The effects of a highly branched β-1, 3-glucan, SSG, obtained from a culture filtrate of a fungus, Sclerotinia sclerotiorum IFO 9395, on the growth of syngeneic tumors and antitumor effector cells were examined. In the Meth A solid tumor systems, SSG administered intraperitoneally (i.p.), intralesionally (i.l.), or intravenously (i.v.) showed significant antitumor activities. Furthermore, SSG administered i.p. also showed effective activities against IMC carcinoma. SSG enhanced nonspecific antitumor effector functions, such as natural killer activity of spleen cells and the cytolytic activity of peritoneal macrophages. Additionally, SSG increased the specific immune response (cytotoxic T lymphocyte activity) against allogeneic tumor cells.

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The positive inotropic action (PIA) of ouabain was analyzed kinetically using isolated perfused rabbit heart. The input function of the ouabain concentration in the perfusate (C_i) into the heart was controlled by changing the volume of the reservoir and the rate of ouabain infusion into the reservoir fixed in front of the heart. The time courses of PIA were measured continuously with different infusion rates. The relationship between C_i and PIA clearly depended on the infusion rate in isolated perfused rabbit heart. The binding kinetics of ouabain to Na⁺, K⁺-adenosine triphosphatase (ATPase) in the cardiac homogenate showed two kinds of binding sites. The association rate constant (k₁), the dissociation rate constant (K₁) and the binding capacity of each site was estimated by the simultaneous fitting method. The occupation curve of the high affinity site corresponded well with the PIA measured in the isolated perfused heart at steady state. These results indicate that ouabain binding to the high affinity site is related to the PIA, and the slow binding process of ouabain to Na⁺, K⁺-ATPase may be one of the principal reasons for the infusion-rate dependence of ouabain PIA.

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To clarify the diuretic response to furosemide in a diseased state, the urinary excretion of furosemide, water, and electrolytes was examined after a single intravenous injection of furosemide in control rats and rats with mild acute renal failure (ARF) induced by glycerol. The urinary recovery of furosemide was similar in the control and ARF rats. However, the diuretic response to furosemide was increased in ARF rats compared with control rats. Although the relationship between the urine flow rate (UFR) and the urinary excretion rate of (Na⁺+K⁺) (UV_Na+K) was the same in both groups, the urinary excretion rate of K⁺(UV_K) was decreased in ARF rats. The concentrating ability in ARF rats was also decreased compared with that in control rats. By infusion of aldosterone in ARF rats, both UV_K and the concentrating ability were increased and the diuretic response to furosemide was decreased, whereas the relationship between UFR and UV_Na+K was not changed. Therefore, it is concluded that the increased diuretic response to urinary excretion of furosemide in ARF rats may be caused, at least in part, by the decreased concentrating ability along the nephron.

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The plasma pharmacokinetics of sulfamonomethoxine (SMM) and sulfamethazine (SMZ) in the pig were examined after the oral and intravenous (i.v.) administration of the sodium salt solutions. Eight pigs from a commercial breed and 8 Goettingen minipigs were used. Both the C_max and t_max of SMM and SMZ ranged widely. A flipflop phenomenon was found after the SMM solution but not after the oral SMZ. Duodenal cannulae were inserted in 5 pigs. The SMM solution and the SMM suspension were directly injected into the duodenum through the duodenal cannula. Both C_max values were in a narrow range. Both t_max values were in a narrow range and were reached within 30 min. There was no flipflop phenomenon. Gastric emptying in the pig was examined using duodenal cannulated pigs. Phenol red solution and SMM suspension were administered orally. The time courses of gastric emptying of the two markers were nearly coincident and they approximated an exponential decrease. The times required for the 50% passage of the marker from the stomach ranged widely between 0.06-7.7h, which may cause the variation in the C_max and t_max of the sulfadrugs after oral administration. The k-GE (rate constant of the terminal phase of gastric emptying) also ranged widely. Nine k-GE values among 22 were smaller than the minimum value of the SMM k_el values, which may cause the flipflop phenomenon of the oral SMM. In contrast, all of the k_el values of SMZ were smaller than the minimum value of k-GE. And no flipflop phenomenon was found after the oral SMZ. Accordingly, the pharmacokinetics after the oral sulfonamides solution may be intimately influenced by the gastric emptying.

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A series of α-and β-monoglycerides and triglyceride derivatives of naproxen or nicotinic acid were synthesized and investigated in order to elucidate the molecular form of the derivative with properties that enhanced lymphatic absorption. The lymphatic absorption rate was increased by adjusting the length of an n-alkyl chain introduced between the α-or β-position of glycerol and the drug residue. The α-and β-monoglyceride derivatives (containing an n-alkyl chain) were approximately equal in lymphatic absorption rates, but differed markedly in the concentration of the di-and triglyceride analogues in the lymph lipids. The lymphatic absorption of triglyceride derivatives, drugs combined directly with β-position of glycerol, was low in comparison with the monoglyceride derivatives. Compared with nicotinic acid, the α-monoglyceride derivative (n-alkyl chain length, C_n=20) of nicotinic acid provided a higher AUC_0-8h value of free nicotinic acid and maintained a lower level of free fatty acids in blood.

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The gastric emptying rates of oral dosage forms of different sizes were studied in humans and beagle dogs measuring of marker drugs such as acetaminophen, aspirin and pyridoxal phosphate in plasma or urine. The marker drugs, except acetaminophen, were contained in enteric-coated granules or tablets which did not dissolve in the stomach but dissolved rapidly in the upper intestine. The gastric emptying rate of a dosage form of smaller size was faster than that of a larger size. The gastric emptying rates of dasage forms with different sizes did not correlate with each other inter-individually. The gastric emptying rates of dosage forms of any size were delayed when drugs were administered after taking a meal. The gastric emptying rates of dosage forms were extremely prolonged in beagle dogs after drug administration postprandially, and this restricted the use of beagle dogs as an animal model in bioavailability tests.

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Enteric-coated granules with different densities and tablets of different sizes were prepared in order to study the effect of these physical properties of dosage forms on the gastric emptying rates in humans. The effect of food on the gastric emptying rate was also studied. Aspirin contained in an enteric-coated product as a marker drug was used to determine the gastric emptying rate by measuring salicylates excreted into the urine. The larger the size of the dosage form, the larger were the values of parameters for estimating the gastric emptying rate such as t_lag, t_max and the mean absorption time. There was a significant correlation between the gastric emptying rates and sizes of dosage forms. On the other hand, no effects of density of enteric-coated granules on the gastric emptying rate were observed. The gastric emptying of dosage forms of various sizes or densities tested were prolonged by food. However, the gastric emptying rate of granules was less affected by food than that of tablets.

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The role of deacetylation in the pharmacokinetics of sulfamonomethoxine (SMM) in pigs was studied using 6 Goettingen minipigs and a pig from a commercial breed. The rapid decrease of plasma concentration of the parent compound followed by the rapid increase of plasma concentration of the deacetylated metabolite, SMM, was observed after an i.v. injection of N⁴-acetylsulfamonomethoxine (AcSMM ; 10mg/kg). The concentration of the metabolite, SMM, was greater than that of AcSMM and after reaching peak, both compounds decreased in parallel on a semilogarithmic graph. On the other hand, the acetylated compound of SMM (AcSMM) appeared in the plasma and reached peak after an i.v. injection of SMM. After reaching the peak, both SMM and AcSMM decreased in parallel. The slopes of the terminal phases of SMM and AcSMM after both injections showed no significant difference. After the i.v. injection of a high dose of SMM (100mg/kg), a nonlinear pharmacokinetics profile with capacity limited elimination type of SMM was observed. The concentration of plasma AcSMM increased rapidly and the parallel decrease of SMM and AcSMM was observed in both nonlinear and linear phases, while the renal excretion of AcSMM was saturated in the nonlinear phase. The results suggest that the deacetylation in pigs is so strong that it largely affected the pharmacokinetics of SMM in both high and low doses. In spite of the saturation in renal excretion of the main metabolite, AcSMM, after the high dose, the profile of the parallel decrease remained unchanged, which may be due to the rapid conversion of the excess AcSMM to SMM. The converted SMM was added to the existing plasma SMM. As a result, the nonlinear pharmacokinetics of SMM may have occurred after a high dose of SMM in pigs.

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Furosemide diuresis is occasionally reduced in cirrhotic patients with ascites. To define this phenomenon, the amounts of water, electrolytes, and furosemide excreted in urine were measured in control and CCl₄-induced acute hepatic failure (AHF) rats. The diuretic action of furosemide (10mg/kg, i.v.) was reduced in AHF rats, accompanied by increased plasma aldosterone concentration and accelerated urinary K⁺ excretion rate. Furosemide transiently increased the urinary inulin excretion rate (UV_IN) in both control and AHF rats. Then the UV_IN quickly returned to the baseline value in control rats, but rapidly dropped below the baseline in AHF rats. To clarify the contribution of aldosterone in these phenomena, AHF rats were adrenalectomized (ADX) and treated with or without exogenous aldosterone. The UV_IN in ADX rats given no infusion or a low-dose aldosterone infusion was similar in pattern to that of the control group, but the UV_IN in the ADX rats given a high-dose aldosterone infusion showed a pattern similar to that of the AHF rats not adrenalectomized. These findings indicate that an increase in plasma aldosterone concentration is an important factor responsible for the decreased diuretic action of furosemide, along with the reduced glomerular filtration rate.

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