Background of the Homatropine Invention

Hot flushes, also known as hot flashes, and night sweats are common and salientsymptoms experienced by menopausal woman that typically occur during the transition time from peri-menopause to menopause. They can continue to occur to up to 5 years post-menopause (75% of women experience hot flushes, and of those, 25% experience them for more than 5 years; Belchetz (1994) New Engl. J. Med. 330:1062-71).

The “hot flush” is a result of sudden or acute drop in estrogen levels. This sudden drop can be due to natural events (menopause), or as a result of surgical (oophorectomy) or medical (hormone therapy, chemotherapy) removal of ovarian function. It is estimated that 80% of women undergoing natural or iatrogenic menopause experience hot flushes. Over time, the frequency and intensity of hot flushes do diminish, but they are still present in up to 50% of women for up to 5 years.

A hot flush is subjectively described as a sensation of intense warmth lasting as little as 30 seconds or as long as 5 minutes. It can be accompanied by tachycardia or palpitations, headache, faintness, or vertigo, and typicallyends in profuse sweating and a cold sensation. At night, the frequency and severity of hot flushes increase, affecting a woman’s sleep and ultimately her overall quality of life.

Estrogen therapy has been the mainstay of treatment for menopausal symptoms over theyears, but concerns about the risks of hormone replacement therapy have made the search for alternative therapies critical for many women.

Mild symptoms may be improved by avoidance of triggering substances or situations. Caffeine, alcohol, spicy foods, and hot beverages may trigger hot flushes. Exercise, lowering stress levels, and smoking cessation are thought to helprelieve the symptoms. Dressing in layers, wearing breathable clothing such as cotton and natural linen, and using fans, may also aid in comfort.

Studies investigating the benefits of dietary soy and vitamin E have mixed results as to the benefits on hot flashes (Krebs, et al. (2004) Ob. Gyn. 104:824-836).There is up to a 40% placebo effect in most studies on hot flashes, and randomized, blinded studies involving phytoestrogens derived from soy or red leaf clover do not show additional benefit (Fitzpatrick (2003) Med. Clin. N. Am. 87:1091-1113; Tice, et al. (2003) JAMA 290:207). There is a concern that phytoestrogens are not risk-free as they stimulate cellular activity in breast cysts and can contribute to postmenopausal bleeding.

Black cohash is an herbal supplement which has been shown to have benefit for hotflashes without altering FSH levels or endometrial thickness (Fitzpatrick (2003) supra; Tice, et al. (2003) supra). Side effects such as nausea, headaches, dizziness and liver toxicity have been reported (Fitzpatrick (2003) supra; Tice, et al. (2003) supra). A black cohash/St John’s Wort combination has been shown to reduce the Menopause rating scale by 50% and the HamiltonDepression Scale by 41% (Uebelhack, et al. (2006) Ob. Gyn. 107:247-55).

There are no prescription medications that are as effective as estrogen for the treatment of hot flushes, but many have a positive impact in some women. Unfortunately, all have side effects that balance their clinical use. Venlafaxine, paroxetine, and fluoxetine have all shown an approximate 60% reduction in hot flushes but with side effects common to the SSRIs. Veralipride reduces hot flushes but caused weight gain and galactorrhea.

Clonidine has a 50% reduction in symptoms, but causes dry mouth, sedation and hypotension. Gabapentin has a 45% reduction in frequency, and 54% decrease in severity but can cause somnolence, fatigue, tremors, nausea, edema and ataxia. High dose progestins or megace may help, but can cause PMS symptoms, depression and fluid retention. Bellergal was used in the past, but has addictive potential (Fitzpatrick (2004) Ob. Gyn. 104:106s-117s).

The Women’s Health Initiative (WHI) was the largest placebo controlled study of hormone replacement therapy to date, and showed an increase in thromboembolism, stroke, and breast cancer in the estrogen-progestin group, leaving many women with the uncomfortable feeling that they were compromising their long-term health by using hormone therapy.

In certain severe cases, medication is prescribed by a physician.  Progestins such as megestrol acetate (Megace) have been prescribed. The hormone estrogen is the most effective treatment for hot flushes. It can help not only in this aspect, but also in lubricating the vagina and urinary tract, improving sexual function, and decreasing and preventing the incidence of urinary tract infections.

However, drawbacks of standard estrogen replacement therapy include the potential for increased risk of breast cancer, cardiovascular disease, general discomfort, and ineffectiveness. Recent studies have linked hormone replacement therapy to an increase risk of breast cancer. Furthermore, not all women can or want to take HRT, depending on their medical history and family history. Documenting the effectiveness of alternative treatments, and the development of new, non-hormonal treatments with low incidence of side effects and lower costs are desirable (Belchetz (1994) supra; Krebs, et al. (2004) supra; Fitzpatrick (2003) supra; Tice, et al. (2003) supra; Uebelhack, et al. (2006) supra; Fitzpatrick (2004) supra). At present, other than SSRI’s which are marginally effective, there are no pharmaceutical or over the counter products that offer effective palliation of hot flushes.

U.S. Patent Nos. 6,395,757 and 5,962,505 disclose the use of glycopyrrolate and glycopyrrolate analogs for alleviating menopausal hot flashes.

Accordingly, there is a need in the art for effective treatment regimes for relieving symptoms of the climacteric. The present invention meets this long-felt need.