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排序方式: 共有219条查询结果,搜索用时 31 毫秒
1.
Krondahl Eva Orzechowski Achim Ekström Gunilla Lennernäs Hans 《Pharmaceutical research》1997,14(12):1780-1785
Purpose. To study intestinal transport and metabolism of three new -selective tetrapeptide enkephalin analogues, LEF537, LEF553 and TAPP These peptides are stabilized against enzymatic hydrolysis by having a D-aminoacid in position 2 and a blocked COOH-terminal.
Methods. We used a single-pass perfusion technique to study the transport of the peptides in rat jejunum. To reduce luminal and/or brush-border metabolism during the perfusion we used protease inhibitors (Pefabloc® SC, bestatin and thiorphan). The rate of metabolism was studied by incubations in rat jejunal homogenate, rat jejunal fluid and human gastric and jejunal fluid with and without these inhibitors.
Results. The jejunal permeabilities (Peff) of the peptides were 0.43–0.78 10–4 cm/s without inhibitors and 0.09–0.45 10–4 cm/s in presence of the inhibitors. All three peptides were rather rapidly degraded by enzymes in rat jejunal homogenate with half-lives of between 11.9 ± 0.5 and 31.7 ± 1.5 min. The addition of inhibitors to the homogenate prolonged the half-lives substantially for LEF553 (167 ± 35 min) and TAPP (147 ± 2 min), but only slightly for LEF537 (16.4 ± 0.5 min). LEF553 and TAPP were both hydrolyzed in rat and human jejunal fluid, while LEF537 was metabolized less in these fluids. When LEF553 and TAPP were incubated with intestinal fluid in the presence of inhibitors, metabolism was almost completely inhibited. There was no metabolism for any of the peptides in human gastric juice.
Conclusions. The replacement of the terminal free carboxylic group with an amide group did not increase the stability of the peptides in jejunal tissue enough to allow successful oral drug delivery. 相似文献
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3.
Antonios Douros Elisabeth Bronder Frank Andersohn Andreas Klimpel Michael Thomae Hans-Dieter Orzechowski Reinhold Kreutz Edeltraut Garbe 《European journal of clinical pharmacology》2014,70(4):453-459
Purpose
The hepatotoxic potential of the analgesic flupirtine has attracted increased attention over the past years. Recently, risk minimisation measures such as maximum treatment duration of 2 weeks have been requested by the European Medicines Agency (EMA). This study was conducted to further elucidate the clinical pattern of flupirtine-induced liver injury (FILI).Methods
Seven FILI patients were ascertained in all Berlin hospitals in the Berlin Case–control Surveillance Study (FAKOS) between 2002 and 2011. Furthermore, we reviewed the severe cases of flupirtine-associated hepatotoxicity included in the adverse drug reaction database of the Federal Institute for Drugs and Medical Devices (BfArM) in Germany from between 1991 and 2012.Results
All seven FILI patients of FAKOS were hospitalised. Six of them were female, mean age was 55 years, and the most common symptoms were fatigue and jaundice. Three patients developed acute liver failure (ALF). Discontinuation of flupirtine invariably led to clinical and laboratory improvement. Review of the BfArM cases (n?=?248) showed female sex predominance and high prevalence of jaundice and ALF. Time to onset of symptoms was less than 2 weeks in 9 % of the patients with respective data.Conclusions
Our results corroborate previous findings on FILI’s clinical pattern and on its potentially severe course. Although the hepatotoxic risk might be higher after the first 2 weeks of treatment, earlier onset of severe FILI cannot be ruled out. Postauthorisation safety studies are needed to evaluate EMA’s risk minimisation measures and to quantify flupirtine’s risk according to its duration of use. 相似文献4.
Piotr Orzechowski MD Ryszard Piotrowicz MD PhD Wojciech Zaręba MD PhD Renata Główczyńska MD PhD Dominika Szalewska MD PhD Sławomir Pluta MD PhD Robert Irzmański MD PhD Zbigniew Kalarus MD PhD Maciej Banach MD PhD Grzegorz Opolski MD PhD Michael J. Pencina PhD Ilona Kowalik PhD Ewa Piotrowicz MD PhD FESC 《Annals of noninvasive electrocardiology》2021,26(6):e12887
5.
Rossana Patricia Basso Vanice Rodrigues Poester Jssica Louise Benelli David A. Stevens Melissa Orzechowski Xavier 《Emerging infectious diseases》2022,28(3):721
We evaluated disseminated histoplasmosis (DH) in HIV patients over 10 years in southern Brazil. The incidence was 12 cases/1,000 hospitalizations (2010–2019); the mortality rate was 35%. Tuberculosis frequently obscured the diagnosis of DH. We emphasize the need in our region to suspect and investigate DH using more sensitive methods. 相似文献
6.
Orzechowski Achim; Schrenk Dieter; Bock-Hennig Barbara S.; Bock Karl Walter 《Carcinogenesis》1994,15(8):1549-1553
Since carcinogenic arylamines are sequentially oxidized andconjugated with glucuronic acid, differences in glucuronidationmay critically determine the toxic potential of these compounds.Therefore, N-glucuronldation of 1- and 2-naphthylamine (1-NAand 2-NA), 4-aminobiphenyl (4-ABP) and their N-hydroxy derivativeswas investigated using rat and human liver microsomes and V79cell-expressed phenol UDP-glucuronosyltransferases (UGT) ofthe UGTl gene complex. Cell-expressed UGTs included rat andhuman UGT 1.6, which are known to conjugate planar phenols,and human UGT1.7, conjugating both planar and bulky phenols,(i) N-Glucuronidation of 1- and 2-NA and of N-hydroxy-2-NA wasinducible by 3-methylcholanthrene in rat liver microsomes whereasN-glucuronidation of the bulky arylamines 4-ABP and N-hydroxy-4-ABPwas not In support of these findings mutagenicity of N-hydroxy-2-NAin the Ames test was markedly reduced upon addition of UDP-glucuronicacid using liver homogenates from 3-methylcholanthrene-treatedrats, (ii) With cell-expressed rat UGT1.6, non-carcinogenic1-NA was conjugated with the highest rate and with higher affinitythan 2-NA. UGT1.6 showed poor activity towards N-hydroxy-4-ABPand 4-ABP. (iii) Substrate specificity of human UGT1.6 alsoappeared to be limited to planar 1-NA, 2-NA and its N-hydroxyderivative, whereas UGT1.7 showed broader substrate specificity,including the bulky arylamine 4-ABP and its /V-hydroxy derivative.The results suggest marked differences in substrate specificityof different UGT isozymes for arylamines and their N-hydroxyderivatives. 相似文献
7.
Bock KW Bock-Hennig BS Münzel PA Brandenburg JO Köhle CT Soars MG Riley RJ Burchell B von Richter O Eichelbaum MF Swedmark S Orzechowski A 《Biochemical pharmacology》2002,63(9):1683-1690
UDP-glucuronosyltransferases (UGTs) are regulated in a species- and tissue-dependent manner by endogenous and environmental factors. The present study was undertaken to further our knowledge about regulation of UGTs in dogs, a species widely used in preclinical safety evaluation. beta-Naphthoflavone (BNF) was selected as a known aryl hydrocarbon receptor agonist and antioxidant-type inducer. The latter group of inducers is intensively investigated as dietary chemoprotectants against colon cancer. Dog UGTs were investigated in comparison with related human UGTs by examples, (i) expression of dog UGT1A6, the first sequenced dog phenol UGT, and (ii) morphine UGT activities, responsible for intestinal and hepatic first-pass metabolism of morphine. The following results were obtained: (i) dog UGT1A6 was found to be constitutively expressed in liver and marginally increased by BNF treatment. Expression was low in small intestine but ca. 6-fold higher in colon than for example in jejunum. Conjugation of 4-methylumbelliferone, one of the substrates of dog UGT1A6, was also enhanced 7-fold in colonic compared to jejunal microsomes. (ii) Compared to the corresponding human tissues, canine 3-O- and 6-O-morphine UGT activities were found to be >10-fold higher in dog liver and ca. 10-fold lower in small intestinal microsomes. Small intestinal morphine and 4-hydroxybiphenyl UGT activities appeared to be moderately (2- to 3-fold) induced by oral treatment with BNF. (iii) In contrast to dogs, morphine UGT activities were found to be similar in homogenates from human enterocytes and liver. The results suggest marked differences in tissue-specific regulation of canine vs. human hepatic and intestinal phenol or morphine UGTs. 相似文献
8.
Artur Krawczyk Leszek Morasiewicz Wiktor Orzechowski Szymon Dragan Jacek Czapiński Miroslaw Kulej 《Chirurgia narzadów ruchu i ortopedia polska》2004,69(5):305-309
AIMS: The purpose of this study is the assessment of efficiency of distraction osteogenesis (DO) as a method of operative treatment of knee arthrosis with co-existent varus deformity. MATERIAL AND METHODS: Authors undertook an attempt of evaluation of results of tibial corticotomy in 21 patients (25 operated knee joints) treated in Orthopaedic Clinic of Wroclaw Medical University in years 1995-2001, with the use of circular, external Ilizarov's fixator. All the operated patients underwent corticotomy of proximal tibial metaphysis followed by slow axis correction and bone regenerate formation started at 7th postoperative day. In orthopaedic examination functional evaluation of knee joint with modified point scale according to Ranawat (HSS-score) there were taken into account. In rentgenometric examination the limbs axis in the frontal plane and joint space morphology according to Ahlback were evaluated. RESULTS: The results in our group of patients were very encouraging. Accordingly to Ranawat scale, in majority of patients assessed before the treatment as poor and fair moved to group assessed as fair and good and even excellent. We observed decelerated regenerate formation and remodeling probably caused by advanced age of patients in 6 cases. In 3 cases persistent lose of entire correction was observed. CONCLUSIONS: In author's opinion DO as a method of operative treatment of unicompartmental knee arthrosis could be advocated as alternative method to traditional tibial osteotomy considering its biological effect stimulating regeneration of all tissues including cartilage even in advanced unicompartmental arthrosis. 相似文献
9.
10.
Krondahl E Von Euler-Chelpin H Orzechowski A Ekström G Lennernäs H 《The Journal of pharmacy and pharmacology》2000,52(7):785-795
The metabolism of three opioid tetrapeptides, Tyr-D-Arg-Phe-Nva-NH2, Tyr-D-Arg-Phe-Phe-NH2 and Tyr-D-Ala-Phe-Phe-NH2, was investigated in the presence of pure pancreatic enzymes (trypsin, chymotrypsin, elastase, carboxypeptidase A and carboxypeptidase B), as well as in the presence of pure carboxylesterase and aminopeptidase N. The cleavage patterns of the pure pancreatic enzymes were then compared with those found in rat and human jejunal fluid. Metabolism was also studied in homogenates from different intestinal regions (duodenum, jejunum, ileum and colon) and in enterocyte cytosol from rats. The effect of various protease inhibitors was investigated in the jejunal homogenate. The parent peptides were assayed by high-performance liquid chromatography and metabolites were identified by means of liquid chromatography-mass spectrometry. Of the pure enzymes, the quickest hydrolysis of the peptides was observed for the pancreatic enzymes chymotrypsin, trypsin and carboxypeptidase A. In most cases they formed the corresponding deamidated tetrapeptides (chymotrypsin and trypsin) or tripeptides with a missing C-terminal amino acid (carboxypeptidase A). Regional differences in intestinal metabolism rates were found for all three peptides (P < 0.001), with the highest rates observed in jejunal and/or colonic homogenates. The deamidated tetrapeptides were formed both in rat intestinal homogenates and in enterocyte cytosol. Metabolism in the jejunal homogenate was markedly inhibited by some serine and combined serine and cysteine protease inhibitors. In conclusion, the C-terminal amide of these tetrapeptides did not fully stabilise them against intestinal deamidase and carboxypeptidase activities. The significant hydrolysis of the peptides by pure chymotrypsin, trypsin and carboxypeptidase A showed that lumenal pancreatic proteases might be a clear metabolic obstacle in oral delivery even for small peptides such as these tetrapeptides. 相似文献