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Biomedical subjects

G J Frank

Publications and source records attributed to G J Frank.

18 recordsLinked to original sources
PubMed1994

Quinapril and hydrochlorothiazide combination for control of hypertension: assessment by factorial design. Quinapril Investigator Group.

A factorial design method was applied in this multicentre trial of the angiotensin-converting enzyme inhibitor quinapril hydrochloride (Accupril) in combination with the diuretic hydrochlorothiazide (HCTZ) to assess the additive effects of the combination versus monotherapy, to characterise the dose-response relationship of each drug in the presence of the other and to determine if quinapril would attenuate the hypokalemic effect of HCTZ. Following a two to four week placebo-baseline period, 460 qualifying patients with a DBP > or = 100 mmHg and < or = 115 mmHg were randomised to an eight week double-blind phase with one of 16 parallel treatments: placebo, one of three doses of quinapril monotherapy, one of three doses of HCTZ monotherapy or one of nine possible corresponding combinations of quinapril and HCTZ. Mean reductions in sitting SBP/DBP at trough with combination therapy ranged from 7.8 mmHg/7.2 mmHg to 19.6 mmHg/15.1 mmHg (n = 458). Results of the response surface analyses indicate that the effects of the two drugs were additive and that the maximum antihypertensive effect of quinapril in combination with HCTZ within the doses studied is achieved approximately at a dose of 26 mg quinapril and 25 mg HCTZ. The degree of attenuation of the hypokalemic effect of HCTZ was directly related to the dose of quinapril. At 40 mg quinapril, the HCTZ dose-related decreases of serum potassium were not apparent and overall hypokalemic effects were attenuated by quinapril. Thus, the combination of quinapril and HCTZ given once daily provided additive antihypertensive effects of predictable degrees and the addition of quinapril attenuated the hypokalemic effect of HCTZ.

Adult↗
PubMed1990

Multiple-dose propranolol administration does not influence the single dose pharmacokinetics of quinapril and its active metabolite (quinaprilat).

To evaluate the influence of multiple dose propranolol administration on the single dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, a drug-drug interaction study was performed in ten healthy volunteers. Each subject received a single 20 mg quinapril oral dose on Days 1 and 16 of the study. Oral propranolol doses of 40 mg BID were initiated on Day 3, titrated gradually to 80 mg TID by Day 10, and continued at 80 mg TID through Day 17. Comparable mean quinapril pharmacokinetic parameter values as well as comparable mean quinaprilat pharmacokinetic parameter values determined following quinapril administered alone and following quinapril administered with propranolol, indicate that propranolol does not alter the single dose pharmacokinetics of quinapril or quinaprilat.

Adult↗
PubMed1990

Overview of the clinical development of quinapril.

Quinapril hydrochloride is the newest member of a family of angiotensin-converting enzyme (ACE) inhibitors. On completion of laboratory and animal studies, a clinical program was initiated to evaluate the antihypertensive and other properties of the drug in human subjects. The initial phase of clinical development was concerned with the pharmacokinetics and pharmacology of quinapril. The latter studies established a dose range for the drug and explored its effect on human hemodynamics and blood pressure. Safety and interactions with other drugs were also examined. Subsequent studies explored the safety and efficacy of quinapril in patients with mild to moderate hypertension and, later, in patients with more severe hypertension. Results of these studies supported the recommendation of a once daily dosage of quinapril, 10-40 mg, as first-line therapy in the management of hypertension, with diuretics as concomitant therapy as required in patients with severe hypertension. Quinapril has also been found to be the most potent of all available ACE inhibitors in binding to tissue ACE, which may contribute to its potent and sustained duration of action. Clinical evaluation of quinapril has also been undertaken in patients with congestive heart failure. Initial findings indicate that doses of 10-20 mg/day, given twice daily, are therapeutic when administered with diuretic or digitalis. Safety of the drug has been established in 2700 patients.

Aged↗
PubMed1990

The safety profile of quinapril: is there a difference among ACE inhibitors?

The safety of quinapril hydrochloride, a new nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor with an intermediate duration of action, has been evaluated in 3,031 patients with hypertension and congestive heart failure (CHF) and has been compared with other ACE inhibitors. A comparison of double-blind studies showed quinapril to have a lower incidence of adverse effects and withdrawals than reported for captopril or enalapril. Analysis of onset of adverse events or withdrawals did not show either a time-dependent or dose-dependent relationship with quinapril. The proportion of patients who experienced orthostatic hypotension was less than that of patients on captopril or enalapril. Double-blind, long-term, and open-label studies with quinapril showed no increase in the incidence of events reported in patients with CHF compared with hypertensive patients. Quinapril produced minimal adverse effects on renal function in both patients with normal renal function and in those with pre-existing renal impairment. Age analysis of data from all studies showed no increase in total reporting of adverse events in older patients who did not take concomitant diuretics.

Aged↗
PubMed1990

Overview of quinapril, a new ACE inhibitor.

Quinapril has been extensively studied for efficacy and safety in patients with hypertension or congestive heart failure (CHF) in the United States and Europe. Thirty-nine clinical pharmacology studies involving 383 patients have been completed. Moreover, 12 controlled, multicenter clinical studies and 3 single-center studies involving 1,793 patients have been conducted in hypertension. Three hemodynamic trials, two of which included both acute and long-term phases, and one placebo-controlled, dose-response study have been conducted in 333 patients with CHF. An additional 519 patients who completed studies on comparative agents were started on quinapril at the initiation of six long-term, open-label trials, which extended for up to 3 years. Twelve of 15 hypertension trials evaluated quinapril as first-line monotherapy in 1,452 patients with hypertension. Comparative agents included placebo in five trials (524 patients), enalapril in three trials (339 patients), captopril in four trials (335 patients), and chlorthalidone in one trial (74 patients). A total of 510 patients received quinapril in addition to a diuretic in double-blind trials: 341 patients with moderate to severe hypertension participated in three trials, and 169 patients with CHF participated in one trial. Quinapril administered once daily (o.d.) was evaluated in four placebo-controlled studies and in two studies of o.d. vs. twice-daily doses. The safety of quinapril has been evaluated in almost 2,700 patients in controlled, double-blind studies or in open-label extensions, for a total of more than 1,600 patient-years of exposure to quinapril. More than one-half of all patients participated in long-term trials: 980 patients were studied for 1 year and 315 patients were studied for 2 years at the time of data analysis. Safety data are available for 451 older patients (aged greater than or equal to 65 years), and comparative safety data from other compounds in the controlled studies are available for 1,058 patients. Quinapril's efficacy is comparable to that of other angiotensin-converting enzyme (ACE) inhibitors, and it has a lower incidence of adverse events or withdrawals due to adverse events than has been associated with captopril or enalapril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

The safety and tolerability of quinapril.

Quinapril, a new angiotensin-converting enzyme (ACE) inhibitor with an intermediate duration of action, has been extensively studied in patients with hypertension and congestive heart failure (CHF) during a worldwide clinical development program. A comprehensive safety data base was established to allow appropriate analyses of the extensive patient safety data. The safety of quinapril has been evaluated in 2,697 patients with hypertension and CHF, including 451 elderly patients (greater than or equal to 65 years), and has been compared with safety data from a total of 1,058 patients receiving a comparative therapy. A comparison of the double-blind studies demonstrated that quinapril has a lower incidence of adverse events and/or withdrawals than reported for captopril or enalapril. An analysis of the onset of adverse events did not show either an increase with time on quinapril therapy or a dose relationship. The proportion of patients who experienced orthostatic hypotension or hypotension was less than that of patients who were treated with captopril or enalapril. An analysis of all events (from both double-blind and long-term, open-label studies) showed no increase in the incidence of events reported in patients with CHF compared with hypertensive patients. When the data for all studies were combined, an age analysis showed no increase in the total reporting of adverse events in elderly patients compared with the younger patients studied. The incidence of adverse events was lower in those patients not receiving concomitant diuretic therapy. An overall analysis of clinical laboratory data indicated that quinapril did not have significant adverse effects on clinical laboratory parameters when compared with captopril, enalapril, or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The pharmacokinetics and pharmacodynamics of quinapril and quinaprilat in renal impairment.

1. The pharmacokinetics and pharmacodynamics of quinapril and its active metabolite quinaprilat were studied in 20 subjects with renal function varying from normal to severe renal failure, during the approach to and at steady-state, and for 72 h after cessation of quinapril 20 mg orally for 7 days. 2. The apparent oral plasma clearance of quinaprilat (dose of quinapril equivalent/AUC of quinaprilat) was directly related to creatinine clearance (CLCr). The predicted apparent oral clearance of quinaprilat was zero when CLCr was zero, suggesting minimal extrarenal elimination. 3. Peak and trough concentrations of quinaprilat, and its apparent elimination half-life, varied inversely with CLCr. 4. Trough concentrations of quinaprilat showed no accumulation between 2 and 7 days, even in severe renal impairment. 5. There was a weak relationship between the oral plasma clearance of quinapril and CLCr. 6. ACE inhibition was marked and prolonged in all subjects, with 50% inhibition at 2.7 +/- 1.9% ng ml-1 of quinaprilat. The time for which ACE inhibition was greater than 90% was related inversely to CLCr. 7. Aldosterone concentrations and plasma renin activity responded in a predictable way, but with no clear relationship To CLCr. 8. Atrial natriuretic peptide concentrations were not affected by quinapril administration. 9. Glomerular filtration rate, as measured by Tc99mDTPA clearance, was not affected by quinapril administration. 10. Blood pressure at steady-state decreased significantly in the subjects with hypertension. The changes in blood pressure were not related to renal function. 11. These results suggest that the dosage rate of quinapril may have to be altered in renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1989

The safety of ACE inhibitors for the treatment of hypertension and congestive heart failure.

Angiotensin-converting enzyme (ACE) inhibitors are being increasingly prescribed for the treatment of hypertension and heart failure. Not only are they efficacious but the incidence of serious adverse events with ACE inhibitors is similar to that with placebo. 'First-dose hypotension' mainly affects the renin-dependent patient. Neutropenia and agranulocytosis have been reported rarely for the nonsulfhydryl compounds. Comparative safety data are provided for captopril, enalapril, and quinapril, a new nonsulfhydryl ACE inhibitor that has been investigated extensively in over 2,000 patients. Results show that the proportion of patients reporting associated adverse events was lower with quinapril (11%) than with captopril (17%) or enalapril (15%). Similarly, there was a lower proportion of patients withdrawn due to adverse events with quinapril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Overall tolerance and safety of quinapril in clinical trials.

A comprehensive analysis of the reporting of adverse events, withdrawals due to adverse events, and serious adverse events has been conducted on 2,010 patients treated with quinapril hydrochloride. An analysis of all events (from both double-blind and open label studies combined) showed no increase in the incidence of events reported in congestive heart failure (CHF) patients compared to hypertensive patients. When the data for all studies were combined, an age analysis showed no increase in the total reporting of adverse events in the 379 elderly patients studied. The incidence of events was lower in those patients who did not take concomitant diuretic therapy. A comparison of the double-blind phases showed quinapril to have a lower incidence of adverse events than captopril, enalapril, or chlorthalidone. An analysis of the onset of events, or withdrawals, did not show an increase with time on quinapril therapy, and no dose-relationship. A review of serious adverse events did not reveal an unexpected occurrence or a high incidence of serious events considered to be related to quinapril therapy. The proportion of patients who experienced "first-dose" hypotension, or symptomatic hypotension was similar to captopril or enalapril. Quinapril, a nonsulfhydryl ACE inhibitor, has been extensively studied and is equally well tolerated in the young and elderly for the treatment of hypertension and CHF.

Aged↗
PubMed1989

Does the duration of action of angiotensin converting enzyme inhibitors affect their safety and adverse effects?

The results of more than 1600 patient years of experience with the new angiotensin converting enzyme (ACE) inhibitor, quinapril, suggest that it is safe for the treatment of hypertension and congestive heart failure. A once-daily regimen of quinapril minimizes adverse effects on renal function compared with a twice-daily regimen, and compared with enalapril. This may be because long-acting agents, or frequent doses of ACE inhibitors, produce a prolonged reduction in the glomerular filtration pressure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

The pharmacokinetics of angiotensin converting enzyme inhibitors in patients with renal impairment.

The clearance of drugs excreted entirely unchanged by the kidneys is assumed to relate directly to renal function. The clearance of drugs which are entirely metabolized is usually not altered in patients with renal impairment, although there are examples of both increased and decreased metabolic clearance rates. The clearance of metabolites which are excreted unchanged through the kidneys is also directly related to renal function. The angiotensin converting enzyme (ACE) inhibitors enalapril, ramipril, cilazapril and quinapril are prodrugs that are rapidly converted to active metabolites which are excreted unchanged through the kidneys. Studies have consistently demonstrated reduction in the apparent oral clearance of the active metabolites, in proportion to the degree of impairment of renal function. In addition, for quinapril at least, the metabolic clearance of the parent drug is slightly reduced in renal impairment. The activity of captopril and lisinopril lies in the parent molecule itself. Lisinopril is excreted renally unchanged, while captopril is both metabolized and excreted renally unchanged. The duration of ACE inhibition after administration of any of the ACE inhibitors is prolonged in proportion to the degree of renal impairment. From these pharmacokinetic and pharmacodynamic properties, it follows that the dose rate of the ACE inhibitors should be reduced in direct proportion to the degree of reduction in renal function. Reducing the dose, rather than prolonging the dose interval, is more logical for compliance and for maintaining a consistent degree of ACE inhibition over 24 h.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

A comparison of isoxicam pharmacokinetics in young and elderly subjects.

1 The pharmacokinetics of isoxicam have been compared in 57 volunteers with an average age of 31.3 years and 48 elderly subjects with an average age of 71.9 years. 2 Isoxicam was given in a single daily dose of 200 mg for up to 22 days. Similar plasma concentrations were obtained in the two age groups, average maximum concentrations being 39.7 mg l-1 in those under 65 and 38.1 mg l-1 in the elderly. There were no significant differences in the half-life which averaged 30.4 and 32.1 h respectively. 3 Approximately 9% of all those studied had half-life values in excess of 50 h. The results are consistent with the possibility of genetic polymorphism of isoxicam hydroxylation. 4 It is concluded that isoxicam is suitable for use in once daily dosage and that there are no clinically significant differences in its pharmacokinetics between young and elderly subjects.

Adolescent↗
PubMed1983

Report of a double-blind crossover study to compare flurbiprofen with paracetamol in the treatment of primary dysmenorrhoea.

Thirty-one patients suffering from primary dysmenorrhoea completed a double-blind crossover study which demonstrated flurbiprofen (100 mg three times a day) to be significantly more effective than paracetamol (1 g three The study revealed an explicit patient preference for flurbiprofen. The incidence of side-effect was low for both treatments though one patient was withdrawn because of lack of efficacy and side-effects while taking paracetamol.

Acetaminophen↗
PubMed1981

Backward, simultaneous, and forward masking as a function of signal delay and frequency.

Backward, simultaneous, and forward masking were investigated in 7 normal-hearing adults using a 1-kc/s sinusoid masker of 250 msec duration and 60 db SPL. 10-msec sinusoidal signals (probes) were varied in frequency (.4, .8, .9, .95, 1.05, 1.1, 1.2, 1.6 kc/s) and temporal location, delta t, prior to (-250, -150, -40, -20, -10, -2 msec re: masker onset), during (2, 10, 20, 40, 125, 250 msec re: masker onset), or following (2, 10, 20, 40, 125, 250 msec re: masker offset). The double random staircase psychophysical method (Cornsweet, 1962) was used in all conditions. Monotic thresholds were obtained for the backward and forward masking conditions. Dichotic and monotic thresholds were collected for the simultaneous condition. Results showed: (a) Backward masking. The greatest masking (up to 25 db) occurred between 0.0 and -40 msec when the signal probe was within +/- .2 cps of the masker. There was a linear decrease in masking as a function of delta t; masking effects extended to 250 msec. (b) Forward masking. The data revealed no masking beyond 125 msec delta t, an asymmetry in the masking pattern, relatively large threshold shifts (up to 33 db) when delta t was less than 40 msec and the signal was approximately +/- .2 kc/s within the masker. (c) Simultaneous masking. Overshoot occurred at onset and offset for both dichotic and monotic conditions; onset overshoot was larger in both conditions. The data revealed more forward masking than backward masking at equivalent absolute delta t values. Data were discussed in terms of cochlear vibration patterns and hypothesized central mechanisms.

Adult↗
PubMed1980

Decrease in aspirin-induced gastric mucosal damage in rats by oral administration of the cytotoxic drugs melphalan and methotrexate.

Gastric mucosal damage by aspirin and chemotherapeutic drugs was studied in Wistar rats. Aspirin 60 mg given by stomach tube caused substantial gastric mucosal damage as judged by visual examination of the stomachs removed four hours later. Melphalan and methotrexate given daily for four days had no significant macroscopic effect on the gastric mucosa, but reduced the damage caused by aspirin. This protective effect my involve a stimulation of prostaglandin synthesis by the stomach, increased mucus secretion, and/or inhibition of acid secretion.

Animals↗