Rationale for treating oedema in Duchenne muscular dystrophy with eplerenone.
Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place.
Department of Neurophysiology, Ulm University, Ulm, Germany. frank.lehmann-horn@uni-ulm.de
Frank
F
Lehmann-Horn
Marc-André
MA
Weber
Armin M
AM
Nagel
Hans-Michael
HM
Meinck
Simon
S
Breitenbach
Johannes
J
Scharrer
Karin
K
Jurkat-Rott
D000328:Adult; D000818:Animals; D003964:Diaphragm / Q000187:drug effects; D004487:Edema / Q000188:drug therapy* / Q000209:etiology; D000077545:Eplerenone; D005260:Female; D005542:Forearm; D006801:Humans; D066298:In Vitro Techniques; D007866:Leg; D008279:Magnetic Resonance Imaging; D008564:Membrane Potentials / Q000187:drug effects; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D053580:Muscle Strength; D020388:Muscular Dystrophy, Duchenne / Q000150:complications* / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone