oxadiazoles and Respiratory-Insufficiency

Duchenne muscular dystrophy [DMD] is the most common inherited myopathy and is caused by a defect in the dystrophin gene on the X chromosome causing production of a dysfunctional dystrophin protein. Over the last decade there have been advances in disease modifying pharmacotherapy beyond the widely used strategy of corticosteroids into products to impact both dystrophin production itself and also some of the downstream effects of absent of dysfunctional dystrophin. This manuscript will explore the respiratory progression of DMD including some proposed functional and clinical correlations and the overlap between loss of function in different muscle groups. Options for symptomatic treatment and support are presented and direction as to when the different options should be considered is provided. The manuscript will also review the currently available and late phase developmental pharmacotherapies for DMD.

Topics: Disease Progression; Glucocorticoids; Humans; Morpholinos; Muscular Dystrophy, Duchenne; Oxadiazoles; Prednisone; Pregnenediones; Respiratory Function Tests; Respiratory Insufficiency

The use of opioid drugs for pain relief can induce life-threatening respiratory depression. Although naloxone effectively counteracts opioid-induced respiratory depression, it diminishes the efficacy of analgesia. Our studies indicate that ampakines, in particular, a brain-targeted compound XD-8-17C, are able to reverse respiratory depression without affecting analgesia at relatively low doses. Mice and rats were subcutaneously or intravenously injected with the opioid agonist TH-030418 to induce moderate or severe respiratory depression. XD-8-17C was intravenously administered before or after TH-030418. The effect of XD-8-17C on opioid-induced respiratory depression was evaluated in terms of the opioid-induced acute death rate, arterial blood gas analysis and pulmonary function tests. In addition, the hot-plate test was conducted to investigate whether XD-8-17C influenced opioid-induced analgesia. Pre-treatment with XD-8-17C significantly reduced opioid-induced acute death, and increased the median lethal dose of TH-030418 by 4.7-fold. Blood gas analysis and pulmonary function tests demonstrated that post-treatment with XD-8-17C alleviated respiratory depression, as indicated by restoration of arterial blood gas (pO

Topics: Analgesics, Opioid; Animals; Blood Gas Analysis; Brain; Female; Male; Mice; Oxadiazoles; Rats; Respiratory Insufficiency