The present invention is a method for alleviating at least one climactericsymptom in a climacteric subject. The method involves administering to a climacteric subject a therapeutically effective amount of an anticholinergic agentthereby alleviating at least one climacteric symptom in the subject. In some embodiments, the anticholinergic agent is homatropine, or a salt thereof.

The climacteric is defined as the syndrome of endocrine, somatic and psychological changes occurring at the termination of the reproductive period in the female. According to the Greene Climacteric scale (Greene (1998) Maturitas 29:25-31), there are 21 common symptoms associated with a woman’s climacteric stage, namely heart beating quickly or strongly, feeling tense or nervous, difficulty in sleeping, excitability, attacks of panic, difficulty in concentrating, feeling tired or lacking in energy, loss of interest in most things, feeling unhappy or depressed, crying spells, irritability, feeling dizzy or faint, pressure or tightness in head or body, parts of the body feel numb or tingling, headaches, muscle and joint pains, loss of feeling in hands and feet, breathing difficulties, hot flushes, sweating at night, and loss of interest in sex. Other symptoms commonly experienced in climacteric women include urinary frequency and urgency, palpitations, and anxiety.

It has now been found that anticholinergic agents, such as homatropine, alleviate hot flushes in peri-menopausal and post-menopausal women. In general, anticholinergic agents work by modulating the activity of muscarinic receptors which mediate a variety of cellular responses. For example, muscarinic receptors in smooth muscle regulate cardiac contractions, gut motility and bronchial constriction, whereas muscarinic receptors in exocrine glands stimulate gastric acid secretion, salivation and lacrimation. Muscarinic receptors also are found in the superior cervical ganglion, cerebral cortex, the striatum, the hippocampus, thalamus and brainstem.

Generally speaking, overstimulation of these receptors leads to diarrhea, frequent urination, miosis, bradycardia, bronchorrhea, emesis, lacrimation, and salivation. Other symptoms resulting from overstimulation of these receptors include nausea, vomiting, as well as eye pain, blurred or dim vision. Similarly, nicotinic stimulation causes muscle pain, tremors, weakness, hypertension, and fasciculations. Advantageously, anticholinergic agents result in antimuscarinic and antinicotinic actions. For example, anticholinergic agents are routinely given to people with urinary incontinence to prevent frequent urination (see, e.g., U.S. Patent No. 6,919,092.

It is believed that anticholinergics act peripherally and not in the central nervous system, i.e., hypothalamus, to block the muscarinic receptors located on tissues which receive parasympathetic postganglionic nerves. One exception is the sweat glands; which receive sympathetic-cholinergic nerves. The hypothalamus is one of several brain areas that regulate the discharge rate of parasympathetic and sympathetic nerves by descending nerve fibers that synapse with either the parasympathetic preganglionic or sympathetic preganglionic nerves. It appears that the hypothalamus is the major brain area that regulates the discharge rate of the autonomic nerves (which may increase or decrease). The pathophysiology of how the decrease in estrogen affects the hypothalamic regulation of body temperature is largely unknown. However, not wishing to be bound by theory, it is believed that the anticholinergic agent disclosed herein modulates hypothalamic regulation of body temperature via muscarinic receptor activity thereby reducing climacteric symptoms such as hot flushes in climacteric subjects.

Accordingly, Tropine 3 is a method for alleviating at least one climacteric symptom in aclimacteric subject by administering to the climacteric subject a therapeutically effective amount of an anticholinergic agent, thereby alleviating at least one climacteric symptom in the climacteric subject. Asused in the context of the present invention, “an anticholinergic agent” can be a compound that acts as an antagonist at the muscarinic receptor.  In particular, the muscarinic receptor can be M1 and/or M2 muscarinic receptors.

In particular embodiments, the anticholinergic agent can be a belladonna alkaloid including, but not limited to, atropine, scopolamine, methscopolamine, homatropine, hyoscyamine, wherein these compounds are normally administered as a salt, i.e., tertiary amines.  For example, the atropine can be selected from a group consisting of atropine sulfate, atropine oxide, atropine-HCl salt, and methylatropine nitrate.  The scopolamine can be selected from a group consisting of hydrobromide salt and methylbromide salt of scopolamine.  The homatropine can be selected from a group consisting of hydrobromide salt and methylbromide salt of homatropine.  The hyoscyamine can be selected from a group consisting of hydrobromide salt and sulfate salt of hyoscyamine.

The amount of anticholinergic agent or salt thereof which is required to achieve a therapeutic effect will, of course, vary with the particular agent, the route of administration, the subject under treatment. The compounds of the invention can be administered in a dose ranging from 0.005 mg to 100 mg per day, or more suitably 0.05 mg to 50 mg per day, with the particular dose adjusted by a skilled clinician based on the severity of the symptoms and the subject being treated. Effectiveness of the dose employed can be ascertained by monitoring the subject based upon, e.g., the Menopause Rating Scale (MRS) and the Greene Climacteric Scale (GCS).

In accordance with the instant method, a therapeutically effective amount of an anticholinergic agent, such as a belladonna alkaloid, and in particular, homatropine, can be administered to a climacteric subject, which includes peri-menopausal and post-menopausal woman, wherein said effective amount alleviates, reduces, or ameliorates at least one climacteric symptom in thesubject.

Climacteric symptoms which can be alleviated by the anticholinergic agent include rapid heart beat, strong heart beat, feeling tense, feeling nervous, difficulty in sleeping, excitability, attacks of panic, difficulty in concentrating, feeling tired, lacking in energy, loss of interest in most things, feeling unhappy, feeling depressed, crying spells, irritability, feeling dizzy, feeling faint, pressure in head, pressure in body, tightness in head, tightness in body, numbness in a body part, tingling in a body part, headaches, muscle pains, joint pains, loss of feeling in hands, loss of feeling in feet, breathing difficulties, hot flushes, sweating at night, and loss of interest in sex.  In some embodiments, the anticholinergic agent alleviates climacteric symptoms resulting from overstimulation of the muscarinic receptors.

In particular embodiments, themuscarinic receptor is the M1 or M2 receptor. In other embodiments, the anticholinergic agent alleviates hot flushes.  In a preferred embodiment, homatropine can be administered to alleviate hot flushes. In still other embodiments, the anticholinergic agent generally improves the quality of life (e.g., a decrease in night sweat episodes which affect a woman’s sleep).

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