Myotonia induced by clofibrate and sodium chlorophenoxy isobutyrate

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Communication

Myotonia Induced by Clofibrate and Sodium Chlorophenoxy Isobutyrate’ INTRODUCTION Myotonia. characterized by a contraction accompanied by an electrical discharge, is commonly seen in myotonia congenita. myotonic dystrophy, paramyotonia, and in a form of hereditary myotonia that occurs in goats ( I ). Myotonia is induced in animals by administration of monocarboxylic aromatic acids (2-4) or certain steroid inhibitors of cholesterol synthesis (536). We report myotonia induced in rats by clofibrate (ethyl ester of chlorophenoxyisobutyrate. “Atromid-S”) which is rapidly hydrolyzed to the free carboxylic acid (chlorophenoxyisobutyric acid. CPIB) i/7 I?I-O (7). Myotonia was also induced in rats by the intravenous and oral administration of the sodium salt of this acid (sodium CPIB). METHODS White, male Wistar rats weighing 300-500 g were used. Atromid-S (Ayerst Laboratories) in mineral oil, was given orally to four groups of six rats. The dosages were 30, 60, 120, and 240. mg/kg. Control rats received only mineral oil. Sodium CPIB (100 mg/ml) was given orally as a single dose of 200 mg/kg (10 rats). and 500 mg/kg (four rats). Ten rats received intravenous sodium CPJB (100 mg/kg). Electromyography (Medic electromyograph Type V2) was performed using a coaxial needle electrode inserted into the thigh muscles of the unanesthetized rats. The observers did not know whether the animals were drug-treated or controls. RESULTS The onset of myotonia in the Atromid-S treated rats directly related to the logarithm of the drug dosage (Y = 0.89). Oral Atromid-S in a dose of 30 mg/kg/day induced myotonic discharges after I 1 days. the discharges appearing 1 hr after drug administration, and remained for 3 to 4 hr. Rats given the largest dose (240 mg/kg) were myotonic 80 to 90 min after the first dose. ’ Supported Fellow of the

by the Muscular

USPHS Grants NS10403 Dystrophy Association.

and Inc

GMl5759.

S. H.

I>. is ;t Postdoctoral

SHORT

COMMUNICATION

239

I

20msec Fig. 1. Electromyogram of a rat gastrocnemius muscle 5 min after intravenous administration of sodium chlorophenoxyisobutyrate (100 mg/kg). Tracings A to D are continuous.

Myotonic discharges appeared within 5 intravenously, and persisted for 3 to 9 myotonia in 20 to 35 min and lasted 24 to myotonia after 50 to 65 min, the myotonia

min of 100 mg sodium CPIB/kg hr. CPIB (500 mg/kg) caused 32 hr; 200 mg/kg orally caused being sustained for 9 to 12 hr.

DISCUSSION

Lipicky, Bryant, and Salmon (8), and Bryant (9) demonstrated that a decrease in the chloride conductance of resting muscle is a prominent defect in patients with myotonia congenita, and the hereditary myotonia of goats. Monocarboxylic aromatic acids such as 3-chloro-2,5,6-trimethylbenzoic acid and anthracene-9-carboxylic acid also cause myotonia by reducing chloride conductance (2). The rapid onset of myotonia observed here, as with the myotonia induced by other aromatic monocarboxylic acids (2-4), is probably due to a direct action on the membrane. This may be by an anchoring of the chlorophenoxyisobutyrate to the outer rim of a “putative” chloride conductance channel or alternatively, it may interact with a “chloride transport carrier,” and thus cause a steric block (10). Rats given the same daily dose of Atromid-S (30 mg/kg) as used clinically to reduce cholesterol levels in patients became myotonic after 11 days of drug treatment. It is, therefore, possible that the muscle cramping, aching, and weakness observed in seven patients (11, 12) on long-term Atromid-S therapy could be due in part to the myotonic action of clofibrate that we report here. Such patients, therefore, merit careful and repeated electromyographic examination. ACKNOWLEDGMENTS The sodium chlorophenoxyisobutyrate was a generous gift from Mr. B. Mollov of Ayerst Laboratories, Inc., New York. The authors are very grateful for the technical assistance of Mark Gittler and John Taylor.

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SYD c)AVID

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CAMPION

JAMES H. PETER Nearomrrscrclar Disease Research Department qf Medicine UCLA School of Medicine Los Angeles, Californiu 90024 Received

August

28.

1975

Luhoruror?