Biomedical subjects

K Okonogi

Publications and source records attributed to K Okonogi.

At least 37 records · Page 2Linked to original sources

PubMed1997

[Possibility of drug design of beta-lactam antibiotics effective for multiresistant gram-positive pathogens].

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.

Animals↗

PubMed1996

Penicillin-binding protein 5 as an inhibitory target of cefozopran in Enterococcus faecalis.

The concentration of cefozopran which inhibits binding of [14C]benzylpenicillin to penicillin-binding protein (PBP) 5 of Enterococcus faecalis TN2OO5 by 50% was 11 mg/L, and its MIC was 12.5 mg/L. Ceftazidime and cefmenoxime, which were inactive at 100 mg/L, showed no affinity for PBP 5 at this concentration. Ampicillin, benzylpenicillin and imipenem showed higher affinity for PBPs 3/4 and PBP 5 than cefozopran, and their MICs were lower than that of cefozopran. No correlation between MICs of the test compounds and the affinity for PBP 1, 2 or 6 was found. These results suggest that cefozopran exhibits antimicrobial activity against E. faecalis TN2OO5 by binding to PBP 5.

Anti-Bacterial Agents↗

PubMed1996

Avoidant personality disorder and taijin kyoufu: sociocultural implications of the WHO/ADAMHA International Study of Personality Disorders in Japan.

This paper discusses the characteristics of avoidant personality disorder in a cultural context based on the Japanese concept of taijin kyoufu as well as that of DSM-III-R and DSM-IV social phobia. Sixty-six patients were given the International Personality Disorder Examination and questionnaires including the Beck Anxiety Inventory. Among the 23 DSM-III-R personality disorder patients, 8 patients were diagnosed as having avoidant personality disorder. Six of them were suffering from taijin kyoufu symptoms. Among 27 ICD personality disorder patients, 22 patients were diagnosed as having ICD anxious personality disorder. All DSM avoidant patients were included in the ICD anxious group. These findings suggest that patients with avoidant personality disorder have had a long history of difficulties and share common personality problems with a milder form of taijin kyoufu, which is conceptually different from social phobia.

Adolescent↗

PubMed1996

Gastrointestinal colonization by methicillin-resistant Staphylococcus aureus in immunosuppressed mice.

ICR mice were inoculated intranasally with methicillin-resistant Staphylococcus aureus (MRSA) N133, and the inoculated MRSA was quantitatively recovered from the ceca and feces. The viable counts of the MRSA recovered from ceca correlated well with those from feces. Some mice eliminated MRSA from the cecum by 14 days after inoculation. Intraperitoneal administration of cyclophosphamide at a dose of 200 mg/kg 3 days before inoculation inhibited the elimination of the MRSA from both ceca and feces. All mice treated with cyclophosphamide excreted more than 10(4) CFU of the MRSA per g of feces for at least 70 days, indicating persistent colonization of the MRSA in the gastrointestinal tract. Some beta-lactam antibiotics decreased the colonization level, but others did not. The colonization level was suggested to depend on the antibacterial activity of the antibiotic against the MRSA and the degree of disturbance of intestinal flora by the antibiotic.

Animals↗

PubMed1996

Optically active antifungal azoles. VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazo l-1- yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones.

A new series of optically active antifungal azoles, N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones (1,2) and 5(1H,4H)-tetrazolones (3), were prepared from the triflate derivative of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (13) by an SN2 displacement reaction with the anion of an azolone (17-19) and subsequent ring-opening reaction with 1H-1,2,4-triazole. The optically active oxiranylethanol 13 was synthesized from methyl (R)-lactate in a stereo-controlled manner. The azolones 1-3 prepared showed potent antifungal activities in vitro and in vivo.

Antifungal Agents↗

PubMed1995

Optically active antifungal azoles. IV. Synthesis and antifungal activity of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols.

(2R,3R)-3-Azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols (III) were prepared from (2R,3S)-3-methyl-2-(substituted phenyl)-2-(1H-1,2,4-triazol-1-yl)methyloxiranes (21a-f) by a ring-opening reaction with 1H-1,2,3-triazole and 1H-tetrazole and evaluated for antifungal activity against Candida albicans in vitro and in vivo. The optically active oxiranes (21a--f) which serve as the key synthetic intermediates, were synthesized from 1-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxypropanoyl]morpholin e (24) and substituted phenylmagnesium bromide (23) via six steps in a stereocontrolled manner. The 3-(1H-1,2,3,-triazol-1-yl)-(IIIa) and 3-(2H-2-tetrazolyl)-2-butanol (IIId) derivatives showed strong protective effects against candidosis in mice.

Animals↗

PubMed1995

Optically active antifungal azoles. V. Synthesis and antifungal activity of stereoisomers of 3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2- butanols.

The (2S,3S)-, (2R,3S)- and (2S,3R)-stereoisomers of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols [(2R,3R)-1a--d] were prepared and evaluated for antifungal activity against Candida albicans in vitro and in vivo to clarify the relationships between stereochemistry and biological activities. The results revealed that the in vitro antifungal activity in each set of the four stereoisomers [(2R,3R)-, (2S,3S)-, (2R,3S)- and (2S,3R)-1a--d] definitely paralleled the in vivo antifungal activity against candidosis in mice, and the order of potency was (2R,3R) >> (2R,3S) > or = (2S,3S) > or = (2S,3R). In addition, the four stereoisomers in each set were assessed for sterol biosynthesis-inhibitory activities in C. albicans and rat liver. The (2R,3R)-isomer was found to exert a strong and selective inhibitory effect on the sterol synthesis in C. albicans as compared with that in rat liver.

Animals↗

PubMed1994

Enterococcus faecalis aggravates pyelonephritis caused by Pseudomonas aeruginosa in experimental ascending mixed urinary tract infection in mice.

Mixed urinary tract infection was caused by simultaneous inoculation of 10(4) CFU each of Enterococcus faecalis TN2005 and Pseudomonas aeruginosa P9 into the bladders of CBA/J mice. Both organisms proliferated in the kidneys, and viable cell counts of E. faecalis TN2005 reached a peak level of 4.1 x 10(5) CFU per pair of kidneys within the first 24 h, while P. aeruginosa P9 counts increased more slowly. The number of P. aeruginosa P9 cells peaked at 8.3 x 10(6) CFU per pair of kidneys 5 days after infection. Five days after mixed infection, infiltration of neutrophils into the renal pelvis and renal medulla was observed. Immunohistochemical staining revealed the presence of E. faecalis antigen in the renal medulla. P. aeruginosa antigen was detected mainly in the renal pelvis 5 days after infection and in the renal medulla as well as the renal pelvis 14 days after infection. Mixed infection induced pyelonephritis within 5 days after mixed infection, while it was not observed until 14 days after infection with P. aeruginosa P9 alone. P. aeruginosa P9 inoculated together with E. faecalis TN2005 was more resistant to eradication from the kidneys by beta-lactam antibiotics than P. aeruginosa P9 inoculated alone. These results suggest that E. faecalis TN2005 invades the renal medulla first in mixed urinary tract infection and induces histological changes which lead to aggravation of the pyelonephritis caused by P. aeruginosa P9.

Animals↗

PubMed1994

Effectiveness in psychiatric care. III: Psychoeducation and outcome for patients with major affective disorder and their families.

This hypothesis-generating study had the objective of dissecting the process of psychiatric care in an attempt to understand outcomes for patients and their families. In all, 24 patients who carried a DSM-III diagnosis of major affective disorder were identified 12-18 months after hospital admission. The patients, their families, and their doctors were interviewed using instruments measuring delivery of treatment and achievement of treatment goals; findings were then correlated with resolution of the index episode and patient global outcome. Delivery of patient and family psychoeducation was associated with better resolution of the index episode and better global outcome.

Depressive Disorder↗

PubMed1994

Optically active antifungal azoles. III. Synthesis and antifungal activity of sulfide and sulfonamide derivatives of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-b utanol.

In an effort to find potent antifungal agents, optically active sulfur-containing triazole derivatives, sulfides (3) and sulfonamides (4), were prepared and evaluated for antifungal activity against Candida albicans in vitro and in vivo. The sulfides (3) were prepared by the reaction of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl )-2-butanol (1) with various heteroarylmethyl chlorides in the presence of sodium methoxide. The sulfonamides (4) were synthesized starting from the disulfide (15) in three steps including oxidation of the corresponding sulfenamides (17). Some of the sulfur-containing triazole derivatives (3, 4) showed strong protective effects against candidosis in mice.

Antifungal Agents↗

PubMed1993

Therapeutic effect of cefozopran (SCE-2787), a new parenteral cephalosporin, against experimental infections in mice.

The therapeutic effect of cefozopran (SCE-2787), a new semisynthetic parenteral cephalosporin, against experimental infections in mice was examined. Cefozopran was more effective than cefpiramide and was as effective as ceftazidime and cefpirome against acute respiratory tract infections caused by Klebsiella pneumoniae DT-S. In the model of chronic respiratory tract infection caused by K. pneumoniae 27, cefozopran was as effective as ceftazidime. The therapeutic effect of cefozopran against urinary tract infections caused by Pseudomonas aeruginosa P9 was superior to that of cefpirome and was equal to those of ceftazidime and cefclidin. In addition, cefozopran was more effective than ceftazidime and was as effective as flomoxef in a thigh muscle infection caused by methicillin-sensitive Staphylococcus aureus 308A-1. Against thigh muscle infections caused by methicillin-resistant S. aureus N133, cefozopran was the most effective agent. The potent therapeutic effect of cefozopran in those experimental infections in mice suggests that it would be effective against respiratory tract, urinary tract, and soft tissue infections caused by a variety of gram-positive and gram-negative bacteria in humans.

Animals↗

PubMed1993

Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-b utanol and its stereoisomers.

(2R,3R)-2-(2,4-Difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl )-2-butano l [(2R,3R)-7] and its stereoisomers [(2S,3R)-, (2S,3S)- and (2R,3S)-7] were prepared from the optically active oxiranes 6 by a newly developed ring-opening reaction and evaluated for antifungal activity. The thiol (2R,3R)-7 showed extremely potent antifungal activity in vitro and in vivo. The optically active oxirane (2R,3S)-6, a useful intermediate for the synthesis of sulfur-containing antifungal azoles 5, was synthesized from methyl (R)-lactate [(R)-8] via eight steps in a stereocontrolled manner. The key step in the synthesis is the Grignard reaction of an amide derivative [(R)-12a] of (R)-lactic acid with 2,4-difluorophenyl-magnesium bromide (13).

Animals↗

PubMed1993

Optically active antifungal azoles. II. Synthesis and antifungal activity of polysulfide derivatives of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H- 1,2,4-triazol-1-yl)-2-butanol.

In an effort to find potent antifungal agents, a variety of optically active triazole derivatives with a polysulfide structure, 3, 4 and 5, were prepared and evaluated for antifungal activity against Candida albicans in vitro and in vivo. The symmetrical polysulfides 3 (m = 2-4) were obtained by an oxidative coupling reaction of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl )-2-butanol (1) or by the treatment of its thiocarbonate derivative 8 with potassium tert-butoxide. The unsymmetrical disulfides 5 were synthesized by the reaction of the thiol 1 with Bunte salts 11 or the thiosulfinate 12 or by the reaction of the thiocarbonate 8 with various thiols 13. All of these polysulfides showed potent antifungal activity against candidosis in mice.

Animals↗

PubMed1993

Ferrocins, new iron-containing peptide antibiotics produced by bacteria. Taxonomy, fermentation and biological activity.

A Gram-negative bacterium was found to produce new iron-containing peptide antibiotics, ferrocins A, B, C and D, and the producing bacterium was characterized and identified as Pseudomonas fluorescens YK-310. These new antibiotics showed antibacterial activity against Gram-negative bacteria in vitro. Although the ferrocins showed similar antibacterial activity against both Escherichia coli and Pseudomonas aeruginosa on the standard assay media, they showed strong therapeutic effects selectively against P. aeruginosa in experimentally infected mice.

Animals↗

PubMed1992

Molecular cloning and nucleotide sequence determination of the regulator region of mecA gene in methicillin-resistant Staphylococcus aureus (MRSA).

Molecular cloning and nucleotide sequence analysis were performed for the identification of the regulator genes of methicillin resistance in the genome of a MRSA strain N315. Two open reading frames (orfs) were identified in the 5'-flanking region of the mecA gene. Predicted amino acid sequences of these orfs showed extensive homology to the co-inducer and the repressor protein of the penicillinase (PCase) production in Staphylococcus aureus as well as in Bacillus licheniformis. These orfs are considered to encode putative co-inducer and repressor proteins specific for the regulation of methicillin resistance in MRSA.

Amino Acid Sequence↗

PubMed1992

[A case of penicillin-resistant pneumococcal pneumonia and penicillin-binding proteins of the clinical isolates].

We experienced a case of a 68-year-old female with beta-lactam antibiotics including penicillin G (PCG) resistant pneumococcal pneumonia, leading to death during the treatment with ceftizoxime (CZX). We reported the clinical course and the mechanism of resistance of isolated bacteria. The present case is the first in Japan. Minimum inhibitory concentration (MIC) against Streptococcus pneumoniae 88031 isolated from the present case was 1.56 micrograms/ml in PCG and 6.25 micrograms/ml in CZX, showing PCG resistance. The isolate was no beta-lactamase production and serotype 23. The drug susceptibility in 34 strains of S. pneumoniae which were isolated as causative organism of respiratory infection in our department in 1988 was studied. PCG high resistant strain (PCG MIC greater than 1.56 micrograms/ml) was only observed in the isolated strain in the present case and PCG low sensitive strains (PCG MIC = 0.1-1.0 micrograms/ml) were observed in 3 strains (8.8%). The CZX resistance was observed only in the present case. The detection of penicillin-binding protein (PBP) and binding affinity of beta-lactam antibiotics were studied using PCG sensitive strain, S. pneumoniae type I (preserved strain PCG MIC = 0.05 micrograms/ml, CZX MIC = 0.1 micrograms/ml, CMX MIC = 0.025 micrograms/ml) and PCG resistant strain, S. pneumoniae 88031. The result obtained showed that PBP1a, detected in sensitive strain type I, was not detected in resistant strain 88031 and PBP1b was increased. The binding of 14C-PCG of PCG resistant strain to PBP1b showed lower affinity for CZX and CMX than PCG sensitive strain.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1992

In vitro and in vivo activities of SCE-2787, a new parenteral cephalosporin with a broad antibacterial spectrum.

SCE-2787, a new cephalosporin having a condensed azolium moiety in the 3 position and an aminothiadiazolyl group in the 7 beta side chain, was evaluated for its in vitro and in vivo activities in comparison with those of ceftazidime, flomoxef, cefpirome, and E1040. Against methicillin-susceptible strains of Staphylococcus aureus and Staphylococcus epidermidis, SCE-2787 was more active than ceftazidime and E1040 and was as active as flomoxef and cefpirome, with MICs for 90% of strains tested (MIC90s) being 1.56 micrograms/ml or less. SCE-2787 was also active against Pseudomonas aeruginosa, for which the MIC90 was 6.25 micrograms/ml, which was lower than that of cefpirome and comparable to that of ceftazidime. SCE-2787 was marginally active against methicillin-resistant strains of staphylococci and Enterococcus faecalis, although its MIC90s were the lowest among those of the antibiotics tested. The activities of SCE-2787 against Streptococcus species, most members of the family Enterobacteriaceae, and Haemophilus influenzae exceeded those of ceftazidime and flomoxef and were comparable to those of cefpirome. Furthermore, MIC90s of SCE-2787 were significantly lower than those of ceftazidime for ceftazidime-resistant isolates of Citrobacter freundii and Enterobacter cloacae. SCE-2787 was resistant to hydrolysis by various types of beta-lactamases, including the Bush group 1 beta-lactamases, and had low affinities for these enzymes, with Km or Ki values of greater than 100 microM. The in vitro activity of SCE-2787 was reflected in its efficacy in mouse protection tests. Thus, SCE-2787 appears to be a promising cephalosporin that should be further evaluated in clinical trials.

Animals↗

PubMed1991

Inhibition of prostaglandin E2-stimulated cAMP accumulation by lipopolysaccharide in murine peritoneal macrophages.

Treatment of murine peritoneal macrophages with 100 nM prostaglandin E2 (PGE2) produced a rapid biphasic increase in intracellular cAMP that was maximal at 1 min and sustained through 20 min. Pretreatment of macrophages with 100 ng/ml of lipopolysaccharide (LPS) for 60 min prior to PGE2 decreased the magnitude of cAMP elevation by 50%, accelerated the decrease of cAMP to basal levels, and abolished the sustained phase of cAMP elevation. The effect of LPS was concentration-dependent, with maximal effect at 10 ng/ml in cells incubated in the presence of 5% fetal calf serum and at 1 microgram/ml in the absence of fetal calf serum. LPS also inhibited cAMP accumulation in cells treated with 100 microM forskolin, but the decrease was about half that seen in cells treated with PGE2. LPS concentrations that inhibited cAMP accumulation produced a 30% increase in soluble low Km cAMP phosphodiesterase activity while having no effect on particulate phosphodiesterase activity. The nonspecific phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, as well as the more specific inhibitors rolipram and Ro-20-1724 were effective in inhibiting soluble phosphodiesterase activity in vitro, producing synergistic elevation of cAMP in PGE2-treated cells, and blocking the ability of LPS to inhibit accumulation of cAMP. Separation of the phosphodiesterase isoforms in the soluble fraction by DEAE chromatography indicated that LPS activated a low Km cAMP phosphodiesterase. The enzyme(s) present in this peak could be activated 6-fold by cGMP and were potently inhibited by low micromolar concentrations of Ro-20-1724 and rolipram. Using both membranes from LPS-treated cells and membranes incubated with LPS, no decrease in adenylylcyclase activity could be attributed to LPS. Although effects of LPS on the rate of synthesis of cAMP cannot be excluded, the present evidence is most consistent with a role for phosphodiesterase activation in the inhibitory effects of LPS on cAMP accumulation in murine peritoneal macrophages.

3',5'-Cyclic-AMP Phosphodiesterases↗