[Effect of Flax lignans on apoptosis of growth plate chondrocytes in rats].

OBJECTIVE: To compare the effects of different concentrations of linolenin on inhibiting apoptosis of chondrocytes in the growth plate, and to screen the optimal concentration of linolenin, so as to provide theoretical support for delaying epiphyseal closure and promoting long bone growth in rats. METHODS: Two 4-week-old male SD rats (SPF grade) with a body mass of 80 g were selected. The growth plate cartilage of rat tibia and femur was dissected and isolated in vitro to obtain growth plate chondrocytes for culture. The chondrocytes were observed and identified by inverted phase contrast microscope and typeⅡ collagen immunofluorescence test, and then 20 ng/ml IL-1ß was used to induce apoptosis of growth plate chondrocytes as model group, and added with 1, 10, 20, 40 µM linolenin as the experimental group, and 5 µM letrozole as the positive control group. The cells were cultured for 24 and 48 hours respectively. The drug promoted cell proliferation was observed by MTT method, and the drug inhibited cell apoptosis was detected by flow cytometry. RESULTS: Contents 1, 10, 20, 40 µM could promote cell proliferation in varying degrees, and the principle was that the drug inhibits IL-1ß induced chondrocyte apoptosis in the growth plate, and the optimal concentration of drugs to inhibit apoptosis was 20 µM. CONCLUSION: The appropriate concentration of linseed lignans can significantly inhibit the apoptosis of chondrocytes in the growth plate of rats, and the optimal drug concentration is 20 µM. It provides possibility for delayed bone closure and longer growth time to promote bone growth during development.

Population Pharmacokinetic Analysis of Tacrolimus in Adult Chinese Patients with Myasthenia Gravis: A Prospective Study.

BACKGROUND AND OBJECTIVES: Tacrolimus is a widely used immunosuppressive agent with narrow therapeutic window. Nowadays, tacrolimus has gained acceptance as a therapeutic option in myasthenia gravis (MG) treament, however, little is known about its pharmacokinetic characteristics in MG population. In this study, we aimed to investigate the population pharmacokinetic (PopPK) of tacrolimus in patients with MG and to develop model-informed dosing regimens. METHODS: Trough concentrations of tacrolimus (267 measurements) and cytochrome P450 (CYP) genotypes were determined in 97 Chinese adults. The non-linear mixed-effects model was used for PopPK modeling. Monte Carlo simulations based on the established model were employed to design dosing regimens. RESULTS: The PopPK model was described using a one-compartment model with first-order absorption and elimination. The mean apparent clearance (CL/F) of tacrolimus was 17.1 L/h, with a between-subject variability of 20.1%. Covariate screening of demographic characteristics, blood test results, co-medications, and CYP3A5*3 or CYP3A4*1G polymorphisms showed that the CYP3A5*3 genotype and co-administration of a Wuzhi capsule significantly affected tacrolimus CL/F. CONCLUSIONS: For patients with the CYP3A5*3*3 allele, the required tacrolimus dose for 75% of subjects to achieve target trough concentrations of 4.8-15 ng/mL was 2 mg every 12 h (q12h). For patients with the CYP3A5*1*1 allele, the required dose was 2 mg tacrolimus q12h with a Wuzhi capsule, and for patients with the CYP3A5*1*3 allele, the required dose was 3 mg of tacrolimus q12h or 4 mg q24h co-administered with a Wuzhi capsule. This model could be employed to optimize individualized therapies for patients with MG.

How to Handle Delayed or Missed Doses: A Population Pharmacokinetic Perspective.

Delayed or missed doses are unavoidable in clinical practice and remain as a challenge that threatens a patient's health and quality-of-life, especially in the pharmacotherapy of chronic disease treatment. Unfortunately, information or guidance concerning the management of delayed or missed doses is scarce, precluding clinicians or clinical pharmacologists from instructing patients in a precision dosing manner. It is therefore urgent to develop remedial strategies to inform patients of alternative dosing regimens in compensation for the loss of efficacy due to delayed or missed doses and minimize unintended clinical consequences. Studies aiming to establish remedial regimens have been conducted since the 1980s for oral contraceptives and antihypertensive agents, using the controlled substitution of placebos for active medications. However, it appeared to be unethical in many areas of pharmacotherapy due to deliberately discontinuing or restarting the medication. Alternatively, pharmacometric modeling and simulation offers an opportunity to investigate the effect of various non-adherence scenarios on pharmacokinetic profiles and establish the optimum remedial dosing regimen in a time-effective and systematical way. This review provides a general overview of procedures and strategies on how to develop remedial dosing regimens based on pharmacometric approaches through the scrutiny of case examples in the literature.