Hydroxy propyl cellulose (HPC)-ethyl cellulose (EC) microcapsules containing piretanide were newly prepared by a solvent evaporation technique and their slow-release properties were evaluated on dissolution properties in vitro and pharmacokinetic and pharmacodynamic parameters in beagle dogs. The dissolution behavior of piretanide from the microcapsules in dissolution media of pH 1.2-6.8 and the plasma piretanide level in beagle dogs varied dependently on the contents of HPC and EC. As compared with the ordinary piretanide tablet on the market, the HPC-EC₁₀ (5 : 3) microcapsule showed the controlled dissolution behavior, sustained plasma piretanide level, almost same AUC (area under curve), slow urinary piretanide excretion, decreased urine excretion maximum rate, and no difference in the cumulative urine volume and cumulative urinary electrolytes (Na⁺, K⁺, Cl^-) excretion. HPC-EC microcapsules containing piretanide sufficiently satisfied the conditions which slow-release preparations must have.

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To elucidate the mechanism (s) of the decrease of the volume of distribution at steady state (V_dss) and the tissue-to-plasma concentration ratio (K_p) of quinidine after cimetidine treatment, the following were studied ; (1) the effect of cimetidine on the tissue binding of quinidine in vitro, (2) the non-linear tissue distribution of quinidine and (3) the effect of cimetidine on tissue pH. The in vitro binding of quinidine to rat tissue homogenates was not affected by cimetidine treatment. The tissue distribution of quinidine in rats was linear from 1 to 5 μg/ml of plasma concentration except for lung. The plasma disappearance of 5, 5-dimethyl-2, 4-oxazolidinedione (DMO) after a 200 mg/kg intravenous injection was fitted to a two compartment open model. In the cimetidine-treated rats (50 mg/kg), the pharmacokinetic parameters of DMO, such as the plasma total body clearance (Cl_tot), V_dss and the rate constant at the terminal phase (β) increased to 230, 110 and 210% of those of the non-treated rats, respectively. The intracellular pH calculated by K_p of DMO increased significantly in liver, spleen, intestine, brain, muscle and skin. This suggests that cimetidine decreased the tissue-to-plasma pH partition coefficient (q) of unbound quinidine in several tissues. The decreases of V_dss and K_p of quinidine by cimetidine was attributed to the decrease of q resulting from the increase of tissue pH.

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The drug concentration profile at non-steady state in the intestine was simulated using a laminar flow model. The transport equation with cylindrical coordinates was solved by a finite difference method to simulate the concentration profile in the tube and the exit cup-mixing concentration. A drug with a various wall permeability coefficient (P_w=zero or 10^-5 to 10^-3 cm/s) and diffusion constant (D=10^-6 to 10^-4 cm²/s) was assumed to be introduced into the tube in a pulse form. The spatial intervals of the grid and the time step were varied to yield the optimum condition for calculation. The concentration profile in the tube as the time elapsing and the exit cup-mixing concentration versus time profile were shown graphically. P_w and D influenced the concentration profiles. This suggests the possibility of the estimation of P_w and D by determining the exit cup-mixing concentration after a pulse input to a perfused intestine under a laminar flow condition.

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Immunohistochemical localization of P-450 HFLa, a form of cytochrome P-450 in human fetal livers was in vestigated in human hepatocellular carcinoma. The cytoplasm of carcinoma cells positively reacted with anti-P-450 HFLa antibodies. It was found that the carcinoma cells showing a pseudo-glandular pattern or poorly differentiated appearance exhibited a weaker reactivity with anti-P-450 HFLa antibodies than did relatively differentiated carcinoma cells. In the case of hepatoblastoma, the polygonal or round-shaped tumor cells which differentiated into epithelial structure exhibited a positive reaction with anti-P-450 HFLa antibodies, whereas the spindle-shaped tumor cells which showed a sarcomatous appearance did not react with the antibodies.

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4-Nitrophenyl vinyl ether (1), umbelliferyl vinyl ether (2), 4-cyanophenyl vinyl ether (3), and 4-acetylphenyl vinyl ether (4) were mutagenic toward Salmonella typhimurium TA 100 and TA 100NR in the presence of the hepatic 9000×g supernatant fraction fortified with a reduced nicotinamide adenine dinucleotide phosphate generating system (S9mix), but no significant mutagenicity of 4-chlorophenyl vinyl ether (5), phenyl vinyl ether (6), n-butyl vinyl ether (7), and ethyl vinyl ether (8) was found. The epoxides of 1-4 were highly mutagenic toward the bacteria without the S9mix. Also, epoxides of 5 and 6 showed relatively weak mutagenicity. Studies on the metabolism of 1 showed that the epoxide (1a) formed from 1 by microsomes behaved as a labile intermediate in the incubation mixture. Untreated rat hepatic microsomes accumulated 1a and induced mutagenicity of 1 most effectively among the activation systems used. Mutagenic activities of vinyl ethers in the presence of the S9mix were correlated with stabilities of their epoxides. From these results, it is suggested that the critical factor for the mutagenicity of vinyl ethers is the formation and stability of epoxide intermediate in the biological system.

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Both testosterone (T) and 5α-dihydrotestosterone (DHT) significantly increased colony-stimulating factor (CSF) as well as colony-inhibitory factor (CIF) in the submandibular gland (SMG) in female mice. The CIF activity was completely inactivated by heating at 60°C for 15 min, while the CSF activity was stable against the heat treatment. It was found that the CSFs obtained from the androgen-treated female mice and from normal male mice behaved identically in chromatography on hydroxylapatite and Ultro-gel AcA 34 columns. The potency of DHT to increase CSF activity was about 10 times greater than that of T.

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Derivatives of adenosine 3', 5'-cyclic monophosphate (cAMP) with modifications at the 8-position were synthesized and examined for their cytotoxic effects on FM3A mouse mammary tumor cells and ZR-75 human mammary tumor cells. On in vitro tests of these derivatives, 8-amino (8-NH₂) cAMP was the most effective against both cell lines. This compound showed the dose-dependent inhibition of FM3A cell growth in the concentration of over 2.5 μM with the ID₅₀ value of 4 μM. Furthermore, antitumor activity of 8-NH₂ cAMP was also tested against FM3A cells in vivo. T/C% values of 8-NH₂ cAMP were respectively 162% and 138% in response to doses of 30 and 10 mg/kg by intraperitoneal injections of 8-NH₂ cAMP for 5 d. 8-NH₂ cAMP was converted to 8-NH₂ adenosine via 8-NH₂ adenosine 5'-monophosphate by some enzymes in the fetal bovine serum and the cytotoxic effect of 8-NH₂ cAMP on FM3A cells was actually stemmed from 8-NH₂ adenosine.

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Rat serum obtained at 24 h after subcutaneous injection of carrageenin significantly suppressed chemotaxis of rat polymorphonuclear leukocytes (PMNs) in vitro. α₂ Acute-phase macroglobulin (α₂APM), α₁ proteinase inhibitor (α₁PI) and cysteine-proteinase inhibitors (CPIs) are present at high concentration in the 24-h serum and known as acute-phase reactants in rats. These acute-phase proteinase inhibitors were purified from inflamed rat serum or exudate and their effect on PMN chemotaxis was studied by Boyden's method in vitro. α₂APM (4 mg/ml) significantly suppressed PMN chemotaxis while α₁M was without effect, though both α₂APM and α₁M had a similar anti-proteinase activity. The results suggest that α₂APM suppressed PMN chemotaxis through the mechanism unrelated to its anti-proteinase activity. On the other hand, α₁PI (1 and 3 mg/ml) slightly but significantly suppressed PMN chemotaxis, whereas CPI-1 and CPI-2 had no inhibitory effect. These results suggest that α₂APM and α₁PI play a role in suppression of PMNs infiltration into the inflammatory site in the late-phase of acute inflammation.

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