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81.
82.
Cyclosporine is a powerful immunosuppressant with a narrow therapeutic window and considerable inter- and intrapatient variability.
The pre-dose trough concentration (Cmin) is commonly used for therapeutic drug monitoring. With the new microemulsion (Neoral), intrapatient variability was reduced.
However, the usefulness of Neoral Cmin was questioned. Firstly, because of the improved and more-rapid absorption, accidental intake before blood sampling has a
greater impact on Cmin than with classic cyclosporine. Secondly, Cmin may be low despite high drug exposure, due to rapid clearance in children. A full pharmacokinetic (PK) profile with determination
of the area under the curve (AUC) is expensive and cumbersome, and therefore a search for an abbreviated AUC began. Here,
we present a retrospective analysis of 84 PK profiles from 78 pediatric renal transplant recipients. By analysis of rejection
episodes and toxicity, we estimated a target AUC above 5,000 ng×h/ml in the early post-transplant period and 3,900 ng×h/ml
beyond 100 days. The abbreviated AUC using the 2- and 6-h concentrations (C2 and C6) and a simple estimate derived from the
3-h concentration (C3) were equally well correlated with the AUC. From our data, we recommend a target C3 at approximately
800 ng/ml early after transplantation and 450–550 ng/ml beyond 100 days.
Received: 28 January 1998 / Revised: 10 June 1998 / Accepted: 15 June 1998 相似文献
83.
The blood-brain barrier (BBB) restricts the entry of antiviral agents into the CNS thereby facilitating the creation of a reservoir of HIV that could potentially reinfect peripheral tissues. We characterized the efflux from brain of radioactively labeled viral coat HIV-1 gp120 (I-gp120) after intracerebroventricular (i.c.v.) injection. The half-time disappearance rate of I-gp120 from brain was 12.6 min, which was faster than could be explained by the reabsorption of cerebrospinal fluid into blood but could not be explained by a saturable transporter. After i.c.v. injection, I-gp120 appeared in the serum and was sequestered by spleen and the cervical nodes, demonstrating a potential for virus within the CNS to reinfect peripheral tissues. However, the amount of I-gp120 appearing in serum was less than that expected based on the efflux rate, whereas uptake by the cervical nodes was much greater after i. c.v. than after i.v. injection of I-gp120. These findings were explained by drainage from the brain directly to the cervical lymph nodes through the brain's primitive lymphatic system. These lymphatics potentially provide a pathway through which CNS reservoirs of HIV-1 could directly reinfect lymphoid tissue without being exposed to circulating antiviral agents. 相似文献
84.
Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function 总被引:1,自引:0,他引:1
Buter H Navis GY Woittiez AJ de Zeeuw D de Jong PE 《European journal of clinical pharmacology》1999,54(12):953-958
Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day
in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1)
receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound.
Methods: Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A >60 nl · min−1 · 1.73 m−2, group B 30–60 ml · min−1 · 1.73 m−2 and group C 15–30 ml · min−1 · 1.73 m−2).
Results: Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after
multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the
concentration-time curve extrapolated to time infinity (AUCinf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal
function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well
as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure
was lower and both PRA and angiotensin II were higher compared with baseline.
Conclusion: Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired
renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This
dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment.
Received: 3 August 1998 / Accepted in revised form: 19 October 1998 相似文献
85.
Bioavailability of intranasal formulations of dihydroergotamine 总被引:1,自引:0,他引:1
van der Kuy PH Lohman JJ Hooymans PM Ter Berg JW Merkus FW 《European journal of clinical pharmacology》1999,55(9):677-680
Objective: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM)
with a commercially available intranasal preparation.
Methods: Two intranasal formulations of DHEM in combination with randomly methylated β-cyclodextrin (RAMEB) were prepared. Subsequently,
in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2%
RAMEB nasal spray ( =two puffs of 100 μl); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray ( =four puffs of 125 μl);
0.5 mg DHEM i.m., and 2 mg DHEM solution p.o.
Results: No statistically significant differences were found in maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under plasma concentration–time curve (AUC0–8 h), Frel(t=8 h) and Cmax/ AUC(t=8 h) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal
powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration.
The relative bioavailability after oral administration was 8%.
Conclusion: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially
available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number
of puffs and (3) a preference by the volunteers.
Received: 12 February 1999 / Accepted in revised form: 23 August 1999 相似文献
86.
T. B. Vree E. W. J. Van Ewijk-Beneken Kolmer E. W. Wuis Y. A. Hekster 《Pharmacy World & Science》1992,14(5):325-331
Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, thet
1/2 increased from 3 to 6 h. TheC
max was 14g/ml with a dosage of 250 mg, 31g/ml with 500 mg, 70g/ml with 1,000 mg and 120g/ml with 1,500 mg. Thet
max remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6–0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34–59%). The protein binding of probenecid glucuronidein vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate-time profile of probenecid glucuronide shows a plateau value of approximately 700g/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects itsV
max of formation. 相似文献
87.
Aetiologically different models of experimental acute renal failure were induced in rats by the administration of glycerol, mercuric chloride and gentamicin, respectively, to different groups. Quinine levels in plasma and urine of the rats with induced renal failure were determined and pharmacokinetic parameters (eliminationt
1/2, CL
p
,V, CLR AUC0–) of the drug were derived and compared with values obtained from control rats following intraperitoneal administration of a 10 mg/kg body-weight dose of quinine. Results showed that each of the three compounds caused an up to 25-fold increase in the plasma levels of the drug and a marked decrease in the levels of the metabolite 3-hydroxyquinine. All the pharmacokinetic parameters determined for the rats with renal impairment were markedly different when compared to control. The high plasma quinine levels observed in the rats with renal failure could be largely due to the marked decrease inV and reduced metabolism. Also, in the rats with renal impairment, no correlation was observed between the increased plasma urea levels and plasma quinine levels or disposition of the drug. The results of the study suggest that quinine should be used with caution in patients with renal impairment. The plasma urea levels, as a measure of renal function, might not provide a suitable index for determining quinine dosage. 相似文献
88.
Viloxazine HCl is evaluated as an anticonvulsant in a wide range of rodent seizure models and in the epileptic baboon (Papio papio). In the maximal electroshock test, the oral ED50 for abolition of tonic extension was 9 mg/kg-1 after 30-min pretreatment (mouse) rising to 30 mg/kg-1 after 60 min (mouse and rat). Comparable ED50 values were also found for protection against tonic extension in the mouse induced by the administration of the chemical convulsants metrazole or 3-mercaptopropionic acid. In DBA/2 mice the ED50 for abolition of tonic extension during sound-induced seizures was 6.8 mg/kg-1 IP (30-min pretreatment). Pharmacokinetic studies in the mouse showed peak plasma levels to occur 30 min following oral doses, with a mean half-life of 58 min. The anticonvulsant plasma concentration was within 0.5–1 g/ml-1. In the baboon, significant protection against photomyoclonic responses is observed 1–2 h after viloxazine (2.6 mg/kg-1 IV), during which period the plasma concentration was again 0.5–1 g/ml-1. After administration of approximately ten-times this latter dose level, i.e. 24 mg/kg-1 IV, a syndrome characterised by an abnormal EEG and, in some instances, seizure activity was observed. 相似文献
89.
Summary A total of 20 children with various types of epilepsy were treated with valproate, 11 with monotherapy and 9 with valproate in combination with phenobarbitone, phenytoin, or carbamazepine. Valproate was given either every 8 or 12 h. At least two different dose levels were tried in each patient. The pharmacokinetics of valproate during the interval between doses was determined using a gas chromatographic technique. The clinical effect of the treatment was assessed by interviewing the parents.The plasma concentrations showed considerable fluctuation during the intervals between doses. The mean increase from pre-administration to peak level was 82% when the dose interval was 12 h, and 62% when it was 8 h. The mean plasma half-life of valproate, using a one-compartment model, was 10.9±1.3 h (mean±SD). The plasma half-life of valproate was decreased when the drug was combined with the other anti-epileptics. The calculated area under the concentration versus time curve was linearly related to dose, both in a single patient on four dose levels and when different patients were compared. The clinical effect of valproate monotherapy was best in patients with absences, usually good in myoclonus and less favourable in other types of epilepsy. For children with absences, the optimal dose range of valproate was between 20 and 40 mg/kg/24 h. In comparison, the myoclonic types of epilepsy needed a slightly higher dose level, between 30 and 60 mg/kg/24 h. In the latter group a therapeutic window seems to exist, since patients below and above the suggested dose levels were not well-controlled. Therapeutic monitoring of valproate does not appear meaningful when the drug is used as monotherapy. However, in combination therapy, determination of the plasma levels of all anti-convulsants used may be helpful. The large fluctuations of valproate during a dose interval must be taken into consideration when the clinical effects are analysed.Supported by the Swedish Medical Research Council (Project No. 522), Stiftelsen Margarethahemmet, and Sällskapet Barnavård 相似文献
90.
Jan-Erik Lindgren Agneta Ohlsson Stig Agurell Leo Hollister Hamp Gillespie 《Psychopharmacology》1981,74(3):208-212
9-Tetrahydrocannabinol (9-THC) was administered in a crossover design by smoking and IV injection to groups of heavy and light users of marihuana. Plasma concentrations of 9-THC were similar for the groups after IV injection of 5.0 mg 9-THC, but the AUC0–240 min showed a trend towards lower values for the heavy user group. To achieve a maximum desired high, both groups smoked similar amounts (about 13 mg) of 9-THC. Heavy users tended to have higher plasma levels than light users. The systemic availability of smoked 9-THC was significantly higher for the heavy users (heavy users 23±16% vs 10±7% for light users). These results also indicate that heavy cannabis users smoke more efficiently than casual smokers.Both light and heavy users showed more clinical effect following IV administration than after smoking. The response of the heavy users, both with respect to effect on heart and high, was quite comparable to that of light users.The present study does not suggest that tolerance readily develops in heavy users. 相似文献