Pharmacokinetics of oral and transdermal triprolidine.

In this open, nonrandomized, three-way crossover study, six healthy male volunteers received single doses of triprolidine (TPL) hydrochloride syrup orally (2.5 mg) and wore transdermal TPL patches (5 mg and 10 mg doses) to compare the pharmacokinetic profiles and dose tolerance of the two formulations. A washout period of at least 1 week was scheduled between the three dosing periods. Blood samples were collected at defined times, and plasma concentrations were determined using a radioimmunoassay. Maximum plasma drug concentration (Cmax) decreased from 5.6 +/- 2.9 ng/mL (mean +/- SD) with oral dosing to 2.0 +/- 1.0 ng/mL and 4.2 +/- 2.0 ng/mL following 5 mg and 10 mg transdermal doses, respectively. Time to reach peak concentration (tmax) increased from 2.0 +/- 1.2 hours with oral dosing to 12.0 +/- 5.9 and 14.3 +/- 9.9 hours following 5 mg and 10 mg transdermal doses, respectively. The differences between AUC0-alpha values with the oral syrup and the 5 mg and 10 mg transdermal doses were not significant when normalized to 2.09 mg (TPL base). The bioavailabilities of the 5 mg and 10 mg transdermal doses relative to the oral 2.09 mg doses were 0.89 +/- 0.32 and 1.04 +/- 0.33, respectively. Mild erythema and pruritus were the most common adverse effects secondary to TPL transdermal application. Drowsiness observed following oral TPL, was not evident following either transdermal dose. The results of this study, therefore, indicate that TPL can be absorbed transdermally, providing consistent plasma concentrations.

Absorption of digoxin from tablets and capsules in subjects with malabsorption syndromes.

The relative steady-state bioavailability of two oral digoxin dosage forms was studied in 17 subjects with malabsorption syndromes. Male subjects received the following treatments in randomized crossover fashion for 14 days: three 0.125-mg digoxin tablets or three 0.1-mg digoxin capsules once daily. Female subjects received digoxin on the same schedule but at two-thirds the dose. Serum and urine samples were collected and analyzed for digoxin by radioimmunoassay, and treatments were compared by evaluating pharmacokinetic parameters. The mean area under the serum concentration versus time curve for tablets (28.1 h.nmol/L [21.9 h.ng/mL]) was smaller (p less than 0.03) than that for capsules (31.1 h.nmol/L [24.3 h.ng/mL]), and the mean maximum serum digoxin concentration for tablets (2.9 nmol/L [2.3 ng/mL]) was lower (p less than 0.02) than that for capsules (4.0 nmol/L [3.1 ng/mL]). There was no difference in cumulative urinary excretion of digoxin between the two treatments. In contrast to previous reports, we observed that digoxin from Lanoxin Tablets appears to be well absorbed in subjects with malabsorption. Nevertheless, these subjects absorbed digoxin from capsules better than from tablets, with the greatest differences occurring in subjects without a colon and in those subjects with the lowest serum carotene concentrations.

Pharmacokinetics of acrivastine after oral and colonic administration.

Six healthy male volunteers participated in this randomized, crossover open-label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1-receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean +/- SD pharmacokinetic parameters were obtained: Cmax 179 +/- 11 and 13.8 +/- 5.2 ng/ml; tmax, 0.85 +/- 0.13 and 3.60 +/- 0.56 hr; AUC0-12 hr, 576 +/- 57 and 104 +/- 46 hr.ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P less than 0.001). The mean +/- SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 +/- 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.

Propranolol-hydralazine combination in essential hypertension.

The efficacy of a propranolol-hydralazine combination tablet was compared with that of each of its two components in the twice-daily treatment of mild to moderate essential hypertension (diastolic blood pressure: 100 to 125 mmHg). After a three-week, single-blind, placebo period, a 9- to 18-week, single-blind, dose-finding phase with the combination was performed. The daily doses of propranolol/hydralazine were 40 mg/25 mg, 80 mg/25 mg, 80 mg/50 mg, 120 mg/50 mg, 160 mg/50 mg, and 160 mg/100 mg. Of 83 patients, 73 (88%) had decreases in diastolic blood pressure equal to or greater than 10 mmHg. Thirty-eight (46%) patients had a diastolic blood pressure equal to or less than 90 mmHg while taking 80 mg propranolol/50 mg hydralazine or less given BID. Mean systolic and diastolic pressures were reduced by 16.8 mmHg (10.9%) and 17.6 mmHg (16.7%), respectively (P less than 0.001). A ten-week, double-blind, parallel-treatment phase followed in which patients were randomly assigned to the combination tablet or to propranolol or hydralazine. There were significantly larger increases in mean systolic (P less than 0.01) and mean diastolic (P less than 0.03) blood pressure when the components were taken alone than with the combination from the mean of the last three weekly dose-finding visits to the mean of the last four biweekly parallel-treatment visits. The changes in systolic/diastolic blood pressures were: hydralazine (n = 30), 14.43/8.62 mmHg; propranolol (n = 24), 9.87/6.09 mmHg; and the combination (n = 27), 1.47/1.53 mmHg. During the parallel-treatment phase, the proportions of patients with new complaints were: hydralazine, 16/31 (52%); propranolol, 10/25 (40%); and the combination, 11/27 (41%). In the hydralazine group, three patients had cardiovascular events (severe tachycardia, mild palpitations, and skipped heart beats) and two patients had mild anxiety; no such occurrences were noted in the propranolol or combination group. The mean change (increase) in heart rate from the end of dose-finding to the end of the double-blind period was significantly larger for patients taking hydralazine than for patients taking propranolol or the combination. Mean changes for these groups were: hydralazine, 12.4 beats/min; propranolol, 2.9 beats/min; and the combination, 1.8 beats/min (P = 0.0001). This study found the combination of propranolol plus hydralazine to be safe and more effective than either component.

Training the "clinical scientist" through a combined industrial/academic fellowship.

A novel two-year fellowship program is described which provides specialized training both in clinical drug research and drug development methodology for pharmacists with previous clinical experience. Pharmaceutical industry, university and hospital research facilities are used as the training laboratories, and collectively offer theoretical as well as practical research skills development. Traditional didactic and laboratory training are provided within university and hospital environments with emphasis in the conduct of clinical trials. Extramural experience with pharmaceutical industry provides a corollary experience which includes exposure to ethical, legal and regulatory issues involving both investigational and marketed drugs. Following successful completion of the fellowship, the pharmacist is expected to have developed the fundamental skills necessary for a career in academia, pharmaceutical industry, or clinical practice.

Hypertension control in a rural biracial community: successes and failures of primary care.

Through a total community survey and a medical record review, we examined hypertension awareness, treatment, and control in a biracial rural community rich in primary care resources. The overall prevalence of hypertension among the 2,939 respondents was 20.5 per cent; 82 per cent of hypertensives were aware of their condition; 68 per cent were on treatment; and 55 per cent were under control. Comparison of data sources revealed discrepancies and misconceptions about diagnosis and treatment. Nearly one-third of the population reported a history of hypertension despite the fact that most of them were untreated and were normotensive. Conversely, one-third of "undetected" hypertensives had notation of the diagnosis in their medical records. Discontinuation of treatment accounted for over one-half of aware but untreated hypertension. Misconceptions about therapy contributed to failures of control in the treated group. These findings suggest that difficulties in the transmission of information about hypertension contribute importantly to failures of control.

Development of radioimmunoassay for guanethidine.

A radioimmunoassay was developed for measuring plasma concentrations of the antihypertensive agent guanethidine at the nanogram level. Guanethidine was conjugated covalently to human serum albumin by two procedures, and the degree of conjugation was determined using tracer amounts of 3H-guanethidine. Immunization of sheep ethidine, as determined in competitive binding studies using 3H-guanethidine and a dextran-coated charcoal technique for the separation of free and antibody-bound drug. The major human metabolities, an N -oxide and a ring-opened derivative, were not cross-reactive in antibody binding studies. Constituents of human plasma or serum do not appear to interfere with the assay. Preliminary results from immunoassay of plasma samples from patients receiving guanethidine indicate potential use for assessing dosage regimens and studying pharmacokinetics.

Echocardiographic assessment of the effect of an antihypertensive regimen on left ventricular performance.

A regimen consisting of chlorthalidone, hydralazine and propranolol would be useful in some hypertensive patients with coronary artery disease or aortic dissection if it could be shown that reflex cardiac stimulation induced by hydralazine is completely neutralized by propranolol. Nine hypertensive patients were treated with chlorthalidone during week 1, chlorthalidone and hydralazine during week 2 and a combination of chlorthalidone, hydralazine and propranolol during week 3. Blood pressure, heart rate, mean velocity of circumferential fiber shortening (VCF) measured echocardiographically and plasma renin activity were measured weekly. This potent three drug regimen reduced mean blood pressure from 142 to 102 mm Hg, and with the third drug, propranolol, heart rate, VCF and plasma renin activity returned to control levels from the greater elevated levels produced by the diuretic drug and hydralazine. In six additional patients VCF (an index of left ventricular contractility) was found to be proportionate to the rate of rise of aortic pressure (dP/dt) or aortic shearing force. This regimen appears safe for use in patients with ischemic heart disease and aortic dissection.

Renin profiling in hypertension and its use in treatment with propranolol and chlorthalidone.

We compared methods of classifying hypertension according to plasma renin activity in 54 patients with essential hypertension and examined the validity of using these classifications to choose between two hypotensive drugs. A prospective, double-blind crossover study was used. Normal values for plasma renin activity were established from 111 control subjects. Plasma renin activity was related to race and inversely to age in hypertensive patients (P less than 0.05) but not in normal subjects. Three methods of classification correlated well but did not identify exactly the same renin-suppressed patients. Chlorthalidone produced a greater reduction in blood pressure and restored blood pressure to normal in a larger percentage of patients in both low-renin (59 per cent) and normal-renin (32 per cent) subgroups than propranolol (12 and 16 per cent). Renin determinations are of limited benefit in the choice of therapy for most patients with essential hypertension.