Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-01-20
2003-12-30
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S688000
Reexamination Certificate
active
06670349
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention concerns itself with a method of treating adenosine depletion by the administration of folinic acid or a pharmaceutically acceptable salt thereof. This invention further concerns itself with a method of treating asthma by administering dehydroepiandrosterone, analogs thereof, or their pharmaceutically acceptable salts.
2. Description of the Background
Adenosine is a purine which contributes to intermediary metabolism and participates in the regulation of physiological activity in a variety of mammalian tissues. Adenosine participates in many local regulatory mechanisms, such as those occuring in synapses in the central nervous system (CNS) and at neuroeffector junctions in the peripheral nervous system. In the CNS, inhibits the release of a variety of neurotransmitters, such as acetylcholine, noradrenaline, dopamine, serotonin, glutamate, and GABA; depresses neurotransmission; reduces neuronal firing to induce spinal analgesia and possesses anxiolytic properties. See A. Pelleg and R. Porter,
Pharmacotherapy
10(2), 157 (1990); J. Daval, et al.,
Life Sciences
49:1435 (1991). In the heart, adenosine suppresses pacemaker activity, slows AV conduction, possesses antiarrhythmic and arrhythmogenic effects, modulates autonomic control and triggers the synthesis and release of prostaglandins. See K. Mullane and M. William,
In addition adenosine and Adenosine receptors
p. 289 (M. Williams, ed. Humana Press, 1990). Adenosine has potent vasodilatory effects and modulates vascular tone. See A Deuseen et al.,
J. Pflugers Arch.
406: 608 (1986). Adenosine is currently being used clinically for the treatment of superventricular tachycardia and other cardiac anomalies. See C. Chronister,
American Journal of Critical Care
2(1): 41-47 (1993). Adenosine analogues are being also investigated for use as anticonvulsant, anxiolytic and neuroprotective agents. See M. Higgins et al.,
Pharmacy World
&
Science
16(2): 62-68 (1994).
Adenosine has also been implicated as a primary determinant underlying the symptoms of bronchial asthma. It induces bronchoconstriction and the contraction of airway smooth muscle. See J. Thorne and K. Broadley,
American Journal of Respiratory
&
Critical Care Medicine
149(2 pt. 1): 392-399 (1994); S. Ali et al.,
Agents
&
Actions
37(3-4): 165-167 (1992). Adenosine causes bronchoconstriction in asthmatics but not in non-asthmatics. See Bjorck et al.,
American Review of Respiratory Disease
145(5): 1087-1091 (1992); S. Holgate et al.,
Annals of the New York Academy of Sciences
629: 227-236 (1991).
In view of the foregoing, it is readily apparent that (i) adenosine depletion may lead to a broad variety of deleterious conditions, and that methods of treating adenosine depletion may be an extremely useful means of therapeutic intervention; and (ii) methods of inducing adenosine depletion may also be useful in treating conditions such as asthma.
Folinic acid is an intermediate product of the metabolism of folic acid; the active form into which that acid is converted in the body. Ascorbic acid is required as a necessary factor in the conversion process. Folinic acid has been used therapeutically as an antidote to folic acid antagonists such as methotrexate which block the conversion of folic acid into folinic acid. Additionally, folinic acid has been used as an anti-anemic (combating folate deficiency). See The Merck Index, Monograph No. 4141 (11th Ed. 1989). The use of folinic acid in patients afflicted with adenosine depletion, or in a method to therapeutically elevate adenosine levels in the brain or other organ, has heretofor neither been suggested nor described.
SUMMARY OF THE INVENTION
The present invention is a method of treating adenosine depletion in a subject in need of such treatment which comprises administering to the subject folinic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat the adenosine depletion. The method may be applied to subjects afflicted with steroid-induced adenosine depletion, subjects afflicted with anxiety, subjects afflicted with a wasting disorder, or subjects afflicted with any other disorder attributable to adenosine depletion, or where an increase in adenosine levels would be therapeutically beneficial.
The present invention also relates to the use of folinic acid or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating adenosine depletion in a subject in need of such treatment, as set forth above.
The present invention, moreover, relates to method of treating asthma in a subject in need of such treatment by administering to the subject dehydroepiandrosterone, an analog thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to treat asthma.
The present invention also relates to use of dehydroepiandrosterone, an analog thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating asthma.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The method of treating adenosine depletion disclosed herein may be used to treat steroid-induced adenosine depletion; to stimulate adenosine synthesis and thereby treat or control anxiety (e.g., in treating premenstrual syndrome); to increase weight gain or treat wasting disorders; and to treat other adenosine-related pathologies by administering folinic acid. Thus, the term “adenosine depletion” is intended to encompass both conditions where adenosine levels are depleted in the subject as compared to previous adenosine levels in that subject, and conditions where adenosine levels are essentially the same as previous adenosine levels in that subject but, because of some other condition or alteration in that patient, a therapeutic benefit would be achieved in the patient by increased adenosine levels as compared to previous levels. Preferably, the method is carried out on patients where adenosine levels are depleted as compared to previous adenosine levels in that subject. The present invention is concerned primarily with the treatment of human subjects but may also be employed for the treatment of other mammalian subjects, such as dogs and cats, for veterinary purposes.
Folinic acid and the pharmaceutically acceptable salts thereof (hereafter sometimes referred to as “active compounds”) are known, and can be made in accordance with known procedures. See generally The Merck Index, Monograph No. 4141 (11th Ed. 1989); U.S. Pat. No. 2,741,608.
Pharmaceutically acceptable salts should be both pharmacologically and pharmaceutically acceptable. Such pharmacologically and pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts, of the carboxylic acid group of Folinic acid. The calcium salt of folinic acid is a preferred pharmaceutically acceptable salt.
The active compounds are preferably administered to the subject as a pharmaceutical composition. Pharmaceutical compositions for use in the present invention include those suitable for inhalation, oral, topical, (including buccal, sublingual, dermal and intraocular) parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular) and transdermal administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art.
Compositions suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such compositions may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier. In general, the compositions of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrie
East Carolina University
Halluin Albert P.
Hui San-ming
Padmanabhan Sreeni
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