Aim To establish the hyperlipidemic model and ex-plore the mechanism of hypercholesterolemia in hamster. Meth-ods Hamsters were randomly divided into the control and model groups. The hamsters in the control group were fed with the standard chow and the model group were fed with the high fat di-et. Serum lipids and CYP7A1 activity were detected by enzymat-ic method. The molecular mechanism of cholesterol metabolism was investigated by real-time PCR. Results In comparison with the control group, the concentrations of serum TC, LDL-C, TG and hepatic TC, TG were significantly increased in the model
group. The mechanism research showed that in hamsters fed with the high fat diet, the CYP7A1 activity and the mRNA expres-sions of hepatic LDL-R, SREBP-2, CYP7A1, LXRαwere down-regulated, the expression of hepatic FXR was up-regulated. Conclusion The hyperlipidemic model could be developed in hamsters fed with the high fat diet for 4 weeks. LDL-R, SREBP-2, CYP7A1, FXR and LXRαare the biomarkers of hypercholes-terolemia, and also the targets of hypolipidemic drugs.

Aim To establish hyperlipidemic model and study the molecular mechanism of triglyceride (TG)disorder in hamsters.Methods The male ham-sters were randomly divided to control group fed with standard diet and model group fed with high-fat diet, both of the groups had been fed with diet for 4 weeks. The levels of serum TG,TC,LDL-C,FFA were detec-ted at the end of 2nd and 4th week.The hepatic TG, TC,LPL activity were detected by enzymatic method at the end of 4th week.The molecular mechanism was tested by real-time PCR.Meanwhile the effect of posi-tive drug fenofibrate on the model of hyperlipidemia in hamsters was investigated.Results Compared with the control,the serum levels of TG,TC,LDL-C,FFA in the model group increased 2.57,1.93,2.49,1.25 times at the end of2nd week,and 3.93,1.90,2.27, 2.29 times at the end of 4th week,respectively.The positive drug significantly decreased the concentrations of serum TG and FFA. The mechanism research showed that the hepatic AMPK,PPARα,CPT-1 mRNA decreased in hamsters fed with high-fat diet,and the SREBP-1 c,ACC,SCD-1 ,AGPAT2,DGAT2 mRNA ex-pressions increased.The hepatic ApoB mRNA expres-sion was up-regulated while the MTTP and LPL mRNA expressions were down-regulated slightly.LPL activity significantly decreased in model hamsters compared with the control.The alternations of these enzymes and receptors were the critical factors for TG disorder. Conclusion The hamsters fed with high-fat diet for 4 weeks can form a good hyperlipemic model with HTG feature.AMPK,SREBP-1 c,ACC,SCD-1 ,DGAT2,AG-PAT2,PPARα,CPT-1 and LPL are not only the main mechanisms of TG disorder,but also the biomarkers of hypotriglyceridemic drugs.

Orally inhaled drug products (OIDPs) have a pivotal position and great clinical demand in the treatment of asthma and chronic obstructive pulmonary disease. The development of local generic drugs which are bioequivalent to branded drugs in efficacy and safety while with less price will not only help to solve the problem of drug accessibility, but also greatly reduce the public health burden.OIDPs are complex combinations of formulation and device, and have special drug delivery route and characteristic of local release. Thus, generic drugs of OIDPs are difficult to develop and get registration. Until now, Food and Drug Administration (FDA), European Medicines Association (EMA), Health Canada (HC) and National Medical Products Administration (NMPA) all consider that pharmacokinetics (PK) method can be used to evaluate systemic exposure (safety) in human bioequivalence (BE) study of OIDPs, but there is no consensus on its role in the evaluation of pulmonary deposition (efficacy). The possible reason lies in that the efficacy of OIDPs is determined by both the amount and the region of drug pulmonary deposition. Nevertheless, PK study is still more sensitive and economical in assessing potential differences among products, when compared with pharmacodynamics or clinical endpoint study. Here we mainly compared the domestic and international guidelines and evaluation methods of OIDPs BE study, and introduced the experimental design of PK study and its application and progress in lung deposition study.

Orally inhaled drug products (OIDPs) play a great role in the pharmacological treatment of chronic obstructive pulmonary disease (COPD) and asthma. There is an unmet clinical need for OIDPs. Pharmacodynamics-Bioequivalence studies (PD-BE) are recommended by several national guidelines as important research methods for bioequivalence study of OIDPs. It can effectively bridge the gap between in vitro studies and PK-BE studies in evaluating the efficacy and safety consistency of generic drugs with the original drugs. There are two research methods for PD-BE, using a diastolic model or an excitation model. The different methods use different metrics to evaluate efficacy. The more commonly used metrics include Forced Expiratory Volume in the First Second (FEV1), Specific Airway Conductance (sGaw), Peripheral Airway Resistance (R5-20), and stimulant concentration/dose (PC20/PD20). PD-BE studies using FEV1 as an efficacy metric is also recommended by the FDA (Food and Drug Administration), EMA (European Medicines Agency) and NMPA (National Medical Products Administration) guidelines and is widely accepted by investigators. In such PD-BE studies, the trial protocols for different OIDPs drugs are relatively consistent in terms of trial design, trial data processing, and equivalence evaluation criteria, while there are detailed differences in terms of target population, single/multiple dosing, dose administration, and collection site design. This paper reviews the progress of PD-BE studies in the bioequivalence evaluation of OIDPs by combining national guidelines and PD-BE-related studies of OIDPs published in the last five years, with a view to providing important theoretical information for PD-BE studies of OIDPs.