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1.
Summary The pharmacokinetics of a single 400 mg oral dose of valnoctamide (VCD) has been investigated in seven healthy, adult, male volunteers. VCD was not biotransformed rapidly to its corresponding acid valnoctic acid (VCA), unlike its isomer valpromide (VPD). It had a mean residence time of 13.2 h and a terminal half-life of 9.3 h. Throughout the study, only low plasma levels of VCA could be detected. Thus, unlike VPD, which is a prodrug of the corresponding acid, (valproic acid, VPA). VCD appears to act as a drug in its own right, and it does not undergo similar hydrolysis. The pharmacokinetic difference may account for the different pharmacological activities of the two isomers.  相似文献   
2.
Much of the literature on research design in clinical pharmacology and pharmacokinetics emphasizes statistical concerns, thus suggesting that a primary ingredient of a valid research design is an appropriate plan for statistical analysis of data. However, statistical validity is only one of several ways to evaluate an experimental study. The present paper reviews the underlying logic and sources of invalidity of experimental drug research suggesting influences and factors which may deceive or lure an experimenter into erroneous conclusions.  相似文献   
3.
1. Metabolism of the 1",1"-dimethylheptyl analogue of cannabidiol (DMH-CBD) was studied using an isolated perfused rat liver preparation and in rat and dog urine. 2. Metabolites were identified using g.l.c.-mass spectrometry of the trimethylsilyl (TMS), methyl ester/TMS and [2H9]TMS derivatives. 3. In contrast with the metabolism of cannabidiol, the dimethylheptyl analogue gave low concentrations of metabolites in all media examined. 4. Four metabolites were found in the perfusion fluid. Two were identified as 6- and 7-hydroxy-DMH-CBD and the other two were found to be hydroxylated in the dimethylheptyl chain but at undetermined positions. 5. Five metabolites were identified in dog urine; these were the 6- and 7-mono-hydroxy and 6,7-dihydroxy derivatives of acids formed by one stage of beta-oxidation of the dimethylheptyl chain, and the 6- and 7-hydroxy derivatives of corresponding acids formed by loss of three carbon atoms from the chain. 6. Metabolic routes were very similar to those found earlier for cannabidiol.  相似文献   
4.
PURPOSE: The goal of this study was to develop a new method, based on robust pharmacokinetic (PK) parameters, for determining t(max) (time of peak plasma concentration) and the magnitude of difference between the absorption (k(a)) and elimination (k) rate constants in the one compartment body model with first order input and output. METHODS: The function F(X) that describes the ratio of the AUC (area under the curve) from MRT (mean residence time) to infinity and the AUC from zero to MRT as a function of ratio between the first-order absorption and elimination constants (X) was derived and its limits were determined. Similarly, the function G(X) that describes the ratio between MRT and t(max) was derived and its limits were determined. RESULTS: The functions F(X) and G(X) depend only on the ratio between k and k(a). Thus, the different values of the functions F(X) (a-values) and G(X) (b-values) were calculated as a function of the ratio k/k(a). A table with 1% increments of the relevant b-value for every a-value was derived. The appropriate t(max) was thus calculated from the quotient MRT and the relevant b-value. A useful application of the new method to a drug product with prolonged absorption and long half life was presented. CONCLUSIONS: A new method that allows the calculation of t(max) and the k/k(a) ratio and derivation of a simple criterion of the equality between k and k(a) has been developed. This method is applicable to the one compartment open body model with first order absorption and elimination and is not based on single point parameters but on robust pharmacokinetic parameters such as AUC and MRT.  相似文献   
5.
Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the position to the carbonyl, such as in the case of TMCD, or a substitution in the and in the positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.  相似文献   
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Background

RIPPLY2-associated spondylocostal dysostosis is a rare disorder that leads to segmentation defects of the vertebrae. These vertebral defects can result in severe instability of the cervical spine, leading to cardiac arrest after only minor whiplash injury.

Case Report

We present the case of a healthy 7-year-old child who experienced an out-of-hospital cardiac arrest. He was reported to have profound respiratory distress and collapsed after going down a slide, without trauma. He was resuscitated in the field, and presented to the emergency department, where return of spontaneous circulation was achieved. Imaging of his cervical spine revealed multiple abnormalities. It was determined that a whiplash injury led to hypoxia and bradycardia due to the anatomic abnormalities of his cervical spine, resulting in cardiovascular collapse. He recovered fully and was later diagnosed with SCDO6, an autosomal recessive inherited disorder caused by a mutation in the RIPPLY2 gene.

Why Should an Emergency Physician Be Aware of This?

Unfamiliarity of providers with this mechanism of cardiac arrest, and the rarity of the syndrome itself, make early recognition very difficult. Late diagnosis and lack of preventative measures, including immediate cervical spine stabilization, can lead to catastrophic outcomes. In patients with cardiac arrest of unclear etiology, early consideration of cervical spine immobilization and evaluation can be lifesaving.  相似文献   
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OBJECTIVE: We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP. METHOD: The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP. RESULTS: Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A>T observed in the prenatal benign form of HP and common in USA was not found in this series. CONCLUSION: The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP.  相似文献   
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