摘要:

AbstractAcadesine (AICA‐riboside) is a nucleoside analog with cardioprotective properties. Most previous studies demonstrating cardioprotection with acadesine have been conducted in buffer‐perfused hearts, and no study has investigated the dose‐response relationship to acadesine in a blood‐perfused model. The objective of this study was to investigate the dose‐related cardioprotective effects of acadesine in donor‐perfused, isolated rabbit hearts subjected to 12 × 3 min episodes of global ischemia with intervening periods of reperfusion of 5 min duration. Five groups of hearts were studied: saline control and four treatment groups of acadesine, 0.1, 0.2, 0.5, 2.0 gm/kg/min (0.4, 0.8, 2.0, 8.0 μmol/kg/min) constant intravenous infusion to the support animal. Left ventricular (LV) pressure and coronary blood flow (CBF) in the isolated hearts were measured. In control hearts, baseline LV developed pressure averaged 129 ± 7 mmHg and declined to 43 ± 3% of baseline after 12 periods of ischemia and reperfusion. Acadesine significantly improved recovery of function at the lower doses tested, i.e., hearts treated with 0.1, 0.2, and 0.5 mg/kg/min (0.4, 0.8, 2.0 μmol/kg/min) recovered 61 ± 5%, 67 ± 7%, and 65 ± 7% of LV pressure, respectively (P<0.05 vs. saline). This protective effect was not observed with the highest dose of acadesine, 2.0 mg/kg/min (8.0 μmol/kg/min) (52 ± 6%). The greatest recovery of function corresponded to plasma acadesine concentrations of 27 ± 6.0 μM, but the beneficial effect was lost when plasma concentrations reached 205 ± 28 μM. These results suggest that repetitive episodes of ischemia and reperfusion induced stunning in isolated blood‐perfused rabbit hearts, and that the severity of this dysfunction is attenuated by treatment with acades

ISSN:0272-4391    

DOI:10.1002/ddr.430310302

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe metabolic action of an extract ofGinkgo biloba(EGb 761) has been examined in an ex vivo study of rat erythrocytes. Oral administration of EGb 761 (100 mg/kg/day) for 5 days to Wistar rats caused an increase in the in vitro uptake of glucose by erythrocytes, especially in high‐glucose (13.32 mM) medium, an effect that was associated with an increase in intracellular energy metabolism and reflected as a significant reduction in free glucose concentration. In contrast, the lactate concentration of the erythrocytes and lactate release to the bathing medium were not modified. Conversion of glucose into glycogen was significantly increased in the erythrocytes of EGb 761‐treated animals. Taken together, these findings indicate that in vivo administration of EGb 761 exerts an action favoring the transformation of glucose into glycogen, its storage form. Oral administration of the EGb 761 constituent bilobalide (4 or 8 mg/kg/day) for 5 days caused similar changes in the uptake of glucose and its conversion into glycogen. However, in contrast to the total extract, bilobalide treatment did not increase the energy‐yielding consumption of glucose. © 1994 Wiley‐L

ISSN:0272-4391    

DOI:10.1002/ddr.430310303

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

年代:1994

数据来源: WILEY

摘要:

Abstract“Xiao‐Chai‐Hu‐Tang” is a herbal medicine that has been used for the treatment of pyretic diseases in China for several thousand years. In Japan, this medicine was modified into “Sho‐saiko‐to,” a prescription drug with standard quality and volume of ingredients. It is widely used as a biological response modifier in the treatment of chronic viral liver diseases. Several researchers have reported improvement of general physical conditions and the drug's usefulness in preventing liver cancer development. In this in vitro study, peripheral blood mononuclear cells (PBMC) were obtained from 12 healthy volunteers, and Sho‐saiko‐to (TJ‐9) was added to the cultures of the PBMC. Dose‐dependent increases in the levels of tumor necrosis factor‐α (TNF‐α) were observed in the cultures. Similar but smaller increases in the TNF‐α levels were also observed when other Japanese herbal medicines, Dai‐saiko‐to (TJ‐8) or Saiko‐keishi‐to (TJ‐10), were added to the cultures. These results demonstrated that the increases of TNF‐α levels are specifically due to Sho‐saiko‐to and other drugs with similar ingredients. TNF‐α is believed to have anti‐tumor effects and also to have an important role as IL‐1 in the defense mechanism of the body. Therefore, the induction of TNF‐α could also be useful in clinical treatment, and this effect could be one of the mechanisms by which Sho‐saiko‐to demonstrates efficacy in the treatment of

ISSN:0272-4391    

DOI:10.1002/ddr.430310304

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe effect of sertindole in models of mesolimbic dopamine excess in the rat was evaluated. Sertindole (0.0057–0.011 μmol/kg = 2.5–5 μg/kg, sc) and haloperidol (0.13–0.27 μmol/kg = 50–100 μg/kg, ip) inhibited the hyperactivity caused by the acute intra‐accumbens injection of amphetamine (20 μg). The administration of sertindole (0.0057–2.8 μmol/kg = 2.5 μg–1.25 mg/kg, sc daily), haloperidol (0.027–0.40 μmol/kg = 10–150 μg/kg, ip bd) or clozapine (15–31 μmol/kg = 5–10 mg/kg, ip, bd) during a 13‐day period of dopamine infusion (25 μg/24 h) into the nucleus accumbens reduced the dopamine‐induced hyperactivity response to control levels, except at the highest dose which reduced activity to below control levels. Locomotor activity remained at control levels after discontinuing the dopamine/sertindole treatment regimen, whereas discontinuation of the dopamine/haloperidol treatment regimen resulted in rebound hyperactivity. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc) given either once daily or once every 2 days prevented the development of hyperactivity in the intra‐accumbens dopamine infusion model. One injection given every 4 days failed to modify the response to a dopamine infusion. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc daily) inhibited hyperactivity caused by unilateral infusion of dopamine (50 μg/24 h, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test). In contrast to haloperidol, sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusion, sertindole, like haloperidol and clozapine, can reduce raised mesolimbic dopaminergic activity in the rat. Sertindole differs from haloperidol by its ability to return the hyperactivity respons

ISSN:0272-4391    

DOI:10.1002/ddr.430310305

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

年代:1994

数据来源: WILEY

摘要:

AbstractLinopirdine (DuP 996) has been shown to enhance K+‐stimulated release of acetylcholine from cerebral cortex, striatum, and hippocampus of rats in vitro. X9121 is a structurally different compound identified as having similar release properties. The present experiments compare the effects of linopirdine and X9121 on cognitive deficits in aged rats, and on the pharmacological properties in young rats. For cognitive testing, aged male Fischer‐344 rats (24 months old, n = 116) received either vehicle or one of 5 doses of linopirdine or X9121 prior to behavioral testing; young rats (4 months old, n = 13) were controls and received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze, and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. Linopirdine (0.25, 2.5, and 8.5 mg/kg po [0.64, 7.4, and 25 μmol/kg]) and X9121 (0.85 and 8.5 mg/kg po [2.1 and 24 μmol/kg]) moderately improved place discrimination. None of the doses tested improved repeated acquisition or sensorimotor function. No behavioral indications of toxicity were observed. Acetylcholine release, acetylcholinesterase (AChE) inhibition, and nicotinic and muscarinic binding were measured in vitro in cerebral cortical tissue from young male Wistar rats (2 months old). Both linopirdine and X9121 enhanced K+‐stimulated release from cerebral cortex; X9121 produced greater release with a broader range of active concentrations. Linopirdine weakly inhibited AChE (1,000 × weaker than physostigmine) and X9121 did not. Neither drug bound significantly to muscarinic or nicotinic cholinergic receptors. These results support the hypothesis that linopirdine and X9121 have some cognition enhancing properties which may be due to enhancement of stimulation induced acetylcholine release. These results suggest that linopirdine and X9121 may be useful in treating disorders involving cognitive impairment. © 1994 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430310306

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe evaluation of gross structural homologies between the competitive cholecystokinin‐A (CCK‐A) receptor antagonists lorglumide and devazepide formerly enabled the development of compact hybrid analogues [Van der Bent et al. (1992): J Med Chem 35:1042–1049]. In the follow‐up study described here, we aimed to closely examine the structural and functional relationship between N‐acyglutamic acids like lorglumide and our hybrid derivatives. For this purpose, the most potent hybrid CCK‐A antagonist (Ki= 0.09 μM) was modified by the addition of the propionic acid moiety that is unique to the N‐acylglutamic acids. Additionally, a number of propionic acid and butyric acid derivatives were prepared in order to explore the SAR profile of the carboxylic acid moiety in this series. The prepared compounds were tested in vitro as antagonists of the binding of [3H]‐(±)‐L‐364,718 to rat pancreas membranes. With CCK‐A affinities above 1 μM, all derivatives of the initial hybrid structure, including the propionic acid derivative that closely resembles lorglumide, proved to be considerably less potent. It would appear that the retained structural differences between lorglumide and the novel hybrid antagonists result in a divergence of their binding modes that precludes a favourable interaction of the added functionality of the latter compounds. Alternatively, the obtained results may question the vital role that has been attributed to the carboxylic acid function of the N‐acylglutamic acids as a counterion to a cationic residue in the binding si

ISSN:0272-4391    

DOI:10.1002/ddr.430310307

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe structure‐activity relationships for a variety of adenine nucleotide analogues at P2Xand P2Y‐purinoceptors were investigated. Compounds formed by structural modifications of the ATP molecule including substitutions of the purine ring (C2, C8, N1, and N6‐substituents, and a uridine base instead of adenine), the ribose moiety (2′ and 3′‐positions), and the triphosphate group (lower phosphates, bridging oxygen substitution, and cyclization) were prepared. Pharmacological activity at P2Y‐purinoceptors was assayed in the guinea pig taenia coli, endothelial cells of the rabbit aorta, smooth muscle of the rabbit mesenteric artery, and turkey erythrocyte membranes. Activity at P2X‐purinoceptors was assayed in the rabbit saphenous artery and the guinea‐pig vas deferens and urinary bladder. Some of the analogues displayed selectivity, or even specificity, for either the P2X‐ or the P2Y‐purinoceptors. Certain analogues displayed selectivity or specificity within the P2X‐ or P2Y‐purinoceptor superfamilies, giving hints about possible subclasses. For example, 8‐(6‐aminohexylamino)ATP and 2′,3′‐isopropylidene‐AMP were selective for endothelial P2Y‐purinoceptors over P2Y‐purinoceptors in the guinea pig taenia coli, rabbit aorta, and turkey erythrocytes. These compounds were both inactive at P2X‐purinoceptors. The potent agonist N6‐methyl ATP and the somewhat less potent agonist 2′‐deoxy‐ATP were selective for P2Y‐purinoceptors in the guinea pig taenia coli, but were inactive at P2X‐purinoceptors and the vascular P2Y‐purinoceptors. 3′‐Benzylamino‐3′‐deoxyATP was very potent at the P2X‐purinoceptors in the guinea pig vas deferens and bladder, but not in the rabbit saphenous artery and was inactive at P2Yreceptors. These data suggest that specific compounds can be developed that can be utilized to activate putative subt

ISSN:0272-4391    

DOI:10.1002/ddr.430310308

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe chronic toxicity of amesergide, a selective (5HT2/5HT1c) serotonin antagonist, was evaluated in rhesus monkeys given daily nasogastric doses of 0, 5, 10, or 22.5 mg/kg for 1 year. An initial high dose of 25 mg/kg was reduced after approximately 1 week of dosing due to severe behavioral effects, including lethargy, a trance‐like appearance, and rigidity, that interfered with the animal's ability to eat and drink. The behavioral effects, although still present at the new high dose of 22.5 mg/kg were less intense and subsided prior to subsequent daily dosing. All animals survived the treatment period. Clinical signs associated primarily with early treatment at the 25‐mg/kg dose level resulted in reductions of body weights and food consumption. After the high dose was reduced from 25 mg/kg to 22.5 mg/kg, there were no significant effects on body weight gain or food consumption when compared to controls. Plasma concentrations of amesergide and its metabolites increased in a dose‐dependent fashion. Areas under the plasma concentration‐time curve (AUC) and peak plasma concentrations (Cmax) decreased substantially as the study progressed. Stress‐related decreases occurred in leukocytic and erythrocytic parameters of high‐dose males, but values returned to near pretest by study termination. Organ weights as well as gross and histological examination of tissues from animals of all treatment groups revealed no treatment‐related lesions. No adverse effects occurred at daily doses of 5 or 10 mg/kg. © 1994 W

ISSN:0272-4391    

DOI:10.1002/ddr.430310309

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

年代:1994

数据来源: WILEY

摘要:

AbstractThis study examined the effect of acute and chronic administration of the selective 5‐HT3receptor antagonist BRL 46470A, an analog of granisetron, on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (A9 or SNC) and the ventral tegmental area (A10 or VTA) in the rat. In the A10 area, the acute administration of BRL 46470A decreased the number of spontaneously active DA cells at a dose of 0.1 mg/kg (0.28 μmol/kg) ip, yet increased the number of spontaneously active DA cells at a dose of 0.3 mg/kg (0.84 μmol/kg). The chronic administration (21 days) of BRL 46470A appeared to produce a multiphasic dose‐response curve. Thus, the chronic treatment with BRL 46470A increased the number of spontaneously active A10 DA cells at 0.03 (0.084 μmol) and 0.3 mg/kg, but decreased the number of spontaneously active A10 DA cells at a dose of 0.1 mg/kg. In contrast, BRL 46470A did not decrease the number of spontaneously active A9 DA cells after either acute or chronic administration (0.01‐0.3 mg/kg). However, BRL 46470A did increase the number of spontaneously active A9 DA cells at acute and chronic doses similar to those that were effective in A10. The iv administration of (+)‐apomorphine (APO) not only failed to reverse the decrease produced by chronic administration of BRL 46470A at 0.1 mg/kg, but further decreased the number of spontaneously active A10 DA cells. Similar to the results obtained with granisetron, the pretreatment of naive rats with either 0.01 or 0.1 mg/kg iv of BRL 46470A significantly potentiated (2‐fold) the suppressant action of APO on the basal firing rate of A10, but not A9 DA cells. Overall, our results indicate that similar to granisetron, chronic BRL 46470A at 0.1 mg/kg selectively decreases the number of spontaneously active A10 DA cells, via a mechanism not related to depolarization inactivation. Presently, it is not clear what factors may contribute to the multiphasic dose‐response curve of BRL 46470A. © 1994

ISSN:0272-4391    

DOI:10.1002/ddr.430310310

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

年代:1994

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430310311

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

年代:1994

数据来源: WILEY