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Biomedical subjects

W H Frishman

Publications and source records attributed to W H Frishman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Antianginal and anti-ischemic effects of mibefradil in the treatment of patients with chronic stable angina pectoris.

Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either beta blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of mibefradil. The 25-mg dose of mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic beta-blocker or long-acting nitrate therapy. Taken together, these studies indicate that mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.

Aged↗
PubMed1997

Use of calcium antagonists in patients with ischemic heart disease and systemic hypertension.

Ischemic heart disease (IHD) and systemic hypertension commonly coexist in a large number of patients, and the presence of hypertension is a risk factor for worsening IHD. A monotherapy that would effectively treat both is thus an attractive idea, and calcium antagonists have been evaluated in this role. Calcium antagonists exert therapeutic effects through a combination of actions, including systemic and peripheral vasodilation, negative inotropy, and reduced nodal conduction. In randomized, double-blind clinical trials, verapamil compares favorably with propranolol in the alleviation of angina and hypertension. Both diltiazem and nifedipine, as well as long-acting diltiazem, are also effective in treating the combined condition. In addition, each of these drugs enhances exercise tolerance and favors compliance with calcium antagonist therapy. Recent questions regarding the safety of this class of drug have tempered the enthusiasm for their use as first-line therapy in cardiovascular disease. In particular, short-acting dihydropyridine derivatives, including nifedipine and isradipine, may increase cardiovascular morbidity and mortality because of reflex sympathetic stimulation. The results of appropriately controlled, prospective clinical trials will provide more definitive conclusions. For now, we must be cautious in the use of calcium antagonist monotherapy for combined IHD and hypertension.

Calcium Channel Blockers↗
PubMed1997

Matrix metalloproteinases and coronary artery disease: a novel therapeutic target.

Matrix metalloproteinases (MMP) are a family of enzymes that selectively digest individual components of the extracellular matrix. Their function has been studied in both normal physiologic processes and pathologic states. In the blood vessel, MMPs play an important role in maintaining the vessel's integrity by breaking down extracellular matrix while new matrix is being synthesized. This is necessary to avoid weakening from continuous mechanical stresses. However, in certain environments, these MMPs may contribute to cardiovascular pathologic processes. The purpose of this review is to first discuss the role of MMPs in coronary vascular disease. Evidence suggests that MMPs contribute to the development of de novo atherosclerotic plaques and postangioplasty restenotic plaques by allowing smooth muscle cells to migrate from the vascular media to the intima. Evidence also suggests that MMPs contribute to the rupture of these plaques by degrading the fibrous cap that surrounds them. With this increased molecular information that concerns the pathogenesis of coronary vascular disease, new molecular therapies aimed at altering these processes are being investigated. The rationale, mode of delivery, and prospects for success of these therapies will also be discussed here.

Angioplasty, Balloon↗
PubMed1997

The pharmacologic approach to the treatment of obesity.

Obesity is a major risk factor for morbidity and mortality, and a series of pharmacologic approaches are available for helping to manage the problem. Obesity is caused by an imbalance between caloric intake and energy expenditure, which is influenced by both environmental and genetic factors. Pharmacologic treatments include anorexigenic agents, which fall into two broad categories: those that act via brain catecholamine pathways and those that act via serotonin pathways. The most recent oral agents approved are dexfenfluramine, which is currently being marketed, and sibutramine. Both agents inhibit the control reuptake of serotonin but in addition may have effects on thermogenesis. Under investigation are agents that increase energy expenditure: the beta 3-adrenergic receptor agonists and drugs that prevent the intestinal absorption of free fatty acids and cholesterol. In development are innovative approaches to influence leptin and its receptors, various obesity genes, and biologic substances thought to influence satiety (neuropeptide Y, enterostatin, cholecystokinin, bombesin, and amylin). Obesity has now become a major target for drug development not only for affecting obesity per se but also for managing and preventing comorbid conditions such as diabetes and cardiovascular disease.

Adrenergic beta-Agonists↗
PubMed1996

Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] Study).

This report focuses on the subset of 235 patients from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study receiving randomly assigned medical therapy to treat angina and suppress ischemia detected on ambulatory electrocardiography: 121 patients received the sequence of atenolol and nifedipine, and 114 diltiazem and isosorbide dinitrate. After 12 weeks of therapy, the primary end point (absence of ambulatory electrocardiographic (ECG) ischemia and no clinical events) was reached in 47% of atenolol/nifedipine- versus 31% of diltiazem/isosorbide dinitrate-treated patients (adjusted p = 0.03). A trend to increased exercise time to ST depression was seen in the atenolol and nifedipine versus diltiazem and isosorbide dinitrate regimens (median treadmill duration 5.8 vs 4.8 minutes; p = 0.04). However, when adjusted for baseline imbalances in ambulatory ECG ischemia, the 2 medical combinations were similar in suppression of ambulatory ECG ischemia. In both medication regimens, an association between mean heart rate and ischemia on ambulatory electrocardiography after 12 weeks of treatment was observed so that patients on either regimen with a mean heart rate > 80 beats/min had ischemia detectable almost twice as often as those with a mean heart rate < 70 beats/min (p < 0.001).

Angina Pectoris↗
PubMed1996

Imidazoline receptor agonist drugs: a new approach to the treatment of systemic hypertension.

The imidazoline receptors have recently been discovered to be involved in central nervous system control of blood pressure (I-1 receptor) and in neuroprotection for cerebral ischemia (I-2 receptor). A new class of central-acting antihypertensive agents has been developed, the imidazoline receptor agonists (rilmenidine and moxonidine), which control blood pressure effectively without the adverse effects of sedation and mental depression that are usually associated with central-acting antihypertensives. This new generation of central-acting antihypertensive agents are highly selective for the imidazoline receptor, while having a low affinity for alpha 2-adrenergic receptors.

Animals↗
PubMed1996

Nicorandil: a potassium channel opening drug for treatment of ischemic heart disease.

Nicorandil is the first oral potassium channel activating drug to be used for the treatment of symptomatic coronary artery disease. It appears to relax vascular smooth muscle through membrane hyperpolarization via increased transmembrane potassium conductance and, like nitrates, through an increase in intracellular cyclic GMP. In addition, nicorandil, in a nitrate-like manner, dilates normal and stenotic coronary arteries and reduces both ventricular preload and afterload. In contrast to nitrates, however, nicorandil does not appear to cause tolerance with long-term administration. In placebo and comparison clinical trials, nicorandil has demonstrated some efficacy and safety in patients with both stable and vasospastic angina pectoris, and it was found to be a myocardial protective agent in animal studies. The antianginal activity of nicorandil, however, is relatively short lived after dosing, which will necessitate the development of extended-release formulations of the drug.

Clinical Trials as Topic↗
PubMed1996

Renin inhibition: a novel therapy for cardiovascular disease.

The renin-angiotensin system (RAS) is a major contributor in the regulation of blood pressure, and pharmacologic manipulation of this system has resulted in a beneficial class of therapeutic agents, which include angiotensin-converting enzyme (ACE) inhibitors. However, ACE inhibitors are not specific for RAS, and in addition, they can affect bradykinin and prostaglandin, which can also cause changes in vascular tone. Under development are renin inhibitors that are specific for angiotensinogen and act at the initial, rate-determining step of the RAS cascade. The various pharmacologic approaches to renin inhibition include specific renin antibodies, synthetic derivatives of the prosegment of renin precursor, pepstatin analogs, and angiotensinogen analogs. The last approach is the most promising for patient therapy. Multiple studies have shown the effectiveness of the renin inhibitors in both primates and human beings. Further research is now directed toward the development of an agent with good oral bioavailability for patient treatment and as a biologic probe for helping to understand the role of the RAS in control of blood pressure and blood volume.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Selective and nonselective dopamine receptor agonists: an innovative approach to cardiovascular disease treatment.

Dopamine and a new group of selective and nonselective peripheral dopaminergic receptor effectors are being evaluated for the treatment of various cardiovascular disorders, including shock, CHF, and systemic hypertension. Dopamine, in relatively low intravenous doses, will stimulate both peripheral DA1 receptors, which mediate arterial vasodilation of different vascular beds, and the DA2 receptors, which mediate the inhibition of norepinephrine release. Ibopamine is a new oral, nonspecific peripheral dopaminergic agonist with an active metabolite (epinine) that is being evaluated in patients with CHF. Fenoldopam is a selective peripheral DA1 agonist now being developed as a parenteral treatment for hypertensive emergencies. Dopexamine is a parenteral agent that selectively activates both DA1 and beta 2 adrenergic receptors and is being evaluated in patients with CHF and in individuals with postoperative left ventricular dysfunction. A group of selective DA2 receptor agonists is being evaluated as long-term treatment for systemic hypertension.

Cardiovascular Diseases↗
PubMed1996

Twenty-four-hour ambulatory electrocardiography in elderly subjects: prevalence of various arrhythmias and prognostic implications (report from the Bronx Longitudinal Aging Study).

Functional, ambulatory, community-dwelling subjects (n = 423, aged 75 to 85 years) underwent baseline 24-hour ambulatory electrocardiography (ECG) examinations as part of the Bronx Aging Study, a 10-year prospective cohort study designed to identify risk factors and disease markers for cardiovascular, cerebrovascular, and dementia illnesses in old people. Premature ventricular contractions were the most commonly observed arrhythmia noted (93% of subjects), with a low prevalence of nonsustained ventricular tachycardia (5%), paroxysmal atrial tachycardia (13%), atrial fibrillation (4%), and atrioventricular blocks (4%). A 24-hour sinus rate of < 60 beats/min was noted in 13% of subjects, and 11% of subjects were noted to have transient episodes of severe bradycardia (< 40 beats/min). In a multivariate analysis, nonsustained ventricular tachycardia was an independent predictor of death (p = 0.015; relative risk [RR] 2.8; 95% confidence interval [CI] 1.4 to 5.8) and myocardial infarction (p = 0.031; RR 3.2; CI 1.2 to 9.4). Transient atrioventricular block was an independent predictor of stroke (p - 0.0006; RR 9.7; CI 3.3 to 28.9), as was sinus bradycardia over a 24-hour period (p = 0.033; RR 2.7; CI 1.2 to 6.4). Ventricular tachycardia approached significance as an independent predictor of multiinfarct dementia (p = 0.052; RR 6.3; CI 1.4 to 28.7). Episodes of paroxysmal atrial fibrillation, a trial tachycardia, and severe bradycardia were not associated with adverse outcomes. Some arrhythmias found on the ambulatory ECG in very old subjects can predict an increased risk for subsequent death, myocardial infarction, stroke, and multiinfarct dementia.

Aged↗
PubMed1996

Recombinant growth hormone: a new cardiovascular drug therapy.

GH has an important role in normal cardiovascular physiologic functioning, working indirectly through effects on IGF-1. An excess or deficiency of GH causes an increased rate of cardiovascular disease, including cardiomyopathy. A relative GH deficiency in older subjects may also increase cardiovascular morbidity and mortality risk. In replacement doses, GH can enhance myocardial contractility; can decrease peripheral vascular resistance; and can reduce total cholesterol and LDL-cholesterol values and fibrinogen and PAI levels. These effects of GH, coupled with the ability to improve skeletal muscle function and reduce adiposity, make it an attractive treatment for patients with CHF and a potential maintenance drug for elderly people. Clinical trials, including studies with GHRH that may reduce the adverse effects of GH therapy, such as hyperglycemia and hypertension, are now in progress.

Animals↗
PubMed1996

Cardiac involvement in HIV infection.

Cardiac involvement in HIV infection was previously believed to be an unusual manifestation of the disease, but is now being described with increasing frequency. It may be a well-characterized cardiac disease occurring coincidentally in an AIDS patient, a complication of AIDS or its treatment, or possibly a direct result of HIV infection of the heart. In this article, the authors describe the emerging patterns of heart and vascular diseases in HIV-infected patients, pathogenic mechanisms, and implications for treatment.

AIDS-Related Opportunistic Infections↗
PubMed1996

Left ventricular hypertrophy on electrocardiogram: prognostic implications from a 10-year cohort study of older subjects: a report from the Bronx Longitudinal Aging Study.

OBJECTIVE: The objective of this study was to report on the prevalence, incidence and prognosis of left ventricular hypertrophy (LVH) on the electrocardiogram (ECG) in a cohort of ambulatory older men and women. DESIGN: A prospective, longitudinal study of 10 years duration with ECGs obtained at baseline and on an annual basis. SETTING AND PATIENTS: A community-based cohort study consisting of 459 subjects (aged 75-85, mean age 79 years). MEASUREMENTS: Baseline and follow up ECGs were interpreted using the Minnesota Code. Prevalence and incidence of LVH and ECG were determined as well as regression of ECG LVH. Clinical event rates measured were incidence of total mortality, myocardial infarction (MI, fatal and non-fatal), cardiovascular mortality, cardiovascular disease (fatal and non-fatal), stroke (fatal and non-fatal), all-cause dementia, and multi-infarct dementia. Differences in event rates between groups (those subjects with and without LVH) were compared as tests between proportions. A Cox Proportional Hazards Regression Analysis was performed to compare the relative independent predictive values of different competing factors, including age, gender, serum cholesterol, digitalis use, body mass, index, Blessed Dementia Scale, cigarette smoking, LVH at baseline, LVH ar baseline (persisting), new LVH, new LVH (persisting), new LVH (regressed), previous MI by history of ECG, hypertension by history, and cardiomegaly by X-ray (cardiothoracic ratio > or = 50%). RESULTS: At baseline, 9.2% of subjects (n = 42) had LVH on ECG and a mortality rate of 11.7/100 persons years versus 4.9/100 persons years for subjects without baseline LVH (P < .0001), and MI rate of 7.5/100 persons years with LVH versus 2.6/100 persons years without LVH (P < .0001), and a cardiovascular mortality rate of 7.2/100 persons years without LVH versus 2.7/100 person years without LVH. Subjects who developed new LVH on ECG (n = 39) had a mortality rate of 14.4/100 person-years compared with 4.4/100 person-years for those without LVH (P < .0001), a cardiovascular mortality rate of 11.1/100 person years versus 2.0/100 person years without LVH (P < .0001), and an MI rate of 6.1/100 person years versus 2.0/100 person years without LVH (P < .01). Subjects in whom the ECG LVH pattern disappeared over time had fewer cardiovascular mortal and morbid events than those with persistent LVH. According to the regression analyses, persistent LVH from baseline was an independent predictor of MI, overall cardiovascular disease, and total mortality. Newly developing LVH with subsequent regression was an independent predictor of overall cardiovascular disease and death. CONCLUSIONS: An increased prevalence and incidence of LVH on ECG, irrespective cause, is associated with a poor prognosis in very old men and women. Regression of ECG LVH in older people, irrespective of cause, may confer improvement in risk for cardiovascular disease.

Aged↗
PubMed1995

Insulin resistance in systemic hypertension: pharmacotherapeutic implications.

Systemic hypertension, a vascular disease with multiple origins, now is being linked to subtle abnormalities in glucose metabolism, which include insulin resistance and hyperinsulinemia. These conditions often occur together in patients with obesity, noninsulin-dependent diabetes, or both. Hyperinsulinemia and insulin resistance may cause systemic hypertension through multiple mechanisms. Insulin has a salt-retaining effect on the kidney. Also, insulin can augment catecholamine release, increase vascular sensitivity to vasoconstrictor substances, and decrease vascular sensitivity to vasodilator substances. In addition, insulin can increase production of tissue growth factors and help retain sodium and calcium in cells. Insulin resistance in patients can be treated with regular aerobic exercise, weight reduction, and a high-fiber diet. Pharmacologic approaches include hypoglycemic drugs, weight-reducing agents, and certain antihypertensive drugs that may have a favorable impact on both blood pressure and insulin resistance.

Antihypertensive Agents↗