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51.
The cytochrome P450 isoenzymes are a superfamily of haemoprotein enzymes that catalyse the metabolism of a large number of endogenous and exogenous compounds. Recently, the cytochrome isoenzymes have been shown to be important in the synthesis of steroid hormones and bile acids, the arachidonic acid cascade and in central nervous function. These enzymes are a major determinant of the pharmacokinetic behaviour of numerous drugs. Furthermore, alterations in cytochrome P450 activity have been implicated in some diseases. 相似文献
52.
Kortunay S Bozkurt A Bathum L Basci NE Calgüneri M Brøsen K Kayaalp SO 《European journal of clinical pharmacology》1999,55(1):21-25
Objectives: To determine whether patients with idiopathic systemic lupus erythematosus (SLE) are associated with impaired CYP2D6 activity
and to gain insight into whether there is an association between particular CYP2D6 genotypes and susceptibility to SLE, and whether CYP2D6 polymorphism is linked to any specific clinical features of SLE.
Methods: Debrisoquine sulfate (10 mg p.o.) was given to 159 healthy volunteers and 39 idiopathic SLE patients. Genotypic assay was
carried out in 80 healthy volunteers and 32 patients. A 10-ml blood sample was drawn for genotypic assay. Debrisoquine and
4-hydroxydebrisoquine were determined in 8-h urine samples. Blood samples were analysed for the presence of mutations in the
CYP2D6 gene, by using polymerase chain reaction (PCR) specific for CYP2D6*3 and CYP2D6*4 alleles.
Results: The metabolic ratio of debrisoquine to 4-hydroxydebrisoquine ranged from 0.01 to 86.98 in healthy subjects and from 0.02
to 96 in SLE patients. We observed the poor metabolizer(PM) debrisoquine phenotype in three of 39 patients with idiopathic
SLE (7.6%) and five of 159 healthy subjects (3.1%). There was no significant difference in the frequency of PM phenotypes
between idiopathic SLE and healthy subjects (Fisher's exact test, P = 0.19). No significant difference in the distribution of overall genotypes and allele frequencies were observed between
the two groups. No significant relationships were found between specific clinical features and the overall genotype.
Conclusion: The results of this study confirm that CYP2D6 activity is not impaired in SLE and that there is no association between SLE
and phenotypic CYP2D6 status. The results also showed that there was no difference in the frequency of CYP2D6A and CYP2D6B alleles between controls and patients with SLE.
Received: 14 May 1998 / Accepted in revised form: 19 October 1998 相似文献
53.
Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on
overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors.
The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine,
would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In
addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show
that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5–1.0 mg/ kg), and enhanced the increased
dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration
of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating
and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine
by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes.
Received: 5 May 1998/Final version: 7 July 1998 相似文献
54.
55.
Effects of Diethyl Phthalate and Other Plasticizers on Laurate Hydroxylation in Rat Liver Microsomes
Diethyl phthalate (DEP) is used in pharmaceutical coatings, cosmetics, and plastic films to wrap foods. There is a health concern associated with the exposure to certain phthalate esters because they belong to a class of compounds referred to as peroxisome proliferators which have been shown to increase the incidence of liver tumors when administered to rats. In this study, we have compared DEP to four other commonly used plasticizers, 2-diethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), 2-diethylhexyl adipate (DEHA), and acetyltributyl citrate (ATBC), for their ability to induce the cytochrome P450-mediated fatty acid -hydroxylation system, which is one of the initial cellular responses when animals are treated with peroxisome proliferators. The administration of DEHP, DBP, and DEHA to rats increased the specific activity of laurate 12-hydroxylase from 2.8 ± 1.1 in control rats to 30.3 ± 11.6, 14.5 ± 4.1, and 9.7 ± 1.9 nmol 12-hydroxylaurate formed/min/nmol P450, respectively. In contrast, laurate 12-hydroxylase activity in DEP-and ATBC-treated rats were 4.4 ± 1.2 and 4.4 ± 1.0 nmol 12-hydroxylaurate formed/min/nmol P450, respectively. In addition, whereas DEHP increased peroxisomal palmitoyl-CoA oxidation 6-fold, DEP increased this activity only 1.3-fold. Two protein bands, at 51 and 52 kDa, were found to increase 6- to 12-fold in microsomes of DEHP-, DBP-, and DEHA-treated rats, but these bands were increased only 2-fold in DEP- or ATBC-treated rats. 相似文献
56.
V. Rogiers A. Callaerts A. Vercruysse M. Akrawi E. Shephard I. Phillips 《Pharmacy World & Science》1992,14(3):127-131
Male Wistar rats werein vivo exposed for 2 weeks to 100 g/ml sodium valproate by subcutaneous implantation of osmotic pumps and hepatocytes were isolated. As anin vitro model co-cultures of rat hepatocytes with epithelial cells were daily treated with valproate (25, 50, 100, 200g/ml) for 2 weeks. In both models the cytochrome P-450 content and the enzymatic activities of 7-ethoxycoumarinO-deethylase, aldrin epoxidase and glutathioneS-transferase were determined in valproate-treated hepatocytes, in controls and in phenobarbital-induced cells. It appeared that in both systems the cytochrome P-450 content and the 7-ethoxycoumarinO-deethylase activity increased significantly after valproate treatment. On the other hand, the activities of aldrin epoxidase and glutathioneS-transferase decreased. A cDNA probe, encoding rat P450IIB2 was used to determine whether mRNAs encoding the P450IIB subfamily were induced by valproate. It became clear that the inducing effect of valproate was even more pronouncedin vitro thanin vivo. 相似文献
57.
Michal Laniado-Schwartzman Nader G. Abraham 《Pediatric nephrology (Berlin, Germany)》1992,6(5):490-498
In addition to cyclooxygenase and lipoxygenase, arachidonic acid (AA) is metabolized by the cytochrome P-450 monooxygenase system. The kidney is one of the major extrahepatic tissues that display cytochrome P-450 enzyme activities, in particular the cortex, specifically the proximal tubule demonstrate the highest concentration. AA is metabolized by the renal cytochrome P-450 epoxygenase and /-1 hydroxylases to epoxyeicosatrienoic acids and /-1 alcohols (20- and 19-mono-hydroxyeicosatetraenoic acids), respectively. These metabolites possess a broad spectrum of biological and renal effects which include: vasodilation, vasoconstriction, inhibition and stimulation of Na+–K+-ATPase, inhibition of ion transport mechanisms, natriuresis, inhibition of renin release and stimulation of cell growth. These metabolites are endogenous constituents of the kidney and are present in urine with increasing concentration under pathological conditions such as pregnancy-induced hypertension. The cytochrome P-450-dependent metabolism of AA is specifically localized to the proximal tubule and exhibits developmental changes, i.e., renal production of metabolites is very low in the fetus, newborn and up to 3 weeks of age, after which a remarkable increase in enzyme activities is observed. These characteristics call attention to the importance of this enzyme system in producing cellular mediators for regulating renal function in normal and diseased states. 相似文献
58.
Summary Diazepam was metabolized by human foetal liver microsomes to N-desmethyldiazepam and N-methyloxazepam as early as the 13th week of gestation. The metabolic activity was lower than that of microsomes from adult human liver. Diazepam was shown mainly to be hydroxylated to N-methyloxazepam at substrate concentrations higher than 0.1 mM. Diazepam levels above 1.0 mM were inhibitory to the overall metabolic reaction. SKF 525-A inhibited diazepam metabolism by foetal liver microsomes at a concentration of 0.1 mM. The addition of diazepam to foetal and adult human liver microsomes resulted in a type II spectral change. Its inhibition by carbon monoxide indicated that biotransformation of diazepam was performed by the cytochrome P-450-linked mono-oxygenase system. 相似文献
59.
氯氮平在体内代谢与细胞色素P450 1A2-2964位点多态性的关系 总被引:1,自引:0,他引:1
目的:探讨氯氮平在精神分裂症患者体内代谢和细胞色素P450 1A2-2964位点多态性关系,指导临床对不同患者合理使用氯氮平。方法:采用固定剂量给药,用高效液相色谱法(HPLC)测定血药浓度,用限制性片段长度多态性(RFLPs)分析基因型。结果:吸烟组和非吸烟组之间比较,吸烟组血浆氯氮平浓度低,去甲氯氮平/氯氮平比值高(P<0.05,P<0.01),P450 1A2-2964位点等位基因G的频率为0.75,A的频率为0.25,在非吸烟患者中,去甲氯氮平/氯氮平在w/w基因型与非w/w基因型(w/m m/m)之间无显著的统计学意义(P>0.05),在吸烟患者中,w/w基因型去甲氯氮平/氯氮平要高于非w/w基因型(P<0.05),在吸烟患者和非吸烟患者中w/w基因型之间比较,吸烟患者的去氯氮平/氯氮平明显高于非吸烟患者(P<0.01);而非w/w基因型之间无显著的统计学意义(P>0.05),结论:吸烟能诱导P450 1A2的活性。P450 12-2964位点等位基因均为G(w/w)时诱导能力最强,发生G→A突变时,诱导能力降低,分析患者P450 1A2 G-2964A的多态性,对合理使用氯氮平有意义。 相似文献
60.