Rosuvastatin is a novel statin that has been shown to produce large dose-dependent reductions in low-density lipoprotein cholesterol (LDL-C) in Western hypercholesterolemic patients. Rosuvastatin dose response was assessed in a randomized, double-blind phase II trial in which 112 Japanese patients with fasting LDL-C > 160 and < 220 mg/dl and triglycerides < 300 mg/dl received placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg once daily for 6 weeks. LDL-C change from baseline showed a linear dose response (p < 0.0001 for slope of regression line) over the rosuvastatin dose range, with each doubling of dose producing an additional 5.12% reduction. Mean reductions (least-squares mean percentage change from baseline from ANOVA) in LDL-C were 35.8% to 66.0% and significantly different from placebo at all doses (p < 0.0001). Linear dose response was also observed for total cholesterol (TC) and apolipoprotein (apo) B, but not for triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), or apo A-I or A-II. Mean changes at 6 weeks were − 25.5 to − 45.1% for TC, − 16.0 to − 26.2% for TG, + 7.5 to + 12.8% for HDL-C, − 31.9 to − 57.8% for apo B, + 5.5 to + 10.0% for apo A-I, and + 0.4 to + 8.1% for apo A-II. Rosuvastatin was well tolerated. Although there was some suggestion of increased frequency of treatment-related adverse events at higher doses, there were no clear dose relationships in safety parameters. Only one patient withdrew from the study because of a treatment-related adverse event. No patients had clinically significant elevations in liver transaminases or creatine kinase. Rosuvastatin produces good dose-related reductions in LDL-C and beneficial changes in other lipid fractions in Japanese hypercholesterolemic patients and is well tolerated.
Human serum paraoxonase (PON1) exists in 2 major polymorphic forms: Q (glutamine) or R (arginine) at codon 192. The PON1192 activity polymorphism is substrate dependent. The PON1Q192 isoform has a higher rate of in vitro hydrolysis of diazoxon, sarin, and soman, whereas the PON1R192 isoform has higher activity for the hydrolysis of paraoxon and chlorpyrifos oxon. Both isoforms hydrolyze phenyl acetate at approximately the same rate. The present study described and evaluated a kinetic method of arylesterase activity determination with a modified fixed incubation method that used the oxidative coupling of phenol with 4-aminoantipyrine of phenyl acetate as the substrate. Our improved method shows that arylesterase activity is lower with the PON1R192 isoform than with the PON1Q192 isoform. The average activities of serum of individuals of a specific PON1Q192 genotype showed higher arylesterase and lower paraoxonase activity than the PON1R192 genotype. The ratio of paraoxonase/arylesterase activity showed a clear separation of all three PON1192 genotypes with no overlap between the groups (QQ: < 5.0, QR: 5.0−11.0, RR: > 11.0). PCR has suggested that the PON1192 phenotypes correspond to the PON1192 genotypes. Therefore, when conducting epidemiological or mechanistic studies that examine the role of PON1 in organophosphorus or lipid metabolism, this ratio is more useful and informative than a PCR-based genotype alone.
The effects of fluvastatin on levels of urinary 8-iso-prostaglandin F2α (iPF2αIII), a marker of oxidative stress, and low-density lipoprotein (LDL) particle size in serum were investigated in patients with hypercholesterolemia. After 6 months of fluvastatin therapy, levels of urinary iPF2αIII decreased from 1, 720.1 ± 392.0 to 539.6 ± 75.5 pg/mg (p < 0.01), and LDL particle size increased from 24.3 ± 0.3 to 26.5 ± 0.2 nm (p < 0.001). These changes from the treatment of fluvastatin were not correlated with those of the serum LDL cholesterol (LDL-C) levels. The results imply that fluvastatin, with its unique antioxidant property among statins, reduces oxidative stress and increases LDL particle size simultaneously in hyperlipidemic patients.
To clarify the recovery of platelet function after abrupt withdrawal of cilostazol, we studied platelet function and cilostazol concentration in elderly who received cilostazol, 100 mg twice a day (200 mg/day), for a long period. After interviewing the time of final cilostazol intake, platelet aggregability was determined with an aggregometer using four different concentrations of adenosine-5'-diphosphate as an inducer, which showed the grading curve (GC) type and platetet aggregatory threshold index (PATI). Serum cilostazol concentration was also determined by high-performance liquid chromatography. The GC type and PATI showed suppressed platelet function until 15 hours after withdrawal in half of patients. Bleeding time measured by the Simplate method was prolonged within 4 hours, but recovered by 12 hours after the withdrawal. Some serum cilostazol concentrations were still high 15 hours after withdrawal, while platelets were inhibited even in patients with low serum concentration of cilostazol. In the group receiving the drug for less than 6 months, PATI correlated with serum cilostazol concentration, but platelets in the long-term administration group (more than 48 months) were suppressed at the low serum cilostazol concentration. These findings indicated that platelet function recovered within 12−16 hours after withdrawal in these patients.