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Biomedical subjects

H Kitagawa

Publications and source records attributed to H Kitagawa.

At least 541 records · Page 30Linked to original sources
PubMed1983

Studies to increase the antitumor activity of 1-(tetrahydro-2-furanyl)-5-fluorouracil and its metabolic aspects by combined administration with L-cysteine.

The plasma and liver concentrations of both 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and 5-fluorouracil (5-FU), an active metabolite of FT, increased very markedly after administration of FT (500 mg/kg, p.o.) combined with L-cysteine (L-CYS, 500 mg/kg, i.p. or p.o.) when compared to FT alone in rats. On the other hand, the oral acute toxicity of FT was also enhanced with the combined administration of FT and L-CYS. There was no difference in the in situ absorption rate of FT from the small intestine between rats treated with L-CYS (500 mg/kg, i.v.) and vehicle-treated controls. The inhibition of the disappearance of FT and the increase of the formation of 5-FU was observed in vitro after incubation of FT with liver microsomes from rats treated with L-CYS (500 mg/kg, p.o.) when compared to vehicle-treated controls. The presence of L-CYS significantly inhibited the in vitro degradation of 5-FU by non-treated rat liver homogenate. In the drug metabolizing enzyme activity of rat liver microsomes, aniline p-hydroxylase activity was inhibited, but aminopyrine N-demethylase activity was conversely activated by the combined administration of FT and L-CYS, but not by FT alone; furthermore, no change of cytochrome P-450 content was observed. In sarcoma 180 bearing mice, the oral antitumor activity of FT in combination with L-CYS (500 mg/kg, i.p. or p.o.) was about 1.1-2.0 times higher than that of FT alone. It was concluded from these findings that the drug metabolizing enzymes in liver involved in the conversion of FT into an active metabolite, 5-FU, are influenced by the combined administration of FT and L-CYS to give an increased organ level of 5-FU; and this resulted in the enhancement of the antitumor activity of FT.

Absorption↗
PubMed1983

[Difference in the effects of antitussive drugs on respiration and cough reflex].

In order to understand the relationship between the cough and respiratory centers in the brain stem, we investigated the effects of antitussive drugs such as codeine, dextromethorphan, eptazocine and fominoben on respiratory movement and the cough reflex. Coughs were induced using electrical stimulation of the central cut end of the right superior laryngeal nerve in lightly anesthetized dogs. The drugs were administered intraarterially into the vertebral artery. Rate (RR), amplitude (RA) and volume (RV) of the respiration and number (NC) and amplitude (AC) of the cough reflex evoked were measured as indices. Codeine produced a decrease in RR, RV and NC at 0.3 mg and, additionally, AC at 1 mg. Dextromethorphan increased RR and RV and rather enhanced NC and AC at 0.3 mg, but the agent reduced NC and AC at 3 mg even if it increased RR and RV. Eptazocine produced decreases in RA, NC and AC at 1 mg, and, additionally, RV at 10 mg. Fominoben increased RR, RA and RV dose-dependently at 0.3-3 mg, although it depressed NC and AC at 3 mg. These findings suggest that the thresholds for the cough responses and respiratory responses to antitussive drugs are different from drug to drug and that the respiratory centers and cough center in the brain stem are affected in a different manner even qualitatively.

Analgesics↗
PubMed1983

Toxicity and biotransformation of acetaminophen in rat hepatocytes (I). Uptake and release.

Uptake and conjugation of acetaminophen were studied in isolated rat hepatocytes. Acetaminophen was taken up by the cells and the conjugates formed in the cells were rapidly released from the cells at a constant rate. The kinetic analysis demonstrated that uptake was due to a saturable process as well as a simple diffusion. Decrease in uptake of acetaminophen by metabolic inhibitors suggested that uptake of acetaminophen by hepatocytes might be, at least in part, due to an energy dependent process.

2,4-Dinitrophenol↗
PubMed1983

Alleviation of acetylsalicylic acid-induced fetal toxicity by calcium.

Alleviation of aspirin-induced fetotoxicity by calcium was investigated in rats. ASA (500 mg/kg s.c.) decreased the plasma Ca level in pregnant rats and that in the feto-placenta units. 0.05 M CaCl2 given to dams as tap water on days 8 through 20 of gestation inhibited ASA-induced hypocalcemic effect in maternal plasma. Tap water of 0.002-0.05 M CaCl2, Ca(OH)2 and Ca-lactate on days 8 through 20 of gestation alleviated malformations elicited by the administration of ASA (500 mg/kg s.c.) on the 11th day of gestation resulting in a decrease in the fetotoxicity in rats.

Abnormalities, Drug-Induced↗
PubMed1982

Perturbation of hepatic glutathione level and glutathione-related enzyme activities by repeated administration of aminopyrine in rats.

The influence of repeated administration of aminopyrine on the tissue glutathione level and related enzyme activities was investigated in rats. Reduced glutathione level in the liver was not changed after 5 days of treatment but a significant increase was seen after 15 days of aminopyrine treatment. Oxidized glutathione level was unaltered throughout the experiment. Repeated administration of aminopyrine for 5 days caused a marked increase in gamma-glutamyl transpeptidase activities in liver whole homogenates as well as in the nuclear fraction, but not in liver microsomes. These results suggest that gamma-glutamyl transpeptidase located in plasma membrane may be induced by repeated administration of aminopyrine for 5 days. The activities of cytosolic glutathione peroxidase, which modulates glutathione level, were also significantly increased by aminopyrine treatment. Under the same conditions, glutathione peroxidase activity with H2O2 as a substrate was unaltered, while a time-dependent increase in the activity was found when cumene hydroperoxide was used as a substrate, even after a single administration of aminopyrine. The intracellular cysteine level was increased accompanying the increased gamma-glutamyl transpeptidase activities. Therefore, induced gamma-glutamyl transpeptidase may play a role in the reclamation of extracellular oxidized glutathione.

Administration, Oral↗
PubMed1982

Effect of disulfiram in combination with L-tryptophan and lithium on pentylenetetrazol-induced seizure.

Disulfiram prolonged the latency to clonic seizure caused by pentylenetetrazol (PTZ, 100 mg/kg SC). The effect of disulfiram was augmented by combination with tryptophan plus lithium, although neither tryptophan or lithium prolonged the latency to clonic seizure. The latency to tonic seizure was also prolonged in disulfiram-treated animals in parallel with the prolongation of the latency to clonic seizure. Lithium treatment completely prevented the incidence of tonic seizure, while this effect was cancelled in disulfiram-treated animals. Disulfiram acts on the clonic and tonic seizures in different ways.

Animals↗
PubMed1982

Augmentation of vagal reflex bradycardia be central alpha2-adrenoceptors in the cat.

Vagal reflex bradycardia was induced in anaesthetized cats with high level spinal axotomy by electrical stimulation of either the carotid sinus nerves or a depressor nerve. In both preparations reflex bradycardia increased with the rate of stimulation. Injection of 1 microgram/kg clonidine into a lateral cerebral ventricle augmented reflex bradycardia in response to carotid sinus nerve stimulation while the same dose of clonidine was ineffective when given intravenously. The antagonistic effect of intracerebroventricular yohimbine (50 micrograms/kg) indicated that the effect of clonidine was due to its alpha2-agonistic action. In contrast to carotid nerve stimulation the reflex bradycardia in response to depressor nerve stimulation was affected neither by intracerebroventricular injection of clonidine (2 micrograms/kg) nor by yohimbine (100 micrograms/kg). It is concluded that in the cat, the function of the central parts of the baroreceptor reflex which originate from the carotid sinus area is augmented by stimulation of alpha2-adrenoceptors while the function of those parts originating from the aortic area is not.

Animals↗
PubMed1982

Disulfiram-like effect of diethyl maleate on barbiturate-induced hypnosis and 5-hydroxytryptamine metabolism.

Diethyl maleate (DEM, 600 mg kg-1 i.p.) significantly potentiated hexobarbitone hypnosis and lowered plasma hexobarbitone level on awakening. Sleeping time following intracerebroventricular (i.c.v.) injection of phenobarbitone was also prolonged by DEM treatment. When administered to DEM-treated rats, L-tryptophan (50 mg kg-1 i.p.) significantly potentiated hexobarbitone hypnosis, although alone it had no effect in control rats. DEM markedly diminished the activity of brain low-Km aldehyde dehydrogenase (A1DH) and the formation of 5-hydroxyindoleacetic acid from 5-hydroxytryptamine (5-HT) without affecting MAO activity in various areas of the brain. Conversely, the protein-bound radioactivity derived from i.c.v. [14C]-5-HT was increased by DEM treatment. These results showed that DEM is comparable with disulfiram, a brain A1DH inhibitor, in terms of its effect on 5-HT metabolism and barbiturate hypnosis.

Aldehyde Dehydrogenase↗
PubMed1982

A new screening method for evaluating antitussives in conscious guinea pigs.

In order to evaluate the effects of antitussive agents, a new method for inducing the cough reflex in guinea pigs was devised. Male guinea pigs weighing 300-450 g were fixed in a supine position under non-anesthesia. A puncture electrode made by a stainless steel wire (0.2 mm diameter, 10 cm length) was inserted into the trachea through a guiding cannula (needle size 23G, Terumo). The optimal parameters of electrical stimulation given on the tracheal mucous membrane were a square-wave pulse with a 40 Hz frequency, duration of application 5 s. Fifty percent of antitussive doses (AtD50) of the drugs used in this study were as follows: codeine, 3.35 mg/kg (i.p.), 7.5 mg/kg (p.o.); morphine, 1.2 mg/kg (i.p.), 2.5 mg/kg (p.o.); picoperidamine, 10.9 mg/kg (i.p.), 22.6 mg/kg (p.o.); benproperine, 14.5 mg/kg (i.p.), 22.6 mg/kg (p.o.); fominoben, 13.9 mg/kg (i.p.), 477 mg/kg (p.o.). These AtD50s are much less as compared with those obtained using other methods. These results suggest that the present method for inducing the cough reflex in guinea pigs is useful for the first screening of antitussives, especially when only a small quantity of the materials is available.

Animals↗