Shift from surrogate end point to outcome trials: implications for cardiovascular safety assessment in development programs for antidiabetic drugs.

We assessed the effect of extending the range of cardiovascular (CV) end points to include hospitalization for unstable angina and hospitalization for coronary revascularization (Extended Major Adverse Cardiac Event criteria (MACE)) in addition to the standard ones, namely, CV-related death, nonfatal stroke, and nonfatal myocardial infarction (Core MACE). The trials selected for the analysis had a duration/follow-up period of ≥1 year and involved more than 1,000 subjects. Annual event rates (AERs) for Core MACE in patients with type 2 diabetes were estimated, and the duration of an event-driven CV outcome trial necessary to exclude ≥80% risk increase was modeled. All the studies revealed hazard ratios ≤1.0 for Core MACE end points whereas in 21% of the studies, the hazard ratio for hospitalization for unstable angina or coronary revascularization (Extended MACE) was >1 and was therefore discordant with Core MACE. The AERs for Core MACE ranged from 0.5% (recent clinical programs) to 6% (epidemiological studies); these low rates observed in recent programs would have the effect of increasing the duration required for a CV outcome trial. The addition of Extended MACE end points to the primary composite outcome in antidiabetic clinical trials is unlikely to obscure CV-related risk and may improve the feasibility of CV outcome trials.

Dopamine and norepinephrine increase venous return by stimulating alpha and beta adrenoceptors in the dog.

The cardiopulmonary bypass technique was used to compare the effects of dopamine and norepinephrine on venous return, and to identify the adrenoceptors involved in the responses. Intraarterial boluses of dopamine and norepinephrine produced similar increases in mean arterial pressure and similar increases in venous return, but dopamine required 10-30 x larger doses than norepinephrine to produce the same effect. Phenoxybenzamine virtually abolished the venous responses to the lowest doses of both agonists and diminished the venous responses to larger doses. Propranolol had little or no effect on venous responses to the low doses but substantially diminished the responses to larger doses. These results indicate that the increase in venous return produced by dopamine or norepinephrine involves both alpha and beta adrenoceptors. To determine whether the beta adrenoceptor belonged to subtype beta 1, the "selective" beta 2 agonist, salbutamol, was used. The reported affinity of salbutamol in dogs for arterial beta 2 receptors is fivefold greater than that for cardiac beta 1 receptors. However, the dose-response curves of salbutamol on the venous and arterial systems overlapped, indicating that the increase in venous return represents a combination of properties common to both beta 1 and beta 2 adrenoceptors.

Pharmacology of enoximone.

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration, that is being studied clinically for the treatment of patients with congestive heart failure. The animal pharmacology pertinent to the clinical development of enoximone is reviewed. Direct positive inotropic, positive chronotropic and vasodilator properties have been demonstrated for enoximone in several in vivo and in vitro preparations. However, positive inotropism and vasodilation are the principal effects of this agent with the inotropic effect being the most prominent. In anesthetized dogs, the cardiovascular effects produced by enoximone (0.1 to 1 mg/kg) were not accompanied by significant alterations in myocardial oxygen consumption. Cardiac function was improved by enoximone in anesthetized dogs given myocardial depressant amounts of propranolol. Studies in vivo and in vitro have indicated that the actions of enoximone are direct and not mediated by stimulation of adrenergic receptors, histaminic receptors, cholinergic receptors, Ca++-adenosine triphosphatase, Mg++-adenosine triphosphatase, adenyl cyclase or inhibition of Na+, K+-adenosine triphosphatase. However, enoximone reversed the depressant effects of verapamil in the dog heart-lung preparation; this suggests that its action resulted in the activation of slow calcium channels. Enoximone was found to be potent and highly selective inhibitor of a high affinity cyclic adenosine monophosphate-phosphodiesterase type IV-phosphodiesterase from dog heart, whereas standard inhibitors (e.g., 3-isobutyl-1-methylxanthine and papaverine) inhibit all 3 cardiac phosphodiesterases. Further, enoximone produced an increase in cyclic adenosine monophosphate, but not cyclic guanosine monophosphate, in the isolated, blood perfused dog papillary muscle during the peak inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro and in vivo assessment of the cardiovascular effects of the cardiotonic drug MDL 19205.

Various in vitro and in vivo techniques were used to evaluate the cardiovascular actions of MDL 19205, a new cardiotonic agent. In the anesthetized dog, intravenous administration of MDL 19205 (0.1-1 mg/kg) produced marked increases in cardiac contractile force which were accompanied by small increases in heart rate and minor decreases in blood pressure. These effects were not altered by alpha- or beta-adrenergic receptor blockade, reserpine pretreatment, or bilateral carotid sinus denervation. In isolated cat cardiac tissues, MDL 19205 (10(-5)-10(-3) M) produced a selective inotropic effect relative to isoproterenol and, unlike isoproterenol, was nonarrhythmogenic. Adrenergic beta-receptor or histamine H1-receptor blockade did not modify the inotropic effects of MDL 19205 in guinea pig atria. The vasodilatory effect of MDL 19205 in the canine isolated pump-perfused hindlimb preparation was not significantly attenuated by surgical sympathectomy, alpha- or beta-adrenergic receptor blockade, cholinergic or histaminergic receptor blockade, or indomethacin pretreatment, indicating that MDL 19205 produced direct relaxation of vascular smooth muscle. MDL 19205 was found to be safe and effective when administered acutely in combination with ouabain, hydralazine, nitroglycerin, or furosemide, agents commonly used in the treatment of congestive heart failure. The pharmacological profile revealed by these and other studies suggests that MDL 19205 should be useful in the clinical treatment of congestive heart failure.

Cardiovascular properties of a new cardiotonic agent, MDL 19205.

The cardiovascular properties of a new cardiotonic agent, MDL 19205, were investigated in anesthetized and conscious dogs and in a dog heart-lung preparation. MDL 19205 (0.1-1 mg/kg), administered to anesthetized dogs by intravenous injection, produced a dose-related increase in cardiac contractile force lasting up to 1 h. It also produced a relatively minor increase in heart rate and a brief decrease in blood pressure. These effects did not involve beta-adrenergic receptor stimulation, as they were observed in dogs after a myocardial-depressant dose of propranolol. Given orally to conscious dogs, MDL 19205 (1 and 3 mg/kg) produced a dose-related increase in dP/dt without producing a significant alteration in heart rate or blood pressure. When administered to anesthetized dogs by constant intravenous infusion, MDL 19205 (0.1 mg/kg/min) produced a marked and sustained increase in cardiac contractile force and decreases in blood pressure and left atrial pressure, but did not produce a significant change in cardiac output or stroke volume, indicating an enhancement of cardiac pump function. Intravenous MDL 19205 reversed the hemodynamic characteristics of heart failure produced by propranolol in anesthetized dogs. In addition, it reversed the depressant effect of pentobarbital on cardiac function in a dog heart-lung preparation. These studies show that MDL 19205 is a potent, direct-acting cardiotonic agent in animals.

Characterization of the cardiovascular activities of a new cardiotonic agent, MDL 17043 (1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazole-2-one).

The cardiovascular actions of 1,3-dihydro-4-methyl-5[4-(methylthio)-benzoyl]-2H-imidazol-2-one (MDL 17043), a new noncatecholamine, nonglycoside cardiotonic agent, were examined in vivo in anesthetized dogs and in vitro in isolated cat atrial and papillary muscle preparations and guinea pig atria. In the anesthetized dog, intravenous administration of MDL 17043 (0.1--1 mg/kg) produced marked increases in cardiac contractile force which were accompanied by minor increases in heart rate and small decreases in blood pressure. These effects were not altered by alpha- or beta-adrenergic receptor blockade, catecholamine depletion produced by reserpine, bilateral vagotomy, or by bilateral carotid sinus denervation. MDL 17043 (10(-5)--10(-3) M) produced positive inotropic effects in isolated papillary muscle and left atrial strips of the cat that were much greater than the positive chronotropic effects seen in the spontaneously beating right atrium of the cat. The in vitro inotropic effects of MDL 17043 in guinea pig electrically driven left atrial strips were not modified by adrenergic beta-receptor or histamine H1-receptor blockade. The vasodilatory effect of MDL 17043 in the canine isolated pump-perfused hindlimb preparation was not attenuated by surgical sympathectomy, alpha- or beta-adrenergic receptor blockade, cholinergic or histaminergic receptor blockade, or by prostaglandin synthesis inhibition, indicating that MDL 17043 produces direct relaxation of vascular smooth muscle. MDL 17043 was found to be safe and effective when administered acutely in combination with ouabain, hydralazine, nitroglycerin, or furosemide, agents commonly used in the treatment of congestive heart failure.

Cardiovascular properties of a new cardiotonic agent: MDL 17,043 (1.3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one).

The cardiovascular properties of a new noncatechol, nonglycoside cardiotonic agent, MDL 17,043, were investigated in anesthetized and conscious dogs and the dog heart-lung preparation. MDL 17,043 (0.1-1 mg/kg), administered to anesthetized dogs by intravenous injection, produced dose-related increases in cardiac contractile force lasting more than 1 h. It also produced relatively minor and shorter-lasting increases in heart rate, and brief decreases in blood pressure. These effects were not blocked by propranolol. Of these effects, the increase in cardiac contractile force was, by far, the most prominent. the cardiac effects were also observed in the dog heart-lung preparation. When administered to anesthetized dogs by constant intravenous infusion, MDL 17,043 (09.03 and 0.1 mg/kg/min) produced a marked and sustained increase in cardiac contractile force and a sustained decrease in blood pressure without altering heart rate, suggesting a wide separation between the inotropic instrumented dogs, MDL 17,043 (3-30 mg/kg) produced a sustained increase in dP/dt without altering heart rate or blood pressure. It reversed the depressant effect of pentobarbital on the ventricular function curve in the dog heart-lung. When the hemodynamic characteristics of compensated heart failure were produced by propranolol in anesthetized dogs, MDL 17,043 reversed these effects. These studies suggest that MDL 17,043 may have a beneficial effect in the treatment of heart failure.

Comparative gastrointestinal and biliary tract effects of morphine and butorphanol (Stadol).

Butorphanol, levo-N-cyclobutylmethyl-3,14 beta-dihydroxy-morphinan, is a new agonist-antagonist type analgetic agent which is 4 to 8 times more potent than morphine in experimental animals and man. Butorphanol and morphine were evaluated in mice and dogs for their gastrointestinal and biliary tract smooth muscle effects. Morphine decreased the propulsion of a charcoal meal through the gastrointestinal tract of the mouse in a dose related manner with the maximal inhibition obtainable being 90%. Butorphanol produced a maximal inhibition of motility of only 40% with very high doses producing less of an inhibitory effect than lower doses. In dogs, morphine caused a dose-dependent increase in duodenal smooth muscle activity and a dose-dependent decrease in bile duct flow. A clinically effective i.v. dose of morphine (0.1 mg/kg) produced a statistically significant spasmogenic effect on dog biliary tract and gastrointestinal smooth muscle, while a clinically effective equianalgetic i.v. dose of butorphanol (0.025 mg/kg i.v.) had little or not effect on the biliary or gastrointestinal systems. These findings indicate that at equianalgetic doses, butorphanol should produce less constipation and less biliary tract and gastrointestinal smooth muscle spasm than morphine.

Comparative first dose effects of prazosin and tiodazosin (BL-5111) in spontaneously hypertensive rats.

Prazosin produces a "first-dose" phenomenon in man clinically characterized by an exaggerated hypotensive response to the initial dose of the drug, with subsequent doses not producing this exaggerated effect. In spontaneously hypertensive rats (SHR), prazosin (1 mg kg po) produced a similar effect, appreciably reducing systolic blood pressure at 12 hours after the first dose but having little or no effect at 12 hours after the subsequent doses. In contrast, BL-5111, an antihypertensive agent similar in chemical structure and shown in previous studies to be slightly less potent than prazosin but with appreciably less alpha-adrenergic receptor antagonist activity, had no effect on blood pressure at 12 hours after dosing (1 and 2 mg/kg po). Pretreatment of rats with an ineffective blood pressure lowering dose of prazosin (0.03 mg/kg po) significantly attenuated the first dose effect of prazosin, resembling the clinical observations seen in patients. Thus, the SHR may be a useful model for predicting the prazosin-like "first-dose" phenomenon with related analogs.

Pharmacological effects of a combination of butorphanol and acetaminophen.

Isobolographic analysis was used to study in mice the combined oral analgetic action of butorphanol, a new centrally acting analgetic, and acetaminophen, an antipyretic analgetic. Combinations of butorphanol-acetaminophen exhibited analgetic effects which were greater than were expected from just an additive analgetic action of each drug. Consequently, a significant synergistic effect occurred after the simultaneous oral administration of butorphanol and acetaminophen. Furthermore, oral administration of butorphanol-acetaminophen mixture to conscious dogs at approximately 20 times the recommended human dose resulted in little or no effect on aortic blood pressure and arterial blood pH,pCO2 and pO2. Heart rate was slightly reduced and this resulted in a small increase in the PR interval and a prolongation of the QT interval of the lead II surface electrocardiogram.