不同注射剂量的雷帕霉素对小型猪全身情况的影响

目的 研究不同注射剂量的雷帕霉素对小型猪全身情况的影响。方法 选择12头小型猪分为4组,连续7 d分别注射不同浓度的雷帕霉素(0、0.05、0.10、0.15 mg/kg),观察12周,期间每2周进行血常规和血生化检测。12周后,对小型猪主要脏器进行组织学观察。结果 注射不同剂量的雷帕霉素2周后,各组小型猪的白细胞、血小板及淋巴细胞比率会出现剂量依赖性的下降,4周后恢复正常水平,血生化各项指标未见明显异常,12周后,小型猪的主要脏器的组织结构未见明显异常。结论连续7 d注射雷帕霉素不会对小型猪全身情况产生长期影响。     

Saturable kinetics of intravenous chlorothiazide in the rhesus monkey

A range of bolus doses of ¹⁴ C-chlorothiazide and unlabeled drug (6.7–30 mg/kg) were administered to each of three unanesthetized rhesus monkeys with and without concurrent probenecid dosing. Plasma up to 4 h and urine up to 24 h were sampled frequently. Apparent terminal plasma half-lives ranged from 18 to 25 min in the absence of probenecid. No apparent trend was noted for the volume of distribution of the central compartment calculated from estimated plasma concentrations at time zero. For chlorothiazide studies, an average of 92% of the dose was recovered in urine by 24 hr. Plasma and urinary clearances at low doses were 20 to 50% higher than those found with higher doses. These dose-dependent clearances for chlorothiazide were found at doses parallel to the most often prescribed clinical doses in humans on a g chlorothiazide per kg body weight basis. Clearances in the presence of probenecid decreased two-to four-fold over those seen without probenecid. Incremental renal clearances of chlorothiazide in the studies with and without probenecid were also evaluated. Curvilinear segments characteristic of dose-dependent kinetics were demonstrated in graphs of urinary excretion rate versus plasma concentrations. Values of Michaelis-Menten constants V_max and K_m were calculated for renal excretion of chlorothiazide by active transport after intravenous doses in all three monkeys. The contribution of glomerular filtration to chlorothiazide renal clearance was found to be negligible. Values of the constant K_I (the concentration of the probenecid competitive inhibitor of chlorothiazide, which doubles the apparent K_m value of chlorothiazide) were calculated using the previously calculated V_max and K_m values.Supported in part by NIH grants GM 26691 and AM 20884. During the course of this work, Dr. Gustafson received support as an NIH Predoctoral Fellow (GM 00752) and as a Fellow of the American Foundation for Pharmaceutical Education.     

Properties of the Michaelis-Menten equation and its integrated form which are useful in pharmacokinetics

Some old equations are reviewed and some new equations have been derived which indicate certain properties of the Michaelis-Menten equation and its integrated forms. Simulated data which obey Michaelis-Menten kinetics have been plotted in various ways to illustrate special relationships. An equation is derived which accurately estimates the slope of the apparently linear decline (k_o)of concentrations from the values of C_o, K_m,and V_m.This indicates the hybrid nature of k_o.It is pointed out that if a metabolite is formed by Michaelis-Menten kinetics, then (a)one would not expect linear plots of cumulative amount of metabolite excreted in the urine vs. time, and (b)the plasma clearance of the drug will change with dose, and the plasma clearance of the drug would be expected to be different following administration of the same dose in a rapidly available and a slowly available dosage form. The distortion in parameter values when data arising from Michaelis-Menten kinetics are evaluated by classical linear pharmacokinetics is indicated.     

左旋精氨酸在急性胰腺炎治疗中的剂量效应

目的:探讨左旋精氨酸(L-Arg)在急性胰腺炎治疗中的剂量效应。方法:观察不同剂量L-Arg治疗急性水肿性胰腺炎(AEP)大鼠后,血浆和胰组织一氧化氮(NO)浓度、血浆淀粉酶、平均动脉压(MAP)、胰组织病理等的变化。结果:(1)AEP大鼠血浆、胰组织NO浓度明显降低,小剂量L-Arg(50mg,100mg/kg)升高了血浆、胰组织NO浓度,改善了大鼠AEP;随着L—Arg剂量的增加,达800mg、1600mg/kg时,血浆、胰组织NO浓度过度升高,加重AEP成为急性出血坏死性胰腺炎(AHNP),且以80mg/kg组最明显;(2)实验所用的L—Arg对MAP的影响较小。结论:L—Arg的作用机理与NO的生物学行为有密切关系,临床应用L-Arg治疗急性胰腺炎应注意其类似NO的“双刃性”,尤其大剂量应用要慎重。     

葛根素保护大鼠颈椎间盘纤维环细胞的最佳浓度

背景：葛根素能抑制椎间盘纤维环细胞凋亡,在一定程度上延缓椎间盘退变。目的：观察最佳浓度葛根素对大鼠颈椎间盘纤维环细胞的保护作用。方法：用不同质量浓度Fas配体（5,20,50pg／L）诱导大鼠颈椎间盘纤维环细胞凋亡,用流式细胞仪AnnexinV-FITC-PI双染法检测纤维环细胞凋亡情况,通过MTT法和流式细胞仪观察不同质量浓度葛根素（0．01,O．1,1g／L）对纤维环细胞的保护作用。结果与结论：5pg／LFas配体诱导的纤维环细胞存活率及早期凋亡率与胎牛血清对照组比较差异无显著性意义（P〉0．05）,20pg／L及50Iυg,LFas配体组纤维环细胞存活率及早期凋亡率高于胎牛血清对照组（P〈0．01）,且随着Fas配体质量浓度的增加,大鼠成熟纤维环细胞活性比例逐渐降低,而早期凋亡率逐渐增加。3种浓度的葛根素作用20pg／LFas配体诱导的纤维环细胞,随着葛根素质量浓度的增加,纤维环细胞存活比例逐渐增加,而早期凋亡率逐渐减少（P〈0．01）。结果提示：①Fas配体能够诱导大鼠颈椎间盘纤维环细胞凋亡,增加大鼠成熟颈椎间盘纤维环细胞的凋亡率。②3种质量浓度葛根素均有抑制椎间盘纤维环细胞死亡作用,且呈剂量依赖型。③葛根素对大鼠颈椎间盘纤维环细胞有明显保护作用。     

Advancing human health risk assessment: Integrating recent advisory committee recommendations

Abstract

Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose–response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose–response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches.     

Characterization of the Dose-Dependent Time of Peak Effect in Indirect Response Models

The general conceptual model for non-steady state pharmacokinetic/pharmacodynamic data includes a distribution phase between the plasma and the biophase compartments, which can be expressed by a link model, and inhibition or stimulation of the production or removal of a mediator, which can be expressed by an indirect response model. The inhibition or the stimulation step modeled by an indirect response model generates dose-dependent time of peak effect. This report provides a mathematical expression for this time of peak effect which is then used to determine how this time depends on dose, the endogenous elimination rate of the mediator, and the pharmacokinetic parameters of the drug. The report then uses this time of peak effect to find the response versus time curve. The mathematical relationship for the time of peak effect and the response vs. time curve are then developed for a cascade of two indirect steps. The approach presented here is easily implemented on a spreadsheet and does not require numerically solving nonlinear differential equations. The approach should help to analyze various issues related to fitting indirect response models to non-steady state pharmacokinetic/pharmacodynamic data, especially, when one is trying to fit data to a cascade of indirect steps.     

Neuroprotection of photoreceptors by direct delivery of erythropoietin to the retina of the retinal degeneration slow mouse

The primary objectives of this study were to determine if erythropoietin (EPO) is neuroprotective to the photoreceptors in the retinal degeneration slow (rds) mouse in the absence of an increase in hematocrit and to determine if deglycosylated EPO (DEPO) is less neuroprotective. We performed subretinal injections of 10U EPO, DEPO or hyperglycosylated EPO (HEPO) in postnatal day 7 rds mice. Whole eye EPO levels were quantified by ELISA at specified time points post-injection. TUNEL analysis, hematocrit, and immunohistochemistry were performed at postnatal day 20. Half of the amount of EPO measured immediately after injection was detected less than 1 h later. Twenty four hours later, EPO levels were 1000 times lower than the amount originally detected. Uninjected rds mice contained 36 ± 2 TUNEL-positive cells/mm retina and PBS injected mice contained 17 ± 3 TUNEL-positive cells/mm retina. EPO, DEPO, and HEPO treated rds retinas contained 5 ± 2, 9 ± 2, and 3 ± 1 TUNEL-positive cells/mm retina, respectively. The hematocrit was 43% in control and 41% in treated rds mice Previous studies have shown neuroprotection of the retina by treatment with as little as 24-39 mU EPO/mg total protein in the eye. In this study, we detected 40 mU/mg EPO in the eye 11 h after injection of 10 U EPO. Treatment with all forms of EPO tested was neuroprotective to the photoreceptors without a concomitant increase in hematocrit.