive phase of inflammation . Doing that the ultrasonographic investigation constitutes harmless, accessible, informative method of the disease course control . Ultrasonographic data permit to follow up the affection dynamics and to estimate the antibacterial therapy efficacy . The combined application of ultrasonography, computed tomography and the puncture biopsy have permitted to establish the renal abscess diagnosis in all observations . In purulent melting of the inflammation nidus the treatment ought to be combined with transcutaneous drainage . If the renal abscess diameter do not exceed 4 cm, it is enough to perform aspiration of the content for once . In diameter of the inflammation nidus more than 4 cm, it is expedient to install a constant drain into the abscess cavity up to the time when the content excretion would stop . Inefficacy of transcutaneous drainage of the renal abscess constitutes indication for surgical treatment.

Planta Med, 2004 Aug, 70(8), 706 - 10
Anthranoid compounds with antiprotozoal activity from Vismia orientalis; Mbwambo ZH et al.; A phytochemical investigation of the 80% ethanolic extract of stem bark of Vismia orientalis Engl . (Guttiferae or Clusiaceae), a plant used in traditional medicine in Tanzania, resulted in the isolation and spectroscopic characterisation of 3-geranyloxy-6-methyl-1,8-dihydroxyanthraquinone, emodin, vismione D and bianthrone A1 . Vismione D exhibited a broad range of antiprotozoal activities against Trypanosoma brucei rhodesiense and T . cruzi (IC50 < 10 micrograms/mL), Leishmania donovani (IC50 0.37 micrograms/mL) and Plasmodium falciparum strain K1 (IC50 1.0 microgram/mL) . However, it was also slightly cytotoxic against human L6 cells (IC50 4.1 micrograms/mL) . Emodin showed antileishmanial activity (IC50 2.0 micrograms/mL), while its IC50 against L6 cells was 20.3 micrograms/mL . Other antiprotozoal activities observed for emodin against both Trypanosoma species and P . falciparum, for bianthrone A1 against T . b . rhodesiense and P . falciparum, and for 3-geranyloxy-6-methyl-1,8-dihydroxyanthraquinone against T . b . rhodesiense, L . donovani and P . falciparum were in the range of 10 to 50 micrograms/mL . None of the compounds showed antibacterial or antiviral (including also HIV) activity.

J Biomed Mater Res, 2004 Oct 1, 71A(1), 1 - 5
Biocompatibility and antibacterial activity studies of polyamidoamine (PAMAM) dendron, side chain dendritic oligourethane (SCDOU); Ghosh S et al.; Cytotoxicity of both polyamidoamine dendritic diol (PAMAM) and side chain dendritic oligourethane (SCDOU) was studied through interaction with mammalian fibroblast cells (L929) . Cell metabolic activity in the presence of dendritic polymers was measured using an MTT assay exhibiting significant cell viability . Additionally, the antibacterial activity of PAMAM dendron, SCDOU, as well as their silver-doped structures was studied against Escherichia coli bacteria . The results showed that the silver-doped structures attain high antibacterial activity . Formation of silver-doped dendritic polymers was investigated from the UV-visible plasmon absorption band of silver particles.

Intensive Care Med, 2005 Jan, 31(1), 5 - 11 Epub 2004 Sep 11.
Efficacy of heat and moisture exchangers in preventing ventilator-associated pneumonia: meta-analysis of randomized controlled trials; Kola A et al.; OBJECTIVE: Several randomized controlled trials (RCT) have examined the effect of antibacterial humidification strategies, particularly the replacement of heated humidifiers (HH) by heat and moisture exchangers (HME), in preventing ventilator-associated pneumonia (VAP) . The present meta-analysis reviews these RCTs.METHODS: RCTs were identified by searching the Medline and Cochrane Central Register of Controlled Trials databases from 1990 to 2003 . We included RCTs using HMEs in the treatment group and HHs in the control group and reporting the incidence of pneumonia as a study outcome . Two investigators independently abstracted key data on design, population, intervention and outcome of the studies.RESULTS: Between 1990 and 2003 eight RCTs met the inclusion criteria of this analysis . Pooling the results from these studies revealed a reduction in the relative risk of VAP in the HME group (0.7), particularly in MV with a duration of at least 7 days (five RCTs, relative risk 0.57).CONCLUSIONS: This meta-analysis found a significant reduction in the incidence of VAP in patients humidified with HMEs during MV, particularly in patients ventilated for 7 days or longer . This finding is limited by the exclusion of patients at high risk for airway occlusion from some of the studies . Moreover, contraindications (tenacious secretions, airway obstructive disease, hypothermia) and technical issues of HMEs must be considered . Further RCTs are necessary to examine the wider applicability of HMEs and their extended use.

World J Surg, 2004 Jun, 28(6), 625 - 30
Combined assessment of beta-D-glucan and degree of candida colonization before starting empiric therapy for candidiasis in surgical patients; Takesue Y et al.; The purpose of the study was to investigate whether examination for plasma beta-D-glucan, a cell wall constituent of fungi, is useful for selecting surgical patients with Candida colonization who would benefit from empiric antifungal therapy . We administered fluconazole to postoperative patients with Candida colonization who have risk factors for candidemia and complained of persistent fever despite prolonged antibacterial therapy . We then analyzed the clinical outcomes regarding the number of sites colonized with Candida spp . and plasma beta-D-glucan . Of the 32 patients positive for alpha-D-glucan, 15 (46.9%) responded to the empiric therapy; only 9% of those who were negative responded (p < 0.01) . In the multiple logistic regression analysis, being positive for alpha-D-glucan was a significant factor predicting response, with an adjusted odds ratio of 12.9 in patients with Candida colonization {95% confidence interval (CI) 2.07-80.73) (p < 0.01) . In addition, the number of sites colonized with Candida spp . was a significant factor predicting response, with an estimated exposure odds ratio of 7.57 for those who were colonized at three or more sites compared with those colonized at one site (95% CI 1.20-47.70) (p = 0.031) . In patients with Candida colonization, assessment of beta-D-glucan was useful for deciding whether to start empiric therapy for suspected candidiasis in surgical patients.

Toxicology, 2004 Oct 15, 203(1-3), 27 - 40
Toxicity classification and evaluation of four pharmaceuticals classes: antibiotics, antineoplastics, cardiovascular, and sex hormones; Sanderson H et al.; Four different classes of environmental concern are quantitatively and qualitatively assessed for environmental hazards; antibiotics (n = 226), antineoplastics (n = 81), cardiovascular (n = 272), and sex hormones (n = 92) . These along with an ECOSAR scan of all pharmaceuticals (n = 2848) were then classified according to the OECD aquatic toxicity classification system . The predicted species susceptibility is: daphnid > fish > algae, and the predicted rank order of relative toxicity: sex hormones > cardiovascular = antibiotics > antineoplastics (Table 1) . Generally, a relatively large proportion (1/3) of all pharmaceuticals are potentially very toxic to aquatic organisms (Table 2) . The qualitative risk assessment ranking relative to probability and potential severity for human and environmental health effects is: antibiotics > sex hormones > cardiovascular > antineoplastics . (Q)SARs and pharmacodynamic information should be used to prioritize and steer experimental risk assessments of pharmaceuticals, and potentially, also be used in new drug discovery optimizing efficacy and in minimising environmental hazards of new products . Nuclear receptors are relatively well conserved in evolution . Currently, antibacterial resistance represents the most significant human health hazard, and potentially the largest non-target organism hazard is sex hormones acting as endocrine modulators in wildlife . Data for the individual compounds are accessible via.

Zhonghua Nan Ke Xue, 2004 Aug, 10(8), 598 - 600
{Effect of chronic abacterial prostatitis on semen quality and efficacy of antibacterial agents}; Zhang J et al.; OBJECTIVE: To appraise the effect of chronic abacterial prostatitis (CAP) on semen quality and the efficacy of antibacterial agents . METHODS: The semen of 86 cases of CAP and 20 normal men were analysed together with the antisperm antibodies in their blood and semen, and the antisperm antibodies in the blood and spermatic fluid were determined . Then the 86 patients were randomized into two groups, one treated with Chinese traditional medicine, indomethacin and three kinds of antibacterial agents, the other with Chinese traditional medicine and indomethacin only . The treatment lasted 3 months, and a follow-up visit was paid every month . RESULTS: Sperm motility and normal modality of the CAP group were 59.8% and 52.8%, respectively, significantly lower than those of the normal group (P < 0.005) . The positive rates of the antisperm antibodies in the blood and spermatic fluid were 46.5% and 50%, respectively, significantly higher than those of the normal group . The clinical efficacy was significantly better in the group treated with antibacterial agents than the one without (P < 0.05) . CONCLUSION: CAP can affect sperm quality and decrease fertility . Antibacterial agents can obviously enhance sperm quality and the cure rate of CAP.

Aust Vet J, 2004 Aug, 82(8), 485 - 9
Antibiotic responsive ulcerative dermatoses in German Shepherd Dogs with mucocutaneous pyoderma; Bassett RJ et al.; Mucocutaneous pyoderma is a disease of unknown aetiology affecting mucocutaneous skin and is responsive to antibacterial therapy . It is reported to affect the lips, nasal planum, nares, perioral skin and less commonly, the eyelids, vulva, prepuce and anus . Three cases of mucocutaneous pyoderma are presented . Two of the cases showed ulcerative lesions in the inguinal and axillary regions in addition to more typically reported lesions . Two of the dogs had concurrent atopic dermatitis and the third had clinical signs suggestive of hyper-sensitivity disease . The clinical and histopathological features, differentiation of mucocutaneous pyoderma from discoid lupus erythematosus, and long-term management of mucocutaneous pyoderma are discussed.

Kansenshogaku Zasshi, 2004 Jul, 78(7), 566 - 73
{The performance of (1, 3)-beta-D-glucan and Aspergillus galactomannan measurement for early diagnosis of invasive aspergillosis in patients with hematological diseases}; Horiguchi Y; We analyzed the performance of (1, 3)-Beta-D-glucan (measurement by the alkaline-kinetic chromogenic Limulus method (FUNGITEC G test-MK, Fungitec) and the kinetic turbidimetric Limulus method {Beta-Glucan test WAKO, Wako}) and we carried out Aspergillus galactomannan antigen detection (enzyme-linked immunosorbent assay, ELISA test) for the early diagnosis of invasive aspergillosis in patients with hematological diseases at the time of febrile episodes of unknown origin that did not respond to antibacterial therapy for more than 3 days . During a one-year period (April 2002 to March 2003), a total of 69 febrile episodes in 58 patients were studied; 8 cases of invasive aspergillosis were diagnosed according to the definition of the European Organization for Research and Treatment of Cancer/Mycosis Study Group, and 61 cases were found to be non-mycotic diseases . Based on the analysis of 69 results with confirmed disease status, the overall performance of the Fungitec, the Wako, and the ELISA test were as follows: sensitivity was 0.88, 0.63, and 0.50, respectively, whereas the specificity was 0.85, 0.98, and 1.0, respectively . Moreover, there was a strong relationship between the log-transformed values of the (1, 3)-Beta-D-glucan levels measured by the two methods (r = 0.92 {95%CI, 0.89-0.94} ; p<0.001) . For the statistical analysis of these serological tests a receiver operating characteristic curve (ROC) was used, as well as the resulting area under the ROC curve (ROC AUC) . The ROC AUC and the cut-off values that gave the highest accuracy were as follows: 0.92, 24.9 pg/ml for the Fungitec, 0.84, 7.3 pg/ml for the Wako, and 0.89, 0.9 COI for the ELISA test, respectively . In conclusion, these results indicate that both of the two (1, 3)-Beta-D-glucan measurement approaches served equally well as surveillance tools for determining the extent of invasive aspergillosis; in addition, the log-transformed value of these tests can be used for comparison . Moreover, the ELISA test was found to have clinical utility, both as a surveillance and as a diagnostic tool when invasive aspergillosis was suspected . It should be noted that the galactomannan assay had sensitivity-related limitations; lowering the cut-off value is expected to increase the diagnostic value for use in cases of invasive aspergillosis.

Eur J Obstet Gynecol Reprod Biol, 2004 Oct 15, 116(2), 157 - 63
Preterm birth reduction after clotrimazole treatment during pregnancy; Czeizel AE et al.; OBJECTIVE: We have previously found an association between the combination of topical and vaginal clotrimazole treatment during pregnancy and a decreased prevalence of preterm births in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities . Thus the objective of this secondary analysis in the expanded data set was to evaluate potential confounders and to examine the possible interaction of clotrimazole with other drugs . STUDY DESIGN: Medically recorded birth weight/gestational age, in addition the prevalence of preterm birth and low birthweight infants of newborn infants without birth defects born to mothers with or without clotrimazole treatment during pregnancy were compared in the expanded control data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996 . RESULTS: The 17-year data set included 38,151 newborn infants and 8.1% were born to mothers who received clotrimazole treatment during pregnancy . There was an increase in mean gestational age among the exposed relative to the unexposed, resulting in a significant (34-64%) reduction in the prevalence of preterm births . This finding could not be explained by confounders and/or interaction with other drugs . CONCLUSION: The protective effect of clotrimazole for preterm birth was confirmed . We conclude that the protective effect of topical clotrimazole during pregnancy may be attributable to the beneficial effect of clotrimazole in the restoration of the abnormal colonization of the female genital organs and its known antibacterial and/or antiprotozoal effect.

Bioorg Med Chem Lett, 2004 Sep 6, 14(17), 4495 - 9
Synthesis and antibacterial activity of C-6 carbamate ketolides, a novel series of orally active ketolide antibiotics; Henninger TC et al.; A new series of antibacterial ketolides is reported, which features the use of a C-6 carbamate for tethering the arylalkyl sidechain to the macrolide core . The best members of this series display in vitro and in vivo activity comparable to telithromycin . Partial epimerization at C-2, unobserved in previously reported ketolides, was noted for this series.

Bioorg Med Chem Lett, 2004 Sep 6, 14(17), 4405 - 9
Synthesis and structural-activity relationships of 3-hydroxyquinazoline-2,4-dione antibacterial agents; Tran TP et al.; A series of 3-hydroxyquinazoline-2,4-diones was synthesized and evaluated for antibacterial activity . This series represents a novel addition to the DNA gyrase inhibitor class of antibacterials . Appropriate substitutions onto the core template yielded compounds with excellent potency against E . coli gyrase and significant in vitro Gram-negative and Gram-positive antibacterial activity.

Bioorg Med Chem Lett, 2004 Sep 6, 14(17), 4389 - 93
Synthesis of an unusual branched-chain sugar, 5-C-methyl-L-idopyranose for SAR studies of pyranmycins: implication for the future design of aminoglycoside antibiotics; Wang J et al.; The syntheses of a challenging branched-chain sugar and several L-sugars have been accomplished . Their application in studies of the antibacterial activity of pyranmycins is reported, which could provide new strategies for the future design of aminoglycoside antibiotics.

Bioorg Med Chem, 2004 Oct 1, 12(19), 5115 - 31
Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA-FtsZ interaction; Jennings LD et al.; The ZipA-FtsZ protein-protein interaction is a potential target for antibacterial therapy . The design and parallel synthesis of a combinatorial library of small molecules, which target the FtsZ binding area on ZipA are described . Compounds were demonstrated to bind to the FtsZ binding domain of ZipA by HSQC NMR and to inhibit cell division in a cell elongation assay.

Fitoterapia, 2004 Sep, 75(6), 599 - 602
Antibacterial activity of essential oils of Pimenta racemosa var . terebinthina and Pimenta racemosa var . grisea; Saenz MT et al.; The antibacterial activity of essential oils of Pimenta racemosa var . terebinthina and P . racemosa var . grisea was determined against Gram (+) and Gram (-) bacteria . P . racemosa var . grisea demonstrated a more pronounced activity . These data would indicate the potential usefulness of the variety grisea as a microbiostatic, antiseptic or disinfectant agent.

Fitoterapia, 2004 Sep, 75(6), 589 - 91
Antibacterial activity of Salacia beddomei; Deepa MA et al.; Leaves and stems of Salacia beddomei were extracted successively with petroleum ether, ethyl acetate and chloroform and tested for their antibacterial activity . Ethyl acetate extracts were found to be most effective against all the tested organisms.

Fitoterapia, 2004 Sep, 75(6), 573 - 6
Germacranolides from Anvillea radiata; El Hassany B et al.; The aerial parts of Anvillea radiata yielded a new germacranolide, 8alpha,9alpha-epoxyparthenolide (3), together with two known compounds, 9alpha-hydroxyparthenolide (1) and parthenolid-9-one (2) . The structures of the compounds were elucidated from IR, HRMS, 1H and 13C-NMR, COSY, HETCOR, HMBC and HOHAHA spectral data . The major component 1 was tested for its cytotoxicity and antibacterial activity.

Insect Biochem Mol Biol, 2004 Sep, 34(9), 937 - 49
Differential gene expression between alate and dealate queens in the red imported fire ant, Solenopsis invicta Buren (Hymenoptera: Formicidae); Haisheng Tian et al.; The transition of fire ant queens from alates to dealates, following a mating flight, is associated with numerous important physiological changes . A molecular analysis of gene expression differences that occur between alates and dealates was performed using the suppression subtractive hybridization (SSH) method . 983 SSH clones were arrayed and screened by dot blot hybridization, followed by Northern blot analysis for selected clones . Gene expression profiles throughout fire ant development were determined using semi-quantitative reverse transcriptase polymerase chain reactions (RT-PCR) . The cytochrome c oxidase subunit II and STARS (striated muscle activator of Rho signaling) transcripts were expressed at higher levels in dealates compared to alates and may be involved in the programmed cell death of the flight muscles . Three different vitellogenin genes and two unique yellow g-like genes were identified that may be closely associated with the reproductive system and/or nutrient transport . Two putative antibacterial peptides, abaecin and hymenoptaecin precursors, were highly expressed in dealate queens, suggesting that they are present as an immune system component during this important stage of fire ant development . The genes identified in this study may be utilized as novel targets for fire ant control and will also provide molecular markers for studies of other social insects .

Zh Mikrobiol Epidemiol Immunobiol, 2004 May-Jun, (3), 105 - 12
{Role of proteins of the macroglobulin family in the mechanisms of infection}; Zorin NA et al.; Information on the properties of proteins of the macroglobulin family taking part in the host protection from viral, fungal and bacterial pathogens is reviewed . High plasticity and polyfunctional character of these proteins makes it possible to realize different protective functions . They inhibit the lysis of the cell wall by binding the hydrolases of the pathogen thus blocking its penetration into the cell, directly participate in the presentation of antigens to immunocompetent cells, transport antibacterial substances (interferons, lysozyme) to the zone of infection . In addition, macroglobulins take part in the apoptosis regulation in infected cells, utilization of the lysosomal enzymes of annihilated pathogens . The complexes of macroglobulins with some proteins are powerful inductors of antibody production . Further studies of the properties of these proteins will result in a better understanding of the nature of infectious process . The possibility of artificial formation of macroglobulin complexes with pathogen components or with substances possessing protective or anti-inflammatory properties opens prospects for using these proteins in the fields of vaccinology, gene therapy and molecular biology.

DNA Seq, 2004 Apr, 15(2), 123 - 34
Analysis of a 108-kb region of the Saccharopolyspora spinosa genome covering the obscurin polyketide synthase locus; Zirkle R et al.; A 108-kb genomic DNA region of Saccharopolyspora spinosa NRRL 18395, producer of the agriculturally important insecticidal antibiotics spinosyns, has been cloned, sequenced and analyzed to reveal clustered genes encoding a type I polyketide synthase (PKS) complex . The genes for the PKS are flanked by genes encoding homologs of enzymes that are involved in the urea cycle, valine, leucine and isoleucine biosynthesis and energy metabolism . While the disruption of the PKS genes by insertional inactivation was not expected to abolish the production of spinosyns, no differences were found in the antibacterial, antifungal, or insecticidal activities either of the parental and the knockout mutant strains under the growth conditions tested . Deduction of the most likely structure of the polyketide core of the cryptic metabolite, termed obscurin, from the predicted modules and domains of the PKS suggests the formation of a highly unsaturated substituted C22 carboxylic acid that might undergo further processing after its release from the PKS.

Acta Crystallogr C, 2004 Sep, 60(Pt 9), o636 - 8 Epub 2004 Aug 11.
Two biologically active thiophene-3-carboxamide derivatives; Vasu et al.; The compounds 2-{{(E)-(4-methoxyphenyl)methylene}amino}-N-(3-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide, C24H24N2O2S, (I), and N-(4-methylphenyl)-2-{{(E)-(4-methylphenyl)methylene}amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide, C24H24N2OS, (II), show antibacterial and antifungal activities . The m-toluidine ring in (I) and the p-toluidine ring in (II) are coplanar with their respective thiophene rings . In (I), an intermolecular C-H...O hydrogen bond is present, whereas (II) does not exhibit any significant intermolecular interactions . However, in both compounds, an intramolecular N-H.N hydrogen bond forms a pseudo-six-membered ring, thus locking the molecular conformation and eliminating conformational flexibility.

J Physiol, 2004 Nov 15, 561(Pt 1), 183 - 94 Epub 2004 Nov 15.
Transcellular thiocyanate transport by human airway epithelia; Fragoso MA et al.; Human airway mucosa synthesizes and secretes lactoperoxidase (LPO) . As H(2)O(2) and thiocyanate (SCN(-)) are also present, a functional LPO antibacterial defence system exists in the airways . SCN(-) concentrations in several epithelial secretions are higher than in serum, although the mechanisms of transepithelial transport and accumulation in these secretions are unknown . To examine SCN(-) accumulation in secretions, human airway epithelial cells, re-differentiated at the air-liquid interface, were used in open-circuit conditions . {(14)C}SCN(-), in the basolateral medium, was transported across the epithelium and concentrated tenfold at the apical surface . Measurement of the transepithelial potential showed that the basolateral compartment was positive relative to the apical surface (13.7 +/- 1.8 mV) and therefore unfavourable for passive movement of SCN(-) . Transport was dependent on basolateral {SCN(-)} and saturable (K(m,app) = 69 +/- 25 microM); was inhibited by increased apical {SCN(-)}; and was dependent on the presence of basolateral Na(+) . Perchlorate (K(i,app) = 0.6 +/- 0.05 microM) and iodide (K(i,app) = 9 +/- 8 microM) in the basolateral medium reversibly inhibited transport, but furosemide did not . Iodide was also transported (K(m,app) = 111 +/- 69 microM) . RT-PCR and immunohistochemistry confirmed expression of Na(+)-I(-) symporter (NIS) in the airways . SCN(-) transport was insensitive to apical disulphonic acid Cl(-) channel blockers, but sensitive to apical glibenclamide and arylaminobenzoates . Forskolin and dibutyryl cAMP increased transport . These data suggest SCN(-) transport may occur through basolateral NIS-mediated SCN(-) concentration inside cells, followed by release through an apical channel, perhaps cystic fibrosis transmembrane conductance regulator.

Pharmacoeconomics, 2000 Oct, 18(4), 369 - 81
Cost effectiveness of cephalosporin monotherapy and aminoglycoside/ureidopenicillin combination therapy . For the treatment of febrile episodes in neutropenic patients; Paladino JA et al.; OBJECTIVE: To assess the relative cost effectiveness of cephalosporin monotherapy options and aminoglycoside/ureidopenicillin combination therapy for the treatment of febrile episodes in adult patients with neutropenia . DESIGN AND SETTING: This was a retrospective cost-effectiveness analysis conducted from the institutional perspective . METHODS: The analysis was based on 741 febrile episodes in adult patients with neutropenia enrolled in 5 randomised trials: 3 comparing monotherapy with ceftazidime or cefepime, and 2 comparing cefepime monotherapy versus aminoglycoside/ureidopenicillin combination therapy . Resource utilisation included costs for study antibacterials, treatment of adverse effects and failures, and hospitalisation . The primary end-point was the overall cost of treatment per patient . Cost-effectiveness ratios were also analysed . RESULTS: No significant differences in clinical success rates were detected . Median per-patient costs in the monotherapy comparisons were $US7849 for cefepime and $US7788 for ceftazidime {1997 values; not significantly different (NS)} . Corresponding costs for the monotherapy versus combination therapy comparisons were $US9780 for cefepime and $US10 159 for gentamicin/ureidopenicillin (NS) . Despite a higher acquisition cost for cefepime, there were no statistically significant differences in cost effectiveness compared with either ceftazidime monotherapy or gentamicin/ureidopenicillin combination therapy . Sensitivity analyses revealed that monotherapy can be cost effective compared with combination therapy in many situations . CONCLUSION: There were no economic differences between the 3 regimens tested . Therefore drug cost should not be a deciding factor when choosing antibacterial therapy for the treatment of febrile episodes in adult patients with neutropenia.

Eksp Klin Farmakol, 2004 May-Jun, 67(3), 30 - 3
{Antiulcer activity of furoxanopyrimidine derivatives}; Kaminka ME et al.; A series of four new furoxanopyrimidine derivatives was synthesized and studied with respect to antiulcerous, antisecretory, and antibacterial activity . Two compounds exhibit antiulcerous effect not accompanied (in contrast to the well-known H2 receptor blockers, quiditene, and other antiulcerous drugs) by inhibition of gastric acid secretion . No one of the studied compounds exhibited antibacterial activity in the tests with Helicobacter pylori.

Int J Pharm, 2004 Sep 10, 282(1-2), 87 - 94
Pharmacokinetics of a cephalone (CQ-M-EPCA) in rats after oral, intraduodenal and intravenous administration; Perez-Guille B et al.; As part of the development of a new series of antibacterial agents derived from coupling a beta-lactamic precursor with a fluoroquinolone and named cephalones, the pharmacokinetics of one derivate: CQ-M-EPCA in rats after intravenous, intragastric and intraduodenal routes, was carried out . After the IV injection of 20 mg/kg or 40 mg/kg of this cephalone, plasma concentrations at the time zero (Cp0) were 3.1 and 11.26 microg/ml, respectively . Plasma concentrations decreased rapidly to almost disappear in both instances . Forty-five minutes later, a surge in concentrations, in the 40 mg/kg group, with a maximal plasma concentration (Cpmax) of 2.97 microg/ml was observed . An elimination half-life (T1/2el) of 2.36 +/- 0.33 h . was calculated . The drug was undetected by the ninth hour . Intragastric administration of the drug resulted in Cpmax of 3.78 +/- 0.26 microg/ml with a time to reach Cpmax (Tmax) of 25 min and T1/2el = 3.22 h . Same variables after intraduodenal administration were Cpmax 4.71 microg/ml; Tmax 1h, and T1/2el 3.41 h . Outstandingly high bioavailabilities after intragastric and intraduodenal administration (169 and 246%, respectively), together with the shape of the concentration versus time profiles after IV administration suggest that the drug undergoes a complex redistribution phenomenon, while showing high tissue diffusion with an apparent volume of distribution of 3.33 l/kg.

Expert Opin Drug Saf, 2004 Sep, 3(5), 405 - 14
The safety and efficacy of linezolid in orthopaedic practice for the treatment of infection due to antibiotic-resistant organisms; Harwood PJ et al.; Linezolid is the first of a new class of antibacterial agents, the oxazolidinones . It is particularly effective against Gram-positive infections and little resistance has been reported, even amongst methicillin- and vancomycin-resistant bacteria . The compound's excellent oral bioavailability and reasonable safety profile, along with the increasing incidence of resistant infections, means that linezolid offers a valuable alternative to more traditional therapies such as vancomycin . Although no large randomised trials have been carried out in patients with orthopaedic infections such as osteomyelitis and septic arthritis, early results are encouraging . However, the apparent increase in observed adverse events, particularly bone marrow suppression, seen with prolonged administration, means that treatment of such patients must be undertaken with careful surveillance, at least until these complications are better understood.

Skin Therapy Lett, 2004 Aug-Sep, 9(7), 4 - 5, 9
Ciclopirox (Loprox) gel for superficial fungal infections; Gupta AK et al.; Ciclopirox (Loprox) is a broad-spectrum antifungal medication that also has antibacterial and anti-inflammatory properties . Its main mode of action is thought to be its high affinity for trivalent cations, which inhibit essential co-factors in enzymes . Clinical trials have shown that ciclopirox gel is a successful treatment for seborrheic dermatitis of the scalp as well as for tinea pedis . Adverse effects are generally mild and include a skin-burning sensation, contact dermatitis, and pruritus . Ciclopirox is indicated in the US for the treatment of tinea pedis, tinea corporis, pityriasis versicolor, seborrheic dermatitis, and cutaneous candidiasis.

J Nat Prod, 2004 Aug, 67(8), 1423 - 5
New sphingosines from a gorgonian, Pseudopterogorgia australiensis Ridley, of the Indian Ocean; Krishna N et al.; Two new sphingosines, (2S,3R)-2-(docosanoyl amino)nonadecane-1,3-diol (1) and (2S,3S,4R)-2-{(2'R)-2'-hydroxynonadecanoylamino}nonadecane-1,3,4-triol (3), along with the known (2S,3R,4E)-2-(heptadecanoylamino)octadec-4-ene-1,3-diol, have been isolated from Pseudopterogorgia australiensis, of the Indian Ocean . The structures were deduced from spectral and chemical methods . Compounds 1-3 showed moderate antibacterial activity.

J Nat Prod, 2004 Aug, 67(8), 1262 - 7
Nagelamides A-H, new dimeric bromopyrrole alkaloids from marine sponge Agelas species; Endo T et al.; Eight new dimeric bromopyrrole alkaloids, nagelamides A-H (1-8) and a monomeric one, 9,10-dihydrokeramadine (9), have been isolated from the Okinawan marine sponge Agelas sp., and the structures were elucidated from spectroscopic data . Nagelamides A-H (1-8) exhibited antibacterial activity against Gram-positive bacteria . Nagelamide G (7) inhibited protein phosphatase 2A activity.

J Environ Sci Health A Tox Hazard Subst Environ Eng, 2004, 39(8), 1969 - 78
Determination of nonsteroidal anti-inflammatory drugs, caffeine, and triclosan in wastewater by gas chromatography-mass spectrometry; Thomas PM et al.; Pharmaceuticals are a class of chemicals whose fate in the environment has received increasing attention in the past few years . A quantitative method was developed for the determination of acidic pharmaceuticals (ibuprofen, naproxen, ketoprofen, mefenamic acid, and diclofenac), caffeine and the antibacterial triclosan in wastewater effluent . The compounds were extracted from wastewater samples on Waters Oasis HLB solid-phase extraction columns, derivatized with N,O-bis {Trimethylsilyl} trifluoroacetamide (BSTFA) and analyzed using gas chromatography-mass spectrometry . Estimated method detection limits ranged from 6 to 45 ng/L based on replicate analyses (n = 10) . This method was applied to the analysis of effluent from a wastewater treatment plant and compounds were detected at concentrations of 18-72 ng/L.

Trends Biotechnol, 2004 Sep, 22(9), 434 - 6
Drugs against superbugs: private lessons from bacteriophages; Brown ED; Bacterial genomics has provided a plethora of potential targets for antibacterial drug discovery, however, success in the hunt for new antibiotics will hinge on selecting targets with the highest potential . A recent paper by Liu and coworkers describes a new approach to target selection that uncovers strategies used by bacteriophage to disable bacteria . The method uses key phage proteins to identify and validate vulnerable targets and exploits them further in the identification of new antibacterial leads.

Pharmacoeconomics, 2004, 22(13), 829 - 37
Acute rhinosinusitis : a pharmacoeconomic review of antibacterial use; Wasserfallen JB et al.; Acute rhinosinusitis is a common disease, in both children and adult patients, and happens most often in the setting of a viral infection with or without bacterial superinfection . Although spontaneous resolution is common, antibacterials are often prescribed and have a tremendous impact on costs, either directly or through the emergence of resistance in causative or colonising micro-organisms . The purpose of this work was to review published literature from 1989 to 2002 on antibacterial treatment in acute rhinosinusitis from a clinical and economical perspective . A relatively small number of studies have compared antibacterials with placebo and few have suggested that antibacterials are superior to placebo, except when a bacterial cause is established or in the presence of specific CT-scan findings . On the other hand, 58 randomised controlled trials were published between 1989 and 2002, that compared the relative efficacy of various antibacterials . Most of these studies had serious methodological flaws, and no single antibacterial proved superior to its comparators . Economic data are scarce and indicate cost of disease is high . Of the different treatment strategies assessed symptomatic treatment (patients being treated with antibacterials only if they failed to improve after 7 days) was the most cost-effective approach, compared with treating patients on the basis of specific clinical criteria, empirical treatment (all patients initially treated with antibacterials), or radiology-guided treatment . Cost effectiveness varied with disease prevalence . In conclusion, this pharmacoeconomic review of antibacterial use in acute rhinosinusitis shows the need for improvement in the quality of the studies feeding economic analyses, but suggests that huge financial interests are at stake . Savings achievable, by better targeting patients needing antibacterial treatment, could be substantial, and more practical and precise diagnostic procedures are clearly needed . Acute rhinosinusitis is a typical example of a clinical dilemma in which good clinical practice must be balanced against imperfect information and patients' individual interests balanced against society's interest.

Antimicrob Agents Chemother, 2004 Sep, 48(9), 3436 - 41
In vivo imaging of bioluminescent Escherichia coli in a cutaneous wound infection model for evaluation of an antibiotic therapy; Jawhara S et al.; A rapid, continuous method for noninvasively monitoring the effectiveness of several antibacterial agents in real time by using a model of wound infection was developed . This study was divided into three steps: (i) construction of a plasmid to transform Escherichia coli into a bioluminescent variant, (ii) study of the bioluminescent E . coli in vitro as a function of temperature and pH, and (iii) determination of the MIC and the minimal bactericidal concentration of sulfamethoxazole-trimethoprim (SMX-TMP) . Finally, the efficacy of SMX-TMP was monitored in vivo in a cutaneous wound model (hairless rat) infected with this bioluminescent bacterium by using a bioluminescence imaging system . E . coli was transformed by electroporation with a shuttle vector (pRB474) containing the firefly (Photinus pyralis) luciferase gene, resulting in a bioluminescent phenotype . It was found that pH 5.0 was optimal for incorporation of the susbstrate D-luciferin for the luciferase reaction . In vitro, when the agar dilution method, standard turbidity assays, and the bioluminescence imaging system were used, E . coli(pRB474) proved to be susceptible to SMX-TMP . In vivo, at 4 h, SMX-TMP treatment was already efficient compared to no treatment (P = 0.034) . At 48 h, no bioluminescence was detected in the wound, demonstrating the susceptibility of E . coli to SMX-TMP . In conclusion, this study points out the advantage of using bioluminescence imaging to evaluate the effects of antibiotics for the treatment of acute infections in vivo in a nondestructive and noninvasive manner.

Dermatol Ther, 2004, 17(4), 279 - 88
Photocontact dermatitis; Deleo VA; Photocontact dermatitis is not a common condition, but neither is it rare . Both photo-irritant contact dermatitis (PICD) and photoallergic contact dermatitis (PACD) are seen by most dermatologists in general practice . PICD is diagnosed on clinical grounds and is usually caused by furocoumarins in plants like limes and celery . PACD is caused primarily by sunscreens but can also be the result of fragrances and antibacterial agents . PACD can only be diagnosed by photo-patch testing that most dermatologists, even those who patch test and give phototherapy in their office, do not perform . The procedure as outlined in this manuscript is relatively simple and can easily be accomplished in the dermatologist's office.

Contraception, 2004 Sep, 70(3), 227 - 31
A phase I comparative postcoital testing study of three concentrations of C31G; Mauck CK et al.; BACKGROUND: C31G is a broad-spectrum antibacterial agent that shows contraceptive properties in vitro . This postcoital testing study evaluated the ability of three C31G concentrations, 0.5%, 1.0% and 1.7%, administered as a 3.5-mL dose of a vaginal gel to prevent sperm from entering mid-cycle cervical mucus . Irritation of the genitalia and acceptability were also assessed . METHOD: At baseline, a mid-cycle cervical mucus test and a postcoital test were performed within 24 h of each other without use of any study products to establish normal mid-cycle cervical mucus and sperm penetration . Subjects then completed up to three test cycles using one of the three concentrations of study product during intercourse . RESULTS: Twenty-two of the 61 women enrolled completed a baseline cycle and at least one test cycle . An average of 14.6 progressively motile sperm per high power field was seen at baseline . This was reduced to 0.3 after use of 0.5% C31G, 0.5 after use of 1.0% C31G, and 0.4 after use of 1.7% C31G . There was no significant difference between test products (p >/= 1.000) but each test product was significantly different from baseline (p < 0.002) . Very little genital irritation was observed . There were more reports of leakage and messiness with increasing C31G concentration . CONCLUSION: This study suggests that all three concentrations of C31G are likely to give reasonable results in a contraceptive effectiveness trial . Based on the results of this and other trials, the 1.0% concentration has been selected for further development, including Phase III trials of contraceptive effectiveness.

J Ethnopharmacol, 2004 Oct, 94(2-3), 205 - 17
Assessing African medicinal plants for efficacy and safety: pharmacological screening and toxicology; Fennell CW et al.; This paper reviews progress in establishing the scientific rationale for and safety of traditional medicine use in Africa . Selected plants were screened for antibacterial, antifungal, anthelmintic, anti-amoebic, antischistosomal, antimalarial, anti-inflammatory and antioxidant activity, as well as psychotropic and neurotropic activity using appropriate in vitro tests . Isolation of active compounds, in almost all cases, provided scientific validation for the use of the plants in traditional medicine . Although plants used medicinally are widely assumed to be safe, many are potentially toxic . Where poisoning from traditional medicines has been reported, it is usually because the plants used have been misidentified in the form in which they are sold, or incorrectly prepared and administered by inadequately trained personnel . The issue of quality control may, in the interim, be addressed using chromatographic techniques.

Dev Comp Immunol, 2005, 29(1), 43 - 51
Effects of two hemolymph proteins on humoral defense reactions in the wax moth, Galleria mellonella; Park SY et al.; Two hemolymph proteins were isolated from the wax moth, Galleria mellonella, larvae by a two-step procedure consisting of acid extraction and reversed phase (RP)-HPLC . One was an apolipophorin III (apoLp-III) previously characterized as a lipopolysaccharide (LPS) binding protein in the hemolymph of G . mellonella . The other was confirmed to be a new protein with a molecular mass of 23,768.69 Da, referred to as Gm protein-24 . The full-length cDNA of Gm protein-24 was cloned from the fat body . The cDNA structure showed that it is a 219-residues protein derived from the precursor of 236 amino acids . The effects of apoLp-III and Gm protein-24 have been tested on the insect humoral immunity . ApoLp-III enhanced the activity of antibacterial peptide such as cecropin but Gm protein-24 had no effect on cecropin activity . On the other hand, Gm protein-24 and apoLp-III were both involved in the activation of prophenoloxidase (PPO) cascade, which has been regarded as a critical immune reaction in insect hemolymph . Of note, the Gm protein-24 was a significantly stronger activator of PPO cascade than apoLp-III .

Int J Antimicrob Agents, 2004 Sep, 24(3), 213 - 8
Antibiotic use in German university hospitals 1998-2000 (Project INTERUNI-II); de With K et al.; In a pilot study we established a hospital antibiotic use database from which estimates for antibiotic consumption in German hospitals (expressed as defined daily doses per 100 patient days, DDD/100) can be retrieved for both benchmarking and antibiotic use and resistance research purposes . Data from eight university hospitals (1998-2000) showed a mean antibiotic use density of 60.1 DDD/100 in the surgical and 79.3 DDD/100 in the medical services . Antibiotic use was higher in the intensive care units (surgery: 146 DDD/100, medicine: 187 DDD/100) than in haematology-oncology services (110.8 DDD/100) or in other surgical (51.6 DDD/100) and medical (66 DDD/100) service areas . There were major differences in the use of specific antibacterial drug classes between service areas . The established database allows detailed analysis in antibacterial drug use and can be linked to bacterial resistance surveillance databases.

Biochem Biophys Res Commun, 2004 Sep 17, 322(2), 490 - 6
Processing of crayfish hemocyanin subunits into phenoloxidase; Lee SY et al.; Hemocyanin and phenoloxidase are both copper-binding proteins involved in the immune system for a wide range of animal species . In crayfish, these proteins were purified and characterized from plasma and hemocytes, respectively . Recently, we have reported that the processing of one of the hemocyanin subunits occurs by a proteolytic cleavage under acidic conditions which results in the release of an antibacterial peptide designated as astacidin 1 from the C-terminus {J . Biol . Chem . 278 (2003) 7927} . In the present paper, we show that cleavage of crayfish hemocyanin subunit 2 at the N-terminal part results in that the processed hemocyanin exhibits phenoloxidase activity . The calculated mass of the cloned hemocyanin 2 is 78,372Da, which corresponds to the size obtained after SDS-PAGE under reducing conditions of the purified hemocyanin and pI is estimated to be 5.70 . The complete hemocyanin 2 sequence shows 74% and 44% similarity with hemocyanin 1 and prophenoloxidase of crayfish, respectively . Crayfish hemocyanin exhibited phenoloxidase activity in presence of trypsin, but no activity could be detected if treated with sodium dodecyl sulfate . These results show that hemocyanin of crayfish is involved in several immune responses such as an oxygen carrier protein, as a precursor for an antibacterial peptide, and a molecule with phenoloxidase function.

Ann Fr Anesth Reanim, 2004 Jul, 23(7), 704 - 13
{Monitoring of antibiotic treatment of patient with a severe bacterial infection}; Aubert G et al.; OBJECTIVES: To provide a summary of useful up-to-date knowledge regarding experimental and clinical bacteriology, pharmacokinetics and pharmacodynamics in order to optimise efficacy of antibiotic treatment of hospital patients with serious bacterial infections . DATA SOURCES: Record of references from national and international journals in Medline . STUDY SELECTION: Extraction of the most relevant theoretical and practical data from studies published over the last 5 years . DATA SYNTHESIS: Changes in resistance to antibiotics, as well as the limited number of new antibacterial drugs available and the cost of therapeutic failure all militate in favour of a more elaborate approach to therapeutic strategies involving antibiotics, particularly regarding hospitalised patients . The efficacy of antibiotic therapy can be optimised through the utilization of bacteriological, pharmacokinetic and pharmacodynamic data, thereby increasing the likelihood of a successful outcome . While the antibiogram constitutes the fundamental analytical tool for evaluating the activity of antibiotics, the minimum inhibitory concentration (MIC) is of value in selecting appropriate drugs and dosages, particularly for bacterial strains having lower susceptibility . Screening for genes of resistance to antibiotics provides more accurate analysis of bacterial resistance . In recent years, the efficacy of antibiotics has been improved through the use of a number of pharmacodynamic parameters: inhibitory quotient (IQ), area under the serum concentration-time curve to MIC ratio (AUC/MIC) and the time the serum concentration is greater than the MIC (T > MIC) . In standard practice, data readily available to the clinician comprise the MIC and serum antibiotic concentrations . There is some discussion concerning optimisation of antibiotic efficacy through the use of these parameters . CONCLUSION: Close collaboration between clinicians and microbiologists results in improved quality of antibiotic therapy and better management of antibiotics.

Bioorg Med Chem Lett, 2004 Sep 20, 14(18), 4647 - 50
Synthesis and antibacterial activity of some aryloxy/thioaryloxy oxazolidinone derivatives; Arora V et al.; A series of aryloxy/thioaryloxy oxazolidinone derivatives has been synthesized and tested for in vitro antibacterial activity by MIC determination against a panel of susceptible and resistant Gram-positive and Gram-negative microorganisms, some of which are resistant to methicillin and vancomycin . Compounds 12a, 12b, 14a, and 14b from this series were found to be equipotent or more potent than linezolid in vitro.

J Pharm Pharmacol, 2004 Sep, 56(9), 1143 - 53
An investigation into the biological activity of the selected histidine-containing diketopiperazines cyclo(His-Phe) and cyclo(His-Tyr); McCleland K et al.; Although cyclic diketopiperazines have been known since the beginning of the century, only now have they attracted considerable interest with respect to their biological activity . The aim of this study was to determine if the diketopiperazines cyclo(L-histidyl-L-phenylalanyl) (cyclo(His-Phe)) and cyclo(L-histidyl-L-tyrosyl) (cyclo(His-Tyr)) have significant biological activity relevant to the treatment of cardiovascular-related disease states, cancer and infectious diseases . Haematological studies were performed, including thrombin substrate binding, blood clotting time, platelet adhesion, platelet aggregation and fibrinolysis assays . A cytotoxicity screening utilizing a tetrazolium-based assay on the cell lines HeLa, WHCO3, and MCF-7 was performed . The whole-cell patch-clamp technique was used to investigate ion-channel activity in ventricular myocytes of rats, and isolated rat heart studies were performed to investigate the cardiac effects involving heart rate and coronary flow rate . Cyclo(His-Tyr) produced a significant prolongation of blood clotting time, slowing of clot lysis and inhibition of ADP-induced platelet adhesion and aggregation (P < 0.05) . Cyclo(His-Phe) showed significant (P < 0.05) anti-tumour activity, causing greatest reduction of cell viability in cervical carcinoma cells . Preliminary results from patch-clamp studies indicate that both diketopiperazines caused blocking of sodium and calcium ion channels, but opening of inward rectifying potassium ion channels . In the rat isolated heart studies, cyclo(His-Phe) caused a gradual reduction in heart rate (P = 0.0027) and a decrease in coronary flow rate (P = 0.0017) . Cyclo(His-Tyr) significantly increased the heart rate (P = 0.0016) but did not cause any significant change of coronary flow rate (P > 0.05) . Cyclo(His-Tyr) showed notable (P < 0.05) antibacterial activity and both diketopiperazines showed excellent antifungal activity (P < 0.05) . These observations reveal diketopiperazines to be ideal lead compounds for the rational design of an agent capable of preventing metastasis, inhibiting tumour growth, and as potential chemotherapeutic, antiarrhythmic and antihypertensive agents, as well as potential antibacterial and antifungal agents.

Biosci Biotechnol Biochem, 2004 Aug, 68(8), 1821 - 3
Proteomic studies of lipopolysaccharide-induced polypeptides in the silkworm, Bombyx mori; Wang Y et al.; Silkworm larvae at the 5th instar were injected with lipopolysaccharide from Escherichia coli and inducible polypeptides were examined within a pI range of 3-10 and a size range of 14-97 kDa by proteomics, including peptide mass fingerprinting . No polypeptides were induced in the midgut . FB1 and H1-4 polypeptides were significantly induced in fat body and hemolymph, respectively . FB1 and H1 were estimated to be antitrypsin and serpin-2 proteinase inhibitors respectively . H2 and H3 were novel polypeptides . H4 was estimated to be attacin antibacterial polypeptide with high coverage of sequence . The amounts of all the induced polypeptides decreased at 48 h after the injection.

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