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R Okachi

Publications and source records attributed to R Okachi.

At least 19 recordsLinked to original sources
PubMed1989

Synthesis and biological evaluation of 3-chloro-1-carbacephem compounds.

The 3-chloro-1-carbacephem nucleus was prepared for the first time from a 3H-1-carbacephem compound through a sequence of reactions involving addition of thiophenol, oxidation of sulfide to sulfoxide, and alpha-chlorination of the sulfoxide, followed by elimination of phenylsulfinic acid. The 2-beta-methyl analog was similarly prepared, but the 2 alpha-methyl analog was not obtained. Optical resolution of the 3-chloro-1-carbacephem compound was achieved by the employment of penicillin acylase. That is, the 7-phenylacetamido derivative was enantioselectively hydrolyzed to afford the optically active 7-amino-3-chloro-1-carbacephem compound. Carbacefaclor, the carbacephem analog of cefaclor, was directly and efficiently prepared by enzymatic phenylglycylation of the racemic 7-amino-3-chloro-1-carbacephem compound by using immobilized penicillin acylase. Carbacefaclor thus prepared exhibited comparable antibacterial activity against most gram positive bacteria tested and higher activity against typical gram negative bacteria as compared with cefaclor. Moreover, carbacefaclor possessed remarkably high chemical stability.

Cephalosporins↗
PubMed1989

In vitro and in vivo antibacterial activity of KT3777, a new orally active carbacephem.

KT3777 is a novel carbacephem antibiotic structurally identical to cefaclor (CCL), except that the sulfur atom of position 1 of the cephem nucleus has been replaced by carbon. KT3777 was investigated for in vitro and in vivo antibacterial activities in comparison with CCL, cephalexin (CEX) and amoxicillin. The MIC50 of KT3777 ranged from 0.2 to 3.13 micrograms/ml for clinical isolates of Staphylococcus aureus, Streptococci, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, and Neisseria gonorrhoeae. KT3777 possessed an antibacterial spectrum and potency similar to that of CCL. However, against E. coli and K. pneumoniae, KT3777 was about twice as active as CCL. KT3777 was more active than CEX against all strains tested. Killing-curve studies demonstrated bactericidal activity of KT3777 at concentrations above the MIC. KT3777 showed good affinity for penicillin-binding proteins 1A, 1Bs, 3 and 4 of E. coli NIHJ JC-2. The protective effect of KT3777 against systemic infections in mice was comparable to that of CCL with a few exceptions and about 3 to 7 times greater than that of CEX. KT3777 also proved effective against localized infections such as acute pneumonia and ascending urinary tract infections in mice.

Administration, Oral↗
PubMed1989

Synthesis and antibacterial activity of novel 3-substituted carbacephems.

A series of novel 3-heterocyclothio substituted carbacephems having phenylglycyl side chain have been prepared starting from 3-H carbacephem. The compounds exhibit better chemical stability than the corresponding cephalosporin and strong activity against Gram-negative and Gram-positive organisms including Enterococcus faecalis.

Cephalosporins↗
PubMed1987

Aminothiazolylglycyl derivatives of carbacephems. I. Synthesis and antibacterial activity of novel carbacephems with substituted aminothiazolyl groups.

A series of new carbacephem compounds which have substituted aminothiazolylglycyl side chain have been prepared starting from corresponding carbacephems with aminothiazolylmethoxyimino group. Among them, the compound having 3,4-dihydroxybenzoyl group showed very sharp activity against Pseudomonas aeruginosa. Moreover, the optical resolution of alpha carbon of aminothiazolylglycyl moiety was carried out through preparation of optically active side chain and the (S)-isomer (KT-4380) was found to be the most active against Pseudomonas sp. as well as other Gram-negative strains.

Anti-Bacterial Agents↗
PubMed1987

Aminothiazolylglycyl derivatives of carbacephem antibiotics. II. Synthesis and antibacterial activity of novel aminothiazolyl cephem compounds with hydroxypyridone moiety.

The synthesis and antimicrobial activity of novel carbacephem antibiotics which have amido moiety of (S)-aminothiazolylglycyl side chain are described. Among them, the compound having 5-hydroxy-4-pyridon-2-carboxyl group (KT-4697) showed exceptionally strong activity against Pseudomonas aeruginosa as well as Gram-negative bacteria. A cephalosporin with this acyl group namely KT-4788 with methylpyridiniumthiomethyl group at C-3 was found to be the most active against Gram-positive and Gram-negative strains including P. aeruginosa.

Catechol O-Methyltransferase↗
PubMed1987

[Combined effects of astromicin and human gamma-globulin prepared for intravenous use].

Combination therapy of antibiotics and human intravenous gamma immunoglobulin (IgG) prepared for intravenous use is widely applied to control severe infectious diseases. To evaluate the antimicrobial activity of astromicin (ASTM, Fortimicin), the combination effect of ASTM with IgG was investigated in vitro and in mice with experimental infection (i.p.) with Pseudomonas aeruginosa BMH No. 1. Sulfonated IgG (Venilon, VL), and plasmin-treated IgG (Venoglobulin, VG) were administered (i.v., 42 mg/kg) 90 minutes before the infection, and ASTM was administered (s.c.) 60 minutes after the infection. Polyethyleneglycol-treated IgG (Venoglobulin-I, VG-I) was administered (i.v., 42 mg/kg) 90 minutes before or 60 minutes after the infection. ED50 of ASTM alone and that of combination with VL were 31.0 mg/kg and 24.2 mg/kg, respectively. ED50 of ASTM alone and that of combination with VG were 38.9 mg/kg and 15.5 mg/kg, respectively (P less than 0.05). When VG-I was administered prophylactically, ED50 of ASTM alone and that of combination were 51.5 mg/kg and 13.6 mg/kg, respectively (P less than 0.05). When VG-I was administered simultaneously with ASTM at 60 minutes after the infection, ED50 of ASTM alone and that of combination were 28.5 mg/kg and 15.5 mg/kg, respectively (P less than 0.05). Prophylactic effect of VG-I in immunosuppressed mice treated with cyclophosphamide (250 mg/kg, i.p., 4 days before infection) was also examined. ED50 of ASTM alone and that of combination were 126.1 mg/kg and 46.1 mg/kg, respectively (P less than 0.05). VG-I also enhanced in vitro synergistic bactericidal activity of ASTM and fresh mouse serum.

Aminoglycosides↗
PubMed1986

K-4, a novel inhibitor of angiotensin I converting enzyme produced by Actinomadura spiculosospora.

A novel inhibitor of angiotensin I converting enzyme (ACE), named K-4, was isolated from the culture broth of Actinomadura spiculosospora nov. sp. K-4. The K-4 was an oligopeptide containing L-phenylalanine with (R)-1-amino-2-(4-hydroxyphenyl)ethylphosphonic acid as the C-terminal residue. The compound proved to be a specific and reversible inhibitor of ACE with the inhibition constant (Ki) of 0.18 microM, and inhibited ACE non-competitively by use of hippuryl-L-histidyl-L-leucine (HHL) as a substrate. When administrated intravenously to rats, K-4 inhibited the pressor response to angiotensin I.

Angiotensin I↗
PubMed1986

K-26, a novel inhibitor of angiotensin I converting enzyme produced by an actinomycete K-26.

A novel inhibitor of angiotensin I converting enzyme (ACE), designated K-26, was isolated from the broth filtrate of an actiomycete K-26. K-26 is a water soluble, acidic peptide composed of an equal mol of L-isoleucine, L-tyrosine and 1(R)-1-amino-2-(4-hydroxyphenyl)-ethylphosphonic acid. The IC50 of K-26 for ACE inhibition was 6.7 ng/ml when hippuryl-L-histidyl-L-leucine was used as a substrate of ACE. K-26 possesses hypotensive activity in vivo.

Actinomycetales↗
PubMed1986

[In vivo combination effects of astromicin and beta-lactam antibiotics against Pseudomonas aeruginosa].

Astromicin (ASTM, Fortimicin) is a pseudodisaccharide aminoglycoside antibiotic. The ASTM exhibited excellent activity against Gram-positive and Gram-negative bacteria but was only weakly active against Pseudomonas aeruginosa. In vitro synergistical activities of ASTM combined with beta-lactam antibiotics have been reported against P. aeruginosa previously. In this paper, we investigated the in vivo combination efficacies of ASTM and beta-lactam antibiotics (latamoxef (LMOX), cefoperazone (CPZ), piperacillin (PIPC) and cefsulodin (CFS) against experimental infection with P. aeruginosa in both normal and immunosuppressed mice. In normal mice, the combination of ASTM with these beta-lactam antibiotics produced significantly greater protective effects than the single use of individual antibiotics against both strains of P. aeruginosa BMH No. 1 and E-2. In mice immunosuppressed with cyclophosphamide, the combination of ASTM with LMOX or CFS also exhibited synergistic protective effects against P. aeruginosa BMH No. 1, but PIPC and CPZ did not. From the above results, the combination therapy of ASTM with beta-lactam antibiotics appeared to be effective against experimental infections with P. aeruginosa in mice.

Aminoglycosides↗
PubMed1986

[Effects of astromicin on a host defence mechanism].

We investigated the effect of astromicin (ASTM) on a defence mechanism. The existence of ASTM (100 micrograms/ml) did not influence the ability of phagocytizing and killing by the mouse peritoneal exudated polymorphonuclear leukocyte (PMN). We observed no change of either phagocytizing and killing or phagocytizing ability of PMN by a pretreatment with ASTM (100 micrograms/ml). When the luminol-dependent chemiluminescence of PMN was examined, a slight decrease of relative light intensity in the presence of ASTM was observed at a concentration of 100 micrograms/ml or 50 micrograms/ml. There was, however, no change of relative light intensity in the presence of 20 micrograms/ml of ASTM. The chemotaxis of PMN was not influenced in the presence of even 100 micrograms/ml of ASTM. We also examined whether a combination effect existed between ASTM and either fresh human serum or fresh mouse serum in vitro. Considerable combination effects were observed against E. coli, P. aeruginosa, S. marcescens, K. pneumoniae and S. aureus. From these results, we concluded that ASTM did not exert a detrimental effect on examined functions of PMN which is important in the nonspecific host defence mechanism in the early phase of bacterial infections. We also concluded that ASTM, which had a synergic effect with a human serum factor, was a safe and effective chemotherapeutic agent.

Aminoglycosides↗
PubMed1985

Synthesis and antibacterial activity of 2,2'-dithiobis(benzamide) derivatives against Mycobacterium species.

A series of compounds, which are analogues of 2,2'-dithiobis(benzamide), were synthesized and tested for in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv including resistant strains against streptomycin, kanamycin, or isonicotinic acid hydrazide. MICs of these compounds against atypical mycobacteria, Mycobacterium kansasii and Mycobacterium intracellulare were also examined. Structure-activity relationships were found in a series of (acyloxy)alkyl ester derivatives depending upon the length of alkyl carbon chain. The MIC of the most potent compound, 2,2'-dithiobis[N-[3-(decanoyloxy)propyl]benzamide] [56] was superior or at least equivalent to streptomycin, kanamycin, and ethanbutol. All the compounds showed no cross-resistance between the current antitubercular agents.

Animals↗
PubMed1985

Chemical modification of spiramycins. VI. Synthesis and antibacterial activities of 3,3''-di-O-acyl-4''-O-sulfonyl and 3,3''-di-O-acyl-4''-O-alkyl derivatives of spiramycin I.

3,3''-Di-O-acyl-4''-O-sulfonyl and 3,3''-di-O-acyl-4''-O-alkyl derivatives of spiramycin I were synthesized and evaluated by four parameters, antibacterial activity, affinity to ribosomes, lypophilicity and therapeutic effects. Among them, 3,3''-di-O-acetyl-4''-O-mesyl and 3,3''-di-O-acetyl-4''-O-methylspiramycin I having relatively small substituents at 4''-position were the most effective in mouse protection tests, and the results were comparable to acetylspiramycin.

Animals↗
PubMed1985

Chemical modification of spiramycins. V. Synthesis and antibacterial activity of 3'- or 4''-de-N-methylspiramycin I and their N-substituted derivatives.

The 3'- and 4''-de-N-methylspiramycins were synthesized selectively, and then were converted to various N-substituted derivatives. 4''-De-N-methyl derivatives were more active than 3'-de-N-methyl ones. Among the derivatives, 4''-N-Fmoc-glycyl and 4''-N-benzyl-4''-de-N-methylspiramycin I were the most active in vitro, and were comparable to spiramycin I. 4''-De-N-methylspiramycin I was about half as active as spiramycin I in vivo.

Animals↗
PubMed1985

[In vitro combination effects of astromicin and beta-lactam antibiotics against Pseudomonas aeruginosa. In vitro synergistic activities].

In vitro synergistic activities of astromicin (ASTM), a new aminoglycoside antibiotic, combined with beta-lactam antibiotics (cefsulodin (CFS), cefoperazone (CPZ), latamoxef (LMOX) were investigated against P. aeruginosa by the checkerboard technique, FIC index and the killing curve. FIC indexes of ASTM in combination with beta-lactam antibiotics against 11 fresh clinical isolates of P. aeruginosa, P. aeruginosa BMH No. 1 and E-2 were synergistic or partially synergistic in most cases. Checkerboard of P. aeruginosa BMH No. 1 and E-2 to ASTM and 3 beta-lactam antibiotics showed the synergism, too. Bacteriostatic concentrations of ASTM, CFS, CPZ or LMOX showed synergistically bactericidal effects when these antibiotics were added in combination to the culture of P. aeruginosa BMH No. 1.

Aminoglycosides↗
PubMed1984

Chemical modification of spiramycins. III. Synthesis and antibacterial activities of 4''-sulfonates and 4''-alkylethers of spiramycin I.

Among the derivatives protected with t-butyldimethylsilylether of spiramycin I, 2'-O-acetylspiramycin I 3,18-(O-t-butyldimethylsilyl)acetal was found to be a suitable intermediate for 4''-modification of spiramycin I. Seven 4''-sulfonates and four 4''-alkylethers were synthesized, which were more active against bacteria in vitro than spiramycin I. 4''-Substituted derivatives with relatively small sulfonyl and alkyl groups were comparable in therapeutic effect to spiramycin I.

Animals↗
PubMed1984

Chemical modification of spiramycins. IV. Synthesis and in vitro and in vivo activities of 3'',4''-diacylates and 3,3'',4''-triacylates of spriamycin I.

3'',4''-Diacylates and 3,3'',4''-triacylates of spiramycin I were synthesized and evaluated by the four parameters, MIC against bacteria, affinity to ribosomes, retention time in HPLC and therapeutic effect. Among them, 3,3'',4''-tri-O-propionyl and 3,4''-di-O-acetyl-3''-O-butyryl-spiramycin I were the most active in vivo, which were superior to acetylspiramycin.

Animals↗
PubMed1984

[The pharmacokinetic studies on astromicin in rats. Intramuscular, intravenous or drip intravenous administration].

Absorption, tissue distribution and excretion of astromicin (ASTM) were studied in rats after intramuscular (i.m.), intravenous (i.v.) or drip intravenous (d.i.v.; for 15, 30 min. or 60 min.) administration at a dose of 20 mg/kg. The pharmacokinetic studies of ASTM were carried out using one-compartment open model (i.m.) or two-compartment open model (i.v. and d.i.v.). The peak values of ASTM observed in serum were 48.6 micrograms/ml (i.m.), 255.3 micrograms/ml (i.v.), 57.5 micrograms/ml (15 min. d.i.v.), 45.9 micrograms/ml (30 min. d.i.v.) and 39.1 micrograms/ml (60 min. d.i.v.). The pharmacokinetic parameters of ASTM after 15 min. d.i.v. administration were calculated as follows: Kel 0.110 min-1, T1/2 21.4 min., Vd beta 0.310 L/kg, Tmax 15.0 min., Cmax 58.6 micrograms/ml, AUC 1,991 micrograms X min/ml. ASTM was rapidly distributed into the kidneys and lungs. The peak values of ASTM in the kidneys were 156.8 micrograms/g (i.m.), 185.2 micrograms/g (i.v.), 132.9 micrograms/g (15 min. d.i.v.), 135.3 micrograms/g (30 min. d.i.v.) and 117.3 micrograms/g (60 min. d.i.v.). Urinary recovery rates of ASTM amounted to 85.5% (i.m.), 99.5% (i.v.) or 87.9% (30 min. d.i.v.). After i.m. or 30 min. d.i.v. administration of ASTM, no active metabolite was found in urine of rats.

Aminoglycosides↗