Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
1999-07-30
2001-08-21
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
Reexamination Certificate
active
06277890
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of emphysema using retinoic acid, their esters and analogues thereof.
BACKGROUND OF THE INVENTION
Pulmonary emphysema is a common disease in which destruction of the lung's gas-exchange structures (alveoli) leads to inadequate oxygenation, disability and, frequently, death. Lung transplantation has previously provided the only means of remediation.
Alveoli are formed by the developmentally regulated subdivision of saccules that constitute the gas-exchange region of the immature lung. The molecular signals responsible for the formation of septa and for their spacing are poorly understood. However, in the rat retinoids may play a key regulatory role. Fibroblasts rich in vitamin A (retinol) storage granules occupy a large fraction of the alveolar wall when septa are being formed. During the same period, the concentration of cellular-retinol binding protein I, cellular retinoic acid-binding Protein I, and nuclear retinoic acid receptor-&tgr; mRNA peak in the lung. Treatment with dexamethasone, a glucocorticosteroid hormone, prevents septation in a seemingly irrevocable fashion, and diminishes the expression in the lung of cellular retinol-binding protein and retinoic acid receptors-&bgr; mRNA.
The use of all-trans retinoic acid for treatment of diseases relating to growth and tissue maintenance has previously been known. Retinoic acid receptors belong to a family of nuclear receptors that includes receptors for steroids, thyroid hormone, and calcitriol. It has previously been disclosed that retinoic acid prevents inhibition of alveoli in rats arising from exposure to dexamethasone. (
Am. J. Physiol.
270: L305-L310 (1996)). There is no teaching therein regarding use of retinoic acid for treatment of emphysema.
U.S. Pat. No. 3,171,781 teaches use of vitamin A and guaiacol for treatment of contagious “air sac disease” in fowl. It is not clear what the pathology or nature of the infectious agent of the disease condition might have been. There is no teaching therein regarding retinoic acid or treatment of emphysema.
U.S. Pat. No. 4,606,920 teaches use of vitamins A and C for treatment of inflammatory changes in the bronchial mucosa. There is no teaching seen therein regarding treatment of diseases involving the alveoli.
U.S. Pat. No. 5,534,261, which is incorporated herein in its entirety as though fully copied herein, teaches use of retinoic acid to prevent formation of adhesion between organ surfaces in body cavities, especially in the peritoneal cavity. No teaching of use for treatment of emphysema is seen therein.
U.S. Pat. No. 5,556,611, which is incorporated herein in its entirety as though fully copied herein, teaches use of retinoic acid and esters thereof in the form of aerosols for treatment of mucosal diseases. Diseases to be treated by use of such aerosols include bronchial carcinoma, acute and chronic bronchitis, acute and chronic functional disturbances due to impairment of the trachealbronchial epithelium following inhalation of dusts and gases, bronchopulmonary dysplasia of newborns and carthagena syndrome. There is no suggestion therein that retinoic acid, its esters or analogues thereof can be administered for treatment of emphysema, which arises from destruction of the lung alveoli.
DESCRIPTION OF THE INVENTION
This invention relates to the use of retinoic acid, its esters and analogues thereof for treatment of emphysema. Retinoic acid and its analogues are lipophilic compounds and may be administered by any means known in the art for systemic administration of lipophilic medicinals, including oral and parenteral administration. The method comprises administration of a composition containing an alveoli formation-inducing effective amount of a retinoic acid, its esters and analogues of retinoic acid.
Materials and Methods
Production of emphysema and treatment with all-trans retinoic acid. Porcine pancreas elastase (2.0 units.g
−1
body mass) or an equal volume of saline was instilled into the trachea of anesthetized adult male Sprague-Dawley rats, which were killed 25 days later. Other rats were treated with saline or elastase as just described and used twenty-five days later to form three groups. Rats initially treated with saline (Group 1), and some rats initially treated with elastase (Group 2), were begun on daily intraperitoneal injections of cottonseed oil containing all-trans retinoic acid. Other rats initially treated with elastase were begun on daily intraperitoneal injections of all-trans retinoic acid (500 &mgr;g.kg
−1
) dissolved in cottonseed oil (Group 3). Rats were treated daily for 12 days and killed on day 13.
Fixation, tissue sampling, and tissue preparation. Rats were anesthetized with xylazine (~10 mg.kg
−1
) and ketamine (~75 mg.kg
−1
) and killed by cutting the abdominal aorta. Cold 2.5% glutaraldehyde in 0.1 M sodium cacodylate, pH 7.4, was infused into the trachea at a transpulmonary pressure of 20 cm H
2
O. The trachea was ligated, lungs were removed from the thorax, and fixation was continued for 2 h at 0-4° C. Lung volume was measured by volume displacement. Lungs were cut into blocks; blocks were selected for study using a systematic sampling technique. Selected blocks were processed further; we corrected for linear shrinkage and volume changes that occur during postfixation, dehydration, and embedding.
Alveolar airspace was distinguished from alveolar duct airspace by analysis of serially sectioned lung. The selector method, which allows structures to be selected for analysis based on number rather than on size, shape, or orientation, was used to choose alveoli for analysis. The volume of an alveolus was estimated by the point-sampled intercepts method (for references)
5
. The volume of an individual alveolus was calculated as previously described. The number of alveoli per lung was calculated using the identity
N
=
V
L
×
V
v
a
v
_
a
,
Where VL is lung volume (measured by water displacement), Vva is the volume density of alveolar airspace, and {overscore (v)}a is the mean alveolar volume. Vva and Sa of the gas-exchange region were determined by point and intersection counting.
Statistical Methods. For each parameter measured or calculated from measurements, values for individual animals were averaged per experimental group, and the SE was calculated. The significance of the difference between two groups was obtained using the Mann-Whitney test. The Kruskal-Wallis test was used when more than two groups were compared and the Mann-Whitney test was then used to compare two populations at a time; the Bon-ferroni adjustment was used to adjust the significance level to the number of tests performed.
Results
Treatment with retinoic acid reversed the anatomical characteristics and increased lung volume of elastase-induced emphysema in rats.
In rats killed 25 days after the intratracheal instillation of 0.15 M NaCl (saline) the distance between alveolar walls (Lm) was 71±1.9 &mgr;m and alveolar surface area (Sa) 4952±259 cm
2
(mean ±SE, N=3). Twenty-five days after the instillation of elastase (N=5) Lm was 93±7 &mgr;m and Sa 3992±118 cm
2
(P<0.03 between groups for the same parameter). The larger Lm and smaller Sa in elastase-treated rats indicate their lungs were emphysematous. Emphysema produced by elastase becomes progressively worse for 1-2 months without spontaneous recovery.
Lung volume was 18% greater in emphysematous rats treated with cottonseed oil, the diluent for RA, (elastase-oil rats) than in rats given saline followed by cottonseed oil (saline-oil rats) or in rats given elastase then RA (elastase-RA rats) (Table 1). Because body mass was the same in all groups (Table 1), and lung volume is proportional to body mass, the larger lungs of elastase-oil rats reflect diminished elastic recoil, a characteristic feature of experimental and human emphysema, rather than lung growth. This effect of elastase on lung volume was completely revers
Massaro Donald
Massaro Gloria
Georgetown University School of Medicine
Nixon & Peabody LLP
Spivack Phyllis G.
LandOfFree
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