Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-17
2001-08-21
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S418000, C514S421000
Reexamination Certificate
active
06277875
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the treatment of fibromyalgia using non-ergot dopamine D
2
/D
3
agonists. More specifically, tetrahydro-benzthiazoles, in particular, 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzo-thiazole or the (-)-enantiomers thereof, and certain 3(H)-indolone derivatives, in particular, 4-[2-(dipropylamino)-ethyl]-1,3-dihydro-2H-indol-2-one, and the pharmacologically acceptable salts thereof, alone or in association with a pharmaceutically acceptable carrier, can be used to treat fibromyalgia patients.
BACKGROUND OF THE INVENTION
Fibromyalgia is a common disabling disorder characterized by chronic musculoskeletal aches and pain, stiffness, general fatigue, and sleep abnormalities including diminished stage four sleep. Fibromyalgia is a chronic, painful disorder commonly seen in rheumatology practice and is often viewed as a musculoskeletal pain process. Fibromyalgia is characterized as a reproducible, neurosensory processing abnormality associated with fatigue, and generalized muscular spasm, which most rheumatologists suspect is related to stage IV sleep deprivation. Examination of affected patients reveals increased tenderness at muscle and tendon insertion sites, known as “tender points”. Fibromyalgia patients experience severe morning stiffness and a generalized decreased of overall physical function, and they are often prone to headaches, memory and concentration problems, dizziness, numbness and tingling, and crampy abdominal or pelvic pain. Fibromyalgia affects 2-4% of the population and is most frequently found in women between 20 and 50 years old, though it can also affect men, the elderly and minors.
Diagnosis of fibromyalgia is often overlooked due to the general nature of the symptoms and the lack of diagnostic lab or x-ray abnormalities. The disorder is often concomitant with, masked by or confused with other diseases such as rheumatoid arthritis, chronic fatigue syndrome or irritable bowl syndrome. A physician can positively diagnose fibromyalgia syndrome by finding the symptoms of generalized musculoskeletal pain and pain at more than 11 of 18 defined characteristic “tender points” when finger pressure of about 4 kg is applied to the area. The total pain score for all 18 tender points is referred to as the “tender point index” of that patient. The efficacy of a particular fibromyalgia therapy is demonstrated by a observation of a statistically significant improvement in a patient's tender point index.
The etiology of fibromyalgia is not known but consideration has been given to genetic, traumatic, affective, and infectious processes as possibilities. Currently the best treatment available for fibromyalgia consists of a combination of analgesics, sleep aids, exercise programs emphasizing stretching and cardiovascular fitness, relaxation techniques and other measures to reduce muscle tension, and educational and psychological support programs to reduce emotional and physical stress; the resulting benefits are usually disappointing. Numerous pharmaceutical regimes have been tried including treatment with serotonin modulators and antisera to endogenous psychoactive agents. Therapeutic response can be assessed by the reduction of pain in the tender point index and improvement in several generalized criteria such as physical function, stiffness, fatigue, depression, tenseness, etc. Responses to these various therapies have proven variable within a patient pool and have rarely exceeded modest relief of some symptoms.
For example, Hitzig (U.S. Pat. No. 5,658,955) discloses the treatment of a broad range of immune disorders, including fibromyalgia, with an effective amount of a serotonin agonist and a dopamine agonist. The preferred dopamine agonist discussed in Hitzig is phentermine which is an adrenergic compound. Further, none of the dopamine agonists cited in Hitzig are non-ergot dopamine receptor D
2
/D
3
agonists. Hitzig also includes no data in support of their statement that fibromyalgia can be treated with a serotonin agonist and a dopamine agonist. Also, fibromyalgia is no longer thought of as an autoimmune disorder, indeed the clinical name associated with the disease was changed from fibrositis to fibromyalgia to specifically remove any connotation of an immune or inflammatory condition.
Cincotta et al. (U.S. Pat. Nos. 5,905,083, 5,872,133, 5,872,127, and 5,696,128) also discloses the use of a serotonin agonist and a dopamine agonist at particular times of the day to treat a wide variety of immune disorders. More specifically they suggest that a variety of immune disorders can be treated by providing patients with an amount of the serotonin and dopamine agonists sufficient to adjust the prolactin profile of the patient. The Cincotta et al. patents list fibromyalgia as one of the many immune disorders that can be treated by prolactin management. However, other clinical studies have not validated the association between prolactin and fibromyalgia (Alder et al.,
Am. J. Med
. 106:534-543 (1999); Griep et al., J. Rheumatol. 21:2125-2130 (1994)).
U.S. Patent Serial No. 6,036,949 discloses that low doses of interferon can be used to treat fibromyalgia. However, the clinical study disclosed in the patent showed only a modest improvement in the severity of morning stiffness, one of the secondary symptoms of fibromyalgia. The pressure point pain index for fibromyalgia patients receiving interferon did not show any statistically significant improvement relative to a placebo group.
In the past, there was a tendency to view fibromyalgia as a benign disorder which did not justify aggressive therapy which might carry with it any risk of adverse experience. However, that philosophy can no longer be justified considering the impact of this condition on the quality of life of affected individuals. Considering that the annual direct cost of fibromyalgia to the United States economy is estimated at $16 billion, there exists a significant need for more effective therapy for patients afflicted with fibromyalgia.
The tetrahydro-benzthiazoles useful in the present invention, are dopamine-D
2
/D
3
agonists the syntheses of which are described in European Patent 186 087 and its counterparts, U.S. Pat. Nos. 4,843,086 and 4,886,812. These compounds are known primarily for the treatment of schizophrenia and Parkinson's disease. It is known from German patent application DE 38 43 227 that 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzo-thiazole (pramipexole) can be used in the treatment of drug dependency. Further, it is known from German patent application DE 39 33 738 that pramipexole can be used to decrease abnormal high levels of thyroid stimulating hormone (TSH). U.S. Pat. No. 5,112,842 discloses the transdermal administration of the compounds and transdermal systems containing these active compounds. The WO patent application PCT/EP 93/03389 describes pramipexole as an antidepressant agent, while U.S. Pat. No. 5,650,420 discloses the neuroprotective effects of pramipexole. U.S. Pat. No. 6,001,861 discloses the use of pramipexole in the treatment of restless legs syndrome.
Similarly, the indolone compounds, useful in the present invention, are also dopamine receptor D
2
/D
3
agonists, the syntheses of which are described in U.S. Pat. No. 4,452,808. U.S. Pat Nos. 4,912,126 and 4,824,860 further disclose that these indolone compounds, in particular, 4-[2-(dipropylamino)-ethyl]-1,3-dihydro-2H-indol-2-one, can be used to treat Parkinson's disease.
Dopamine receptor D
2
/D
3
agonists have been reported as not being capable of producing the central behavioral effects often seen with other classes of dopamine agonists (see Gallagher et al.,
J. Med. Chem
. 28:1533-1536 (1985)). Furthermore, it has been reported that D
2
/D
3
agonists show minimal liability to cause dyskinesia. Dyskinesia is a common problem associated with postsynaptic dopamine agonists, for example ergo alkaloids such as bromocriptine.
The present invention is directed to a method for treating the disease condition (as measu
Christensen O'Connor Johnson & Kindness PLLC
Fay Zohreh
Kwon Brian-Yong
LandOfFree
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