Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

inc, increased; dec, decreased; HTN, hypertension.

Binding of PGI2, PGE1, and PGD2 to their platelet receptors inhibits platelet aggregation by activating adenylyl cyclase. This leads to increased intracellular cAMP levels, which in turn activates specific protein kinases. These kinases phosphorylate internal calcium pump proteins, an action that decreases free intracellular calcium concentration. In contrast, the binding of TXA2 to its specific receptors activates phosphatidylinositol metabolism, leading to the formation of IP3. IP3 causes mobilization of Ca2+ stores and an increase of free intracellular calcium. LTB4 also generates IP3 release and causes activation, degranulation, and superoxide anion generation in polymorphonuclear leukocytes.

Subtypes are described for PGE2 receptors (EP1, EP2, EP3, and EP4), each of which activates distinct signaling pathways. EP1 is coupled to activation of phospholipase C, EP2 and EP4 to stimulation of adenylyl cyclase. EP3 appears to have multiple effects depending on concentration. The recent description of isoforms of receptor subtypes with coupling to different G proteins makes the issue of second messenger activation more complex. However this multiplicity of pathways may help clarify seemingly paradoxical experimental results.

The contractile effects of eicosanoids on smooth muscle are mediated by the release of calcium, while their relaxing effects are mediated by the generation of cAMP. The effects of eicosanoids on many target systems, including the immune system, can be similarly explained (see below). Many of the eicosanoids' contractile effects on smooth muscle can be inhibited by lowering extracellular calcium or by using calcium channel blocking drugs.

Action on nuclear PPAR receptors has also been proposed but the physiologic role of this interaction has not been determined.

Effects of Prostaglandins & Thromboxanes

The prostaglandins and thromboxanes have major effects on four types of smooth muscle: airway, gastrointestinal, reproductive, and vascular. Other important targets include platelets and monocytes, kidneys, the central nervous system, autonomic presynaptic nerve terminals, sensory nerve endings, endocrine organs, adipose tissue, and the eye (the effects on the eye may involve smooth muscle).

Smooth Muscle

Vascular

TXA2 is a smooth muscle cell mitogen and is the only eicosanoid that has convincingly been shown to have this effect. The mitogenic effect is potentiated by exposure of smooth muscle cells to testosterone, which up-regulates smooth muscle cell TXA2 receptors. In addition to its mitogenic effect, TXA2 is a potent vasoconstrictor. PGF2 is also a vasoconstrictor (via FP receptors) but is not a mitogen for smooth muscle cells. Another potent vasoconstrictor is 8-epi-PGF2 . In patients with cirrhosis, it is produced in large amounts in the liver and is thought to play a pathophysiologic role as an important vasoconstrictor substance in the hepatorenal syndrome.

Vasodilator prostaglandins, especially PGI2 and PGE2, promote vasodilation by increasing cAMP and decreasing smooth muscle intracellular calcium, primarily via IP and EP4 receptors. Vascular prostacyclin is synthesized by both smooth muscle and endothelial cells, with the latter as the major contributor. PGI2 undergoes rapid metabolism in a few seconds to more stable but inactive products. In the microcirculation, PGE2 is an endothelial vasodilator product.

Gastrointestinal Tract

Most of the prostaglandins and thromboxanes activate gastrointestinal smooth muscle. Longitudinal muscle is contracted by PGE2 (via EP3) and PGF2 (via FP), while circular muscle is contracted strongly by PGF2 and weakly by PGI2, and relaxed by PGE2 (via EP4). Administration of either PGE2 or PGF2 results in colicky cramps (see Clinical Pharmacology of Eicosanoids, below).

Airways

Respiratory smooth muscle is relaxed by PGD2, PGE1, PGE2, and PGI2 and contracted by TXA2 and PGF2 . Although PGD2 is less well-studied than the other prostaglandins, studies of PGD2 receptor knockout mice suggest an important role of this receptor in asthma.

Platelets and Blood Cells

Platelet aggregation is markedly affected by eicosanoids. PGE1 and especially PGI2 effectively inhibit aggregation, while TXA2 is a potent platelet aggregator. Platelets release TXA2 during activation and aggregation, suggesting that thrombotic events such as myocardial infarction may result in the release of TXA2. In fact, urinary metabolites of TXA2 increase in patients experiencing a myocardial infarction even if they are receiving low-dosage aspirin. At this aspirin dosage, thromboxane synthesis is significantly inhibited only in platelets. This suggests that other cells may contribute to the increase in TXA2; these other cells may be monocytes, since monocytes have a high capacity for sustained release of TXA2. Neutrophils and lymphocytes synthesize little if any prostaglandins, while monocytes have a substantial capacity for prostaglandin and thromboxane synthesis through both constitutive and inducible COXs. Human eosinophils also seem to have a high capacity for prostaglandin and thromboxane synthesis.

Kidney

Both the renal medulla and the renal cortex synthesize prostaglandins, the medulla substantially more than the cortex. The kidney also synthesizes several hydroxyeicosatetraenoic acids, leukotrienes, cytochrome P450 products, and epoxides. These compounds play important autoregulatory roles in renal function by modifying renal hemodynamics and glomerular and tubular function. This regulatory role is especially important in marginally functioning kidneys, as shown by the decline in kidney function caused by COX inhibitors in elderly patients and those with renal disease.

The major eicosanoid products of the renal cortex are PGE2 and PGI2. Both compounds increase renin release; normally, however, renin release is more directly under 1 adrenoceptor control. The glomeruli synthesize small amounts of TXA2 but this potent vasoconstrictor does not appear to be responsible for regulating glomerular function in healthy humans.

PGE1, PGE2, and PGI2 increase glomerular filtration through their vasodilating effects. These prostaglandins also increase water and sodium excretion. The increase in water clearance probably results from an attenuation of the action of antidiuretic hormone on adenylyl cyclase. It is uncertain whether the natriuretic effect is caused by the direct inhibition of sodium resorption in the distal tubule or by increased medullary blood flow. Loop diuretics, eg, furosemide, produce some of their effect by stimulating COX activity. In the normal kidney, this increases the synthesis of the vasodilator prostaglandins. Therefore, patient response to a loop diuretic will be diminished if a COX inhibitor is administered concurrently (see Chapter 15: Diuretic Agents).

TXA2 causes intrarenal vasoconstriction (and perhaps an ADH-like effect), resulting in a decline in renal function. The normal kidney synthesizes only small amounts of TXA2. However, in renal conditions involving inflammatory cell infiltration (such as glomerulonephritis and renal transplant rejection), the inflammatory cells (monocyte-macrophages) release substantial amounts of TXA2. Theoretically, TXA2 synthase inhibitors or receptor antagonists should improve renal function in these patients, but no such drug is clinically available.

Hypertension is associated with increased TXA2 and decreased PGE2 and PGI2 synthesis in some animal models, eg, the Goldblatt kidney model. It is not known whether these changes are primary contributing factors or secondary responses. Similarly, increased TXA2 formation has been reported in cyclosporine-induced nephrotoxicity, but no causal relationship has been established.

PGE2 may also be involved in renal phosphate excretion, because exogenous PGE2 antagonizes the inhibition of phosphate resorption by parathyroid hormone in the proximal tubule. However, the physiologic role of this eicosanoid may be limited because the proximal tubule, the major site for phosphate transport, produces few prostaglandins.

Reproductive Organs

Female Reproductive Organs

The effects of prostaglandins on uterine function are of great clinical importance. They are discussed below. (See Clinical Pharmacology of Eicosanoids.)

Male Reproductive Organs

The role of prostaglandins in semen is still conjectural. The major source of these prostaglandins is

the seminal vesicle; the prostate and the testes synthesize only small amounts. Thus, the term prostaglandin (referring to the prostate gland) is now known to be a misnomer. Semen from fertile men contains about 400 g/mL of PGE and PGF and their 19-hydroxy metabolites. There is about 20 times more PGE than PGF in fertile semen, although this ratio varies greatly among individuals. However, within individuals, this ratio remains fairly constant as long as the sperm characteristics are unchanged. The factors that regulate the concentration of prostaglandins in human seminal plasma are not known in detail, but testosterone does promote prostaglandin production. Thromboxane and leukotrienes have not been found in seminal plasma. Men with a low seminal fluid concentration of prostaglandins are relatively infertile. Large doses of aspirin reduce the prostaglandin content of seminal plasma.

Smooth muscle–relaxing prostaglandins such as PGE1 enhance penile erection by relaxing the smooth muscle of the corpora cavernosa. (See Clinical Pharmacology of Eicosanoids.)

Central and Peripheral Nervous Systems

Fever

PGE1 and PGE2 increase body temperature, probably via EP3 receptors, especially when administered into the cerebral ventricles. Pyrogens release interleukin-1, which in turn promotes the synthesis and release of PGE2. This synthesis is blocked by aspirin and other antipyretic compounds.

Sleep

When infused into the cerebral ventricles, PGD2 induces natural sleep (as determined by electroencephalographic analysis) in a number of species, including primates.

Neurotransmission

PGE compounds inhibit the release of norepinephrine from postganglionic sympathetic nerve endings. Moreover, NSAIDs increase norepinephrine release in vivo, suggesting that the prostaglandins play a physiologic role in this process. Thus, vasoconstriction observed during treatment with COX inhibitors may be due to increased release of norepinephrine as well as to inhibition of the endothelial synthesis of the vasodilators PGE2 and PGI2.

Neuroendocrine Organs

Both in vitro and in vivo tests have shown that some of the eicosanoids affect the secretion of anterior pituitary hormones. PGE compounds promote the release of growth hormone, prolactin, TSH, ACTH, FSH, and LH. However, endocrine changes reflecting significant release of these hormones have not been reported in patients receiving PGE compounds. LTC4 and LTD4 stimulate LHRH and LH secretion (see below).

Bone Metabolism

Prostaglandins are abundant in skeletal tissue and are produced by the osteoblasts and the adjacent hematopoietic cells. The major effect of prostaglandins (especially PGE2, acting on EP4 receptors) in vivo is to increase bone turnover, ie, stimulation of bone resorption and formation.

Prostaglandins may mediate the effects of mechanical forces on bones and some of the changes that occur in bones with inflammation. Finally, prostaglandins may play a role in the bone loss that

occurs at menopause.

Eye

PGE and PGF derivatives lower the intraocular pressure. The mechanism of this action is unclear but probably involves increased outflow of aqueous humor from the anterior chamber via the uveoscleral pathway (see Clinical Pharmacology of the Eicosanoids).

Effects of Lipoxygenase & Cytochrome P450-Derived Metabolites

The actions of lipoxygenases generate compounds that can regulate specific cellular responses important in inflammation and immunity. Cytochrome P450-derived metabolites affect nephron transport functions either directly or via metabolism to active compounds (see below). The biologic functions of the various forms of hydroxyand hydroperoxyeicosaenoic acids are largely unknown, but their pharmacologic potency is impressive.

Blood Cells and Inflammation

LTB4 is a potent chemoattractant for neutrophils; LTC4 and LTD4 are potent chemoattractants for eosinophils. These leukotrienes also promote eosinophil adherence, degranulation, and oxygen radical formation. The leukotrienes have been strongly implicated in the pathogenesis of inflammation, especially in chronic diseases such as asthma and inflammatory bowel disease. Lipoxin A seems to exert effects similar to those of LTB4 on neutrophils. Lymphocyte proliferation and differentiation are modified by LTB4. Both lipoxin A and lipoxin B inhibit natural killer cell cytotoxicity.

Heart and Smooth Muscle

Cardiovascular—1

2(S)-HETE is a potent chemoattractant for smooth muscle cells, causing migration at concentrations as low as 1 fmol/L; it may play a role in myointimal proliferation that occurs after vascular injury such as that caused by angioplasty. Its stereoisomer, 12(R)-HETE, is not a chemoattractant but is a potent inhibitor of the Na+/K+ ATPase in the cornea. LTC4 and LTD4 reduce myocardial contractility and coronary blood flow, leading to cardiac depression. Lipoxin A and lipoxin B seem to exert coronary vasoconstrictor effects.

Gastrointestinal

Human colonic epithelial cells synthesize LTB4, a chemoattractant for neutrophils. The colonic mucosa of patients with inflammatory bowel disease contains substantially increased amounts of LTB4.

Airways

The peptidoleukotrienes, particularly LTC4 and LTD4, are potent bronchoconstrictors and cause increased microvascular permeability, plasma exudation, and mucus secretion in the airways. Controversies exist over whether the pattern and specificity of the leukotriene receptors differ in animal models and humans. LTC4-specific receptors have not been found in human lung tissue, whereas both highand low-affinity LTD4 receptors are present.

Renal System

The roles of leukotrienes and cytochrome P450 products in the human kidney are currently speculative. Recently, the 5,6-epoxide has been shown to be a powerful vasodilator in animal experiments. Another recent discovery is that free radicals attack arachidonic acid-containing phospholipids to yield an 8-epi-PGF2 that has powerful thromboxane-like properties. Synthesis is not blocked by COX inhibitors but can be blocked by antioxidants. This vasoconstrictor, which is present in humans, is thought to be another important mediator causing renal failure in the hepatorenal syndrome.

Miscellaneous

The effects of these products on the reproductive organs remain to be elucidated. Similarly, actions on the nervous system have been suggested (recent data indicate that 12-HPETE acts as a neurotransmitter in Aplysia neurons), but this has not been confirmed in higher organisms. Very low concentrations of LTC4 increase and higher concentrations of arachidonate-derived epoxides augment LH and LHRH release from isolated rat anterior pituitary cells.

Inhibition of Eicosanoid Synthesis

Corticosteroids block all the known pathways of eicosanoid synthesis, perhaps by stimulating the synthesis of several inhibitory proteins collectively called annexins or lipocortins. They inhibit phospholipase A2 activity, probably by interfering with phospholipid binding and thus preventing the release of arachidonic acid.

The NSAIDs (eg, aspirin, indomethacin, ibuprofen) block both prostaglandin and thromboxane formation by inhibiting COX activity. For example, aspirin is a long-lasting inhibitor of platelet COX and of TXA2 biosynthesis because it irreversibly acetylates the enzyme. Once acetylated, platelet COX cannot be restored via protein biosynthesis because platelets lack a nucleus.

The development of selective thromboxane synthase inhibitors and TXA2 receptor antagonists has required considerable effort. The resulting compounds, eg, sulotroban, have been useful for characterizing TXA2-related effects in vitro and in vivo. They are being tested in the treatment of thromboembolism, pulmonary hypertension, and preeclampsia-eclampsia.

Selective inhibitors of the lipoxygenase pathway are also mainly investigational. With a few exceptions, NSAIDs do not inhibit lipoxygenase activity at concentrations that markedly inhibit COX activity. In fact, by preventing arachidonic acid conversion via the COX pathway, NSAIDs may cause more substrate to be metabolized through the lipoxygenase pathways, leading to an increased formation of the inflammatory leukotrienes. Even among the COX-dependent pathways, inhibiting the synthesis of one derivative may increase the synthesis of an enzymatically related product. Therefore, researchers are attempting to develop drugs that inhibit both COX and lipoxygenase.

Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds >

Clinical Pharmacology of Eicosanoids

Several approaches have been used in the clinical application of eicosanoids. First, stable oral or parenteral long-acting analogs of the naturally occurring prostaglandins have been developed.

Several such compounds have been approved for clinical use overseas and are being introduced in the USA (Figure 18–4). Second, enzyme inhibitors and receptor antagonists have been developed to interfere with the synthesis or effects of the "pathologic" eicosanoids (ie, thromboxanes and leukotrienes). For example, knowledge of eicosanoid synthesis and metabolism has led to the development of new NSAIDs that inhibit COX (especially COX-2), with improved pharmacokinetic and pharmacodynamic characteristics. One objective, described earlier, is to develop dual inhibitors that block both the COX (especially COX-2) and lipoxygenase pathways. Another goal is to decrease gastrointestinal and renal toxicity. Third, dietary manipulation—to change the polyunsaturated fatty acid precursors in the cell membrane phospholipids and so change eicosanoid synthesis—is used extensively in over-the-counter products and in diets emphasizing increased consumption of cold water fish.

Figure 18–4.

Chemical structures of some prostaglandins and prostaglandin analogs currently in clinical use.

Female Reproductive System

The physiologic role of prostaglandins in reproduction has been intensively studied since the discovery of prostaglandins in the seminal plasma of primates and sheep. It has been suggested that

the prostaglandins in seminal plasma facilitate blastocyst implantation or egg transport and that uterine secretion of prostaglandins causes luteolysis. The latter is not true in humans but appears to be true in cattle and pigs. This finding has led to the marketing of veterinary preparations of PGF2 and its analogs for synchronizing ovulation in animals.

Abortion

PGE2 and PGF2 have potent oxytocic actions. The ability of the E and F prostaglandins and their analogs to terminate pregnancy at any stage by promoting uterine contractions has been adapted to routine clinical use. Many studies worldwide have established that prostaglandin administration efficiently terminates pregnancy. The drugs are used for firstand second-trimester abortion and for priming or ripening the cervix before abortion. These prostaglandins appear to soften the cervix by increasing proteoglycan content and changing the biophysical properties of collagen.

Early studies found that intravenous PGE2 and PGF2 produced abortion in about 80% of cases. The success rate is dependent on the dose, the duration of the infusion, and parity of the woman. Dose-limiting adverse effects include vomiting, diarrhea, fever, and bronchoconstriction.

Hypotension, hypertension, syncope, dizziness, and flushing can occur and may be related to the vasomotor and vasovagal effects of PGE2.

In current practice, dinoprostone, a synthetic preparation of PGE2, is administered vaginally for oxytocic use. In the USA, it is approved for inducing abortion in the second trimester of pregnancy, for missed abortion, for benign hydatidiform mole, and for ripening of the cervix for induction of labor in patients at or near term.

Dinoprostone stimulates the contraction of the uterus throughout pregnancy. As the pregnancy progresses, the uterus increases its contractile response, and the contractile effect of oxytocin is potentiated as well. Dinoprostone also directly affects the collagenase of the cervix, resulting in softening. The vaginal dose enters the maternal circulation, and a small amount is absorbed directly by the uterus via the cervix and the lymphatic system. Dinoprostone is metabolized in local tissues and on the first pass through the lungs (about 95%). The metabolites are mainly excreted in the urine. The plasma half-life is 2.5–5 minutes.

For the induction of labor, dinoprostone is available either as a gel (0.5 mg PGE2) or as a controlled-release formulation (10 mg PGE2) that releases PGE2 in vivo at a rate of about 0.3 mg/h over 12 hours. An advantage of the controlled-release formulation is a lower incidence of gastrointestinal side effects (< 1%). A further advantage of this delivery system is that the medication is contained within a vaginal insert that can be retrieved at any time.

For abortifacient purposes, the recommended dosage is a 20 mg dinoprostone vaginal suppository repeated at 3- to 5-hour intervals depending on the response of the uterus. The mean time to abortion is 17 hours, but in more than 25% of cases the abortion is incomplete and requires additional intervention.

For softening of the cervix at term, the preparations used are either a single vaginal insert containing 10 mg PGE2 or a vaginal gel containing 0.5 mg PGE2 administered every 6 hours. The softening of the cervix for induction of labor substantially shortens the time to onset of labor and the delivery time.

The use of PGE analogs for "menstrual regulation" or very early abortions—within 1–2 weeks after the last menstrual period—has been explored extensively. There are two problems: prolonged

vaginal bleeding and severe menstrual cramps.

Antiprogestins (eg, mifepristone) have been combined with an oral oxytocic prostaglandin (eg, misoprostol) to produce early abortion. This regimen is now available in the USA (see Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists). The ease of use and the effectiveness of the combination have aroused considerable opposition in some quarters. The major toxicities are cramping pain and diarrhea.

market. Carboprost is used to induce second-trimester abortions and is usually administered as a single 2.5 mg intra-amniotic injection. The abortion is normally completed in less than 20 hours. The most serious adverse effects of this route of administration involve cardiovascular collapse. Most of the reported cases have been diagnosed as anaphylactic shock, but others may have been due to the drug escaping into the circulation and causing severe pulmonary hypertension. In pregnant anesthetized women, PGF2 , 300 g/min intravenously, doubles pulmonary resistance and increases the work of the right side of the heart three-fold. Thus, only minimal amounts of the 40 mg intra-amniotic dose need to reach the circulation to cause cardiovascular effects. This problem may be avoided by instilling the drug under ultrasonic guidance.

Intramuscular injection of carboprost tromethamine can also be used to induce abortion. Unlike the one-time intrauterine instillation of dinoprost, carboprost is given repeatedly up to the total dose of 2.6 mg normally required to cause abortion. Intra-amniotic administration has close to a 100% success rate, with fewer and less severe adverse effects than intravenous administration.

Facilitation of Labor

Numerous studies have shown that PGE2, PGF2 , and their analogs effectively initiate and stimulate labor. However, this is an unlabeled use. There appears to be no difference in the efficacy of the two drugs when they are administered intravenously, but PGF2 is one tenth as potent as PGE2. These agents and oxytocin have similar success rates and comparable induction-to-delivery intervals. The adverse effects of the prostaglandins are moderate, with a slightly higher incidence of nausea, vomiting, and diarrhea than that produced by oxytocin. PGF2 has more gastrointestinal toxicity than PGE2. Neither drug has significant maternal cardiovascular toxicity in the recommended doses. In fact, PGE2 must be infused at a rate about 20 times faster than that used for induction of labor to decrease blood pressure and increase heart rate. PGF2 is a bronchoconstrictor and should be used with caution in persons with asthma; however, neither asthma attacks nor bronchoconstriction have been observed during the induction of labor. Although both PGE2 and PGF2 pass the fetoplacental barrier, fetal toxicity is uncommon.

The effects of oral PGE2 administration (0.5–1.5 mg/h) have been compared with those of intravenous oxytocin and oral demoxytocin, an oxytocin derivative, in the induction of labor. Oral PGE2 is superior to the oral oxytocin derivative and in most studies is as efficient as intravenous oxytocin. However, the only available form of PGE2 in the USA at present is dinoprostone for vaginal administration, and by this route of administration the drug is slightly less effective than oxytocin. Vaginal PGE2 is also used to soften the cervix before inducing labor. Oral PGF2 causes too much gastrointestinal toxicity to be useful by this route.

Theoretically, PGE2 and PGF2 should be superior to oxytocin for inducing labor in women with preeclampsia-eclampsia or cardiac and renal diseases because, unlike oxytocin, they have no antidiuretic effect. In addition, PGE2 has natriuretic effects. However, the clinical benefits of these

effects have not been documented. In cases of intrauterine fetal death, the prostaglandins alone or with oxytocin seem to cause delivery effectively. In some cases of postpartum bleeding, 15-methyl- PGF2 will successfully control hemorrhage when oxytocin and methylergonovine fail to do so.

Dysmenorrhea

Primary dysmenorrhea is attributable to increased endometrial synthesis of PGE2 and PGF2 during menstruation, with contractions of the uterus that lead to ischemic pain. NSAIDs successfully inhibit the formation of these prostaglandins (see Chapter 36: Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout) and so relieve dysmenorrhea in 75–85% of cases. Some of these drugs are available over the counter. Aspirin is also effective in dysmenorrhea, but because it has low potency and is quickly hydrolyzed, large doses and frequent administration are necessary. In addition, the acetylation of platelet COX, causing irreversible inhibition of platelet TXA2 synthesis, may have an adverse effect on the amount of menstrual bleeding.

Male Reproductive System

Intracavernosal injection or urethral suppository therapy with alprostadil (PGE1) is useful in the treatment of erectile dysfunction, especially in spinal cord injury. Doses of 2.5–25 g are used. Penile pain is a frequent side effect that may be related to the algesic effects of PGE derivatives; however, only a few patients discontinue the use due to pain. Prolonged erection and priapism are less frequent side effects that occur in fewer than 4% of patients and are minimized by careful titration to the minimal effective dose. When given by injection, alprostadil may be used as monotherapy or in combination with either papaverine or phentolamine.

Cardiovascular System

The vasodilator effects of PGE compounds have been studied extensively in hypertensive patients. These compounds also promote sodium diuresis. Practical application will require derivatives with oral activity, longer half-lives, and fewer adverse effects.

Pulmonary Hypertension

Prostacyclin lowers peripheral, pulmonary, and coronary resistance. It has been used to treat both primary pulmonary hypertension and secondary pulmonary hypertension, which sometimes occurs after mitral valve surgery. A commercial preparation of prostacyclin (epoprostenol) is approved for treatment of primary pulmonary hypertension, in which it appears to improve symptoms and prolong survival. However, because of its extremely short plasma half-life, the drug must be administered as a continuous intravenous infusion through a central line. Several prostacyclin analogs with longer half-lives have been developed and treprostinil was recently approved for use in pulmonary hypertension (Horn, 2002). This drug is administered by continuous subcutaneous infusion.

Peripheral Vascular Disease

A number of studies have investigated the use of PGE and PGI2 compounds in Raynaud's phenomenon and peripheral atherosclerosis. In the latter case, prolonged infusions have been used to permit remodeling of the vessel wall and to enhance regression of ischemic ulcers.

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