摘要:

AbstractFluoxetine is a selective inhibitor of serotonin uptake that does not have direct effects on catecholaminergic neurons. Like other serotonergic drugs, fluoxetine reduces food intake in rats, and the characteristics of these serotonergic drugs differ from those of amphetaminelike drugs. For instance, fluoxetine and other serotonergic drugs have been reported to suppress stress‐induced eating, to suppress carbohydrate intake selectively, and to suppress eating elicited by insulin injection. Tolerance to the food intake‐reducing effect of fluoxetine has not been seen in experimental conditions in which other anorectic agents have shown tolerance. Clinical trials in overweight, depressed patients and in nondepressed obese subjects have shown the ability of fluoxetine to reduce body weight in humans. Fluoxetine may represent a new appetite suppressant drug that will be useful in the management of obes

ISSN:0272-4391    

DOI:10.1002/ddr.430170102

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe cardiovascular effects of ascending doses (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg i.v.) of two angiotensin l‐converting enzyme (ACE) inhibitors, REV 6207 and enalapril, were assessed in conscious furosemide‐treated (3 mg/kg s.c.) monkeys. Both ACE inhibitors produced a dose‐related inhibition of the pressor response to angiotensin l (0.66 μ/kg i.v.) with concomitant decreases in mean arterial pressure and no change in heart rate. The calculated ED50values for REV 6207 (0.316 mg/kg) and enalapril (0.275 mg/kg) were similar and both abolished the pressor response to angiotensin l at a dose of 3 mg/kg. The results of the study show that REV 6207 is a potent nonsulfhydryl‐containing ACE‐inhibitor with blood‐pressure‐lowering activity comparable to enalapril in the conscious monkey with high

ISSN:0272-4391    

DOI:10.1002/ddr.430170103

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe interaction of the new antipsychotic risperidone (RIS) and haloperidol (HAL) with amphetamine (AMP) was studied in rats using an activity meter which measured horizontal, vertical, and stationary components of motility. All three components increased markedly and progressively after AMP doses between 0.63 and 5.00 mg/kg (hyperactivity dose range). At still higher doses of 10.0 to 80.0 mg/kg, stationary movements (reflecting stereotypy) further increased, whereas horizontal activity was much reduced and vertical activity virtually abolished. Both HAL and RIS were potent AMP antagonists. Doses on the order of 0.02 to 0.04 mg/kg significantly reduced hyperactivity and reversed stereotypy to a motility pattern equivalent to that of a lower AMP dose. Both compounds were able to restore normal motility at any dose level of AMP stimulation. At the lowest dose of AMP (0.63 mg/kg), the required normalization doses were comparable for HAL (0.022–0.046 mg/kg) and RIS (0.034–0.16 mg/kg). In order to normalize motility induced by higher AMP doses up to 5.00 mg/kg, however, a relatively small dose increment of HAL (to 0.045–0.071 mg/kg), but a large dose increment of RIS (to 0.50–0.96 mg/kg) was required. In other words, the dose‐normalization curves of RIS and HAL diverged at low doses of AMP (0.63–5.0 mg/kg). At higher doses of AMP (10–80 mg/kg), however, this difference disappeared, and the slopes of the dose‐normalization curves became comparable for the two antagonists. It is suggested from these experiments that RIS and HAL are equipotent in controlling a low level of dopaminergic overactivity by partially occupying dopamine‐D2receptors. Higher levels of functional dopamine antagonism up to saturation of the D2receptors require a much higher dose of RIS than of HAL. Therefore, the risk of dopaminergic overblockade (and induction of EPS) is considered to be much smaller with

ISSN:0272-4391    

DOI:10.1002/ddr.430170104

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

年代:1989

数据来源: WILEY

摘要:

AbstractThis study compareo the effects of diprafenone, a new class lc antiarrhythmic agent, and 5‐hydroxydiprafenone (5‐OHDP), an active metabolite of diprafenone, to standard class l antiarrhythmic agents (propafenone, flecainide, or lidocaine), in several pharmacologic models, to ascertain the potential for side effects relative to the currently available class l antiarrhythmic agents. Diprafenone and propafenone decreased blood pressure and heart rate in anesthetized rabbits at 3 and 7 mg/kg, i.v., respectively. Neuromuscular transmission in rabbit gastrocnemius muscle was partially (38%) inhibited after 3 mg/kg of diprafenone and 7 mg/kg of propafenone. Diprafenone and 5‐OHDP (10−4M), but not lidocaine, inhibited aggregation of human platelets evoked by sodium arachidonate and adenosine diphosphate. Diprafenone, fleoainide, and 5‐OHDP (10−4M) inhibited the contractile responses of guinea pig vas deferens to norepinephrine and spontaneous and bradykinin‐evoked contractions of the guinea pig uteri. Diprafenone and 5‐OHDP, but not flecainide, relaxed rabbit bronchial smooth muscle contracted by acetylcholine. Diprafenone, 5‐OHDP and propafenone (10−5M and 10−4M) also depressed the contractile responses of canine mesenteric arteries to transmural nerve stimulation. Thus, high concentrations of diprafenone (10−5M and 10−4M) depress smooth muscle and neural function. The depressant effects occur with 4ndash;40 times the antiarrhythmic concentration of diprafenone and are shared by propafenone and, in part, by 5‐OHDP and flecainide. It is unlikely that major peripheral side effects will occur with therapeutic

ISSN:0272-4391    

DOI:10.1002/ddr.430170105

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe voltage‐, rate‐, and concentration‐dependent effects of a new antiarrhythmic agent, SC‐40230, which is chemically similar to disobutamide, on cardiac action potentials were evaluated. Racemic SC‐40230 and its two stereoisomers caused equipotent reduction of the maximum rate of depolarization (V̇max) of action potentials recorded from guinea pig papillary muscle. Action potential duration and effective refractory period were shortened by the drug in papillary muscle and canine Purkinje fibers, but were not altered in guinea pig atria. Depression of V̇max by racemic drug was similar in all three preparations. SC‐40230 did not cause significant reduction of V̇max following a long rest period (no “rested state” reduction). Rate‐dependent depression of V̇max was observed when papillary muscles were stimulated at rates slower, but not greater than 30 pulses/min. In papillary muscles depolarized by 10 mK Ko+, steady‐state depression of V̇max during a stimulus train of 200 pulses/min was 18% in the absence of drug and 56% in the presence of 30 μM SC‐40230. Onset of V̇max reduction was monoexponential (rate constant = 0.064 [action potentials]−1). Recovery from depression of V̇max following the train of stimuli was monoexponential in both control (tau = 11.0 sec) and in the presence of 30 μM SC‐40230 (tau = 27.8 sec). Thus, SC‐40230 appears to slow recovery from slow inactivation of Na current. Rate‐dependent depression of V̇max was voltage dependent. The V1/2 for the relationship between V̇max and resting membrane potential was shifted by −8 mV when determined at a stimulation rate of 120 pulses/min, but was not altered at 12 pulses/min by the drug. Thus, SC‐40230 has typical class I activity on isolated cardiac mu

ISSN:0272-4391    

DOI:10.1002/ddr.430170106

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe in vitro binding of the tricyclic compound (+)‐[3H]MK‐801 to membranes from rat brain cerebral cortex has been shown to be enhanced by L‐glutamic acid and inhibited by the noncompetitive N‐methyl‐D‐aspartate (NMDA) antagonist phencyclidine (PCP) and the competitive NMDA antagonist 3‐[(±)‐2‐carboxypiperazin‐4‐yl]propyl‐1‐phosphonic acid (CPP). We characterized these interactions in ligand saturation experiments. As noted by others, the KDwas decreased by L‐glutamic acid. In addition, we noted a slight but significant increase in Bmax in the presence of the excitatory amino acid. PCP increased the KDin a fashion characteristic of competitive inhibition, but it also increased Bmax in a fashion which mimicked L‐glutamic acid. That this effect might be mediated by a direct action of PCP at the NMDA binding site was confirmed by the ability of CPP to block the PCP‐induced increase in Bmax. These data suggest that the chemical structure of PCP may represent a new starting point for the development of agents which

ISSN:0272-4391    

DOI:10.1002/ddr.430170107

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

年代:1989

数据来源: WILEY

摘要:

AbstractInvestigation of a novel series of rigid heterocyclic compounds revealed that U‐66444B caused hypothermia in mice which was blocked by haloperidol but not by yohimbine. Inhibition of locomotor activity by U‐66444B was also blocked by haloperidol, andd‐amphetamine‐stimulated motor activity was antagonized by U‐66444B. These results suggest that this compound might be a dopamine receptor agonist acting at presynaptic receptors to inhibit the release of dopamine. Evaluation of dopamine release by the measurement of 3‐methoxytyramine levels in the corpus striatum revealed that U‐66444B decreased apparent dopamine release. In support of the involvement of presynaptic receptors in the action of this compound, the ability of U‐66444B to reduce the rate of dopamine synthesis (dihydroxyphenylalanine [DOPA] accumulation) was enhanced by gamma butyrolactone and synthesis and metabolism (dihydroxyphenylacetic acid [DOPAC]and homovanillic acid [HVA]) of dopamine in the striatum was not markedly altered by prior kainic acid lesions. Thus, feedback pathways from postsynaptic dopamine receptors did not seem to be principally involved. The measurement of U‐66444B brain levels at various time intervals after s.c. or p.o. administration of the drug to mice revealed that the drug was bioavailable by either route and persisted in brain for up to 2 hr. Studies with the enantiomers of U‐66444B demonstrated that the (+) enantiomer (U‐68553B) was by far the more potent and that this was not related to pharmacokinetics as both enantiomers generated comparable brain levels of drug. U‐68553B appears to be a structurally novel dopamine receptor agonist that has effects at presynaptic dopamine receptors that may be

ISSN:0272-4391    

DOI:10.1002/ddr.430170108

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

年代:1989

数据来源: WILEY

摘要:

AbstractCholecystokinin octapeptide (CCK‐8) has been shown to be involved in memory processes. For example, in the absence of endogenous CCK‐8 in the brain, memory processes are imparied. In order to extend the understanding of this relationship, the present study observed the effect of novel potent CCK‐8 antagonists, L‐364,718 and CR 1409, on active avoidance responding in the rat. These antagonists caused marked impairment in the performance of the learned task when administered intracerebroventricularly immediately after the learning trials. The results suggest that CCK‐8 is indispensable for memory

ISSN:0272-4391    

DOI:10.1002/ddr.430170109

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

年代:1989

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430170110

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

年代:1989

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430170111

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

年代:1989

数据来源: WILEY