G

Decreased response of colon to carcinogens Impaired ovulation and fertilization; salt sensitive hypertension Resistance to pyrogens

Patent ductus arteriosus Failure of parturition T Thrombotic response,

■!• response to vascular injury T Bleeding time, T response to vascular injury Some suppression of inflammatory response

■!• Innate and adaptive immune vascular permeability response, T pulmonary inflammatory and fibrotic response ■!• Pulmonary inflammatory and fibrotic response

This table lists the major classes of eicosanoid receptors and their signaling characteristics. Splice variants are indicated where appropriate. Major phenotypes in knockout mouse models are listed.

ABBREVIATIONS: Ca2+i, cytosolic Ca2+; cAMP, cyclic AMP; PLC, phospholipase C (activation leads to increased cellular IP3 and diacyl glycerol generation and increased Ca2+i); IsoPs, isopostanes; DP2 is a member of the fMLP receptor super-family; fMLP, formyl-methionyl-leucyl-phenylalanine. 15d-PGI2, 15 deoxy PGI2.

exercise and exposure to antigen, and decrease the patient's requirement for the use of ^-adrenergic agonists. Their effectiveness in patients with aspirin-induced asthma also has been shown.

The use of eicosanoids or eicosanoid derivatives themselves as therapeutic agents is limited in part because systemic administration of prostanoids frequently is associated with significant adverse effects and because of their short half-lives in the circulation. Despite these limitations, several prostanoids are of clinical utility.

Therapeutic Abortion

There has been intense interest in the effects of the PGs on the female reproductive system. When given early in pregnancy, their action as abortifacients may be variable and often incomplete and accompanied by adverse effects. PGs appear, however, to be of value in missed abortion and molar gestation, and they have been used widely for the induction of midtrimester abortion. Systemic or intravaginal administration of the PGE1 analog misoprostol in combination with mifepristone (RU486) or methotrexate is highly effective in the termination of early pregnancy.

PGE2 or PGF2a are used to facilitate labor by promoting ripening and dilation of the cervix.

Gastric Cytoprotection

The capacity of several PG analogs to suppress gastric ulceration is a property of therapeutic importance. Of these, misoprostol (cytotec), a PGE1 analog, is approved by the FDA. Misopros-tol appears to heal gastric ulcers about as effectively as the H2-receptor antagonists (see Chapter 36);

however, relief of ulcerogenic pain and healing of duodenal ulcers have not been achieved consistently with misoprostol. This drug currently is used primarily for the prevention of ulcers that often occur during long-term treatment with NSAIDs. In this setting, misoprostol appears to be as effective as the proton pump inhibitor omeprazole.

Impotence

PGE1 (alprostadil) may be used in the treatment of impotence. Intracavernous injection of PGEt causes complete or partial erection in impotent patients who do not have disorders of the vascular system or cavernous body damage. The erection lasts for 1-3 hours and is sufficient for sexual intercourse. PGE1 is more effective than papaverine. The agent is available as a sterile powder that is reconstituted with water for injections (caverject), although it has been superseded largely by the use of PDE5 inhibitors, such as sildenafil, tadalafil, and vardenafil (see Chapter 31).

Maintenance of Patent Ductus Arteriosus

The ductus arteriosus in neonates is highly sensitive to vasodilation by PGE. Maintenance of a patent ductus may be important hemodynamically in some neonates with congenital heart disease. PGE1 (alprostadil, prostin vr pediatric) is highly effective for palliative, but not definitive, therapy to maintain temporary patency until surgery can be performed. Apnea is observed in —10% of neonates so treated, particularly those who weigh <2 kg at birth.

Pulmonary Hypertension

Primary pulmonary hypertension is a rare idiopathic disease that mainly affects young adults. It leads to right-sided heart failure and frequently is fatal. Long-term therapy with PGI2 (epoprostenol, flolan) has either delayed or precluded the need for lung or heart-lung transplantation in a number of patients. In addition, many affected individuals have had a marked improvement in symptoms after receiving treatment with PGI2. Epoprostenol also has been used successfully to treat portopulmonary hypertension that arises secondary to liver disease, again with a goal of facilitating ultimate transplantation.

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