A double-blind placebo controlled trial of diltiazem in duchenne dystrophy

Abstract

The role of calcium accumulation in the pathogenesis of Duchenne muscular dystrophy (DMD) has already been discussed. Several trials with different calcium-blocking drugs have revealed no clinical benefit. In addition, the present study includes histological investigations and computer tomography to verify therapeutic effects. In a randomized placebo-controlled double-blind study, 13 DMD patients aged from 3-10 years (mean, 7 years) were treated with 5 mg/kg diltiazem daily for 1 year. Compared with before therapy, the number of calcium-positive muscular fibres was remarkably reduced in the treated DMD patients, but not in the placebo group. The evaluation of all other biochemical and clinical parameters revealed no significant effects of the diltiazem therapy. The muscular X-ray density measured by computer tomography decreased under treatment. After the evaluation of the double-blind study, the code was broken. Therapy, however, was continued in the treated group and started in the placebo group. After 3 years of diltiazem therapy the clinical status of all 26 patients of the study and 20 additional DMD patients who were treated with diltiazem was compared with 46 untreated DMD patients of the same age and stage in our department. No obvious clinical benefit of diltiazem therapy could be observed.

Diltiazem and verapamil protect dystrophin‐deficient muscle fibers of MDX mice from degeneration: A potential role in calcium buffering and sarcolemmal stability

“…In addition, basal activities of Ca 2+ ‐selective leak channels have been reported to be significantly elevated in dystrophin‐deficient myotubes or dystrophic skeletal muscle fibers,17 and this may explain the increased calcium concentration in mdx fibers seen in the present study. The plasma emission spectrometry technique used here seems to be a valuable tool for the evaluation of overall changes in calcium as a result of drug therapy or other experimental conditions,53 and the results may be best compared to those obtained for DMD patients, in whom muscle biopsies are taken for the determination of muscle calcium content 5, 35. In DMD, muscle Ca 2+ was not found to be affected by diltiazem 5.…”

“…Several studies have investigated the use of diltiazem for the treatment of DMD. Although these studies indicated some positive effects of diltiazem, there were no statistically significant data supporting its treatment efficacy 5, 29, 35. In a hamster model of dystrophy, diltiazem was found to be effective in protecting against muscle degeneration 25, 27.…”

“…Calcium channel blockers such as verapamil and diltiazem are used widely for the treatment of hypertension due to their ability to control the influx of calcium into cardiac cells 26. Diltiazem and verapamil act through L‐type voltage‐dependent calcium channels,26 and the potential usefulness of these drugs for the treatment of muscular dystrophy has been investigated in dystrophic hamsters25, 27 and humans 5, 35. In DMD, diltiazem has shown no beneficial effect, but technical difficulties inherent to clinical trials such as the small number of subjects, the reduced number and size of biopsy specimens, and differences in the individual courses of muscle degeneration have been reported 35…”

Modulation by prednisolone of calcium handling in skeletal muscle cells

“…It has already been shown that the Ca2+ entry blocker, diltiazem, alleviates the symptoms presented by a cardiomyopathic hamster model (Johnson & Bhattacharya, 1993). This compound also has a slight beneficial effect in DMD patients (Bertorini et al, 1988) although no effect was found in another clinical study (Pernice et al, 1988). The mechanism involved in PDN-triggered reduction in…”

Effect of Citrus aurantium L. Essential Oil on Muscle Regeneration in Mdx Mice

“…Serum enzymes such as creatine kinase (CK), creatine kinase MB (CK-MB), aldolase (ALD), and lactate dehydrogenase (LDH) present increased activity under DMD conditions during the first three years of life, which indicates muscular degeneration (Pernice et al, 1988). The activity of these muscle enzymes is important for the diagnosis of muscular diseases.…”