Yasunobu Yoshinaka

Triglyceride-lowering effect of pitvastatin in a rat model of postprandial lipemia

Abstract The triglyceride-lowering effect of pitavastatin, a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was investigated in a rat model of postprandial lipemia. Plasma triglyceride levels started to increase 4 h after the fat load, reached the maximum at 6 h and then gradually decreased. A single dose of pitavastatin (1 mg/kg) significantly suppressed chylomicron-triglyceride secretion into the lymph by 40% and delayed the elevation of plasma triglyceride. Pitavastatin at 1 mg/kg decreased the 6-h plasma triglyceride levels by 53% and at 0.5 mg/kg decreased the 0–12 h area under the curve (AUC) of triglyceride levels by 56%. Atorvastatin also caused decreases, but to a lesser extent. Pitavastatin, and atorvastatin to a lesser extent, reduced the activity of the intestinal microsomal triglyceride transfer protein (MTP) at 6 h. These results suggested that a single dose of pitavastatin lowered postprandial triglyceride levels in rats by decreasing chylomicron-triglyceride secretion, probably through a reduction of intestinal MTP activity and triglyceride droplet formation in the endoplasmic reticulum.

Effects of Mepartricin, a polyene macrolide agent, on fecal excretion and serum concentration of estrogen and number of prostatic estrogen receptors in immature rats

Mepartricin, an antifungal agent, was investigated for effects on fecal excretion and serum concentration of sex steroids and the number of sex steroid prostatic receptors in immature rats.

Effects of Mepartricin (S–160) on Spontaneous Canine Benign Prostatic Hyperplasia

Objective: The effects of mepartricin (S–160) on spontaneous canine benign prostatic hyperplasia (BPH) were investigated by histological, histochemical and biochemical analysis.Methods: Aged beagle dogs (5–9 years old) with spontaneously developed BPH were treated orally with a placebo or S–160 (5, 10 or 20 mg/kg/day) for 8 weeks. The methodology included measurement of prostatic volume by transrectal ultrasonography, qualitative evaluation of prostatic morphology, determination of plasma and intraprostatic estradiol level by radioimmunoassay and immunohistochemical detection of estrogen receptors and androgen receptors in the prostate.Results: S–160 significantly reduced the prostatic volume and regressed histologically the hyperplastic grade of prostate, and also fairly decreased the plasma and intraprostatic estradiol concentration and the estrogen and androgen receptors in the prostate.Conclusions: These results suggest that the reduction of estradiol and estrogen receptors in the prostate may play a crucial role in the regression of BPH by S–160.

Design, synthesis and pharmacology of aortic-selective acyl-CoA: Cholesterol O-acyltransferase (ACAT/SOAT) inhibitors

We describe our molecular design of aortic-selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also abbreviated as SOAT) inhibitors, their structure-activity relationships (SARs) and their pharmacokinetic (PK) and pharmacological profiles. The connection of two weak ligands-N-(2,6-diisopropylphenyl)acetamide (50% inhibitory concentration [IC50] = 8.6 μM) and 2-(methylthio)benzo[d]oxazole (IC50 = 31 μM)-via a linker comprising a 6 methylene group chains yielded a highly potent molecule, 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide (3h) that exhibited high potency (IC50 = 0.004 μM) toward aortic ACAT. This head-to-tail design made it possible to markedly enhance the activity to 2150- to 7750-fold and to discriminate the isoform-selectivity based on the double-induced fit mechanism. At doses of 1 and 3 mg/kg, 3h significantly decreased the lipid-accumulation areas in the aortic arch to 74 and 69%, respectively without reducing the plasma total cholesterol level in high fat- and cholesterol-fed F1B hamsters. Here, we demonstrate the antiatherosclerotic effect of 3hin vivo via its direct action on aortic ACAT and its powerful modulator of cholesterol level. This molecule is a potential therapeutic agent for the treatment of diseases involving ACAT-1 overexpression.