Investigation of the abuse liability of buspirone in alcohol-dependent patients.

By use of the Addiction Research Center Inventory, the Amphetamine Self-Rating Scale, the Single-Dose Questionnaire, and selected physiologic measures (blood pressure, pulse and respiratory rates, oral temperature, and pupil diameter), the abuse liability of buspirone (10, 20, and 40 mg) was compared with that of diazepam (10 and 20 mg) and placebo in 19 subjects who were hospitalized for the treatment of alcohol dependency. Each treatment was given as a single dose at intervals of at least three days according to a double-blind, six-period, crossover Latin square design. Neither buspirone nor diazepam had any effect on blood pressure, pulse and respiratory rates, or body temperature. A small, transient pupillary constriction was evident in the 20- and 40-mg buspirone groups, but it dissipated within two hours after dosing. Both buspirone and diazepam had only a small stimulating effect on appetite. On the Pentobarbital-Chlorpromazine-Alcohol Group and Sedation subscales of the Addiction Research Center Inventory, the 40-mg dose of buspirone yielded effects suggestive of a mild sedative-type drug. Only the 20-mg dose produced a significant effect on the Euphoria scale. Diazepam appeared to be more active as a sedative-hypnotic type of drug, by virtue of its effects on both the Amphetamine and Euphoria subscales and its greater effects on the Morphine-Benzedrine Group, Pentobarbital-Chlorpromazine-Alcohol Group, and Sedation subscales, suggesting euphoria. Not only does the lack of effect of buspirone on the Amphetamine and Morphine-Benzedrine Group subscales indicate lack of a euphorigenic property, but the score on the Lysergic Acid Diethylamide subscale, especially in the 40-mg group, suggests a dysphorigenic property at high doses. On the Amphetamine Self-Rating Scale, buspirone and diazepam affected only the sleep factor and only the 40-mg buspirone dose was distinguishable from placebo. On the Single-Dose Questionnaire, both buspirone and diazepam tended to be rated more as sedative-type drugs, but buspirone was generally less well liked than diazepam. Overall, the results, which suggest a lack of euphoria and the presence of dysphoria at high doses, indicate that buspirone has only limited, if any, abuse liability.

Antiarrhythmic properties of MJ 9067 in acute animal models.

A novel benzanilide derivative, MJ 9067, has been shown to abolish experimental atrial and ventricular arrhythmiase effectively and promote the return of normal sinus rhythm in a variety of animal models. At intravenous dose levels ranging from 0.5 to 3.2 mg/kg, MJ 9067 successfully converted atrial fibrillation induced by either local application of aconitine or electrical stimulation, and ventricular tachycardia elicited by intravenous injection of ouabain or digoxin. The compound was equally effective in vagotomized or nonvagotomized dogs, and in intact cats and monkeys. The ventricular ectopic rate in conscious dogs 18 to 20 hours after two-stage ligation of a coronary artery was also markedly reduced by the drug at 2 mg/kg i.v. At antiarrhythmic dose levels, there were no undesirable effects noted on peripheral blood pressure, heart rate or the configuration of the electrocardiogram.

Cyclic nucleotides as mediators of drug action.

PIP: Literature on the influence of cyclic nucleotides on the mechanism o f action of various drugs is reviewed. Cyclic nucleotides seem to participate in all aspects of nervous activity and thus mediate the effects of drugs acting on the central nervous system. They also seem to have a role in the actions of drugs on the cardiovascular system, the gastrointestinal tract, smooth muscle activity, and the immune response. The drugs which are discussed whose effects may be mediated by cyclic nucleotides include morphine, apomorphine, ethanol, local anesthetics, drugs affecting cardiac contractility, antihypertensive agents, drugs that reduce intraocular pressure, diuretics, anticancer and antiproliferation drugs, antiinflammatory agents, oral antidiabetic agents, muscle relaxants, carcinogenic agents, and contraceptive agents.^ieng

Aberrations of cyclic nucleotide metabolism in the hearts and vessels of hypertensive rats.

In the aortas and mesenteric arteries from spontaneous hypertensive rats and in the aortas from stress- and desoxycorticosterone-acetate-hypertensive rats, the intracellular cGMP: cAMP ratios were significantly elevated when compared to the ratios in the aortas of the respective controls. Decreases in the intracellular cAMP or cGMP levels were consistently associated with increased activity of the cyclic-nucleotide-specific low K(m) phosphodiesterase (3':5'-cAMP 5' nucleotidohydrolase, EC 3.1.4.17). Increases in intracellular cGMP levels were associated with elevated guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity. Furthermore, adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity was less sensitive to stimulation by the beta-adrenergic stimulant isoproterenol in both the aortas and the hearts of the hypertensive animals. These changes could provide the biochemical basis for the (a) increased vascular smooth muscle tone and peripheral resistance observed in these animals, (b) increased reactivity to norepinephrine, and (c) decreased ability of aortas from hypertensive rats to relax. The presence of these same effects in different etiologic types of hypertension indicates that this aberration in cyclic nucleotide metabolism may represent a common metabolic defect basic to the hypertensive syndrome irrespective of etiology.