Myotoxicity

Acquired disease of muscle is more common than is generally appreciated. It may result from the use of drugs—prescription or nonprescription—that have a recognized capacity to compromise the structure or function of skeletal muscle. Drugs particularly well recognized as myotoxic include clofibrate and its derivatives, anabolic steroids, penicillamine, and emetine. Many nonprescription drugs, including alcohol and laxatives, are directly or indirectly myotoxic. Other forms of acquired myopathies include the acute myopathic conditions caused by the bites of many snakes. 

A second group of myotoxic toxins, found almost exclusively in the venoms of cobras, are the cytotoxins (often called cobratoxins, cytolysins, cardiotoxins, or direct lytic factors). These, rather than phospholipases, are almost certainly the primary cause of muscle damage following bites by cobras. Their mechanism of action is not properly known, but it is certainly the case that their action is potentiated by the presence of phospholipases in the venom, even if the phospholipases concerned are not, themselves, myotoxic. The cytotoxins of cobra venom possess no hydrolytic activity of any kind. 

A third group of myotoxic factors are very short polypeptides, devoid of hydrolytic activity. These toxins, found in the venom of a few species of North American rattlesnakes, cause a dilatation of sarcoplasmic reticulum and can cause severe muscle damage. 

Although it is possible to identify a group of particularly toxic components in venom, it should be noted that the venoms are complex mixtures of components, many of which are synergistic. Muscle damage is particularly severe if myotoxic activity is combined with hemorrhagic activity. In this case, muscle regeneration is impaired, because the regenerating tissue is rendered anoxic at a time of intense metabolic activity. 

While most investigations show that sea snake neurotoxins are postsynaptic type, Gawade and Gaitonde (23) stated that Enhydrina schistosa major toxin has dual actions or postsynaptic as well as presynaptic toxicity. E, schistosa venom phospholipase A is both neurotoxic and myotoxic. Neurotoxic action of the enzyme is weak so that there is sufficient time for myonecrotic action to take place (24), Sea snake, L. semifasciata toxin also inhibits transmission in autonomic ganglia, but has no effect on transmission in choroid neurons. 

The clinical features depend upon the type of snake bite. There are three main patterns neurotoxic, as with elapidae such as cobras and kraits vasculotoxic with alteration in blood coagulation as with vipers and myotoxic as with sea snakes although they are all often complicated by local tissue damage. The severity of poisoning will depend on the amount and potency of venom injected and the patient s general health. 

Al-Suwayeh SA, Tebbett IR, Wielbo D, Brazeau GA. In vitro-in vivo myotoxicity of intramuscular liposomal formulations. Pharm Res 1996 13 1384-1388. 

Myotoxicity linked to ezetimibe has been described in a 45-year-old overweight man with McArdle disease, which is the most common disorder of muscle carbohydrate metabolism, caused by mutations in the gene that encodes myophosphorylase (5). 

Colchicine is cleared by a different CYP450 isozyme than fluvastatin and pravastatin are, but another possible mechanism is synergistic myotoxicity, since colchicine causes myopathy by disrupting tubular function with subsequent vacuolization. Patients taking colchicine should be informed about possible muscular and gastrointestinal adverse effects and advised to stop. 

A potential drug interaction between simvastatin and danazol, causing rhabdomyolysis and acute renal insufficiency, has been reported (43). Rhabdomyolysis can occur with all statins when they are used alone and particularly when they are combined with other drugs that are themselves myotoxic or that increase the concentration of the statin. Statins are particularly susceptible to the latter effect because of their metabolism by the CYP450 system and their low oral systemic availability. 

Al-Suwayeh, S.A, Tebbett, I.R, Wielbo, D, and Brazeau, (BiA/itro-in vivo myotoxicity of intramuscular liposomal formulationBharm. Res, 13, 1996,1384-1388. 

Zink W, Seif C, BohlJR, et al. The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades. Anesth Analg. 2003 97 1173-1179. 

Myotoxic side effects, including myopathy or rhabdomyolysis, have been observed with the usage of atorvastatin calcium. Painful myalgia with a significant creatine kinase release (> 2000IU/1) is also associated with the use of atorvastatin [35]. 

Josephs, J. L. 1996. Detection and characterization of fumonisin myotox-ins by liquid chromatography/electrospray ionization using ion trap and triple quadrupole mass spectrometry. Rapid Cornmun. Mass Spectrom., 10,1333-1344. 

In a similar manner, troponin-T can greatly increase the sensitivity of safety labs to detect subclinical cardiac myotoxicity. Rat, dog, and pig troponin-T can all be determined using the automated Roche clinical diagnostic system for human Troponin-T [30], This would have been of obvious relevance to the safety pharmacology of Herceptin , where the association with cardiomyopathy was only established after widespread clinical use. 

Several studies were performed on myotoxicity of local anesthetics. 

Basson (1978), Basson Carlson (1980) described myotoxicity after single and repeated injections of mepivacaine in the rat. Young rats received single or repeated injections of 2% mepivacaine into the tibialis anterior or extensor digitorum longus muscles. Repeated injections consisted of 6 injections of the anesthetic (100 il per injection into the tibialis anterior) on different schedules, at intervals of 21/2 hours, 24 hours, or 4 days. The muscles were examined histologically for evidence of myotoxicity at 0 to 7 and 20 days after the last injection. Single injections showed that mepivacaine is a myotoxic... 

Carabot et al. (1988) tried to explain the myotoxicity by effects of mepivacaine on the microcirculation of the skeletal muscle. Mepivacaine was inoculated directly into the anterior tibialis muscle of rats. Capillaries... 

Basson MD (1978) Effects of multiple mepivacaine (Carbocain) injections on rat skeletal muscle. Clin Res 26 730A Basson MD, Carlson BM (1980) Myotoxicity of single and repeated injections of mepivacaine (Carbocain) in the rat. Anesth Analg 59 275-282... 

Benoit PW, Yagiela JA, Fort NF (1980) Pharmacologic correlation between local anesthetic-induced myotoxicity and disturbances of intracellular calcium distribution. Toxicol Appl Pharmacol 52 187-198... 

Neuroleptic malignant syndrome and subsequent acute interstitial nephritis has been reported in a 44-year-old woman (102). This patient met the main criteria for neuroleptic malignant syndrome, although she did not develop rigidity or a rise in creatine kinase activity. On the other hand, abnormal creatine kinase activity and signs of myotoxicity were respectively found in 14% and 2.1% of patients who took clozapine for an average of 18 months (n = 94) (103). 

Spivak B, Weizman A. Myotoxicity and neurotoxicity during clozapine treatment. Clin Neuropharmacol 124. 

Gupta, R.C., Milatovic, D., Dettham, W-D. (2002). Involvement of nitric oxide in myotoxicity produced by diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity. Arch. Toxicol. 76 715-26. 

Fig. 5 Myotoxicity of various cosolvents as a function of % cosolvent in water. O = propylene glycol, A = ethanol, = Polyethylene glycol 400. (From Ref...

Reznik I, Volchek L, Mester R, Kotler M, Sarova-Pinhas I, Spivak B, Weizman A. Myotoxicity and neurotoxicity during clozapine treatment. Clin Neuropharmacol 2000 23(5) 276-80. 

It has been proposed that the risk of myotoxicity increases when statins are prescribed concurrently with erythromycin (83). There are no data for any pharmacokinetic interaction with fluvastatin or pravastatin, but as in the case of simvastatin the major route of metabolism of these drugs is by CYP3A4 and there is potential for an adverse interaction. 

On the other hand, headache after bupivacaine-induced block has been traced to the use of a vasoconstrictor additive, and is more likely to occur with noradrenahne than adrenaline (300). Unwanted effects on the eye muscles, occurring in some 1% of retrobulbar blocks, extend to ptosis, horizontal rectus muscle palsy, and lagophthalmos all recover spontaneously within a matter of weeks (301). It has been postulated that local anesthetics can be myotoxic, causing contracture and subsequent diplopia (302). Tissue pressure, causing ischemia, can also lead to muscle damage and subsequent contracture and strabismus (SEDA-22, 139). 

Rao VA, Kawatra VK. Ocular myotoxic effects of local anesthetics. Can J Ophthalmol 1988 23(4) 171-3. 

II. Charge density distribution and the myotoxicity of presynaptically neurotoxic phospholipases. Toxicon 24,895—905. 

Snake venoms are complex mixtures of several different components or fractions that can vary considerably within Crotalinae members. A complete review of venom components is beyond the scope of this review. Depending on the content of the venom, multiple organ systems may be affected. Historically, Crotalinae venom was classified as neurotoxic, hemotoxic, cardiotoxic, or myotoxic, depending on the species of snake involved in the envenomation. This oversimplifies the complex nature of Crotalinae venom. Clinically, a patient may develop such multisystem disorders as platelet destruction, internal bleeding, hypotension, paresthesias, and rhabdomyolysis. 

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