Blepharospasm and other diseases involving muscle spasms, particularly those of the face and neck, including hemifacial spasm, orofacial dystonias and torticollis, are extremely debilitating to those who suffer from these afflictions. Persons with these conditions may withdraw from ordinary social and economic activities. Inability to drive a vehicle commonly leads to loss of employment and independence. Indirect treatment with orally administered medications, even when efficacious, is usually accompanied by unacceptable central nervous system side effects. The current medical treatment involves intramuscular injection with Botulinum toxin, and although effective, only provides temporary relief. Surgical therapies include removal of the orbicularis oculi muscles that close the eyes or cutting branches of the facial nerve that innervate these muscles. The surgical therapies are unsatisfactory and costly. there is no permanent treatment for blepharospasm and other related diseases. We recently demonstrated that doxorubicin (Adriamycin), a naturally occurring cytotoxic anthracycline antibiotic, may be a safe and effective agent to provide permanent treatment for blepharospasm. Our results show, for the first time, that it can permanently reduce the muscle mass of the orbicularis oculi muscle. We will examine at the light and electron microscopic levels changes in the gross and fine structure of the treated muscles, as well as quantify the chemomyotoxic effects of the drug. Others have explored the barriers to the diffusion through skeletal muscle tissue and the cellular barrier to uptake of docorubicin. We will extend these studies to the facial musculature. We will attempt to maximize the muscle toxicity by co-treatment with factors that increase the spread of injected material and as well as with the use of doxorubicin membrane pump antagonists. We will examine the chemoneurotoxic effects of doxorubicin injection into the eyelid musculature on the integrity of the injected facial nerves and the facial motor neurons in the brainstem. We will assess the permanence of the doxorubicin treatment by assessing the eyelid muscles for regeneration of the injured nerves or sprouting of nearby intact nerves into the injured muscles. We will also assess potential side effects of doxorubicin treatment both locally at the injection site and systemically, by examining the CNS and heart and limb muscles for pathologic changes. The first three years we will assess doxorubicin effects in rabbits. In years 4 and 5 we will examine the myotoxic effects of doxorubicin in monkeys based on our rabbit experiments. The anatomical structure of the monkey eyelid, facial muscles and nerve are significantly more like the human structure than is the rabbits. Because the use of doxorubicin for treatment of blepharospasm has immediate clinical use, it is essential to examine its effects in the monkey prior to extensive clinical use in humans.
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