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11.
P. J. Pentikäinen P. J. Neuvonen K. -G. Jostell 《European journal of clinical pharmacology》1980,17(4):275-284
Summary The pharmacokinetics of chlormethiazole after oral and intravenous administration was studied in six healthy volunteers and eight patients with alcoholic cirrhosis of the liver. Plasma concentration-time curve after the intravenous infusion could adequately be described by two- or three-compartment open models both in healthy volunteers and in the patients. Based on the areas under the plasma concentration-time curves, the systemic bioavailability of oral chlormethiazole was about ten times greater in the patients than in healthy controls. The elimination of chlormethiazole was relatively less retarded in the patients, as indicated by a decrease of about 30% in its plasma clearance. In the patients the plasma protein binding of chlormethiazole was decreased, but the volume of distribution and half-life of elimination were unchanged. The increase in bioavailability of chlormethiazole was associated with significant alteration in the serum levels of bilirubin, albumin, alkaline phosphatase, prothrombin-proconvertin activity (P + P) and elimination rate of antipyrine or14C-aminopyrine. The increased bioavailability of oral chlormethiazole was due to impaired first-pass metabolism in the cirrhotic liver. A considerable reduction in dose seems to be indicated if oral chlormethiazole is used in patients with advanced cirrhosis of the liver. A substantial fraction of dose, averaging 15%, was lost during the intravenous infusion, presumably due to adsorption to the infusion tubing. 相似文献
12.
《Nutrition reviews》1981,39(6):232-234
The macronutrient composition of the diet has been shown to influence the oxidative biotransformation of two prototype drugs, antipyrine and theophylline, in both normal adults and asthmatic children. 相似文献
13.
P. V. Luoma A. Rautio J. Steng»rd E. A. Sotaniemi J. Marniemi 《European journal of clinical pharmacology》1990,38(6):625-627
Summary Serum high density lipoprotein (HDL) subfractions HDL2 and HDL3, apolipoproteins, and plasma antipyrine clearance (AP-CL) rate, an index of liver microsomal enzyme activity, were determined in 21 healthy subjects. High HDL cholesterol and HDL2 cholesterol concentrations and HDL cholesterol/cholesterol and HDL2/HDL3 cholesterol ratios were associated with high AP-CL. Phenobarbital enhanced antipyrine elimination and increased the apolipoprotein A-I/A-II ratio. Subjects who had high AP-CL had a more antiatherogenic HDL subfraction and apolipoprotein profile than those with low AP-CL. 相似文献
14.
Kay Brune MD 《Acute Pain》1997,1(1):33-40
The late 19th century gave rise to the discovery of the three prototypes of modern non-opioid antipyretic analgesics: acetaminophen (acetanilide), aspirin and salicylic acid, and phenazone. At three different sites at almost the same time in Germany the zest for finding substitutes for quinine, ie antipyretic drugs, led to synthetic efforts culminating at Erlangen in the synthesis of phenazone (antipyrine), at Strasbourg of acetanilide (antifebrin), and at Wuppertal of aspirin (acetylsalicylic acid). The rationales for synthesising these drugs were not stringent, but proved, nonetheless, successful. Thereafter chemists concentrated their attempts merely on modifying the drugs discovered with the help of the rapidly expanding and improving organic chemistry. Although no new principles were discovered, the ‘relatives’ of the originals, namely aspirin and its modifications, acetaminophen and propyphenazone, as well as dipyrone, still make up for about 50% of the market of the antipyretic analgesics worldwide.Some of these compounds have attracted new interest recently. This is particularly the case with dipyrone (metamizole, Novalgin). After more than 50 years of clinical use (without major research efforts) state of the art investigation was commenced, and at its 75th birthday this compound is now thoroughly investigated. The side effect profile and risks, as well as the pharmacokinetic parameters, are defined and the mode of action has been elucidated. Although several clinical studies show effectiveness, probably due to the 75 year-long worldwide experience, modern therapy orientated studies proving usefulness in specific indications, claimed by many physicians and patients (eg after bone marrow transplantation, against migraine, and in osteoarthrosis), are still unavailable. In this respect, further research efforts and extension of knowledge is required, since this drug lacks gastrointestinal and renal toxicity, blood coagulation is only marginally influenced, and the widely discussed agranulocytosis is extremely rare and nearly never fatal. 相似文献
15.
The inactivation of endogenous steroids and foreign compounds by the liver hydroxylative pathway, can be modified by androgenic substances. The inhibitory or inductory activity, can be estimated by measuring the half-life of antipyrine. Androgens (testosterone propionate, 5α-dihydro-testosterone and mesterolone) reduce antipyrine metabolism in male rabbits. In females, androgens are not inhibitors, but one of them, 5α-dihydrotestosterone, shows an inductive effect on liver oxidative mechanisms. 相似文献
16.
J. M. C. Connell W. G. Rapeport S. Gordon M. J. Brodie 《European journal of clinical pharmacology》1984,26(4):453-456
Summary The effect of short-term hepatic enzyme induction with carbamazepine (CBZ) on circulating thyroid hormone concentrations was studied in 10 healthy male subjects. CBZ 400 mg per day was given for 21 days in 6 subjects and for 14 days in a further 4. In the former group the effect of therapy on the pituitary/thyroid axis was also assessed by measuring thyroid stimulating hormone (TSH) response to thyrotrophin-releasing hormone. CBZ therapy resulted in induction of hepatic monooxygenase activity, evidenced by a fall in antipyrine half-life (11.1±0.7 to 7.6±0.7 h; p<0.001), and a rise in antipyrine clearance (0.72±0.06 to 0.98±0.1 ml min–1 kg–1; p<0.001). A significant fall in total serum thyroxine (T4) (81.9±2.9 to 75.1±2.9 nmol l–1), and triiodothyronine (T3); (1.59±0.07 to 1.37±0.05 nmol l–1) and free T4 (16.03±0.82 to 14.2±0.8 pmol l–1) was seen after CBZ therapy. (all p<0.05). No significant change in reverse T3 or thyroid binding globulin occurred. In the 6 subjects studied for 21 days, maximal changes were found following 14 days' treatment. Basal and stimulated TSH remained unaltered. These effects on circulating thyroid hormone concentrations are likely to be secondary to hepatic enzyme induction leading to accelerated nondeiodinative hepatic hormone disposal. The reason for the failure of pituitary TSH secretion to rise in response to the fall in circulating T4 and T3 is unclear but may have implications for chronic treatment with CBZ in epileptic patients. 相似文献
17.
E. A. Sotaniemi O. T. Hokkanen J. T. Ahokas R. O. Pelkonen J. Ahlqvist 《European journal of clinical pharmacology》1977,12(6):429-435
Summary The clinical picture and drug metabolism in 36 consecutive patients with alpha-methyldopa — induced hepatic injury were investigated. The diagnosis was based on case history and biochemical, histological and follow-up studies after withdrawal the drug. Alpha-methyldopa-induced liver damage was found to occur in two phases, acutely within months and chronically within years after beginning treatment. Differences were also found in clinical symptoms and the results of liver tests on the patients if they were divided on the basis of the time factor. Drug metabolism was impaired in patients with alpha-methyldopa-induced liver damage, as indicated by low cytochrome P-450 level in liver biopsies and prolonged antipyrine elimination rate from plasma. Disappearance of the symptoms and normalisation of the liver tests after drug withdrawal occurred faster in patients with an acute type of hepatotoxicity than in subjects with delayed onset of the symptoms. The occurrence of hepatotoxicity in four members of a family suggests a genetic disposition to alpha-methyldopa-induced hepatic injury. The occurrence of two phases of liver damage suggests that a possible mechanism for acute hepatotoxicity might be an allergic reaction to metabolic intermediates produced during breakdown of alpha-methyldopa in the liver. For cases of delayed onset the cause might be increasing damage to microsomal liver protein due to covalent binding during long-term exposure to the drug. 相似文献
18.
M. Danhof A. van Zuilen J. K. Boeijinga D. D. Breimer 《European journal of clinical pharmacology》1982,21(5):433-441
Summary The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8±1.9% of the dose was excreted in urine as unchanged antipyrine in 48h, 24.9±6.3% as 4-hydroxyantipyrine, 16.5±3.2% as norantipyrine, 13.0±2.2% as 3-hydroxymethyl-antipyrine and 5.8±1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine. 相似文献
19.
P. V. Luoma E. A. Sotaniemi R. O. Pelkonen A. Arranto C. Ehnholm 《European journal of clinical pharmacology》1982,23(3):275-282
Summary The relationship between high-density lipoproteins (HDL) in plasma and hepatic structure and microsomal function has been investigated in 54 patients undergoing diagnostic liver biopsy. Plasma HDL cholesterol and major apoproteins were correlated with hepatic histology and microsomal enzyme activity assessed directly as liver cytochrome P-450 concentration and indirectly by plasma antipyrine clearance rate. HDL cholesterol, the concentrations of apoproteins A-I and A-II, the HDL cholesterol/total cholesterol ratio and cytochrome P-450 were low in subjects with moderate or severe hepatic fatty infiltration or cirrhosis when compared with the values for subjects with a normal liver. HDL cholesterol and apoprotein A-I and the HDL cholesterol/total cholesterol ratio were directly proportional to the amount of non-fatty parenchyma in the livers. Subjects with a normal liver undergoing treatment with enzyme-inducing drugs, such as phenytoin, phenobarbital and primidone, had higher HDL cholesterol, apoproteins A-I and A-II, HDL cholesterol/total cholesterol ratio, cytochrome P-450 and antipyrine clearance rate than subjects not receiving such therapy. Treatment with inducers appeared to have compensated for the effect of liver disease in lowering plasma HDL. In the entire population, and also in subjects not taking inducing drugs, when considered separately, plasma HDL cholesterol, apoproteins A-I and A-II and the HDL cholesterol/total cholesterol ratio were significantly correlated with cytochrome P-450 concentration. In subjects on enzyme inducers, HDL cholesterol and apoprotein A-I levels and the HDL cholesterol/total cholesterol ratio were proportional to the magnitude of the induction. Serum triglycerides were inversely proportional to the measures of liver microsomal enzyme activity. The lipoprotein pattern, high HDL cholesterol and apoproteins A-I and A-II, and high HDL cholesterol/total cholesterol ratio that accompany microsomal induction are characterized by a reduced risk of atherosclerotic vascular disease and a prolonged expectation of life. The plasma changes presumably reflect the effect of enzyme inducers, such as phenytoin and phenobarbital on hepatic lipids and proteins.The results have been presented at the annual meetings of the American Society for Clinical Pharmacology and Therapeutics, Kansas City, Missouri, 21–23 March 1979 [24] and the Scandinavian Society for Atherosclerosis Research, Turku, Finland, 31 August-1 September 1979 [23] 相似文献
20.
H. I. Pirttiaho E. A. Sotaniemi J. Ahlqvist U. Pitkänen R. O. Pelkonen 《European journal of clinical pharmacology》1978,13(1):61-67
Summary The role of liver size in drug metabolism was investigated in 34 chronic alcoholics and 28 controls by comparing antipyrine half-life with biopsy content and total amount of hepatic cytochrome P-450 (P-450) and liver weight. Liver size was significantly greater in alcoholics than in controls. Total P-450 was increased and antipyrine metabolism was enhanced in alcoholics with normal histology of the liver. In subjects with alcoholic hepatitis or cirrhosis, the antipyrine half-life was prolonged and P-450 was decreased. Alcoholics with fatty liver had a reduced P-450 content, but the total amount of P-450 and the antipyrine half-life were normal. The results demonstrate in alcoholics that an enlarged liver of normal histological appearance is associated with enhanced drug metabolism. In subjects with fatty liver the drug metabolizing capacity per unit weight of liver is often impaired, but the increase in liver size leads to undisturbed total oxidizing capacity and normal in vivo metabolism. In alcoholic hepatitis drug metabolism is impaired in spite of hepatomegaly. In cirrhosis the enlargement of the liver appears to compensate for the decreased P-450 content resulting in only slightly decreased total P-450, and the severely impaired in vivo drug metabolism may be due to derangement of blood flow. 相似文献