Saburo Kanai

A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin

AbstractA 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 patients 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 patients 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.

Age-Related Changes in Alpha-Adrenoceptor Mediated Blood Pressure in the Rat: Relationship between the Potency for Phenylephrine and the Maximum Number of Binding Sites

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 (Bmax) significantly increased with age from 6 to 10 weeks, but decreased thereafter from 10 to 40 weeks. However, the dissociation constant of [3H]prazosin (Kd) 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 alpha 1-adrenoceptors.

Importance of Efficient Coordination of Long-Term, Large-Scale Clinical Trials and Problems Arising-Role of Hospital Pharmacists in this Activity-

We felt that pharmacists should participate more actively in the evaluation of efficacy and safety in clinical trials. To improve the capability of pharmacists in this respect, we evaluated the support we gave to the investigators of the Japan EPA Lipid Intervention Study (JELIS), a long-term, large-scale clinical trial conducted at the Department of Pharmacy of our hospital. To identify the problems in our support, we investigated the number of days required to complete the Case Report Form (CRF) and the reliability of the data collected, by considering the adequacy of the items observed and the clinical inspection terms. Our findings indicated that it was feasible for pharmacists to handle the coordination of JELIS in addition to their everyday workload and we also noted an improvement in the clinical inspection rate, from 76.6% to 100% for JELIS I and from 97.5% to 100% for JELIS II. Moreover, we found the number of days required to complete the CRF was reduced from 109.8 days to 20.3 days for JELIS I and from 79.5 days to 21.0 days for JELIS II. These results show that the pharmacists in our hospital helped to maintain the reliability of clinical data.

Effects of Treatment with Probucol, a Hypolipidemic Agent, on Diabetic Nephropathy.

A year-long prospective study was conducted to elucidate the effects of probucol, an anti-oxidative hypolipidemic agent, on the progression of diabetic nephropathy.A total of 152 diabetic outpatients with an urinary albumin level of 200mg/g·Cr or more, and who routinely visited our hospital were divided into two groups of 75 patients treated with probucol (500mg/day) and 77 non-treated patients. All patients were observed for 12 months. The results reveled no significant difference in the blood pressure or HbA1clevel between the two groups. However, the serum lipid levels in the probucol-treated group decreased by 16 to 18% (p< 0.01) for total cholesterol, 19 to 28% for neutral fat, and 17 to 21% (p<0.01) for HDL-cholesterol, while they did not significantly change in the non-treated group. As for the renal function, probucol suppressed the progression of nephropathy in a patients group with a moderate to severe serum creatinine and urinary albumin level and another patient group with a mild to moderate urinary protein level at severity level of from ± to 2 +. Kidney dialysis was required in 2 probucol-treated patients and 9 nontreated patients, where the rate of dialysis shift after the serum creatinine concentration exceeded 2.0mg/dL was 15% in the probucol-treated group and 58% in the non-treated group.From the present results, it was suggested that probucol suppresses the progression of diabetic nephropathy, thereby extending the period until dialysis is required.