纳洛酮治疗急性重型颅脑损伤的量效关系

目的观察盐酸纳洛酮治疗急性重型颅脑损伤病人的剂量疗效关系。方法将120例急性重型颅脑损伤病人随机分为6组(空白对照组以及0.1、0.2、0.4、0.6、0.8 mg.kg-1.d-1纳洛酮组),分别给予生理盐水及相应分组剂量纳洛酮,观察GCS、血压、脉搏、呼吸等生命体征,测定血浆β-内啡肽(-βEP)和C-反应蛋白(CRP)含量。随访3个月,观察GOS、肢体和语言功能评分。结果GCS、β-EP、CRP在小剂量纳洛酮组(0.1 mg.kg-1.d-1)与对照组间差异无统计学意义;大剂量纳洛酮组各组间(≥0.4 mg.kg-1.d-1)差异无统计学意义,但与空白对照组、小剂量组、中剂量组(0.2 mg.kg-1.d-1)间差异有统计学意义。血压、脉搏、呼吸在纳洛酮各组间差异无统计学意义,但与对照组间差异有统计学意义。随访3个月,GOS、肢体功能及语言功能评分在大剂量组与对照组、小剂量组、中剂量组之间的差异有统计学意义,且小剂量组恢复最差(P<0.05);但大剂量各组之间的差异无统计学意义结论①盐酸纳洛酮(≥0.2 mg.kg-1.d-1)对急性重型颅脑损伤有显著的治疗作用,能促进神经功能的恢复;②小剂量盐酸纳络酮(≤0.1 mg.kg-1.d-1)对颅脑损伤后的神经功能保护无意义,临床不提倡使用;③盐酸纳络酮剂量0.4～0.6 mg.kg-1.d-1为最佳临床推荐剂量。     

Amiodarone pharmacokinetics. I. Acute dose-dependent disposition studies in rats

Single intravenous bolus doses of amiodarone hydrochloride of 30, 60, 90 and 120 mg/kg were administered to male Sprague-Dawley rats to determine the effects of dose on amiodarone pharmacokinetics. Serial blood samples and total urine were collected over 48 hr and assayed for amiodarone and desethylamiodarone by HPLC. The blood amiodarone concentration-time curves for the four doses were best described by a triexponential equation with terminal half-lives (t _1/2 ) ranging from 17 to 20 hr. Over the dose range studied, no changes in , t _1/2 , or central compartment volume (Vc=1.2–1.4 L/kg) were observed. On the other hand, reductions in amiodarone clearance (CL and steady-state volume of distribution (V _ss of 44% (17.7 to 10.0 ml/min per kg) and 50% (16.4 to 8.2 L/kg), respectively, were noted as the dose of amiodarone increased. The conversion of amiodarone to desethylamiodarone (fm was dose-independent and amounted to approximately 10% of each amiodarone dose. No amiodarone or desethylamiodarone was detected in the urine of any of the treated animals. The blood-to-plasma concentration ratio of amiodarone was concentration-independent and therefore did not account for the dose-dependent changes in V_ss and CL observed. The data suggested that the dose-dependent changes noted were due to an alteration in the volume (s) of the peripheral tissue compartment(s).Supported by a Grant-in-Aid from the American Heart Association, Nebraska Affiliate.     

Dose dependent pharmacokinetics of prednisone and prednisolone in man

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m ² for the 5mg dose to 2271 ml/min/1.73 m ² for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m ² over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.This work was supported in part by Grant 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Kinetics of diphenylhydantoin elimination in rats

Concentrations of diphenylhydantoin (DPH) in the blood of male Sprague-Dawley rats after intravenous injection of 10 and 40 mg/kg ¹⁴C-DPHwere determined over a sufficiently wide range to permit comparison of rates of decline at the same absolute and relative concentrations. This comparison leads to the conclusion that the elimination of DPH in the rat cannot be described by first-order or simple Michaelis-Menten kinetics but that it is qualitatively consistent with product inhibition of DPH metabolism.Supported in part by grant GM 19568 from the National Institutes of Health.On leave from the School of Pharmacy, University of Sydney, Sydney, Australia.     

Dose-Dependent Pharmacokinetics of the Aldose Reductase Inhibitor Imirestat in Man

The pharmacokinetics of imirestat were studied in healthy volunteers following single and multiple oral doses. After single doses of 20 to 50 mg, imirestat plasma concentrations declined with an apparent elimination half-life of 50 to 70 hr over the 168 hr in which levels were measured. However, with lower doses (2 to 10 mg), an initial rapid decline in drug concentration was followed by a very slow terminal elimination phase with plasma concentrations decreasing little over the 1 week of sampling. This resulted in a decrease in apparent t 1/2 with increasing dose, from 272 +/- 138 hr at 2 mg to 66 +/- 30 hr at 50 mg. During once-daily dosing of 2 to 20 mg/day for 4 weeks, mean steady-state imirestat concentration appeared to be dose proportional, although the time required to achieve steady state decreased with increasing dose. The mean effective half-life for accumulation ranged from 54 to 98 hr, suggesting that the very slow elimination of drug at low concentrations did not produce disproportionate accumulation of drug at these doses. Mean oral clearance was independent of dose, ranging from 30 to 45 ml/min. At the 2-, 5-, and 20-mg doses, one subject in each group had steady-state concentrations two- to fourfold greater than any of the other five subjects at the same dose, although the reason for this was not apparent from these data. The overall kinetic profile of these data was suggestive of dose-dependent pharmacokinetics resulting from nonlinear tissue binding of imirestat.(ABSTRACT TRUNCATED AT 250 WORDS)     

乌司他丁对大鼠肺脏热缺血再灌注损伤的保护作用

 目的 探讨乌司他丁对大鼠肺脏热缺血再灌注损伤的保护作用并比较两种不同剂量的保护效果。方法 30只清洁级SD大鼠,随机分成3组,每组10只。单纯热缺血再灌注组（ischemia-reperfusion group,IR group）阻断左肺门1 h后,开放左肺门再灌注2 h,取左肺静脉血行血气分析后,处死大鼠。左肺上段测湿干比（Wet/Dry Ratio,W/D）,中段做组织切片,下段检测MPO浓度;乌司他丁常规剂量组（ulinastatin conventional dose group,UC group）阻断左肺门前,阴茎背静脉注入乌司他丁10 000 IU/kg,其余程序同IR组;乌司他丁大剂量组（ulinastatin high-dose group,UH group）阻断左肺门前,阴茎背静脉注入乌司他丁20 000 IU/kg,其余程序同IR组。结果 IR组与UH组比较,血气分析中肺静脉血的氧分压（PO₂）与W/D的差异均有统计学意义［（109.5±18.3）mmHg vs.（128.5±17.7）mmHg,（5.30±0.13）vs.（5.08±0.25）,P<0.05］;MPO浓度检测结果,IR组、UC组与UH每两组间的差异均存在统计学意义［（57.36±10.51）ng/mL,（45.74±8.13）ng/mL与（28.30±6.28）ng/mL,P<0.05］;组织切片可见IR组较UC组和UH组炎性细胞浸润明显。结论 乌司他丁对大鼠肺脏的热缺血再灌注损伤有一定的保护作用,并且存在剂量相关性。     

A Modified Product Inhibition Model Describes the Nonlinear Pharmacokinetics of Nicorandil in Rats

Nicorandil, a vasodilator which acts through both cyclic GMP accumulation and K⁺ channel opening, has been used in the treatment of various cardiovascular diseases. We have examined the pharmacokinetics of nicorandil in the rat as a function of dose, as both i.v. boluses (9 doses, 0.75 – 12 mg, n = 1-4 per dose), and as a 5-hr infusion followed by a 5-hr washout (6 doses, 10-500 µg/kg/min, n = 3 per dose). Plasma nicorandil concentrations were determined by HPLC. Nicorandil plasma concentrations increased disproportionately with dose, but nicorandil elimination obeyed apparent monoexponential kinetics, and the apparent half-life (t_1/2) increased with dose. In addition, the approach to apparent steady-state during the infusion phase was not overtly sensitive to the drastic changes in t_1/2observed. Pharmacokinetic modelling with several nonlinear models, viz: Michaelis-Menten with parallel first-order, cosubstrate depletion and competitive product inhibition, were carried out. Addition of the sulfhydryl donor, N-acetyl-L-cysteine, did not change the pharmacokinetics of nicorandil, providing experimental indication that a cosubstrate depletion model might not be applicable. To describe the unique pharmacokinetics, a modified product inhibition model was developed. This new model includes the classic competitive product inhibition equation, describing both parent and product kinetics, and it incorporates, in addition, separate first-order elimination rate constants for both nicorandil and the inhibiting metabolite. Experimental evidence showed that N-(2-hydroxyethyl) nico-tinamide, the major metabolite of nicorandil in rats, and nicotinamide (niacinamide) itself, indeed inhibited nicorandil elimination.     

Pharmacokinetics of lopromide Liposomes in Rabbits

Purpose. The dose-proportionality of pharmacokinetics of an iodinated contrast medium, iopromide, encapsulated into liposomes was investigated. Methods. Following single intravenous administration of 150 mg iodine/kg (potential diagnostic dose) and a five-fold higher dose in rabbits the pattern of elimination was studied until 7 d and the blood concentrations were monitored up to 72 h after administration. The iodine concentration in the liver was calculated on the basis of the blood concentration and related to the concentration measured in the rabbit liver. Results. The dose-normalized blood concentration-time profiles of the encapsulated iodine were not superimposable. Contrary to the low dose a steady-state concentration of 2.8 mg iodine/mL was observed in blood for 60 min after the high dose administration indicating a saturation of the liposomal liver uptake. For both doses the elimination of iodine occurred predominantly via the kidneys and was complete 7 d after administration. The dose-normalized amounts of iodine excreted with the urine were similar for both dose groups. From the blood data it was calculated that doses up to about 300 mg iodine/kg should result in a dose-proportional increase of liposomal liver uptake before saturation occurs. This was confirmed by the measured iodine liver concentrations after increasing the doses stepwise from 150 to 750 mg iodine/kg. Conclusions. In rabbits for the dose range 150 to 750 mg iodine/kg iopromide liposomes reveal dose-dependent pharmacokinetics due to a saturation in liver uptake which occurs for doses of 300 mg iodine/kg corresponding to 300 mg lipid/kg onwards.     

SATURABLE METABOLIC PATHWAYS FOR ETHOTOIN IN MAN

1. The urinary excretion pattern of ethotoin and five metabolites were examined in three patients receiving continuous treatment with ethotoin at two dose levels, in order to investigate the mechanism behind the dose-dependent kinetics of this anticonvulsant drug. 2. The results suggest a partial saturation in the dealkylation process at high dose levels in three patients. 3. A rough approximation of the Michaelis-Menten constants for different enzymatic processes was attempted. On the basis of the results obtained, the p-hydroxylation may be a saturable process. 4. The dose-dependent kinetics of ethotoin in man seem to be explicable by the existence of partly saturable enzymatic pathways.