ISSN:0272-4391    

DOI:10.1002/ddr.430280102

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

年代:1993

数据来源: WILEY

摘要:

AbstractAlzheimer's disease (AD) is the most common form of senile dementia and it is a neurodegenerative disorder associated with a progressive deterioration of memory and cognitive capacity. Although one of the most characteristic abnormalities in AD patients is the reduced cholinergic input to the cortex, AD is a disorder that affects different neuronal populations in the brain, including the GABAergic neurons. The data regarding the participation of the central GABAergic system on memory indicate that: (1) drugs that facilitate GABA‐A and GABA‐B neurotransmission impair memory in experimental animals and in humans; (2) drugs that reduce GABA‐A neurotransmission facilitate memory in rodents; (3) the facilitatory effect of thee drugs has not been corroborated at the clinical level, as they show a small therapeutic window, but new drugs are presently being evaluated in clinical studies; (4) the cognitive effects of the GABAergic agents are dose‐ and time‐related, and cannot be explained by state‐dependency; (5) the effects of the GABAergic antagonists are centrally mediated, as peripherally acting drugs are ineffective in memory tests; (6) GABA and endogenous benzodiazepines are released in different brain areas during learning of different tasks and after the induction of long‐term potentiation (LTP); (7) GABA‐A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices; and (8) the amygdala, the basal forebrain, the septo‐hippocampal pathway, the trisynaptic circuit and the entorhinal cortex are likely candidate regions for the central actions of GABAergic drugs. The consolidation process of memory storage can be presently envisioned as multiple consolidation process that takes place in different brain circuits and at different times after the learning experience. The anatomical evidence on the presence of GABAergic neurons in brain areas relevant to memory (and affected in Alzheimer's patients) like the cortex, amygdala, septum, hippocampus and NBM, together with the electrophysiological and biochemical changes induced by the learning experience, suggest that the GABAergic neurons can critically modulate the electrical activity of these brain areas during the “multiple consolidation” process of memory storage. © 1993 Wiley‐Liss, Inc

ISSN:0272-4391    

DOI:10.1002/ddr.430280103

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

年代:1993

数据来源: WILEY

摘要:

AbstractComplexation of various equipotent doses of fentanyl‐like opioids in hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) results in a potentiation of the spinal activity of these opioids after both epidural and intrathecal administration in a fixed diluent volume of 10 μl. The first active and mot optimal concentrations of HP‐β‐CD after epidural administration differed between the opioids and varied from 1 to 20% HP‐β‐CD. The duration of deep surgical analgesia increased at optimal concentrations of HP‐β‐CD with a factor 3 for fentanyl (15% HP‐β‐CD), 3.6 for sufentanil (5–10% HP‐β‐CD), respectively. Increasing the concentrations of HP‐β‐CD above these optimal concentrations did not further potentiate the analgesic activity of the opioids. The complexation of the opioids in HP‐β‐CD also increased the duration of supraspinal side‐effects. However, except for lofentanil, the potentiations of the analgesic activity were always longer lasting than those for the secondary side‐effects. As a consequence, there was a gain in the total time of analgesia without side‐effects. After intrathecal administration, there was no gain in the duration of deep surgical analgesia after complexation of fentanyl, carfentanil and alfentanil in HP‐β‐CD. For both sufentanil and lofentanil, maximal potentiation of analgesia was measured at 10% HP‐β‐CD with, respectively, 2.8‐ and 1.7‐fold increases in the duration of analgesia. Also intrathecally, there was some gain in the duration of duration of analgesia without supraspinal side‐effects. These results on the potentiation of the opoids with HP‐β‐CD are discussed in

ISSN:0272-4391    

DOI:10.1002/ddr.430280104

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

年代:1993

数据来源: WILEY

摘要:

AbstractRG 12915, N‐(1‐azabicyclo[2.2.2.]octan‐3(S)‐yl)‐2‐chloro‐(5aS, 9aS)‐5a,6,7,8,9,9a‐hexahydrodibenzofuran‐4‐carboxamide, a potent antiemetic agent active in reducing emesis produced by antieoplastic agents, was examined in tests of 5‐hydroxytryptamine3(5‐HT3) receptor blockade. RG 12915 was found to be a potent antagonist of 5‐HT3receptor activation both in blocking 5‐HT‐induced contractions of guinea‐pig ileum and in blocking the Bezold‐Jarisch effect in the rat. Compared to several other 5‐HT3antagonists, RG 12915 had a greater pA2 value (11.2) for blocking 5‐HT‐induced contractions of guinea pig ileum than zacopride (8.3); BRL 43694 (granisetron) (9.1); and GR 38032F (ondansetron) (7.4). Falls in heart rate due to 5‐HT3receptor activation following intravenous (i.v.) administration of 5‐HT (the Bezold‐Jarisch effect) were also potently reduced by RG 12915. Minimum effective dose (MED) levels (in parentheses), defined as the lowest dose at which each compound produced a significant reduction in the Bezold‐Jarisch effect, were determined for RG 12915 (1.0μg/kg, i.v.); zacopride (3.0); granisetron (9.0); and ondansetron (27.0). The order of potency in blocking 5‐HT3receptor activation was generally the same as the order of potency in 5‐HT3receptor binding. RG 12915 had a lower Kivalue (0.17±0.02 nM, mean ± SEM) in binding studies using3H‐GR‐65630 as the ligand in rat entorhinal cortex tissue than either zacopride (1.5±0.4); granisetron (1.7±0.3); or ondansetron (6.2±2.1). RG 12915 was also found active in blocking contractions of guinea pig ileum and the Bezold‐Jarisch effect induced by the somewhat selective 5‐HT3receptor agonist 2‐methyl‐secrotonin. The results support the idea that this orally active antiemetic agent is

ISSN:0272-4391    

DOI:10.1002/ddr.430280105

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

年代:1993

数据来源: WILEY

摘要:

AbstractDiphosphonates are known to affect skeletal and soft tissue mineralization; however, several studies have shown that these compounds effectively suppress adjuvant‐induced polyarthritis in the rat, reducing the edematous inflammatory component as well as skeletal changes. Therefore, we investigated the specific anti‐inflammatory potential of two diphosphonates, ethane‐1‐hydroxy‐1,1 diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP), using several different models of acute, non‐immune‐ and immune‐driven inflammation in the pleural cavity of rats and guinea pigs which afforded both a qualitative and quantitative assessment of leukocyte infiltration and exudate fluid (edema) formation. EHDP and Cl2MDP, administered at doses which suppressed the chronic inflammatory lesions induced in adjuvant arthritis, failed to inhibit acute inflammation regardless of the stimulus used (carrageenan; calcium pyrophosphate dihydrate crystals; hydroxyapatite crystals; immune complexes (Arthus reaction); delayed‐type hypersensitivity to purified protein derivate). At the highest dose tested (15 mg/kg subcutaneously [sc]) both EHDP and Cl2MDP exacerbated hydroxyapatite‐ and delayed‐type hypersensitivity‐induced leukocyte infiltration; hydroxyapatite crystals precoated with EHDP or Cl2MDP caused a small but significant inhibition of the chronic inflammatory response to sc cotton pellet implantation. We conclude that EHDP and Cl2MDP may be effective in chronic rather than acute inflammation. Our observations suggest that further studies are warranted on the potential of diphosphonates as novel therapeutics for chronic inflammatory disease.

ISSN:0272-4391    

DOI:10.1002/ddr.430280106

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

年代:1993

数据来源: WILEY

摘要:

AbstractA‐75169 HCI (1,2,3,4‐tetrahydro‐6‐hydroxy‐1‐[N‐methylamino)‐methyl‐N‐phenethyl]‐naphthalene HCI, a racemate, is derived from a series of compounds that combine selective α‐2 receptor antagonism and amine uptake inhibition in a single molecule. A‐75169 HCI showed high affinity (pK1= 8.79) for cerebral cortex‐derived α‐2 adrenoceptors assayed with [3H] rauwolscine. The R‐enantiomer showed a tenfold greater affinity (pk1= 9.09) for these receptors than the S‐enantiomer (pK1= 8.10). A‐75169 HCI and both enantiomers had potent antagonistic effects at postsynaptic α‐2 adrenoceptors (pA2values 7.31–7.49, dog saphenous vein). The racemate and the R‐enantiomer were moderately potent as antagonists for presynaptic α‐2 adrenoceptors (pA2values 7.06 and 7.09, respectively, rat vas deferens), and they were more potent inhibitors (ID50= 1.50 mg/kg, i.v., and 0.60 mg/kg, i.v., respectively) of clonidine‐induced mydriasis, an α‐2 mediated effect, than the S‐enantiomer. The S‐enantiomer was a more potent inhibitor of norepinephrine synaptosomal uptake than the R‐enantiomer (pIC50= 6.00 and 5.79, respectively). When applied topically to the eyes of rabbits (3.0% solution) and monkeys (0.3% solution), the racemate significantly reduced intraocular pressure (IOP). The topical administration of A‐75169 HCI (0.5% solution) to dog cornea did not affect blood pressure or heart rate. A‐75169 HCI, a selective α‐2 antagonist possessing amine uptake blocking properties, is

ISSN:0272-4391    

DOI:10.1002/ddr.430280107

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

年代:1993

数据来源: WILEY

摘要:

AbstractCl‐966 (1‐[2‐[bis[4‐(trifluoromethyl)phenyl]methoxy]]‐1,2,5,6‐tetr5ahydro‐3‐pyridinecarboxylic acid, HCl salt) is an anticonvulsant agent that blocks the re‐uptake of gammaaminobutyric acid (GABA) into presynaptic nerve terminals and glial cells. The preclinical toxicology of Cl‐996 was evaluated in male and female B6C3F1 mice, Wistar rats, and beagle dogs. Doses were administered orally and are expressed as free acid equivalents. Acute (gavage) toxicity was characterized principally by CNS signs (hypoactivity, atasia, tremors, convulsions, and prostration); diarrhea and urine scald; and delayed mortality (2–3 days in mice and 2–11 days in rats) with 14 day median lethal doses of 653 and 825 mg/kg in male and female mice and 1,019 and 830 mg/kg in male and female rats, respectively. In a 4‐week rat study in which Cl‐966 was given in the diet, the high dose of 500 mg/kg/day was not tolerated, with marked decreases in body weight and food consumption necessitating sacrifice during the second week. The 150 mg/kg/day dose caused reduced body weight gain, lower food consumption, and hyperactivity, while 50 mg/kg/day was clearly a no‐effect level. In dogs, Cl‐966 was given in gelatin capsules at doses of 2 to 25mg/kg/day in an exploratory study and at 2,6, and 15 mg/kg/day in a 4‐week study. Prostration, ataxia, disorientation, and other mainly CNS‐related clinical signs occurred at 5 to 25mg/kg. Aspartate and/or alanine aminotransferase activities were elevated at 20 and 25 mg/kg in the exploratory dog study. However, there were no histopathologic findings in either species directly attributable to Cl‐966 treatment. Enhanced GABAergic activity was considered to be the cause of most of the clinical signs elicited by Cl‐966 in rodents and dogs. Blood Cl‐966 levels were dose‐dependent, but higher in females than males for both rats and dogs. These results were used to support initial clinical trials

ISSN:0272-4391    

DOI:10.1002/ddr.430280108

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe novel existence of multiple binding sites for the potent nucleoside transporter Probe, [3H]nitrobenzylthioinosine, was identified in guinea pig platelet membranes and the binding characteristics compared to those of guinea pig erythrocyte membranes. Scatchard analysis of the binding in platelets reveled two high affinity binding sites with affinity constant (KD) of 0.94 ± 0.07 nM and 83 ± 13 nM with corresponding maximal binding capacities (Bmax) of 21 ± 7 and 110 ± 25 fmol/mg protein, respectively. In comparison, guinea pig erythrocyte membranes revealed a homogeneous population of the binding sites with KDof 0.17 ± 0.04 nM and a Bmaxvalue of 73 ± 11 fmol/mg protein. Biphasic semi‐log plots of the binding site heterogeneity in erythrocytes not reveled by Scatchard plots. Determination of the potencies of selected drugs in inhibiting the binding showed evidence of differential interacitons with the binding sites by various agents which may be exploited pharmacologically. © 1993 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430280109

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

年代:1993

数据来源: WILEY

摘要:

AbstractWe attempted to clarify the effect of hippocampal function on the spatial memory of rats by creating a lesion in the hippocampus with ethylcholine aziridinium ion (AF64A). The hippocampus was damaged by injecting AF64A into the lateral ventricles, 3 nmol/3 μl per side. At 1 or 4 weeks after the injection, acetylcholine (ACh) was measured in perfusion samples collected via brain dialysis of the hippocampus of freely moving rats. The release of ACh stimulated by scopolamine was reduced at 1 week but not at 4 weeks post‐injection. A behavioral change on the eight‐arm radial maze test was also observed in the acquisition or retention trials to determine the deficit in spatial memory, whether acquisition or retention. In the acquisition trial, the initial correct response was decreased and the total error count was increased at 1.5 to 2.5 weeks, but not at 3 weeks, after the AF64A injection. However, those indices remained unchanged in the retention trial. These observations suggest that the hippocampus may be required for the acquisition of spatial memory, but that the stored memory, but the stored memory is located outside the hippocampus, the hippocampus is not concerned with the retrieval process, or the retrieval process may be hippocampal but not cholinergic. The hippocampal cholinergic system would be concerned with the acquisition of spatial memory. Thus, AF64A‐treated rats may serve a model for hippocampal cholinergic dysfunction and the recovery from hippocampal cholinergic damage. © 1993 Wiley‐

ISSN:0272-4391    

DOI:10.1002/ddr.430280110

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

年代:1993

数据来源: WILEY

摘要:

AbstractIn the rabbit isolated perfused hear, dolasetron (MDL 73,147) was found to be a potent (PA2= 9.8) antagonist at 5‐hydroxytryptamine3(5‐HT3) receptors present on sympathetic nerve terminals. In anesthetized rats, intravenous (iv), intraduodenal (id), or oral administration of dolasetron blocked the von Bezold‐Jarisch reflex elicited by iv injection of 5‐HT; the iv ED50was approximately 3 μg/kg and following a dose of 140 μg/kg iv the reflex was abolished for>85 min. The compound displayed no significant affinity for 5‐HT1, 5‐HT2, or a variety of other radioligand binding sites at concentration of 10 μM. In conscious ferrets, dolasetron suppressed the vomiting induced by an iv injection of the anti‐cancer drug cisplatin (10 mg/kg). Intravenous doses (0.05–0.5 mg/kg) administered 30 min before and 45 min prior to cisplatin, were clearly anti‐emetic and single oral doses of 0.5 or 2 mg/kg, given 30 min prior to cisplatin were also effective. Minimal changes in the behaviour of mice were observed at doses up to 100 mg/kg given ip or subcutaneously (sc). It is concluded that dolasetron is a potent, selective, and reversible antagonist at neuronal 5‐HT3receptors, which is well tolerated. The compound is effective at low doses in an animal model predictive of clinical efficacy in cytotoxic drug‐induced vomiting

ISSN:0272-4391    

DOI:10.1002/ddr.430280111

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

年代:1993

数据来源: WILEY