Uses For Collagenase?

Uses for Collagenase

Dupuytren’s Disease • Peyronie’s Disease • Glaucoma
Wound Healing • Dermal Ulcers • Burns • Bibliography

This is a deforming condition of the hand in which one or more fingers, usually the ring finger and little finger, contract toward the palm, often resulting in functional disability. The disease predominantly affects older Caucasian males and there appears to be a hereditary aspect. It may be noted that famous sufferers include Ronald Reagan and Margaret Thatcher.

Currently, the only proven approach to treating Dupuytren's disease is through surgery. Clinical trials are in progress to investigate non-operative therapy for Dupuytren's disease using BioSpecifics injectable Collagenase (Cordase tm). The FDA has accorded "Orphan Drug Status" to this usage and a U.S. patent has been granted. A research grant for continued clinical investigation in this area at Stony Brook Medical Center was awarded to BioSpecifics by the New York State Center for Advanced Technology in Medical Biotechnology. The FDA Office of Orphan Product Development has provided some of the funding for the trials in Stony Brook. A second double blind controlled trial is now underway to further define collagenase's usefulness for this condition.

Dupuytren's Disease Links:

http://www.pncl.co.uk/~belcher/dupuytrn.htm
http://www.centerwatch.com/studies/STU2496.HTM
Dupuytren's Disease Patient Discussion Forum

Back to top Peyronie’s Disease
Another instance of deformity due to excessive deposition of collagen is Peyronie's disease, which causes the penis to bend in a way that makes intercourse difficult, frequently painful, and even impossible in severe cases. Currently, the only proven treatment is surgery which is not widely performed. Clinical studies are in progress.

Peyronie's Disease Links:

http://www.niddk.nih.gov/health/urolog/pubs/peyronie/peyronie.htm http://www.centerwatch.com/studies/CAT118.HTM

Glaucoma

Glaucoma is a condition in which excess pressure develops inside the eye and damages the optic nerve, often leading to blindness. Glaucoma occurs when the ducts that drain fluid from the anterior chamber of the eye are restricted as a result of abnormal buildup of collagen. Use of collagenase offers prospects for reversing this process. An estimated three million Americans have glaucoma, leading to 50,000 cases of blindness per year. Glaucoma accounts for some 14% of world blindness.

ENZYMATIC SCLEROSTOMY: HUMAN STUDY ((J.A. Dan ^1,4,
S. Honavar², G.C. Sekhar², A. Mandl², R. Ramakrishnan³,
R. Krishnadads³, M. F. Lieberman⁴, R.L. Stamper⁴, D.A. Belyea ^4,5,)) Weizmann Institute of Science, Rehovot, Israel¹; L.V. Prasad Eye Institute Hyderabad India ²; Aravind Eye Hospital, Madurai, India ³; California Pacific Medical Center, San Francisco CA⁴; Maine Eye Center, Portland, ME⁵.

Wound Healing
In vitro studies on wound healing conducted at a major New England University showed that collagenase treatment of skin cells significantly enhances cell growth and migration after injury. An article relating to this development was published in the March/April 1996 issue of Wounds and a report on the results was presented at the 1996 International Burn Foundation conference.

Dermal ulcers are skin lesions that include:

1)Pressure Ulcers Any lesion caused by unrelieved pressure resulting in damage of underlying tissue. Also called decubitus ulcer, pressure sore, and bedsore. Pressure ulcers are usually located over bony prominences and are graded or staged to classify the degree of tissue damage observed. Pressure ulcers are staged as follows: Stage I: Nonblanchable erythema of intact skin, the heralding lesion of skin ulceration. In individuals with darker skin, discoloration of the skin, warmth, edema, induration, or hardness may also be indicators. Stage II: Partial thickness skin loss involving epidermis, dermis, or both. The ulcer is superficial and presents clinically as an abrasion, blister, or shallow crater. Stage III: Full thickness skin loss involving damage to or necrosis of subcutaneous tissue that may extend down to, but not through, underlying fascia. The ulcer presents clinically as a deep crater with or without undermining of adjacent tissue. Stage IV: Full thickness skin loss with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structure (e.g., tendon, joint capsule). Undermining and sinus tracts also may be associated with Stage IV pressure ulcers.⁽¹⁾

2)Arterial Ulcers These ulcers are caused by aterial occlusion or insufficiency which may include atherosclerosis or diabetes. They commonly occur in the lower leg and foot.

3)Venous Ulcers Result from impairments to the venous system. They are often associated with chronic venous insufficiency (CVI). They are commonly located around the ankle, medial malleolus (from instep to above the ankle).

4)Diabetic Ulcers A serious complication of diabetes mellitus.Peripheral neuropathy is the most prevalent cause of diabetic foot ulcers. They are most often found on the foot.

Collagenase Santyl® Ointment provides effective debridement for all of the above chronic dermal ulcers. Santyl® is the only topical enzyme to lyse denatured collagen.Denatured collagen is the main constituent of necrotic wounds. Santyl® acts by supplementing the natural process for removing non-viable tissue. Santyl® is the only topical enzymatic debriding product to conduct double blind randomized controlled clinical trials showing effectiveness against placebo.

1)Bergstrom N, Bennett MA, Carlson CE, et al. Treatment of Pressure Ulcers. Clinical Practice Guideline, No. 15. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research. AHCPR Publication No. 95-0652. December 1994.

Burns

Burn wounds may be classified as follows:

A) First-degree burn Only the epidermis sustains injury. Cutaneous erythema and mild pain are usually evident.

B) Second degree burn The entire epidermis and some portions of the dermis are injured.Superficial second degree burns normally heal in 7 to 14 days.

C) Third degree burns In these wounds, the dermis and epidermis are completely destroyed.These are also known as full thickness burns.

There are approximately 2.0 million burn victims in the U.S. each year. Approximately 100,000 people are hospitalized; 10,000 people die. Some 825,000 burn victims are under the age of 15. The cost of treating a hospitalized burn victim can be as much as $10,000 per day, not including costs for advanced treatment modalities. The average hospital stay for a major burn patient in this country is 30-60 days; this creates a major impact fiscally on society. Approximately 10%-15% of these patients will have co-morbidity or mortality (Demling & Lalonde, 1989).⁽¹⁾

Treatment of burns using Collagenase Santyl® is already FDA approved. To renew the data, a pilot study was conducted which compared the efficacy of Collagenase Santyl® to standard treatment for deep second degree burns. Positive results from this study were published in the Journal of the American Burn Association⁽²⁾. Based on the successful results, a multi-center study was conducted in which eight medical centers specializing in the treatment of burns participated. The study, which involved 79 patients, showed collagenase treatment resulted in faster cleaning and healing than deep second degree burn wounds receiving standard treatment. A paper on the study has been reported in the Journal of the American Burn Association⁽³⁾. Effectiveness of Collagenase Santyl® for burn treatment was noted favorably during the March 1996 annual meeting of the American Burn Association in Nashville, TN and at the February 1997 meeting of the International Burn Foundation.

(1) George Rodeheaver, PhD, Mona Baharestani, Ph.D., CETN, Mary Ellen Brabec, MHS, RD, H Joseph Byrd, Pharm D, C. Andrew Salzberg, MD, Paul Scherer, DPM, and Theresa Vogelpohl, MNSc, CNS. Wound Healing and Wound Management: Focus on Debridement, Vol. 7, No. 1, January 1994, The Journal for Prevention and Healing Advances in Wound Care.

(2) H.S. Soroff, D. Sasvary, "Collagenase Ointment and Polymyxin B Sulfate/Bacitracin Spray Versus Silver Sulfadiazine Cream in Partial-Thickness Burns: A Pilot Study", Journal of Burn Care & Rehabilitation Vol. 15, No. 1, (January/February 1994) pp. 13-17.

(3) J.F. Hansbrough et al, "Wound Healing in Partial-Thickness Burn Wounds Treated with Collagenase Ointment Versus Silver Sulfadiazine Cream". Journal of Burn Care & Rehabilitation 1995; 16:241-7.

BIBLIOGRAPHY

CLINICAL APPLICATIONS OF COLLAGENASE FOR INJECTION

A. PURIFIED COLLAGENASE FOR DUPUYTREN'S DISEASE

1. Badalamente, M.A., Hurst, L.C.
Enzyme Injection as a Nonoperative Treatment for Dupuytren's Disease
Drug Delivery, 3:35-40, 1996

2. Starkweather, KD., Lattuga, S., Hurst, L.C., Badalamente, M.A., Stony Brook, NY, Guilak, F., Durham, NC, Sampson, S.P., Dowd, A., Stony Brook, NY, Wisch, D., Torrington, Ct.
Collagenase in the Treatment of Dupuytren's Disease: An In Vitro Study The Journal of Hand Surgery, 1996; 21A: 490-495.

1. Gelbard, M.K., Lindner, A., Kaufman, J.J. The Use of Collagenase in the Treatment of Peyronie's Disease. J. of Urology: 134, August 1985, 280-283

2. Gelbard, M.K., Walsh, R., Kaufman, J.J. Collagenase for Peyronie's Disease Experimental Studies. Urol. Res. (1982) 10:135-140

3. Hamilton, R.G., Mintz, G.R., Gelbard, M.K. Humoral Immune Responses in Peyronie's Disease Patients Receiving Clostridial Collagenase Therapy. J. of Urology 135: 641-647, March 1986

4. Gelbard, M.K., James, K., Riach, P., Dorey, F. Collagenase Versus Placebo in the Treatment of Peyronie's Disease: A Double-Blind Study. J. of Urology Vol. 149: 56-58 January 1993

1. Friedman, K., Pollack, S.V., Manning, T., and Pinnell, S.R. Degradation of porcine dermal connective tissue by collagenase and hyaluronidase. British J. of Dermatology (1986) 115, 403-408

2. Injectable Bacterial Collagenase Appears Promising for Keloids.. Skin & Allergy News Feb. 1988

3. Goldstein, R.D., Ford-Keyes, M., Strauch, B. Montefiore Medical Center/Albert Einstein College of Medicine "Preliminary Results of Injectable Collagenase for the Treatment of Keloids and Hypertrophic Scars (H.S.)" Internation Burn Foundation, Hawaii, February 1997

D. PURIFIED COLLAGENASE FOR POTENTIATION OF WOUND HEALING

1. Herman, I.M., Stimulation of Human Keratinocyte Migration and Proliferation In Vitro: Insight into the Cellular Responses to Injury and Wound Healing. Wounds, Vol.8, No.2, March/April 1996

E. PURIFIED COLLAGENASE AS AN ADJUNCT TO VITRECTOMY

1. Moorhead, L.C., Redburn, D.A., et al. Bacterial Collagenase Proposed Adjunct to Vitrectomy with Membranectomy Archives of Ophthalmology, October 1980, Vol. 98, 1829-1839

2. Moorhead, L.C., Chu, H.H., Garcia, C.A. Enzyme-assisted Vitrectomy with Bacterial Collagenase Time Course and Toxicity Studies. Archives of Ophthalmology, February 1983, Vol. 101, 265-274

3. Moorhead, L.C., Radtke, N. Enzyme-assisted Vitrectomy with Bacterial Collagenase. Retina: 5, 98-100, No. 2, 1985

F. PURIFIED COLLAGENASE FOR NERVE REGENERATION

1. Wehling, P. et al. The Influence of Bacterial Collagenase on Regeneration of Severed Rat Sciatic Nerves. Acta Neurochirurgica (Wien) 119: 121-127 (1992).

G. NUCLEOLYSIN LITERATURE 1. Bromley, J.W., Hirst, J.W., Osman, M., Steinlauf, P. Gennace, R.E., Stern, H. Collagenase: An Experimental Study of Intervertebral Disc Dissolution. SPINE 5, No. 2: 126-131, March/April 1980

2. Bromley, J.W., and Gomez, J.G. Lumbar Intervertebral Discolysis with Collagenase. SPINE 8: No. 3: 322-324, 1983

3. Bromley, J.W., Varma, A.O., et al. Double-Blind Evaluation of Collagenase Injections for Herniated Lumbar Discs. SPINE 9: 486-488, 1984

4. Bromley, J.W. Intervertebral Discolysis with Collagenase Advances in Orthopaedic Surgery, Vol. 9, No. 2, Sept./Oct. 1985 Williams & Wilkins, Baltimore, MD.

Back to tops 5. Brown, Mark D., Tompkins, Janet S. Chemonucleolysis (Discolysis) with Collagenase SPINE 11, No. 2, 1986

6. Coin, C.G., Coin, J.T., Garrett, J.K. Computed Tomography of Canine Disc Herniation: A Potential Diagnostic Model for the Evaluation of Disc Disease and Discolysis in Humans. Computed Tomography of the Spine, Chap. 26: 471-476 Ed. by M. Judith Donovan Post, M.D. Williams & Wilkins, Baltimore, MD, 1984

7. Coin, C.G., Coin, J.T., Garrett, J.K. Experimental Computed Tomographic Controlled Discolysis. Computed Tomography of the Spine, Chap. 27: 477-484 Ed. by M. Judith Donovan Post, M.D. Williams & Wilkins; Baltimore, MD, 1984

8. Fisher, R.G., Bromley, J.W., et al. Surgical experience following intervertebral discolysis with collagenase J. Neurosurg, 64: 613-616, April 1986

9. Fisher, R.G. Injection therapy for herniated disks. Background and usefulness. Postgraduate Medicine: 75, No. 8, June 1984

10. Hedtmann, A., Steffen, R., Kramer, J. Prospective Comparative Study of Intradiscal High-Dose and Low-Dose Collagenase Versus Chymopapain SPINE, Vol. 12, No. 4, 1987

11. Kraemer, J., Kolditz, D. et al. Prospective comparative study of collagenase (Nucleolysin) vs. chymopapain (Chymodiactin). Alternatives in Spinal Surgery: 2, No. 2, May 1985

12. Lenz, G., Schulitz K.-P. Results of Intradiscal Therapy Using Collagenase in Cases of Dislocated Lumbar Intervertebral Discs (German) Orthopade, 14: 133-142, 1985

13. Oimarker, K., Rydevik, B., et al. Effects of Epidural and Intrathecal Application of Collagenase in the Lumbar Spine: An Experimental Study in Rabbits SPINE Volume 12, Number 5, 477-482, 1987

14. Rydevik, B., Branemark, P. et al. Effects of Chymopapain on Nerve Tissue, An Experimental Study on the Structure and Function of Peripheral Nerve Tissue in Rabbits After Local Application of Chymopapain. SPINE 1, No. 3: 137-148, 1976

15. Rydevik, B., Brown, M.D., Ehira, T., Nordborg, C. Effects of Collagenase on Nerve Tissue, An Experimental Study on Acute and Long-Term Effects in Rabbits. SPINE 10, No. 6: 562-566, 1985

16. Rydevik, B., Ehira T., Linder, L., Olmarker K., Romanus, M., Branemark, P.L Microvascular Response to Locally Injected Collagenase Journal of Plastic and Reconstructive Surgery, 23: 17-21, 1989

Back to top 17. Steffen, R., Muller, U., Schulitz, K.P., Kraemer. "Double Blind Evaluation of High and Low Dose Intradiscal Collagenase" International Society of the Study of the Lumbar Spine Seattle, 21-25, June 1994

18. Sussman, B.J., Bromley, J.W., Gomez, J.C. Injection of Collagenase in the Treatment of Herniated Lumbar Disk Initial Clinical Report JAMA 245, No. 7: 730-732, Feb. 20, 1981

19. Wintermatel, E., Emde, H., Loew, F. Intradiscal Collagenase for Treatment of Lumbar Disc Herniations, A Comparison of Clinical Results and Computed Tomography Follow-up Acta Neurochirurgica 78, 98-104 (1985)

20. Wehling, P., Schulitz, K.P., Hanley, E., Pak, M.A. Short and Long Term Effects on Spinal Cord Evoked Potentials of Collagenase and Chymopapain Applied into the Rat Lumbar Spinal Canal. International Society for the Study of the Lumbar Spine. Miami, Florida April 1988.

21. Zook, B.C., Kobrine, A. Effects of Collagenase and Chymopapain on Spinal Nerves and Intervertebral Discs of Chynomolgus Monkeys. J. Neurosurg, 64: 474-483, March 1986.

CLINICAL APPLICATIONS OF COLLAGENASE FOR INJECTION

A. NUCLEOLYSIN LITERATURE

1. Bromley, J.W., Hirst, J.W., Osman, M., Steinlauf, P. Gennace, R.E., Stern, H. Collagenase: An Experimental Study of Intervertebral Disc Dissolution. SPINE 5, No. 2: 126-131, March/April 1980

2. Bromley, J.W., Varma, A.O., et al. Double-Blind Evaluation of Collagenase Injections for Herniated Lumbar Discs. SPINE 9: 486-488, 1984

3. Brown, Mark D., Tompkins, Janet S. Chemonucleolysis (Discolysis) with Collagenase SPINE 11, No. 2, 1986

4. Coin, C.G., Coin, J.T., Garrett, J.K. Experimental Computed Tomographic Controlled Discolysis. Computed Tomography of the Spine, Chap. 27: 477-484 Ed. by M. Judith Donovan Post, M.D. Williams & Wilkins; Baltimore, MD, 1984

5. Hedtmann, A., Steffen, R., Kramer, J. Prospective Comparative Study of Intradiscal High-Dose and Low-Dose Collagenase Versus Chymopapain SPINE, Vol. 12, No. 4, 1987

6. Steffen, R., Muller, U., Schulitz, K.P., Kraemer. "Double Blind Evaluation of High and Low Dose Intradiscal Collagenase" International Society of the Study of the Lumbar Spine Seattle, 21-25, June 1994

Back to top 7. Wehling, P., Schulitz, K.P., Hanley, E., Pak, M.A. Short and Long Term Effects on Spinal Cord Evoked Potentials of Collagenase and Chymopapain Applied into the Rat Lumbar Spinal Canal. International Society for the Study of the Lumbar Spine. Miami, Florida April 1988.

8. Zook, B.C., Kobrine, A. Effects of Collagenase and Chymopapain on Spinal Nerves and Intervertebral Discs of Chynomolgus Monkeys. J. Neurosurg, 64: 474-483, March 1986.

9. Hurst, M.D., Lawrence C., Badalamente, PhD., Marie A. ENZYME INJECTION AS A NONOPERATIVE TREATMENT IN DUPUYTREN'S DISEASE. Paper #77, 3:23 pm, American Society for Surgery of the Hand, 54th Annual Meeting, September 2-4, 1999, Boston, MA

10. Badalamente, Marie A., Hurst, L.C., ENZYME INJECTIONS AS A NON-OPERATIVE TREATMENT FOR DUPUYTREN'S DISEASE State University of New York @ Stony Brook, Dept. of Orthopaedics, Stony Brook, New York, USA 11794-8181, IFSSH 98, May 24-28 1998, Vancouver, Canada

B. PURIFIED COLLAGENASE FOR PEYRONIE'S DISEASE

1. Hamilton, R.G., Mintz, G.R., Gelbard, M.K. Humoral Immune Responses in Peyronie's Disease Patients Receiving Clostridial Collagenase Therapy. J. of Urology 135: 641-647, March 1986

2. Gelbard, M.K., James, K., Riach, P., Dorey, F. Collagenase Versus Placebo in the Treatment of Peyronie's Disease: A Double-Blind Study. J. of Urology Vol. 149: 56-58 January 1993

C. PURIFIED COLLAGENASE FOR KELOIDS

1. Injectable Bacterial Collagenase Appears Promising for Keloids.. Skin & Allergy News Feb. 1988

2. Goldstein, R.D., Ford-Keyes, M., Strauch, B. Montefiore Medical Center/Albert Einstein College of Medicine Preliminary Results of Injectable Collagenase for the Treatment of Keloids and Hypertrophic Scars (H.S.) Internation Burn Foundation, Hawaii, February 1996D. PURIFIED COLLAGENASE AS AN ADJUNCT TO VITRECTOMY 1. Moorhead, L.C., Radtke, N. Enzyme-assisted Vitrectomy with Bacterial Collagenase. Retina: 5, 98-100, No. 2, 1985

E. PURIFIED COLLAGENASE FOR NERVE REGENERATION

1. Wehling, P. et al. The Influence of Bacterial Collagenase on Regeneration of Severed Rat Sciatic Nerves. Acta Neurochirurgica (Wien) 119: 121-127 (1992).

F. PURIFIED COLLAGENASE FOR DUPUYTREN'S DISEASE

1. Badalamente, M.A., Hurst, L.C. Enzyme Injection as a Nonoperative Treatment for Dupuytren's Disease Drug Delivery, 3:35-40, 1996

2. Starkweather, KD., Lattuga, S., Hurst, L.C., Badalamente, M.A., Stony Brook, NY, Guilak, F., Durham, NC, Sampson, S.P., Dowd, A., Stony Brook, NY, Wisch, D., Torrington, Ct. Collagenase in the Treatment of Dupuytren's Disease: An In Vitro Study The Journal of Hand Surgery, 1996; 21A: 490-495.

G. PURIFIED COLLAGENASE FOR POTENTIATION OF WOUND HEALING

1. Herman, I.M., Stimulation of Human Keratinocyte Migration and Proliferation In Vitro: Insight into the Cellular Responses to Injury and Wound Healing. Wounds, Vol.8, No.2, March/April 1996