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Liquid inhalation formulations of dehydroepiandrosterone derivatives

Liquid inhalation formulations of dehydroepiandrosterone derivatives description/claims

This application is a continuation application of Ser. No. 10/072,010 filed Oct. 25, 2001, which is a divisional patent application of Ser. No. 09/841,426, filed Apr. 24, 2001, now abandoned, which is a continuation-in-part of Ser. No. 09/488,236, filed Jan. 20, 2000, now U.S. Pat. No. 6,670,349, which is a divisional of Ser. No 08/861,962, filed May 22, 1977, now U.S. Pat. No. 6,087,351, which is a divisional of Ser. No 08/393,863, filed Feb. 24, 1995, U.S. Pat. No. 5,660,835, all incorporated herein by reference in their entirety.

The work leading to this invention was made at least in part with U.S. Government support under National Cancer Institute Grant No. CA7217. The U.S. Government may have certain rights in the invention.

1. Field of the Invention

This invention concerns itself with a method of treating bronchoconstriction, lung inflammation and allergies, asthma, and cancer by administering an epiandrosterone, analogs thereof, a ubiquinone, and/or their pharmaceutically acceptable salts. This invention also concerns itself with a method of treating adenosine depletion by administration of folinic acid or a pharmaceutically acceptable salt thereof.

2. Description of the Background

Adenosine is a purine that 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 occurring in synapses in the central nervous system (CNS) and at neuroeffector junctions in the peripheral nervous system. In the CNS, adenosine 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. 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. In addition, adenosine has potent vasodilatory effects and modulates vascular tone. Adenosine is currently being used clinically for the treatment of super ventricular tachycardia and other cardia anomalies. Adenosine analogues also are being investigated for use as anticonvulsant, anxiolytic and neuro protective agents. Adenosine has also been implicated as a primary determinant underlying the symptoms of bronchial asthma and other respiratory diseases, the induction of bronchoconstriction and the contraction of airway smooth muscle. Moreover, adenosine causes bronchoconstriction in asthmatics but not in non-asthmatics. Other experimental data suggest the possibility that adenosine receptors may also be involved in allergic and inflammatory responses. It has been postulated that the modulation of signal transduction at the surface of inflammatory cells influences acute inflammation. Adenosine is said to inhibit the production of super-oxide by stimulated neutrophils. Moreover, the treatment of experimental allergic uveitis produced a marked reduction in inflammation. Adenosine may attenuate this behavior by reducing the hyperactivity of the central dopaminergic system.

Diseases and conditions, such as asthma, are common diseases in industrialized countries, and in the United States alone account for extremely high health care costs. These diseases or conditions have recently been increasing at an alarming rate, both in terms of prevalence, morbidity and mortality. In spite of this, their underlying causes still remain poorly understood.

Dehydroepiandrosterone (DHEA) is a naturally occurring steroid secreted by the adrenal cortex with apparent chemoprotective properties. Epidemiological studies have shown that low endogenous levels of DHEA correlate with increased risk of developing some forms of cancer, such as pre-menopausal breast cancer in women and bladder cancer in both sexes. The ability of DHEA, DHEA analogues and their salts to inhibit carcinogenesis is believed to result from their uncompetitive inhibition of the activity of the enzyme glucose 6-phosphate dehydrogenase (G6PDH). G6PDH is the rate limiting enzyme of the hexose monophosphate pathway, a major source of intracellular ribose-5-phosphate and NADPH. Ribose-5 phosphate is a necessary substrate for the synthesis of both ribo- and deoxyribonucleotides required for the synthesis of RNA and DNA. NADPH is a cofactor also involved in nucleic acid biosynthesis and the synthesis of hydroxmethylglutaryl Coenzyme A reductase (HMG CoA reductase). HMG CoA reductase is an unusual enzyme that requires two moles of NADPH for each mole of product, mevalonate, produced. Thus, it appears that HMG CoA reductase would be ultra sensitive to DHEA-mediated NADPH depletion, and that DHEA-treated cells would rapidly show the depletion of intracellular pools of mevalonate. Mevalonate is required for DNA synthesis, and DHEA arrests human cells in the G1 phase of the cell cycle in a manner closely resembling that of the direct HMG CoA. Because G6PDH produces mevalonic acid used in cellular processes such as protein isoprenylation and the synthesis of dolichol, a precursor for glycoprotein biosynthesis, DHEA inhibits carcinogenesis by depleting mevalonic acid and thereby inhibiting protein isoprenylation and glycoprotein synthesis. Mevalonate is the central precursor for the synthesis of cholesterol, as well as for the synthesis of a variety of non-sterol compounds involved in post-translational modification of proteins such as farnesyl pyrophosphate and geranyl pyrophosphate; for dolichol, which is required for the synthesis of glycoproteins involved in cell-to-cell communication and cell structure; and for ubiquinone, an anti-oxidant with an established role in cellular respiration. It has long been known that patients receiving steroid hormones of adrenocortical origin at pharmacologically appropriate doses show increased incidence of infectious disease.

DHEA, also known as 3β-hydroxyandrost-5-en-17-one or dehydroiso-androsterone, is a 17-ketosteroid which is quantitatively one of the major adrenocortical steroid hormones found in mammals. Although DHEA appears to serve as an intermediary in gonadal steroid synthesis, the primary physiological function of DHEA has not been fully understood. It has been known, however, that levels of this hormone begin to decline in the second decade of life, reaching 5% of the original level in the elderly.) Clinically, DHEA has been used systemically and/or topically for treating patients suffering from psoriasis, gout, hyperlipemia, and it has been administered to post-coronary patients. In mammals, DHEA has been shown to have weight optimizing and anti-carcinogenic effects, and it has been used clinically in Europe in conjunction with estrogen as an agent to reverse menopausal symptoms and also has been used in the treatment of manic depression, schizophrenia, and Alzheimer's disease. DHEA has also been used clinically at 40 mg/kg/day in the treatment of advanced cancer and multiple sclerosis. Mild androgenic effects, hirsutism, and increased libido were the side effects observed. These side effects can be overcome by monitoring the dose and/or by using analogues. The subcutaneous or oral administration of DHEA to improve the host's response to infections is known, as is the use of a patch to deliver DHEA. DHEA is also known as a precursor in a metabolic pathway which ultimately leads to more powerful agents that increase immune response in mammals. That is, DHEA acts as a biphasic compound: it acts as an immuno-modulator when converted to androstenediol or androst-5-ene-3β,17β-diol (βAED), or androstenetriol or androst-5-ene-3β,7β,17β-triol (βAET). However, in vitro DHEA has certain lymphotoxic and suppressive effects on cell proliferation prior to its conversion to βAED and/or βAET. It is, therefore, believed that the superior immunity enhancing properties obtained by administration of DHEA result from its conversion to more active metabolites.

Adequate ubiquinone levels have been found to be essential for maintaining proper cardiac function, and the administration of exogenous ubiquinone has recently been shown to have beneficial effect in patients with chronic heart failure. Ubiquinone depletion has been observed in humans and animals treated with lovastatin, a direct HMG CoA reductase inhibitor. Such lovastatin-induced depletion of ubiquinone has been shown to lead to chronic heart failure, or to a shift from low heart failure into life-threatening high grade heart failure. DHEA, unlike lovastatin, inhibits HMG CoA reductase indirectly by inhibiting G6PDH and depleting NADPH, a required cofactor for HMG CoA reductase. However, DHEA's indirect inhibition of HMG CoA reductase suffices to deplete intracellular mevalonate. This effect adds to the depletion of ubiquinone, and may result in chronic heart failure following long term usage. Thus, although DHEA was once considered a safe drug, it is now predicted that with long term administration of DHEA or its analogues, chronic heart failure may occurs as a complicating side effect. Further, some analogues of DHEA produce this side effect to a greater extent because, in general, they are more potent inhibitors of G6PDH than DHEA.

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). 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 heretofore neither been suggested nor described.

In view of the foregoing, it is readily apparent that (i) methods of inducing adenosine depletion may be useful in treating respiratory and airway conditions such as asthma, surfactant depletion, bronchoconstriction, lung inflammation, and allergies; and (ii) adenosine depletion may lead to a broad variety of deleterious conditions, and that methods of treating adenosine depletion and those conditions may be an extremely useful means of therapeutic intervention.

The population of the U.S. and of the world in general living longer lives, many of these diseases and conditions have become more prevalent given the more advanced age of this segment of the population, and would benefit from new products and preventative and therapeutic treatments. The availability of a novel strategy to prevent and/or treat disorders such as bronchoconstriction, impeded respiration, asthma, and lung inflammation and allergies, among others, is of great practical importance. Such technology is clearly applicable to the treatment of heart, brain, lung, kidney, skin and other conditions, e.g. asthma and cancers such as leukemias, lymphomas, carcinomas, and the like, including colon cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, hepatocellular carcinoma, kidney cancer, melanoma, etc., as well as all types of cancers which may metastasize or have metastasized, for instance, to the lung(s), breast, liver and prostate Similarly, a composition and method which are suitable for regular administration during a subject's daily routine, and that may be effectively administered preventatively, prophylactically and therapeutically, in conjunction with other therapies, or by itself for conditions without known therapies or as a substitute for therapies that have significant negative side effects is also of immediate clinical application.

Accordingly, there is still a need for improved treatments for respiratory, diseases associated with asthma, bronchoconstriction, and lung inflammation and allergies, whether or not accompanied by adenosine depletion, which are effective and easy to administer while being substantially non-toxic and cost effective.

The present invention relates to the use of an epiandrosterone, analogues thereof, a ubiquinone, and/or pharmaceutically or veterinarily acceptable salts thereof, for the manufacture of a medicament for treating asthma and its associated symptoms.

The present invention also relates to a method of treating asthma and symptoms associated with it, such as bronchoconstriction, lung inflammation and allergies, and cancer in a subject in need of treatment by administering to the subject an epiandrosterone, an analog thereof, a ubiquinone, or a pharmaceutically or veterinarily acceptable salt thereof, in an amount effective to treat asthma or its associated symptoms.

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