摘要:

AbstractThe effect of santonin pretreatment on gastric mucosal injuries caused by 80% ethanol, 25% NaCl, 0.2 M NaOH, indomethacin, and combined treatment of ethanol and indomethacin was investigated in rats. The effects caused by ethanol on gastric mucus secretion, gastric levels of non‐protein sulfhydryl groups, and malondialdehyde and histopathological effects were also investigated. Santonin pretreatment at oral doses of 30, 60, and 120 mg/kg (121.8, 243.6, and 487.2 μmol/kg) provided a dose‐dependent protection against the ulcerogenic effects of different necrotising agents used. Further pretreatment with santonin afforded a dose‐dependent inhibition of ethanol‐induced depletion of stomach wall mucus, proteins, nucleic acids, non‐protein sulfhydryl groups, and an increase in malondialdehyde levels in gastric tissue. The histopathological lesions induced by ethanol in the gastric mucosa were also protected by santonin pretreatment. The protective effect of santonin against alcohol damage to the gastric‐wall mucosa may be mediated through its effects on mucus production, nucleic acids, and non‐protein sulfhydryl generation and its free‐radical scavenging.

ISSN:0272-4391    

DOI:10.1002/ddr.430340102

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe antimuscarinic profile of vamicamide, a novel compound for the treatment of pollakiuria, was investigated in both in vitro and in vivo preparations. Vamicamide (10 nM–10 μM) inhibited the contractile response of isolated guinea‐pig detrusor muscle to transmural electrical stimulation. In isolated guinea‐pig detrusor muscle, vamicamide also inhibited contractile response to carbachol with an IC50value of 0.71 μM, whereas it had little or no effect on detrusor contractions induced by KCl, BaCl2, or α, β‐methylene ATP. In binding studies with dog membrane preparations, the dissociation constant (Ki) of vamicamide against tritiated N‐methylscopolamine ([3H]NMS) binding was 172 ± 8 nM for the urinary bladder, which was lower (P<0.01) than those for the heart (322 ± 31 nM), stomach (317 ± 29 nM), and salivary gland (321 ± 32 nM). The Ki value for the cerebral cortex (95 ± 4 nM) tended to be lower than that for the urinary bladder. In binding studies with cloned human muscarinic receptor subtypes (m1–m3), the dissociation constant (Ki) of vamicamide against [3H]NMS binding was 89.0 ± 3.5 nM for the m3 receptor subtype, which was lower than those for the m1 (235 ± 5 nM,P<0.05) and m2 (593 ± 49 nM,P<0.01) receptor subtypes. In anesthetized dogs, vamicamide (3.2–100 μg/kg; 11–336 nmol/kg, iv) inhibited the carbachol‐induced contractile responses of the urinary bladder with an ID50value of 16.1 μg/kg (54 nmol/kg), the stomach with a value of 31.3 μg/kg (105 nmol/kg), the descending colon with a value of 10.1 μg/kg (34 nmol/kg), and secretory response of the salivary gland to carbachol with a value of 43.3 μg/kg (146 nmol/kg); the inhibitory effects of the compound on the stomach and salivary gland were weaker (P<0.01) than that on the urinary bladder. Furthermore, duration of the action of vamicamide was longer on the urinary bladder and descending colon than those on the stomach and salivary gland. These results suggest that vamicamide has a selective binding affinity to the muscarinic m3 receptor subtype and exhibits greater and longer inhibitory action on the urinary bladder than the other

ISSN:0272-4391    

DOI:10.1002/ddr.430340103

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe anxiolytic potential of the putative neuroleptic sertindole was assessed in various animal models of anxiety in rodents and in the marmoset human threat test. Sertindole facilitates the exploratory behaviour of mice and rats in the black and white two‐compartment box over a large dose range. Sertindole is more potent than diazepam, i.e., minimal effective doses (MED) in the mouse are 0.00023 nmol (0.1 ng/kg) and 0.46 μmol/kg (0.13 mg/kg), respectively, and MED in the rat are 0.23 nmol/kg (0.10 μg/kg) and 35 nmol/kg (10 μg/kg), respectively. Sertindole increases the time that pairs of rats spend in active social interaction (unfamiliar high light conditions) at extremely low doses (MED = 0.000023 nmol/kg [0.01 ng/kg]) being some 19 million‐fold more active than diazepam (MED = 0.44 μmol/kg; 0.13 mg/kg). Sertindole inhibits isolation‐induced aggressive behaviour in the mouse, but only at high doses, and sertindole does not inhibit shock‐induced suppression of drinking or footschock‐induced ultrasonic vocalization in rat. Sertindole similarly shows potent anxiolytic‐like activity in the marmoset human threat test (MED = 23 nmol/kg; 10 μg/kg). The range between anxiolytic doses and sedative doses is very large for sertindole, i.e., sedation is observed at 2,300 nmol/kg (1 mg/kg).

ISSN:0272-4391    

DOI:10.1002/ddr.430340104

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

年代:1995

数据来源: WILEY

摘要:

AbstractAdenosine and other adenosine receptor agonists have been shown to inhibit seizures in a variety of in vivo and in vitro models. In the present study, the anticonvulsive effects of the partially selective A2aagonist, N‐[(2‐methylphenyl)methyl]‐adenosine (metrifudil), were examined using both the amygdala kindling and 0‐Mg++‐induced bursting hippocampal slice seizure models. Fully amygdala‐kindled rats were injected with 1, 10, or 25 mg/kg (2.7, 27.0, or 67.4 μmol/kg) ip metrifudil, or vehicle (dimethyl sulfoxide), 20 min prior to receiving the kindling stimulus. Metrifudil significantly reduced after‐discharge duration in a dose‐related fashion compared to vehicle injections. After‐discharge threshold and behavioral seizure stage were not significantly affected. In the in vitro hippocampal slice preparation, stimulation of Schaffer collateral axons under 0‐Mg++conditions resulted in spontaneous and evoked epileptiform burst activity in the CA1 region. The addition of 1, 10, or 100 μM metrifudil to the 0‐Mg++media abolished this epileptiform activity in a concentration‐related fashion. These findings indicate that the adenosine agonist, metrifudil, may have anticonvulsive properties, and are in support of the premise that the adenosine system plays an anticonvulsive role in the central nervous

ISSN:0272-4391    

DOI:10.1002/ddr.430340105

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

年代:1995

数据来源: WILEY

摘要:

AbstractNaturally occurring and synthetic prostaglandins acting at EP type receptors have a number of physiological actions, including cytoprotective and antisecretory effects, that are therapeutically useful. In addition they can produce other effects, such as diarrhea. It is possible that these actions are mediated by different EP receptor subtypes. The actions of a subtype‐selective prostaglandin agonist has suggested that diarrhea is not due to activity at the EP3 receptor, while cytoprotection and antisecretory actions may be. The recent development of a bioavailable EP1 antagonist, SC‐51089, has made it possible to examine this more directly. SC‐30249, the active isomer of misoprostol, protects against indomethacin‐induced gastric lesions and produces diarrhea in rats. SC‐51089, ig, shifted the dose‐response curve for SC‐30249‐induced diarrhea significantly to the right. ED50values (assessed at 5 hr following administration of SC‐30249) were 13.8 μ/kg (0.036 μmol/kg) for SC‐30249 alone and 110.8 μg/kg (0.290 μmol/kg) for SC‐30249 plus SC‐51089. This antagonism of diarrhea was overcome by higher doses of SC‐30249. SC‐30249 dosedependently inhibited gastric lesions induced by indomethacin (ED50= 3.4 μg/kg, 0.009 μmol/kg, ig). SC‐51089 did not reduce the cytoprotective effects of SC‐30249 (ED50= 1.1 μg/kg, 0.003 μmol/kg, ig, SC‐30249 in combination with SC‐51089). These results are consistent with the hypothesis that the EP1 receptor subtype mediates the diarrheagenic effect of EP receptor agonists, but not their cytoprotective actions. These results provide a mechanistic basis for cytoprotective prostaglandins with grea

ISSN:0272-4391    

DOI:10.1002/ddr.430340106

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

年代:1995

数据来源: WILEY

摘要:

AbstractABT‐418 was functionally characterized as a neuronal nicotinic acetylcholine receptor (nAChR) channel agonist using preparations that contain nAChRs characteristic of the ganglionic subtypes. In PC12 cells, ABT‐418, like (−)nicotine, activated an inward current that decayed within seconds in the continued presence of agonist. ABT‐418 was 4‐fold less potent than (−)nicotine (EC50= 214 ± 30 μM and 52 ± 4 μM, respectively) while the efficacy of ABT‐418 was not significantly different from (−)nicotine when the peak response amplitude was measured. Responses to 300 μM ABT‐418 were reversibly inhibited 81 ± 3% by 10 μM mecamylamine, 38 ± 1% by 10 μM dihydro‐β‐erythroidine, and 82 ± 2% by 100 μM dihydro‐β‐erythroidine. These nAChR antagonists affected the response to (−)nicotine similarly. Furthermore, responses to maximal concentrations of ABT‐418 (3 mM) and (−)nicotine (1 mM) were not additive, consistent with ABT‐418 and (−)nicotine acting through the same receptor(s). However, the Hill coefficient for ABT‐418 (1.18 ± 0.20) was smaller than that for (−)nicotine (1.77 ± 0.18), and high concentrations of ABT‐418 appeared to elicit a more rapidly decaying response than did (−)nicotine. In the rat superior cervical sympathetic ganglion also, ABT‐418 was 2.5‐fold less potent than (−)nicotine in blocking nicotinic transmission, presumably through nicotinic receptor desensitization. These studies provide the most direct evidence that ABT‐418 activates nicotinic cholinergic channels, and suggest that ABT‐418 would have reduced potency compared to (−)nicotine in peripheral ganglia, consistent with the reduce

ISSN:0272-4391    

DOI:10.1002/ddr.430340107

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe effect of different ligands for the GABA‐BZD receptor and the NMDA receptor were studied in rats trained to discriminate (−)‐nicotine (1.9 μmol/kg) from saline in a standard two‐bar operant conditioning paradigm with food reinforcement. MK‐801 (0.03–0.3 μmol/kg), flumazenil (10–30 μmol/kg), and Ro 15–4513 (3–10 μmol/kg) did not generalize to (−)‐nicotine on nicotine‐trained rats, and when tested as antagonists they did not block the nicotine cue. Diazepam (3–10 μmol/kg) and ethanol (11–22 mmol/kg) did not have any effect by themselves, but they significantly attenuated the nicotine cue by 53 and 65%, respectively, without affecting the response rates of the animals. Pre‐treatment with flumazenil (30 μmol/kg) reversed the effect of diazepam but it did not reverse the effect of ethanol on the discriminative stimulus properties of (−)‐nicotine. The effect of ethanol was not blocked by Ro 15–4513 (10 μmol/kg). These data indicate that diazepam and ethanol modulate the expression of the nicotine cue and that the effect of diazepam is mediated via a benzodiaze

ISSN:0272-4391    

DOI:10.1002/ddr.430340108

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

年代:1995

数据来源: WILEY

摘要:

AbstractIn a clinical trial of tacrine in patients with Alzheimer's disease, improvement, measured by changes on both total (ADAST) and the cognitive sub‐component (ADASC) of the Alzheimer's Disease Assessment Scale (ADAS) over a 6‐week period, correlated significantly with plasma levels of tacrine. Change on the ADAS (both total and the cognitive subcomponent) also correlated significantly with three monohydroxylated metabolites of tacrine 1, hydroxy‐tacrine (1‐OH‐THA), 2, hydroxy‐tacrine (2‐OH‐THA), and 4, hydroxy‐tacrine (4‐OH‐THA). However, changes of the relatively small non‐cognitive component of the ADAS were not significantly correlated with plasma levels of tacrine. Multiple correlational analysis revealed that the combined influences of these metabolites were no greater than the effects of tacrine alone in ameliorating the symptoms of Alzheimer's disease. An alternative measure of cognitive performance, the Mini Mental State Exam (MMSE) did not correlate significantly with plasma concentrations of tacrine or its metabolites. Tacrine and these metabolites are bound to plasma proteins. In 10 patients with Alzheimer's disease receiving tacrine, the percentage of tacrine, 1‐OH‐THA, 2‐OH‐THA, and 4‐OH‐THA, that was free in plasma was found to be 19.7 ± 3.3, 51.3 ± 7.7, 40.7 ± 6.9, and 42.4 ± 6.3 (mean

ISSN:0272-4391    

DOI:10.1002/ddr.430340109

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

年代:1995

数据来源: WILEY

摘要:

AbstractLY274600 and LY274601 are the S (−) and R (+) enantiomers, respectively, of 8‐thiomethyl‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT). In in vitro studies, both enantiomers have high and selective affinity for the 5‐HT1Areceptor. However, LY274600 produced submaximal inhibition of forskolin‐stimulated cyclase activity, which indicates that it is a partial agonist, whereas LY274601 produced maximal inhibition of cyclase activity, which indicates that it is a full agonist in this model. Both of these enantiomers had potent in vivo pharmacological effects in rats that are characteristic of 5‐HT1Areceptor agonists including (1) a reduction of hypothalamic 5‐HIAA levels, (2) an increase in serum corticosterone levels, (3) a reduction in hypothalamic 5‐HTP accumulation after decarboxylase inhibition, (4) an induction of 5‐HT1Abehavioral responses, e.g., flat posture and lower lip retraction, and (5) a lowering of body temperature. In these general pharmacological tests, both compounds had a potency equal to or greater than 8‐OH‐DPAT but had a greater oral activity. LY274601 appeared to be either slightly more potent or efficacious than LY274600. In the drug‐discrimination studies using pigeons trained to identify the effects of 8‐OH‐DPAT, LY274601 was significantly more potent than LY274600, but both were less potent than 8‐OH‐DPAT. Both enantiomers restored full sexual reflex function to rats that had reduced sexual capacity. In rats with normal capacity for sexual reflexes but reduced performance, the enantiomers caused decreases in ejaculatory latencies and postejaculatory latencies and increases in copulatory efficiency and rate. No consistent differences between the enantiomers could be demonstrated in these estimates of total sexual performance, erectile capacity, and sexual drive. Both enantiomers increased punished responding at lower doses than were needed to decrease unpunished responding in pigeons, an effect that is indicative of anxiolytic activity. LY274600, a partial agonist, produced a significantly greater change in punished responding than did LY274601, a full agonist. Both compounds induced dose‐related decreases in immobility time and defecation rate in the rat forced swim model, which represent reductions in stress‐induced “behavioral despair” and stress‐induced gastrointestinal motility. Collectively, these pharmacological studies have shown that the substitution of a thiomethyl for hydroxyl group at the 8 position on the 2‐(di‐n‐propylamino) tetralin structure resulted in selective and potent agonists for the 5‐HT1Areceptor similar to that of 8‐OH‐DPAT but with improved oral potency. The preclinical efficacy studies demonstrated possible utilites for these compounds in the treatement of either sexual res

ISSN:0272-4391    

DOI:10.1002/ddr.430340110

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

年代:1995

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430340111

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

年代:1995

数据来源: WILEY