Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2000-08-02
2002-01-15
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C424S045000
Reexamination Certificate
active
06339107
ABSTRACT:
1. FIELD OF THE INVENTION
The invention relates to methods of treating emphysema with 13-cis-retinoic acid, pharmaceutical compositions of 13-cis-retinoic acid useful in the treatment of emphysema and methods for delivering formulations of 13-cis-retinoic acid to the lung of a mammal suffering from emphysema.
2. BACKGROUND OF THE INVENTION
2.1. 13-CIS-Retinoic Acid
Chemically, 13-cis-retinoic acid is (13Z)-retinoic acid and has the following structure:
13-cis-retinoic acid is also known as isotretinoin, AGN 190013, Neovitamin A acid, Ro-4-3780, 13-cis-&bgr;-Retinoic acid and 13-cis-Vitamin A acid. 13-cis-retinoic acid is sold under the tradenames Accutane®, Roaccutan® and Roaccutane® for the treatment of severe recalcitrant nodular acne (
Physicians'Desk Reference
54
th
Ed., p. 2610, 2000; Peck et al.,
N. Eng. J Med.;
Peck et al., U.S. Pat. No. 5,698,593). 13-cis-Retinoic acid has also been reported to be effective in treating psychotic illnesses such as schizophrenia (Straw, U.S. Pat. No. 4,808,630) and cancer of head, neck and lung (Tomas et al.,
Annals of Oncology,
1999, 10, 95; Benner et al.,
Seminars in Hematology,
1994, 31, 26). 13-cis -Retinoic acid is currently in clinical trials for treatment of these forms of cancer at a number of locations (e.g., University of Texas SW Medical Center, Dallas Tex.; University of Texas MD Anderson Cancer Center, Houston, Tex.; Department of Veteran Affairs Medical Center, Temple, Tex.).
13-cis-retinoic acid is a member of the retinoid class of compounds which are structural analogues of vitamin A and include both natural and synthetic compounds. Naturally occurring retinoid compounds such as all trans retinoic acid (“ATRA”), 9-cis -retinoic acid, trans 3-4 didehydroretinoic acid, 4-oxo retinoic acid and retinol are pleiotrophic regulatory compounds that influence a large number of inflammatory, immune and structural cells.
For example, retinoids modulate epithelial cell proliferation, morphogenesis in lung and differentiation through a series of nuclear receptors that belong to the steroid/thyroid receptor superfamily. In tissues other than pulmonary tissues, retinoids typically have anti-inflammatory effects, can alter the progression of epithelial cell differentiation and may inhibit stromal cell matrix production. These biological effects of retinoids have led to the development of many topical agents for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other medicinal applications of retinoids include the control of acute promyelocytic leukemia, adeno and squamous cell carcinoma and hepatic fibrosis. However, retinoids often lack selectivity and consequently exert harmful pleiotrophic effects when used in therapeutically effective amounts, which may cause patient death. Thus, the therapeutic use of retinoids in diseases other then cancer has been limited by toxic side effects. A general review of retinoids can be found in Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, 9
th
edition (1996, McGraw-Hill) Chapters 63-64.
2.2. Emphysema
Chronic Obstructive Pulmonary Disease (“COPD”) refers to a large group of lung diseases which prevent normal respiration. Approximately 11% of the population of the United States has COPD and available data suggests that the incidence of COPD is increasing. Currently, COPD is the fourth leading cause of mortality in the United States.
COPD is a disease in which the lungs are obstructed due to the presence of at least one disease selected from asthma, emphysema and chronic bronchitis. The term COPD was introduced because these conditions often co-exist and in individual cases it may be difficult to ascertain which disease is responsible for causing the lung obstruction (1987
Merck Manual
). Clinically, COPD is diagnosed by reduced expiratory flow from the lungs that is constant over several months and in the case of chronic bronchitis persists for two or more consecutive years. The most severe manifestations of COPD typically include symptoms characteristic of emphysema.
Emphysema is a disease where the gas-exchange structures (e.g., alveoli) of the lung are destroyed, which causes inadequate oxygenation that may lead to disability and death. Anatomically, emphysema is defined by permanent airspace enlargement distal to terminal bronchioles (e.g., breathing tubes) which is characterized by reduced lung elasticity, decreased alveolar surface area and gas exchange and alveolar destruction that results in decreased respiration. Thus, the characteristic physiological abnormalities of emphysema are reduced gas exchange and expiratory gas flow.
Cigarette smoking is the most common cause of emphysema although other environmental toxins may also contribute to alveoli destruction. The injurious compounds present in these harmful agents can activate destructive processes that include, for example, the release of excessive amounts of proteases that overwhelm normal protective mechanisms, such as protease inhibitors present in the lung. The imbalance between proteases and protease inhibitors present in the lung may lead to elastin matrix destruction, elastic recoil loss, tissue damage, and continuous lung function decline. The rate of lung damage may be decreased by reducing the amounts of toxins in the lung (i.e., by quitting smoking). However, the damaged alveolar structures are not repaired and lung function is not regained. At least four different types of emphysema have been described according to their locations in the secondary lobule: panlobar emphysema, centrilobular emphysema, distal lobular emphysema and paracicatrical emphysema.
The major symptom of emphysema is chronic shortness of breath. Other important symptoms of emphysema include but are not limited to chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity and wheezing. Additional symptoms that may be associated with emphysema include but are not limited to vision abnormalities, dizziness, temporary cessation of respiration, anxiety, swelling, fatigue, insomnia and memory loss. Emphysema is typically diagnosed by a physical examination that shows decreased and abnormal breathing sounds, wheezing and prolonged exhalation. Pulmonary function tests, reduced oxygen levels in the blood and a chest X-ray may be used to confirm a diagnosis of emphysema.
No effective methods for reversing the clinical indications of emphysema currently exist in the art. In some instances, medications such as bronchodilators, &bgr;-agonists, theophylline, anticholinergics, diuretics and corticosteroids delivered to the lung by an inhaler or nebulizer may improve respiration impaired by emphysema. Oxygen treatment is frequently used in situations where lung function has been so severely impaired that sufficient oxygen cannot be absorbed from the air. Lung reduction surgery may be used to treat patients with severe emphysema. Here, damaged portions of the lung are removed, which allows the normal portions of the lung to expand more fully and benefit from increased aeration. Finally, lung transplantation is another surgical alternative available to individuals with emphysema, which may increase quality of life but does not significantly improve life expectancy.
2.3. Lung Development, Alveolar Septation and Use of Atra in Treating Emphysema
Alveoli are formed during development by division of sacchules that constitute the gas-exchange elements of the immature lung. The precise mechanisms governing formation of septa and their spacing remain currently unknown in primates. Retinoids such as ATRA, which is a multifunctional modulator of cellular behavior that may alter both extracellular matrix metabolism and normal epithelial differentiation, have a critical regulatory role in mammals such as the rat. For example, ATRA modulates critical aspects of lung differentiation through binding to specific retinoic acid receptors that are selectively temporally and spatially expressed. Coordinated activation of different retinoic acid receptors subtypes has b
Bawa Raj
Pennie & Edmonds LLP
Peries Rohan
Syntex (U.S.A.) LLC
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