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Title:  Method of treating palmar and plantar fibromatosis

United States Patent:  6,710,083

Issued:  March 23, 2004

Inventors:  Parks; L. Dean (2420 SE. 15th St., Ocala, FL 34471)

Appl. No.:  191253

Filed:  July 9, 2002

Abstract

A method of treating palmar and plantar fibromatosis is disclosed. The method includes administering to a patient of a therapeutically effective amount of a composition comprising 13-cis-retinoic acid. Preferably, the treatment method includes 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 composition.

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 treating palmar and plantar fibromatosis, which combines a surgical procedure and administration of a therapeutically effective amount of composition comprising 13-cis-retinoic acid.

It is accordingly an object of the present invention to provide a medicine for treating palmar and plantar fibromatosis and related symptoms.

It is further object to provide a non-surgical method for treating palmar and plantar fibromatosis.

The above and yet other objects and advantages of the present invention will become apparent from the hereinafter set forth Detailed Description of the Invention and claims appended herewith.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the method of the present invention is directed to a method of treating palmar and plantar fibromatosis. The method comprises administering to a patient of a therapeutically effective amount of a composition comprising 13-cis-retinoic acid. The therapeutically effective amount is in a range from about 10 mg to about 80 mg of 13-cis-retinoic acid of an average daily intake (about 0.14 mg to about 1.1 mg per kilogram (kg) of body weight).

The composition further comprises a pharmaceutical carrier. Common pharmaceutical carriers include liquid carriers such as water, glycols, oils, alcohols, syrups, and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solution; and solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets; and other pharmaceutical carriers known in the art. The composition used for the purpose of the present invention can be in various forms, such as powders, pills, capsules, tablets, and liquids. Although oral administration is preferred because of its convenience, other suitable systemic administrations can also be used for the purpose of the present invention.

13-cis-retinoic acid is commercially available as a medicine under the trade name Accutane.RTM. from Hoffmann-La Roche Inc., Nutley, N.J. for treating certain dermatological diseases. Accutane.RTM. has three available doses, 10 mg, 20 mg, and 40 mg soft gelatin capsules.

Preferably, the treatment method further includes two treatment periods: an initial treatment, and a maintenance treatment. First, in the initial treatment a patient administrates an initial dosage of 13-cis-retinoic acid for a period from about ten days to about five months. Thereafter, the patient administrates a lower maintenance dosage of 13-cis-retinoic acid.

Preferably, the initial treatment period is about two to three weeks, because beyond two to three weeks side effects of the medicine, such as tenderness at sites of old injuries to the fibro-musculo-skeletal system, dry skin, chapped lips, dry eyes, and dry nose, tend to occur. If these side effects occur during the initial treatment period, they normally subside after the maintenance dosage is instituted. However, if a patient does not have adverse side effects, the initial treatment period can be extended accordingly to enhance the effect of the medication on the fibromatosis. Based on the fact that currently 13-cis-retinoic acid is used to treat severe acne patients for a continuous period of 20 weeks, the initial treatment period of the present invention can be substantially longer than several weeks depending on the responses and conditions of individual patients.

The low maintenance dosage has two functions. First, the treatment with the maintenance dosage, after the initial treatment, needs about eight to twelve months to eliminate or reduce already formed contracture, and to inhibit further progress of existing contracture for the patient who has severe conditions. Secondly, a long term administration of the maintenance dosage can prevent reoccurrence of contracture when it diminished with the treatment, and inhibit further progress of existing contracture. Therefore, preferably, the maintenance dosage is administered for long term.

The dosage is determined based on the patient's body weight. The initial dosage is in a range from about 10 mg to 80 mg 13-cis-retinoic acid daily (about 0.14 mg to about 1.1 mg per kilogram (kg) of body weight). For average men having a body weight about 160 lbs (72.6 kg), the average initial dosage is about 40 mg daily. The maintenance dosage is in a range from about 10 mg to 80 mg 13-cis-retinoic acid every three to seven days (about 0.14 mg to about 1.1 mg per kilogram (kg) of body weight). The average maintenance dosage for average men having a body weight about 160 lbs is about 40 mg every three to seven days. It is known that some children have been diagnosed with palmar and/or plantar fibromatosis. The dosages should be adjusted accordingly for children or those who weigh substantially less than or above the average body weight.

The daily dosage can be administrated in a single dose, or divided doses. Since Accutane.RTM. has three commercially available doses, 10 mg, 20 mg, and 40 mg soft gelatin capsules, for a 40 mg initially dosage, the patient can either take a 40 mg capsule, or take two 20 mg capsules daily, or take four 10 mg capsule daily. The same applies to the dosage in the maintenance treatment. For convenience, during the maintenance treatment the patients can take one 40 mg dose about every three to seven days.

It has been found that with the treatment using the method of the present invention the patients who were diagnosed with Dupytren's contracture achieved various degrees of improvements of their disease conditions. The observed improvements include reduction of fibrotic band in size and scope, softening or complete disappearance of fibrotic band of the affected fingers; reduction or disappearance of dimple overhead; recovery or improvement of the flexibility of the affected fingers; and reduction of pain and tenderness caused by the contracture. Furthermore, no serious adverse side effects were observed by using the described treatment.

Importantly, it has been found that the method of the present invention inhibits further progression of the contracture for patients who has either early stage of the disease, or advanced conditions. Therefore, the method of the present invention has an important clinical value in treating early stage of Dupytren's contracture to prevent progression of the disease into a disabling condition. In view of the disabling nature of this disease, and lack of prevention and non-surgical treatment, the discovery of the present invention is a significant breakthrough in terms of advancement of clinical treatment of palmar and plantar fibromatosis.

In a further embodiment, the method of the present invention can be used as an adjuvant to surgical procedures. A surgical procedure, conventional or newly developed procedure, can be utilized to remove the affected fascia, and administration of an effective amount of 13-cis-retinoic acid can be used to prevent or reduce reoccurrence of the disease. 13-cis-retinoic acid can be administered immediately after the surgery, and it can also be administered prior to the surgery to hinder the progression of the contracture.

Example 1 to 3 illustrate clinical effectiveness of the above described treatment method. An initial treatment and a maintenance treatment as described above were prescribed to the patients. It is noted that the patients described in the Examples were in the average weight range, therefore, an average dosage of 40 mg was used.

EXAMPLE 1

A white male patient was diagnosed of palmar fibromatosis on both hands. The patient's left hand middle finger was about 15 degree displaced in the flexed position, and his right hand middle finger was about 7 degree displaced in the flexed position, respectively.

The patient was treated with orally administering Accutane.RTM. (Hoffmann-La Roche Inc., Nutley, New Jersey) about 40 mg daily for 14 days. Then the dosage was decreased to a maintenance dosage of 40 mg about twice a week for twelve months.

After twelve month of therapy, the fibrotic band and dimpling overlying the flexor tendon of the middle fingers, bilaterally, softened and diminished in size and scope. On the left hand, the fibrotic band-completely disappeared, and on the right hand, it reduced from 4 mm to 2 mm. The dimple overhead of the third methocarpal bone disappeared on both hands.

Physical examination confirmed that range of "fixed" flexon of the left middle finger changed from 7 degree of flexon to none, leaving a full, normal range of motion, both for flexion and extension. The right middle finger improved from a fixed 15 degree of flexion as compared to the adjacent digits prior to the treatment to only 3 degree of fixed flexion. Furthermore, the patient described that pain and tenderness in the flexor tendon area of his hands completely abated.

No adverse side effects were noted other than drying of lips. Blood chemistries remained normal with the low maintenance dosage.

EXAMPLE 2

A 63 year old white male patient presented with history of long standing Dupytren's contracture of the left palm, with advanced disease conditions. The patient previously had a plastic repair and a "Z" plasty (a plastic surgery technique used for reducing scars and soft tissue contracture), but both treatments failed to improve or control his condition. His ring finger was about 90 degree displaced in the flexed position.

The patient was treated with orally administering Accutane.RTM. about 40 mg daily for 14 days. Then the dosage was decreased to 40 mg about twice a week for eight months.

During the eight month of therapy, the patient's conditions slowly improved. Physical examination found that the fibrotic ridge of the patient's left hand reduced in scope and size. The patient's ring finger's disposition from the flexed position reduced from about 90 degree to about 70 degree. The patient felt less tender of his left hand caused by the contracture.

The medication was well tolerated with the lower maintenance dosage. The patient had some musculoskelatal pain, which diminished after the third month of the treatment. No laboratory abnormality was observed.

EXAMPLE 3

A 61 year old white male patient presented with recently developed fibroplasia of his right hand. The condition had caused a 30 degree deflection of the right hand ring finger. The overlying skin was hypertrophic and hyperkeratotic from rubbing of his golf club. The Dupuytren's contracture band was thick and rigid, but without pain.

The patient was placed on Accutane.RTM. 40 mg daily for two weeks. Thereafter, the patient had a maintenance dosage of 40 mg about twice a week for nine months.

During the nine month of treatment, the patient achieved slow and steady improvement. The thickness of the fibrotic band reduced, and the restriction of extension of the ring finger lessened. Physical examination showed that the 30 degree deflection of the right hand ring finger prior to the treatment reduced to 20 degree. The patient described less tenderness in the flexor tendon area.

While there has been shown and described the preferred embodiment of the instant invention it is to be appreciated that the invention may be embodied otherwise than is herein specifically shown and described and that, within said embodiment, certain changes may be made in the form and arrangement of the parts without departing from the underlying ideas or principles of this invention as set forth in the claims appended herewith.

Claim 1 of 12 Claims

What is claimed is:

1. A method of treating palmar and plantar fibromatosis comprising administering to a patient suffering from palmar or plantar fibromatosis a therapeutically effective amount of a composition comprising 13-cis-retinoic acid.



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