Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2002-07-09
2004-03-23
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S725000, C514S801000, C514S802000, C514S859000, C514S863000, C514S885000, C514S962000, C424S464000, C424S489000
Reexamination Certificate
active
06710083
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for treatment of palmar and plantar fibromatosis. More specifically, the method utilizes 13 cis-retinoic acid to effectively treat palmar and plantar fibromatosis.
BACKGROUND OF THE INVENTION
Palmar fibromatosis, also called Dupuytren's contracture, Dupuytren's disease, palmar fasciitis, and Viking disease, is a thickening and tightening of the fibrous tissue beneath the skin on the palm of the hand, causing bending of fingers. Plantar fibromatosis is the same problem occurring on the soles of the feet.
In the palms of our hands and the soles of our feet, there are strips of fibrous tissue called fascia (the palmar fascia and plantar fascia, respectively), which are usually soft and pliable. For people having palmar fibromatosis, this tissue becomes thickened and contracted, causing tight cords or nodules under the skin and resulting progressive bending of the fingers. The process starts usually at the crease on the palm of the hand, and progresses to involve the joint at the base of the finger, then the next joint of the same finger. A small, painless nodule develops in the connective tissue and eventually develops into a cord-like band. Extension of the fingers becomes difficult to impossible with advanced cases. The fingers are relentlessly drawn inward into a rigid fist. As flexibility goes away, so does the useful functions of the hand. It has been found clinically that the ring finger is affected most-often followed by the little, middle, and index fingers. The condition can appear suddenly, but usually it is a slow, progressive process.
Dupuytren's contracture is common. It occurs most commonly in men over 45 years of age. The incidence is higher among people who are alcoholics, and people with diabetes, epilepsy, and pulmonary disease such as emphysema or chronic bronchitis.
In plantar fibromatosis, this same relentless contracture happens in the soles of the feet, drawing the toes downward, folding the feet into a frozen fist, and making it impossible to walk. Plantar fibromatosis is much less common, but patients suffer a severe pain because structural distortions of the feet affects walking. Presently, most plantar fibromatosis patients are constrained to the wheelchairs because of the structural distortion of their feet.
The cause of palmar and plantar fibromatosis is unknown, but genetic predisposition appears to play a role. It is commonly seen that the diseases pass on in a family from generation to generation. Palmar fibromatosis was first described by Baron Guillaume Dupuytren, French surgeon of the early 1800's who was successful with the surgical treatment of this condition, and hence named after him as Dupuytren's contracture. By carefully cutting the involved fascia, Dupuytren was able to achieve good results, for a period of time. However what had caused the fascia to grow abnormally before, caused the regrowing fascia to eventually contracture and thicken again. Therefore, for over 100 years the condition was thought to be relentlessly progressive.
Current treatment involves observation at first when the process is in the early stages. Exercises, warm water baths, or splints may be helpful. Injection of a corticosteroid medication into the nodule may help the tenderness and delay the progression of the diseases. Currently, surgery is essentially the only treatment for the disease, because surgery divides the cords and removes scar tissue, which allows the fingers to straighten. Surgery is usually recommended when the contracture is significant, for example, for patient of palmar fibromatosis when the hand cannot be placed flat on a table. However, reoccurrence of the diseases after surgery is frequent. It is also believed that surgery accelerates the reoccurrence, and worsening of the condition. Additionally, the small nerves and blood vessels to the fingers are at risk of injury during surgery. Other problems with surgery include bleeding under the skin. As well as infection is possible after any surgical operation.
Because of the lack of effective treatment for palmar and plantar fibromatosis, and the disabling nature of the disease, there are active research projects seeking for solutions for treating the disease. In one recent approach, physicians can differentiate between normal fascia and abnormal fascia which maybe normal-appearing by means of electron microscopy and DNA analysis. By carefully removing all of the involved plantar fascia with a wide margin of normal fascia, surgeons at Brown University have achieved excellent results in treating plantar fibromatosis (Plastic and Reconstructive Surgery, Feb. 1989). However, this surgery is technically very difficult.
Another recent development in the treatment of Dupuytren's contracture is the continuous elongation technique, pioneered by Doctors Messina and Messina of Turi, Italy, which appears to enhance both short- and long-term results (Plastic and Reconstructive Surgery, July 1993). With this method, a device is affixed to a bone in the hand or foot to provide a steady, painless stretching of the contracting fascia. This preparatory step is used in severe Dupuytren's contracture before excision of the affected fascia (Journal of Hand Surgery, June 1996). The nonsurgical treatments, radiotherapy and injections of superoxide dismutase, have now been shown not to work.
Currently, no systemic medication is known that can treat palmar and plantar fibromatosis.
13-cis retinoic acid, more generally known as retinoic acid, also referred to as isotretinoin, and sold under the trademark Accutane® from Hoffmann-La Roche Inc., Nutley, New Jersey, has long been known as a topical and oral dermatological agent used in the treatment of acne vulgaris and several other skin diseases. 13-cis retinoic acid inhibits sebaceous gland function and keratinization. The exact mechanism of action of Accutane in treating acne is unknown. Since retinoic acid is a teratogenic drug and, because of the mutagenic effects associated with such drugs, it is only used for treating severe acne vulgaris when other treatments are not effective.
Since 1992 there have been literature reports on the potential effect of 13-cis-retinoic acid upon human prostate cancer cells. U.S. Pat. No. 5,612,354 (to Sanz et al) discloses a method of treating mammals suffering from disorders which are characterized by an increased proliferation or abnormal differentiation of cells by the systemic or topical administration to the mammals of an effective amount of (1H-azol-1-ylmethyl) substituted quinoline derivatives, including 13-cis-retinoic acid. It is believed that because of the capability to delay the metabolism of retinoic acid, (1H-azol-1-ylmethyl) substituted quinoline derivatives may potentially be used in treating cancers.
As described above, it is apparent that there is a strong need for medications that can effectively treat palmar and plantar fibromatosis. Because of complete lack of non-surgical treatments, and frequently recurrence of the diseases after surgeries, a medication that can cure the disease or inhibit further progress of the contracture will have important clinical significance for millions of people who suffer from palmar and plantar fibromatosis.
SUMMARY OF THE INVENTION
In one embodiment, the present invention relates to a method of treating palmar and plantar fibromatosis, which comprises administering to a patient of a therapeutically effective amount of a composition comprising 13-cis-retinoic acid. The composition further comprises a pharmaceutical carrier, and the composition can be in the forms of powder, pill, capsule, tablet, and liquid. Preferably, the method of treating palmar and plantar fibromatosis comprises the steps of: administering to a patient of an initial dosage of a composition comprising 13-cis-retinoic acid for an initial treatment period; and thereafter administering a maintenance dosage of the 13-cis-retinoic acid composition.
In a further embodiment, the present invention relates to a method of trea
Krass Frederick
Li Yi
Ostrup Clinton
Silverman Melvin K.
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