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Biomedical subjects

D A Willard

Publications and source records attributed to D A Willard.

32 records · Page 2Linked to original sources
PubMed1982

Captopril kinetics.

Captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was given by mouth and intravenously in 10-mg doses to five healthy subjects. After intravenous dosing, semilogarithmic plots of captopril blood levels : time showed a triexponential decay. Data were analyzed using an open three-compartment model. The average volume of distribution (Vd) was 0.2 l/kg for the central compartment and 2 l/kg for the elimination (beta) phase. The Vd at steady-state was 0.7 l/kg. The total body clearance of captopril averaged 0.8 l/kg/hr and the mean blood half-life during the beta phase was 1.9 hr. In the 0- to 96-hr urine, after intravenous and oral drug, excretion of radioactivity accounted for 87% and 61% of dose. In the 0- to 24-hr urine, averages of 38% (intravenous) and 24% (oral) of the doses were excreted as unchanged captopril. Absolute absorption of the radioactive oral dose was 71% and the absolute oral bioavailability of captopril was 62%.

Absorption↗
PubMed1980

Effects of nadolol beta-blockade on blood pressure in hypertension.

Nadolol, a nonselective beta adrenoceptor antagonist, was evaluated in 9 normal sybjects with essential hypertension for ability to inhibit exercise-induced changes in double-product (systolic pressure x heart rate). Propranolol and placebo were included as positive and negative controls. The beta antagonists were administered orally in single doses at 10, 20, 40, and 80 mg on a crossover basis. Both nadolol and propranolol induced comparable dose-related inhibition of double-product. Duration of beta receptor blockade was greater with nadolol than with propranolol; significant inhibition of double-product occurred 24 hr after a single 80-mg dose of nadolol. The antihypertensive effect of nadolol was evaluated in another series of 46 subjects with essential hypertension. The dose of nadolol ranged from 80 to 320 mg once daily. Consistent decreases in supine heart rate (20%) and diastolic blood pressure (9%) from baseline were observed. During steady state, the oral daily dose of nadolol was proportional to the minimum steady-state serum concentration (Cmin) of nadolol (r = 0.75, p less than 0.001) obtained just before the next dose of nadolol. Statistically significant correlation was observed between the antihypertensive effect and the Cmin for nadolol (r = 0.45, p less than 0.05).

Adrenergic beta-Antagonists↗
PubMed1980

Disposition of captopril in normal subjects.

The disposition of captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100-mg tablet of 35S-labeled drug. Average absorption parameters for unchanged captopril in blood were Tmax 0.93 +/- 0.08 hr and Cmax 800 +/- 76 ng/ml. For total radioactivity in blood the values were Tmax 1.05 +/- 0.08 hr and Cmax 1,580 +/- 90 ng/ml (as captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of captopril:time, elimination half-life (t1/2) of unchanged drug could not be determined. At 1 hr unchanged captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24-hr urine sample (66% of the dose) was 58% captopril (38% of dose), 2% captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).

Absorption↗
PubMed1979

Effect of beta-blockers on exercise double product (systolic blood pressure x heart rate).

1 The effect of single oral doses of six beta-receptor antagonists on exercise-induced changes in double product (systolic blood pressure x heart rate) were studied in 25 human volunteers. 2 Three doses of propranolol, nadolol, oxprenolol, pindolol, timolol and atenolol were selected for study on the basis of in vivo beta-blocking potency. 3 Although all beta-blockers studied reduced the double product response to exercise, the pharmacodynamics of this effect differed markedly. 4 Pharmacodynamic half-lives, estimated for the drug tested, were 39 h for nadolol, atenolol 21 h, timolol 15 h, oxprenolol 13 h, propranolol 11 and pindolol 8 h. 5 These results suggest that the clinical choice of a beta-blocker with the least problems of compliance can be made on the basis of pharmacodynamics as well as pharmacological profile.

Adolescent↗
PubMed1978

Pharmacokinetics of iodamide in normal subjects and in patients with renal impairment.

The pharmacokinetic characteristics of iodamide, a contrast agent for excretion urography, were studied in seven normal subjects and in 15 patients with various degrees of renal impairment. Two different formulations were administered, namely, a 65% solution (iodamide 300) by slow intravenous injection and a 24% solution by slow intravenous (drip) infusion. Both preparations of iodamide exhibited characteristics of an open two-compartment model. In both normal subjects and patients, the contrast agent was excreted almost exlusively in urine. In normal subjects, the pharmacokinetic parameters of both formulations were similar, with a distribution half-life (1/2alpha) of about 3 minutes and a disposition half-life (t1/2beta) of about 69 minutes. An average of 84 per cent of the dose was excreted in urine within 4 hours after administration of iodamide with net renal tubular secretion of about 38 per cent. The binding of iodamide to plasma proteins was negligible, and the extent of biotransformation of iodamide was minimal. In patients with renal impairment, the disposition half-life (t1/2beta) of iodamide ranged from 4.1 to 16.4 hours. Other changes in pharmacokinetic parameters were also seen in patients with renal impairment.

Clinical Trials as Topic↗
PubMed1977

Endocrine and cardiovascular consequences of angiotensin converting enzyme inhibition.

One of several novel peptidic inhibitors of angiotensin converting enzyme (CEI) has been studied intravenously both in normal male volunteers and severely hypertensive patients without any clinically significant adversity or intolerance. Hypertensive patients experienced a significant yet gradual reduction in resting arterial pressure without hypotension. The addition of a diuretic agent was observed to potentiate this antihypertensive effect. Normal, sodium replete volunteers received this nonapeptide intravenously in doses up to 2-0 mg/kg without any significant cardiovascular effect. Both patients and normal subjects exhibited reversible dose related increases in angiotensin I and renin levels after receiving the peptide. The plasma renin response to tilting was also potentiated by CEI. These findings suggest that intravenous CEI may be of value in the treatment of severely elevated hypertension and as a tool to evaluate vasoconstrictor and volume factors in hypertension.

Aldosterone↗
PubMedDate not supplied

Metabolic studies in patients with nadolol: oral and intravenous administration.

Nadolol-14C, 2,3-cis-5-(3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy)-1,2,3,4-tetrahydro-2,3-naphthalenediol, a nonselective beta-adrenergic blocking agent, was administered orally and intravenously at 2-mg doses to patients with mild cases of essential hypertension. Terminal plasma half-times after oral and intravenous doses were an average of 12.2 and 9.8 hours, respectively. After oral doses, an average of 24.6 and 76.9 per cent of the dose was excreted in urine and feces, respectively, whereas, after intravenous doses, an average of 72.9 and 23.3 per cent of the dose was excreted by the same routes. Calculations of absorption, based on urinary excretion and on areas under the plasma concentration-versus-time curves, indicated that oral doses of nadolol-14C were absorbed to the extent of 33.6+/-2.4 per cent (+/- S.E.). The average overall volume of distribution after intravenous administration was 2.09+/-0.51 1./kg (+/- S.E.), and the average volume of the central compartment was 0.30+/-0.04 1./kg. Only unchanged nadolol-14C was excreted in the urine and feces of patients after either oral or intravenous administration of the drug.

Administration, Oral↗
PubMedDate not supplied

Effect of food on the bioavailability of captopril in healthy subjects.

14C-Captopril was administered as 100-mg tablets to 12 subjects in a two-way crossover study in which subjects were either fasted or were given a standard meal immediately prior to dosing. Based on blood level and urinary excretion data, both the absorption of total radioactivity and the bioavailability of captopril were decreased approximately 35 to 40 per cent after a meal. Whether this moderate decrease in the absorption and the bioavailability of captopril caused by food is of clinical significance has not yet been determined.

Adolescent↗
PubMedDate not supplied

The effect of captopril on renal hemodynamics in hypertensive patients.

The effects of captopril (50 or 100 mg t.i.d.) with and without hydrochlorothiazide (25 or 50 mg/day) on renal blood flow, glomerular filtration rate, and the renin-angiotensin system were determined in 20 patients with mild to moderate essential hypertension. Normalization of blood pressure (supine diastolic blood pressure less than 90 mm Hg) was achieved in 12 patients after four or six weeks of captopril alone (147 +/- 3/100 +/- 3 mm Hg after a two-week placebo lead-in vs. 135 +/- 4/83 +/- 1 mm Hg after captopril, P less than 0.01/P less than 0.001). In these 12 patients, no significant alterations in renal blood flow or glomerular filtration rate were observed. Plasma renin activity increased two- to threefold above baseline levels, whereas serum and urinary aldosterone decreased by 23 and 35 per cent, respectively. Eight other patients remained hypertensive after four weeks of captopril alone (165 +/- 6/110 +/- 3 vs. 156 +/- 8/102 +/- 4 mmHg, P greater than 0.05/P less than 0.05). With addition of hydrochlorothiazide, blood pressure fell (P less than 0.001) to 129 +/- 7/84 +/- 3 mm Hg. Captopril alone or in combination with diuretic had no significant effect on renal hemodynamics. In the eight patients requiring diuretic, plasma renin activity remained constant after captopril monotherapy, but rose threefold after hydrochlorothiazide was added. The combination of these two antihypertensive agents significantly lowered serum aldosterone levels and urinary aldosterone excretion by 53 and 50 per cent, respectively. In summary, captopril with and without a thiazide diuretic reduced blood pressure without altering renal hemodynamics.

Aldosterone↗
PubMedDate not supplied

Comparative efficacy of once-daily versus twice-daily pravastatin in primary hypercholesterolemia.

The efficacy of once-daily versus twice-daily dosing of pravastatin was determined in men with primary hypercholesterolemia. The same group of patients was used in the two studies. In the once-daily study, 18 patients took 20 mg of pravastatin at bedtime for four weeks and then 40 mg of pravastatin for an additional four weeks. In the twice-daily study, 22 patients took 10 mg or 20 mg of pravastatin twice daily for four weeks. Total cholesterol was reduced 18% in the 20-mg once-daily group, 20% in the 10-mg twice-daily group, 23% in the 40-mg once-daily group, and 24% in the 20-mg twice-daily group; the respective reductions in low-density cholesterol were 27%, 28%, 32%, and 34%. All these reductions were statistically significant; no between-group differences were significant. Pravastatin was well tolerated and no patients dropped out because of side effects.

Anticholesteremic Agents↗