Combined isosorbide dinitrate and ibuprofen as a novel therapy for muscular dystrophies: evidence from Phase I studies in healthy volunteers

Abstract

We designed two Phase I studies that assessed healthy volunteers in order to evaluate the safety and to optimize the dosing of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a nonsteroidal antiinflammatory drug. We designed these studies with the aim of designing a Phase II trial to evaluate the drugs’ efficacy in patients affected by Duchenne muscular dystrophy. For the first trial, ISOFEN1, a single-dose, randomized-sequence, open-label, active control, three-treatment cross-over study, was aimed at comparing the pharmacokinetics of ibuprofen 200 mg and isosorbide dinitrate 20 mg when given alone and concomitantly. The pharmacokinetics of ibuprofen given alone versus ibuprofen given concomitantly with isosorbide dinitrate were similar, as documented by the lack of statistically significant differences in the main drug’s pharmacokinetic parameters (time to maximal concentration [Tmax], maximal concentration [Cmax], area under the curve [AUC]0–t, and AUC0–∞). Similarly, we found that the coadministration of ibuprofen did not significantly affect the pharmacokinetics of isosorbide dinitrate. No issues of safety were detected. The second trial, ISOFEN2, was a single-site, dose titration study that was designed to select the maximum tolerated dose for isosorbide dinitrate when coadministered with ibuprofen. Eighteen out of the 19 enrolled subjects tolerated the treatment well, and they completed the study at the highest dose of isosorbide dinitrate applied (80 mg/day). One subject voluntarily decided to reduce the dose of isosorbide dinitrate from 80 mg to 60 mg. The treatment-related adverse events recorded during the study were, for the large majority, episodes of headache that remitted spontaneously in 0.5–1 hour – a known side effect of isosorbide dinitrate. These studies demonstrate that the combination of isosorbide dinitrate and ibuprofen does not lead to pharmacokinetic interactions between the two drugs; they also demonstrate that the combination of isosorbide dinitrate and ibuprofen has optimal tolerability and safety profiles that are similar to those previously reported for isosorbide dinitrate and ibuprofen given alone.

Current Understanding of Molecular Pathology and Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy

“…In addition the combination of a non-steroidal anti-inflammatory drug, ibuprofen, and an NO donor, isosorbide dinitrate, were capable of preventing morphological changes in the heart of mdx mice [105]. A recent phase 1 clinical trial using this combinatory therapy, demonstrated an excellent safety profile in healthy patients [106]. This provides a solid basis for further trials in muscular dystrophy patients.…”

Deficient nitric oxide signalling impairs skeletal muscle growth and performance: involvement of mitochondrial dysregulation

“…The importance of NO in muscle repair also emerges from the observation that nNOS signalling is defective in many genetically diverse skeletal muscle diseases in which muscle repair is dysregulated, including Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophies 2C, 2D and 2E, Ullrich congenital muscular dystrophy and inflammatory myositis [ 3 , 10 - 13 ]. Based on this evidence and on the fact that the restoration of NO signalling by nNOS overexpression ameliorates muscle function [ 14 , 15 ], genetic and pharmacologic strategies to boost nNOS/NO signalling in dystrophic muscle are being tested with encouraging results: in particular, the combination of NO donation with non steroidal anti-inflammatory activity limits muscle damage and favours muscle healing in vivo [ 16 - 18 ] such that it is currently being tested as a therapeutic for Duchenne muscular dystrophy in humans [ 19 , 20 ].…”

Evaluation of Ibuprofen Use on the Immune System Indicators and Force in Disabled Paralympic Powerlifters of Different Sport Levels

“…However, the use of ibuprofen did not show good results related to the immune system, where the ingestion of drinks with carbohydrates during intense and prolonged exercises attenuated the increase in plasma cytokines and stress hormones, superior to the use of ibuprofen, however, partially limited [ 64 ]. The use of ibuprofen alone or in combination with other drugs in patients affected by Duchenne muscular dystrophy, being evaluated in maximum concentration, did not affect these indicators [ 65 ]. Yet another study that evaluated the influence of ibuprofen use on hypertrophy showed that ibuprofen presented a reduction in inflammation-induced muscle weakness.…”