The effects of repeated administration of haloperidol (HAL) and clofluperol (CLO) on the responsiveness of pituitary-adrenal system to these drugs were studied in rats. Chronic treatment of animals with a daily i.p. dose of 5 μmol/kg of the drugs resulted in markedly attenuated responses of plasma corticosterone (CS) to challenge of the same dose of the same drug as compared to the acute treatment which caused a large increase in the plasma CS levels. Animals receiving a chronic HAL treatment showed a complete cross-tolerance to the stimulatory effect of CLO and a nearly complete cross-tolerance to that of chlorpromazine. The adrenal cortices of animals tolerant to HAL responded normally to exogenous ACTH. This result indicates that the tolerance to the stimulatory action of the butyrophenones may occur in the hypothalamo-pituitary axis.

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Chikusetsusaponin IV and V, whose genin is oleanolic acid, exhibited weak hemolytic activities. Removal of glucose residue at position 28 of chikusetsusaponin V by partial hydrolysis increased the activity more than 30-fold. Methylation of the carboxyl group at position 28 increased the activity furthermore by about 10-fold, showing HD₅₀ value of 3.77 μM. On the other hand, removal of the sugar chain at position 3 of chickusetsusaponin V by partial hydrolysis completely lost the activity. These facts suggest that the sugar chain at position 3 of oleanolic acid is essential but that at position 28 is pernicious for the activity. The cytolytic agents, whose target has been regarded as membrane cholesterol, were inactivated not only by cholesterol but also by sapogenins such as oleanolic acid, gitogenin and hederagenin. Among saponins tested, akebia saponin B and C were inactivated by cholesterol, but not by the genins, probably because their affinities for the genins are too low to form complexes.

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The relationship between gastric mucosal hemorrhage and coagulation-fibrinolysis of fasting, restraint and water immersion stress (FS) rats was studied in comparison with normal (N) and fasting (F) rats. In this case, the FS group was fasted for 18 h prior to the stress application and then subjected to restraint and water immersion stress for various intervals. The F group was fasted for 18 h plus the time comparable to the stress load. Gastric mucosal erosions with bleeding were recognized from 1 h after the stress load only in FS group and the hemorrhagic erosion index progressively increased 1 to 16 h. In the FS group, prothrombin time and active partial thromboplastin time gradually prolonged with time course from 8 and 1 h, respectively, and plasma prothrombin level remarkably decreased from 1 h, although no changes in these parameters were observed in the F group. Plasminogen activator activity in gastric mucosa significantly increased in not only FS group but also F group from 0.5 h as compared with N group. However, no significant difference was seen between F and FS groups on this activity. Plasma plasminogen and antiplasmin levels in FS group were lower than those of N group, 3 h later. It is suggested from these results that sustained hemorrhage from the gastric mucosa in this stress ulcer may be associated with high fibrinolytic activity in the gastric mucosa and the delay of blood coagulation.

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We examined the inhibitory activities of branched-chain fatty acids of iso-C_{12 : 0} to iso-C_{16 : 0} on gastric secretion in rats. Consequently, iso-C_{13 : 0} and iso-C_{15 : 0} were found to have strong inhibitory activities on gastric secretion in rats. In the case of intraduodenal administration, iso-C_{15 : 0} also showed a significant inhibition of gastric juice secretion. Therefore, the effects of iso-C_{13 : 0} and iso-C_{15 : 0} on ulceration in pylorus-ligated rats and aspirin-induced ulcer were examined. At the doses of 10 and 25 mg/kg, iso-C_{13 : 0} and iso-C_{15 : 0} significantly decreased the ulcer index in pylorus-ligated rats, and aspirin-induced ulcer was also significantly inhibited at the doses of 25 and 50 mg/kg. Finally, effect of iso-C_{15 : 0} on pepsin, Mg⁺⁺-ATPase and carbonic anhydrase, which are considered to play an important role in the mechanism of gastric juice secretion, was examined in vitro, centering around iso-C_{15 : 0} which showed a marked effect in gastric juice secretion inhibitory and anti-ulcerogenic activities. Iso-C_{15 : 0} showed inhibitory activity on pepsin and Mg⁺⁺-ATPase, but entirely no activity on inhibiting carbonic anhydrase.

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The characteristics of the binding site in the first binding class of naphthol yellow-S (NY-S) on bovine serum albumin (BSA) were studied. The binding of NY-S to BSA at an equimolar ratio of each material resulted in a marked quenching of intrinsic fluorescence of BSA and a decrease in the binding capacity of 1-anilinonaphthalene-8-sulfonate to BSA. The binding of NY-S to BSA was diminished by the chemical modification of tryptophan residue in the BSA molecule with 2-hydroxy-5-nitrobenzyl bromide and o-nitrophenylsulfenyl chloride. The higher modification rate of tryptophan residue decreased the binding constant of NY-S to BSA. These results suggest that the first binding site of NY-S to BSA is located in a hydrophobic area including tryptophan which is position 134 on the amino acid sequence of BSA. Studies on BSA modified with diethylpyrocarbonate demonstrated that a histidine residue also may participate in the binding of NY-S to BSA.

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The bioavailability of aspirin from an aspirin aluminum tablet was compared with that from an aspirin tablet in humans by determining total salicylate excreted in the urine. The effects of concomitant intakes of antacid or food on the bioavailability of aspirin were also investigated. The bioavailability of aspirin from an aspirin aluminum tablet was nearly 60% of that from an aspirin tablet. The low bioavailability of aspirin from an aspirin aluminum tablet was caused by slow release of aspirin from the aluminum complex, and not increased by concomitant intake of food. Intake of food, however, reduced both rate and extent of bioavailability of aspirin from an aspirin tablet, but dried aluminum hydroxide gel granules had no effect on the bioavailability of it.

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The binding of three loop diuretics, piretanide, bumetanide and furosemide, to serum proteins from patients with liver cirrhosis of fulminant hepatitis was investigated using equilibrium dialysis. A good correlation was found between serum albumin concentration and the percentage of each unbound (free) loop diuretic in patients with liver disease. The binding data obtained from patients with liver cirrhosis was compared with that of patients with chronic renal failure. Calculations made according to the Sandberg-Rosenthal's formula revealed that the maximum binding concentration (nP) varied in some cases. These findings necessitated a detailed investigation into whether the increased percentage of each unbound loop diuretic in patients with liver disease is attributable not only to lowered serum albumin concentration but also to inhibition of the protein binding by some endogenous substances. Thus, similar experiments were performed using rats with experimental liver cirrhosis. The binding of the loop diuretics to serum proteins in cirrhotic rats differed greatly from the findings obtained from cirrhotic patients. The percentage of unbound loop diuretic was well correlated with serum albumin concentration but not with the concentration of serum bilirubin (an endogenous substance) in cirrhotic rats.

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The effect of stannous chloride on bone metabolism was examined in weanling male rats given oral dose of 1.0 mg Sn/kg at 12-h intervals for 28 days. Tin administration produced progressive increase in tin content of the femoral diaphysis and epiphysis. Calcium content in the femoral epiphysis but not diaphysis was significantly decreased by tin administration for 28 days, while inorganic phosphorus contents in the femoral diaphysis and epiphysis were not changed significantly. Acid and alkaline phosphatase activities in the femoral diaphysis and epiphysis were markedly reduced by tin administration for 3 days, and significant decreases in the femoral epiphysis were also observed at 28 days. Meanwhile, ATPase and pyrophosphatase activities in the femoral diaphysis and epiphysis were not altered significantly by tin administration. From the present study, of mineral composition and its related enzyme activity, the decreases of acid and alkaline phosphatase activities in the femoral epiphysis were regarded as the biochemical manifestation of the toxic action of inorganic tin.

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A nonlinear least squares program (MULTI) for microcomputers was developed. The program is written in BASIC programming language. Four algorithms, (1) Gauss-Newton method, (2) damping Gauss-Newton method, (3) modified Marquardt method and (4) simplex method, can be used for nonlinear curve fitting in MULTI. Up to five pharmacokinetic equations, which are voluntarily defined by the user, are simultaneously fitted to observed time courses. The executions of MULTI are demonstrated for time courses of ampicillin and oxacillin in man.

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Gliclazide, an oral hypoglycemic drug having sulfonylurea structure, is stable in native human serum, but the drug is easily degraded in an albumin-removed serum. It was found that the degradation was inhibited by readdition of serum albumin. Then, the protein fractions possessing gliclazide-degrading activity were separated from the human serum on a gel filtration using Sephadex G-150 column, and some characterizations and kinetic analysis of the degradation were performed. Moreover, the protective effects of native and modified serum albumin (BSA) on the degradation were studied. The degrading factor was found in both protein fractions of IgM (fraction M) and IgG (fraction G), but was not found in a fraction of albumin (fraction A). The degradation of gliclazide by the fraction G was inhibited in proportion to the amount of albumin in the fraction A. Several commercial albumins, bovine serum albumin (fraction V) and human serum albumin (fraction V and fatty acid-free), showed also the protective effect on the degradation. The degrading activities of the fraction M and G were completely lost by a heat-treatment at 100°C for 10 min. The maximal rate of degradation was obtained by incubation at 37-40°C for 16-24 h. The dose-response curve for the degradation of gliclazide by the fraction G was represented as an enzyme-reaction like sigmoidal curve. The double-reciprocal plot for the degradation was a parabolic profile, suggesting to be n order reaction (n > 1) and Hill plot was a straight line with a slope of 3.0. Each kinetic parameter of reaction order (Hill constant, n), Michaelis constant (K_m) and equilibrium constant (K) was 3.0, 17.8 mM and 1.74×10^-4mM^-n, respectively. Since the degradation rate highly correlated with the binding capacity of the secondray binding site on the BSA molecule (r=0.915), it was suggested that the protective effect of BSA on the degradation of gliclazide closely associated with the interaction of gliclazide in the secondary binding site on the BSA molecule.

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The glucuronidation of 17-hydroxycorticosteroids (17-OHCS) and its effectiveness as an index of salicylamide (SAM) glucuronidation were examined in guinea pigs, the same cortisol type animals as man, treated with carbon tetrachloride (CCl₄), D-galactosamine, phenobarbital, D, L-ethionine and alloxan. There was not a statistically significant correlation between the plasma clearance of SAM glucuronidation (CL_glu) and the urinary excretion ratio of 17-OHCS glucuronide to total 17-OHCS in the intact, and CCl₄, D-galactosamine, alloxan and D, L-ethionine treated guinea pigs (r=0.158). However, there was a statistically significant correlation between the CL_glu and the clearance of 17-OHCS glucuronidation obtained as urinary 17-OHCS glucuronide/plasma cortisol concentration (r=0.738, p < 0.1). It was proposed that the clearance of 17-OHCS glucuronide metabloized from endogenous cortisol could be used as an index to assess the drug glucuronidation activity.

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Biochemical and biophysical analyses were made to study the properties of serum albumin from nephrotic patients of two types, remissive stage and relapsed state, and the results were compared with those in normal subjects. Two different ion exchange columns were prepared to isolate and purify each albumin sample and the materials eluted through the two columns were identified. The nephrotic elution materials, especially in the state of relapse, were of some difference from those of normal subjects. α-Helix contents estimated by circular dichroism spectra were found to be closer to normal albumin in remissive stage than in the state of relapse. The binding of fluorescent probe, 1-anilino-8-naphthalene sulfonate, to albumin was examined by calculating the binding parameter, the dissociation constant and number of binding sites. The binding parameters were closer to those of normal albumin in remissive stage than the state of relapse.

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