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Biomedical subjects

A H Gradman

Publications and source records attributed to A H Gradman.

At least 19 recordsLinked to original sources
PubMed2002

AT(1)-receptor blockers: differences that matter.

The available angiotensin II type 1 (AT(1))-receptor blockers differ markedly in their pharmacological properties and clinical efficacy. Losartan shifts the dose-response curve for angiotensin II to the right without affecting the maximal response; this antagonism can be overcome by increasing concentrations of angiotensin II and thus losartan acts as a surmountable antagonist. By contrast, other agents suppress the maximal response to angiotensin II to varying extents; this can not be overcome by increasing angiotensin concentrations and hence these agents are insurmountable antagonists. Receptor binding studies have shown that candesartan has the highest affinity for the AT(1)-receptor, followed by irbesartan, valsartan and losartan, and that candesartan dissociates from the receptor more slowly than other antagonists. A meta-analysis using an E(Max) model has shown that differences in receptor binding activity are reflected in differences in maximal antihypertensive effect, and this finding is supported by the results of comparative clinical trials. Moreover, the prolonged binding of candesartan to the receptor is reflected in a longer duration of action, compared with losartan; the antihypertensive effect of candesartan persists for 48 h after dosing, compared with approximately 24 h with losartan. Candesartan thus offers extended therapeutic coverage, an important consideration since a majority of patients miss occasional doses of antihypertensive medication. There is currently no evidence that differences in receptor binding between AT(1)-receptor blockers translate into differences in tolerability. In summary, therefore, pharmacological differences between AT(1)-receptor blockers are reflected in clinically important differences in maximal antihypertensive effect, response rate, and duration of action.

Angiotensin II↗
PubMed2000

Underutilization and clinical benefits of angiotensin-converting enzyme inhibitors in patients with asymptomatic left ventricular dysfunction.

Despite evidence of therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors for congestive heart failure and asymptomatic left ventricular (LV) dysfunction, recent studies suggest that in heart failure patients, rates of ACE inhibitor usage in clinical practice remain low. In this study, the medical records of 107 patients with documented LV dysfunction were investigated for patterns of ACE inhibitor usage; 6-month and 1-year outcomes and event rates were evaluated. At index admission, 48% patients did not receive ACE inhibitor treatment, 32% were initiated on treatment, 19% continued on a prior regimen, and 1% were discontinued. Patients seen by a cardiologist were more likely to receive ACE inhibitor treatment (53% vs 35%, p = 0. 172), as were patients with histories of hypertension (60% vs 40%, p = 0.044) or myocardial infarction (56% vs 44%, p = 0.221). Significantly shorter hospitalizations (5.9 vs 9.5 days, p = 0.001) were noted for patients with on-going ACE inhibitor treatment compared with those receiving newly initiated treatment or no treatment. At time of hospital discharge, 102 patients were alive. Of 54 patients who received ACE inhibitors, 67% received an insufficient dose. At a 6-month follow-up, of 51 patients on ACE inhibitors, 23% died or were readmitted to hospital compared with 55% of nonusers (p = 0.001). At 1 year, this event rate was 31% among ACE inhibitor users versus 71% among nonusers (p < 0.0001). Bivariate and multivariate analysis revealed absence of ACE inhibitor use as the only significant variable associated with the event rate (p < 0.0011). Thus, about half of patients with asymptomatic LV dysfunction received ACE inhibitors; 2/3 of these did not receive a sufficient dose. ACE inhibitor usage increased with involvement of a cardiologist, presence of coexistent hypertension, or prior myocardial infarction. Ongoing ACE inhibitor therapy was associated with shorter hospitalizations and fewer hospital readmissions or deaths.

Adult↗
PubMed1999

Long-term benefits of angiotensin II blockade: is the consensus changing?

The treatment of hypertension and heart failure has evolved in recent years. It may no longer be sufficient to lower blood pressure per se or correct hemodynamics alone in these conditions to achieve optimal long-term outcomes; rather, the effects of drugs on the cellular events and structural alterations that occur in the vasculature, heart, and kidney must be considered. Drugs that target angiotensin II, which include the angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may protect target organs from damage and thereby improve outcomes. Nevertheless, it remains to be demonstrated whether these agents are more effective in reducing cardiovascular morbidity and mortality in hypertensive patients than conventional treatment with diuretics and beta blockers. In certain subgroups of hypertensive patients, including those with heart failure, type 1 diabetes with proteinuria, or after myocardial infarction with systolic dysfunction, there is compelling evidence for use of ACE inhibitors. The results from animal models and initial clinical studies suggest that ARBs are also highly effective in these patients. Several large-scale clinical studies, comparing the effect of ARBs and other drug classes on morbidity and mortality outcomes, have been initiated to better define the long-term benefit of ARBs in the treatment of hypertension and heart failure.

Adrenergic beta-Antagonists↗
PubMed1999

Effects of candesartan cilexetil in patients with severe systemic hypertension. Candesartan Cilexetil Study Investigators.

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) > or =110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP > or =90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24+/-3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p <0.001/p <0.001, respectively. Patients with higher sitting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p <0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP <90 mm Hg or > or =10 mm Hg decrease) and 32% were controlled (diastolic BP <90 mm Hg). Tolerability and safety profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.

Adult↗
PubMed1999

Assessment of once-daily eprosartan, an angiotensin II antagonist, in patients with systemic hypertension. Eprosartan Study Group.

A multicenter, randomized, double-masked, placebo-controlled trial was conducted to assess the efficacy of once-daily eprosartan, a nonbiphenyl, nontetrazole angiotensin II-receptor antagonist, in 243 patients with mild-to-moderate systemic hypertension (sitting diastolic blood pressure [SitDBP], 95-114 mm Hg). After a 3-to 5-week single-masked placebo run-in period to obtain baseline values, patients were randomly allocated to receive 600 mg eprosartan once daily or placebo for 8 weeks. All clinic blood pressure measurements were made 24 hours +/-90 minutes after dosing. Eprosartan produced statistically and clinically significant reductions in SitDBP(-7.5+/-0.8 mm Hg) and sitting systolic blood pressure (SitSBP) (-6.0+/-1.3 mm Hg) compared with placebo (SitDBP -1.9+/-0.7 mm Hg; SitSBP 0.8+/-1.2 mm Hg). The 95% confidence intervals for the difference from placebo were -8.1 to 4.1 for SitDBP and -11.0 to -4.0 for SitSBP (both, P<0.0001). The proportion of patients responding (SitDBP was <90 mm Hg or had decreased by > or =10 mm Hg from baseline at study end point) to eprosartan was significantly higher than the proportion of those responding to placebo (42% vs. 21%, respectively; P = 0.0003). Similar results were obtained in a subgroup analysis comparing patients aged <65 years with those aged > or =65 years. The total number of adverse events was similar in the eprosartan and placebo groups. Eprosartan 600 mg once daily was both well tolerated and effective, providing significant blood pressure reduction 24 hours after dosing in patients with mild-to-moderate systemic hypertension, regardless of age.

Acrylates↗
PubMed1999

Comparison of two strategies for intensifying antihypertensive treatment: low-dose combination (enalapril + felodipine ER) versus increased dose of monotherapy (enalapril). LEVEL (Lexxel vs Enalapril) Study Group.

To compare two popular strategies for intensifying treatment for hypertension, a double-blind, randomized, prospective, parallel-group, and partial crossover study was done. After 2 weeks of placebo run-in (baseline) and 3 weeks of 5 mg enalapril once daily, 217 patients were randomized to 6 weeks of treatment with either a low-dose combination therapy (5 mg enalapril + 5 mg felodipine ER once daily, Lexxel, Astra Merck, Inc.), or a higher dose of monotherapy (10 mg enalapril once daily, Vasotec, Merck & Co., Inc.). The group randomized to the combination had significantly greater reductions in sitting systolic/diastolic blood pressure (BP)--14.2/10.6 mm Hg compared with baseline versus 9.6/7.4 mm Hg (P < .05/.01)--as well as a greater percentage of patients having achieved either diastolic BP < 90 mm Hg or a decline of at least 10 mm Hg (responders), 59% v 41% (P < .01). When patients originally taking 10 mg enalapril were crossed over to the combination therapy for a further 6 weeks, there was a further BP reduction and increase in response rate, with loss of significant differences compared with those treated continuously with the combination for the entire 12 weeks. The greater BP-lowering efficacy of the combination was independent of age, gender, and race. There were no significant differences in tolerability between the regimens. These data support the hypothesis that in patients who do not achieve goal BP reduction with a low dose of an antihypertensive agent, a combination of two drugs with complementary mechanisms of action is more effective than increasing the dose of the first agent.

Aged↗
PubMed1998

A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Tasosartan Investigator's Group.

Tasosartan, a new, long-acting, nonpeptide angiotensin II receptor antagonist was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial at 21 sites in the United States and Canada. After a 2-week, placebo washout qualification period, 278 patients (187 men/91 women) with a mean age of 53.4+/-9.5 years (range, 30 to 70 years) and a baseline sitting diastolic blood pressure (DBP) of 95 to 114 mm Hg were randomly assigned to receive placebo (n = 56), or 10 mg (n = 57), 30 mg (n = 55), 100 mg (n = 55), or 300 mg (n = 55) tasosartan for 4 weeks. The treatment period was followed by a 2-week washout period. Ambulatory blood pressure (BP) monitoring was performed at the end of the placebo washout period and after at least 4 weeks of double-blind treatment. Clinically significant placebo-adjusted differences in baseline sitting systolic blood pressure (SBP)/DBP were observed in the 10 mg (5/3 mm Hg), 30 mg (5/4 mm Hg), 100 mg (10/7 mm Hg) and 300 mg (10/7 mm Hg) dose groups (P < .05). A dose-response relationship (P < .001) was observed within 1 to 2 weeks of treatment initiation and was maintained throughout the double-blind period. Discontinuation of tasosartan therapy was not associated with rebound hypertension. Moreover, significant (P < .05) placebo-adjusted differences in ambulatory SBP/DBP and a significant dose-response relationship (P < .001) were observed with all tasosartan dosages during the 24-h, daytime, and nighttime periods. Placebo-adjusted trough-to-peak ratios ranged from 87% to 100% for ambulatory SBP and 64% to 81% for DBP. In general, no significant differences were observed between the tasosartan treatment groups and the placebo group in the incidence of adverse events. Headache incidence was significantly lower in the 300 mg dose group than the placebo group. In conclusion, tasosartan at dosages of 10, 30, 100, or 300 mg given once daily produced a significant and dose-related reduction in both clinic and ambulatory BP that was maintained over the 24-h period. Tasosartan was generally well tolerated.

Adult↗
PubMed1997

Combined enalapril and felodipine extended release (ER) for systemic hypertension. Enalapril-Felodipine ER Factorial Study Group.

This multicenter, placebo-controlled, double-blind trial of factorial design evaluated the safety and efficacy of combination treatment with the angiotensin-converting enzyme inhibitor, enalapril, and the vascular selective calcium antagonist felodipine extended release (ER) in patients with essential hypertension. After a 4-week, single-blind placebo baseline period, 707 patients with sitting diastolic blood pressures (BPs) in the range of 95 to 115 mm Hg received placebo, enalapril (5 or 20 mg), felodipine ER (2.5, 5, or 10 mg), or their combinations for an 8-week double-blind treatment period. All doses of enalapril and felodipine ER had a statistically significant (p < 0.05) additive effect in reducing both systolic and diastolic BP. The trough to peak ratios for the combinations ranged from 0.63 (enalapril 5 mg-felodipine ER 2.5 mg) to 0.79 (enalapril 20 mg-felodipine ER 10 mg) and were consistent with effective BP control with 1 dose/day. Patients aged > or = 65 years demonstrated a greater reduction in diastolic BP. Combinations of enalapril-felodipine ER were associated with less drug-induced peripheral edema (4.1%) compared to felodipine ER monotherapy (10.8%). There were no serious drug-related adverse effects observed during the study. In this trial, the combination of enalapril and felodipine ER effectively lowered BP and was generally well tolerated with an excellent safety profile when used in the treatment of hypertension.

Aged↗
PubMed1995

A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension.

The efficacy and safety of various doses of losartan potassium, a specific and selective angiotensin II receptor antagonist, were compared with those of placebo and enalapril maleate 20 mg in patients with mild to moderate essential hypertension in a randomized, double-blind, parallel study. We randomly allocated 576 patients at the end of a 4-week placebo baseline period to 8 weeks of once-daily double-blind treatment with losartan potassium 10, 25, 50, 100, or 150 mg, enalapril maleate 20 mg, or placebo. After 8 weeks of treatment, mean reductions from baseline in supine systolic/diastolic pressure 24 hours after dosing (trough) for losartan potassium 10, 25, 50, 100, and 150 mg, enalapril maleate 20 mg, and placebo were 7.6/7.9, 7.8/6.8, 13.0/10.1, 8.9/9.9, 10.5/9.7, 14.7/11.2, and 3.8/5.6 mm Hg, respectively. Compared with mean changes in supine diastolic pressure in the placebo group, losartan potassium 50 to 150 mg and enalapril maleate 20 mg produced clinically important and statistically significant reductions (P < or = .01) in blood pressure. At 24 hours after dosing, the blood pressure changes obtained with losartan potassium 50 mg were essentially identical to those obtained with enalapril maleate 20 mg. While there was a dose-related effect with losartan potassium from 10 to 50 mg at peak (6 hours after dosing), doses of 10 and 25 mg were not consistently different from placebo 24 hours after dosing. To assess the once-daily effect of losartan potassium, trough-to-peak ratios of the mean changes in supine diastolic pressure after 8 weeks of treatment were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

The evolving role of calcium channel blockers in the treatment of angina pectoris: focus on felodipine.

Calcium channel blockers are used extensively in the treatment of the three major anginal syndromes. In the treatment of Prinzmetal's angina, their antivasospastic properties account for their therapeutic effectiveness. Calcium channel blockers are drugs of first choice in this syndrome. In chronic stable angina, calcium channel blockers may be used as monotherapy or in combination with beta-blockers and/or nitrates. In patients with unstable angina, reduction in the incidence of ischemic episodes produced by calcium channel blockers is well documented. Recent data suggest that calcium channel blockers should generally be used in combination with beta-blockers, nitrates and antithrombotic agents. Patients with ischemic heart disease often exhibit reduced ventricular function. All of the first generation calcium channel blockers exacerbate symptoms in patients with established heart failure and may precipitate heart failure, particularly when combined with beta-blockers. Second generation vascular-selective dihydropyridines have been introduced recently. Vascular selectivity determines the drug's degree of negative inotropic effect. Felodipine is one of the most vascular selective of the available dihydropyridines and has no negative inotropic effects at clinically administered doses. In a long term study, felodipine, 20 mg/day, abolished symptoms and chronic ischemic episodes in 81% of treated subjects with Prinzmetal's angina. In patients with stable angina, felodipine has been found to be effective either as monotherapy or in combination with beta-blockers. In patients with known or suspected ventricular dysfunction, vascular-selective dihydropyridines such as felodipine offer advantages over the nonselective calcium channel blockers, particularly in patients receiving beta-blockers.

Adrenergic beta-Antagonists↗
PubMed1994

Predictors of mortality in patients with heart failure.

Identification of accurate predictors of mortality in patients with heart failure is important in making rational treatment decisions as well as in the design of clinical trials. The following four categories of variables have been found to be independent predictors of mortality: 1) functional capacity, 2) hemodynamic measures of cardiac pump performance, 3) spontaneous arrhythmias, and 4) laboratory evidence of neurohormonal activation. Within each category, multiple variables are predictive and are correlated with each other. These variables are operative only over a 1- to 5-year time period. Most patients with clinically manifest heart failure undergo inexorable disease progression and die within 10 years of diagnosis, despite important recent advances in the pharmacologic treatment of this syndrome.

Heart Failure↗
PubMed1993

Treatment of hypertension with felodipine in patients with concomitant diseases.

Coexisting medical conditions often complicate the selection of antihypertensive drugs. Felodipine, a new vascular-selective calcium antagonist with demonstrated antihypertensive efficacy, has not been found to alter lipid profiles in hypertensive patients. Studies in additional patient populations have yielded insights into the effects of the drug on other diseases that may coexist with hypertension. In individuals with stable angina pectoris or congestive heart failure, acute administration of felodipine reduces systemic vascular resistance and increases cardiac output and total coronary blood flow; myocardial contractility is not depressed at doses that produce a clinically significant reduction in vascular resistance. In patients with coronary stenoses, the drug increases vessel diameter in the vicinity of obstructive lesions. Single-dose and long-term studies in patients with exertional angina have found that felodipine reduces anginal frequency and improves exercise tolerance. In patients with congestive heart failure, chronic dosing with felodipine produces a persistent reduction in vascular resistance and an increase in cardiac output, both at rest and during exercise. Symptomatic improvement and increased exercise tolerance have been noted in some studies. In patients with Raynaud's phenomenon, felodipine has been associated with a dose-dependent improvement in symptomatology. Among individuals with exercise-induced bronchospasm, the drug has no effect on resting bronchial tone and may exert some positive effects during exercise. In hypertensive patients with Type II diabetes, felodipine has not been found to raise glucose levels significantly. The data obtained thus far suggest that felodipine is safe for use in hypertensive patients with a variety of concomitant diseases.

Disease↗
PubMed1993

Hypertension in the elderly: age- and disease-related complications and therapeutic implications.

Effective treatment of hypertension in the elderly requires an understanding of both the progressive course of the disease and the impact of aging on the cardiovascular system, including physiological, genetic, lifestyle, and environmental factors. Review of the literature that has attempted to define the impact of an "aging process" on cardiovascular structure and function reveals a diversity of findings and interpretations. However, in general, normotensive elderly subjects exhibit the heart and vascular characteristics of "muted" hypertension, including many features of younger hypertensive patients: cardiac hypertrophy, diminution in resting left ventricular early diastolic filling rate, increased arterial stiffness and aortic impedance, diminution in the baroreceptor reflex, a diminished response to catecholamines and diminished renal blood flow, and an increase in peripheral vascular resistance (PVR). Treatment of elderly hypertensives is more challenging because of the greater likelihood of the presence of concomitant diseases, most importantly, coronary and peripheral atherosclerosis, renal dysfunction, and diabetes mellitus. Isolated systolic hypertension (ISH), the most common form of hypertension in the elderly, has also been clearly shown to be an important predictor of cardiovascular morbidity and mortality, including coronary artery disease, congestive heart failure, and stroke. Treatment of ISH has been shown to lower systolic pressure safely and effectively in the elderly. By reducing PVR, and possibly the arterial stiffness, and thus the early reflected pulse waves, vasodilators, including calcium antagonists, may lower these three components of arterial impedance, and hence lower the arterial load on the heart. The cardiac hypertrophy and reduced left ventricular filling rate associated with hypertension in older individuals can also be ameliorated, to some extent, by calcium channel blockers.

Aged↗
PubMed1993

Double-blind evaluation of the dose-response relationship of amlodipine in essential hypertension.

To determine the dose-response efficacy of once-daily administration of placebo or a new long-acting calcium channel blocker amlodipine in patients with mild to moderate hypertension, a randomized, multicenter, placebo-controlled, double-blind trial was conducted. The study included 210 patients with diastolic hypertension (blood pressure 95 to 114 mm Hg) without major hematologic, renal, hepatic, cardiac, or endocrine abnormalities. After a 4-week single-blind placebo run-in period, patients were given placebo or amlodipine (1.25, 2.5, 5, or 10 mg) daily for 4 weeks. To assess the antihypertensive effect of amlodipine over a 24-hour period, blood pressure and pulse rate at weeks 0 and 4 were recorded for 12 hours after the dose and then again at 24 hours. At the end of the study patients treated with all doses of amlodipine greater than 1.25 mg daily had significantly reduced diastolic blood pressure in both supine and standing than 1.25 mg daily had significantly reduced diastolic blood pressure in both supine and standing positions. Amlodipine, 1.25 mg daily, was also associated with a decrease in standing diastolic blood pressure. Response to treatment was greater in all amlodipine-treated patients than in those receiving placebo. Pulse rate in both the supine and standing positions was not significantly affected by amlodipine. At doses of 2.5, 5.0, or 10.0 mg daily, amlodipine maintained blood pressure below values obtained with placebo throughout the 24-hour period. Treatment with amlodipine was well tolerated and the incidence of side effects was low.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Comparison of sustained-release formulations of nicardipine and verapamil for mild to moderate systemic hypertension.

In this double-blind, parallel, multicenter study, sustained-release (SR) preparations of 2 calcium antagonists, nicardipine and verapamil, were compared for the treatment of mild to moderate systemic hypertension. Two hundred eighteen patients with supine diastolic blood pressures (BP) 95 to 114 mm Hg were randomly assigned to receive nicardipine-SR 45 mg twice daily (n = 73), nicardipine-SR 60 mg twice daily (n = 73) or verapamil-SR 240 mg once daily in the morning (n = 72). All 3 regimens significantly reduced supine and sitting systolic and diastolic BPs compared with baseline values (p < 0.005). The efficacy of drugs became apparent after 2 weeks of therapy, and was sustained throughout the 12-week study. Reductions in sitting diastolic BP and supine and sitting systolic BPs were statistically greater with nicardipine-SR 60 mg twice daily compared with verapamil, and nicardipine-SR 45 mg twice daily was equivalent to verapamil. Asthenia and constipation occurred more frequently in patients treated with verapamil (9.7 and 11.1%, respectively, compared with 6.8 and 4.1% in either nicardipine group). Adverse events reported more frequently with nicardipine were headache (17.8% with nicardipine-SR 60 mg and 15.1% with nicardipine-SR 45 mg vs 13.9% with verapamil) and edema (15.1% in the nicardipine-SR 60 mg group, 8.2% with nicardipine-SR 45 mg vs 4.2% with verapamil). Verapamil, but not nicardipine, produced significant reductions in heart rate. SR preparations of calcium antagonists offer options for effective monotherapy of systemic hypertension. Side-effect profiles differ and may affect choice of therapy.

Delayed-Action Preparations↗