A hypercholesterolemic patient medicated with cerivastatin for 22 days resulted in acute rhabdomyolysis. CYP2C8 and CYP3A4 are the major enzymes responsible for the metabolism of cerivastatin, and a transporter, OATP2, contributes to uptake of cerivastatin to the liver. In this study, the patient's DNA was sequenced in order to identify a variant that would lead to the adverse effect of cerivastatin. Three nucleotide variants, 475delA, G874C, and T1551C, were found in the exons of CYP2C8. The patient was homozygous for 475delA variant that leads to frameshift and premature termination. Accordingly, the patient is most likely lacking the enzyme activity. The patient's children were both heterozygous for the mutation. The patient had three nucleotide variants in exon 4 (A388G) and exon 5 (C571T and C597T) of OATP2 that were all heterozygous. No nucleotide variation in the exons of CYP3A4 was identified. To our knowledge, this is the first report showing that the adverse effect of cerivastatin might be caused by the genetic variant of CYP2C8.

The effects of combination therapy of angiotensin receptor blockers (ARBs) and a calcium antagonist, benidipine hydrochloride, on glucose and lipid metabolism and pulse pressure were studied in elderly hypertensive patients with type 2 diabetes mellitus. Twenty-five hypertensive diabetic patients aged 65 years or older, who had been receiving candesartan cilexetil, were administered benidipine hydrochloride (4 mg/day) and followed for 4 months. After 4 months, systolic and diastolic blood pressure decreased significantly from 154/91 mmHg to 139/78 mmHg (p 0.01 versus before benidipine hydrochloride administration). Body mass index (BMI) and glycosylated hemoglobin (HbA1c) were apparently reduced but the changes were not statistically significant. The serum lipid profile showed no significant changes in serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Serum lipoprotein lipase mass levels (preheparin LPL mass) increased significantly from 51 to 59 ng/dL (p 0.01 versus before benidipine hydrochloride administration), and the LDL/HDL motility ratio calculated from PAG disc electrophoresis decreased significantly (p 0.05 versus before benidipine hydrochloride administration). When patients were divided into a systolic hypertension group (systolic blood pressure ≥ 140 mmHg and diastolic blood pressure 90 mmHg) and non-systolic hypertension group (others), preheparin LPL mass was significantly lower in the systolic hypertension group, and the decrease in pulse pressure and increase in preheparin LPL mass were significantly greater in the systolic hypertension group. Stepwise regression analysis showed that low preheparin LPL mass at baseline was associated with a decrease in pulse pressure. Add-on benidipine hydrochloride therapy in elderly hypertensive patients with type 2 diabetes mellitus significantly decreases the LDL/HDL motility ratio and pulse pressure, and significantly increases preheparin LPL mass, in addition to improving blood pressure control. These findings suggest that combination therapy with benidipine hydrochloride and candesartan cilexetil may contribute to the suppression of arteriosclerosis and may be useful for elderly hypertensive patients with diabetes mellitus.

To study the effects of aging on the blood pressure potency of phenylephrine, 6-, 10- and 40-week-old rats were used. In anesthetized rats, the potency (pD₂ value) of phenylephrine on the blood pressure tended to increase with age from 6 to 10 weeks, but significantly decreased thereafter with age from 10 to 40 weeks. Similarly, in pithed rats, the potency of phenylephrine significantly increased, but decreased thereafter. In isolated rat thoracic aorta, the pD₂ value of phenylephrine from the contractile responses significantly increased with age from 6 to 10 weeks, but decreased thereafter from 10 to 40 weeks. The change in the potency of phenylephrine on the blood pressure was proportional to the pD₂ value of phenylephrine estimated in aortic preparations. The specific binding of [³H]prazosin to single smooth muscle cells of thoracic aorta from different aged rats was saturable. The maximum number of binding sites (B_max) significantly increased with age from 6 to 10 weeks, but decreased thereafter from 10 to 40 weeks. However, the dissociation constant of [³H]prazosin (K_d) did not alter with age. The changes in the potencies (pD₂ values) of phenylephrine on the pressure responses and on the contractile responses were proportional to the logarithm of the maximum number of binding sites. The present study suggests that age-related changes in blood pressure are due to changes in the maximum number of binding sites (receptor density) of α₁-adrenoceptors.

This study was conducted to clarify the characteristics of colestimide responders. Forty-seven non-diabetic patients with high levels of low-density lipoprotein cholesterol (LDL-C) received colestimide at 3,000 mg/day and were followed up for 4 months. After 4 months, body weight was reduced but the change was not statistically significant. Total serum cholesterol (TC) and LDL-C levels significantly decreased from 280 to 232 mg/dl and from 195 to 150 mg/dl, respectively (p < 0.01 versus before colestimide was administered). Serum triglyceride (TG) levels increased, but the change was not significant. Preheparin lipoprotein lipase mass (preheparin LPL mass) at baseline was significantly higher in colestimide responders (greater than a 20% decrease of LDL-C: n = 28) than non-responders (76.2 ng/ml versus 50.3 ng/ml, p < 0.05: n = 19). Next, the subjects were divided into those with a high (n = 33) and low (n = 14) preheparin LPL mass at baseline. LDL-C levels were significantly decreased in patients with a high preheparin LPL mass while TG levels were significantly increased in patients with a low preheparin LPL mass. These results suggest that baseline preheparin LPL mass may be a marker of the response to colestimide. J Atheroscler Thromb, 2005; 12: 218-224.

Early detection and early treatment of adverse drug reactions have recently become more important. It is natural that physicians should treat adverse drug reactions carefully, but it is also important to establish a system for their early systematic detection and treatment. Therefore, by comparing current data with that preserved in our clinical laboratory's data management registry and identifying values signiˆcantly diŠerent from earlier values, we established a screening system for any condition which may have a possible relationship with drugs and feeds back the results to the physician(s) in charge (drug safety management monitoring system). The eŠectiveness of the system was then evaluated. The subjects were outpatients who visited the Diabetes Endocrine Metabolism Center of our hospital during a sixmonth period. Cases where the possibility of a relationship between abnormal changes of laboratory data and drugs was not ruled out were reported to the attending physician using a drug safety monitoring report form. In 14 of 34 cases reported, a relationship with drugs could not be ruled out. Two of these 14 cases were reported to the Ministry of Health, Labour and Welfare because they were serious. Therefore, it was concluded that this system was useful for early detection of adverse reactions.