摘要:

AbstractAlpha‐2 agonists by an effect on alpha‐2 adrenoreceptors in the stomach (and probably in the brain also) suppress vagal nerve acetylcholine release thereby inhibiting gastric motility and secretion and inhibiting the development of gastric lesions in rats in the stress‐, reserpine‐, and cysteamine‐induced ulcer models. Since the effects of the alpha‐2 agonists are consistently inhibited by alpha‐2 blocking agents, their effects appear to be selectively mediated via the alpha‐2 receptor. It seems appropriate therefore that the role of the alpha‐2 receptors be recognized in studies of gastric function and

ISSN:0272-4391    

DOI:10.1002/ddr.430020202

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

年代:1982

数据来源: WILEY

摘要:

AbstractMK‐801 prevented tonic extensor seizures in the rat induced by bicuclline with the ED50being 23 μg/kg p.o. Clonazepam, phenobarbital, diazepam, phenytoin, γ‐acetylenic GABA, sodium valproate, and trimethadione were all less potent. In mice, MK‐801 was likewise the most potent (ED50= 0.35 mg/kg p.o.) compound in protecting against tonic seizures induced by electroshock. Clonazepam (ED50= 0.41 mg/kg p.o.) and MK‐801 (ED50= 0.67 mg/kg p.o.) were by far more potent than any of the other anticonvulsants tested versus bicuculline‐elicited seizures in mice. Besides being a potent anticonvulsant, MK‐801 demonstrated selectivity, since much higher doses were required in mice to block clonic convulsions produced by pentylenetetrazol (ED50= 11 mg/kg p.o.) and tonic seizures caused by strychnine (ED50>15 mg/kg p.o.) than were needed against electroshock or bicuculline.The anticonvulsant (electroshock) effect of MK‐801 in mice was unaffected by pretreating the animals with various receptor antagonists (atropine, mecamylamine, chlorpheniramine, tripelennamine, cyproheptadine, cinanserin, methysergide, cimetidine, and propranolol). MK‐801 was slightly, but significantly, antagonized by methergoline, naloxone, and theophylline, whereas haloperidol and especially α‐adrenoceptor blockers (prazosin, HEAT, phenoxybenzamine) markedly reduced the anticonvulsant effect of MK‐801. Haloperidol was selective for MK‐801, not affecting the anticonvulsant actions of phenytoin or phenobarbital. Prazosin antagonized phenytoin and phenobarbital, but to a much lesser extent than it antagonized MK‐801.MK‐801 is an extremely potent and selective anticonvulsant acting at least partly via a

ISSN:0272-4391    

DOI:10.1002/ddr.430020203

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

年代:1982

数据来源: WILEY

摘要:

AbstractMK‐801 at doses<100 μg/kg given orally induced an ipsilaterally directed directed rotational response in rats with a unilateral nigrostriatal lesion produced by 6‐hydroxydopamine. (+)‐Amphetamine, amfonelic acid, and methylphenidate also evoked ipsilateral turning with their dose‐response lines lying considerably to the right of that for MK‐801. Rotations caused by a standard test dose of 50 μg/kg of MK‐801 were reduced by pretreatment with haloperidol (ED50= 0.068 mg/kg IP), clozapine (ED50= 3.35 mg/kg IP), or prazosin (ED50= 0.15 mg/kg SC). MK‐801‐induced turning was also inhibited by pretreatment with α‐methyl‐p‐tyrosine (α‐MPT) and blocked by reserpine.Locomotor activity in mice was increased by MK‐801, amfonelic acid, (+)‐amphetamine, and methylphenidate. Following administration p.o., MK‐801 was the most potent in this regard and methylphenidate the least. Stimulation of locomotor activity by equivalent doses of the four compounds was differentially affected by pretreatment with α‐MPT or reserpine, Reserpinization abolished the increase in activity usually produced by MK‐801, amfonelic acid and methylphenidate, whereas (+)‐amphetamine was only partially (36%) inhibited. Locomotor stimulation by (+)‐amphetamine was, on the other hand, markedly reduced in α‐MPT‐pretreated mice, while the actions of the other three compounds were not singnificantly altered. The ability of all four compounds to increase motor activity was significantly antagonized by haloperidol, but prazosin at the dose (3 mg/kg SC) examined was an effective antagonist of only MK‐801 and (+)‐amphetamine.MK‐801 has effects in rodents resembling indirect‐acting central sympathomimetic substances such as amfonelic acid, (+)‐amphetamine, and methylphenidate. The central sympathomimetic actions of MK‐801 are mediated via catecholamine‐dependent processes. Results from the drug‐interaction studies in mice (locomotor activity) indicate that the precise mechanism of

ISSN:0272-4391    

DOI:10.1002/ddr.430020204

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

年代:1982

数据来源: WILEY

摘要:

AbstractMK‐801 was evaluated in rats for “antipunishment” and “anticonflict” activity in two procedures: (1) A conditioned emotional response (CER) test involving the suppression of lever‐pressing by unaviodable shock and (2) a simple conflict test in water‐deprived animals that were shocked for licking water. The effect of MK‐801 in both procedures was qualitatively similar to the benzodiazepines. Lever‐pressing in the CER test was increased by MK‐801 at doses ranging from 50–400 μg/kg administered orally (p.o.) at either 0.5 or 2 hours prior to testing. The number of shocks received in the “thirsty rat” conflict procedure was increased by MK‐801 at doses from 110–1,000 μg/kg p.o., providing the compound was given 2 or more hours before test. MK‐801 was without anticonflict activity when administered 1 hour prior to study.In squirrel monkeys trained in a response‐contingent conflict paradigm, a specific anticonflict effect for MK‐801 (50–400 μ/kg p.o.) was not demonstrable. As assessed by observing the overt behavior of squirrel monkeys, MK‐801 at doses greater than 100 μg/kg p.o. caused apparent “taming” or “tranquilization.” Chlordizepoxide and diazepam given, respectively, at doses above 1 and 2 mg/kg p.o. had a similar “taming” action. The benzodiazepines possessed a greater separation between doses producing “taming” and those causing ataxia than did MK‐801.The mode of action for the antipunishment effect of MK‐801 in rats is not known, but it was found that naloxone (2 or 5 mg/kg SC) antagonized the anticonflict actions of both MK‐801 and chlordiazepoxide. In vitro, MK‐801 was inactive (IC50>2 μM) with respect to competing for binding to rat brain tissue by various radioligands (diazepam, muscimol, apomorphine, spiroperidol, serotonin, LSD, WB‐4101, dihydroalprenolol, QNB, and 2‐chloroadenosine). An increase in3H‐diazepam binding in vitro in rat brain tissue wa

ISSN:0272-4391    

DOI:10.1002/ddr.430020205

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

年代:1982

数据来源: WILEY

摘要:

AbstractThe cardiovascular effects of two N‐di‐alkyl substituted analogs of dopamine and dopamine were tested in the dog. Intravenous administration of N, N‐diethyldopamine (DEDA) decreased mean arterial pressure, heart rate, and mildly depressed cardiac output. Intravenously administered N, N‐dipropyldopamine (DPDA) decreased mean arterial pressure, heart rate, and total peripheral vascular resistance. Both compounds inhibited reflex sympathetic responses produced by a bilateral common carotid occlusion. Femoral artery injections of DEDA or DPDA produced biphasic responses. A transient increase in femoral bed vascular resistance was followed by a decrease in femoral bed vascular resistance sensitive to alpha adrenoceptor antagonism. In contrast to DEDA and DPDA, intravenously administered dopamine increased cardiac output and heart rate while reducing arterial pressure and total peripheral vascular resistance. Femoral artery injections of dopamine resulted in a dose‐dependent constrictor response which was antagonized by alpha receptor blockade. These data demonstrate that DEDA and DPDA induce different cardiovascular responses from

ISSN:0272-4391    

DOI:10.1002/ddr.430020206

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

年代:1982

数据来源: WILEY

摘要:

AbstractNormotensive rats of the Sprague‐Dawley strain were administered either the centrally acting hypotensive drug clonidine (0.16 mg/kg IP) or the peripherally acting hypotensive drug hydralazine (1.25 mg/kg IP) to induce reliable hypotension (blood pressure reductions of 60–90 mm Hg), as measured by a tail cuff procedure. The opiate antagonist, naloxone (10–20 mg/kg IP), reversed clonidine but not hydralazine hypotension. Naloxone also failed to reverse hydralazine's hypotensive action in rats made hypertensive by renal ligation. Naloxone's reversal of clonidine (0.01 mg/kg IV) hypotension was confirmed in experiments in which blood pressure was measured through direct cannulation of the carotid artery. It is suggested that naloxone's antagonism of clonidine hypotension is located at a central nervous system site, and that clonidine hypotension may be mediated through an interaction with the brain opiate sy

ISSN:0272-4391    

DOI:10.1002/ddr.430020207

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

年代:1982

数据来源: WILEY

摘要:

AbstractThe antihistaminic effect of terfenadine was studied in the isolated guinea pig ileum, histamine skin wheals in guinea pigs and monkeys, and i.v. histamine‐induced death in guinea pigs. In the guinea pig ileum, terfenadine, 1 × 10−7M, shifted the histamine dose‐response curve to the right in a parallel fashion without affecting the dose‐response curve of acetylcholine and barium chloride. However, as the dose of terfenadine was increased (3.16 × 10−7and 1 × 10−6M) the histamine dose‐response curves were displaced to the right with a depression of the maximum response and a reduction of the slope. Thus an unsurmountable type of antagonism was observed. Acetylcholine was also antagonized in a similar fashion by these two concentrations. In contrast, terfenadine appeared to displace the barium chloride dose‐response curve to the right in a parallel fashion. At 0.4 and 0.8 mg/kg p.o., terfenadine shifted the histamine skin wheal dose‐response curves to the right in a parallel fashion, but at 1.6 to 6.4 mg/kg, terfenadine antagonized the histamine wheal dose‐response curves with a depression of the maximum and the slope of the curve. These results were also similar to those of cyproheptadine but were different from those of chlorpheniramine, which produced parallel shifts. In monkeys, terfenadine produced a substantially greater effect on the histamine wheal than did chlorpheniramine (both administered at 30 mg/kg p.o.). Terfenadine also completely protected against i.v. histamine‐induced death in guinea pigs. Terfenadine produced no atropine‐like effect against pilocarpine‐induced salivation in rabbits, no demonstrable histamine H2antagonism, no antiserotonin activity, no α or β antagonism, and no untoward cardiovascular effects. Most significantly, terfenadine had no overt central nervous system (CNS) effects in mice, rats, guinea pigs, or monkeys; whereas chlorpheniramine produced tremors and convulsions in mice and monkeys when tested at much lower doses than those used for terfenadine. It is concluded that terfenadine is an effective and specific antihistaminic compound with the potential advantage of

ISSN:0272-4391    

DOI:10.1002/ddr.430020208

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

年代:1982

数据来源: WILEY

摘要:

AbstractPower spectral analysis was applied to beagles' EEGs to determine if clinically effective antidepressants produce changes different from those produced by related drugs. Bipolar EEGs were recorded from screws chronically implanted in the skull 5 mm anterior and 10 mm posterior to bregma, 4 mm left of midline. The normalized spectral estimates obtained after intravenous drug injection (minus the temporally corresponding spectral estimates after saline) were averaged across dogs. Drug effects were related to dose and time. Reliable effects of imipramine, amitriptyline, desipramine, and mianserin were an increase in the percent of power in the 4.5–7.5 Hz (theta) band, an increased percent of power in the alpha band at low doses, a decreased percent of power above 22 Hz (beta‐2), and an increased total spectral absolute power, at doses that produced no symptoms. Chlorpromazine's EEG effects were similar to the antidepressants'. Atropine increased percent theta and decreased percent beta‐1 and beta‐2, but was distinguished from the above drugs since it also increased percent delta and produced symptoms at the lowest effective dose. The other drugs either had no effect on percent theta (physostigmine) or decreased it (chlordiazepoxide, dextroamphetamine, and cocaine); cocaine increased only percent delta. Chlordiazepoxide, dextroamphetamine, and physostigmine increased percent beta‐1 and/or beta‐2, and they either decreased total power (dextroamphetamine) or produced no change in this parameter, and thus were distinguished from antidepressants. The results support the conclusion that antidepressants have distinct acute effects on brain electrical activity, and suggest that novel antidepressants can be detected by EEG spectral analy

ISSN:0272-4391    

DOI:10.1002/ddr.430020209

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

年代:1982

数据来源: WILEY

摘要:

AbstractIn a double‐blind clinical trial carried out on 20 outpatients with the diagnosis of endogenous depression, amitriptyline (75–225 mg) was found to be somewhat faster in its therapeutic effects on depression than viloxazine (150–450 mg), whereas viloxazine was somewhat faster in its therapeutic effect on anxiety. Cardiovascular adverse effects were only encountered with amitriptyline, whereas gastrointestinal side effects were present with vilox

ISSN:0272-4391    

DOI:10.1002/ddr.430020210

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

年代:1982

数据来源: WILEY

摘要:

AbstractSeven aromatic bisguanylhydrazones and two related compounds were screened againstTrypanosoma brucei(EATRO 110M) in mice. The four most active were then screened againstT. congolense(TREU 1183) in mice and rats. Eradication of parasitemia through 28 (T. brucei) or 42 days (T. congolense) resulting from a single dose of drug administered IP either 4 or 24 hours (respectively) after infection was used as the criterion of activity. 1,3‐Diacetylbenzene bisguanylhydrazone dihydrochloride clearedT. congolensefrom 50% of the animals (ED50) at a dose of approximately 10 mg/kg and from mice infected withT. bruceiat approximately 15 mg/kg. This drug was also active when given 5 days after infection withT. congolense(ED50≅ 15 mg/kg). The isomorphous pyridine derivative, 2,6‐diacetylpyridine bisguanylhydrazone dihydrochloride, was active againstT. bruceiin mice (ED50≅ 8 mg/kg), but noncurative againstT. congolense. At therapeutic doses of these two compounds, reversal and clearance of parasitemia was often not observed for 2–4 days, suggesting a delayed mode of action. Moreover, 1–2 days after drug treatment, the infectivity of parasites obtained from treated animals was significantly reduced, if not abolished. These findings indicate that more intensive screening of aromatic bisguanylhydrazones against various species of trypanosomes i

ISSN:0272-4391    

DOI:10.1002/ddr.430020211

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

年代:1982

数据来源: WILEY