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Biomedical subjects

M Shintani

Publications and source records attributed to M Shintani.

At least 37 records · Page 2Linked to original sources
PubMed1999

Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine.

We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure-activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to the delineation of a set of structural charateristics that appear to afford an orally available HIV protease inhibitor. Optimum structures, exemplified by 21f (JE-2147), incorporated 3-hydroxy-2-methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl-1,3-thiazolidine-4-carbonyl (Dmt) residue at the P1' site, and 2-methylbenzylcarboxamide group as the P2' ligand. The present study demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.

Administration, Oral↗
PubMed1999

Down regulation of peroxisome proliferator-activated receptorgamma expression by inflammatory cytokines and its reversal by thiazolidinediones.

AIMS/HYPOTHESIS: Previous studies show that inflammatory cytokines play a part in the development of insulin resistance. Thiazolidinediones were developed as insulin-sensitizing drugs and are ligands for the peroxisome proliferator-activated receptory (PPARgamma). We hypothesized that the anti-diabetic mechanism of thiazolidinediones depends on the quantity of PPARgamma in the insulin resistant state in which inflammatory cytokines play a part. METHODS: We isolated rat PPARgamma1 and gamma2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPARgamma mRNA expression in rat mature adipocytes. RESULTS: Various inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), IL-1beta, IL-6 and leukaemia inhibitory factor decreased PPARgamma mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13-acetate also decreased the expression of PPARgamma. The suppression of PPARgamma mRNA expression caused by 10 nmol/l of TNF-alpha was reversed 60% and 55% by treatment with 10(-4) mol/l of troglitazone and 10(-4) mol/l of pioglitazone, respectively. The suppression of glucose transporter 4 mRNA expression caused by TNF-alpha was also reversed by thiazolidinediones. Associated with the change of PPARgamma mRNA expression, troglitazone improved glucose uptake suppressed by TNF-alpha. CONCLUSION/INTERPRETATION: Our study suggests that inflammatory cytokines could be factors that regulate PPARgamma expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPARgamma mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones.

Adipocytes↗
PubMed1999

Thyrotropin decreases leptin production in rat adipocytes.

Leptin, which is secreted from adipocytes, has a role in the regulation of appetite and energy expenditure. The thyrotropin receptor (TSH-R) was recently found in adipocytes. We examined the effects of TSH on leptin production and lipolysis in rat epididymal adipocytes. TSH decreased the concentration of leptin in the medium time (approximately 24 hours)- and dose (approximately 10(-7) mol/L)-dependently (half-maximal inhibition [IC50] approximately 10(-9) mol/L). TSH also decreased the ob mRNA level approximately 55% in adipocytes. We confirmed the presence of TSH-R mRNA in the adipocytes by reverse transcription-polymerase chain reaction (RT-PCR). TSH stimulated glycerol release dose-dependently (IC50 approximately 10(-8) mol/L) in adipocytes. This TSH-induced glycerol release was further enhanced by adenosine deaminase (ADA). In summary, TSH reduced leptin production and stimulated lipolysis in rat epididymal adipocytes. Although the pathophysiological relevance of the regulation of leptin production and lipolysis by TSH is unknown, we speculate that TSH may affect the regulation of appetite and energy expenditure in pathophysiological states.

Adipocytes↗
PubMed1999

A phase I trial of the pharmacokinetics, toxicity, and activity of KNI-272, an inhibitor of HIV-1 protease, in patients with AIDS or symptomatic HIV infection.

The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial. After an initial phase in which the pharmacokinetics were assessed, 37 patients with AIDS or symptomatic HIV infection and 100-400 CD4 cells/mm3 were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg/kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log10 copies/ml plasma HIV RNA; these decreases persisted through 7-8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Association of plasma fibrinogen level and blood pressure with diabetic retinopathy, and renal complications associated with proliferative diabetic retinopathy, in Type 2 diabetes mellitus.

AIM: To clarify the association of several clinical parameters, including plasma fibrinogen level, with diabetic retinopathy in patients with Type 2 diabetes mellitus (DM). METHODS: A total of 294 Japanese patients with Type 2DM were studied; 53 patients with no diabetic retinopathy (NDR), 90 with background diabetic retinopathy (BDR), and 151 with proliferative diabetic retinopathy (PDR). Multiple logistic regression analysis was performed to assess variables independently associated with diabetic retinopathy in two settings: presence of retinopathy of any severity and presence of advanced retinopathy. RESULTS: The following parameters were identified as independent factors associated with the presence of diabetic retinopathy (NDR vs. BDR + PDR): type of therapy (P<0.0005), log-transformed plasma fibrinogen level (P < 0.05), mean blood pressure (P < 0.05), and duration of diabetes (P < 0.05). The independent variables associated with advanced retinopathy were type of therapy (P<0.00005), age (P<0.0005) and nephropathy (P<0.05). Body mass index, smoking and hypertensive status, HbA1c and total cholesterol levels were not independently associated. CONCLUSIONS: These data suggest that in patients with Type 2 DM, an increased blood viscosity due to high fibrinogen level as well as an elevated intravessel pressure play a role in the development of diabetic retinopathy, and that the progression to PDR is influenced or accompanied by the deterioration of renal status.

Aged↗
PubMed1999

A dose-finding study of nedaplatin and cyclophosphamide for patients with gynecological malignancies.

BACKGROUND: Nedaplatin is a new analogue of cisplatin with similar efficacy but less renal toxicity. We investigated the appropriate dose of nedaplatin in combination with cyclophosphamide for patients with gynecological malignancies. METHODS: Nine patients (five with ovarian cancer and four with uterine cervical cancer) were studied. Three patients received 60 mg/m2 of nedaplatin combined with 500 mg/m2 of cyclophosphamide every 4 weeks. Another three patients were each administered 80 or 100 mg/m2 of nedaplatin with the same dose of cyclophosphamide. A total of 27 courses was given. RESULTS: No patient needed dose reduction due to myelosuppression and no severe adverse events were observed. CONCLUSIONS: Treatment with 100 mg/m2 of nedaplatin and 500 mg/m2 of cyclophosphamide is feasible for patients with gynecological malignancies. However, phase II studies are needed to clarify the efficacy of this combination chemotherapy.

Adult↗
PubMed1998

Meta-analysis of association of insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy.

An insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene has repeatedly been shown to be associated with ischaemic heart disease, but the association of this genetic marker with diabetic microangiopathy is controversial. To assess the association of the genotypes with the development of diabetic nephropathy or retinopathy, we performed a meta-analysis of data from the literature, using Mantel-Haenszel method followed by the Breslow-Day test for assessing homogeneity among data. In a total of 4773 diabetic patients from 18 studies with (n = 2495) and without (n = 2278) renal complications, the D allele was significantly associated with diabetic nephropathy (p < 0.0001) in a dominant model (summary odds ratio 1.32, 95% confidence interval: 1.15 to 1.51). There was no significant evidence against homogeneity of the odds ratios (chi(2) = 18.9, 20 df; p = 0.53). The association was significant both in non-insulin-dependent (p < 0.005) and in insulin-dependent diabetes mellitus (p < 0.05). Likewise, in a total of 2010 diabetic patients with (n = 1008) and without (n = 1002) retinopathy, there was no association of the I/D polymorphism with diabetic retinopathy. These data suggest that the ACE I/D polymorphism affects the risk for diabetic nephropathy, but not for diabetic retinopathy.

Alleles↗
PubMed1998

Association of distal chromosome 2q with IDDM in Japanese subjects.

An insulin-dependent diabetes mellitus (IDDM)-susceptibility gene (IDDM13) has recently been mapped to a region of distal chromosome 2q, which is syntenic to the region of mouse chromosome 1 containing a murine susceptibility gene for IDDM, Idd5. To determine the contribution of this region to IDDM disease susceptibility further and to narrow the region for positional cloning of susceptibility genes, we have studied the association of distal chromosome 2q with IDDM in the genetically distinct Japanese population. A 137 mobility unit (mu) allele at D2S137 locus was significantly associated with IDDM (odds ratio 1.92, p = 0.0016). Other markers, D2S301 and D2S143, located in the same region were not associated with IDDM, indicating that IDDM13 is in linkage disequilibrium with D2S137, but not with D2S301 or D2S143. The association of D2S137 with IDDM was observed in patients lacking one of two high risk HLA alleles, DQBI*0303 and DQBI*0401, but not in patients with either of these alleles. The frequency of high risk HLA alleles was significantly lower in patients with the susceptible allele at D2S137, suggesting that IDDMI3 contributes to IDDM susceptibility in subjects without high risk genotypes at IDDM1. Demonstration of allelic association of D2S137 with IDDM localizes IDDM13 in the close vicinity (<2 centiMorgans) of D2S137, greatly facilitating fine structure mapping and positional cloning of IDDM13.

Adolescent↗
PubMed1998

Hepatocyte nuclear factor-1alpha gene and non-insulin-dependent diabetes mellitus in the Japanese population.

Recently, hepatocyte nuclear factor-1alpha(HNF-1alpha, which is encoded by the TCF1 gene) mutations were reported in a subset of patients with maturity onset diabetes of the young (MODY3). We studied the contribution of TCF1 to genetic susceptibility to common non-insulin-dependent diabetes mellitus (type 2) in Japanese subjects by investigating allelic association with type 2 diabetes use of three markers. We also studied the frequency of the G191D mutation, the only mutation of TCF1 reported so far in late-onset type 2 diabetes. A total of 356 subjects were studied. There were no significant differences in allele frequency of the three markers between patients with type 2 diabetes and control subjects. A G191D mutation was not found in the subjects studied, giving a frequency of less than 0.4% in common type 2 diabetes. The lack of association of type 2 diabetes with three markers in and near TCF1 suggests that mutations in TCF1 derived from a limited number of founders are not a major cause of common type 2 diabetes even in the genetically homogeneous Japanese population. The data also indicate that the G191D mutation in TCF1 plays little, if any, role in susceptibility to common type 2 diabetes in the Japanese.

Adult↗
PubMed1998

Asp905Tyr polymorphism of the gene for the skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 in NIDDM.

OBJECTIVE: To clarify the contribution of the Asp905Tyr polymorphism of the muscle-specific glycogen-targeting subunit of protein phosphatase 1 (PP1G) to insulin resistance and related diseases. RESEARCH DESIGN AND METHODS: We investigated the Asp905Tyr polymorphism of the PPP1R3 gene, which encodes the muscle-specific glycogen-targeting subunit of PP1G, in 259 Japanese patients with NIDDM and 194 healthy control subjects. RESULTS: No significant difference was found in the genotype distribution between NIDDM patients (N = 259; Asp/Asp = 0.10, Asp/Tyr = 0.44, Tyr/Try = 0.46) and healthy control subjects (n = 194; Asp/Asp = 0.13, Asp/Tyr = 0.37, Tyr/Tyr = 0.50) or between patient groups subdivided by the mode of treatment: NIDDM patients with insulin therapy (Asp/Asp = 0.14, Asp/Tyr = 0.46, Tyr/Tyr = 0.40) and those without insulin therapy (Asp/Asp = 0.07, Asp/Tyr = 0.43, Tyr/Tyr = 0.50). However, NIDDM patients with the Tyr allele, which was previously reported to be associated with insulin resistance, tended to have lower BMIs than those without this allele (Asp/Asp: 24.5 +/- 1.1 kg/m2, Asp/Tyr: 22.6 +/- 0.4 kg/m2, Tyr/Tyr: 22.8 + 0.3 kg/m2, P = 0.06 by analysis of variance). CONCLUSIONS: These data suggest that the Asp905Tyr polymorphism of the PPP1R3 gene is not associated with NIDDM or high BMI, both of which are known to be insulin-resistant states, in the Japanese population.

Adult↗
PubMed1997

Insulin-dependent diabetes mellitus associated with autoimmune thyroiditis and rheumatoid arthritis.

A case associated with insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis (RA), and autoimmune thyroid disease (AITD) was reported. A high titer of anti-glutamic acid decarboxylase antibody (GAD) and a positive islet cell antigen were observed. The patient's human leukocyte antibody (HLA) haplotype was a homozygote of DQA1*0301, DQB1*0401, and DRB1*0405. Because this haplotype was in linkage disequilibrium with DPB1*0501, an allele associated with AITD in Japanese patients, the patient was homozygous for alleles susceptible to IDDM, RA, and AITD. A specific HLA haplotype susceptible to several autoimmune disease may result in the development of IDDM, RA, and AITD.

Alleles↗
PubMed1996

Evaluation of current sterility tests for human live viral vaccines.

Current sterility tests for human viral vaccines were evaluated. A total of 43 lots of bulk suspension of live viral vaccines (measles, mumps, rubella and oral poliomyelitis) produced by six manufacturers in Japan were evaluated for bacteriostatic and mycoplasmastatic activities. Some of them showed fairly high bacteriostatic and mycoplasmastatic activities, due to antibiotics added during vaccine production. It was concluded that the current sterility test for mycoplasmas is not reliable to detect viable mycoplasmas in live viral vaccines.

Acholeplasma laidlawii↗
PubMed1996

Application of PCR for detection of mycoplasma DNA and pestivirus RNA in human live viral vaccines.

PCR techniques were applied for the detection of mycoplasma DNA and pestivirus RNA to 43 lots of live viral vaccines (measles, mumps, rubella, and oral poliomyelitis) produced by six manufacturers in Japan. Although mycoplasma DNA was not detected in any of the vaccines tested, pestivirus RNA was detected in 12 lots (28%). The incidence of contamination among the four viral vaccines was in the range of 20 to 37%, and the incidence among the six manufacturers varied from 0 to 56%.

Animals↗
PubMed1996

Association of Trp64Arg mutation of the beta3-adrenergic-receptor with NIDDM and body weight gain.

A possible pathogenic mutation in the beta 3-adrenergic-receptor gene (Trp64Arg) has been reported to be associated with an earlier age of onset of non-insulin-dependent diabetes mellitus (NIDDM) and clinical features of the insulin resistance syndrome in Pima Indian, Finnish and French subjects. Since marked heterogeneity has been reported in the association of mutations of candidate genes with NIDDM between Japanese and other ethnic groups, we investigated the association of Trp64Arg with NIDDM in Japanese subjects. The allele frequency of the mutation (Arg) was slightly, but not significantly, higher in NIDDM than in control subjects (70 out of 342 alleles [20.5%] vs 40 out of 248 [16.1%], respectively, p > 0.2). When our data were combined with those of Pima Indian and Finnish subjects, however, the Arg/Arg genotype was significantly associated with NIDDM as compared with the other two genotypes (p < 0.005, relative risk [RR] 2.13, 95% confidence interval [CI] 1.28-3.55). The Arg allele was also associated with NIDDM (p < 0.05, RR 1.27, 95% CI 1.06-1.52). Japanese subjects homozygous for the mutation had a significantly higher body mass index (mean +/- SD: 25.5 +/- 3.9 kg/m2) than heterozygotes (22.6 +/- 4.1, p < 0.05) and normal homozygotes (22.8 +/- 3.8, p < 0.05). NIDDM patients homozygous for the mutation tended to have an earlier age of onset of NIDDM than those with other genotypes. These data suggest that the Trp64Arg mutation not only contributes to weight gain and age-at-onset of NIDDM but is also associated with susceptibility to NIDDM.

Age of Onset↗
PubMed1996

A novel microsatellite polymorphism in the human OB gene: a highly polymorphic marker for linkage analysis.

The mouse ob gene and its human homologue OB have recently been cloned. The mutations in the ob gene are known to be associated with extreme obesity. The relationship between the human OB gene and disease, however, is largely unknown due to the lack of suitable markers within or adjacent to the OB gene. To obtain informative markers, we searched for simple tandem repeat polymorphisms in the genomic sequence of the human OB gene and identified a novel tetranucleotide repeat in the 3' flanking region. Fifteen alleles were detected in this marker with a heterozygosity of 0.85 and polymorphism information content of 0.83, indicating a highly informative nature of this marker. Two-point linkage mapping in two Centre Etude Polymorphisme Humaine (CEPH) reference families suggested that this marker is located in the interval between D7S514 and D7S530, the same interval where the OB gene is located (recombination fractions with D7S514 and D7S530 were 0.026 and 0.034, respectively). Although allele frequency distributions of this marker did not differ between 84 control subjects and 69 NIDDM patients, there was a tendency to higher body weight in control subjects with class I/class I genotype than in those without this genotype (68.8 +/- 11.1 vs 60.8 +/- 10.3 kg, p = 0.05). The highly polymorphic nature of this marker and its location in the OB gene makes this marker useful for linkage studies of the OB gene with a number of phenotypes, such as obesity, non-insulin-dependent diabetes mellitus, hypertension and the insulin resistance syndrome.

Alleles↗