摘要:

AbstractPsychotropic drugs from various classes were tested in a set of behavioural test models for antidepressant activity in order to establish the validity of these models for predicting such activity. The drugs included six recently developed antidepressants with proven clinical effectiveness, namely zimelidine, viloxazine, ciclazindol, amoxapine, bupropion, and trazodone. They were tested in the following models: The muricide rat model (with a measure of specificity provided by the shuttle‐box test); the acquired immobility (behavioural despair) test with mice; potentiation of amphetamine‐induced exploratory behaviour of rats; and potentiation of yohimbine lethality in mice. None of the models is in itself sufficient to predict antidepressant activity in the compounds tested. A combination of the muricidal rat/shuttle‐box paradigm and the acquired immobility test with mice would detect all known antidepressant compounds. This combination can be used to detect compounds comparable to those antidepressants possessing clinically established antidepressant act

ISSN:0272-4391    

DOI:10.1002/ddr.430050402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractPronounced lesions of the gastric mucosa were induced by Compound 48/80 (1.0 mg/kg, i.v.) in rats protected from lethal shock of released histamine by the experimental histamine H1‐antagonist R 37 617. The intensity score of the lesions correlated with serum pepsinogen levels. Generally the stomachs were greatly distended and contained blood and regurgitated food residues. Compounds from many different pharmacological classes were tested in this procedure. Complete protection was obtained with serotonin antagonists. Also isoproterenol and salbutamol fully protected, apparently by counteracting the serotonin‐induced circulatory stasis. No obvious effect was obtained with antagonists of acetylcholine, dopamine, and histamine, with α‐ and β‐adrenergic blocking agents, with narcotic analgesics, and with various other agents unless doses were administered that by far exceeded the range of their primary activity. The lowest ED50 of ketanserin for protection was 0.15 mg/kg (time—2 hr, both s.c. and p.o.), indicating its high oral effectiveness against venoconstriction induced by endogenous serotonin. These doses also abolished cyanosis and reduced stomach distension, abnormal gastric contents, and serum pepsinogen levels. In view of the recently elucidated differences between serotonin antagonists, the mast cell 5‐HT gastric lesion test appears appropriate to measure the peripheral serotonin S2‐antagoni

ISSN:0272-4391    

DOI:10.1002/ddr.430050403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractLY53857 is a potent antagonist at vascular 5HT2receptors that lacks prominent α1or dopamine antagonist activity. The present report investigates the interaction of LY53857 with other receptor mechanisms. LY53857 showed no agonist activity in the guinea pig trachea, guinea pig atria, guinea pig ileum, or rat vas deferens. Furthermore, LY53857 did not antagonize histamine (H1) or β2receptors in the guinea pig trachea, β1in the guinea pig atria, muscarinic, or angiotensin I receptors in the guinea pig ileum. However, LY53857 did block α2receptors (−log KB= 6.51) as determined by antagonism of the inhibitory effects of the selective β2agonist, UK‐14,304, on the twitch response in the guinea pig ileum. LY53857 antagonized β2receptors at concentrations approximately 6000‐fold higher than necessary to block 5HT2receptors (−log KB= 10.3). Taken in concert, these data support the contention that LY53857 is a highly selective antagonist of 5HT2receptors, and that LY53857 is a useful tool with which to probe 5HT2receptors and serotonerg

ISSN:0272-4391    

DOI:10.1002/ddr.430050404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractPirlindole, a tetracyclic drug, is known to have a reversible and short‐lived monoamineoxidase inhibitory activity. When administered after a supramaximal inhibitory dose of a classic monoamineoxidase inhibitor, pirlindole continues to antagonize reserpine‐induced ptosis and oxotremorine‐induced akinesia in mice. These results indicate that some central effects of pirlindole are partially independent of its monoamineoxidase inhibitor act

ISSN:0272-4391    

DOI:10.1002/ddr.430050405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractThe effect of 6(2‐isopropylaminopropyl)‐3‐pyridinol fumarate (CGS 5649B) on mechanical function and tissue energy levels of the isolated rat heart subjected to 35 min of global ischemia and 25 min of reperfusion was examined. Hearts perfused with buffer supplemented with the drug (0.03–0.4 mM) showed an improvement in the recovery of mechanical function and an attenuation in the loss of tissue adenosine triphosphate (ATP) levels following the 25‐min reperfusion period. In nonischemic tissue, the drug mediated a positive inotropic effect, a slight increase in glucose utilization and oxygen consumption, and a significant change in the levels of some key glycolytic intermediates. It also quenched hydroxyl radicals produced by a hypoxanthine‐xanthine oxidase reaction system. These results suggest that CGS 5649B has a beneficial effect on hearts subjected to ischemia by reducing energy demand. This may be related to its ability to scavenge highly reactive oxy

ISSN:0272-4391    

DOI:10.1002/ddr.430050406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractThe direct vasoaction of inosine was examined and compared to that of adenosine in small coronary arterial rings (0.3–0.6 mm o.d.) from the dog heart. Rings were contracted with KCI, and relaxation responses to increasing nucleoside concentrations were recorded. Both inosine (16 rings) and adenosine (12 rings) elicited relaxation responses that were linearly related to the logarithm of nucleoside concentration. In eight rings for which both inosine and adenosine responses were obtained, the geometric mean ED50for adenosine was 0.54 μM, compared to 242 μM for inosine (p0.05). In four rings studied, aminophylline abolished the response to adenosine. In five rings studied, aminophylline abolished the response to adenosine. In five rings studied, aminophylline abolished the inosine response in only two rings; in the remaining three rings, the inosine response was attenuated but not abolished. These results indicate that inosine exerts a direct vasodilatory action on small coronary arteries and that this vasoaction is in part aminophylline‐sens

ISSN:0272-4391    

DOI:10.1002/ddr.430050407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractA characteristic profile of activity was obtained in six isolated tissues for the calcium channel antagonists nifedipine, diltiazem, verapamil, and lidoflazine. All drugs produced relaxation of K+depolarized guinea pig ileal longitudinal muscle strips and K+depolarized canine coronary artery, depression of electrically stimulated basal contractions of guinea pig left atria, and depression of guinea pig right atrial rate. Also, all drugs produced parallel dextral displacement of concentration‐response curves to calcium in guinea pig depolarized taenia caeci. The potency for this effect was quantified by Schild analysis yielding the following pA2estimates: nifedipine 9.5, diltiazem 7.65, verapamil 7.8, and lidoflazine 7.0. Nifedipine, diltiazem, and lidoflazine produced no relaxation of methoxamine‐contracted rabbit aortae while weak effects were observed with verapamil at concentrations 100 times greater than those required to reverse calcium effects in other tissues. In general, nifedipine and diltiazem displayed selectivity for smooth muscle over cardiac muscle while verapamil showed the least selectivity in this reg

ISSN:0272-4391    

DOI:10.1002/ddr.430050408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractIsolated strips of rabbit thoracic aorta, contracted to a steady‐state isometric tension by measured doses of α‐adrenoceptor agonists, exhibit a transient loss in tension when exposed to a flash of ultraviolet light. This response consists of an initial decrease in tension followed by a spontaneous restoration to equilibrium tension. The time course of the return to equilibrium from maximum relaxation is a biphasic exponential, resolvable into a fast phase and a slow phase. Previous work has shown that the fast phase of recovery is drug‐independent, but that the slow phase of recovery is drug‐dependent; i.e., the rate of return to equilibrium tension is unique for each agonist used to produce the initial contraction. When a system in equilibrium is perturbed in a manner such as this, the return to equilibrium is characterized by a time constant that is a function of the drug concentration. A plot of this time constant against drug consentration yields a straight line of slope and y‐intercept equal to the forward and reverse rate constants, respectively, of the chemical reaction. In this study, equilibrium perturbation by UV light was used to determine the forward and reverse rate constants (k1and k2) of the drug‐receptor interaction and the dissociation constants (KA= k2/k1) of each of three α‐adrenoceptor agonists, norepinephrine, phenylephrine, and methoxamine. The values of KAreported here for all three agents and for different degrees of passive stretch (0.25‐g and 10‐g preload for norepinephrine, 10‐g preload for phenylephrine and methoxamine) are not significantly different from the corresponding values reported using the method of partial irreversible blockade of receptors. These findings are compatible with the hypothesis that the radiation disrupts the drug‐receptor equilibrium. Regardless of mechanism, however, the photorelaxation phenomenon may provide an additional tool for classifyi

ISSN:0272-4391    

DOI:10.1002/ddr.430050409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractCardiovascular effects of prenalterol, a partial beta adrenoceptor agonist, were investigated in pentobartial anesthetized dogs. In these preparations, in which the heart was acutely denervated, intravenous administration of prenalterol significantly enhanced contractility (left ventricular max dP/dt) as well as heart rate, and reduced left atrial pressure. Hence the data confirmed that this agent is an effective inotropic as well as a chronotropic agent. Ventricular function curves were determined in these studies to establish the efficacy of the myocardium in handling volume loads at various filling pressures. In order to relate the increased output directly to increases in inotropy, heart rate was kept constant by electrical pacing. Prenalterol significantly shifted these curves upward and to the left, indicating enhanced contractility. In a separate series, it was demonstrated that the inotropic effect of prenalterol persists for longer durations as indicated by the significant shift that occurred in left ventricular function curves 70 min after administration of a single dose of the drug. The data collectively suggest that prenalterol, an orally effective inotropic agent, possesses prolonged duration of action; hence, this drug may be more preferable than dopamine or dobutamine in the treatment of heart failure since the effects of these two agents are transient and are subjected to tolerance during continuous intravenous infusions.

ISSN:0272-4391    

DOI:10.1002/ddr.430050410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractEight healthy female volunteers received 150, 300, and 450 mg of HWA 285 and placebo according to a randomized, double‐blind crossover design. The subjects completed a battery of psychological tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings of drug effects (LARS), and a Sternberg memory scanning test (SMST) 1 and 2 hr following treatment. No statistically significant changes from placebo were observed on CFF, CRT, or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was significantly improved with respect to placebo 1 hr following treatment with HWA 285 at 150, 300, and 450 mg dose levels. The action of the drug was found to be specific in its effects on the central serial comparison stage of the information processing mode

ISSN:0272-4391    

DOI:10.1002/ddr.430050411

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY