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Biomedical subjects

C V Leier

Publications and source records attributed to C V Leier.

At least 19 recordsLinked to original sources
PubMed1992

Current status of non-digitalis positive inotropic drugs.

Considerable effort and resources have been directed at the development and study of positive inotropic drugs over the past 10-15 years. Much has been learned about the physiology and pharmacology of myocardial contraction, the application of agents to augment contractility, and, importantly, the general and specific limitations of positive inotropic therapy. Studies on acute inotropic intervention have now shown that a drug's ability to augment overall cardiac performance is heavily dependent on its effects on vasculature, vascular control, and ventricular-vascular coupling. The clinical research on new agents has served to remind us how difficult it is to formulate the "ideal" positive inotropic or cardiovascular support drug for the critical care setting. The vast effort to develop a chronically and orally administrable drug to replace or even supplement digitalis has generally been disappointing. The dopaminergic agents (e.g., ibopamine, levodopa) act primarily via vasodilation and their effectiveness and role in managing heart failure remain unresolved. The initial excitement about the phosphodiesterase III inhibitors (e.g., amrinone, milrinone, enoximone) has been tempered by the results of large well-designed trials indicating variable effectiveness and a prominent adverse effect profile. During long-term oral administration none of these agents has been shown to improve clinical status or exercise capacity beyond that achieved by digoxin, when administered either separately or in combination with digoxin. The Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial, showing that repeated oral administration of milrinone can increase mortality in heart failure, is having a devastating effect on the further development of this class of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiotonic Agents↗
PubMed1992

Regional blood flow in human congestive heart failure.

Despite the total-body consequences of congestive heart failure, little information is available on the distribution of cardiac output and regional-organ hemodynamics in this condition in humans. Technical and methodologic limitations probably account for the paucity of data in this area. Available data indicate that blood flow to the regions or organs studied, namely, the kidneys, hepatosplanchnic region, and upper limbs, decreases in proportion to the reduction in cardiac output. However, renal blood flow appears to be protected in human heart failure by a form of "autoregulation" during marked depression of cardiac output (less than 2.0 L/min/m2). Results of preliminary studies suggest that the regulation of regional-organ hemodynamics is disturbed in this human condition. Cardioactive drugs profoundly affect regional-organ hemodynamics independent of changes in central hemodynamics and cardiac output. The determination of regional blood flow responses in human heart failure will become more important as we expand our knowledge base of the pathophysiology of heart failure, learn more about local vascular control mechanisms, and pursue the potential therapeutic objective of selectively augmenting regional-organ hemodynamics and function.

Adult↗
PubMed1992

Remodeling and reparation of the cardiovascular system.

Growth or altered metabolism of nonmyocyte cells (cardiac fibroblasts, vascular smooth muscle and endothelial cells) alters myocardial and vascular structure (remodeling) and function. However, the precise roles of circulating and locally generated factors such as angiotensin II, aldosterone and endothelin that regulate growth and metabolism of nonmyocyte cells have yet to be fully elucidated. Trials of pharmacologic therapy aimed at preventing structural remodeling and repairing altered myocardial structure to or toward normal in the setting of hypertension, heart failure and diabetes are reviewed. It is proposed that these are therapeutic goals that may reduce cardiovascular morbidity and mortality. Although this hypothesis remains unproved the primary goal of therapy should be to preserve or restore tissue structure and function.

Animals↗
PubMed1992

Clinical pharmacology of nicorandil in patients with congestive heart failure.

Nicorandil is a nicotinamide derivative with a potential role in human therapeutics because of its potent vasodilating properties. The pharmacokinetics of oral nicorandil administration and the relationships between plasma nicorandil concentration and hemodynamic responses were examined in 25 patients with moderate to severe congestive heart failure. The dose range from 10 to 60 mg was studied. Elimination half-life for this dose range was substantially longer than that previously reported in normal volunteers. Total area under the curve increased in a curvilinear fashion with progressive dose increments, indicating a disproportionate increase in systemically available drug at higher doses. Hemodynamic responses generally correlated well with plasma nicorandil concentration, with rapid loss of cardiovascular activity corresponding to the efficient clearance of nicorandil.

Administration, Oral↗
PubMed1992

Placebo treatment in congestive heart failure.

In order to evaluate the effect of placebo treatment in congestive heart failure, we retrospectively studied 24 patients with moderately severe congestive heart failure who participated in heart failure treatment trials performed over the past 10 years in the Ohio State University Heart Failure Research Laboratory. Placebo-treated patients from 4 placebo-controlled trials comprised the placebo treatment group (n = 15), while one natural course-controlled trial provided patients for the non-placebo control group (n = 9). Changes in symptoms, left ventricular function and exercise duration were assessed following an 8-week course of therapy. Chronic placebo therapy resulted in an 81-second improvement in exercise duration which was statistically significant when compared to pretreatment baseline and to the duration achieved by the nonplacebo control group. Clinically, functional class improved significantly by 27% above baseline only for the placebo treatment group. Indices of left ventricular function did not change for either group. The salient feature of this study is that the placebo treatment effect, while believed to exist in congestive heart failure, has never been demonstrated in a manner which controlled for the natural course and variability of the disease process. The operative components of the placebo effect remain unknown, and further investigation will be necessary to elucidate the underlying mechanisms involved. However, the importance of this phenomenon lies not only with the response to and effects of placebo therapy but also in the role that the placebo effect plays in what is generally presumed to be the predominant responses, effects and benefits of active drug therapy.

Adult↗
PubMed1991

Acute positive inotropic intervention: the catecholamines.

The catecholamines remain a major therapeutic group in intensive cardiac care; this group of compounds evokes a positive inotropic response and vascular effects ranging from vasoconstriction to little net effect to vasodilatation. Hemodynamics and clinical guidelines now allow a proper selection of the optimal catecholamine. Additional mechanisms of action and a better understanding of the clinical application of this important drug group are continuing to unfold.

Cardiotonic Agents↗
PubMed1991

Dobutamine increases cardiac output of the total artificial heart. Implications for vascular contribution of inotropic agents to augmented ventricular function.

BACKGROUND: The synthetic catecholamine dobutamine increases stroke volume in normal subjects and in patients with congestive heart failure. In addition to its direct influence on myocardial contractility, dobutamine may significantly modulate vascular tone because of its alpha- and beta-adrenergic agonist activity. METHODS AND RESULTS: To test the hypothesis that such vasoactive properties significantly contribute to the improved ventricular performance noted with this agent, hemodynamic parameters were measured during stepped ascension infusion of dobutamine in a model that is insensitive to positive inotropic stimulation. Administration of dobutamine in nine calves that underwent replacement of the native right and left ventricles with pneumatically driven total artificial hearts resulted in a significant (p = 0.0001) increase in cardiac output from 7.0 +/- 1.8 to 8.2 +/- 1.8 l/min and a significant (p = 0.0001) decrease in total peripheral vascular resistance from 1,224 +/- 559 to 745 +/- 317 dyne.sec/cm5. A less marked influence was noted on the pulmonary vasculature, with pulmonary vascular resistance exhibiting a significant (p less than 0.05) decrease from its baseline value only at the peak infusion. Consistent with an increase in venous return, both left and right atrial pressures increased significantly (p less than 0.005) with dobutamine administration. CONCLUSIONS: These data demonstrate that the vasoactive properties of dobutamine significantly contribute to improved ventricular performance independent of direct myocardial stimulation. This effect appears to result in part from a direct modulation of myocardial stimulation. This effect appears to result in part from a direct modulation of arterial and venous tones rather than from a reflex response to primary changes in contractility.

Animals↗
PubMed1991

Depressed aerobic enzyme activity of skeletal muscle in severe chronic heart failure.

A reduction in exercise capacity is a common feature of congestive heart failure. We hypothesized that depressed aerobic enzyme activity of skeletal muscle may contribute to this exercise intolerance. Biopsy samples of vastus lateralis muscle were obtained from seven patients with severe chronic heart failure and analyzed for aerobic enzyme activity. Compared with normal laboratory controls, the patients with heart failure had a moderate reduction (greater than 60%) in skeletal muscle citrate synthase and a marked reduction (greater than 90%) in succinate dehydrogenase and cytochrome oxidase (all p less than 0.001). Depression of aerobic enzyme activity of skeletal muscle is associated with severe chronic heart failure and is likely one of the contributory factors for impaired exercise capacity seen in the advanced stages of this condition.

Aerobiosis↗
PubMed1990

Serum and tissue magnesium concentrations in patients with heart failure and serious ventricular arrhythmias.

OBJECTIVE: To compare magnesium concentrations in serum and tissue from patients with heart failure. Two groups of patients were compared, those with or without serious ventricular arrhythmias. DESIGN: Consecutive enrollment. Blinded laboratory analyses. SETTING: Referral inpatient service of the cardiology division of a university hospital. PATIENTS: Twenty-three patients with idiopathic dilated cardiomyopathy and mild to moderately severe congestive heart failure (New York Heart Association functional class II to IV) were divided into two groups: 9 patients with sustained ventricular tachycardias and 14 patients without serious ventricular arrhythmias (control). INTERVENTIONS: Medications for heart failure were withdrawn 12 hours or more before study. Antiarrhythmic therapy was continued throughout the study. MEASUREMENTS AND MAIN RESULTS: The patients had skeletal muscle biopsies, myocardial biopsies, and blood sampling for the analysis of magnesium concentrations. No statistically significant differences in the mean magnesium concentrations in serum, circulating mononuclear cells, skeletal muscle, and myocardium were found when the 9 patients with ventricular arrhythmias were compared with the 14 control patients without serious ventricular arrhythmias. CONCLUSIONS: In a general, ambulatory sample of patients with heart failure, magnesium depletion in serum and tissue does not appear to occur more commonly in patients with serious ventricular arrhythmias than in patients without serious ventricular arrhythmias.

Adult↗
PubMed1990

Hemodynamic effects of oral nicorandil in congestive heart failure.

Twenty-five patients with congestive heart failure (CHF) underwent a double-blind randomized study of the acute hemodynamic effects of orally administered nicorandil, a newly developed vasodilator drug. A dose range of 10 to 60 mg was studied. Nicorandil, at a dose of 60 mg, caused statistically significant decreases in systemic systolic and diastolic blood pressure, right atrial pressure, pulmonary capillary wedge pressure, systemic and pulmonary vascular resistance and systolic and diastolic pulmonary arterial pressure. A brief increase in cardiac index attributable to an increase in stroke volume without a change in heart rate was also observed. A dose of 40 mg produced similar results in cardiac index and systemic and pulmonary vascular resistance, but changes in other hemodynamic parameters were much smaller in magnitude and usually not of statistical significance. No significant hemodynamic response was seen to doses of 10 and 20 mg of nicorandil. Duration of action was short with nearly all hemodynamic parameters returning close to baseline within 3 hours. This rapid decrease in activity occurred in concert with a rapid plasma clearance of nicorandil as determined by serial measurements of plasma drug concentration. This study suggests that first-dose orally administered nicorandil elicits favorable, but brief, hemodynamic effects in CHF at doses greater than or equal to 40 mg.

Administration, Oral↗
PubMed1990

Rest and exercise cardiovascular effects of terazosin in congestive heart failure.

This study investigated the acute effects of the alpha 1 antagonist terazosin on myocardial circulatory responses at rest and during exercise. Ten patients with congestive heart failure (class III and IV) underwent hemodynamic evaluation before and after a 5-mg oral dose of terazosin. At rest and during exercise, terazosin significantly decreased pulmonary capillary wedge pressure, systemic vascular resistance and mean arterial pressure while cardiac index increased. Stroke volume index increased (p less than 0.01) during exercise while left ventricular stroke work index remained unchanged in both experimental conditions. Terazosin administration significantly decreased both rest and exercise myocardial oxygen consumption while exercise coronary sinus oxygen content increased and arterial-coronary sinus oxygen difference diminished (p less than 0.05). Parallel with these changes, alpha blockade decreased the ratio of coronary blood flow to total cardiac output. Coronary vascular resistance remained unaltered with alpha blockade both at rest and during exercise. Coronary blood flow tended to diminish with decreased myocardial oxygen demand. Alpha 1 blockade induces systemic vasodilation and improves myocardial circulatory parameters without inducing coronary dilation or altering metabolic autoregulation.

Adrenergic alpha-Antagonists↗
PubMed1990

Chronic vasodilator therapy with flosequinan in congestive heart failure.

This study was conducted to determine the long-term effect of flosequinan, a new orally administered arterial and venous dilator, on the clinical course of patients with moderate to severe congestive heart failure. Seventeen patients on chronic digitalis and diuretic therapy were randomized to receive either flosequinan (n = 9) or placebo (n = 8) in a double-blind fashion. Changes in symptomatology, exercise performance, and left ventricular function were assessed serially during the two-month treatment period. During the course of therapy, a modest improvement in the symptom scores and functional classification of the flosequinan-treated patients was observed. Flosequinan evoked a significant increase in maximal exercise capacity. While long-term flosequinan administration also effected a progressive increase in resting heart rate, it did not consistently improve indices of left ventricular systolic function. The addition of chronic vasodilator therapy with flosequinan to standard digitalis-diuretic regimens is capable of inducing clinical improvement in patients with moderate to severe chronic heart failure. Trials involving larger patient populations will be necessary to confirm the results of this preliminary study and to determine the extent of clinical improvement, subpopulations benefited, role in heart failure therapeutics, and so forth.

Adult↗
PubMed1990

Influence of positive inotropic therapy on pulsatile hydraulic load and ventricular-vascular coupling in congestive heart failure.

The aortic input impedance spectrum provides a description of the total hydraulic load imposed on the left ventricle and may be used to assess the coupling of the ventricle to the vasculature. The adaptation of the vasculature to positive inotropic intervention was examined in 10 patients with idiopathic dilated cardiomyopathy to test the hypothesis that increased myocardial contractility is matched by complementary changes in aortic impedance that optimize ventricular-vascular coupling and maximize power transfer to the circulation. High fidelity intravascular recordings of aortic pressure and flow were obtained at baseline study and during infusion of dobutamine to derive the aortic input impedance spectrum. In eight patients in whom increased staged infusion of dobutamine resulted in a significant increase in stroke volume (22.3 +/- 14.5 ml/beat increase over baseline), the significant (p less than 0.05) increase in the maximum of the first derivative left ventricular pressure pulse (dP/dt) was accompanied by significant decreases in characteristic impedance of the aorta (138 +/- 88 to 92 +/- 44 dyne.s.cm-5) wave reflection index (238 +/- 144 to 109 +/- 59 dyne.s.cm-5), and low frequency moduli of impedance. Effective positive inotropic therapy with dobutamine in the setting of congestive heart failure is accompanied by complementary changes in the aortic impedance spectrum, which represent a matching of impedance to the increased contractile state of the ventricle and facilitation of ventricular-vascular coupling.

Adult↗
PubMed1990

The pharmacokinetics of midazolam in patients with congestive heart failure.

The disposition of midazolam was investigated in six patients with congestive heart failure (CHF) and six age- and weight-matched healthy subjects by administering two single doses of the drug (3.75 mg i.v. and 7.5 mg p.o.) separated by 1 week. Serial blood samples were collected for 24 h after each dose and plasma was assayed for midazolam by GC-MS. In the CHF patients, the elimination half-life was prolonged (4 to 4.5 vs less than 3 h), the systemic clearance was lowered (376 vs 551 ml min-1) and the peak plasma drug concentration after the p.o. dose was higher (76 vs 42 ng ml-1). The systemic availability (45 vs 41%), the steady state volume of distribution (111 vs 108 l) and the time of peak plasma drug concentration after the p.o. dose (0.9 vs 0.9 h) were unchanged. The predominant effect of CHF was on the clearance of midazolam which was decreased by 30%. The drug was well tolerated and did not cause any adverse effects.

Adult↗