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151.
评价盐酸二甲双胍缓释片受试制剂和参比制剂在健康受试者餐后单次给药条件下的生物等效性和安全性。试验采用单中心、随机、开放、单剂量、两周期、两序列、双交叉设计,32例健康受试者在餐后状态下单次服用受试制剂或参比制剂0.5 g,在给药前(0 h)至给药后1、3、4、4.5、5、5.5、6、7、8、9、10、12、15、24、36和48 h采集静脉血4 mL,检测血浆样本中二甲双胍的浓度,用Win Nonlin 7.0软件计算药代动力学参数,当受试制剂与参比制剂的cmax、AUC0-t、AUC0-∞几何均值比的90%置信区间均在80.00%~125.00%等效区间内,证明两制剂生物等效。有1例受试者因不良事件脱落。受试制剂和参比制剂的主要药代动力学参数:cmax为(0.68±0.14)和(0.65±0.11) mg/L,AUC0-t为(7.33±1.65)和(7.00±1.89) h·mg/L,AUC0-∞为(7.39±1.67)和(7.06±1.91) h·mg... 相似文献
152.
Chen Sharon A. Perlman Andrew J. Spanski Noreen Peterson C. Matthew Sanders Steven W. Jaffe Robert Martin Mary Yalcinkaya Tamir Cefalo Robert C. Chescheir Nancy C. Menard Mary K. Mordenti Joyce 《Pharmaceutical research》1993,10(6):834-838
The pharmacokinetics of recombinant human relaxin (rhRlx) after intravenous (iv) bolus administration and the absorption of rhRlx after intracervical or intravaginal administration were determined in nonpregnant women. The study was conducted in two parts. In part I, 25 women received 0.01 mg/kg rhRlx iv. After a minimum 7-day washout period, these women were dosed intracervically (n = 10) or intravaginally (n = 15) with 0.75 or 1.5 mg rhRlx, respectively, in 3% methylcellulose gel. Part II was a double-blind, randomized, three-way crossover study in 26 women. At 1-month intervals, each woman received one of three intravaginal treatments consisting of 0 (placebo), 1, or 6 mg rhRlx in 3% methylcellulose gel. The serum concentrations of relaxin following iv administration were described as the sum of three exponentials. The mean (±SD) initial, intermediate, and terminal half-lives were 0.09 ± 0.04, 0.72 ± 0.11, and 4.6 ± 1.2 hr, respectively. Most of the area under the curve was associated with the intermediate half-life. The weight-normalized clearance was 170 ± 50 mL/hr/kg. The observed peak concentration was 98 ± 29 ng/mL, and the weight-normalized initial volume of distribution was 78 ± 40 mL/kg, which is approximately equivalent to the serum volume. If central compartment elimination was assumed, the volume of distribution at steady state (V
ss/W) was 280 ± 100 mL/kg, which is approximately equivalent to extracellular fluid volume. V
ss/W could be as large as 1300 ± 400 mL/kg without this assumption. After intravaginal administration of the placebo gel, endogenous relaxin concentrations were evident (i.e., 20 pg/mL) in 9 of the 26 women (maximum concentrations, 23–234 pg/mL). A similar proportion of women (approximately 35–40%) exhibited measurable serum concentrations of relaxin following intravaginal rhRlx treatment; this proportion increased to 90% following intracervical rhRlx treatment. For both routes of administration, the maximum serum concentrations of relaxin were usually within the range of values observed for endogenous relaxin, suggesting that the absorption of rhRlx was minimal. 相似文献
153.
William R. Gillespie 《Journal of pharmacokinetics and pharmacodynamics》1993,21(1):99-124
The following integrodifferential equation is proposed as the basis for a generalized treatment of pharmacokinetic systems in which nonlinear binding occurs $$\phi '(c_u )c'_u = - q(c_u ) + g*c_u + f$$ where cu≡unbound plasma drug concentration, f≡drug input rate,'indicates the derivative of a function, and * indicates the convolution operation: (g* cu)(t)=∫ 0 t g(t?u)cudu.Possible physical interpretations of the functions q, g and f are: q (cu)≡ rate at which drug leaves the sampling compartment, g * cu ≡ rate at which drug returns to the sampling compartment from the peripheral system (tissues that are kinetically distinct from the sampling compartment), and φ(cu) ≡ amount of drug in the sampling compartment. The approach assumes that drug binding is sufficiently rapid that it may be treated as an equilibrium process. It may be applied to systems in which nonlinear binding occurs within the sampling compartment, i.e., in the systemic circulation or in tissues to which drug is rapidly distributed. The proposed relationship is a generalization of most existing models for drugs with nonlinear binding. It can serve as a general theoretical framework for such models or as the basis for “model-independent” methods for analyzing the pharmacokinetics of drugs with nonlinear binding. Computer programs for the numerical solution of the integrodifferential equation are presented. Methods for pharmacokinetic system characterization, prediction and bioavailability are presented and demonstrated. 相似文献
154.
Jerry R. Nedelman Ekaterina Gibiansky Francis L. S. Tse Christine Babiuk 《Journal of pharmacokinetics and pharmacodynamics》1993,21(3):323-334
Five major objectives for pharmacokinetic investigations in support of toxicity studies are identified as follows: Assess whether animals exhibited measurable blood concentrations in a dose-dependent manner; estimate average area under the concentration- time curve (AUC)and maximal concentration (C
max
)for each treatment group; elucidate general patterns in the concentration-time (CxT)profile, and summarize relationships between CxTand treatment group; determine CxTdependence on day into study; and judge interanimal variability and identify any animals with unusual concentration response. Such objectives are generally addressed in rodent toxicity studies by including satellite animals in the study. Satellite animals are extra animals dosed as per protocol but not subjected to toxicological and pathological observations and tests. Instead, they are used exclusively for the evaluation of pharmacokinetic characteristics of the test compound. In this paper, methods are described for achieving the five listed pharmacokinetic objectives in rodent toxicity studies without the use of satellite animals. A rat toxicity study is presented as an example. 相似文献
155.
Pafenolol is a -blocker with unusual oral absorption properties. The blood concentration–time profile exhibits two peaks, and the bioavailability is low and dose dependent because of incomplete and nonlinear intestinal uptake. We addressed the question whether the intestinal absorption of pafenolol was affected by bile depletion in the gut lumen of rats. Further, the hypothesis that variable gastric emptying accounts for double peaks in blood was tested by duodenal administration of pafenolol. Following intraduodenal administration to rats with intact bile secretion, double peaks were observed in the blood concentration–time curve. The bioavailability was 6.8 ± 0.7% for the low dose (1 µmol/kg) and increased significantly to 28 ± 10% following the high duodenal dose (25 µmol/kg). These blood concentration–time profiles exclude interrupted gastric emptying as cause of the twin peaks. In bile duct-cannulated rats the intestinal absorption of the low dose (1 µmol/kg) was still poor (F = 10.7 ± 5.5%) and the blood concentration–time profile contained two peaks. Following administration of a high duodenal dose (25 µmol/kg) to rats with an almost bile-free small intestine, the absorption rate increased and the double-peak phenomenon disappeared in five of seven rats, while the bioavailability increased significantly, to 62 ± 27%. These results suggest that the low bioavailability of pafenolol is due to a complexation between bile and pafenolol in the gut lumen, preventing intestinal uptake in the major part of the small intestine. Further, such complex formation in the intestinal lumen may be the underlying mechanism of the double peaks observed in the blood concentration–time profile. 相似文献
156.
Susanne Danhauser-Riedl Edith Hausmann Hans-D. Schick Rita Bender Hermann Dietzfelbinger Johann Rastetter Axel-R. Hanauske 《Investigational new drugs》1993,11(2-3):187-195
Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21–28 days. Thirteen patients have received a total of 24 courses (median 2; range 1–3). At the starting dose of 40 mg/m2 doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m2 DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 1/5 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 mg/m2 DOXeq. Hepatotoxicity was noted in 5/5 patients (1 × WHO grade IV, 1 × WHO grade III). Thrombocytopenia was noted in 3/5 patients (1 × WHO grade IV, 2 × WHO grade III). At 12.5 mg/m2 DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 g/ml at 40 mg/m2 DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83–80.21 g/ml*h with dose-dependent elimination half lives (t1/2: 0.02–0.87 h;1/2: 2.69–11.58 h;1/2: 41.44–136.58 h). We conclude that the maximal tolerated dose (MTD) of AD-70 using this schedule is 40 mg/m2 DOXeq. The recommended dose for clinical phase II studies is 12.5 mg/m2 DOXeq.Abbreviations ALT
Alanine Aminotransferase
- AST
Aspartate Aminotransferase
- DOX
Doxorubicin
- DOXeq
Doxorubicin Equivalent
- ECG
Electrocardiogram
- HPLC
High Pressure Liquid Chromatography
- LD10
Lethal Dose for 10% of individuals
- MTD
Maximal Tolerated Dose
- ppc
Peak Plasma Concentration
- WHO
World Health Organisation 相似文献
157.
Pharmacokinetics,cerebrospinal fluid penetration,and metabolism of piroxantrone in the Rhesus monkey
Stacey L. Berg Frank M. Balis Karen S. Godwin David G. Poplack 《Investigational new drugs》1993,11(4):255-261
Summary Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activityin vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluatedin vitro.
The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m2 given over 60 minutes was biexponential with mean t1/2 alpha of 1.0 minutes and a mean t1/2 beta of 180 minutes. The mean area under the curve was 220 M·min and the clearance was 1420 ml/min/m2. Piroxantrone was not detectable in the cerebrospinal fluid.Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cellsin vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite.The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials. 相似文献
158.
Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease 总被引:1,自引:0,他引:1
S. Krähenbühl P. Grass A. Surve K. Kutz J. Reichen 《European journal of clinical pharmacology》1993,45(3):247-253
Summary The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensinconverting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n=10), in patients with chronic, non-cirrhotic liver disease (n=8) and in a control group of healthy subjects (n=16).The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 g·h·l–1, 923 g·h·l–1 and 1300 g·h·l–1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively.Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h–1 in patients vs. 2.00 h–1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls.Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients. 相似文献
159.
Investigation of nimodipine pharmacokinetics in Chinese patients with acute subarachnoid haemorrhage
C. R. Kumana M. Kou Y. L. Yu K. Y. Fong C. F. Fung C. M. Chang W. Mück I. J. Lauder 《European journal of clinical pharmacology》1993,45(4):363-366
Summary Nimodipine pharmacokinetics was investigated in 12 Chinese patients with acute subarachnoid haemorrhage receiving an IV infusion of 1.6 or 2 mg/h (based on estimated body weight) for 10 days. Peripheral venous blood samples were collected for up to 4 days and plasma nimodipine was assayed by GC/ECD. The mean value was taken as the steady state concentration (Css) and Clearance (CL) (hourly dose/Css) was calculated. Eight survivors were given oral nimodipine (60 or 90 mg) every 6h (based on body weight), blood was sampled over 6 h and the plasma nimodipine level determined. The values for Css, CL and CL·kg–1 were 33.5 g·l–1, 58 l·h–1 and 1.0 l·h–1·kg–1 respectively; in survivors receiving the drug orally, bioavailability of the 30 mg tablet was 9%. In one very sick patient given crushed tablets by naso-gastric tube, the AUC was very low; in vitro studies indicated that adsorption of nimodipine by the tubing was unlikely to have been the cause.The pharmacokinetic findings in Chinese patients are comparable to previously reported values in Caucasians. 相似文献
160.
M. Sakai S. Ohkawa T. Kaku K. Kuboki K. Chida T. Imai 《European journal of clinical pharmacology》1993,44(4):387-389
Summary We have investigated the pharmacokinetics of the direct vasodilator flosequinan in elderly patients with congestive heart failure. Eight patients received a single dose of 50 mg, and 8 patients received once-daily treatment with 25 mg for two weeks.In the single dose study, the tmax of flosequinan was 2.5 h, Cmax was 1.17 g · ml–1 and t1/2 was 5.63 h. The tmax of the metabolite BTS 53554 was 20.3 h, Cmax was 1.44 g · ml–1 and t1/2 was 62.0 h.BTS 53554 accumulated gradually in the 14-day repeated dose study and steady-state was reached after approximately 2 weeks. Flosequinan was not found to accumulate.Adverse reactions were not observed in either the single or repeated dose study.It is advisable to consider renal function and body weight when flosequinan is to be administered to elderly patients with congestive heart failure. The initial dose should be 25 mg. 相似文献