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Biomedical subjects

H Kitagawa

Publications and source records attributed to H Kitagawa.

At least 487 records · Page 27Linked to original sources
PubMed1985

Age associated alteration of lidocaine metabolism is position selective.

Patterns of associated alterations in N-deethylation, 3-hydroxylation, and aromatic methylhydroxylation of a single substrate, lidocaine in liver microsomes from 0.7 - 28 months old Fischer 344 rats were examined. These three patterns were all different from one another. In addition to this position selectiveness, a clear sex difference was observed in the pattern of alteration in N-deethylation. These results are consistent with the hypothesis that age associated alterations in drug metabolism are caused by age associated alterations in relative abundance of multiple species of cytochrome P-450.

Aging↗
PubMed1985

The hepatic handling of sulfobromphthalein in aging Fischer-344 rats: in vivo and in vitro studies.

Biliary transport maximum (Tm) and relative storage capacity (S) for sulfobromphthalein (BSP) were compared in male and female Fischer-344 rats of different ages ranging from 3 to 30 mth. When expressed per unit liver weight, the male Tm value decreased rapidly with age reaching 40% of the 3-mth-old value at 30 mth. Female values, which were significantly lower than corresponding male values during the first year also decreased steadily with age but the rate of decrease was much lower than in male values. Consequently, at 30 mth there was no longer any difference between male and female rats. S values expressed per gram liver stayed essentially unchanged with age in both male and female rats, although female values were always lower than male values. The liver's in vitro conjugation capacity for BSP with glutathione also decreased significantly with age in male rats, while in female rats it remained unchanged between 3 and 28 mth of age. Thus, the decrease in BSP Tm value with age could not be fully explained by the decrease in liver's conjugation capacity with glutathione. The results of the present study, coupled with our previous observations on other rat strains suggest that, at least in rats, BSP Tm decreases with age but S does not, despite contrary reports made by other authors on man and rats.

Aging↗
PubMed1985

Sex difference in subunit composition of hepatic glutathione S-transferase in rats.

The activities of hepatic cytosolic glutathione S-transferases (GSTs) towards 1,2-dichloro-4-nitrobenzene in male rats were higher than those in females, however, the enzyme activities towards 1-chloro-2,4-dinitrobenzene were not significantly different between the two sexes. SDS-PAGE analysis of GSTs purified from male and female rat hepatic cytosols by affinity column chromatography showed that there was a significant difference in the subunit composition between the two sexes. With regard to the several isozymes of GSTs in male and female rats, isozymes with basic and neutral/acidic isoelectric points were separated into seven molecular species by chromatofocusing. These sex differences in the quantitative proportions of GST isozymes were also confirmed by immunotitration using anti-GST-BL and -AC antibodies. On the other hand, glutathione peroxidase (GSH-Px) activities in rat hepatic cytosol towards hydrogen peroxide and cumene hydroperoxide were markedly higher in females than in males. Of the two types of GSH-Px, selenoenzyme (Se-GSH-Px) and the Se-independent enzyme (non-Se-GSH-Px), the former was found to be mainly responsible for the sex difference in the enzyme activities. Moreover, the GSH-Px activity of GSTs, non-Se-GSH-Px, was also higher in females than that in males. Since GST isozymes of the BL type are known to possess GSH-Px activity towards cumene hydroperoxide, the increased activities of non-Se-GSH-Px in the female hepatic cytosol seemed to be mainly due to the increased transferase activities of the isozymes, GST-L2 and -BL.

Animals↗
PubMed1985

Studies on immunity in hybridoma-bearing mice. B. Immunity against the hybridoma. I. Studies on the immune state of mice after rejection of the hybridoma.

Anti-dinitrophenyl IgE secreting hybridoma B 53 cells may be rejected when injected subcutaneously in BALB/c mice. These mice are immune as they withstand without any ill effect the intraperitoneal injection of LD100 B 53 cells. Sera from mice which rejected the tumor have cytotoxic antibodies against the hybridoma, as shown by in vitro tests, but serum cannot transfer immunity to naive BALB/c mice against hybridoma B 53. Spleen cells from mice which have rejected the tumor might transfer immunity against B 53 hybridoma, and with Winn tests it has been shown that these spleen cells are very effective against the B 53 cells and also against the myeloma cells which were used for the fusion to construct the B 53 hybridoma. Subcutaneously injected B 53 cells not only produce anti-DNP IgE secreting tumors, but often also metastasize to spleen, and they are sometimes detected in the circulating blood. Mice with splenic metastasis or with detectable circulating B 53 cells generally die. However, we did observe one mouse with splenic metastasis which successfully rejected the tumor and became immune to B 53 cells.

Animals↗
PubMed1985

Attenuation of aspirin analgesia by calcium loading in healthy subjects.

To clarify the mechanism of aspirin analgesia, the relationship among analgesic and hypocalcemic effects and pharmacokinetics of aspirin was investigated in 20 healthy subjects at 20-23 years old. Four experimental groups were made, that is, (1) aspirin 1.0 g, (2) aspirin 1.0 g + calcium gluconate 1.5 g X 2, (3) calcium gluconate 1.5 g X 2, (4) control (placebo). Calcium gluconate was administered orally twice, that is, 30 and 90 min after oral administration of aspirin. The experiments were carried out under a double blind method. As an analgesic test, the ultrasonic method was used. Aspirin (1.0 g) caused a significant analgesia, the effect reaching the maximum at 90 min and prolonging for about 3 h. Simultaneously, plasma calcium level significantly decreased and kept going down, at least, until 180 min after administration of aspirin. However, when calcium gluconate was loaded at 30 and 90 min after administration of aspirin, both the analgesic and hypocalcemic effects of aspirin were significantly inhibited. The plasma aspirin concentration reached a maximum 30-60 min after administration of aspirin in both groups: aspirin alone and aspirin with calcium gluconate. On the other hand, plasma salicylic acid concentration kept increasing up to 180 min after administration of aspirin in either group. The plasma aspirin and salicylic acid levels in both groups were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Mechanism of anti-platelet aggregating action of dilazep.

In vitro effect of Dilazep on the release and metabolism of arachidonic acid (AA) in human platelets was studied. Dilazep reduced in a dose-dependent manner platelet aggregation and thromboxane B2 (TXB2) formation when stimulated by adenosine diphosphate, collagen and epinephrine. Dilazep decreased thrombin-induced release of [14C]arachidonic acid ([14C]AA) from platelets prelabeled with [14C]AA. The conversion of [14C]AA to cyclooxygenase metabolites was reduced by the addition of Dilazep, while that to 12-lipoxygenase metabolite was rather increased. Adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate levels in washed human platelets were not affected by the addition of Dilazep. These results suggest that the decreased TXB2 formation by Dilazep may be ascribed to the impairment of AA release from platelet membrane phospholipids and the reduced conversion of released AA to TXA2.

Adenosine Diphosphate↗
PubMed1985

NAD-coupled enzymatic oxidation of O-ethyl O-p-nitrophenyl phenylphosphonothioate (EPN) to its oxygen analog with liver microsomes of rats.

O-Ethyl O-p-nitrophenyl phenylphosphonothioate (EPN)-induced inhibition of rat liver microsomal carboxylesterase (CEase) and formation of O-ethyl O-p-nitrophenyl phenylphosphonate (EPNoxon), an oxygen analog of EPN, were enhanced remarkably by addition of NAD in vitro. This potentiation of the anti-CEase action of EPN by NAD was significantly inhibited by addition of SKF 525-A or potassium thiocyanate (KSCN); and a simultaneous decrease in cytochrome P-450 contents were also observed. Addition of N-ethylmaleimide (NEM) at various concentrations inhibited potentiation of the anti-CEase action of EPN by NAD in parallel with inhibition of liver microsomal dehydrogenase activities. In conclusion, NAD was enzymatically reduced to NADH, a cofactor of microsomal dehydrogenase(s), and then formation of EPNoxon through microsomal cytochrome P-450-coupled monooxygenase was accelerated. Consequently, inhibition of CEase by EPN was potentiated.

Aldehyde Dehydrogenase↗
PubMed1985

Enhancement of the binding of O-ethyl O-p-nitrophenyl phenylphosphonate (EPNoxon) to microsomal carboxylesterase by NAD in vitro.

Inhibition of rat liver microsomal carboxylesterase (CEase) by O-ethyl O-p-nitrophenyl phenylphosphonothioate (EPN) and binding of EPN oxygen analog to microsomal CEase were enhanced by addition of NAD or NADP. This was more prominent in addition of NAD than NADP. No potentiation of anti-CEase action of EPN by NAD was seen when pure esterase (E.C. 3.1.1.1) instead of liver microsomes was used as an enzyme source. This effect of NAD in microsomal CEase was significantly decreased when N-ethylmaleimide or p-chloromercuribenzoic acid was added. From these findings, it is strongly suggested that NAD-mediated potentiation of the anti-CEase action of EPN might be attributed to the increase in formation of NADH from NAD by microsomal dehydrogenase(s) containing a sulfhydryl group, leading to a subsequent increase in formation of the EPN oxygen analog from EPN, and in turn, CEase inhibition was enhanced.

Animals↗
PubMed1985

Gastric cytoprotection by pirenzepine in rats: evaluating method for cytoprotective activity by antisecretory agents.

The effects of antisecretory agents, pirenzepine, atropine and cimetidine, on gastric mucosal lesions induced in rats by ethanol, HCI (0.6 N), HCI-acidified 50% ethanol and HCI-acidified 50 mM sodium taurocholate (TCA) were comparatively studied with PGE2. The involvement of gastric acid in the formation of ethanol-induced necrosis was also studied. PGE2 and pirenzepine inhibited necrosis induced by all necrotizing agents at the non-antisecretory doses, and the cytoprotective effect of pirenzepine was not abolished by indomethacin. Atropine and cimetidine did not inhibit HCI-induced necrosis even at the antisecretory dose. Atropine and cimetidine at the antisecretory dose inhibited necrosis induced by ethanol, but did not inhibit the red streaks. The ethanol-induced necrosis was also inhibited by neutralizing intragastric H+ with Tris buffer. In gastric fistula rats, alkalinization of the lumen was observed by exposure to ethanol, but necrosis was not produced. There is a close relationship between the necrosis and intragastric acid. Thus it is assumed that gastric acid is involved in the formation of ethanol-induced necrosis. It was suggested that pirenzepine possesses cytoprotective action which is not related to endogenous PGs. On the other hand, the antiulcer actions of atropine and cimetidine may be due, in a part, to antisecretory effects.

Animals↗
PubMed1985

General pharmacological studies of hydroxypropylmethylcellulose acetate succinate in experimental animals.

Extensive general pharmacological studies of hydroxypropylmethylcellulose acetate succinate (HPMCAS) were carried out in mice, rats, guinea pigs, rabbits, dogs and frogs. HPMCAS appeared to have no significant effect on the central nervous system, autonomic nervous system and cardiovascular system. Various biological analyses of the blood (including hemolysis and coagulation properties) and urine were unaffected, and the compound showed no significant local anesthetic or vascular permeability. At higher doses of HPMCAS, an increase in secretion of saliva in guinea pigs, a decrease in gastric juice secretion in rats and an increase in rectal temperature in rats were observed, but these effects did not show clear dose-dependence.

Animals↗
PubMed1985

Toxicological studies of hydroxypropylmethylcellulose acetate succinate--acute toxicity in rats and rabbits, and subchronic and chronic toxicities in rats.

The acute toxicity (in rabbits and rats) and the subchronic and chronic toxicities (in rats) of Hydroxypropylmethylcellulose acetate succinate (HPMCAS), a potentially useful pharmaceutical excipient, were investigated. 1) In the acute toxicity study (single oral dose of 2.5 g/kg), no deaths or behavioral abnormalities were observed. Thus, LD50 is higher than 2.5 g/kg. 2) In the subchronic toxicity study (0.63, 1.25 or 2.5 g/kg daily as a single oral dose in the morning, 6 days per week (not Sunday) for 2 months), no significant behavioral abnormality was observed. There was some decrease in body weight gain in rats of both sexes, but the effect was not statistically significant. 3)In the chronic toxicity study (1.25 or 2.5 g/kg daily as a single oral dose in the morning, 6 days per week (not Sunday) for 6 months), no significant behavioral abnormality was observed. There was some decrease in body weight gain in male rats, but it was not statistically significant. 4)Various biochemical and physiological abnormalities in rats were noted in all groups (including the control groups) in the toxicity studies, but there appeared to be no significant dose-related finding attributable to the administration of HPMCAS.

Administration, Oral↗
PubMed1985

Studies of hydroxypropylmethylcellulose acetate succinate on fertility in rats.

A fertility study was carried out in Slc: SD rats orally administered Hydroxypropylmethylcellulose acetate succinate (HPMCAS), a useful pharmaceutical excipient, at dose levels of 625, 1,250 and 2,500 mg/kg/day. Male rats were treated with HPMCAS from 60 days before pairing until the completion of mating. Female rats received HPMCAS for 22 days, from 14 days prior to mating up to Day 7 of gestation. All pregnant females were sacrificed on Day 21 of gestation and all fetuses were examined for abnormalities. No abnormal signs were seen in mating or fertility in the rat treated with HPMCAS. No external, internal and skeletal anomalies attributable to HPMCAS were observed in the fetuses. It was concluded that HPMCAS had no harmful effect on mating, fertilization, implantation, or embryonic development.

Administration, Oral↗
PubMed1985

Teratological studies of hydroxypropylmethylcellulose acetate succinate in rats.

A teratogenicity study was carried out in S1c: SD rats orally administered Hydroxypropylmethylcellulose acetate succinate (HPMCAS), a useful pharmaceutical excipient, at dose levels of 625, 1,250 and 2,500 mg/kg/day for a period of 11 days from day 7 to day 17 of gestation. Two-thirds of the pregnant females in each group were sacrificed on Day 21 of gestation and their fetuses were examined. The remaining dams were allowed to litter naturally, and the postnatal development of the offsprings was observed. The incidences of external, internal, and skeletal anomalies were not significantly increased in the fetuses of any treated groups. HPMCAS caused no effects on parturition, lactation, postnatal growth and reproductive ability of the male and female offspring.

Abnormalities, Drug-Induced↗
PubMed1985

Teratological study of hydroxypropylmethylcellulose acetate succinate in rabbits.

A teratological study was carried out in New Zealand White rabbits in order to examine the teratogenic potentiality of HPMCAS, a useful pharmaceutical excipient. HPMCAS was orally administered at dose levels of 625, 1,250 and 2,500 mg/kg/day for a period of 13 days from day 6 to day 18 of gestation. All pregnant females were sacrificed on day 29 of gestation and their fetuses were examined. The administration of HPMCAS during a period of organogenesis produced no embryotoxic and teratogenic effects as well as no influence on behavior, appearance and growth of animals.

Abnormalities, Drug-Induced↗
PubMed1985

Effects on offspring induced by oral administration of hydroxypropylmethylcellulose acetate succinate to the female rats in peri- and post-natal periods.

A perinatal and postnatal study was carried out in Slc: SD rats orally administered Hydroxypropylmethylcellulose acetate succinate (HPMCAS), a useful pharmaceutical excipient, at dose levels of 625, 1,250 and 2,500 mg/kg/day for a period from day 17 of gestation to day 21 after delivery. All pregnant rats were allowed to litter naturally, and the postnatal development of the offsprings was observed. In the administered group of 2500 mg/kg, the liver weight was significantly increased in males and showed a tendency to increase in females as compared with control. No significant differences between the control group and the administered groups were found in postnatal growth and differentiation, behavior and reproductive ability of male and female offsprings.

Administration, Oral↗