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1.
Biopharm Drug Dispos ; 21(9): 339-44, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11523062

ABSTRACT

The angiotensin-converting enzyme (ACE) inhibitor enalapril is commonly used to treat pediatric hypertension. Because some children are unable to swallow tablets or require doses less than the lowest available enalapril tablet, an enalapril suspension was developed. This study examined the relative bioavailability of enalapril suspension (10 mg) (S) compared with 10-mg marketed VASOTEC tablets (T) in 16 healthy adult subjects. The geometric mean ratio (S/T) estimate of urinary recovery of free enalaprilat, the active moiety, was 0.92 (90% confidence interval (CI): 0.80, 1.07). Urinary recovery data indicate that approximately 50% of the dose was absorbed (50% recovered in urine as enalapril plus enalaprilat) with about 30% of the dose recovered as free enalaprilat for both S and T. The geometric mean ratios (S/T) of serum AUC and C(max) were 1.01 (90% CI: 0.90, 1.13) and 0.98 (90% CI: 0.83, 1.16), respectively. Suspension T(max) was slightly shorter (0.5 h) than that for tablet, but this difference is not clinically significant. Both formulations were well tolerated and there were no clinically significant adverse experiences. We conclude that the bioavailability of enalapril oral suspension 10-mg is similar to that of VASOTEC 10-mg tablet. Instructions for compounding enalapril are provided.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Enalapril/pharmacokinetics , Administration, Oral , Adolescent , Adult , Area Under Curve , Cross-Over Studies , Enalapril/administration & dosage , Female , Humans , Male , Suspensions
2.
Cardiovasc Drugs Ther ; 10(3): 313-9, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8877074

ABSTRACT

The antihypertensive activity and safety of losartan, a specific and selective antagonist of angiotensin II (subtype 1) receptors, was evaluated in 100 inpatients with mild to moderate essential hypertension. After a 2-week, single-blind, out patient placebo lead-in period, the last 2 days of which included inpatient monitoring of baseline blood pressure, the patients were assigned randomly to receive once-daily doses of either placebo; 50, 100, or 150 mg losartan; or 10 mg enalapril. Patients were treated double blind for 5 days, followed by a day for the study of drug withdrawal. Beginning with the first dose, the three doses of losartan and enalapril significantly decreased peak and trough systolic and diastolic blood pressures compared with placebo (p < or = 0.05). The area under the blood pressure curve was analyzed as an assessment of total blood pressure change throughout the day. On day 1, total blood pressure reduction with losartan (50-150 mg) was slightly less than with enalapril. By day 5 of double-blind treatment, the reduction in blood pressure in these groups was similar, suggesting that losartan has a slower onset of action than enalapril. No rebound hypertension was observed after study-drug discontinuation. Losartan was well tolerated in this trial, with an adverse event profile similar to placebo and enalapril.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , Biphenyl Compounds/therapeutic use , Blood Pressure/drug effects , Enalapril/therapeutic use , Hypertension/drug therapy , Imidazoles/therapeutic use , Tetrazoles/therapeutic use , Adult , Aged , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacology , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/pharmacology , Blood Pressure Monitoring, Ambulatory , Double-Blind Method , Enalapril/administration & dosage , Enalapril/pharmacology , Female , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacology , Inpatients , Losartan , Male , Middle Aged , Placebos , Single-Blind Method , Tetrazoles/administration & dosage , Tetrazoles/pharmacology
3.
Hypertension ; 25(1): 37-46, 1995 Jan.
Article in English | MEDLINE | ID: mdl-7843751

ABSTRACT

We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.


Subject(s)
Angiotensin II/antagonists & inhibitors , Angiotensin Receptor Antagonists , Biphenyl Compounds/pharmacology , Hypertension/drug therapy , Imidazoles/pharmacology , Renin-Angiotensin System/drug effects , Tetrazoles/pharmacology , Adult , Aged , Angiotensin II/blood , Biphenyl Compounds/therapeutic use , Double-Blind Method , Enalapril/pharmacology , Female , Humans , Hypertension/physiopathology , Imidazoles/therapeutic use , Losartan , Male , Middle Aged , Norepinephrine/blood , Renin/blood , Tetrazoles/therapeutic use
4.
Eur J Clin Pharmacol ; 49(1-2): 115-9, 1995.
Article in English | MEDLINE | ID: mdl-8751032

ABSTRACT

This was a 2-period randomized, crossover study in 8 healthy males to determine the effects of cimetidine (400 mg q.i.d. for 6 days) on the pharmacokinetics and pharmacodynamic effects of the angiotensin II receptor antagonist, losartan (100 mg). Cimetidine increased the AUC for losartan 18% without affecting the AUC for E-3174, the active metabolite of losartan. The increase in plasma renin activity following losartan was not affected by cimetidine (maximum mean increases 12.6 and 12.1 ng Ang I.ml-1.h-1 without and with cimetidine, respectively). These results indicate that cimetidine does not appear to alter the pharmacokinetics or pharmacodynamics of losartan to a clinically significant extent.


Subject(s)
Angiotensin Receptor Antagonists , Biphenyl Compounds/pharmacokinetics , Cimetidine/pharmacology , Histamine H2 Antagonists/pharmacology , Imidazoles/pharmacokinetics , Tetrazoles/pharmacokinetics , Adult , Antihypertensive Agents/therapeutic use , Biphenyl Compounds/antagonists & inhibitors , Cross-Over Studies , Humans , Hypertension/drug therapy , Imidazoles/antagonists & inhibitors , Imidazoles/therapeutic use , Losartan , Male , Tetrazoles/antagonists & inhibitors , Tetrazoles/therapeutic use
5.
Hypertension ; 21(5): 704-13, 1993 May.
Article in English | MEDLINE | ID: mdl-8491505

ABSTRACT

Losartan is an orally active, nonpeptide angiotensin II (Ang II) (site-1) receptor antagonist. We conducted a multiple-dose study in healthy male volunteers to investigate the tolerability, blood pressure effects, and changes in plasma renin activity (PRA) and plasma Ang II concentration associated with once-daily administration of 100 mg losartan for a week. Subjects were studied on a standardized sodium diet (24-hour urinary sodium excretion, 98 +/- 37 [SD] mEq per 24 hours on the placebo run-in day). Measurements of blood pressure, heart rate, PRA, Ang II, and aldosterone were taken during a placebo run-in day and after single and multiple (7 days) daily doses of losartan (100 mg, n = 10) or placebo (n = 4). Ang II was measured specifically by high performance liquid chromatography coupled with radioimmunoassay. In subjects given losartan, respective decreases (systolic/diastolic) from run-in in supine blood pressure 6 hours after dosing were (mean +/- SD), compared with the placebo run-in day, first dose: -8.8 +/- 9.6/-6.8 +/- 5.0, last dose: -11.6 +/- 8.9/-7.0 +/- 4.8 mm Hg (p < 0.05 for all changes). At this 6-hour time point, corresponding increases from run-in in PRA were from 1.2 +/- 0.6 to 12.0 +/- 6.3 (first dose) and 9.6 +/- 4.9 (last dose) ng angiotensin I per milliliter per hour and in Ang II were from 4.3 +/- 1.7 to 72.4 +/- 33.3 and 45.7 +/- 14.1 pg/mL. All changes in PRA and Ang II were statistically significant within the losartan-treated group, and the biochemical changes were significantly greater than those in the placebo-treated group. The increment in Ang II was less after the last dose than after the first (p < 0.05). The drug was well tolerated by all subjects. These data indicate that, under the conditions of this study, losartan administration (100 mg/day for eight doses over 9 days) results in treatment-related decreases in blood pressure and increases in PRA and Ang II octapeptide.


Subject(s)
Angiotensin II/blood , Biphenyl Compounds/pharmacology , Blood Pressure/drug effects , Imidazoles/pharmacology , Renin/blood , Tetrazoles/pharmacology , Adolescent , Adult , Angiotensin II/antagonists & inhibitors , Biphenyl Compounds/adverse effects , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Double-Blind Method , Heart Rate/drug effects , Humans , Imidazoles/adverse effects , Losartan , Male , Osmolar Concentration , Radioimmunoassay , Reference Values , Renin-Angiotensin System/drug effects , Tetrazoles/adverse effects
6.
Stat Med ; 12(7): 633-43, 1993 Apr 15.
Article in English | MEDLINE | ID: mdl-8511440

ABSTRACT

Orthogonal polynomial scores (OPS) is a simple, biologically meaningful approach to characterize longitudinal data in phase I and II clinical pharmacology trials. It describes average, linear, quadratic and higher order polynomial characteristics of each subject's response over time with use of composite scores computed from linear combinations of the observed data. The statistical evaluation of the composite scores is univariate. For studies with a small number of experimental units and with many repeated measures, OPS may offer advantages over the use of summary measures such as the maximum response (MAX), the time at which MAX occurred (TMAX), or the area under the response curve (AUC), and other popular approaches such as time-point-by-time-point, split-plot, and multivariate analyses.


Subject(s)
Clinical Trials, Phase I as Topic/statistics & numerical data , Clinical Trials, Phase II as Topic/statistics & numerical data , Drug Therapy/statistics & numerical data , Pharmacokinetics , Adult , Humans , Longitudinal Studies , Male , Models, Statistical , Ophthalmic Solutions/pharmacokinetics , Ophthalmic Solutions/therapeutic use , Stereoisomerism
7.
Aliment Pharmacol Ther ; 5(6): 645-51, 1991 Dec.
Article in English | MEDLINE | ID: mdl-1782307

ABSTRACT

To define the optimum doses of omeprazole appropriate for acute and long-term therapy of patients with gastro-oesophageal reflux disease, 24-h oesophageal pH was measured in 12 patients with symptomatic reflux and an abnormal 24-h oesophageal acid exposure time (greater than 6%) in a randomized, double-blind, four-way crossover study comparing the effects of omeprazole 10, 20, or 40 mg/day and placebo. Total reflux time over 24 hours, number of reflux episodes per hour, and the number of reflux episodes lasting greater than 5 minutes were measured by ambulatory 24-h oesophageal pH monitoring. All doses of omeprazole were superior to placebo in decreasing gastro-oesophageal reflux as measured by each index. With placebo, oesophageal acid exposure was 16.3% of the 24 hours, 10 mg omeprazole/day reduced that to 6.3%, 20 mg/day lowered acid exposure to 0.9%, and 40 mg/day to 0.6%. Thus only the 20 and 40 mg doses reduced acid exposure to within the normal range. Similar results were obtained with the other indices of reflux. These data suggest that a rational dose regimen for reflux oesophagitis is 20 mg/day, a regimen that has proved effective in clinical trials. The present study indicates that 24-hour oesophageal pH monitoring is a practical approach to the determination of drug dosage in patients with gastro-oesophageal reflux.


Subject(s)
Esophagus/drug effects , Gastroesophageal Reflux/drug therapy , Omeprazole/therapeutic use , Adult , Aged , Dose-Response Relationship, Drug , Double-Blind Method , Esophagus/physiology , Female , Heartburn/drug therapy , Humans , Hydrogen-Ion Concentration , Male , Middle Aged , Omeprazole/adverse effects , Time Factors
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