Showing papers by "J. David Spence published in 1996"

Lipids and stroke: a paradox resolved.

Abstract: Background: Although dyslipidemia is a wellestablished risk factor for coronary artery disease, its relationship to ischemic cerebrovascular disease has remained unclear, perhaps because of the heterogeneous nature of strokes. Methods: In a case-control study, we measured the serum concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, serum triglycerides, and lipoprotein(a) levels and determined the apolipoprotein E phenotype and serum ferritin level in 90 consecutive systematically investigated patients with stroke or transient ischemic attack of atherothrombotic origin. Ninety age-, sex-, and community-matched subjects served as controls. Results: Plasma total cholesterol (5.99 vs 5.45 mmol/L [232 vs 211 mg/dL], P =.003), low-density lipoprotein cholesterol (3.96 vs 3.45 mmol/L [153 vs 133 mg/dL], P =.004), and serum triglyceride (2.09 vs 1.82 mmol/L [81 vs 70 mg/dL], P =.03) levels were significantly higher among the patients with atherothrombotic strokes and transient ischemic attacks than among the control subjects. The inverse was true for high-density lipoprotein cholesterol (1.07 vs 1.18 mmol/L [41 vs 46 mg/dL], P =.02) levels. No significant differences were found in lipoprotein(a) levels or in the distribution of apolipoprotein E phenotypes or allele frequency. Serum ferritin levels did not differ significantly between patients and control subjects. Conclusions: Elevated low-density lipoprotein cholesterol and triglyceride levels are significant independent risk factors in patients with proven atherothrombotic cerebrovascular disease manifesting as stroke or transient ischemic attack. The level of stored serum iron, as reflected by serum ferritin levels, does not correlate with the presence of atherothrombotic cerebrovascular or coronary disease.

Erythromycin‐felodipine interaction: Magnitude, mechanism, and comparison with grapefruit juice

Abstract: Objective To investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine. Methods Felodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day. Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite were studied. Results Compared with water, erythromycin produced severalfold higher felodipine area under the plasma drug concentration-time profile (AUC), plasma peak drug concentrations (Cmax), and apparent elimination half-life (t12); however, the effect was variable among individuals. Erythromycin augmented dehydrofelodipine AUC, Cmax, and t12 but decreased dehydrofelodipine/felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were reduced. These findings support inhibition of both metabolic pathways likely mediated by CYP3A4. Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t12. Individually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative felodipine Cmax but not with relative felodipine t12, suggesting felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination. Conclusions Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall. Clinical Pharmacology & Therapeutics (1996) 60, 25–33; doi: