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Primary dysmenorrhea is a disabling condition found in approx. 10-15% of women of childbearing age. Pain is caused by frequent and prolonged uterine contractions that decrease blood flow to the myometrium resulting in ischemia. Prostaglandin F2-alpha (PGF2alpha) also plays a central role in the mediation of these contractions. During menstruation arachadonic acid stored in the endometrium is converted to PGF2alpha, prostaglandin E2 (PGE2) and leukotrienes. The release of prostaglandins from the endometrium at the time of menses induce uterine smooth muscle contractions which manifest as labour-like lower abdominal and back pain. These contractions can last several minutes and may produce uterine pressures of greater than 400mmHg, five times greater than resting pressures.
Excessive concentrations of PGF2alpha are implicated in the uterine hypercontractility associated with primary dysmenorrhea and therefore agents that block prostaglandin production and action such as NSAIDs have been the mainstays of treatment. NSAIDs are typically started at the onset of menses and continued for the initial one to two days of the menstrual cycle, or for the usual duration of 'crampy' pain. However, since the onset of NSAID action is not immediate, patients may begin taking NSAIDs one to two days prior to the onset of menses to avoid experiencing severe symptoms while waiting for NSAIDs to take effect.
The major side effects of treatment are gastrointestinal irritation or bleeding. Additionally, NSAIDs carry the risk of cardiovascular and renal toxicities. There is a need for a safer treatment option, particularly in those women who cannot tolerate NSAIDs, or for whom their use is contraindicated. Blocking the FP receptor directly with PDC's compounds is expected to provide a better safety profile than NSAIDs, with a more rapid onset of action, and therefore more immediate relief of symptoms. PDC plans to develop a topical formulation (eg. nasal spray) of its lead peptide for this indication initially, and ultimately an oral peptidomimetic.
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