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91.
92.
Daniel A. Gonzalez-Carter Zhan Yuin Ong Catriona M. McGilvery Iain E. Dunlop David T. Dexter Alexandra E. Porter 《Nanomedicine : nanotechnology, biology, and medicine》2019,15(1):1-11
The blood–brain barrier (BBB) is a protective endothelial barrier lining the brain microvasculature which prevents brain delivery of therapies against brain diseases. Hence, there is an urgent need to develop vehicles which efficiently penetrate the BBB to deliver therapies into the brain. The drug L-DOPA efficiently and specifically crosses the BBB via the large neutral amino acid transporter (LAT)-1 protein to enter the brain. Thus, we synthesized L-DOPA-functionalized multi-branched nanoflower-like gold nanoparticles (L-DOPA-AuNFs) using a seed-mediated method involving catechols as a direct reducing-cum-capping agent, and examined their ability to cross the BBB to act as brain-penetrating nanovehicles. We show that L-DOPA-AuNFs efficiently penetrate the BBB compared to similarly sized and shaped AuNFs functionalized with a non-targeting ligand. Furthermore, we show that L-DOPA-AuNFs are efficiently internalized by brain macrophages without inducing inflammation. These results demonstrate the application of L-DOPA-AuNFs as a non-inflammatory BBB-penetrating nanovehicle to efficiently deliver therapies into the brain. 相似文献
93.
Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF
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Gráinne C. O'Keeffe Pam Tyers Dag Aarsland Jeffrey W. Dalley Roger A. Barker Maeve A. Caldwell 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(21):8754-8759
A reduction in dopaminergic innervation of the subventricular zone (SVZ) is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson''s disease (PD). Here, we show that this effect involves EGF, but not FGF2. In particular, we demonstrate that dopamine increases the proliferation of SVZ-derived cells by releasing EGF in a PKC-dependent manner in vitro and that activation of the EGF receptor (EGFR) is required for this effect. We also show that dopamine selectively expands the GFAP+ multipotent stem cell population in vitro by promoting their self-renewal. Furthermore, in vivo dopamine depletion leads to a decrease in precursor cell proliferation in the SVZ concomitant with a reduction in local EGF production, which is reversed through the administration of the dopamine precursor levodopa (l-DOPA). Finally, we show that EGFR+ cells are depleted in the SVZ of human PD patients compared with age-matched controls. We have therefore demonstrated a unique role for EGF as a mediator of dopamine-induced precursor cell proliferation in the SVZ, which has potential implications for future therapies in PD. 相似文献
94.
Mahmoudi J Nayebi AM Samini M Reyhani-Rad S Babapour V 《Pharmacological reports : PR》2011,63(4):908-914
In Parkinson's disease (PD), prolonged exposure to L-3,4-dihydroxyphenylalanine (L-DOPA) results in motor fluctuations, such as the on-off phenomenon, and L-DOPA-induced dyskinesia. Previously, we found that activation of 5-HT(1A) in the substantia nigra pars compacta (SNc) decreased catalepsy in parkinsonian rats. In the current investigation, we attempted to evaluate the effect of buspirone on the anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned male Wistar rats. Catalepsy was induced by the unilateral infusion of 6-OHDA (8 μg/2 μl/rat) into the central region of the SNc. After a 3-week recovery period, rats received L-DOPA intraperitoneally (ip; 15 mg/kg) twice daily for 20 days, and the anti-cataleptic effect of L-DOPA was assessed by the bar test at days 5, 10, 15 and 20. The results showed that L-DOPA had an anti-cataleptic effect only until day 15, and its effect was abolished on day 20. On day 21, these rats were co-treated with three different doses of buspirone (0.1, 0.5 and 2.5 mg/kg, ip) and L-DOPA (15 mg/kg, ip). At a dose of 0.5 mg/kg, buspirone improved the anti-cataleptic effect of L-DOPA. Furthermore, the effect of buspirone (0.5 mg/kg, ip) on the anti-cataleptic effect of L-DOPA (15 mg/kg, ip) was reversed by 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine hydrobromide (NAN-190; 0.5 mg/kg, ip), a 5-HT(1A) receptor antagonist. From these results, it may be concluded that buspirone improves the anti-cataleptic effect of L-DOPA in a 6-OHDA-induced animal model of PD through the activation of 5-HT(1A) receptors. In this regard, further investigations should be undertaken to clarify the exact mechanism of the interaction between 5-HT(1A) and dopaminergic neurons. 相似文献
95.
Twenty-four Parkinson's disease (PD) patients who had planned to fast during the 2016 Ramadan were included in this observational study. Twenty patients fasted during the whole Ramadan. Six were able to abstain from drug intakes from dawn to dusk; the others needed 1 or 2 intakes of L-DOPA during the day. There were no serious side effects reported during the Ramadan period. Compared to before Ramadan, there were no significant changes after the fasting period in quality of life (PDQ 39), non-motor symptom scale or clinical impression of severity index scores. 相似文献
96.
The effects of L-DOPA on the heterosexual copulatory behavior of male rats were investigated. L-DOPA (175 mg/kg) + Ro 4-4602 (50 mg/kg) prolonged the time required for copulation; L-DOPA alone produced similar though smaller, non-significant effects. Dose dependent increases in time required for copulation were obtained in males given 100, 150 and 200 mg/kg L-DOPA + Ro 4-4602. It is suggested that L-DOPA acts to inhibit heterosexual copulatory behavior in sexually vigorous males. 相似文献
97.
The effects of L-DOPA and 5-HTP on the tonic stretch reflex (TSR) in the decerebrate rat were studied. L-DOPA facilitated the TSR in a dose-dependent manner. The facilitation of the TSR was blocked by pimozide. A sensitive electromygraphic (EMG) technique capable of recording single motor unit discharges was used. The EMG results suggest that gamma motoneuron sensitivity was increased to a greater degree than alpha motoneuron sensitivity during the facilitation by L-DOPA. The L-DOPA-induced facilitation persisted in animals partly depleted of 5-hydroxytryptamine (5-HT) by reserpine, p-chlorophenylalanine or 5,6-dihydroxytryptamine. 5-HTP inhibited the TSR in a dose-dependent manner. It is concluded that DA not 5-HT is the amine which normally mediates facilitation of the TSR after L-DOPA and that gamma motoneuron activation is more likely to be involved to a greater degree than alpha motoneuron activation in the neural mechanisms of the facilitation. 相似文献
98.
P Fayle D M Jackson O F Jenkins P A Lafferty 《Pharmacology, biochemistry, and behavior》1985,23(5):715-720
Mice were pretreated with haloperidol (HP) (3-4 mg/kg/day in drinking water) or vehicle for 21 days. On the 25th day, HP-pretreated mice were supersensitive to the locomotor stimulant effects of apomorphine (after acute premedication with reserpine and alpha-methyl-p-tyrosine). This behavioural supersensitivity was accompanied by a 25-39% increase in the number of [3H]-spiperone binding sites in the striata of HP-pretreated mice. Short-term repeated administration of the dopamine (DA) agonist drugs d-amphetamine and L-DOPA during the HP withdrawal phase (days 22, 23 and 24) had no effect on either measure of DA receptor supersensitivity. In contrast, the administration of apomorphine on days 22, 23 and 24 enhanced the HP-induced behavioural supersensitivity but decreased the HP-induced elevation of the number of [3H]-spiperone binding sites. Apomorphine treatment alone did not alter either measure. The results do not support the hypothesis that supersensitive DA receptors can be down-regulated by short-term treatment with DA agonist drugs and, moreover, indicate that important discrepancies may exist between behavioural and biochemical measures of DA receptor supersensitivity. 相似文献
99.
This study investigated behavioral and anatomical changes induced by long periods of L-DOPA treatment in the unilateral rat model of Parkinson's disease. After daily injections of L-DOPA (50 mg/kg, ip) given for 1, 4, 8, or 16 weeks, behavioral sensitization, expressed by contralateral turning and changes in its pattern, increased within the first week of treatment and remained unchanged thereafter. Dyskinetic movements, affecting the trunk and limbs of all treated rats, also developed within the first week of treatment and increased further during the 16 weeks of L-DOPA treatment. L-DOPA responsiveness was also accompanied by changes at the neuronal level, as shown by changes in the expression of c-fos in the dopamine-depleted striatum. Following 1 week of L-DOPA treatment there was a marked decrease in striatal c-fos expression, compared to single injections, especially evident in the medial and ventral regions and to a lesser extent in the dorsolateral regions of the striatum. This specific regional expression of c-fos was maintained throughout the 16 weeks of L-DOPA treatment. Overall, our results show that behavioral sensitization to L-DOPA starts relatively early during the treatment and include not only an increase in contralateral turning rate but also an increase in dyskinetic movements. Persisting c-fos expression in the dorsolateral striatum might be implicated in the development of dyskinesias when L-DOPA treatment is extended for periods longer than 1 week. 相似文献
100.
D. E. Schwartz J. C. Jordan W. H. Ziegler 《European journal of clinical pharmacology》1974,7(1):39-45
Summary
14C-labelled benserazide was administered to six patients with parkinsonism and total radioactivity was measured in the plasma, urine and faeces. Three patients received benserazide both orally and intravenously, while three other patients received benserazide orally alone and together with L-DOPA (= MADOPAR®). Plasma levels did not follow first-order kinetics, but indicated rapid absorption of an oral dose. Following intravenous and oral administration, excretion of radioactivity was 88.7 and 57.7% respectively in the urine, 10.1 and 30.7% respectively in the faeces. L-DOPA slightly increased the absorption of benserazide. Following the administration of an oral dose to rats benserazide related radioactivity was distributed almost entirely outside the brain. The drug therefore appears to be suitable for blocking extracerebral decarboxylase whilst leaving the intra-cerebral enzyme almost unaffected. 相似文献