全文获取类型
收费全文 | 175篇 |
免费 | 1篇 |
专业分类
妇产科学 | 1篇 |
基础医学 | 13篇 |
临床医学 | 3篇 |
内科学 | 1篇 |
神经病学 | 44篇 |
特种医学 | 6篇 |
预防医学 | 2篇 |
药学 | 104篇 |
肿瘤学 | 2篇 |
出版年
2018年 | 1篇 |
2015年 | 2篇 |
2014年 | 1篇 |
2013年 | 1篇 |
2012年 | 2篇 |
2011年 | 5篇 |
2010年 | 2篇 |
2009年 | 2篇 |
2008年 | 6篇 |
2007年 | 6篇 |
2006年 | 12篇 |
2005年 | 15篇 |
2004年 | 6篇 |
2003年 | 2篇 |
2002年 | 7篇 |
2001年 | 4篇 |
2000年 | 11篇 |
1999年 | 14篇 |
1998年 | 3篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 5篇 |
1993年 | 1篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 1篇 |
1989年 | 8篇 |
1988年 | 9篇 |
1987年 | 3篇 |
1986年 | 12篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 4篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1968年 | 2篇 |
1966年 | 2篇 |
1965年 | 2篇 |
排序方式: 共有176条查询结果,搜索用时 15 毫秒
11.
Sopala M Schweizer S Schäfer N Nürnberg E Kreuter J Seiller E Danysz W 《Arzneimittel-Forschung》2002,52(3):168-174
The objective of the present study was to characterise the neuroprotective activity of the novel glycineB site NMDA (N-methyl-D-aspartate) receptor antagonist MRZ 2/576 (8-chloro-4-hydroxy-l-oxo- 1,2-dihydropyridazino[4,5-b]quinolin-5-oxide choline salt, CAS 202807-80-5) in a rodent model of focal cerebral ischaemia. Since the solubility of MRZ 2/576 at a physiological pH, is minimal and adequate concentrations can be achieved only at relatively high basic pH the in vivo use of the substance is substantially limited. Therefore, a special nanoparticle formulation was developed to provide means for lengthy i.v. administration of experimentally relevant doses within the physiological range of pH. Focal ischaemia of 75 min duration was induced in rats by a reversible occlusion of the middle cerebral artery (MCAo). MRZ 2/576 (18 mg/kg over 10 min followed by 18 mg/kg/h over 6 h) or placebo treatment was initiated immediately after onset of MCAo. Neurological deficit was evaluated daily for 3 consecutive days and then brain infarct analysis was performed. MRZ 2/576 significantly improved the neurological score at 24 h and 72 h post stroke (p < 0.05 vs. placebo). It also produced a 53.0% reduction of total infarct size, 60.4% of cortical and 42.3% of striatal infarction (p < 0.05 vs. placebo). Temporary drug-induced hypothermia and ataxia were observed during infusions. This leads to the conclusion that prolonged administration of the glycineB site antagonist MRZ 2/576 in form of the nanoparticle suspension ameliorates ischaemic damage induced by the transient MCAo in rats. The results suggest that nanoparticles hold promise as an effective strategy e.g. for substances with physico-chemical characteristics that otherwise would preclude them from pre-clinical development and/or clinical application. 相似文献
12.
Danysz W Parsons CG Jirgensons A Kauss V Tillner J 《Current pharmaceutical design》2002,8(10):835-843
Because of its widespread involvement in the physiology and pathology of the CNS, the glutamatergic system has gained considerable attention as a potential target for development of new agents for a number of therapeutic indications. In this respect, the glutamate receptor subtype of the NMDA type has been most intensively studied. The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on our positive experience with memantine which has been used clinically for many years for the treatment of neurodegenerative dementia. Many amino-alkyl-cyclohexane derivatives have been evaluated in vitro and in animal models, and in turn, one structure, namely neramexane HCl (MRZ 2/579) was selected for further development. This agent shows some similarity to memantine e.g. channel blocking kinetics, voltage dependency, and affinity. Preclinical tests indicated particularly good activity in animal models of alcoholism (self-administration, withdrawal-induced audiogenic seizures etc.) and pain (chronic pain, inhibition of tolerance to the analgesic effects of morphine). It turn, this agent has recently entered phase II of clinical trials in alcoholism after a favourable profile seen in phase I studies. 相似文献
13.
Z Jastrzebski A Danysz H Czyzewska-Szafran A Czarnomska 《Archivum immunologiae et therapiae experimentalis》1988,36(3):335-343
The effect of some sulfhydryl compounds on the uptake of cytosine arabinoside (Ara-C) by normal and neoplastically transformed mouse thymus cells was studied. Sodium 2-mercaptoethanesulphonate (Mesna) was found to greatly inhibit (in 80%) the uptake of Ara-C by normal cells. Two other SH-compounds (cysteine and N-acetyl-cysteine) displayed no such effect. None of the three compounds reduced the uptake of Ara-C by neoplastic thymus cells. The possible pharmacological implications of these findings are discussed. 相似文献
14.
Danysz W 《IDrugs : the investigational drugs journal》2005,8(9):755-762
Eli Lilly and Co is developing LY-544344, a prodrug of the metabotropic glutamate receptor 2/3 agonist LY-354740, for the potential treatment of anxiety disorders. 相似文献
15.
N-Methyl-D-aspartate (NMDA) receptor blockade enhances motor activity and stimulates dopamine metabolism, effects shared with classical psychostimulant drugs. The present study aimed to characterize behavioral effects of two NMDA receptor channel blockers, MK-801 and memantine, in both Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. In Experiment 1, SHR rats demonstrated higher spontaneous locomotor activity and spent more time in the central area of the open field apparatus compared with WKY rats. Rats of both strains pre-treated with MK-801 (0.01-0.3 mg/kg) or memantine (1-32 mg/kg) demonstrated dose-dependent increases in the total distance traveled and time spent in the central area. Experiment 2 was based on the two-lever discrete-trial delayed reinforcement task in which rats could press one lever to obtain one pellet immediately or another lever for four pellets delivered after a variable delay (0-60 s). Tolerance to delay of reward did not differ between strains. MK-801 (0.03-0.3 mg/kg) and memantine (1-10 mg/kg) produced small, but significant, facilitation of the large-reward lever responding and markedly impaired operant performance at higher dose levels (increased number of missed trials). For both experiments, effects of MK-801 and memantine were more pronounced in WKY compared with SHR rats. Additional studies are needed to address the utility of noncompetitive NMDA receptor blockers in the treatment of attention deficit and hyperactivity disorder. 相似文献
16.
Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists show antiparkinsonian-like activity in animal models, and possess neuroprotective properties. However they also induce a number of behavioral side effects in rodents at higher doses; these include learning impairment, hyperlocomotion, and ataxia. The present study focused on the possible development of tolerance, or sensitization, to any of these effects after sustained administration, either by repeated injection or continuous infusion. When memantine or (+)MK-801 (20 and 0.31 mg/kg/day respectively) were either infused or repeatedly injected for 14 days, tolerance was observed to their learning impairing effect at high doses, in a passive avoidance test. Tolerance to their ataxic effect developed after repeated administration ((+)MK-801 and memantine), or after infusion (memantine). Sensitization to the locomotor stimulation was seen following repetitive injections of memantine for 14 days, but not seen with (+)MK-801. In animals with an unilateral 6-OHDA lesion of the nigrostriatal system, acute administration of memantine caused ipsilateral rotations, which were augmented following 14 days of infusion. The potency of amantadine to antagonize neuroleptic-induced catalepsy was unchanged following either infusion or repeated injections. The various acute effects of non-competitive NMDA receptor antagonists were modified differently by sustained treatment (i.e. tolerance to learning impairment and ataxia; sensitization to memantine's locomotor stimulation). The anti-cataleptic activity of amantadine remained unaltered. However, differences between drugs and the two treatment regimens (i.e. repetitive versus continuous treatments) were apparent. 相似文献
17.
On the role of noradrenergic neurotransmission in the action of desipramine and amitriptyline in animal models of depression 总被引:1,自引:0,他引:1
W Danysz W Kostowski W Kozak M Hauptmann 《Polish journal of pharmacology and pharmacy》1986,38(3):285-298
Three weeks of treatment with desipramine (DMI) and amitriptyline (AMI) reduced the hypothermic action of clonidine in rats. Both electrolytic and 6-hydroxydopamine lesions of the locus coeruleus (LC) and administration of DSP-4 counteracted the reduction of clonidine hypothermia produced by antidepressants. Lesions of the LC and DSP-4 administration also antagonized the anti-immobility action of single doses of DMI but failed to modulate the action of AMI in the forced swim test. Chronic DMI action on the rat immobility was reduced by 6-hydroxydopamine lesions of the LC: other lesions (electrolytic, DSP-4) were ineffective. Electrical stimulation of the LC increased the rat activity in the forced swim paradigm, producing an effect similar to that of antidepressants. The anti-immobility effect of DMI as well as LC stimulation were antagonized by drugs blocking alpha-adrenoceptors (phenoxybenzamine, prazosin) but not by propranolol, a non-selective antagonist of beta-adrenoceptors. On the other hand, the anti-immobility action of AMI was unchanged by all adrenolytics used in that study. The results indicate that the LC system and alpha 1-adrenoceptors play an important role in the antidepressive action of DMI, but not AMI, in the forced swim test. 相似文献
18.
Gravius A Laszy J Pietraszek M Sághy K Nagel J Chambon C Wegener N Valastro B Danysz W Gyertyán I 《Behavioural pharmacology》2011,22(2):122-135
5-Hydroxytryptamine 6 (5-HT6) receptors are involved in learning and memory processes and are discussed as promising targets for the treatment of cognitive impairment in central nervous system disorders. A number of 5-HT6 antagonists are currently in the clinical development for schizophrenia and Alzheimer's disease (AD). There is some discrepancy regarding cognitive efficacy in subjects, and only limited data are available on the role of the 5-HT6 receptor in animal models of psychosis. The aim of this study was to investigate the efficacy of the selective 5-HT6 antagonists, Ro-4368554 (1-10 mg/kg, intraperitoneally) and SB-258585 (3-30 mg/kg, intraperitoneally), in animal models for schizophrenia and AD. Both compounds showed cognition-enhancing effects in object recognition, whereas only SB-258585 was able to prevent the scopolamine-induced deficit in the Morris water-maze test. Neither Ro-4368554 nor SB-258585 prevented scopolamine-induced impairment in contextual fear conditioning. Similarly, both compounds were ineffective on MK-801-induced deficits in contextual fear conditioning and spatial working memory. Ro-4368554, but not SB-258585 reversed the apomorphine-induced deficit in prepulse inhibition. Amphetamine-induced hyperlocomotion was not affected by either compound. Taken together, the overall efficacy of Ro-4368554 and SB-258585 in animal models for AD and schizophrenia is rather limited. These data show moderate efficacy in some models for AD but do not support the therapeutic potential of 5-HT6 antagonists for schizophrenia. 相似文献
19.
Kiryk A Aida T Tanaka K Banerjee P Wilczynski GM Meyza K Knapska E Filipkowski RK Kaczmarek L Danysz W 《Neurotoxicity research》2008,13(1):19-30
GLT1 is one of the major transporters responsible for maintenance of glutamate homeostasis in the brain. In the present study, glutamate transporter 1-deficient GLT1 homozygous (-/-) and heterozygous (+/-) mice were investigated with the intention that they may provide a model of hyperglutamatergic state resulting in various behavioral alterations. The GLT1 (-/-) mice had lower body and brain weight, mild neuronal loss in CA1 hippocampal region as well as focal gliosis and severe focal neuronal paucity in layer II of the neocortex. The short life-span of GLT1 (-/-) precluded us from systematic behavioral studies in these mice. In contrast, GLT1 (+/-) mice exhibiting a 59% decrease in GLT1 immunoreactivity in their brain tissue, showed no apparent morphological brain abnormalities, and their life-span was not markedly different from controls. Behaviorally, GLT1 (+/-) presented moderate behavioral alterations compared to their wildtype littermates, such as: mild sensorimotor impairment, hyperlocomotion (at 3 month of age only), lower anxiety (at 6 months), better learning of cue-based fear conditioning but worse context-based fear conditioning. Our results suggest that GLT1 (+/-) mice may serve as a potentially useful model to study neurodegenerative disease conditions with mild hyperglutamatergic activity. 相似文献
20.
The neurotransmitter glutamate activates several classes of metabotropic receptor and three major types of ionotropic receptor--alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA). The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD) is finding increasing scientific acceptance. Central to this hypothesis is the assumption that glutamate receptors, in particular of the NMDA type, are overactivated in a tonic rather than a phasic manner. Such continuous, mild, chronic activation ultimately leads to neuronal damage/death. Additionally, impairment of synaptic plasticity (learning) may result not only from neuronal damage per se but may also be a direct consequence of this continuous, non-contingent NMDA receptor activation. Complete NMDA receptor blockade has also been shown to impair neuronal plasticity, thus, both hypo- and hyperactivity of the glutamatergic system leads to dysfunction. Memantine received marketing authorization from the EMEA (European Medicines Agency) for the treatment of moderate to severe AD in Europe and was subsequently also approved by the FDA (Food and Drug Administration) for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist with strong voltage-dependency and fast kinetics. This review summarizes existing hypotheses on the mechanism of action (MOA) of memantine in an attempt to understand how the accepted interaction with NMDA receptors could allow memantine to provide both neuroprotection and reverse deficits in learning/memory by the same MOA. 相似文献