Effects of Chronic, Maximal Phosphorodiamidate Morpholino Oligomer (PMO) Dosing on Muscle Function and Dystrophin Restoration in a Mouse Model of Duchenne Muscular Dystrophy. | LitMetric
Background: Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is currently used in clinical development to treat Duchenne muscular dystrophy (DMD), with four exon-skipping drugs achieving regulatory approval. Exon skipping elicits a truncated, but semi-functional dystrophin protein, similar to the truncated dystrophin expressed in patients with Becker Muscular dystrophy (BMD) where the disease phenotype is less severe than DMD. Despite promising results in both dystrophic animal models and DMD boys, restoration of dystrophin by exon skipping is highly variable, leading to contradictory functional outcomes in clinical trials.
Objective: To develop optimal PMO dosing protocols that result in increased dystrophin and improved outcome measures in preclinical models of DMD.
Methods: Tested effectiveness of multiple chronic, high dose PMO regimens using biochemical, histological, molecular, and imaging techniques in mdx mice.
Results: A chronic, monthly regimen of high dose PMO increased dystrophin rescue in mdx mice and improved specific force in the extensor digitorum longus (EDL) muscle. However, monthly high dose PMO administration still results in variable dystrophin expression localized throughout various muscles.
Conclusions: High dose monthly PMO administration restores dystrophin expression and increases muscle force; however, the variability of dystrophin expression at both the inter-and intramuscular level remains. Additional strategies to optimize PMO uptake including increased dosing frequencies or combination treatments with other yet-to-be-defined therapies may be necessary to achieve uniform dystrophin restoration and increases in muscle function.
3-Methylmethcathinone (3-MMC) is a designer drug that belongs to the group of synthetic cathinones. The compound has been scheduled in many jurisdictions because of public health concerns associated with excessive use. To date, there are no clinical studies that have evaluated the risk profile of 3-MMC in the recreational range of low to moderate doses.
Objective: To explore the antitumor effect of Inonotus obliquus extract on 4T1 tumor-bearing mice in vivo and its possible mechanism.
Methods: 4T1 tumor-bearing mice model was established. After successful modeling, tumor-bearing mice were randomly divided into model control group, cyclophosphamide(CTX) positive group, and high, medium and low dose groups of Inonotus obliquus extract, with 10 mice in each group, which were administered continuously for 21 days.
Objective: To evaluate the treatment patterns, medication adherence, concomitant corticosteroid use, factors influencing sequence of therapies (SOTs), healthcare resource utilisation (HCRU) and associated costs in adults with SLE in the USA.
Methods: Claims data from the Merative MarketScan Commercial and Medicare Supplemental Database between 2011 and 2019 were used to identify patients with incident SLE. The date of first claim with SLE was defined as the index date, with a 24-month pre-index and ≥24-month post-index period.
Background: Urinary tract infections (UTIs) are among the most common bacterial infections, and appropriate antimicrobial therapy with agents that minimise resistance is crucial. Despite international concern, adherence to guidelines is still suboptimal. This study aims to determine the effect of the absence of national guidelines and the rate of conformity to international guidelines among physicians in antibiotic (ATB) prescriptions for the treatment of UTIs in adults and detect the factors that are associated with a higher rate of non-compliance.
