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Groups of male CF-1 mice received 3 and 10 µmol/kg diazepam, lorazepam, and oxazepam intravenously. Between 1 min and 24 h after injection, benzodiazepine concentrations were determined by gas chromatography (GLC) in plasma and in one brain hemisphere; in the other hemisphere, ex vivo benzodiazepine receptor occupancy was measured using3H-flunitrazepam displacement. Based on GLC data, diazepam entered brain rapidly, and was also cleared rapidly, yielding desmethyldiazepam and oxazepam as metabolites in plasma and brain. However, lorazepam and oxazepam entered brain slowly, with brain:plasma equilibrium achieved at 30–60 min; thereafter, the drugs were eliminated from plasma and brain in parallel. The time course and extent of ex vivo occupancy were highly consistent with GLC data (for diazepam, GLC levels were expressed as the sum of diazepam, desmethyldiazepam, and oxazepam, with metabolite concentrations, normalized for molecular weight and for in vitro benzodiazepine receptor affinity.) Between-method correlations were 0.95 or higher. Thus benzodiazepine receptor occupancy is highly dependent on benzodiazepine concentrations in brain. Differences in the time-course of onset and duration of pharmacologic activity between the highly lipophilic benzodiazepine diazepam and the less lipophilic hydroxylated derivatives lorazepam and oxazepam are largely explained by differences in systemic kinetics and in the rate of uptake into brain.Supported in part by grants MH-34223, DA-05258, and AG-00106 from the United States Public Health Service 相似文献
3.
Summary A rapid and quantitative method for the determination of benzodiazepines using high-performance liquid chromatography (HPLC)
with diode-array detection (DAD) is reported. The drugs were extracted from serum, blood or post-mortem blood using C18 extraction columns. Brotizolam was used as internal standard. Experiments with spiked serum/blood samples resulted in recoveries
between 75% and 94% for all investigated benzodiazepines. Excellent linearity was obtained over the concentration range 5–1500
ng benzodiazepine/ml. The limit of detection was approximately 2 ng/ml. The detection of low therapeutic serum levels of highly
potent benzodiazepines is also possible.
相似文献
4.
The possible occurrence of benzodiazepine-like substances in human breast milk was investigated in 35 healthy, newly delivered women who were known not to be taking benzodiazepines. Maternal blood samples and a sample of breast milk were obtained on the fifth post partum day. A radioreceptor technique (lower limit of detection 1.5 ng/ml; difference between duplicates at various concentrations <7%) was used for measuring benzodiazepine-like substances in blood and breast milk (with and without prior extraction). No benzodiazepine-like substances could be demonstrated in any of the blood samples taken from the 35 women. Measurable concentrations of benzodiazepine-like substances were demonstrated in all but 1 of the 35 breast milk samples. The mean concentration of benzodiazepine-like substances for all 35 women was 4.3±2.3 ng/ml (range 0–9.3 ng/ml) expressed as lorazepam. The corresponding value for extracted breast milk was 2.6±1.5 ng/ml (range 0–7.0 ng/ml). There was no association between concentrations of benzodiazepine-like substances in breast milk and maternal age, weight, height and body mass or parity, or the sex of the infant and infant birth weight. We suggest that non-detectable amounts of benzodiazepine-like substances in serum are concentrated in the mammillary glands and excreted in a higher concentration in breast milk. It is less likely that the relevant benzodiazepines are produced in the mammillary glands. 相似文献
5.
Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function. 相似文献
6.
R. Eugene Ramsay 《Epilepsia》1993,34(S1):S71-S81
Summary: Status epilepticus, particularly the convulsive form, is a medical emergency, warranting prompt and aggressive treatment. To do this, one must have a thorough understanding of the pharmacology of the anticonvulsant agents. Therapy should be directed toward rapid termination of the status epilepticus, prevention of seizure recurrence, and treatment of any underlying cause. Most importantly, one should establish and adhere to a standard treatment protocol for best results. 相似文献
7.
O. SPIGSET M.D. 《Acta anaesthesiologica Scandinavica》1994,38(2):94-103
This review is an update on anaesthetic agents and their excretion into breast milk; it presents the reported effects on suckling infants, and discusses the precautions which should be considered. For most anaesthetic agents, there is very sparse information about breast milk excretion and even less published knowledge about the possible effects on the suckling infant. Generally, when an anaesthetic agent is given on a single–dose basis, there is no evidence that it is excreted in breast milk in clinically significant amounts, even if there are detectable concentrations of the drug in the milk. Most anaesthetics are rapidly cleared from the mother, and, consequently, it should be possible to allow suckling as soon as practically feasible after surgery. However, repeated administration of certain opiates and benzodiazepines has been reported to cause adverse effects in neonates, with premature neonates apparently being more susceptible. Thus, in long–term treatment with these drugs, the importance of uninterrupted breast feeding should be assessed against possible adverse drug effects in the neonate. 相似文献
8.
Douglas N. Johnson Herbert J. Weingartner Paul Andreason David T. George 《Psychopharmacology》1995,121(2):145-149
This study explored whether benzodiazepines selectively affect aspects of attention and/or visual information processing, as they do memory. A cued visual-search paradigm was employed, using normal volunteers and a single dose of triazolam. This paradigm provided for a detailed examination of two aspects of visual attention and information processing: 1) controlled versus automatic attention allocation (via central and peripheral cues), and 2) the extent to which processing an item in a non-cued location affects performance (via cue-validity). Triazolam, compared to placebo, significantly increased response time, and Drug Condition interacted with Cue-Validity but not Cue-Type. Based on these data, we argue that triazolam doesnot affect attention allocation butdoes affect attentional disengagement and/or attention switching mechanisms. 相似文献
9.
10.
H. R. Ochs MD D. J. Greenblatt U. Klehr 《Journal of molecular medicine (Berlin, Germany)》1984,62(16):765-767
Summary The pharmacokinetics of a single 30-mg oral dose of oxazepam was evaluated in seven patients with chronic renal failure on maintenance hemodialysis and in seven healthy controls matched for age and sex. Based on total (free plus bound) serum oxazepam concentrations, elimination half-life was prolonged in renal patients compared to controls (22 vs 8 h,p<0.001) and volume of distribution increased (3.0 vs 1.4 1/kg,p<0.02). However, total clearance was similar between groups (1.8 vs 1.9 ml/min per kilogram). These findings were confounded by the increased oxazepam free fraction in serum of renal failure patients (10.3%) as compared to healthy controls (4.3%). Correction for differences in binding indicates similar distribution of unbound oxazepam between groups, but reduced clearance of pharmacologically active unbound oxazepam in renal patients (18 vs 45 ml/min per kilogram). Oxazepam dosage, therefore, may require downward adjustment for renal failure patients on hemodialysis.Supported in part by grant OC 10/6-3 from the Deutsche Forschungsgemeinschaft, and by grant MH-34223 from the United States Public Health Service 相似文献