A method for treatment of neurodegenerative disease conditions stemming from multiple sclerosis, aging, autoimmune diseases and fibromyalgia. A compound effective to increase neuronal metabolism of histamine to a histamine H.sub.2 agonist is administered in an amount sufficient to stimulate production of cyclic AMP at a level which is sufficient to maintain myelin against undergoing self-degeneration. The compound is selected from the group consisting of histamine M-methyltransferase, monoamineoxidase-A, monoamineoxidase-A agonists and histamine H.sub.3 antagonists. The histamine M-methyltransferase may be administered to increase neuronal metabolism of histamine to tele-methylhistamine, whereas the monoamineoxidase-A or monoamineoxidase-A agonist may be administered so as to increase neuronal metabolism of telemethylhistamine to an H.sub.2 agonist. Separately or in conjunction with the others, the histamine H.sub.3 antagonist may be administered so as to inhibit metabolism of the telemethylhistamine to an H.sub.3 agonist, thereby increasing metabolism of the telemethylhistamine to an H.sub.2 agonist. The increased histamine H.sub.2 agonist levels reduce demyelination and the symptoms that are associated with these conditions.

SUMMARY OF THE INVENTION

The present invention addresses the problems cited above, and is a method for treatment of neurodegenerative disease conditions stemming from multiple sclerosis, aging, autoimmune diseases, and fibromyalgia, the method broadly comprising the step of administering to a patient a compound effective to increase neuronal metabolism of histamine to a histamine H.sub.2-agonist, in an amount sufficient to stimulate production of cyclic AMP at a level which is sufficient to maintain myelin against undergoing self-degeneration.

The method may further comprise the step of selecting the compound from the group consisting of histamine N-methyltransferase, monoamine oxidase-A, monoamine oxidase-A agonists and histamine H.sub.3 antagonists.

The compound may comprise histamine N-methyltransferase, and the step of administering the compound may comprise administering histamine N-methyltransferase to the patient so as to increase neuronal metabolism of histamine to tele-methylhistamine. The step of administering histamine N-methyltransferase may comprise administering isolated histamine N-methyltransferase by injection.

In another embodiment, the compound may be monoamine oxidase-A, and the step of administering the compound may comprise administering monoamine oxidase-A to the patient so as to increase neuronal metabolism of tele-methylhistamine to an H.sub.2 receptor agonist such as 4-methylhistamine.

In another embodiment, the compound may be a monoamine oxidase-A agonist, and the step of administering the compound may comprise administering the monoamine oxidase-A agonist to the patient so as to increase neuronal metabolism of tele-methylhistamine to an H.sub.2 agonist such as 4-methylhistamine. The monoamine oxidase-A agonist may be reserpine, and the step of administering the monoamine oxidase-A agonist may comprise administering reserpine by slow-release transdermal dose. Alternatively, the step of administering the monoamine oxidase-A agonist may comprise administering reserpine by injection, preferably in the range from about 1-10 mg/kg S.C. per day.

In another embodiment, the compound may be a histamine H.sub.3 antagonist, and the step of administering the compound may comprise administering a histamine H.sub.3 antagonist to the patient so as to inhibit neuronal metabolism of tele-methylhistamine to an H.sub.3 agonist such as R-alpha-methylhistamine and thereby increase neuronal metabolism of the tele-methylhistamine to an H.sub.2 agonist such as 4-methylhistamine. The histamine H.sub.3 antagonist may be thioperamide maleate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for treatment of MS and other neurodegenerative conditions, i.e., autoimmune diseases, fibromyalgia, and also of certain related conditions and symptoms usually associated with aging, by stimulating increased cyclic AMP production via increased histamine H2 levels, by application of a histamine H2 agonist so as to compensate for the depleted histamine H2 levels, or by increasing neuronal metabolism of histamine in order to produce increased histamine H2 levels. The increased histamine metabolism is achieved by increasing the activity levels of histamine N-methyltransferase (HMT) or monoamine oxidase-A (MOA-A), or both.

a. Hypothesis

While not intended to be binding with respect to the practice or scope of the present invention, a hypothesis has been developed which explains the results and that have been observed in connection with the treatment described herein.

As was noted above, the conventional theory has been that demyelination is the result of an autoimmune response. However, it is also known that the integrity of the nervous system is highly dependent on cyclic AMP, in that cyclic AMP stimulates the synthesis of myelin components by oligodendrocytes and Schwann cells. Studies have shown that oligodendrocytes will undergo self-induced degeneration in the absence of cyclic AMP, resulting in demyelination, but that the degenerating cells will again become viable and capable of synthesizing myelin if treated with cyclic AMP (e.g., see Kim, "Neurobiology of human oligodendrocytes in culture", J. of Neuroscience Research, Dec. 27, 1990).

Cyclic AMP, in turn, is produced naturally in brain tissue, largely in the pineal gland. In the case of persons suffering from MS, especially in the chronic-progressive phase, the levels of histamine H2 have been observed to be very low, and the pineal gland functions tend to be atrophied. It is also known that production of cyclic AMP by the pineal gland is controlled to a large extent by the presence of histamine H2 in the blood stream. Histamine H2 (as differentiated from histamine H1) is produced by cells in the central nervous system, particularly those in the hypothalamus. In other words, certain cells within the central nervous system produce the histamine H2 that stimulates the pineal gland to produce cyclic AMP, which in turn is essential to protect the myelin against self-degeneration.

It is Applicant's hypothesis that in persons suffering from MS and similar neurodegenerative conditions, the histamine H2-producing cells in the central nervous system are damaged or impaired, possibly by one or more strains of the measles virus, so that over time these cells reduce or cease production of histamine H2, or of the enzymes that are essential to the production of histamine H2. Inadequate production of histamine H2, in turn, results in greatly reduced output of cyclic AMP from the pineal gland, leading ultimately to self-degeneration of the myelin. Hence, under Applicant's hypothesis, the lesions do not result directly from an autoimmune attack on the myelin, but are instead the result of self-degeneration of the myelin precipitated by damage or impairment of the histamine H2-producing cells of the central nervous system.

It is further hypothesized, at least in the case of MS, that the damage is progressive, in that the remissive-relapsive form of the disease represents an earlier phase in which the cells are subjected to ongoing attack but some capacity to produce histamine H2 remains, while the chronic-progressive form represents a subsequent phase in which the capacity to produce histamine H2 is essentially eliminated.

Applicant's hypothesis is consistent with prior observations concerning attempted treatments for the disease. For example, as was noted above, MS symptoms tend to respond favorably to treatment with interferon and other anti-viral agents when the disease in the remissive-relapsive phase, but such treatments become ineffective when the disease enters the chronic-progressive phase. This pattern is consistent with the above hypothesis, since the interferon serves to inhibit viral replication in virus-infected cells and therefore slows damage to the remaining histamine H2-producing cells during the remissive-relapsive phase, but when the disease has reached the chronic-progressive phase virtually all of the histamine H2 producing cells have been destroyed or impaired, so that further interferon treatments can have no effect on histamine H2 output.

Additional corroborating evidence includes observations that the histamine H2 levels of MS patients in the remissive-relapsive phase tend to fluctuate, sometimes being abnormally high and at other times being abnormally low. This observation is also consistent with the above hypothesis, in that it will be understood that as viruses replicate and spread they cause physical disruption of cellular structures, i.e., the cells become filled with replicated virus and ultimately "explode", releasing their contents into the blood stream. In the case of histamine H2-producing cells, these contents would include not only replicated virus bodies, but also the histamine H2 contained in the cell, which may account for the sometimes increased levels of histamine H2 which are observed during periods of exacerbation in the remissive-relapsive phase.

Furthermore, histamine H2 is a known heat stress modulator, and inability to handle heat stress (reflecting a low level of histamine H2) is a classic symptom of MS. Histamine H2 is also believed to regulate the number of T-cells in the body, and research has shown that people with MS tend to have abnormally low numbers of T-cells during periods of exacerbation.

A number of other conditions exhibit symptoms similar to those in MS. Some of these, such as Parkinson's disease and Alzheimer's disease, are neurodegenerative diseases. Other conditions are associated more generally with the aging process (or sometimes genetic disorders or fibromylgia), and may not necessarily involve demyelination per se. Many of the latter conditions produce one or more symptoms similar to those of MS, but often to a lesser degree or without the presence of all of the symptoms that are associated with actual demyelination. Applicant hypothesizes that many of these conditions may stem from a common source, i.e., a reduced production or presence of histamine H2. In short, it is believed that certain of these conditions and symptoms, especially the less acute ones associated with the aging process, reflect a moderately depressed production or presence of histamine H2, while more severely reduced histamine H2 levels lead to demyelination and the severe symptoms associated with the neurodegenerative diseases.

This hypothesis correlates with the results of other recent research. For example, it has been found that aging results in vascular changes due to alterations in endothelial cells and vascular tone regulation. These changes result in hypertension, coronary artery disease, heart failure, and postural hypotension (Marin & Rodriguez-Martinez, Exp Gerontol, July 1999, 34:503-12). H2 receptor stimulation regulates the contractility of the small-diameter arteries (Fernandez et al., Acta Physiol Scan, August 1994, 151:441-51). H2 receptor activation of the Na+/K+/ATPase system stimulates nitric oxide production, which leads to endothelial relaxation in small-diameter arteries (Garcia-Villaon et al., J Pharm Pharmacol, October 1996, 48:1057-62). The Na+ pump activity is stimulated by the Na+/K+/ATPase system, which is activated by H2 receptor stimulation. Na+/K+/ATPase inhibition, such as by ouabian, inhibits the Na+ pump. Thus, deficient H2 stimulation is implicated in decreased Na+ pump activity and the related symptoms. Research confirms that the Na+ pump activity is reduced in aging (Marin & Rodriguez-Martinez, 1999).

Vascular calcium (Ca(2+)) homeostasis is also altered in aging. Extracellular Ca(2+) dependence on contractile responses of the endothelium is enhanced, thus the elderly have increased sensitivity to Ca(2+) antagonists (Marin & Rodriguez-Martinez, 1999). Histamine treatment decreases the release of Ca(2+) from intracellular stores, thus decreasing the contractile responses of the endothelium (Song et al., Eur J Pharmacol, March 1997, 19;322:265-73).

H2 receptor stimulation also increases gastric acid secretion and digestive enzyme production. Research shows that gastric acid secretion decreases about 30% in the elderly, and that production of digestive enzymes such as pepsin is reduced by approximately 40% in the elderly (Feldman et al., Gastroenterology, April 1996, 110:1043-52). Again, reduced H2 levels are implicated.

Still further, it has been demonstrated that aging modifies the basal and stress-stimulated functions of the hypothalamic presynaptic histamine neurons (Ferretti et al., Pharmacol Biochem Behav, January 1998, 59:255-60). These changes in the histaminergic systems in connection with aging may explain the sleep disturbances and immune system suppression that are common in the elderly: H2 agonists stimulate the pineal gland to produce cAMP and melatonin. Melatonin is involved in the Rapid Eye Movement (REM) stage of sleep which is often deficient in the elderly, which can lead to cognitive and memory defects (Schredl et al., Exp Gerontol, February 2001, 36:353-61). Cyclic AMP, in turn, is involved in boosting the immune system response, as has been discussed above.

Therefore, although the invention is described herein largely with reference to the example of multiple sclerosis, it will be understood that the present invention may be also be employed in the treatment of similar conditions that are associated with aging or other causes, where the root problem lies in deficient levels of histamine H2. For example, in addition to MS, Parkinson's disease and Alzheimer's disease, the present invention may be used to treat various other conditions and disorders of the types noted above, including conditions relating to pineal gland, thymus and thyroid functions, gastric disorders, hypertension, and sleep and memory disorders.

b. Histamine H2 Augmentation

For the reasons explained above, it is believed that MS and similar neurodegenerative conditions, as well as certain other symptoms associated with aging, are precipitated by the body's inability to produce adequate levels of histamine H2. Consequently, one embodiment of the present invention employs histamine phosphate or selected beta-adrenergic agents to replace or "mimic" the histamine H2, in an amount that is sufficient to induce increased production of cyclic AMP (i.e., by the pineal gland), at levels that are adequate to eliminate and/or repair the self-degeneration of the myelin. The purpose of the caffeine or other phosphodiesterase inhibitor, in turn, is to reduce the action of phosphodiesterase (the enzyme in the human body which breaks down cyclic AMP), thereby providing higher cyclic AMP levels over longer periods of time without having to rely on excessively high dosages of histamine phosphate.

Histamine phosphate is generally preferred as the histamine H2 analogue component in the present invention because of its wide availability and comparatively low cost, and because it very effectively mimics the action of the body's natural histamine H2 (e.g., see Fact and Comparisons, January 1988). Moreover, in addition to stimulating production of cyclic AMP, the histamine phosphate helps to provide stress modulation, again similar to the natural histamine H2.

Histamine phosphate is most commonly supplied in the form of histamine diphosphate. A suitable source of histamine phosphate for use in the present invention is a solution available from Eli Lily and Company as "histamine phosphate injection, U.S.P."; this material is currently recognized by the US Food and Drug Administration (FDA) for use as a gastric acid test. Other suitable compounds that mimic the presence of histamine H2 for purposes of stimulating cyclic AMP production by the pineal gland may be used in the method of the present invention, either in combination with or in place of the histamine phosphate. For example, isoproterenol and/or other beta-adrenergic agents that are known or determined to be histamine H2 mimicking agents may be used in this component.

Similarly, caffeine is a preferred choice for the phosphodiesterase inhibitor because of its low expense and long half-life, in addition to its comparatively minimal side effects and wider therapeutic index. Other suitable phosphodiesterase inhibitors may also be used in accordance with the present invention to enhance the production of cyclic AMP, however, such as theophylline, theophylline derivatives, and other methylxanthine agents. As was noted above, the purpose of this component is to enhance the effect of the increased levels of cyclical AMP that are produced by the histamine H2 analog, by conserving the cyclical AMP against breakdown by the phosphodiesterase enzymes. In the absence of the phosphodiesterase inhibitor component, much higher levels of histamine phosphate would be required to achieve the same result, increasing the risk of adverse cardiovascular reactions and other negative side effects.

Caffeine citrate is generally preferred for the caffeine component in transdermal applications, due to its solubility and ability to achieve high concentrations in transdermal gel. Also, it should be noted that references to amounts and dosages of caffeine herein refer to measures of caffeine base (i.e., the caffeine molecule), and do not include other materials that are sometimes found associated with the caffeine in a commercially available product.

The treatment composition may be administered by any suitable means, such as orally or by transdermal patch, subcutaneous injection, intravenous injection, or inhaler, to give just a few examples. Administration by transdermal patch may be preferable in many embodiments, in that this provides significant advantages in terms of ease of use and consistent dosage levels. As used in this description and appended claims, the term "transdermal patch" includes both adhesive patches and other systems and devices for transdermal administration of treatment compositions.

 

Claim 1 of 5 Claims

1. A method for therapeutic treatment of multiple sclerosis, said method comprising the steps of: administering to a patient in need thereof monoamine oxidase-A effective for increasing neuronal metabolism of histamine to a histamine H.sub.2 agonist, in an amount sufficient that said histamine H.sub.2 agonist is produced in an amount adequate to stimulate production of cyclic AMP at a level which maintains myelin against undergoing self-degeneration; the step of administering said compound comprising administering monoamine oxidase-A to said patient in accordance with a regimen that provides a predetermined daily dosage of said monoamine oxidase-A so as to increase neuronal metabolism of tele-methylhistamine to an H.sub.2 agonist.

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