Low-dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group.

OBJECTIVES: This study was designed to evaluate the effects of low-dose enoximone on exercise capacity. BACKGROUND: At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated. METHODS: This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring. RESULTS: By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups. CONCLUSIONS: Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events.

Effects of propranolol on myocardial infarct size with and without coronary artery reperfusion in the dog.

The ability of propranolol to limit myocardial infarct size (IS) following coronary artery occlusion with and without reperfusion into a critical stenosis was assessed in the dog. IS was determined by the nitrobluetetrazolium staining method and expressed as percent of the left ventricle (free wall plus septum). In Series 1 dogs the left circumflex coronary artery (LCX) was ligated at its origin. IS at 6 h was similar in groups pretreated with saline (36.0 +/- 1.3%) or propranolol (0.2 mg . kg-1, 34.7 +/- 1.7%; 1.0 mg . kg-1, 36.7 +/- 1.5%; 4.4 mg . kg-1, 34.8 +/- 0.3%). In Series 2 dogs a relatively small infarction was produced by ligating the largest branch of the LCX between the left anterior descending and posterior descending arteries. IS at 6 h was not significantly different in dogs pretreated with saline (8.1 +/- 1.7%) or propranolol (0.2 mg . kg-1, 7.1 +/- 2.5%; 1.0 mg . kg-1, 4.6 +/- 1.2%). In Series 3 dogs the LCX was ligated approximately 10 mm from its origin for 60 min followed by reperfusion into a critical stenosis. IS determined at 24 h was significantly less in dogs treated with propranolol (1.0 mg . kg-1) before LCX occlusion (4.6 +/- 0.6%) or 5 min after LCX reperfusion (9.5 +/- 1.8%) than in dogs treated with saline (22.6 +/- 2.8%). In Series 4 dogs treatment was exactly as in Series 3 except that reperfusion was not instituted. IS was similar in dogs pretreated with saline (29.0 +/- 1.5%) or propranolol (31.1 +/- 3.0%). Thus, in the present study, propranolol limited IS in the presence but not in the absence of reperfusion. In the reperfusion model propranolol was effective when administered before coronary occlusion or after initiation of reperfusion.

N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 2. Derivatives of a hypotensive-positive inotropic agent.

Seven derivatives of 2-[[2-(3,4-dihydroxyphenyl)-1-methylethyl]amino]-6,7-dihydroxy-1,2,3,4- tetrahydronaphthalene, an inotropic agent which also causes a decrease in blood pressure, were synthesized and tested for inotropic potency, cardioselectivity, and inotropic selectivity. The derivatives were designed to explore whether catechol moieties and rigid rotamers of dopamine are necessary for the activity which was found in the parent compound. The derivatives had phenolic functions in place of catechols, and they had phenethylamine in place of the tetrahydronaphthalene moiety. In no case was the profile of activity of the parent compound duplicated in the derivatives.

Conformational analogues of dopamine. Synthesis and pharmacological activity of (E)- and (Z)-2-(3,4-dihydroxyphenyl)cyclopropylamine hydrochlorides.

(E)- and (Z)-(+/-)-2-(3,4-dihydroxyphenyl)cyclopropylamine hydrochlorides were synthesized as part of a program to assess the importance of conformational isomerism with respect to the various peripheral biological actions of dopamine. Although neither of the compounds possessed dopaminergic activity in the canine renal blood-flow model, both agents were weak alpha-adrenergic agonists and exhibited cardiostimulatory properties similar to dopamine. The E isomer was apprxoximately 5 times more potent than the Z isomer in its alpha-adrenergic activity and approximately 15 times as potent in its cardiac effects. Possible reasons for the lack of renal dopaminergic activity exhibited by the E isomer are presented.

N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 1. Cardiac and pressor/depressor activities.

Amino substitution o rigid forms of dopamine [2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5,6-DTN) and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN)] with aralkyl functionalities was carried out to investigate the role of such structural modifications upon cardiac inotropic/chronotropic and blood pressure activity. Derivatives of A-5,6-DTN were strong vasodepressor agents devoid action was associated with the dihydroxyphenyl-1-methylethyl derivative, which was also an inotropic selective compound. The amino substituent of dobutamine was ineffective in reducing peripheral vascular action when combined with the rigid forms of dopamine. It was also ineffective in imparting inotropic selectivity when combined with A-5,6-DTN. An analysis of these observations in light of existing structure-activity relationships of aminoaralkyl substitution of other catecholamine structure is presented.

Ultra-short-acting beta-adrenergic receptor blocking agents. 1. (Aryloxy)propanolamines containing esters in the nitrogen substituent.

In an attempt to produce short-acting beta-adrenergic receptor blocking agents, we prepared several (aryloxy)propanolamines with ester functions incorporated into the nitrogen substituent. Many of these compounds exhibited a short duration of blocking activity after their continuous intravenous infusion for 40 min. However, their durations were found to increase considerably upon longer intravenous infusion.

Ultra-short-acting beta-adrenergic receptor blocking agents. 2. (Aryloxy)propanolamines containing esters on the aryl function.

Several short-acting beta-adrenergic receptor blocking agents have been prepared by incorporating ester functions into the aryl portion of certain (aryloxy)propanolamine systems. In particular, methyl 3-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionate hydrochloride (ASL-8052) was found to be a moderately potent, cardioselective compound with a short duration of action when determined in in vivo canine models.

Ultra-short-acting beta-adrenergic receptor blocking agents. 3. Ethylenediamine derivatives of (aryloxy)propanolamines having esters on the aryl function.

Various ethylenediamine derivatives have been incorporated into the nitrogen substituent of certain short-acting (aryloxy)propanolamine systems that contain esters on their aryl functions. Although several of these compounds showed durations of action comparable to their prototypes, most of the nitrogen substituents significantly prolonged the duration of beta-adrenergic blockade. Similarly, while one of the compounds showed appreciable cardioselectivity in vitro, generally, little enhancement of cardioselectivity was obtained. A brief discussion of structure-activity relationships observed for the ethylenediamine derivatives is presented.

[(Arylcarbonyl)oxy]propanolamines. 1. Novel beta-blockers with ultrashort duration of action.

Novel [(arylcarbonyl)oxy]propanolamines were synthesized and investigated as potential ultrashort-acting beta-adrenergic receptor blockers. Many of these analogues exhibited good potency and short duration. The N-ureidoalkyl analogue 85 (ACC-9089) has a potency equal to propranolol and a duration of action of about 21 min in the dog. It has been selected as a candidate for further clinical study. Structure-activity relationships and structure-duration relationships for these new beta-blockers are also discussed.

Basic pharmacology of esmolol.

Preclinical studies show that esmolol is an ultrashortacting, cardioselective beta blocker that possesses minimal partial agonist action or membrane-depressant properties. The electrophysiologic and hemodynamic actions of esmolol are the result of beta blockade. No direct, beta receptor-independent cardiovascular actions have been identified with beta-blocking doses in laboratory experiments. Because esmolol slows atrioventricular conduction, increases atrioventricular refractoriness and decreases the determinants of myocardial oxygen demand, it should have use in the treatment of supraventricular tachycardias and acute myocardial ischemia. Esmolol, because of its ultrashort duration of action, should be safe for the induction of beta blockade in patients who are critically ill and is ideally suited for rapidly changing levels of beta blockade in this clinical situation.

Comparison of the parasympatholytic activity of ACC-9358 and disopyramide.

ACC-9358 (N-[(3,5-di(pyrrolidinylmethyl)-4-hydroxy)benzoyl]aniline) is a newly developed analogue of changrolin, an antiarrhythmic agent used in the Peoples Republic of China. Since changrolin and other antiarrhythmic agents exert parasympatholytic activity which may limit their clinical usefulness, it was of interest to examine the parasympatholytic effects of ACC-9358. For comparative purposes we also studied the parasympatholytic activity of disopyramide. In guinea-pig isolated ileal strips, disopyramide, 3-30 microM, and ACC-9358, 100-300 microM, competitively antagonized carbachol-induced contractions with pA2 values of 5.78 and 4.17, respectively. In guinea-pig isolated right atria, disopyramide 3-30 microM, competitively antagonized methacholine-induced slowing of spontaneous beating with a pA2 value of 5.99 whereas ACC-9358, 3-300 microM, produced no significant muscarinic blockade in this preparation. Disopyramide (1.9-15 mg kg-1, i.v.), but not ACC-9358 (7.5-1.5 mg kg-1, i.v.), significantly increased rat pupil diameter in vivo. Disopyramide and ACC-9358 blocked vagal-induced reductions in heart rate in dogs anaesthetized with pentobarbitone. ED50 values were approximately 0.65 and 11.25 mg kg-1, respectively. We conclude that ACC-9358 possesses significantly less parasympatholytic activity than disopyramide.

Pharmacology and pharmacokinetics of esmolol.

Esmolol is an ultra-short-acting beta-adrenergic blocking agent that possesses minimal partial agonist activity or direct membrane depressant activity. The short duration of action of esmolol is attributable to rapid enzymatic hydrolysis by red blood cell esterases, forming ASL-8123 and methanol. Experiments in the constant-flow-perfused isolated canine hindlimb indicate that therapeutic (beta blocking) doses of esmolol lack direct vascular effects and alpha-adrenergic blocking activity and that therapeutic doses do not interfere with vascoconstrictor effects of peripheral sympathetic nerve stimulation. Esmolol produces cardiac electrophysiologic and hemodynamic effects consistent with those of beta blockade. Specifically, esmolol decreases heart rate, depresses atrioventricular nodal conduction, and decreases determinants of myocardial oxygen demand. The beneficial antiarrhythmic and infarct-size limiting effects of esmolol have been demonstrated in several experimental models. Whereas beta blockers in general are effective in settings of supraventricular arrhythmias, sinus tachycardia, and myocardial ischemia, esmolol provides the added dimension of "titratability." Thus, the short duration of action of esmolol allows for very rapid titration to a preferred steady-state level of beta blockade; rapid adjustment to different steady-state levels of beta blockade, as may be required by changing status of the patient, and rapid disappearance of beta blockade following discontinuation of esmolol infusion, should this be necessary in the event of deleterious cardiac hemodynamic effects. Thus, esmolol is ideally suited for use in the treatment of patients in whom beta blockade is desirable, but in whom level of beta blockade must be very carefully modulated.

In vitro and in vivo effects of a peptide mimetic (SC-47643) of RGD as an antiplatelet and antithrombotic agent.

Platelet aggregation requires binding of fibrinogen (fgn) to activated platelets and inhibition of this binding blocks platelet aggregation. Synthetic peptides modeled after the platelet binding sequence on fgn block the platelet glycoprotein IIb/IIIa receptor and effectively inhibit aggregation. SC-47643 (SC) is a mimetic of the RGD-containing peptide sequence that is recognized by the platelet IIb/IIIa receptor. SC inhibited fgn binding to activated platelets (IC50: 1.0 x 10(-5) M) and prevented platelet aggregation in response to a variety of platelet agonists in both washed human platelets and platelet rich plasma (IC50's ranging from 4 x 10(-6) to 1 x 10(-5) M, respectively). SC inhibited collagen induced thrombocytopenia in the rat (ED50 0.07 mg/kg and t1/2 36 min). In dogs ex vivo collagen induced platelet aggregation was inhibited 50% after a bolus injection of 1.7 mg/kg. After a steady state infusion (2 hr), the ED50 was 0.03 mg/kg/min, with no effects on blood pressure, heart rate or platelet count. These data demonstrate that SC, a peptide mimetic of the natural fgn binding sequence, is capable of blocking platelet-fgn interactions and platelet aggregation.

Participation of the autonomic nervous system in the cardiovascular effects of milrinone.

The cardiodynamic activity of intravenously administered milrinone was examined in alpha-chloralose anesthetized dogs. Two groups of dogs were used, one pretreated with hexamethonium to block autonomic reflexes, and a second group which received no pretreatment. In the untreated group milrinone produced dose-dependent increases in +dP/dt and heart rate while decreasing both systolic and diastolic blood pressure and left ventricular end diastolic pressure (LVEDP). After treatment with hexamethonium basal heart rate was significantly increased, whereas reflex changes in heart rate in response to i.v. norepinephrine or nitroglycerin were ablated. Systolic, but not diastolic blood pressure was also markedly reduced by hexamethonium. In the presence of hexamethonium responses to milrinone were qualitatively similar to milrinone responses in the absence of hexamethonium. However, the dose-response curves for milrinone were shifted dextrally for changes in +dP/dt and LVEDP, whereas the dose-response curve for blood pressure was shifted sinistrally. Thus, it appears that the autonomic nervous system enhances the effect of milrinone on +dP/dt and LVEDP, but attenuates its effect on blood pressure.

Ultra-short acting beta-blockers: a proposal for the treatment of the critically ill patient.

Beta-blockade is of proven value in the therapy of acute myocardial infarction but, unfortunately, may produce cardiac failure by removal of needed sympathetic support. The long duration of action of available blockers (hours) makes reversal of failure a complicated problem and precludes rapid modification of therapy to match changing autonomic conditions. To improve the safety and efficacy of beta-blockade in this setting we have developed the concept of ultra-short beta-blockade and have identified a novel beta-blocker (ASL-8052) which possesses a duration of action less than 15 minutes. This compound is cardioselective and possesses efficacy in an animal model of acute myocardial infarction. It, therefore, appears to be suitable for rapid attainment of controlled levels of beta-blockade via intravenous infusion and rapid recovery from beta-blockade if required by the clinical situation. The compound should, therefore, be useful for safe therapy in critically ill cardiac patients.

Synthesis and pharmacology of potential beta-blockers.

Several 1-(4-substituted phenoxyl)-2-hydroxy-3-isopropylaminopropanes and 1-(4-substituted phenoxy)-2-hydroxy-3-[3,4-dimethoxyphenethyl]aminopropanes were synthesized for possible beta-adrenergic receptor blockage. The compounds were synthesized by reaction of the 4-substituted phenol with epichlorohydrin and subsequent opening of the resulting epoxide with either N-isopropylamine or N-3,4-dimethoxyphenethylamine. Preliminary biological testing indicated a decrease in the beta-blocking potency and the duration of action.

Cardiovascular pharmacology of ASL-7022, a novel catecholamine. I. Inotropic, chronotropic and pressor actions.

ASL-7022 (2-[3-(3,4-dihydroxy-phenyl)-1-methylethyl]-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene) was examined for inotropic, chronotropic and blood pressure activity in pentobarbital anesthetized, vagotomized dogs instrumented for measurement of right ventricular contractile force, blood pressure and heart rate. The compound produced a dose-dependent increases in contractile force accompanied by bradycardia and hypotension. At high doses, the compound increased heart rate. At doses which increased contractile force by 100%, ASL-7022 produced no significant increase in heart rate, whereas dopamine and dobutamine produced small but significant increase in cardiac rate, ASL-7022 was therefore found to be more inotropic selective with respect to cardiac action than dopamine or dobutamine. Beta blockade reduced the positive inotropic, positive chronotropic and depressor action of the compound and also eliminated the negative chronotropic effect. ASL-7022 appears to be a beta adrenergic receptor agonist which possesses a unique spectrum of cardiovascular action.

Pharmacodynamics and onset of action of esmolol in anesthetized dogs.

The pharmacodynamics and onset of action of esmolol, a novel, cardioselective beta adrenergic receptor antagonist with an ultra short duration of action, were studied in anesthetized dogs. Steady-state levels of beta blockade were attained within 10 min after initiation of esmolol infusion or when changing infusion rates. Similarly, steady-state blood levels of esmolol were attained within 30 min (the earliest sampling point) after starting an infusion and new steady-state blood levels were re-established again within 30 min after changing the infusion rates. Rapid recovery from beta blockade after termination of the esmolol infusion was paralleled by a rapid decline in blood levels of esmolol. The duration of action and elimination half-life both averaged less than 15 min. Excellent linear correlations were obtained between dose and steady-state blood concentration and the logarithm of the steady-state blood concentration and percentage of beta blockade. In a separate study, the onset of beta blockade with esmolol was observed within 15 sec of initiating a 60-sec infusion of 500 micrograms/kg/min. Peak beta blockade occurred at 30 to 45 sec after switching to a maintenance dose of 12.5, 25 or 50 micrograms/kg/min. The duration of peak effect was dependent on the maintenance dose. Peak blood levels of esmolol occurred immediately after stopping the loading dose and decreased to steady-state blood levels at 20 and 10 min after maintenance doses of 25 and 50 micrograms/kg/min, respectively. The results of these studies indicate that the onset, time to steady state and termination of beta blockade with esmolol are rapid and that an excellent correlation exists between the blood level of the drug and degree of beta blockade both during and after an esmolol infusion.