Objectives: A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an evidence-based practice guideline for individualized medication of HDMTX. Methods: The practice guideline was launched by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. The guideline was developed following the WHO handbook for guideline development and the methodology of evidence-based medicine (EBM). The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were conducted to synthesis available evidence. A multicenter cross-sectional study was conducted by questionnaires to evaluate patients’ perception and willingness on individualized medication of HDMTX. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and to grade the strength of recommendations. Results: Multidisciplinary working groups were included in this guideline, including clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic specialists. A total of 124 patients were involved to integrate patient values and preferences. Finally, the guideline presents 28 recommendations, regarding evaluation prior to medication (renal function, liver function, pleural effusion, comedications, genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitoring (necessity, method, timing, target concentration), leucovorin rescue (initial timing, dosage regimen and optimization), management of toxicities. Of them, 12 are strong recommendations. Conclusions: We developed an evidence-based practice guideline with respect to HDMTX medication using a rigorous and multidisciplinary approach. This guideline provides comprehensive and practical recommendations involving the whole process of HDMTX medication to health care providers.
Background and Purpose: Puerarin is an important isoflavone component extracted from Pueraria lobate in traditional Chinese medicine. It has a wide range of pharmacological effects. Increasing evidence indicates that puerarin alleviates hyperglycemia and numerous related complications. In this study, we explored the effect of puerarin on skeletal muscle atrophy caused by type 1 diabetes in rats. Experimental Approach: Male Sprague Dawley (SD) rats with streptozotocin (STZ)-induced type 1 diabetes were used in this study. We measured skeletal muscle weight, size and strength together with the transformation of skeletal muscle types in type 1 diabetic rats. Skeletal muscle L6 cells were used for in vitro study. Key Results: Puerarin increased muscle tissue weights and improved muscle strength. An enhanced skeletal muscle cross-sectional area was accompanied by reduced mRNA expression of muscle atrophy marker genes, including F-box only protein 32 (Atrogin-1) and muscle-specific RING-finger 1(Murf-1), both in vitro and in vivo. The transformation from type I fibers (slow muscle) to type II fibers (fast muscle) was also observed after puerarin administration. In vitro studies suggested that puerarin upregulated Akt/mTOR but downregulated the LC3/p62 signaling pathway, eventually resulting in muscle hypertrophy. Conclusions and Implications: Our study observed that puerarin mitigated skeletal muscle atrophy in type 1 diabetic rats. Subsequently, we found that the related mechanisms closely involved the upregulation of protein synthesis via the Akt/mTOR signaling pathway. Whether this anti-diabetic muscle atrophy effect in mice applies to humans remains unknown.