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Biomedical subjects

U Elkayam

Publications and source records attributed to U Elkayam.

At least 55 records · Page 3Linked to original sources
PubMed1992

Nitrate resistance and tolerance: potential limitations in the treatment of congestive heart failure.

Organic nitrates are commonly used in the treatment of chronic congestive heart failure (CHF). These drugs have been shown to improve exercise capacity and reduce symptoms and in combination with hydralazine to prolong life in patients with mild-to-moderate symptoms of CHF. Recent investigations, however, have indicated that nitrate-mediated benefit to patients with CHF may be limited by resistance to their hemodynamic effects seen in many patients and by early development of tolerance. The incidence, potential mechanisms, and possible methods for prevention of nitrate resistance and tolerance in patients with chronic CHF are reviewed.

Drug Administration Schedule↗
PubMed1991

Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.

BACKGROUND: Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. METHODS: We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). RESULTS: As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. CONCLUSIONS: Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.

Aged↗
PubMed1991

Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention.

OBJECTIVE: To review the available information about nitrate tolerance, its potential mechanisms, clinical implications, and strategies for prevention. DATA IDENTIFICATION: A survey of the National Library of Medicine MEDLINE database and bibliographies of the reviewed articles. STUDY SELECTION AND DATA EXTRACTION: Studies were selected from the English language literature with an emphasis on recent studies and, when available, randomized placebo-controlled studies. Old studies were selected on the basis of their historical value and originality. A total of 134 retrieved articles were considered relevant and were reviewed in depth. RESULTS: The available information about the experimental as well as the clinical evidence for tolerance to organic nitrates has been summarized. In addition, information related to potential mechanisms, clinical implications, and possible methods for prevention have been reviewed. CONCLUSIONS: Evidence indicates that prolonged in-vitro exposure to organic nitrates, continuous intravenous or topical administration of nitrates, and frequent in-vivo oral dosing result in the rapid development of tolerance to the peripheral as well as to the coronary vasodilatory effects of the drugs. This phenomenon leads to the rapid attenuation of the hemodynamic and anti-ischemic effects of nitrates in patients with ischemic heart disease or congestive heart failure, or both. Tolerance development seems to be dose- and time-dependent, and its main mechanism seems to be a depletion of sulfhydryl groups at the vascular cell. Although the repletion of sulfhydryl groups with the use of sulfhydryl-containing drugs may help to prevent tolerance, the efficacy and safety of this approach requires further evaluation. Intermittent therapy allowing a sufficiently long, daily nitrate-washout interval seems to be the most effective and the most safe strategy currently available for the prevention of nitrate tolerance.

Cardiovascular Agents↗
PubMed1991

Efficacy and safety of a short-term (6-h) intravenous infusion of dopexamine in patients with severe congestive heart failure: a randomized, double-blind, parallel, placebo-controlled multicenter study.

Dopexamine hydrochloride is a new synthetic catechol that offers a unique profile of adrenergic and dopaminergic activity. In this multicenter, parallel design, placebo-controlled study, 45 patients with functional class III or IV chronic congestive heart failure were randomized to receive a placebo infusion or one of three different doses of dopexamine. After a 2-h dose titration sequence, patients received a 6-h constant dose infusion. During this 6-h period, dopexamine was infused at rates of 1, 2 and 4 micrograms/kg body weight per min in the low, intermediate and high dose groups, respectively. In patients receiving high dose infusion, dopexamine produced a 78% increase in cardiac index associated with a 43% decrease in systemic vascular resistance and 24% increase in heart rate (p less than 0.05 vs. placebo for all three variables). There was a trend (p = NS) toward a moderate increase in cardiac index at low and intermediate doses. In patients randomized to receive dopexamine, right atrial, systemic arterial, pulmonary artery and pulmonary capillary wedge pressures showed minimal change from baseline and did not differ statistically from the placebo response. Very few patients developed adverse reactions related to dopexamine, although five patients randomized to receive high dose and three patients randomized to receive intermediate dose dopexamine required dose reduction because hemodynamic variables exceeded arbitrary safety limits or the patients developed symptoms related to the study medication. dopexamine in higher doses effectively increases cardiac index in association with a reduction in systemic vascular resistance. Additional clinical studies are indicated to evaluate the merits of dopexamine in comparison with other inotropic and vasodilator medications.

Adrenergic Agonists↗
PubMed1991

Randomized study to evaluate the relation between oral isosorbide dinitrate dosing interval and the development of early tolerance to its effect on left ventricular filling pressure in patients with chronic heart failure.

BACKGROUND: Early development of nitrate tolerance has been shown in patients with chronic congestive heart failure (CHF) receiving continuous nitroglycerin therapy. The influence of dosing interval of oral isosorbide dinitrate (ISDN), the nitrate preparation most widely used for the treatment of CHF, has not been investigated. METHODS AND RESULTS: We performed a prospective, randomized study to evaluate the effect of various regimens of oral ISDN on the development of early tolerance to its effect on left ventricular filling pressure in patients with moderate to severe CHF. Forty-four responders (20% or greater reduction in mean pulmonary artery wedge pressure lasting 1 hour or longer) were divided into four groups of 11 patients each, and randomized to receive their effective ISDN dose (40-120 mg) Q 4 hours, Q 6 hours, Q 8 hours, or t.i.d. (drug given at 0, 6, 12, and 24 hours allowing 12 hours of ISDN washout interval between the third and fourth doses). All groups demonstrated a significant and comparable reduction in LV filling pressure following administration of the first ISDN dose. Early attenuation of hemodynamic response was demonstrated with frequent dosing (Q 4 hours and Q 6 hours) ISDN. Tolerance was with a Q 8-hour regimen as demonstrated by preserved hemodynamic response to each dose. The effect of each dose, however, was short-term, with return of pulmonary artery wedge pressure to baseline level at 2 to 4 hours, resulting in an intermittent effect totaling no longer than 12 hours of the 30-hour study period. The use of a t.i.d. regimen resulted in marked attenuation of response after the third dose with complete restoration of nitrate effect following a 12-hour washout period between the third and fourth doses. ISDN plasma concentration was measured in five patients in each of the Q 4- and Q 8-hour groups. In the Q 4-hour group, plasma levels were significantly higher after administration of the last dose than after the first dose (area under the curve, 242 +/- 216 versus 123 +/- 130 ng/ml, p less than 0.05), and trough levels before administration of the second and the fifth dose (15 +/- 17 and 27 +/- 27 ng/ml, respectively) were both markedly higher than the baseline value of 2 +/- 4 ng/ml. CONCLUSIONS: Our data demonstrate the development of tolerance and early attenuation of effect on left ventricular filling pressure with frequent oral dosing (Q 4 and Q 6 hours) with ISDN in patients with chronic CHF, which may be related to persistently elevated trough blood levels of ISDN. The development of tolerance can be reversed after a washout period of 12 hours and can be prevented with a Q 8-hour administration. These regimens, however, are limited by an inconsistent effect. Although long-term implications of these findings need further evaluation, the present study demonstrates the difficulty of maintaining a persistent ISDN-mediated reduction in left ventricular filling pressure in patients with chronic, moderate to severe CHF. These results suggest the need to use intermittent ISDN therapy allowing a daily nitrate washout interval and the rationale for combined vasodilator therapy in patients with CHF.

Drug Administration Schedule↗
PubMed1990

A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure.

We performed a prospective, randomized, double-blind, crossover study to compare the efficacy and safety of vasodilation with the calcium entry blocker nifedipine with that of isosorbide dinitrate (ISDN) and their combination as treatment for heart failure. Twenty-eight patients with New York Heart Association Functional class II or III chronic heart failure due to left ventricular systolic dysfunction were studied. All patients were maintained on a constant dose of digitalis and diuretics throughout the study. Eight weeks of therapy with nifedipine alone or in combination with ISDN resulted in a significantly higher incidence of heart failure deterioration necessitating hospitalizations and/or additional diuretics. Twenty-four percent of patients required hospitalization during nifedipine therapy and 26% required hospitalization during nifedipine-ISDN combination therapy in comparison to 0% requiring hospitalization during ISDN therapy alone. The total number of heart failure-worsening episodes was nine among patients on nifedipine, three among patients on ISDN (p less than 0.09 versus nifedipine), and 21 among patients on nifedipine-ISDN combination (p less than 0.001 versus nifedipine, p less than 0.0001 versus ISDN). Premature discontinuation of drug administration due to clinical deterioration or other side effects occurred in 29% of patients during nifedipine therapy, 5% of patients during ISDN therapy (p = 0.05 versus nifedipine), and 19% of patients during the combination therapy. A comparison of eight patients who demonstrated clinical deterioration on nifedipine with the remainder of the patients demonstrated no significant difference in left ventricular ejection fraction (0.24 +/- 0.06 versus 0.23 +/- 0.07) or maximal oxygen uptake during exercise (13 +/- 3 versus 14 +/- 2 ml/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Plasma norepinephrine in Chagas' cardioneuromyopathy: a marker of progressive dysautonomia.

Chronic Chagas' disease produces pathologic changes of the cardiovascular, digestive, and autonomic nervous systems. In an attempt to elucidate the nature of the dysautonomia in patients with Chagas' disease, we measured plasma norepinephrine levels, blood pressure, and heart rate, both supine and standing in 26 patients, and compared these values of patients classified according to three clinical subsets of cardiovascular manifestations with the values of nine normal volunteers and 16 patients with nonchagasic heart failure. Results suggested (1) progressive blockade of the alpha receptor in patients with Chagas' disease who have minimal clinical symptoms (group I) and in those who have ECG alterations without congestive symptoms (group II), as reflected by normal or raised plasma norepinephrine levels without change of diastolic blood pressure during standing, which indicates absent postural reflexes; and (2) blockade associated with partial denervation in patients with Chagas' disease who have class III or IV heart failure (group III), as suggested by a lower supine plasma norepinephrine level and a fall in diastolic blood pressure in the upright position. The findings of reduced plasma norepinephrine levels are in contrast to the elevated plasma norepinephrine levels in patients without Chagas' disease with class III and IV heart failure who have sympathetic hyperactivity.

Adult↗
PubMed1989

Central and renal hemodynamic effects of a new agonist at peripheral dopamine- and beta-2 adrenoreceptors (dopexamine) in patients with heart failure.

The effect of dopexamine, a new dopamine analogue, on central and renal hemodynamics was evaluated in nine patients with chronic, congestive heart failure caused by severe left ventricular (LV) systolic dysfunction. The administration of the maximally tolerated dose (7.2 +/- 4 micrograms/kg/min) resulted in a significant increase in cardiac index from 1.9 +/- 0.4 L/min/m2 to 2.6 +/- 0.9 L/min/m2 (p less than 0.05). This increase in cardiac index was largely a result of increase in heart rate (from 88 +/- 20 beats/min to 104 +/- 24 beats/min, p less than 0.05), because stroke volume index demonstrated only a small change (from 23 +/- 10 ml/m2 to 27 +/- 11 ml/m2, p not significant) in spite of a significant fall in systemic vascular resistance from 1992 +/- 717 dynes.sec.cm-5 to 1361 +/- 524 dynes.sec.cm-5 (p less than 0.05) and diastolic blood pressure (from 89 +/- 15 mm Hg to 80 +/- 17 mm Hg, p less than 0.05). No change was seen during dopexamine infusion in systolic blood pressure, right and left ventricular filling pressures, and LV stroke work index. Both renal blood flow and glomerular filtration rate were impaired at baseline in most patients. Dopexamine administration resulted in a significant increase (2x coefficient of variation) in renal blood flow in two patients only. Mean values of both renal blood flow and glomerular filtration rate did not show significant change (485 +/- 183 ml/min vs 563 +/- 221 ml/min and 89 +/- 39 ml/min vs 93 +/- 34 ml/min, respectively, p not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Can prognosis be altered by treating LV dysfunction?

A major scientific effort taking place in the last decade has resulted in better understanding of the pathophysiology of myocardial dysfunction and in the development of new therapeutic modalities for this condition. The purpose of this article is to review available information related to the effect of available therapeutic modalities on mortality rate in patients with left ventricular (LV) systolic dysfunction.

Adrenergic alpha-Antagonists↗
PubMed1988

Electrophysiologic effects of intravenous magnesium in patients with normal conduction systems and no clinical evidence of significant cardiac disease.

Parenteral magnesium has been used for several decades in the empiric treatment of various arrhythmias, but the data on its electrophysiologic effects in man are limited. We evaluated the electrophysiologic effects of magnesium sulfate (MgSO4) administration in eight normomagnesemic patients with normal mononuclear cell magnesium content, who had no clinically significant heart disease and had normal baseline electrophysiologic properties. After administration of intravenous MgSO4, serum magnesium rose significantly from 1.9 +/- 0.1 to 4.4 +/- 1.7 mg/dl (p less than 0.02). During a maintenance magnesium infusion, we observed significant prolongation of the ECG PR interval (145 +/- 18 to 155 +/- 26 msec, p less than 0.05), AH interval (77 +/- 27 to 83 +/- 26 msec, p less than 0.002), antegrade atrioventricular (AV) nodal effective refractory period (278 +/- 67 to 293 +/- 67 msec, p less than 0.05), and sinoatrial conduction time (60 +/- 34 to 76 +/- 32 msec, p less than 0.02). No significant effect was observed on sinus cycle length, sinus node recovery time, intra-atrial or intraventricular conduction times, QRS duration (during both sinus rhythm and ventricular pacing), QT interval, HV interval, paced cycle length resulting in AV nodal Wenckebach block, AV nodal functional refractory period, retrograde ventriculoatrial (VA) effective refractory period, or atrial and ventricular refractory periods. These findings, in conjunction with the demonstrated ability of magnesium to block slow channels for sodium movement, may provide an explanation of the mechanism by which magnesium exerts its effect in the treatment of atrial and junctional arrhythmias.

Adult↗
PubMed1988

Resistance to isosorbide dinitrate in patients with severe chronic heart failure: incidence and attempt at hemodynamic prediction.

Oral isosorbide dinitrate has been widely used to lower elevated left ventricular filling pressure in patients with chronic heart failure. Although the recommended dose of this drug is 40 mg every 6 h, failure to respond to this dose has been observed in many patients with heart failure. In the present study the incidence of resistance to isosorbide dinitrate was evaluated and an attempt was made to identify baseline hemodynamic predictors for this phenomenon in 50 patients with severe chronic heart failure due to left ventricular systolic dysfunction (mean left ventricular ejection fraction 0.23 +/- 0.08). Twenty-seven (54%) of the 50 patients responded to 40 mg of isosorbide dinitrate (greater than 20% decrease in mean pulmonary artery wedge pressure sustained greater than or equal to 1 h) and 23 patients (46%) failed to respond. Nonresponders to 40 mg of isosorbide dinitrate had a significantly higher baseline right atrial pressure than did responders (14 +/- 5 versus 10 +/- 6 mm Hg, p less than 0.02). In addition, all 7 patients with a baseline right atrial pressure of less than 7 mm Hg and 12 of 14 patients with a baseline right atrial pressure less than 10 mm Hg responded to 40 mg. No significant differences were noted between responders and nonresponders in any other baseline hemodynamic or clinical variables, or in peak isosorbide dinitrate serum levels (32 +/- 19 ng/ml in nonresponders versus 44 +/- 36 ng/ml in responders). Of the 23 nonresponders to 40 mg, 22 received a higher dose (80 to 120 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Hemodynamic and volumetric effects of venodilation with nitroglycerin in chronic mitral regurgitation.

To evaluate the potential value of nitrate therapy in patients with chronic mitral regurgitation, the hemodynamic and angiographic effects of intravenous nitroglycerin were studied in 10 such patients. Nitroglycerin infusion, titrated to reduce mean pulmonary artery wedge pressure at least 20%, resulted in a significant reduction in mean blood pressure (from 91 +/- 12 to 77 +/- 13 mm Hg, p less than 0.0001), mean right atrial pressure (12 +/- 6 to 7 +/- 4 mm Hg, p less than 0.001), left ventricular end-diastolic pressure (22 +/- 7 to 13 +/- 5 mm Hg, p less than 0.0001) and peak V wave of indirect left atrial pressure (34 +/- 9 to 20 +/- 10 mm Hg, p less than 0.001). Changes in systemic vascular resistance (1,986 +/- 468 vs 1,582 +/- 534 dynes s cm-5) and forward stroke volume (39 +/- 14 vs 45 +/- 8 ml) were not statistically significant. Angiographic data showed a decrease in both end-diastolic and end-systolic left ventricular volumes (248 +/- 51 to 216 +/- 54 ml, p = 0.06 and 127 +/- 69 to 99 +/- 48 ml, p less than 0.05, respectively) and an improvement in ejection fraction, from 0.52 +/- 0.15 to 0.55 +/- 0.15 (p less than 0.05). There was no significant change in the group values for mitral regurgitant volume and fraction (from 85 +/- 32 to 72 +/- 32 ml and 67 +/- 10 to 64 +/- 5%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗