John V. St. Peter

The Prevalence of Cardiac Valvular Insufficiency Assessed by Transthoracic Echocardiography in Obese Patients Treated with Appetite-Suppressant Drugs

BACKGROUND After case reports of cardiac-valve abnormalities related to the use of appetite suppressants were published, we undertook a study to determine the prevalence of the problem using transthoracic echocardiography. METHODS We examined patients who had taken dexfenfluramine alone, dexfenfluramine and phentermine, or fenfluramine and phentermine for various periods. We enrolled obese patients who had taken or were taking these agents during open-label trials from January 1994 through August 1997. We also recruited subjects who had not taken appetite suppressants and who were matched to the patients for sex, height, and pretreatment age and body-mass index. The presence of cardiac-valve abnormalities, defined by the Food and Drug Administration and Centers for Disease Control and Prevention as at least mild aortic-valve or moderate mitral-valve insufficiency, was determined independently by at least two cardiologists. Multivariate logistic-regression analysis was used to identify factors associated with cardiac-valve abnormalities. RESULTS Echocardiograms were available for 257 patients and 239 control subjects. The association between the use of any appetite suppressant and cardiac-valve abnormalities was analyzed in a final matched group of 233 pairs of patients and controls. A total of 1.3 percent of the controls (3 of 233) and 22.7 percent of the patients (53 of 233) met the case definition for cardiac-valve abnormalities (odds ratio, 22.6; 95 percent confidence interval, 7.1 to 114.2; P<0.001). The odds ratio for such cardiac-valve abnormalities was 12.7 (95 percent confidence interval, 2.9 to 56.4) with the use of dexfenfluramine alone, 24.5 (5.9 to 102.2) with the use of dexfenfluramine and phentermine, and 26.3 (7.9 to 87.1) with the use of fenfluramine and phentermine. CONCLUSIONS Obese patients who took fenfluramine and phentermine, dexfenfluramine alone, or dexfenfluramine and phentermine had a significantly higher prevalence of cardiac valvular insufficiency than a matched group of control subjects.

Quantifying Hepatic Function in the Presence of Liver Disease with Phenazone (Antipyrine) and its Metabolites

SummaryThe disposition of Phenazone (antipyrine), a low extraction compound with low protein binding, is known to be altered in the presence of various types of hepatic dysfunction. As such, its pharmacokinetics may be useful in the objective characterisation of altered liver function. Understanding the known effects of various liver disease states upon the disposition of this probe may provide insight into future applications. This article provides a review of background information about normal plasma Phenazone pharmacokinetics, urinary metabolite disposition and tabulations of reported total body clearances of the drug in the presence of cirrhosis, fatty liver, hepatitis and cholestasis in humans. An estimate is made of the sensitivity and specificity of Phenazone testing for the verification of the presence of cirrhosis based on this compiled literature.

Effect of Conjugated Equine Estrogens on Oxidative Metabolism in Middle‐aged and Elderly Postmenopausal Women

The effects of conjugated equine estrogens (CEE) 0.625 mg daily on cytochrome P450 (CYP) were quantified in 12 middle‐aged and 13 elderly postmenopausal women at baseline and 6 months later. CYP phenotype was characterized by caffeine (CYP1A2), chlorzoxazone (CYP2E1), dapsone (CYP, N‐acetyltransferase 2), dextromethorphan (CYP2D6), and mephenytoin (CYP2C19) metabolism. CEE significantly decreased CYP1A2 (caffeine metabolic ratio: 0.57 ± 0.20 before, 0.40 ± 0.20 after, P = .001) and significantly increased CYP2D6 (dextromethorphan/dextrorphan ratio: 0.0116 ± 0.0143 before, 0.0084 ± 0.0135 after, P = .022) metabolism. CEE had no overall effect on CYP2C19, CYP2E1, CYP‐mediated dapsone metabolism, and N‐acetyltransferase 2. The dextromethorphan metabolic ratio decreased only in the seniors. The dapsone recovery ratio decreased in the middle‐aged group and increased in the seniors. CEE significantly influenced CYP1A2, CYP2D6, and CYP‐mediated dapsone oxidative metabolism but not CYP2C19, CYP2E1, or N‐acetyltransferase 2 metabolism in postmenopausal women. Age influenced CYP2D6 metabolism and dapsone hydroxylation.

The effect of zileuton on antipyrine and indocyanine green disposition

The effects of single and multiple oral doses of zileuton on the pharmacokinetics of antipyrine and indocyanine green were studied in 16 healthy, nonsmoking adult men by means of a double‐blind, randomized, parallel placebo‐controlled design. Indocyanine green disposition was not significantly altered by zileuton. Plasma antipyrine clearance declined by 20% (p < 0.0005) and 52% (p < 0.0005) after single and multiple dose zileuton exposure, respectively. Total urinary recovery of unchanged antipyrine and metabolites decreased with zileuton exposure. Selective declines from baseline of 16% (p = 0.007) and 20% (p = 0.003) after single‐dose zileuton and 30% (p < 0.0005) and 43% (p < 0.0005) after multiple‐dose zileuton were detected in recovery of 4‐hydroxyantipyrine and 3‐hydroxymethylantipyrine, respectively. Urinary recovery of the N‐demethylantipyrine metabolite norantipyrine and percent of conjugation of 3‐hydroxymethylantipyrine were unchanged by zileuton. In conclusion, zileuton therapy has no detectable effect on indocyanine green disposition but exerts marked effects on antipyrine plasma and urine metabolite disposition.

The effect of traditional risk factors for stone disease on calcium oxalate crystal adherence in the rat bladder

Crystal adherence in the urinary tract has been studied using the chemically injured rat bladder and cell cultures. These studies have provided evidence that mucin prevents adherence and have studied various compounds for their ability to promote or inhibit crystal adherence. Little work has been done examining the effect on crystal adherence of traditional risk factors for stone disease. The study reported here examined the effect hypercalciuria, hyperoxaluria and pH on calcium oxalate crystal adherence using the intact rat bladder model. Calcium at levels seen in hypercalciuric stone formers was associated with increased adherence. Oxalate at levels seen in stone formers had no effect on adherence. There was a tendency to increased crystal adherence at higher pH values only when phosphorus was present as the buffer. Hypercalciuria is a risk factor for stone disease by increasing the level of saturation of calcium oxalate and calcium phosphate in the urine and by decreasing inhibitor function. This study suggests that it may also play a role by increasing crystal adherence within the urinary tract.