Harumi Shimakawa

Pravastatin reduces restenosis after coronary angioplasty of high grade stenotic lesions: Results of SHIPS (SHIga Pravastatin Study)

SummaryWe conducted a multicenter prospective, randomized, double-blind, placebo-controlled trial to test whether pravastatin, a hydroxymethyl glutaryl coenzyme A reductase inhibitor, can decrease restenosis after percutaneous transluminal coronary angioplasty (PTCA). Pravastatin 10 mg twice daily was begun at least 10 days prior to elective PTCA in patients with total cholesterol less than 280 mg/dl. The end-point was a between-group comparison of the frequency of restenosis defined as a more than 50% loss of the initial gain in diameter stenosis at the PTCA site at 3 months during follow-up by automated quantitative coronary arteriography. Of 207 patients randomly assigned to study groups, 139 patients underwent PTCA; 133 procedures were successful, and 124 patients underwent follow-up angiography at 3 months, and 179 lesions (85 pravastatin, 94 placebo) in 124 patients (62 pravastatin, 62 placebo) were analyzed. The two groups were comparable for baseline characteristics. Total cholesterol decreased by 19.6% in the pravastatin group (p<0.001) but not in the placebo group. Although the restenosis rate was not different in the two groups (29.4% in pravastatin vs. 39.4% in placebo, p=0.215) as a whole, it was reduced to about one fifth (8.8%) in the pravastatin group compared with 14.8% in the placebo group (p=0.0011) when the comparison was restricted to high grade lesions (≥75% diameter stenosis, 34 lesions in pravastatin, 29 lesions in placebo). Pravastatin thus reduces restenosis after PTCA of high grade lesions.

Fluorimetric determination of mexiletine in serum by high-performance liquid chromatography using pre-column derivatization with fluorescamine.

A simple, specific and sensitive micro-scale method for the assay of the antiarrhythmic agent mexiletine in human serum is described. The method uses high-performance liquid chromatography, with pre-column fluorimetric derivatization by fluorescamine. Following extraction with diethyl ether, mexiletine and 4-methylmexiletine (an internal standard) were derivatized with fluorescamine under weakly alkaline condition (pH 9.0) and chromatographed on a reversed-phase column with aqueous methanol-2-propanol as the mobile phase. The two fluorescent derivatives of mexiletine and the internal standard were separated as clear single peaks, and no interfering peaks were observed on the chromatograms. The detection limit for mexiletine was 0.005 micrograms/ml from only 100 microliters of serum, and the calibration curves in the range 0.01-5 micrograms/ml were linear, with an overall coefficient of variation of less than 5%. The analytical recovery of a known amount of mexiletine added to serum was almost 100%. This method proved to be effective in the rapid monitoring of the serum concentrations in patients who received this potent antiarrhythmic drug.

Inducing effect of feprazone on hepatic drug-metabolizing enzymes in man.

SummaryThe inducing effect of feprazone, a pyrazolone anti-inflammatory agent, on hepatic drug-metabolizing enzymes has been studied in healthy volunteers. The ratio of 6β-hydroxycortisol (6β-OHF) to 17-hydroxycorticosteroids (17-OHCS) in urine, used as an indicator of oxidative drug-metabolizing enzyme activity, was increased up to 1.6-times the original level after 5 days of oral treatment with feprazone 300 mg/day. This indicates that feprazone induces hepatic drug-metabolising enzymes in man as does phenylbutazone.

Evaluation of fluorescence polarization immunoassay for determination of cyclosporin in plasma.

The fluorescence polarization immunoassay (FPIA) method for determination of cyclosporin in plasma was evaluated and compared with the high-performance liquid chromatography (HPLC) and the radioimmunoassay (RIA) methods. The coefficients of variation for the within-run and between-run precision were <5 and <8%, respectively, for samples ranging in concentration from 50 to 600 ng/ml. Recoveries were determined by adding cyclosporin at concentrations from 25 to 1,000 ng/ml to patient plasma; they were, on average, 98.5%. The calibration curve was stable throughout a 10-week study period. There was no clinically significant interference due to hemolysis, icterus, lipemia, or other commonly used drugs. There was considerable variation of the ratio of the FPIA result to the HPLC result, whereas there was a good correlation between the FPIA and the RIA results (r = 0.975, n = 25, y = 1.2x – 36.4), when evaluated using specimens from renal transplant patients receiving cyclosporin orally. It was concluded that the FPIA is an appropriate, rapid method for patient cyclosporin analysis in plasma and serves as a practical alternative to the RIA.

Blood-to-plasma distribution of cyclosporin A in a renal transplant recipient.

For about 2 years therapeutic drug level monitoring of cyclosporin A (CyA) has been done using both plasma and whole blood from renal transplant recipients. An HPLC method [1] was used to assay CyA. Plasma samples were separated from cells at 37 ° C after the collection without delay to avoid any influence of temperature. Except for the patients whose renal and hepatic functions were stable, it is known that changes in the blood-to-plasma distribution of CyA may accompany changes in renal and hepatic function. The purpose of this letter is to describe the clinical course in the most typical cases and to indicate the usefulness of assessing changes in the blood-to-plasma distribution of CyA as an indicator for predicting the occurrence of side effects, such as nephrotoxicity and hepatotoxicity. The clinical course of a patient of renal graft from a related, living donor (23-year-old male) on therapy with CyA, azathioprine and prednisolone is shown in Fig. 1. There were no episodes of acute rejection, but the administration of CyA was stopped after 107 days of treatment because of unstable renal function and serious, complicated cytomegalovirus pneumonia. The concentration (C) of CyA in the non-plasma component of whole blood was calculated from the following relationship:

肝ミクロソームの酸化的薬物代謝酵素(チトクロムP-450)系に対する合成ステロイド剤・Danazolの阻害作用

The inhibitory effect of danazol, a synthetic androgen, on the hydroxylations of testosterone as a model for endogenous steroids and the dealkylations of aminopyrine and 7-ethoxycoumarin as models for xenobiotics in mouse hepatic microsomes in vitro was studied. Danazol inhibited these enzyme activities in a dose-dependent fashion. The inhibition constants (Ki) of danazol for these enzyme activities were 1-4 orders of magnitude lower than those of cimetidine, while there was a great difference among the inhibitory potencies of danazol for each enzyme activity. Addition of danazol to microsomal preparation resulted in a reverse type I difference spectrum and the spectrophotometric analysis revealed that danazol had a high affinity for cytochrome P-450 with dissociation constants (Ks) of 0.9 and 4.2 microM, which were 2 orders of magnitude lower than those of cimetidine. On the other hand, danazol did not significantly affect reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase activity and levels of cytochrome P-450 in the microsomes. These results suggest that danazol is a highly potent inhibitor for several cytochrome P-450-mediated metabolisms of testosterone and xenobiotics in mouse hepatic microsomes.

Comparison of One-Step and Two-Step Dividing Methods for Powder-Granule Combination Preparations by Automatic Dividing and Packing Machine

On the matter of division of powder-granule combination preparations into a prescribed dosage unit, the Guideline for Dispensing by the Japan Pharmaceutical Association recommends separate division of powder and granule (two-step dividing method) rather than the division of the 2 components at the same time (one-step dividing method). As discussed in the previous paper, however, the two-step dividing method is not adequate when the combination preparations are divided by machine, not by hands.In this study, the one-step and two-step dividing methods were compared in terms of the content uniformity of the powder component in the sample after division by machine. The machine used was the modified type (L-2) of Konishi KC-787-K15. The samples used were the powder-granule combination preparations in 5 grades of powder/granule ratio ranging from 1/8 to 8/ 1, containing 1 powder and 1 of 4 granules of different physical properties as component.As a result, the two-step dividing method did not show smaller variation of powder content than one-step dividing method, and it is complicated and requires much time. It is, therefore, concluded that the one-step dividing method is more adequate for division of powder-granule combination preparations so far as the automatic dividing and packing machine, such as L-2, equipped with the feeder that has the function of alternating motion, is used.