Hypoglycemic effect of S(-)-hydroxyhexamide, a major metabolite of acetohexamide, and its enantiomer R(+)-hydroxyhexamide.

A short-lasting hypoglycemic effect was observed when S(-)-hydroxyhexamide (S-HH), a major metabolite of acetohexamide, and its enantiomer R(+)-hydroxyhexamide (R-HH), were administered orally to rats. Since the reductive metabolism of acetohexamide is known to be reversible in rats, oral administration of R-HH may exhibit the hypoglycemic effect through the generation of acetohexamide. However, oral administration of R-HH to rabbits, in spite of their inability to oxidize R-HH to acetohexamide, caused a significant decrease and increase, respectively, of plasma glucose and insulin levels. Furthermore, both S-HH and R-HH were found to stimulate the secretion of insulin from hamster HIT T15 cells (pancreatic beta-cells). These results provide further evidence that both R-HH and S-HH exhibit a significant hypoglycemic effect.

(R)-ACX is a novel sufonylurea compound with potent, quick and short-lasting hypoglycemic activity.

We investigated the mechanism of the hypoglycemic effect of (R)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)benzene-sulfonamide [(R)-acetoxyhexamide; (R)-ACX], a new sulfonylurea compound. (R)-ACX potently stimulated the release of insulin from cultured pancreatic beta-cells (HIT T15 cells), established from hamster islet cells SV40-transformed. When (R)-ACX was orally administered to fasted rats, it decreased the plasma glucose level in a dose-dependent manner. The hypoglycemic effect of (R)-ACX was quick and short lasting, as compared to that of acetohexamide and glibenclamide. The quick and short-lasting hypoglycemic effect of (R)-ACX was thought likely to result from rapid absorption of (R)-ACX and rapid elimination of (R)-ACX and its metabolite, (R)-hydroxyhexamide. Furthermore, (R)-ACX was found to suppress the increase of blood glucose level due to starch loading in fasted mice. (R)-ACX may be useful in the control of postprandial hyperglycemia to patients with non-insulin-dependent diabetic mellitus.

Enzymatic synthesis of (-)- and (+)-acetoxyhexamides and (-)- and (+)-hydroxyhexamides.

The enantioselective hydrolysis of (+/-)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)-benzenesulfona mides 3 with lipase Amano P from Pseudomonas sp. in a water-saturated solvent gave (R)-4-(1-hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2 (39%, > 99% ee) and unchanged (S)-3 (50%, 62% ee). On the other hand, enantioselective esterification of (+/-)-2 with lipase Amano P in the presence of vinyl acetate provided (R)-3 (41%, > 99% ee) and unchanged (S)-2 (46%, 78% ee).

L-arabinose selectively inhibits intestinal sucrase in an uncompetitive manner and suppresses glycemic response after sucrose ingestion in animals.

The objective of this study was to investigate the effects of L-arabinose on intestinal alpha-glucosidase activities in vitro and to evaluate its effects on postprandial glycemic responses in vivo. L-Arabinose inhibited the sucrase activity of intestinal mucosa in an uncompetitive manner (Ki, 2 mmol/L). Neither the optical isomer D-arabinose nor the disaccharide L-arabinobiose inhibited sucrase activity, whereas D-xylose was as potent as L-arabinose in inhibiting this activity. L-Arabinose and D-xylose showed no inhibitory effect on the activities of intestinal maltase, isomaltase, trehalase, lactase, and glucoamylase, or pancreatic amylase. In contrast, a known alpha-glucosidase inhibitor, acarbose, competitively inhibited (Ki, 1.1 mumol/L) sucrase activity and also inhibited intestinal maltase, glucoamylase, and pancreatic amylase. L-Arabinose suppressed the increase of blood glucose after sucrose loading dose-dependently in mice (ED50, 35 mg/kg), but showed no effect after starch loading. The suppressive effect of D-xylose on the increase of blood glucose after sucrose loading was 2.4 times less than that of L-arabinose, probably due to intestinal absorption of the former. Acarbose strongly suppressed glycemic responses in both sucrose loading (ED50, 1.1 mg/kg) and starch loading (ED50, 1.7 mg/kg) in mice. L-Arabinose suppressed the increase of plasma glucose and insulin in rats after sucrose loading, the suppression of the former being uninterruptedly observed in mice for 3 weeks. Thus, the results demonstrated that L-arabinose selectively inhibits intestinal sucrase activity in an uncompetitive manner and suppresses the glycemic response after sucrose ingestion by inhibition of sucrase activity.

Pharmacological studies of mabuterol, a new selective beta 2-stimulant. III: Effects on the central nervous system, striated muscle and carbohydrate and lipid metabolism.

Effects of dl-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butylamino-etha nol hydrochloride (mabuterol) on the central nervous system, the striated muscle and the carbohydrate and lipid metabolism were investigated in comparison with those of isoprenaline and salbutamol. Mabuterol caused the following changes in behavior: increased touch response (10 mg/kg p.o.), decreased spontaneous movement and ptosis (30 and 100 mg/kg p.o., resp.), observed for 240-300 min. Mabuterol (5 mg/kg p.o. and 2.5 mg/kg s.c.) prolonged the sleeping time induced by hexobarbital Na, but not dose-dependently. Mabuterol depressed reactive movement at 80 mg/kg p.o. and 40 mg/kg s.c. in the rotarod test, at 160 mg/kg p.o. and 40 mg/kg s.c. in the traction test and at 200 mg/kg p.o. and 160 mg/kg s.c. in the inclined plane test in mice, whereas isoprenaline and salbutamol were almost ineffective. Analgesic activity of mabuterol was found in the acetic acid writhing test but not in the bradykinin-induced nociception test. An anticonvulsive effect was not observed. Mabuterol (10 mg/kg i.v.) produced a change in the spontaneous EEG of one of three rabbits, showing synchronization of cortical activity with sedation. Equipotent dose (i.v.) ratios of mabuterol to isoprenaline were 10.2, 30 and 133 in the depression of incomplete tetanic contraction of cat soleus muscle, hypotensive effect and tachycardia respectively, whereas neither indirect nor direct electrical stimulation induced contraction of diaphragm and gastrocnemius muscle was affected. Equipotent dose (s.c.) ratios of mabuterol to isoprenaline were 2.07, 4.64 and 3.21 in increasing plasma levels of glucose, lactic acid and free fatty acids respectively. Mabuterol caused no remarkable change in myocardial glycogen content.

Effect of KC-9432, a new hypolipidemic compound, on high density lipoprotein cholesterol in rats.

KC-9432 (a new hypolipidemic compound, alpha-[p-(p-chlorobenzoyl) phenoxy-alpha-cyclohexyl acetic acid ethyl ester) was studied in rats for its effect on plasma lipid and lipoprotein levels. KC-9432 was particularly effective in hyperlipidemia in rats fed with a diet containing 2% cholesterol and 1% sodium cholate. The hypocholesterolemic activity of KC-9432 was far more potent than that of clofibrate. KC-9432 markedly increased the reduced HDL cholesterol level in dietary-induced hyperlipidemia in rats.

Hypolipidemic effects of S-methylmethionine (vitamin U) using various experimental procedures.

The hypolipidemic and anti-atheromatous effect of S-methylmethionine sulfonium chloride (Vitamin U, MMSC) were investigated using various experimental procedures. In the results, orally administered MMSC markedly normalized dietary-induced hyperlipidemia in rats and rabbits, demonstrating the lowering effects on plasma total cholesterol, beta-lipoprotein and phospholipids, and no appreciable effect on plasma triglycerides. In normolipidemic and a surfactant-induced hyperlipidemic rats, MMSC did not decrease plasma lipids level, nor MMSC-affected plasma lipoprotein lipase and liver catalase activities. In contrast, clofibrate showed little or no effect on plasma lipids level of dietary-induced hyperlipidemic rats, with exception of plasma triglycerides, whereas clofibrate lowered plasma lipids level in normolipidemic and surfactant-induced hyperlipidemic rats, and enhanced liver catalase activity. From the results, the lipids lowering effects of MMSC using various procedures were clearly differentiated from those of clofibrate. Additionally, the anti-atheromatous effect of MMSC was histopathologically demonstrated in dietary-induced ahteromatous rabbits. A unique hypolipidemic effect of MMSC is discussed from therapeutic viewpoint.

A possible activation of cholesterol 7-hydroxylation by S-methylmethionine (vitamin U).

The conversion rate from 14 C-cholesterol to its 7 alpha-hydroxylated metabolites was studied in the microsome system prepared from mice liver with the pretreatment of S-methylmethionine (MMSC). In results, the increased amounts of 7 alpha-hydroxylated metabolites by MMSC show a possible activation of cholesterol 7 alpha-hydroxylase.

Comparative effects of S-methylmethionine (vitamin U) and methionine on choline-deficient fatty liver in rats.

A pharmacological difference between S-methylmethionine (MMSC) and methionine (Met) at higher dose p.o. was tested on the fatty liver in choline-deficient rats. MMSC normalized the fatty liver. In contrast, Met accelerated the syndrome accompanying with increased liver weight.

Normalizing effects of S-methylmethionine (vitamin U) on lipoprotein disorder in rats.

S-Methylmethionine (vitamin U) dose-dependently lowered the increased plasma LDL and normalized the decreased HDL in dietary-induced hyperlipidemic rats.

Effects of S-methylmethionine (vitamin U) on experimental nephrotic hyperlipidemia.

The effects of S-methylmethionine sulfonium chloride (MMSC, vitamin U) on aminonucleoside-induced nephrotic hyperlipidemia in rats were investigated. We found that repeated oral administration of MMSC (dose: daily 1000 mg/kg) exhibited significant amelioration of plasma chloresterol and phospholipids levels. Also, the treatment improved nephrotic syndrome itself by producing an increase of urinary volume and a decrease of urinary protein excretion. The results suggest that MMSC may be useful as single or combined therapy for human nephrotic syndrome and its related hyperlipidemia as a safety drug.

Mode of hypocholesterolemic action of S-methylmethionine (vitamin U) in mice.

S-Methylmethionine (vitamin U) markedly increased the fecal excretion of both 14C-bile acids and 14C-neutral sterols in 14C-cholesterol injected mice, and did not inhibit both intestinal absorption of 14C-cholesterol and biosynthesis of 14C-cholesterol from 14C-acetate in mice.

Hypolipidemic effects of S-methylmethionine (vitamin U) using various experimental procedures.

Hypolipidemic effects of S-methylmethionine (MMSC) were compared with clofibrate in 3 experimental procedures. In results, the characteristic effect of MMSC is discussed from therapeutic viewpoint.