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Biomedical subjects

H Morishima

Publications and source records attributed to H Morishima.

At least 37 records · Page 2Linked to original sources
PubMed2000

In vitro antibacterial activity and mechanism of action of J-111,225, a novel 1beta-methylcarbapenem, against transferable IMP-1 metallo-beta-lactamase producers.

IMP-1 beta-lactamase, a class B zinc metallo-enzyme encoded by the transferable bla(IMP) gene, is known to confer high-level resistance to carbapenems as well as to penicillins and cephalosporins. J-111, 225 is a novel 1beta-methylcarbapenem with a structurally unique side chain comprising a trans-3,5-disubstituted pyrrolidinylthio moiety at the C2 position. It inhibited 17 Serratia marcescens and two Pseudomonas aeruginosa IMP-1-producing clinical isolates at a concentration of 32 mg/L (range 4-32 mg/L). It showed synergy with imipenem against IMP-1-producing S. marcescens BB5886 and P. aeruginosa GN17203 with minimal FIC indices of 0.38 and 0.5, respectively. J-111,225 was more resistant than imipenem to hydrolysis by class B metallo-beta-lactamases. In kinetic studies, J-111,225 inhibited the IMP-I enzyme with a K(i) of 0.18 microM when imipenem was used as a substrate. In contrast, J-111,225 was the substrate for hydrolysis by other class B beta-lactamases such as Bacteroides fragilis CcrA, Stenotrophomonas maltophilia L1 and Bacillus cereus type II enzyme with respective K(m) values of 11, 10 and 148 microM. The greater antibacterial activity of J-111,225 against IMP-1-producing bacteria may result from its unique interaction with the beta-lactamase.

Anti-Bacterial Agents↗
PubMed2000

Therapeutic efficacy of J-111,225, a novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenem, against experimental murine systemic infections.

In a murine model of systemic infection with methicillin-resistant Staphylococcus aureus (MRSA), J-111,225 showed an ED(50) value of 5. 83 mg/kg, which was comparable to vancomycin (ED(50) 4.84 mg/kg), whereas imipenem failed to cure infected mice (ED(50) >100 mg/kg). Against a mixed infection caused by MRSA and Pseudomonas aeruginosa, monotherapy with J-111,225 showed an ED(50) value of 7.23 mg/kg, whereas combined treatment with vancomycin plus imipenem (1:1) had an ED(50) of 20.86 mg/kg. J-111,225 showed good therapeutic efficacy against methicillin-susceptible S. aureus, penicillin-resistant Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae and P. aeruginosa. The unusually broad spectrum suggests that monotherapy with this novel carbapenem may be suitable for polymicrobial infections associated with MRSA.

Animals↗
PubMed2000

In vitro activities of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems with potent activities against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

The in vitro activities of the novel 1beta-methylcarbapenems J-111, 225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a trans-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 microgram/ml (MICs at which 90% of isolates are inhibited [MIC(90)s]), respectively, indicating that these agents were 32- to 64-fold more potent than imipenem, which has an MIC(90) of 128 microgram/ml. Although these drugs were less active in vitro than vancomycin, which had MIC(90)s of 1 and 2 microgram/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Clostridium difficile, as well as MRSA, the novel carbapenems are worthy of further evaluation.

Anti-Bacterial Agents↗
PubMed2000

Residential randon exposure and lung cancer risk in Misasa, Japan: a case-control study.

In order to investigate an association between residential radon exposure and risk of lung cancer, a case-control study was conducted in Misasa Town, Tottori Prefecture, Japan. The case series consisted of 28 people who had died of lung cancer in the years 1976-96 and 36 controls chosen randomly from the residents in 1976, matched by sex and year of birth. Individual residential radon concentrations were measured for 1 year with alpha track detectors. The average radon concentration was 46 Bq/m3 for cases and 51 Bq/m3 for controls. Compared to the level of 24 or less Bq/m3, the adjusted odds ratios of lung cancer associated with radon levels of 25-49, 50-99 and 100 or more Bq/m3, were 1.13 (95% confidence interval; 0.29-4.40), 1.23 (0.16-9.39) and 0.25 (0.03-2.33), respectively. None of the estimates showed statistical significance, due to small sample size. When the subjects were limited to only include residents of more than 30 years, the estimates did not change substantially. This study did not find that the risk pattern of lung cancer, possibly associated with residential radon exposure, in Misasa Town differed from patterns observed in other countries.

Adult↗
PubMed2000

Measurements of Rn-222, Rn-220 and their decay products in the environmental air of the high background radiation areas in Yangjiang, China.

For the renewal of dose estimation from internal irradiation in the high background radiation areas (HBRA) of Yangjiang, the measurements of radon, thoron and their decay products in the environmental air were conducted, including: (1) integrating measurements of Rn-222 and Rn-220 concentrations; (2) eqilibrium factor F for Rn-222 and alpha-potential energy value of Rn-220; (3) external gamma radiation in places where radon measurements were undertaken; (4) cumulative exposure to indoor radon for each family in a case-control study on lung cancer. The Rn-Tn cup monitor method was used for the integrating measurement of Rn-222 and Rn-220 concentration. An alpha track detector was used for the integration measurement of Rn-222 concentration in the case-control study on lung cancer. The results of measurements show that although the investigated areas are located between the Equator and the Tropic of Cancer, and that people live in well-ventilated dwellings, the concentrations of radon, especially of Rn-220 are significantly higher in the indoor air of HBRA than those in the control area. The value of equilibrium factors for Rn-222, the alpha potential energy of decay products from Rn-222 and Rn-220 are determined.

Air↗
PubMed2000

Excess relative risk of solid cancer mortality after prolonged exposure to naturally occurring high background radiation in Yangjiang, China.

A study was made on cancer mortality in the high-background radiation areas of Yangjiang, China. Based on hamlet-specific environmental doses and sex- and age-specific occupancy factors, cumulative doses were calculated for each subject. In this article, we describe how the indirect estimation was made on individual dose and the methodology used to estimate radiation risk. Then, assuming a linear dose response relationship and using cancer mortality data for the period 1979-1995, we estimate the excess relative risk per Sievert for solid cancer to be -0.11 (95% CI, -0.67, 0.69). Also, we estimate the excess relative risks of four leading cancers in the study areas, i.e., cancers of the liver, nasopharynx, lung and stomach. In addition, we evaluate the effects of possible bias on our risk estimation.

Adolescent↗
PubMed2000

Chromosome translocation in residents of the high background radiation areas in southern China.

We performed a cytogenetical study using chromosome painting analysis on 9 residents of the naturally high background radiation areas (HBRA) and 8 residents of the control areas in southern China. The estimated dose (air kerma) of each resident measured by an electric pocket dosimeter showed 2.20-4.23 mGy/year in HBRA and 0.56-0.70 mGy/year in the control areas. A total of 14,096 cells (1,566 cells/case) in the former and 17,522 cells (2,190 cells/case) in the latter were analyzed. Children, both in HBRA and in the control areas, had translocations at low frequencies. The frequency of translocations among elder individuals varied widely and it was not possible to detect dose effect although it was detected in dicentrics. The effect of radiation on the induction of chromosome aberrations, which have a statistically potential risk of causing malignant or congenital diseases, seems to be less significant than those of metabolic factors and/or mutagenic agents (excluding radiation) even in HBRA in China.

Aged↗
PubMed2000

Dose measurement, its distribution and individual external dose assessments of inhabitants in the high background radiation areas in China.

As a part of the China-Japan cooperative research on natural radiation epidemiology, we have carried out a dose-assessment study to evaluate the external exposure to natural radiation in the high background radiation areas (HBRA) of Yangjiang in Guangdong province and in the control areas (CA) of Enping prefecture since 1991. Because of the difficulties in measuring the individual doses of all inhabitants directly by personal dosimeters, an indirect method was applied in which the exposed individual doses were estimated from the environmental radiation doses measured by survey meters and the occupancy factors of each hamlet. We analyzed the dose in the hamlets and the variation in the occupancy factors to obtain the parameters of dose estimation on the inhabitants in selected hamlets; Madi and several hamlets of different dose levels in HBRA and Hampizai hamlet in CA. With these parameters, we estimated individual dose rates and compared them with those obtained from direct measurement using dosimeters carried by selected individuals. The results obtained are as follows. 1) The environmental radiation doses are influenced by the natural radioactive nuclide concentrations in building materials, the age of the building and the arrangement of the houses in a hamlet. There existed a fairly large and heterogeneous distribution of indoor and outdoor environmental radiations. The indoor radiation doses were due to exposure from the natural radioactive nuclides in the building materials and were about two times as large as the outdoor radiation doses. The difference between indoor and outdoor doses was not observed in CA. 2) The occupancy factor was influenced by the age of individuals and by the season of the year. The occupancy factor was higher for infants and aged individuals than for other age groups. This lead to higher dose rates of exposure to those age groups. 3) A good correlation was observed between the dose assessed indirectly and that measured directly and the correlation factor was 0.97.

Background Radiation↗
PubMed2000

Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 24). Testicular toxicity of boric acid after 2- and 4-week administration periods.

To assess whether or not male reproductive toxicity can be evaluated in a 2-week administration study, boric acid was administered daily by oral gavage to male Jcl:Wistar rats at dosage levels of 0, 300 and 500 mg/kg for 2 and 4 weeks, and the results obtained with the two different treatment schedules were compared. After a 2-week administration, decreased testis weights were observed in the 500 mg/kg group. Histopathologically, exfoliation of round spermatids, retention of step 19 spermatids and increased numbers of residual body-like structures in the seminiferous tubules and cell debris in the cranial epididymal ducts were observed in the 300 and 500 mg/kg groups. Distorted cytoplasmic lobes of step 19 spermatids, debris in the seminiferous tubules and focal atrophy of the seminiferous tubules with multinucleated giant cells formation and necrosis of spermatocytes were also observed in the 500 mg/kg group. After a 4-week administration, testis and epididymis weights were decreased in the 300 and 500 mg/kg groups. Histopathological changes in the 300 mg/kg group were similar to those found in the 300 and 500 mg/kg groups after a 2-week administration. Diffuse atrophy of the seminiferous tubules was additionally observed in the 500 mg/kg group. These results suggest that 2 weeks is a sufficient treatment period for the detection of the testicular toxicity caused by boric acid.

Administration, Oral↗
PubMed1999

Synthesis and biological activities of NB-506 analogues: Effects of the positions of two hydroxyl groups at the indole rings.

In the course of a study of 6-N-amino-substituted analogues of NB-506 (1), a more potent anticancer drug, J-109,404 (2), in which the formyl group of NB-506 was replaced with a 1,3-dihydroxypropane group, was reported. A study of further modification in the positions of two hydroxyl groups at the indole rings of 2 resulted in the discovery of a 2,10-dihydroxy analogue, J-107,088 (3), which is a promising anticancer agent with a broader therapeutic window than J-109,404.

Animals↗
PubMed1999

Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I.

J-107088 [6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carb azo le-5,7(6H)-dione] is a new derivative of NB-506, an indolocarbazole antitumor agent. J-107088 induced single-strand DNA cleavage only in the presence of topoisomerase I (top1) more effectively than NB-506 or camptothecin. The preferable sequences of the DNA cleaved by J-107088 were C/T / G as in the case of NB-506. This base-preference of J-107088 in top1-mediated cleavage was different from that of camptothecin, which was T / G/A. top1 poisons stabilize the complex between DNA and top1 (cleavable complex). This cleavable complex is released on addition of a high concentration of monovalent cation or removal of top1 poisons. The complex induced by J-107088 was quite stable; it was scarcely released on the addition of NaCl or dilution of J-107088, contrary to the case with camptothecin and NB-506. J-107088-inducing complexes were also stable in cultured cells, when the compound was added to the culture medium. These unique in vitro activities of J-107088 on top1 that differed from those of camptothecin and NB-506 may be relevant to its more potent in vivo antitumor efficacy in a human tumor xenographted nude mouse model.

Animals↗
PubMed1999

Synthesis and biological activities of topoisomerase I inhibitors, 6-N-amino analogues of NB-506.

6-N-Amino analogues of NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione] (3b) were synthesized and tested with respect to topoisomerase inhibition, cytotoxicity and anticancer effects. Among them, a 1,3-dihydroxypropane analogue (J-109,404, 5t) showed more than ten times more potent anticancer activity in MKN-45 human stomach cancer cells implanted in mice than NB-506.

Animals↗
PubMed1999

Neurocysticercosis case with a single cyst in the brain showing dramatic drop in specific antibody titers within 1 year after curative surgical resection.

We report on one Japanese case subject with neurocysticercosis (NCC) who had a single cyst in the brain and had undergone curative surgical resection. Pathological examination revealed that it was a cysticercus of Taenia solium. Serological examination of the pair serum samples just before and 1 year after surgery revealed that antibody responses against the glycoproteins, highly specific to NCC and detected in the serum sample just before surgery by both immunoblot and ELISA became negative within 1 year after the surgery. It is, therefore, strongly suggested that this case had a single cysticercus in his whole body and the presence of a single cysticercus was sufficient to evoke antibody responses against it.

Animals↗
PubMed1999

CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice.

4-Aminobiphenyl (4-ABP), a potent carcinogen in rodents (liver cancer) and human (bladder cancer), is found as an environmental contaminant and in tobacco smoke. Hemoglobin adducts and lung DNA adducts of 4-ABP are found in tobacco smokers. In vitro metabolism studies with human and rat liver microsomes have shown that CYP1A2 is primarily responsible for catalyzing N-hydroxylation, the initial step in the metabolic activation of 4-ABP. To determine whether this P450 is a rate limiting pathway for hepatocarcinogenesis, CYP1A2-null mice were analyzed at 16 months of age and were compared with wild-type mice in their response to 4-ABP using the neonatal mouse bioassay and two different doses of the carcinogen. Overall differences in incidences of hepatocellular adenoma, carcinoma and preneoplastic foci were not significant between either genotypes or 4-ABP doses used, whereas small, but significant, differences were found for specific types of foci. These results suggest that while CYP1A2 levels may not be rate limiting for 4-ABP metabolism to produce tumors and foci, it may modulate the induction process of some types of liver foci in either a positive or negative manner. In vitro studies using CYP1A2-null and wild-type mouse liver microsomes revealed that CYP1A2 is not the sole P450 required for 4-ABP N-hydroxylation and that another, yet to be identified, P450 is likely to be involved.

Adenoma↗
PubMed1999

Role of CYP1A2 in the toxicity of long-term phenacetin feeding in mice.

The mechanisms underlying phenacetin-induced toxicity and carcinogenicity are not clear. In particular, it is not known whether these effects are mediated by metabolic activation of the drug. CYP1A2 is known to metabolize phenacetin in vitro. To determine the role of this enzyme in vivo, the toxicity and carcinogenicity of phenacetin was examined in Cyp1a2-null mice (that lack CYP1A2). Six- to 8-week-old wild type (+/+) or null (-/-) mice were fed either a control diet, or one containing 1.25% phenacetin, ad libitum for up to 67 weeks. Representative groups of mice were examined for phenacetin-induced toxicity and carcinogenicity after 36, 48, 58, or 67 weeks of feeding. Consistent with the known role of CYP1A2 in phenacetin metabolism, plasma levels of phenacetin were higher and acetaminophen levels lower in the (-/-) mice fed phenacetin compared to phenacetin-fed (+/+) controls. Weight gain was significantly depressed in both groups of phenacetin-fed mice after 4 weeks of feeding, and continued to be lower for the remainder of the experiment, compared to controls. Hepatomegaly and splenomegaly were more severe in (-/-) mice but present in both genotypes fed phenacetin at all time points assessed. Histological analysis of liver, kidney, spleen, and urogenital tract also revealed a differential response in the (-/-) mice fed phenacetin compared to (+/+) mice fed the same diet. Further, mortality was the most severe in the (-/-) mice fed phenacetin than in all other groups. Despite significant toxicity in (-/-) mice fed phenacetin, only one renal carcinoma was found among them. Results from this work demonstrate that, in the absence of CYP1A2, phenacetin is more toxic than in controls. This provides evidence that metabolism of phenacetin by CYP1A2 alters toxicity in vivo, and suggests that alternate CYP1A2-independent metabolic pathways contribute to its toxicity.

Acetaminophen↗