匙羹藤酸调节仓鼠血脂机理的研究

目的:研究匙羹藤酸对高脂仓鼠血脂的调节作用,并初步探究匙羹藤酸调节血脂水平的机理。方法:将40只雄性仓鼠随机分为正常对照组、模型对照组和匙羹藤酸低(20 mg/kg BW/d)、中(40 mg/kg BW/d)、高剂量组(80 mg/kg BW/d),正常对照组饲喂正常饲料,其余各组均饲喂高脂饲料,连续喂养8周。每两周称量一次体重,每四周眼眶静脉取血一次,用来检测不同阶段仓鼠血清中的血脂水平,8周后股动脉取血用于检测肝损伤指标谷草转氨酶(AST)、谷丙转氨酶(ALT)水平,胆固醇代谢相关调控酶羟甲基戊二酸单酰辅酶A还原酶(HMGCR)、胆固醇7α羟化酶(CYP7A1)、胆固醇酰基转移酶(ACAT)的酶活,并取肝小叶进行检测肝脏中HMGCR的酶活。结果:干预前,各组仓鼠血清中总胆固醇(TC)、甘油三酯(TG)和非高密度脂蛋白胆固醇(non-HDL-C)水平均无显著性差异(P>0.05)。干预8周后,匙羹藤酸剂量组仓鼠血清中TC、TG、non-HDL-C极显著低于模型对照组(P<0.01);匙羹藤酸剂量组的ALT、AST水平极显著低于模型对照组(P<0.01);匙羹藤酸中、高剂量组HMGCR的活性显著低于模型组(P<0.05),匙羹藤酸中、高剂量组CYP7A1活性显著高于模型组(P<0.05)。结论:匙羹藤酸可以通过抑制HMGCR的活性来降低高脂仓鼠胆固醇的合成,提高CYP7A1的活性来增加胆固醇的排泄,来调节高脂膳食仓鼠血脂水平,因此匙羹藤酸具有降脂、保护肝脏的作用。     

A mechanistic approach for modeling oral drug delivery

A drug release mechanism is combined with a Compartmental Absorption and Transit (CAT) model within a pharmacokinetic framework for predicting orally administered drug release and transport. The developed model is used to evaluate pharmacokinetic metrics such as peak plasma concentration, area under the curve (AUC) and bioavailability. A comparative study has been performed on different cimetidine tablet formulations for which clinical drug profiles are available for model validation. The model predictions are in good agreement with the clinical results. Different scenarios based on induced changes in average patient body weight, fraction of drug in the tablet, tablet radius and their corresponding effects on the model predictions are discussed. The change in average patient body weight has a low effect on the plasma concentration profile while the fraction of drug in the tablet has a strong effect. In a scenario study within an optimization framework, the model has been able to determine the optimal dimensions of a tablet of fixed dosage in order to obtain maximum therapeutic effect from the tablet.     

C. medica cv Diamante peel chemical composition and influence on glucose homeostasis and metabolic parameters

This study evaluated the in vitro inhibition of carbohydrate-hydrolysing enzymes, the stimulation of insulin secretion, and the in vivo metabolic effects in mice of Citrus medica L. cv Diamante peel extract. The quantitative analysis of selected phytochemicals were determined to investigate their relationship with the biological activities. Citrus extract exhibited an inhibitory activity against both α-amylase and α-glucosidase with IC₅₀ values of 258.7 and 263.2 μg/ml, respectively. Measurements of the effects of peel extract on the mouse insulinoma MIN6 β-cells indicated that it did exert direct stimulatory effects on the exocytotic release of insulin in a concentration-dependent manner. The supplementation of the C. medica cv Diamante was able to reduce plasma glucose (GLU) concentration and lowered the levels of plasma cholesterol (COL) and triglycerides (TG). The obtained results underline the potential health benefits as a result of consuming C. medica cv Diamante and suggest that it could be used as new potential source with functional properties for food or nutraceutical products.     

Choosing hamsters but not rats as a model for studying plasma cholesterol‐lowering activity of functional foods

Rats and hamsters are commonly used rodents to test the efficacy of cholesterol‐lowering functional foods. In general, a diet containing 1% cholesterol for rats whereas a diet containing 0.1% cholesterol for hamsters is used to induce the hypercholesterolemia. The present study was carried out to compare hamsters with rats as a hypercholesterolemia model. Golden Syrian hamsters and Sprague Dawley rats were randomly divided into four groups and fed one of the four diets containing 0–0.9% cholesterol. Results demonstrated that serum total cholesterol (TC) in hamsters was raised 73–81% higher than that in rats fed the same cholesterol diets. Unlike rats in which HDL‐C accounted very little for serum TC, the lipoprotein profile in hamsters was closer to that in humans. We investigated interaction of higher cholesterol diets with 3‐hydroxy‐3‐methylglutary‐CoA (HMG‐CoA) reductase, low‐density lipoprotein receptor (LDL‐R) and cholesterol‐7α‐hydroxylase (CYP7A1), sterol regulatory element binding protein‐2 (SREBP‐2), and liver X receptor (LXR‐α). Results showed hamsters and rats metabolized cholesterol differently. In view that hamsters synthesize and excrete cholesterol and bile acids in a manner similar to that in humans, it is concluded that hamsters but not rats shall be chosen as a model to study efficacy of cholesterol‐lowering functional foods.     

Selecting the particle size distribution for drugs with low water solubility – mathematical model

Purpose: To introduce guidelines in selecting the particle size distribution (n₀, cm^?1) that will guarantee optimal oral absorption for drugs with low solubility.

Methods: Unlike other multi-compartmental models the gastrointestinal tract is modeled as a continuous tube with spatially varying properties. The transport through the intestinal lumen is described using the dispersion model. The model accounts for the dissolution of poly-dispersed powders.

Results: The model was used to examine the sensitivity of the absorption on permeability (P) and water solubility (C_s) following administration in different log-normal powders. The absorption exhibits inverse sigmoidal dependence on the mean particle size (r_m, µm) regardless of the administrated dose or drug properties. Thus, there is an optimal r_m that maximizes the benefit-cost ratio of the formulation; finer particles do not improve the absorption while coarser particles decrease it. Using the model we find that the optimal r_m depends mainly on the drug C_s and on the geometrical standard deviation (gSTD).

Conclusions: The results of this work provide the formulator with guidelines to select both r_m and gSTD that guarantee optimal absorption.