Three classes of glycolipids (TMM (trehalose monomycolate), TDM (trehalose dimycolate) and GM (glucose mycolate)) containing mycolic acids as hydrophobic components were isolated from a strain of Nocardia rubra (Rhodococcus rubrum) and their structures have been partially characterized using infrared spectrometry, gas-liquid chromatography and gas chromatography-mass spectrometry. Acid or alkaline hydrolysis of isolated glycolipids revealed that trehalose was the sole water soluble component in TMM and TDM, while glucose was the hydrophilic component in GM. On the other hand, saturated, monoenoic and dienoic mycolic acids with carbon atoms ranging from C₃₆ to C₅₀ contained constituents of fatty acid moiety at C₄₄. From the analytical results, TMM, TDM and GM were tentatively identified as trehalose monomycolate, trehalose dimycolate and glucose monomycolate, respectively. The mycolic acid composition differed significantly by the glycolipid classes : the highest amount of saturated mycolic acids were detected in TMM and GM, while a significant amount of dienoic mycolic acids have been found in TDM and the cell wall bound lipid fraction (BL). All these three classes of glycolipids containing mycolic acids showed strong granuloma forming activity in lungs and spleen of ICR mice 1 week after intravenous injection of 100 to 500 μg glycolipid in W/O/W micelles containing Freund's incomplete adjuvant. These results indicated that glycolipids containing shorter carbon chain mycolic acids ranging C_40-50, corresponding to less acyl numbers or monosaccharides such as glucose, can also produce foreign body-type granuloma in mice without protein antigens.

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The redox level of [¹⁴C] coenzyme Q₁₀ solubilized with HCO-60 in the livers of guinea pigs at 24 h after intravenous injection was approximately 1/4 (18.2% vs. 63.4%) of that of [¹⁴C] coenzyme Q₁₀ solubilized with ethanol-water (1 : 5 by vol). Further, the redox level of coenzyme Q₁₀ (Q₁₀) solubilized with HCO-60 or ethanol-water was 20.2 or 82.3%, respectively, after a 30-min incubation in the liver cytosol. Q₁₀ solubilized with HCO-60 was thus reduced only slightly in vivo or in vitro. The critical micelle concentrations of HCO-60 in the absence and presence of Q₁₀ were 0.02 and 0.002% (w/v), respectively. The concentrations of HCO-60 micelles containing Q₁₀ were estimated to be 0.0048% (w/v) in the incubation mixture with cytosol and 0.0041% (w/v) in blood circulation. These results suggest that HCO-60 micelles containing Q₁₀ would remain more stable not only in blood circulation but also in tissues as compared with ethanol-water emulsion. A possible mode of solubilization of Q₁₀ is discussed.

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Tissue levels of two gastric mucosal acid proteases, pepsinogen and cathepsin D-like acid proteinase, were determined in rat gastric mucosa damaged by various necrotizing agents and the protective effects of prostaglandins against these biological alterations were investigated. Gastric mucosal damage by each necrotizing agent used was associated with a marked decrease in tissue level of cathepsin D-like acid proteinase. Particularly, ethanol ingestion caused its significant reduction parallel to the production of gastric lesions in a time-dependent manner. On the other hand, mucosal pepsinogen level increased markedly only in ethanol-damaged gastric mucosa, indicating that this change was mediated by a different mechanism from that for cathepsin D-like enzyme. In rats pretreated with prostaglandin E₂ and prostaglandin inducers before ethanol administration, these biological alterations of two enzymes were effectively prevented as were gastric lesions. However, ethanol ingestion caused these changes to occur to the same degree in both the necrotic and non-necrotic areas of glandular mucosa. It was considered that cathepsin D-like acid proteinase was released from damaged gastric mucosa through a direct action on cellular membrane different from vasoconstrictor and platelet aggregating actions mediated by arachidonic acid metabolites.

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The mechanism of interorgan variation in tissue distribution of quinidine was investigated from a viewpoint of binding characteristics to phospholipids and the composition of phospholipids in various tissues. The order of binding of quinidine to an individual standard phospholipid, expressed as a product of the association constant (K) and the number of binding sites (n), was : phosphatidyl ethanolamine (PhE)<dipalmitoyl phosphatidyl choline (saturated PhC)≥phosphatidyl choline (unsaturated PhC)<phosphatidyl inositol (PhI)<phosphatidyl glycerol (PhG)<phosphatidic acid (PhA)<phosphatidyl serine (PhS). Thus, quinidine was found to bind preferentially to acid phospholipids such as PhS, PhA, PhG, and PhI. The greatest binding was obtained in PhS among the various phospholipids and was more than 300-fold that of neutral phospholipids such as PhC and PhE. The concentration of individual components of phospholipids in the lung, kidney, liver and heart was determined using a two dimensional thin-layer chromatography. The concentration of PhS, highly responsible for the quinidine binding to phospholipids in each tissue, was ranked in the following order : heart<liver<kidney<lung. The contribution of PhS to quinidine binding was more than 86% in all tissues. A good correlation between the concentration of PhS in each tissue and the C_t/C_p ratio in vivo was obtained (r=0.984). Thus, it was concluded that the tissue distribution of quinidine in vivo depended on the composition of phospholipids in tissues and that a determinant of interorgan variation in the tissue distribution of quinidine was the concentration of PhS in the tissues.

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The effect of some hypolipidemic agents, which are commercially available and those being developed. on certain biochemical values and on hepatic peroxisomal enzyme activities of rats were examined. Clofibrate (0.25% (w/w) in the diet), p-chlorophenoxyisobutyryl-glycinamide (CGA) (0.25%), clinofibrate (0.1%), KCD-232 (0.1%) and MLM-160 (0.1%) increased the activities of peroxisomal fatty acyl-CoA oxidizing system, carnitine acetyltransferase, and mitochondrial carnitine palmitoyltransferase. Of peroxisomal enzymes, catalase activity was increased by the above agents, whereas the activities of D-amino acid oxidase and urate oxidase were decreased by clofibrate and CGA, and but were increased by KCD-232 and MLM-160 which are structurally unrelated to clofibrate. No influence on these enzyme activities by AL-369 and probucol treatments were observed. Hepatomegaly was induced by clofibrate, CGA, KCD-232 and MLM-160. Concerning serum lipid levels, clofibrate, CGA, clinofibrate, KCD-232 and MLM-160 decreased both cholesterol and triglyceride levels, whereas probucol decreased only cholesterol level. AL-369 had no influence on serum lipid levels under this condition using normolipemic rat. From these results, it was concluded that differing clofibrate and CGA, clinofibrate, MLM-160 and KCD-232 might not induce peroxisome proliferation in hepatic cells, although these have an influence on the enzyme composition of hepatic peroxisomes.

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The antitumor activity of a new camptothecin derivative, SN-22, was evaluated by using various murine tumors. SN-22 showed strong activity against the ascites tumors Ehrlich carcinoma, MM46, CCM, L1210, L5178Y, P388, Meth A, and B16 melanoma. In particular, the maximum increase in life span values for Ehrlich, MM46 and CCM were as high as 253-606% and many mice were cured of these tumors. The effect of SN-22 against solid tumors was also determined. The inhibition ratios were higher than 70% for MM46 and L5178Y. The LD₅₀ of SN-22 in ICR mice was about 1.5 times that of the parent camptothecin.

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The effects of quinidine and cimetidine on methamphetamine-induced stereotyped behavior were studied in rats. Quinidine (10, 30 and 50 mg/kg) and cimetidine (100, 250 and 500 mg/kg) were administered orally 60 min prior to subcutaneous injection of a fixed dose of methamphetamine (5 mg/kg). It was found that quinidine and cimetidine very markedly potentiated the intensity of methamphetamine stereotypy. The duration of the stereotypy in the group pretreated with either drug was 2.3-4.0 times longer than that in the control group. Furthermore, the urinary pH levels of rats were measured after administrations of methamphetamine alone and of methamphetamine following the drugs in question. Urinary pH was not changed by pretreatments with those drugs, suggesting that the enhancing effects of quinidine and cimetidine on methamphetamine-induced stereotyped behavior are not derived from a change in urinary pH level. The enhancement of methamphetamine-induced stereotyped behavior may be explained by inhibitory effects of quinidine and cimetidine on the metabolism of methamphetamine.

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