Fatty acids of C_{10 : 0}, C_{12 : 0}, C_{13 : 0}, C_{14 : 0}, and C_{16 : 0} significantly inhibited the amount of gastric juice, total acid output, and total peptic activity, but fatty acids of C_{17 : 0}-C_{20 : 0} entirely failed to show significant inhibitory activity. Only the methyl ester of C_{14 : 0} showed significant inhibition of these parameters at the dose of 100 mg/kg, while at the dose of 200 mg/kg, methyl esters of fatty acids of fatty acids of C_{10 : 0}, C_{12 : 0}, C_{14 : 0}, and C_{16 : 0} significantly inhibited these three parameters. α-Monoglyceride of C_{14 : 0} significantly inhibited the amount of gastric juice at the dose of 100 mg/kg, while α-monoglycerides of C_{10 : 0}, C_{12 : 0}, C_{13 : 0}, C_{14 : 0}, and C_{16 : 0} significantly inhibited the amount of gastric juice, total acid output, and total peptic activity at the dose of 200 mg/kg. In the case of intraduodenal administration, myristic acid also showed significant inhibition of these parameters at 100 and 200 mg/kg doses. The dose-activity correlation in gastric secretion inhibitory activity was examined with myristic acid and this activity was found to increase with increasing dose of the acid administered. Myristic acid significantly decreased the ulcer index in aspirin-induced ulcer, it was entirely ineffective in preventing histamine-induced ulcer. Finally, inhibitory effect of myristic acid on pepsin and histidine decarboxylase was examined in vitro and it was found that myristic acid inhibited peptic activity, but it had almost no effect of inhibiting the histidine decarboxylase activity.

View full abstract

The apparent I₅₀ values of various hippurohydroxamic acids against urease activity of sword bean were mostly 0.5 to 2.0μM regardless of hydrophobicity of their substituents. However, the marked increase of hydrophilicity caused by substitution of trimethoxy groups conspicuously decreased the inhibitory potency. Methylation at α-position of the hydroxamic acid group in these compounds remarkably decreased the inhibitory potency, probably owing to steric hindrance by the α-methyl group. Thenoyl-, furoyl- and nicotino-glycinohydroxamic acids which are bioisostereomers of hippurohydroxamic acid had I₅₀ values of 0.64, 1.3 and 5.3 μM, respectively. Furthermore, the inhibitory potency of some substituted hippurohydroxamic acids against the ureolytic activity of intact Proteus mirabilis isolated from patients with urinary tract infection, were half to one-tenth of those against urease activity of sword bean. On the other hand, m- and p-nitro-, m- and p-methoxy-, m-and p-acetylamino-hippurohydroxamic acid and furoylglycinohydroxamic acid showed high urinary excretion rates of 14 to 16% of the doses administered orally to rats, while most of the others had excretion rates of about 3 to 5%.

View full abstract

Hydroxamic acid, a potent urease inhibitor, having a high urinary excretion rate is expected to be a therapeutic agent for urolithiasis caused by urea-splitting bacterial infection of the urinary tract. Twenty-one new derivatives of N-aliphatic-acylglycinohydroxamic acids (GHAs) were synthesized, and their inhibitory potencies against the urease activity of sword bean in a phosphate buffer and against the ureolytic activity of Proteus mirabilis in human urine, and their urinary excretion rates in rats were also measured for this purpose. I₅₀ values of most of GHAs against the urease activity of sword bean were about 1 to 10 μM and 2-ethyl-n-butyroyl GHA was the most potent inhibitor with the value of 0.79 μM. I₅₀ values of most of the GHAs against the ureolytic activity of Proteus mirabilis were about 5 to 50 μM and n-nonaroyl GHA was the most potent inhibitor with the value of 3.6 μM. 2, 2-Dimethylpropionyl GHA had the highest urinary excretion rate with the recovery of 11%. Routes of administration of 2, 2-dimethylpropionyl GHA and sex of rats used did not affect the amount of urinary excretion at all. The results in this report suggest that DL 2-methyl-n-butyroyl, 2-ethyl-n-butyroyl and 2, 2-dimethylpropionyl GHA are the most hopeful therapeutic agents for urolithiasis among them.

View full abstract

Quantitative structure activity relationships between physico-chemical properties of four series of more than sixty hydroxamic acids [R-(CONHCH₂)_n-CONHOH, R=aromatic or aliphatic, n=1 or 0) and their urease inhibitory activities were examined. The best improved regression equation equation primarily indicated that the inhibitory activities of hydroxamic acids were parabolically varied with the hydrophobic variable, π of the R moiety and the optimal π value was calculated to be 2.58. Furthermore, the inhibitory activities of congeners were found to be significantly affected by the B₁ variable representing the minimum width of steric size of the R moiety. Besides, it was clarified by using two indicator variables that inhibitory activities were not affected by the R moiety, whether aromatic or aliphatic, but positively affected by the presence of the -CONHCH₂-group between the R moiety and the hydroxamic acid group.

View full abstract

The combined effects of polychlorinated biphenyls (PCB) and methylmercury were investigated by assaying the activities of hepatic enzymes and by measuring the binding of bromobenzene to microsomal protein. Rats were fed normal or PCB-diet (KC-400-KC-500, 1 : 1, 50 ppm) for 14 days and methylmercuric chloride (10 mg Hg/kg, s.c.) was given once daily for the last 2 days. The inducing effects of PCB on microsomal cytochrome P-450, cytochrome b₅, aminopyrine N-demethylase, aniline hydroxylase, and p-nitroanisole O-demethylase were counteracted by methylmercury. Glucose 6-phosphatase activity was additively decreased by the combination of PCB and methylmercury. The activity of glucose 6-phosphate dehydrogenase in soluble fraction was increased by PCB but reduced by methylmercury. The toxicity of bromobenzene was enhanced by PCB but the effect of PCB was counteracted by methylmercury. The depletion of liver glutathione and the elevation of serum transaminases by bromobenzene were remarkably potentiated by PCB. Methylmercury counteracted the effect of PCB on serum transaminases but not that on liver glutathione. The amount of bromine covalently bound with liver microsomal protein after an injection of bromobenzene and the radioactivity bound with microsomal protein after in vitro incubation of ¹⁴C-bromobenzene with microsomes were fortified by PCB pretreatment but depressed by the combining administration of methylmercury.

View full abstract

Islet-activating protein (IAP) prepared from the culture medium of Bordetella pertussis cells was very effective in eliminating diabetic symptoms characteristic of hereditary diabetic KK mice over a long period of time. After a single injection of IAP (5 μg/kg body wt) into KK mice, the non-fasting concentration of blood glucose was maintained nearly normal over 2 weeks, with a gradual return to the pre-IAP level 30 days later. During this period, glucose tolerance was normalized and only few animals excreted glucose in urine. The second injection of IAP to these diabetic mice caused a more prolonged restoration of normoglycemia. When KK mice had been injected with IAP, they responded to epinephrine and isoproterenol more readily than did ddY mice in increasing plasma insulin and glycerol.

View full abstract

Antitumor activity of metabolites of 1-hexylcarbamoyl-5-fluorouracil (HCFU) and related compounds was examined in vivo and in vitro. Carboxypentyl and carboxypropyl carbamoyl derivatives of 5-fluorouracil (FU) were moderately active against L1210 by oral administration but less active by intraperitoneal administration. However, 5-hydroxy-and 5-oxo-hexyl carbamoyl derivatives of FU were markedly or moderately active against the leukemia by both oral and intraperitoneal administrations. Therapeutic ratios for the metabolites were less than that for HCFU by both oral and intraperitoneal administrations. Metabolites of HCFU had growth inhibitory activity against L5178Y in vitro similar to alkylcarbamoyl derivatives of FU. Activity of metabolites was lower than that of FU and higher than that of HCFU in vitro. It means that HCFU is converted into FU through active intermediate metabolites in vivo.

View full abstract

UDP-glucuronyltransferase activities for Δ⁸-tetrahydrocannabinol, 11-hydroxy-Δ⁸-tetrahydrocannabinol, cannabidiol and cannabinol were examined using liver microsomes of rabbits. The activities for cannabidiol and cannabinol were 2.5 and 19 times higher, respectively, than those for Δ⁸-tetrahydrocannabinol and 11-hydroxy-Δ⁸-tetrahydrocannabinol. Thus, the present study supports the view that glucuronide formation plays an important role in the metabolism of cannabinol, but does only a minor role in that of Δ⁸-tetrahydrocannabinol and 11-hydroxy-Δ⁸-tetrahydrocannabinol.

View full abstract