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1.
Undersea Hyperb Med ; 30(1): 47-55, 2003.
Article in English | MEDLINE | ID: mdl-12841608

ABSTRACT

This study describes the changes in autonomic nervous activity and stress hormones during a hyperbaric saturation dive up to 4.1 MPa in six subjects. Their autonomic nervous activity was assessed by a power spectrum analysis of heart rate variability (HRV). The levels of plasma epinephrine (E) and norepinephrine (NE), and those of salivary chromogranin A and cortisol, were compared with the pre-dive control levels. Restrained activity of the cardiac vagal nerve was recognized in the early post-dive period by a decrease in high frequency power and by the standard deviation of the HRV. By contrast, enhanced activity of sympathetic nerve was recognized in the early post-dive period by an elevated plasma E, and also in the late 3.1 MPa, 4.1 MPa, and post-dive periods by elevated plasma NE. The levels of plasma E and NE were the most sensitive indicators of sympathetic nervous activity. A joint utilization of HRV parameters with stress hormones may be an effective means of estimating the adaptive responses between hyperbaric and normobaric environments.


Subject(s)
Autonomic Nervous System/physiology , Diving/physiology , Heart Rate/physiology , Adult , Biomarkers/analysis , Blood Pressure , Chromogranin A , Chromogranins/analysis , Epinephrine/blood , Heart/innervation , Humans , Hydrocortisone/analysis , Male , Norepinephrine/blood , Saliva/chemistry
2.
Antimicrob Agents Chemother ; 45(12): 3538-43, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11709336

ABSTRACT

We established a human immunodeficiency virus type 1 (HIV-1) envelope (Env)-mediated membrane fusion assay and examined the small-molecule CCR5 antagonist TAK-779 and its derivatives for their inhibitory effects on HIV-1 Env-mediated membrane fusion and viral replication. The membrane fusion assay is based on HIV-1 long terminal repeat-directed beta-D-galactosidase reporter gene expression in CD4- and CCR5-expressed HeLa (MAGI-CCR5) cells after cocultivation with effector 293T cells expressing HIV-1 Env. Inhibition of HIV-1 replication was also determined in MAGI-CCR5 cells infected with the corresponding cell-free HIV-1. TAK-779 effectively suppressed R5 HIV-1 (strain JR-FL) Env-mediated membrane fusion as well as viral replication. Its 50% inhibitory concentrations (IC(50)s) for membrane fusion and viral replication were 0.87 +/- 0.11 and 1.4 +/- 0.1 nM, respectively. These values corresponded well to the IC(50) for (125)I-RANTES (regulated on activation, T cell expressed, and secreted) binding to CCR5 (1.4 nM). The inhibitory effects of 18 TAK-779 derivatives on membrane fusion differed from one compound to another. However, there was a close correlation among their inhibitory effects on membrane fusion, viral replication, and RANTES binding. The correlation coefficient between their IC(50)s for membrane fusion and viral replication was 0.881. Furthermore, since this assay depends on Env expressed in the effector cells, it is also applicable to the evaluation of CXCR4 antagonists. These results indicate that the HIV-1 Env-mediated membrane fusion assay is a useful tool for the evaluation of entry inhibitors.


Subject(s)
Amides/pharmacology , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , HIV-1/drug effects , Membrane Fusion/drug effects , Quaternary Ammonium Compounds/pharmacology , Viral Envelope Proteins/physiology , Virus Replication/drug effects , Chemokine CCL5/metabolism , Gene Products, tat/biosynthesis , HeLa Cells , Humans , T-Lymphocytes/drug effects , T-Lymphocytes/virology , tat Gene Products, Human Immunodeficiency Virus
3.
Chem Pharm Bull (Tokyo) ; 49(9): 1102-9, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11558595

ABSTRACT

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Azoles/chemical synthesis , Azoles/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Alkylation , Animals , Antifungal Agents/therapeutic use , Aspergillus fumigatus/drug effects , Azoles/therapeutic use , Candida albicans/drug effects , Candidiasis/drug therapy , Candidiasis/microbiology , Half-Life , Hemolysis/drug effects , Imidazoles/therapeutic use , In Vitro Techniques , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Prodrugs/therapeutic use , Rats , Solubility , Tetrazoles/therapeutic use
4.
J Antibiot (Tokyo) ; 54(4): 364-74, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11426661

ABSTRACT

A systematic approach for improving the water-solubility of anti-MRSA (methicillin-resistant Staphylococcus aureus) cephalosporin derivatives is described. We first tried to improve the water-solubility of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (1a) by substitution of the C-3' pharmacophore. Replacement of the C-3' pharmacophore with a 1-methyl-4-pyridinio group improved the water-solubility without decreasing the anti-MRSA activity. Furthermore, we applied the N-modified prodrug strategy to the C-7 acyl group in order to enhance the water-solubility drastically. Among the compounds prepared, the N-phosphono type prodrugs 2a(1-methylimidazo[1,2-b]pyridazinium derivative) and 2b (1-methyl-4-pyridinio derivative) showed water-solubility appropriate for a product intended for intravenous injection and in vivo anti-MRSA activity comparable to that of vancomycin.


Subject(s)
Bacterial Proteins , Carrier Proteins , Cephalosporins/pharmacology , Methicillin Resistance/physiology , Muramoylpentapeptide Carboxypeptidase , Prodrugs/pharmacology , Staphylococcus aureus/drug effects , Animals , Cephalosporins/administration & dosage , Cephalosporins/pharmacokinetics , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hexosyltransferases/metabolism , Hydrogen-Ion Concentration , Injections , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Multienzyme Complexes/metabolism , Penicillin-Binding Proteins , Peptidyl Transferases/metabolism , Prodrugs/administration & dosage , Prodrugs/pharmacokinetics , Protein Binding , Solubility , Spectrophotometry, Infrared
5.
J Antibiot (Tokyo) ; 54(3): 257-77, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11372783

ABSTRACT

In the course of our exploration for a novel cephalosporin derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we modified the C-3 linked spacers of cephem derivatives bearing a 1-methylimidazo[1,2-b]pyridazinium-6-yl group at the C-3' position and 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxy-iminoacetyl group at the C-7 position. The optimal spacers were the (E)-2-vinyl and (E)-2-thiovinyl groups seen in 19a and 29aa, respectively. Their anti-MRSA activity was 16 to 32 times as potent as that of cefozopran (CZOP). Focusing on the (E)-2-vinyl and (E)-2-thiovinyl spacers, we further modified the alkoxyimino groups in the C-7 acyl moiety and the 1-alkylimidazo[1,2-b]pyridazinium moieties at the C-3' position and investigated the structure-activity relationships (SAR) of the derivatives. Consequently, we selected 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (29ca) as a new anti-MRSA parenteral cephalosporin candidate for further biological evaluation. The selected 29ca showed anti-MRSA activity comparable to that of vancomycin (VCM) both in vitro and in vivo, high affinity (IC50)=2.7 microg/ml) for penicillin binding protein 2' (PBP2') of MRSA and potent activity against Gram-negative bacteria as well.


Subject(s)
Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Staphylococcus aureus/drug effects , Cephalosporins/chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Magnetic Resonance Spectroscopy , Methicillin Resistance , Microbial Sensitivity Tests , Molecular Structure , Spectroscopy, Fourier Transform Infrared
6.
AIDS Res Hum Retroviruses ; 16(10): 935-41, 2000 Jul 01.
Article in English | MEDLINE | ID: mdl-10890354

ABSTRACT

The beta-chemokine receptor CCR5 is considered to be an attractive target for inhibition of CCR5-using (R5 or macrophage-tropic) HIV-1. However, R5 HIV-1 cannot replicate in CD4+ T cell or monocyte lines because of the lack of CCR5 expression on their surface, which apparently hampers discovery and development of effective CCR5 antagonists against HIV-1 replication. In this study, we have established the CCR5-expressing T cell line MOLT-4/CCR5, highly permissive to the replication of R5 HIV-1. The cells express a considerable amount of CCR5 on their surface. When the cells were infected with the R5 HIV-1 strains Ba-L and JR-FL, the virus-induced cytopathic effect (syncytium formation) was observed, and the cells produced large amounts of HIV-1 p24 antigen in the culture supernatants. The analyses of progeny viruses for their coreceptor use and gp120 V3 nucleotide sequence revealed that they were R5 HIV-1. The parental cell line MOLT-4 was much less susceptible to Ba-L and totally insusceptible to JR-FL. Furthermore, MOLT-4/CCR5 cells could support the replication of an R5 clinical isolate, but MOLT-4 cells could not. When TAK-779, a novel small-molecule nonpeptide CCR5 antagonist, was examined for its inhibitory effect on R5 HIV-1 replication in MOLT-4/CCR5 cells, the compound displayed potent antiviral activity, as demonstrated in peripheral blood mononuclear cells. These results indicate that the established cell line will be an extremely useful tool for experiments with R5 HIV-1.


Subject(s)
HIV-1/physiology , Receptors, CCR5/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Tumor Cells, Cultured , Amides/pharmacology , Anti-HIV Agents/pharmacology , Cell Culture Techniques/methods , Cell Division , Cell Survival , Cytopathogenic Effect, Viral , HIV-1/drug effects , Humans , Quaternary Ammonium Compounds/pharmacology , Receptors, CCR5/genetics , Transfection , Virus Replication
8.
Chem Pharm Bull (Tokyo) ; 48(12): 1935-46, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11145148

ABSTRACT

New optically active antifungal azoles, N-14-(azolyl)phenyl]- and N-14-(azolylmethyl)phenyl]-N'-[(IR,2R)-2(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(IH-1,2,4-triazol-1-yl)propyllazolones (1, 2, 3), were prepared in a stereocontrolled manner. Compounds 1-3 showed strong antifungal activity against Candida albicans in vitro. Among them, the imidazolidinones 3 showed a broad antifungal spectrum in vitro as well as potent in vivo activity against candidiasis and aspergillosis in mice. The imidazolidinones (3i, j, k) having 1H-1,2,3-triazol-1-yl, 2H-2-tetrazolyl and IH-1-tetrazolyl moieties were found to exert strong protective effect against aspergillosis.


Subject(s)
Antifungal Agents/chemical synthesis , Azoles/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Azoles/chemistry , Azoles/pharmacology , Candida albicans/drug effects , Magnetic Resonance Spectroscopy , Optical Rotation
9.
J Antibiot (Tokyo) ; 53(10): 1053-70, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11132950

ABSTRACT

In order to improve the antibacterial activity of cefozopran (CZOP) against methicillin-resistant Staphylococcus aureus (MRSA), we initiated chemical modification to introduce a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyimino acetyl group at the C-7 position and a 3- or 6-substituted imidazo[1,2-b]pyridazinium or 5-substituted imidazo[1,2-a]pyridinium group at the C-3' position. Although this approach successfully enhanced the anti-MRSA activity of CZOP two to eight times, a slight decrease in the activity against Gram-negative bacteria including Pseudomonas aeruginosa was involved. Among the novel derivatives, 3-(6-aminoimidazo[1,2-b]pyridazinium-1-yl)methyl-7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)hydroxyiminoacetamido]-3-cephem-4-carboxylate (44a) showed an excellent balance of activity against MRSA and Gram-negative bacteria.


Subject(s)
Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Methicillin Resistance , Staphylococcus aureus/drug effects , Animals , Cephalosporins/chemistry , Cephalosporins/therapeutic use , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests/methods , Oximes/chemistry , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/drug effects , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Structure-Activity Relationship , Cefozopran
10.
J Antibiot (Tokyo) ; 53(10): 1071-85, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11132951

ABSTRACT

In an effort to discover a novel cefozopran (CZOP) derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we performed chemical modification of the alkoxyimino moiety and imidazo[1,2-b]pyridazinium group of CZOP. Among the prepared compounds, the cyclopentyloxyimino derivative 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyiminoacetamido]-3-(3,6-diaminoimidazo[1,2-b]pyridazinium-1-yl)methyl-3-cephem-4-carboxylate (20 g) showed the most potent anti-MRSA activity, reflecting its high affinity (IC50 = 1.6 microg/ml) for penicillin binding protein 2' (PBP2'), although its anti-MRSA activity was slightly inferior to that of vancomycin (VCM). In experimental systemic infection in mice, however, 20 g showed activity comparable to that of VCM against MRSA. In addition, 20 g showed activity similar or slightly inferior to that of CZOP against Pseudomonas aeruginosa both in vitro and in vivo. Considering its favorable antibacterial activity profile, 20 g was considered to be the most promising CZOP derivative for further studies.


Subject(s)
Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Gram-Negative Bacteria/drug effects , Staphylococcus aureus/drug effects , Animals , Cephalosporins/chemistry , Cephalosporins/therapeutic use , Magnetic Resonance Spectroscopy/methods , Male , Methicillin Resistance , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests/methods , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/drug effects , Staphylococcal Infections/drug therapy , Structure-Activity Relationship , Cefozopran
11.
Proc Natl Acad Sci U S A ; 96(10): 5698-703, 1999 May 11.
Article in English | MEDLINE | ID: mdl-10318947

ABSTRACT

The beta-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophage-tropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (Mr 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca2+ signaling at nanomolar concentrations. The inhibition of beta-chemokine receptors by TAK-779 appeared to be specific to CCR5 because the compound antagonized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Consequently, TAK-779 displayed highly potent and selective inhibition of R5 HIV-1 replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of R5 HIV-1 clinical isolates as well as a laboratory strain at a concentration of 1.6-3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.


Subject(s)
Amides/pharmacology , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , HIV-1/drug effects , Quaternary Ammonium Compounds/pharmacology , Animals , Binding, Competitive , CHO Cells , Chemokine CCL5/metabolism , Cricetinae , Humans , Jurkat Cells , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Molecular Structure , Protein Binding/drug effects , Receptors, CCR5/metabolism , Transfection , Virus Replication/drug effects
12.
Antimicrob Agents Chemother ; 43(5): 1163-9, 1999 May.
Article in English | MEDLINE | ID: mdl-10223930

ABSTRACT

The sterol 14-demethylase P450 (CYP51) of a fluconazole-resistant isolate of Candida albicans, DUMC136, showed reduced susceptibility to this azole but with little change in its catalytic activity. Twelve nucleotide substitutions, resulting in four amino acid changes, were identified in the DUMC136 CYP51 gene in comparison with a reported CYP51 sequence from a wild-type, fluconazole-susceptible C. albicans strain. Seven of these substitutions, including all of those causing amino acid changes, were located within a region covering one of the putative substrate recognition sites of the enzyme (SRS-1). Polymorphisms within this region were observed in several C. albicans isolates, and some were found to be CYP51 heterozygotes. Among the amino acid changes occurring in this region, only an alteration of Y132 was common among these fluconazole-resistant isolates, which suggests the importance of this residue to the fluconazole resistance of the target enzyme. DUMC136 and another fluconazole-resistant isolate were homozygotes with respect to CYP51, although the typical wild-type, fluconazole-susceptible C. albicans was a CYP51 heterozygote. These findings suggest that part of the fluconazole-resistant phenotype of C. albicans DUMC136 was acquired through a mutation-prone area of CYP51, an area which might promote the formation of fluconazole-resistant CYP51, along with a mechanism(s) which allows the formation of a homozygote of this altered CYP51 in this diploid pathogenic yeast.


Subject(s)
Antifungal Agents/pharmacology , Azoles/pharmacology , Candida albicans/drug effects , Candida albicans/genetics , Cytochrome P-450 Enzyme System/genetics , Drug Resistance, Microbial/genetics , Mutation , Oxidoreductases/genetics , Amino Acid Sequence , Gene Expression Regulation, Fungal , Molecular Sequence Data , Sterol 14-Demethylase
13.
Chem Pharm Bull (Tokyo) ; 47(3): 351-9, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10212385

ABSTRACT

New optically active antifungal azoles, 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl ]-3-(4- substituted phenyl)-2(1H,3H)-imidazolones (1,2) and 2-imidazolidinones (3,4), were prepared in a stereocontrolled manner from (1S)-1-[(2R)-2-(2,4- difluoro- and 2-fluorophenyl)-2-oxiranyl]ethanols (15, 16). Compounds 1-4 showed potent antifungal activity against Candida albicans in vitro and in vivo, as well as a broad antifungal spectrum for various fungi in vitro. Furthermore, the imidazolidinones, 3b--e and 4d, e, were found to exert extremely strong growth-inhibitory activity against Aspergillus fumigatus.


Subject(s)
Antifungal Agents/chemical synthesis , Imidazoles/chemical synthesis , Triazoles/chemical synthesis , Animals , Antifungal Agents/pharmacology , Aspergillus fumigatus/drug effects , Candida albicans/drug effects , Candidiasis/drug therapy , Cryptococcus neoformans/drug effects , Imidazoles/pharmacology , Magnetic Resonance Spectroscopy , Mice , Microbial Sensitivity Tests , Spectrophotometry, Infrared , Stereoisomerism , Triazoles/pharmacology
14.
Kansenshogaku Zasshi ; 72(9): 924-34, 1998 Sep.
Article in Japanese | MEDLINE | ID: mdl-9796192

ABSTRACT

TAK-751S is a synthetic trisaccharide coupled to Chromosorb P using a spacer sequence of 8-methoxycarboyloctyl (MCO). Its chemical structure is similar to a human receptor (Gb3) of Stx produced by enterohemorrhagic Escherichia coli (EHEC). In vitro efficacy of TAK-715S was studied by using ACHN cultured cell assay, which is sensitive and specific for measuring low level of Stx. Under various conditions, TAK-715S was mixed with purified Stx1 and Stx2, and residual free toxins in the solution were measured by using ACHN cells. TAK-715S was demonstrated to bind specifically to Stx1 and Stx2 under the condition similar to a human intestine while Chromsorb P did not bind to any Stx. The binding activity was stable in the presence of various processed foods, fresh vegetables and fruits. Antibiotics such as fosfomycin, kanamycin and norfloxacin did not disturb its binding capability. Minimum inhibitory concentrations of these antibiotics against Staphylococcus aureus FDA209P or E. coli NIHJ JC-2 neither changed after incubating with TAK-751S for 60 min at 37 degrees C. These results suggest that TAK-751S can be given orally with various foods and antibiotics for the elimination of Stx1 and Stx2 in the gut of patients with EHEC infections.


Subject(s)
Bacterial Toxins , Enterotoxins , Trihexosylceramides , Trisaccharides , Adsorption , Diatomaceous Earth , Escherichia coli O157 , Humans , Shiga Toxins
15.
Antimicrob Agents Chemother ; 42(10): 2630-2, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9756767

ABSTRACT

Multiple isolates of Cryptococcus neoformans, including those with fluconazole resistance, were tested to assess the in vitro activity of the new triazole TAK-187. MICs of TAK-187 were at least eightfold lower than those of fluconazole, and fungicidal concentrations for most isolates were 4 microg/ml or less. TAK-187 also was evaluated as intermittent therapy using two dosages in a rabbit model of experimental cryptococcal meningitis. Compared to daily treatment with fluconazole, as little as two doses of TAK-187 given 7 days apart were found to be effective. Plasma and cerebrospinal fluid TAK-187 concentrations were many times higher than MICs and fungicidal concentrations. Based upon its therapeutic efficacy and long half-life in the rabbit model, TAK-187 should be investigated for intermittent dosing in treatment or suppression of cryptococcal infections in humans.


Subject(s)
Antifungal Agents/pharmacology , Cryptococcus neoformans/drug effects , Triazoles/pharmacology , Animals , Cryptococcosis/drug therapy , Microbial Sensitivity Tests , Rabbits
16.
Chemotherapy ; 44(4): 265-71, 1998.
Article in English | MEDLINE | ID: mdl-9681203

ABSTRACT

Antimicrobial regimens for the treatment of pneumococcal meningitis are not established. We have produced a murine model of haematogenous pneumococcal meningitis and have examined its usefulness for determining the required dosage and term of antimicrobial agents. Streptococcus pneumoniae serotype 6 was injected intraperitoneally (inoculum: about 1 x 10(4) CFU) into mice. Although half of the mice died within 2 days, the surviving mice showed positive bacterial cultures, increase of the protein level, decrease of the glucose level and infiltration of polymorphonuclear leucocytes into cerebrospinal fluids (CSF). When cefozopran was administered subcutaneously twice a day for 1-3 days starting 2 days after infection, dose- and duration-dependent effects were observed and all mice treated with 20 mg/kg of cefozopran for 3 days survived. The penetration rate of cefozopran from blood to CSF in infected mice was 44.7%, which was 6 times higher than that obtained in uninfected mice. This model may be useful for investigating the pathogenesis of haematogenous pneumococcal meningitis and its therapy.


Subject(s)
Cephalosporins/therapeutic use , Meningitis, Pneumococcal/drug therapy , Animals , Cephalosporins/administration & dosage , Cephalosporins/pharmacokinetics , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Meningitis, Pneumococcal/blood , Mice , Mice, Inbred ICR , Treatment Outcome , Cefozopran
17.
Antimicrob Agents Chemother ; 41(6): 1349-51, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9174197

ABSTRACT

In vitro activities of antifungal agents, including azole compounds, against yeasts were easily determined by using RPMI-1640 agar medium and by incubating the plates in the presence of 20% CO2. The end point of inhibition was clear by this method, even in the case of azole compounds, because of the almost complete inhibition of yeast growth at high concentrations which permitted weak growth of some Candida strains by traditional methods. MICs obtained by the agar dilution method were similar to those obtained by the broth dilution method proposed by the National Committee for Clinical Laboratory Standards.


Subject(s)
Antifungal Agents/pharmacology , Azoles/pharmacology , Candida/drug effects , Colony Count, Microbial , Cryptococcus neoformans/drug effects , Fluconazole/pharmacology , Microbial Sensitivity Tests , Saccharomyces cerevisiae/drug effects
18.
Nihon Rinsho ; 55(5): 1261-5, 1997 May.
Article in Japanese | MEDLINE | ID: mdl-9155184

ABSTRACT

Since infectious diseases are caused by various bacteria and most of them are treated empirically, broad-spectrum antibiotics are required. To expand the spectrum, an imidazopyridazinium group and aminothiadiazole group were introduced to 3- and 7-side chain of cephem nucleus, respectively. The resulting compound, cefozopran, was able to permeate not only outer membrane of Pseudomonas aeruginosa but also envelope of gram-positive bacteria, which functioned as a barrier to antipseudomonal cephalosporins, and showed potent activity against wide variety of bacteria including those which produced a large amount of cephalosporinase and were resistant to third-generation cephalosporins. In spite of the broad antibacterial spectrum, cefozopran only weakly affected gastrointestinal flora of mice and prevented colonization by MRSA.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Design , Drug Resistance, Multiple , Gram-Positive Bacteria/drug effects , beta-Lactam Resistance , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Bacterial Adhesion/drug effects , Cephalosporins/chemistry , Cephalosporins/pharmacokinetics , Cephalosporins/pharmacology , Digestive System/microbiology , Mice , Cefozopran
19.
J Antimicrob Chemother ; 39(3): 423-5, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9096195

ABSTRACT

The therapeutic activity of cefozopran, a new semisynthetic parenteral cephalosporin, was compared with those of ceftazidime, ampicillin, imipenem/cilastatin and ofloxacin against an ascending mixed urinary tract infection induced in mice with Enterococcus faecalis TN2005 and Pseudomonas aeruginosa P9. Cefozopran significantly reduced viable cell counts of both organisms in the kidneys. Ceftazidime, imipenem/cilastatin and ofloxacin were active against only P. aeruginosa, and ampicillin was active against only E. faecalis.


Subject(s)
Cephalosporins/therapeutic use , Enterococcus faecalis , Gram-Positive Bacterial Infections/drug therapy , Pseudomonas Infections/drug therapy , Urinary Tract Infections/drug therapy , Ampicillin/therapeutic use , Animals , Ceftazidime/pharmacology , Ceftazidime/therapeutic use , Cilastatin/therapeutic use , Female , Imipenem/pharmacology , Imipenem/therapeutic use , Mice , Mice, Inbred CBA , Ofloxacin/pharmacology , Ofloxacin/therapeutic use , Cefozopran
20.
Chem Pharm Bull (Tokyo) ; 45(2): 321-6, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9118446

ABSTRACT

2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-1-yl)propyl]-4-[4-(2,2,3,3,tetrafluoropropoxy) phenyl]-3(2H, 4H)-1,2,4-triazolone [(1R,2R)-1: TAK-187] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2S)-, (1R,2S)- and (1S,2R)-1] of this compound were prepared to clarify the relationship between the stereochemistry and the biological activities. In vitro and in vivo assays of antifungal activity revealed that TAK-187 [(1R,2R)-1] is the most potent among the four stereoisomers. Furthermore, TAK-187 was found to exert strong and selective inhibitory effect on the sterol synthesis in Candida albicans as compared with that in rat liver.


Subject(s)
Antifungal Agents/chemical synthesis , Triazoles/chemical synthesis , Animals , Antifungal Agents/chemistry , Candida albicans/drug effects , Microbial Sensitivity Tests , Rats , Stereoisomerism , Triazoles/chemistry
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