Glen D. Park

Use of hemoperfusion for treatment of theophylline intoxication

We review our experience in the management of patients with plasma theophylline concentrations of 30 micrograms/ml or greater. Over a two-and-a-half-year period, 22 patients (Group 1) had plasma theophylline concentrations of 37 +/- 1 micrograms/ml (mean +/- SE) and experienced no severe toxicity (i.e., ventricular extrasystoles or tachycardia, seizures, cardiovascular collapse, or death). Six patients (Group 2) took overdoses of theophylline (92 +/- 12 micrograms/ml) and one died. Eight patients (Group 3) were iatrogenically intoxicated (48 +/- 6 micrograms/ml) and three died. Six patients from Groups 2 and 3 underwent hemoperfusion and did well, except for one patient, in whom seizures developed before hemoperfusion was initiated. We conclude from this experience that charcoal hemoperfusion is a useful procedure for the treatment of theophylline intoxication because of: (1) the serious morbidity and mortality of theophylline intoxication, (2) the prevention of complications with hemoperfusion, and (3) the relative safety of the procedure. We provide tentative guidelines for the initiation of hemoperfusion for the treatment of theophylline intoxication.

The Effect of Dietary Protein on the Clearance of Allopurinol and Oxypurinol

A decrease in dietary protein is known to depress renal plasma flow and creatinine clearance. Using a randomized crossover design, we investigated the pharmacokinetics of allopurinol and its principal metabolite, oxypurinol, after oral administration of 600 mg of allopurinol in six normal subjects receiving a high-protein (268 g per day) or low-protein (19 g per day) diet. For allopurinol, the area under the curve of plasma concentration versus time increased by a factor of 1.45 (P less than 0.02), the renal clearance decreased by 28 per cent (P less than 0.02), and the ratio of the clearance of allopurinol to that of creatinine (fractional excretion) was unchanged between the low-protein and high-protein diets. For oxypurinol, the area under the curve increased nearly three-fold (P less than 0.02), the renal clearance decreased by 64 per cent (P less than 0.02), the fractional excretion decreased by 49 per cent (P less than 0.02), and the plasma oxypurinol half-life increased nearly threefold from 17.3 +/- 1.5 (mean +/- S.E.M.) to 49.9 +/- 2.9 hours (P less than 0.02) during the low-protein diet, as compared with the high-protein diet. We conclude that with the low-protein diet, the absorption, metabolism, and excretion of allopurinol were minimally altered but the total-body clearance of oxypurinol was greatly reduced because of a large increase in the net renal tubular reabsorption of oxypurinol.

A dose-response trial of once-daily diltiazem

This trial was performed to determine the safe and effective dosage range of once daily diltiazem (diltiazem CD) capsules for treatment of essential hypertension. Patients with essential hypertension having supine diastolic blood pressure values greater than or equal to 95 mm Hg and less than or equal to 110 mm Hg were randomly assigned to receive placebo or one of four doses of diltiazem CD: 90, 180, 360, or 540 mg. Blood pressure was measured at trough, 24 hours after the dose, and at the time of peak effect, 10 hours after the dose. Diltiazem CD lowered both supine diastolic and systolic blood pressure. A linear dose response was seen with changes in diastolic and systolic blood pressure and heart rate for trough and peak measurements. Trough/peak ratios for the 180, 360, and 540 mg doses were all greater than 0.50. Adverse effects were dose related; those most commonly reported were headache (8.6%), bradycardia (8.1%), and edema (7%), with bradycardia and edema possibly dose related. It is therefore concluded that diltiazem CD is a safe and effective antihypertensive agent.

Reduced Renal Clearance of Oxypurinol During a 400 Calorie Protein‐Free Diet

A decrease in dietary protein intake lowers the clearance of a number of substances excreted principally by the kidney including uric acid and oxypurinol, the major metabolite of allopurinol. We studied the kinetics of uric acid and oxypurinol in seven healthy volunteers on a normal protein diet (2600 calories; 100 g protein) followed by a 400 calorie, protein‐free diet. A 600 mg dose of allopurinol was given orally after 6 days of the normal protein diet and again after 2 days of the 400 calorie, protein‐free diet. Two major findings emerged: first, the renal clearance of oxypurinol was reduced from 21.2 ± 1.9 ml/min during the normal protein diet to 12.3 ± 1.2 ml/min (P < .05) during the 400 calorie, protein‐free diet, and second, there was a striking diurnal difference in oxypurinol renal clearance with a 41% decrease in the oxypurinol clearance at night (8 pm to 8 am) versus day (8 am to 8 pm) on the 400 calorie, protein‐free diet.

The Use of Confidence Intervals to Describe the Precision of Trough/Peak Ratios for Diltiazem CD in the Treatment of Hypertension

Once‐daily diltiazem hydrochloride, CARDIZEM® CD (diltiazem CD) 300 mg, was evaluated for safety, efficacy, and the relationship between peak and trough antihypertensive ejects in a multicenter, placebo‐controlled, parallel design trial. After a 4‐ to 6‐week placebo baseline period, 111 patients with essential hypertension were randomized to receive placebo or diltiazem CD for a 4‐week treatment period. Diltiazem CD 300 mg lowered supine diastolic and systolic blood pressure at trough significantly more than placebo (‐7.5 mm Hg vs. −1.3 mm Hg, P = 0.0001 and −6.4 mm Hg vs. 0.5 mm Hg, P = 0.0051, respectively). Supine blood pressure was also measured hourly from 6 to 10 hours after the dose to assess peak effect and trough/peak ratios. Using the largest residual drug effect of−6.3 mm Hg at 6 hours as peak and the 24−hour residual drug effect of−5.9 mm Hg as trough, the trough/peak ratio was estimated to be 71%, with a lower one‐sided 95% confidence limit of 50%. The precision of the trough/peak ratio is estimated by the lower confidence limit of 50%, which establishes the trough/peak ratio as statistically ≥ 50%. No statistically significant differences in supine DBP were noted between the peak effect hours, indicating a plateau of the peak antihypertensive effect from 6 to 10 hours post‐dose. Diltiazem CD therapy was well tolerated, with no serious treatment‐related adverse events reported during the trial and no patients discontinuing the trial due to a treatment‐related adverse event. This trial demonstrates diltiazem CD 300 mg is a safe and effective therapy when administered once daily for the treatment of essential hypertension.

The determinants of response to diltiazem in hypertension

We examined factors (blood pressure, plasma renin activity, and age) influencing the antihypertensive response in essential hypertensive patients given 240 mg/day of slow‐release diltiazem in an unblinded study after a placebo run‐in period. Subjects provided a range of diastolic blood pressures (90 to 115 mm Hg), of age (31 to 70 years), and of plasma renin activity (0.1 to 2.7 ng angiotensin I/ml/hr) on a 70 to 150 mEq sodium diet. Blood pressure, plasma renin activity, and plasma diltiazem concentrations were measured after the first (n = 21) and final dose (n = 19) of 120 mg diltiazem, twice daily for 4 weeks. Multiple linear step wise regression of change in blood pressure versus age, plasma renin activity, and baseline blood pressure showed baseline blood pressure was the only predictor of response (p = 0.0002). For each increase of 10 mm Hg in baseline pressure there was a 7 mm Hg greater decrease in diastolic blood pressure. We conclude that patient age and plasma renin activity are not clinically significant predictors of antihypertensive response to diltiazem in hypertension.

Superactivated Charcoal Versus Cholestyramine for Cholesterol Lowering: A Randomized Cross‐Over Trial

To evaluate the relative abilities of superactivated charcoal (20 g twice daily) and cholestyramine (8 g twice daily) to lower plasma cholesterol concentrations acutely, six hyper‐cholesterolemic patients were studied using a randomized cross‐over design. After a 1‐week dietary control period, each subject received 3 weeks of each treatment regimen on separate occasions. Superactivated charcoal and cholestyramine reduced total plasma cholesterol by 21.8 ± 3.8% and 16.2 ± 2.4%, respectively. Side effects were mild and similar for both treatments. At the dosage regimens studied, superactivated charcoal and cholestyramine have comparable ability to lower plasma cholesterol concentrations.

Hypocitraturic Calcium-Oxalate Nephrolithiasis

Excerpt To the editor: Very convincing arguments have been made for basing therapeutic decisions on data derived from controlled clinical trials when possible (1). There are several examples of tre...