Population pharmacokinetic/pharmacodynamic modeling of warfarin by nonlinear mixed effects model / 药学学报

The study aimed to establish a population pharmacokinetic/pharmacodynamic (PPK/PD) model of warfarin. PCR-RFLP technique was used to genotype the CYP2C9 and VKORC1 polymorphisms of 73 patients. RP-HPLC-UV method was used to determine the 190 plasma concentrations of warfarin. Application of NONMEM, the clinical information and 263 international normalized ratio (INR) monitoring data were used to investigate the effect of genetic, physiological, pathological factors, other medication on clearance and anticoagulant response. The final model of warfarin PPK/PD was described as follows: CL = θCL · (WT/60)θWT · θCYP · eηCL (if CYP2C9*1/*1, θCYP = 1; if *1/*3, θCYP = 0.708); EC50 = θEC50 · θVKOR · eηEC50 (if VKORC1- 1639AA, θVKOR = 1; if GA, θVKOR = 2.01; V = θV; K(E0) = θK(E0); Emax = θEmax; E0 = θE0 · eηE0. Among them, the body weight (WT), CYP2C9 and VKORC1 genotype had conspicuous effect on warfarin PK/PD parameters. The goodness diagnosis, Bootstrap, NPDE verification showed that the final model was stable, effective and predictable. It may provide a reference for opitimizing the dose regimen of warfarin.

Clinical evaluation of dopamine agonists as an adjunct to levodopa and benserazide for Parkinson's disease / 中华神经医学杂志

Objective To evaluate the efficacy, safety and tolerability ofdopamine agonists (pramipexole or piribedil) in the treatment of patients with Parkinson' disease (PD) as an adjunct to levodupa and benserazide. Methods Included in the present study were 40 PD patients who received pramipexole or piribedil as an adjunct to levodopa and benserazide for 12 weeks in our institute. They were divided into a Madopa + pramipexole group (n=20) and a Madopa + piribedil group (n=20)according to the therapeutic drugs they received. The efficacy of dopamine agonist was assessed by the UTDRS score. The safety and tolerability were assessed on the basis of adverse events and blood pressure. Results After respective administration of pramipexole and piribedil for 12 weeks, the UPDRS Ⅰ -Ⅳ scores in the 2 groups were significantly reduced (P＜0.05).The average UPDRS-Ⅰ score improved from 2.85±2.41 to 1.2±l.64 points in the pramipexole group and from 2.8+1.28 to 1.85±1.35points in the piribedil group, with significant differences (P＜0.05). The average UPDRS-Ⅳ score improved respectively from 1.85±2.60 to 0.5±0.83 in the pramipexole group and from 1.75±1.74 to 0.75±0.91 in the piribedil,as compared with base-line and week 12,showing superiority ofpramipexole over piribedil in these aspects.The total clinical efficacy was 80％ in the pramipexole group and 75％ in the piribedil group,with no significant difference between the 2 groups (P＞0.05).No significant difference was found between the pramipexole and piribedil groups in terms of adverse events (55％ versus 70％)(P＞0.05). Conclusions Pramipexole or piribedil is effective and well-tolerated in the treatment of patients with Parkinson's disease as an adjunct to levodopa and benserazide,at least with short-term use.Pramipexole may be superior to piribedil in terms of improvement of complications in psychiatrics,behavior,emotion and motion of the PD patients.

Population pharmacokinetic modeling of flurbiprofen / 药学学报

The paper is to report the establishment of a population pharmacokinetic model for flurbiprofen (FP), an active metabolite of flurbiprofen axetil (FA). 246 FP serum concentration and clinical data were perspectively collected from 23 general anaesthesia patients receiving FA intravenously before operation in Dentofacial Surgery and Otorhinolaryngology Department of the First Affiliated Hospital of Fujian Medical University. Population pharmacokinetic data analysis was performed using NONMEM software. The measure of Bootstrap was applied for internal validation, while Visual Predictive check was adopted for external validation. The data of FP correspond with two-compartment model. The body weight (WT) had conspicuous effect on clearance and volume of central compartment, while sex, age and daily dose of administration had no marked effect on pharmacokinetic parameter of FP. The basic model was described as follows: CL (L x h(-1)) = 1.28x EXP(ETA(1)), V1 (L) = 5.03x EXP(ETA(2)), Q (L x h(-1)) = 8.5 x EXP(ETA(3)), V2 (L) = 4.39 x EXP(ETA(4)). The final model was described as follows: CL (L x h(-1)) = 1.32 x (WT/60) x EXP(ETA(1)), V1 (L) = 5.23 x (WT/60) x EXP(ETA(2)), Q (L x h(-1)) = 8.45 x EXP(ETA(3)), V2 (L) = 4.37 x EXP(ETA(4)). The population typical value of CL, V1, Q and V2 were: 1.32 L x h(-1), 5.23 L, 8.45 L x h(-1) and 4.37 L, respectively. Bootstrap and visual predictive check show that the final model of FP is stable, effective and predictable. A novel population pharmacokinetic model is developed to estimate the individual pharmacokinetic parameter for patients intravenous injecting FA in terms of patients' characteristics and dosing history, and to design a prior dosage regimen.

Therapeutic effect of pramipexole in Parkinson's disease / 中华神经医学杂志

Objective To study the therapeutic effect of pramipexole in Parkinson's disease (PD). Methods Forty patients with PD were treated with pramipexole for 12 weeks and evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) before and after therapy.Among them, 6 cases were treated with pramipexole without any anti-PD drugs, and the rest with pramipexole and other anti-PD drugs. Some cases received follow-up at week 2, 4, 8, 12 to evaluate the therapeutic effect.Results After the therapy ofpramipexole, the symptoms of PD were alleviated in 35 patients (87.5％).The alleviation was statistically significant in UPDRS scores, daily activities, motor function, trembling,splinting, mental symptoms and on-off phenomenon.Futhermore, the post-therapeutic follow-up revealed that the patients get much better. Conclusions Pramipexole is effective in the treatment of PD.It is a safety and good effctive anti-parkinson drug.