Blepharospasm, hemifacial spasm and other diseases involving forceful, uncontrolled muscle spasms of the face and neck are extremely debilitating conditions that result in functional blindness, often causing affected persons to withdraw from social and economic activities. Indirect treatment with orally administered medications is often accompanied by unacceptable side effects. Surgical treatments are costly and often unsatisfactory. Current medical treatment involves the injection of botulinum toxin into the affected muscles. While usually effective, this treatment provides only temporary relief. We have developed a novel permanent, non-surgical treatment for these diseases, doxorubicin chemomyectomy. Doxorubicin (DXN), a potent anti-metabolic and anti-mitotic cancer drug, is injected directly into the eyelids. In laboratory studies injection of DXN results in a loss of up to 70% of the muscle fibers in the orbicularis oculi muscle. This muscle loss is permanent, with no further changes in muscle fiber number after one month. In the Phase I patient clinical trial, over half of the treated patients have now gone over a year with significant relief from their muscle spasms and without requiring further treatment. One problem with the current protocol is that the maximal relief of muscle spasms requires three sets of injections at the maximal safe dose. Each injection results in a substantial inflammatory reaction within the lid, and each injection increases the chance of skin ulceration at the injection site. Inflammation and local pain at the injection site is the major deterrent for patients in choosing this treatment alternative. This proposal focuses on the improvement of this treatment for these patients. First, the acute and chronic inflammatory reactions after doxorubicin administration will be assessed. Attempts will be made to ameliorate inflammation and skin injury with a variety of anti- inflammatory mediators. Issues of skin toxicity are a major concern for patients. The effect of doxorubicin on epithelial cell turnover in the treated eyelids will be assessed and the role of lipid peroxidation on doxorubicin induced skin toxicity will be determined. The generation of oxidants will be assessed in the treated eyelids. Further strategies will be tested that alter anti- and pro-oxidant generating molecules within the eyelid in an attempt to increase doxorubicin myotoxicity and/or decrease skin injury and inflammation. A variety of agents known to increase doxorubicin toxicity will be tested in an effort to improve the efficiency of muscle loss. These studies will allow us to develop the most clinically effective and cost effective treatment for these patients.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007935-11
Application #
2888335
Study Section
Special Emphasis Panel (ZRG1-VISB (03))
Project Start
1989-08-07
Project End
2000-09-29
Budget Start
1999-09-30
Budget End
2000-09-29
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Harrison, Andrew R; McLoon, Linda K (2006) Reduction in touch sensitivity and hyperinnervation in vesicant-injured rabbit eyelid by direct injection of corticotropin releasing factor. Neurosci Lett 400:30-4
McLoon, L K; Sandnas, A M; Nockleby, K J et al. (2002) Reduction in vesicant-induced cellular inflammation and hyperalgesia by local injection of corticotropin releasing factor in rabbit eyelid. Inflamm Res 51:16-23
McLoon, L K; Wirtschafter, J D (2001) Doxil-induced chemomyectomy: effectiveness for permanent removal of orbicularis oculi muscle in monkey eyelid. Invest Ophthalmol Vis Sci 42:1254-7
McLoon, L K; Josephson, K; Wirtschafter, J (1999) Doxorubicin does not spread systemically following a local injection into the eyelids of rabbits. Curr Eye Res 19:285-9
Wirtschafter, J D; Ketcham, J M; Weinstock, R J et al. (1999) Mucocutaneous junction as the major source of replacement palpebral conjunctival epithelial cells. Invest Ophthalmol Vis Sci 40:3138-46
McLoon, L K; Wirtschafter, J D (1999) Direct injection of liposome-encapsulated doxorubicin optimizes chemomyectomy in rabbit eyelid. Invest Ophthalmol Vis Sci 40:2561-7
McLoon, L K; Nguyen, L T; Wirtschafter, J (1998) Time course of the regenerative response in bupivacaine injured orbicularis oculi muscle. Cell Tissue Res 294:439-47
Nguyen, L T; McLoon, L K; Wirtschafter, J D (1998) Doxorubicin chemomyectomy is enhanced when performed two days following bupivacaine injections: the effect coincides with the peak of muscle satellite cell division. Invest Ophthalmol Vis Sci 39:203-6
McLoon, L K; Wirtschafter, J (1997) Local injections of corticotropin releasing factor reduce doxorubicin-induced acute inflammation in the eyelid. Invest Ophthalmol Vis Sci 38:834-41
McLoon, L K; Wirtschafter, J D (1996) N-CAM is expressed in mature extraocular muscles in a pattern conserved among three species. Invest Ophthalmol Vis Sci 37:318-27

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