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Biomedical subjects

M Baba

Publications and source records attributed to M Baba.

At least 19 recordsLinked to original sources
PubMed1992

Potential anti-AIDS naphthalenesulfonic acid derivatives. Synthesis and inhibition of HIV-1 induced cytopathogenesis and HIV-1 and HIV-2 reverse transcriptase activities.

Several naphthalenedi- and trisulfonic acids have been synthesized and evaluated for inhibitory potential against cytopathogenesis and purified recombinant human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptase (RT). The most potent derivative that emerged from the anti-RT study was a small molecule 6 (MW = 840), a dipalmitoylated derivative of 2,7-naphthalenedisulfonic acid. Analog 6 demonstrated 50% inhibitory concentration (IC50) values of 2.42 and 0.86 microM for HIV-1 and HIV-2 RT, respectively. The second most active compound was also a derivative of the same naphthalenedisulfonic acid but contained only one palmitoyl moiety. This compound 9 displayed IC50 values of 4.8 and 3.7 microM for HIV-1 and HIV-2 RT, respectively. Both analogs 6 and 9 are active at noncytotoxic doses, exhibit slightly higher potencies for the RT of HIV-2 over HIV-1, and demonstrate activities superior to the hexasulfonic acid derivative suramin (IC50 values of 9.4 and 15.5 microM for HIV-1 and HIV-2 RT, respectively). In the cytopathogenesis assay, the most active compound is a bis naphthalenedisulfonic acid derivative 17, containing a flexible octamethylene spacer and exhibiting an in vitro therapeutic index of 29.7. Most striking, however, is the influence of the palmitoyl functionality in the naphthalenedisulfonic acid series to confer activity against both HIV-1 and HIV-2 RT.

Enzyme Inhibitors↗
PubMed1992

Synthesis and antiviral activity of deoxy analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents.

The effect of substitution in the acyclic structure of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) on anti-HIV-1 activity was investigated by synthesizing a series of deoxy analogs and related compounds. Preparation of 1-[(2-alkyloxyethoxy)methyl]-6- (phenylthio)thymine (2-4) derivatives was carried out based on alkylation of HEPT with primary alkyl halides. Preparation of the 1-[(alkyloxy)methyl]-6-(phenylthio)thymine (26-31) and 1-[(alkyloxy)methyl]-6-(arylthio)-2-thiouracil (32-45) derivatives was carried out on the basis of LDA lithiation of 1-[(alkyloxy)-methyl]thymine (9-14) and 1-[(alkyloxy)methyl]-2-thiouracil (15-25) followed by reaction with diaryl disulfides. The oxidative hydrolysis of the 2-thiouracil derivatives gave 1-[(alkyloxy)methyl]-6-(arylthio)uracil derivatives (46-57). 1-Alkyl-6-(phenylthio)thymine (59-61) derivatives were prepared on the basis of alkylation of 6-(phenylthio)thymine (58). Methylation of the hydroxyl group of HEPT did not affect the anti-HIV-1 activity of HEPT. Substitution of the 1-(2-hydroxyethoxy)methyl group by ethyl, butyl, methoxymethyl, (propyloxy)methyl, and (butyloxy)-methyl groups somewhat improved the original anti-HIV-1 activity of HEPT. Substitution with ethoxymethyl and (benzyloxy)methyl groups further potentiated the activity [EC50: 1-(ethoxy-methyl)-6-(phenylthio)thymine (27), 0.33 microM; 1-[(benzyloxy)methyl]-6-(phenylthio)thymine (31), 0.088 microM]. When the 5-methyl group of 27 and 31 was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity was improved remarkably [EC50: 5-ethyl-1-(ethoxymethyl)-6-(phenylthio)-uracil (46), 0.019 microM; 5-ethyl-1-[(benzyloxy)methyl]-6-(phenylthio)uracil (52), 0.0059 microM; 5-isopropyl-1-(ethoxymethyl)-6-(phenylthio)uracil (55), 0.012 microM; 5-isopropyl-1-[(benzyloxy)methyl]-6-(phenylthio)uracil (56), 0.0027 microM]. Introduction of two m-methyl groups into the phenylthio ring also potentiated the activity.

Antiviral Agents↗
PubMed1992

Protection by muscimol against gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in spontaneously hypertensive rats.

The effects of prolonged administration of the gamma-aminobutyric acid receptor agonist muscimol on enhanced induction of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in spontaneously hypertensive rats (SHR), and on the norepinephrine concentration in the gastric wall and the labeling index of gastric mucosa were investigated. SHR and normotensive Wistar Kyoto (WKY) rats as controls were given a solution of MNNG (25 micrograms/ml) for 25 weeks and then i.p. injections of 0.5 mg/kg body weight of muscimol every other day. In control WKY rats, gastric cancers were found in 1 (7%) of 14 rats examined at week 52. In SHR treated with NaCl solution only, the incidence of gastric cancers was significantly increased to 50% compared with that in control WKY rats. However, treatment of SHR with muscimol significantly increased its incidence to 12% compared with the value in SHR treated with NaCl solution only. The norepinephrine concentration in the gastric wall and the labeling index of the gastric mucosa were significantly greater in SHR than in WKY rats. Prolonged administration of muscimol to SHR significantly reduced the norepinephrine concentration in the antral portion of the gastric wall or the labeling index of the antral epithelial cells. These findings indicate that long-term treatment of SHR with muscimol attenuated the enhancement of gastric carcinogenesis in SHR.

Analysis of Variance↗
PubMed1992

Inhibition by 6-hydroxydopamine of enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in spontaneously hypertensive rats.

The effects of chemical sympathectomy induced by 6-hydroxydopamine (6-OHDA) on the enhanced induction of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in spontaneously hypertensive rats (SHR), and the norepinephrine (NE) concentrations in their gastric wall and the labeling index of gastric epithelial cells were investigated. SHR rats and normotensive Wistar Kyoto rats (WKY) as controls were given MNNG (25 micrograms/ml) in their drinking water for 25 weeks and then i.p. injections of 6-OHDA (42 mg/kg twice within 24 hr, and then 105 mg/kg every 2 weeks from 1 week later). In control group (WKY rat + NaCl), gastric cancers were found in 2 (11%) of 18 rats examined in week 52. In SHR rats treated with NaCl solution only, the incidence of gastric cancers significantly increased, to 53% compared with that in control WKY rats. Treatment of SHR rats with 6-OHDA significantly decreased its incidence to 12% compared with the value in SHR rats treated with NaCl solution only. Prolonged administration of 6-OHDA to SHR rats significantly reduced the NE concentration in the antral portion of the gastric wall and the labeling index of antral epithelial cells. These findings indicate that prolonged i.p. treatment with 6-OHDA attenuated the normally higher incidence of MNNG-induced gastric cancer in SHR rats.

Animals↗
PubMed1992

Inhibitions by 6-hydroxydopamine and neostigmine singly or together of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effects of chemical sympathectomy induced by 6-hydroxydopamine (6-OHDA) and administration of the acetylcholinesterase inhibitor neostigmine, singly or together, on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and on the tissue catecholamine concentration of the gastric wall and the labeling index of the gastric mucosa, were investigated in inbred Wistar rats. Rats received s.c. injections of neostigmine (0.075 mg/kg), and/or i.p. injections of 6-OHDA (42 mg/kg twice within 24 hr, and then 105 mg/kg every 2 weeks from 1 week later) 25 weeks after oral treatment with MNNG. Prolonged administration of 6-OHDA or neostigmine significantly reduced the incidence of gastric cancers by week 52, and in combination they had a significantly greater inhibitory effect. 6-OHDA and/or neostigmine had no influence on the histology of gastric cancers. Administration of 6-OHDA, but not neostigmine, significantly decreased the norepinephrine concentration in the antral portion of the gastric wall. The labeling index of the antral mucosa was decreased significantly by treatment with 6-OHDA or neostigmine, and decreased even more significantly by 6-OHDA plus neostigmine. Our findings indicate that 6-OHDA and neostigmine have protective effects against gastric carcinogenesis and that in combination their effects are additive. These results imply that the activities of the sympathetic and parasympathetic autonomic systems together influence gastric carcinogenesis.

Animals↗
PubMed1992

Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.

A series of bicyclams have been shown to be potent and selective inhibitors of human immunodeficiency virus (HIV). The compounds are inhibitory to the replication of various HIV-1 and HIV-2 strains in various human T-cell systems, including peripheral blood lymphocytes, at 0.14-1.4 microM, without being toxic to the host cells at 2.2 mM. The bicyclam JM2763 is active against 3'-azido-3'-deoxythymidine (zidovudine; AZT)-resistant HIV-1 strains and acts additively with AZT. Mechanism of action studies revealed that the bicyclams (i.e., JM2763) interact with an early event of the retrovirus replicative cycle, which could be tentatively identified as a viral uncoating event.

Antiviral Agents↗
PubMed1992

Kinetics of inhibition of endogenous human immunodeficiency virus type 1 reverse transcription by 2',3'-dideoxynucleoside 5'-triphosphate, tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thion e, and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives.

Recently, tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) compounds have been shown to be potent, selective, and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in vitro. They interact with the reverse transcriptase of HIV-1 in a way different from that of previously studied reverse transcriptase (RT) inhibitors. We established an endogenous RT assay, starting from intact HIV-1 virions. This assay mimics the reverse transcription process in the HIV-infected cell more closely than RT assays with artificial templates. We investigated the inhibition of endogenous HIV-1 reverse transcription by the TIBO derivative (+)-(S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo [4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (R-82150) in comparison with the HEPT derivative 5-ethyl-1-ethoxymethyl-6-(phenylthio)uracil (E-EPU) and 2',3'-dideoxyguanosine 5'-triphosphate. The kinetics and characteristics of RT inhibition by TIBO in the endogenous RT assay were similar to those found previously for the exogenous RT assay (following addition of exogenous template/primer); thus, RT inhibition by TIBO was specific for HIV-1 and the extent of RT inhibition was dependent on which of the four substrates (dATP, dTTP, dGTP, and dCTP) was present in limited concentrations. Of the three enzymatic activities, RNA-dependent DNA polymerization was preferentially inhibited, and inhibition was not competitive with respect to the natural substrates. HIV-1 RT behaved as an allosteric enzyme, which means that positive cooperativity for binding of the substrate was observed. TIBO behaved as an allosteric inhibitor by causing a concentration-dependent decrease in this cooperativity.

Allosteric Regulation↗
PubMed1992

Rapid quantitative evaluation of plasma D-dimer levels in thrombotic states using an automated latex photometric immunoassay.

To evaluate a recently developed latex photometric immunoassay (LPIA) that which can measure 40 samples quantitatively within 30 minutes, we measured D-dimer levels in blood samples obtained from patients with disseminated intravascular coagulation (DIC). Linearity of D-dimer determination was shown over the range from 0.5 to 36 micrograms/ml, and recovery studies demonstrated 94 to 108% recovery. The intra-assay and inter-assay coefficients of variation ranged from 0.6 to 11.3% at plasma D-dimer levels of 0.54 to 30.1 micrograms/ml. No interference by lipids, bilirubin, haemoglobin, rheumatoid factor, or gamma-globulin was noted. The normal D-dimer range was less than 0.5 microgram/ml in healthy ambulatory subjects, while the level in elderly subjects with atherosclerosis (14%) or in immobilized subjects (38%) was well above this limit. There was a strong correlation between plasma and serum D-dimer levels (r = 0.993). D-dimer levels measured by this LPIA showed a good correlation with those determined using two kinds of ELISA. The LPIA D-dimer levels were elevated in some subjects with diseases predisposing to DIC, but remained below 10.0 micrograms/ml. On the other hand, the LPIA D-dimer levels in DIC subjects were almost always above 10.0 microgramS/ml. Our study showed that a hypercoagulable state should be suspected when the LPIA D-dimer level is greater than 0.5 microgram/ml and that DIC should be diagnosed when the level is greater than 10.0 micrograms/ml in the presence of an appropriate underlying disease. This LPIA system can rapidly evaluate the presence of a hypercoagulable state as accurately as any ELISA, and thus seems potentially valuable for both emergency and routine laboratory use.

Adult↗
PubMed1992

Enhancement by thyroxine of experimental carcinogenesis induced in rat colon by azoxymethane.

The effect of thyroxine (T4) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the labeling index of colon mucosa were investigated in Wistar rats. Rats were given AOM by injection once a week for 10 weeks, together with T4 in depot form until the end of the experiment. Administration of T4 resulted in a significant increase in the incidence of colon tumors in week 35. However, it did not influence the histological appearance of the colon tumors or the histological types and depths of involvement of colon adenocarcinomas. Furthermore, it caused a significant increase in the labeling index of the colon during, but not after, AOM treatment. Our findings indicate that T4 enhances the development of colon tumors, which may be related to its effect in increasing proliferation of epithelial cells in the colon mucosa during administration of the carcinogen.

Adenocarcinoma↗
PubMed1992

Enhancement by bombesin of colon carcinogenesis and metastasis induced by azoxymethane in Wistar rats.

The effects of bombesin on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on their metastases to the peritoneum and/or lymph nodes, were investigated in Wistar rats. Rats received weekly s.c. injections of AOM for 10 weeks, and s.c. injections of bombesin in depot form every other day until the end of the experiment in week 30. Administration of bombesin significantly increased the incidence of colon tumors in week 30. It had no influence on the histological features or depths of involvement of colon adenocarcinomas, but significantly increased the incidence of cancer metastasis to the peritoneum and/or lymph nodes. It also caused a significant increase in the labeling index of the colon epithelial cells. Our findings indicate that bombesin enhances the development and metastasis of colon tumors, and that this effect may be related to its effect in increasing proliferation of epithelial cells of the colon.

Adenocarcinoma↗
PubMed1992

Enhancement by vaso-active intestinal peptide of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

The effects of vaso-active intestinal peptide (VIP) on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats given VIP every other day for 27 weeks after oral administration of MNNG for 25 weeks. In week 52, administration of VIP caused a significant increase in the incidence of gastric cancers, but did not influence their histological appearance. VIP significantly increased the labeling indices of the antral mucosa. Our findings indicate that VIP enhances gastric carcinogenesis, and that this effect may be related to its effect in increasing cell proliferation of the antral epithelial cells.

Animals↗
PubMed1992

Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity.

The effect of substitution on the pyrimidine moiety of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine (HEPT-S) on anti-HIV-1 activity was investigated by synthesizing a series of 5-methyl-6-(arylthio) and 5-substituted-6-(phenylthio) derivatives. Preparation of the 5-methyl-6-(arylthio) derivatives was carried out based on either LDA lithiation of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]thymine (3) and 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiothymine (4) followed by reaction with diaryl disulfides or an addition-elimination reaction of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]-methyl]-6- (phenylsulfinyl)thymine (31) with aromatic thiols. Preparation of the 5-substituted-6-(phenylthio) derivatives was carried out based on either C-5 lithiation of the 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-6-(phenylthio)uraci l (41) with LTMP or the LDA lithiation of 5-alkyl-1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiouraci l derivatives 45-47. Substitution at the meta position of the C-6-(phenylthio) ring by the methyl group improved the original anti-HIV-1 activity of HEPT, and introduction of two m-methyl groups to the phenylthio ring further potentiated the activity [EC50: 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]thymine (28), 0.26 microM; 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]-2-thiothymin e (30), 0.22 microM]. When the 5-methyl group was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity of HEPT was also improved remarkably [EC50: 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (48), 0.11 microM; 5-isopropyl-1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)-2-thiouracil (50), 0.059 microM; 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (54), 0.12 microM; 5-isopropyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (56), 0.063 microM]. 6-[(3,5-Dimethylphenyl)thio]-5-ethyl-1-[(2-hydroxyethoxy)methyl]thymine derivatives 51 and 57 and 6-[(3,5-dimethylphenyl)thio]-5-isopropyl-1-[(2- hydroxyethoxy)methyl]thymine derivatives 52 and 58 inhibited the replication of HIV-1 in the nanomolar concentration range.

Antiviral Agents↗
PubMed1992

Inhibition of azoxymethane-induced experimental colon carcinogenesis in Wistar rats by 6-hydroxydopamine.

The effects of 6-hydroxydopamine (6-OHDA) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on norepinephrine (NE) concentration in the colon wall and the labelling index of the colon mucosa were investigated in Wistar rats. Rats received sub-cutaneous (s.c.) injections of AOM once a week for 10 weeks, and throughout 35 weeks were also given intraperitoneal (i.p.) injections of 6-OHDA. Prolonged administration of 6-OHDA was found to cause a significant reduction in the incidence and number of colon tumors. However, it had no influence on the histological features or depths of involvement of colon tumors and/or adenocarcinomas. Its administration also caused significant decreases in the NE concentration in the colon wall and in the labelling index of the colon mucosa. Our findings indicate that 6-OHDA has a protective effect against colon carcinogenesis, and that the activity of the sympathetic nervous system may have an important influence on colon carcinogenesis.

Adenocarcinoma↗
PubMed1992

Attenuating effect of ornithine decarboxylase inhibitor (1,3-diaminopropane) on bombesin enhancement of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine.

The effects of combined administration of bombesin and the ornithine decarboxylase (ODC) inhibitor 1,3-diaminopropane (DAP) on the incidence and number of gastric tumors induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the ODC activity of the gastric wall and the labelling index of the gastric mucosa were investigated in inbred Wistar rats. Rats were given drinking water containing MNNG (50 micrograms/ml) for 25 weeks and then drinking water containing DAP (2.5 g/l) and/or injections of 40 micrograms/kg body weight of bombesin in depot form every other day. Administration of bombesin alone resulted in significant increases in the incidence of gastric cancers, the ODC activity of the antral portion of the gastric wall and the labelling index of the antral mucosa. Administration of DAP with bombesin significantly reduced enhancement by the latter of gastric carcinogenesis, ODC activity of the antral portion of the gastric wall and the labelling index of the antral mucosa. Our results suggest that ODC inhibition attenuated the enhancement of gastric carcinogenesis by bombesin, and that this enhancement by bombesin was mediated by polyamine biosynthesis.

Adenocarcinoma↗
PubMed1992

Enhanced induction of colon carcinogenesis by azoxymethane in Wistar rats fed a low-protein diet.

The effects of ad libitum feeding of synthetic, low-protein diets on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), on the norepinephrine concentration in the colon wall tissue and on the labelling index of colon mucosa were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of AOM and were given synthetic diets of equal calorie content containing 25% casein (normal-protein diet), 10% casein (low-protein diet) or 5% casein (very-low-protein diet). Administration of the low- and very-low-protein diets resulted in significant increases in the incidence and number of colon tumors at week 30. However, it did not affect the histology of the colon tumors. The low- and very-low-protein diets also resulted in significant increases in norepinephrine concentration in the proximal and distal portions of the colon wall and in the labelling indices of both parts of the colon mucosa. Our findings indicate that low- and very-low-protein diets enhance colon carcinogenesis and that this may be related to their effects in increasing the norepinephrine level in the colon wall and in stimulating proliferation of colon epithelial cells.

Adenocarcinoma↗
PubMed1992

Lymphangioma in the small intestine: report of a case and review of the Japanese literature.

We report herein a rare case of a 53 year old man with a benign lymphangioma of the small intestine. He presented with a complete obstruction of the small intestine and radiological examination revealed a small intestinal tumor. A long intestinal tube was passed, the intestinograms from which detected a submucosal tumor of the small intestine. Partial resection of the small intestine was thus performed and the tumor was found to be located mainly in the submucosa. The final pathological diagnosis was made as cavernous lymphangioma. This case is presented with a description of the roentgen appearance, followed by a review of the Japanese literature.

Adult↗
PubMed1992

Factors influencing survival after endoscopic Nd:YAG laser surgery for unresectable advanced malignancies of the trachea.

The effects of endoscopic Nd:YAG laser surgery were studied in 36 patients with unresectable advanced primary and metastatic malignancies in the trachea with special reference to the factors influencing long-term survival. Overall effectiveness of YAG laser treatment was demonstrated in 34 of the 36 patients (94 per cent), while the overall 1, 3 and 5 year survival rates after the first laser treatment were 25 per cent, 13 per cent and 13 per cent, respectively. Neither histologic type nor the severity of clinical symptoms before laser treatment showed any significant influence on the survival curves, however, endoscopic findings of stenosis, the effect of laser treatment and irradiated longitudinal length were all significantly correlated with the survival curves. In other words, endoscopically protruding type tumors with a longitudinal length of irradiation of 3.0 cm or less, and good responses not only to laser treatment but also to other combined modalities are favorable factors for achieving long-term survival in patients with tracheobronchial malignancies undergoing endoscopic Nd:YAG laser treatment. Endoscopic Nd:YAG laser surgery is considered to be a promising part of the multi-modality treatment for unresectable advanced primary and metastatic malignancies of the trachea.

Aged↗