Prostacyclin

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Prostacyclin
Prostacyclin.svg
Prostacyclin spacefill.png
Clinical data
Trade names Flolan, Veletri
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:B1
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 42 seconds
Identifiers
  • (Z)-5-[(4R,5R)-5-Hydroxy-4-((S,E)-3-hydroxyoct-1-enyl)hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H32O5
Molar mass 352.471 g·mol−1
3D model (JSmol)
  • OC(=O)CCC\C=C1\C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]2O1
  • InChI=1S/C20H32O5/c1-2-3-4-7-14(21)10-11-16-17-12-15(8-5-6-9-20(23)24)25-19(17)13-18(16)22/h8,10-11,14,16-19,21-22H,2-7,9,12-13H2,1H3,(H,23,24)/b11-10+,15-8-/t14-,16+,17+,18+,19-/m0/s1 X mark.svgN
  • Key:KAQKFAOMNZTLHT-OZUDYXHBSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.

Contents

When used as a drug, it is also known as epoprostenol. [1] The terms are sometimes used interchangeably. [2]

Function

Prostacyclin (PGI2) chiefly prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation). It does this by inhibiting platelet activation. [3] It is also an effective vasodilator. Prostacyclin's interactions contrast with those of thromboxane (TXA2), another eicosanoid. Both molecules are derived from arachidonic acid, and work together with opposite platelet aggregatory effects. These strongly suggest a mechanism of cardiovascular homeostasis between these two hormones in relation to vascular damage.

Medical uses

It is used to treat pulmonary arterial hypertension (PAH), [4] [5] pulmonary fibrosis, [6] as well as atherosclerosis. [6] Specifically, epoprostenol is given to patients with class III or class IV PAH.[ citation needed ]

Degradation

Prostacyclin, which has a half-life of 42 seconds, [7] is broken down into 6-keto-PGF1, which is a much weaker vasodilator. A way to stabilize prostacyclin in its active form, especially during drug delivery, is to prepare prostacyclin in alkaline buffer. Even at physiological pH, prostacyclin can rapidly form the inactive hydration product 6-keto-prostaglandin F1α. [8]

Mechanism

Prostacyclin effectMechanismCellular response
Classical
functions		Vessel tone↑cAMP, ↓ET-1
↓Ca2+, ↑K+		↓SMC proliferation
↑Vasodilation
Antiproliferative↑cAMP
↑PPARgamma		↓Fibroblast growth
↑Apoptosis
Antithrombotic↓Thromboxane-A2
↓PDGF		↓Platelet aggregation
↓Platelet adherence to vessel wall
Novel
functions		Antiinflammatory↓IL-1, IL-6
↑IL-10		↓Proinflammatory cytokines
↑Antiinflammatory cytokines
Antimitogenic↓VEGF
↓TGF-β		↓Angiogenesis
↑ECM remodeling

As mentioned above, prostacyclin (PGI2) is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor (prostacyclin receptor) is activated when it binds to PGI2. This activation, in turn, signals adenylyl cyclase to produce cAMP. cAMP goes on to inhibit any undue platelet activation (in order to promote circulation) and also counteracts any increase in cytosolic calcium levels that would result from thromboxane A2 (TXA2) binding (leading to platelet activation and subsequent coagulation). PGI2 also binds to endothelial prostacyclin receptors, and in the same manner, raises cAMP levels in the cytosol. This cAMP then goes on to activate protein kinase A (PKA). PKA then continues the cascade by promoting the phosphorylation of the myosin light chain kinase, which inhibits it and leads to smooth muscle relaxation and vasodilation. It can be noted that PGI2 and TXA2 work as physiological antagonists.

Members [9]

PROSTACYCLINS
Flolan
(epoprostenol sodium)
for Injection		Continuously infused2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achievedClass III
Class IV
Veletri
(epoprostenol)
for Injection		Continuously infused2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achievedClass III
Class IV
Remodulin SC§
(treprostinil sodium)
Injection		Continuously infused1.25 ng/kg/min to start, increased by up to 1.25 ng/kg/min per week for 4 weeks, then up to 2.5 ng/kg/min per week until suitable efficacy/tolerability balance is achievedClass II
Class III
Class IV
Ventavis
(iloprost)
Inhalation Solution		Inhaled 6–9 times daily2.5 μg 6–9 times daily to start, increased to 5.0 μg 6–9 times daily if well toleratedClass III
Class IV

Pharmacology

Ball-and-stick model of prostacyclin Prostacyclin2.png
Ball-and-stick model of prostacyclin

Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation:

The production of prostacyclin is inhibited by the action of NSAIDs on cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid to prostaglandin H2 (PGH2), the immediate precursor of prostacyclin. Since thromboxane (an eicosanoid stimulator of platelet aggregation) is also downstream of COX enzymes, one might think that the effect of NSAIDs would act to balance. However, prostacyclin concentrations recover much faster than thromboxane levels, so aspirin administration initially has little to no effect but eventually prevents platelet aggregation (the effect of prostaglandins predominates as they are regenerated). This is explained by understanding the cells that produce each molecule, TXA2 and PGI2. Since PGI2 is primarily produced in a nucleated endothelial cell, the COX inhibition by NSAID can be overcome with time by increased COX gene activation and subsequent production of more COX enzymes to catalyze the formation of PGI2. In contrast, TXA2 is released primarily by anucleated platelets, which are unable to respond to NSAID COX inhibition with additional transcription of the COX gene because they lack DNA material necessary to perform such a task. This allows NSAIDs to result in PGI2 dominance that promotes circulation and retards thrombosis.

In patients with pulmonary hypertension, inhaled epoprostenol reduces pulmonary pressure, and improves right ventricular stroke volume in patients undergoing cardiac surgery. A dose of 60 μg is hemodynamically safe, and its effect is completely reversed after 25 minutes. No evidence of platelet dysfunction or an increase in surgical bleeding after administration of inhaled epoprostenol has been found. [10] The drug has been known to cause flushing, headaches and hypotension. [11]

Synthesis

Biosynthesis

Eicosanoid synthesis. (Prostacyclin near bottom center.) Eicosanoid synthesis.svg
Eicosanoid synthesis. (Prostacyclin near bottom center.)

Prostacyclin is produced in endothelial cells, which line the walls of arteries and veins, [12] from prostaglandin H2 (PGH2) by the action of the enzyme prostacyclin synthase. Although prostacyclin is considered an independent mediator, it is called PGI2 (prostaglandin I2) in eicosanoid nomenclature, and is a member of the prostanoids (together with the prostaglandins and thromboxane). PGI2, derived primarily from COX-2 in humans, is the major arachidonate metabolite released from the vascular endothelium. This is a controversial point, some assign COX 1 as the major prostacyclin producing cyclooxygenase in the endothelial cells of the blood vessels. [13]

The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI3. [14] The unqualified term 'prostacyclin' usually refers to PGI2. PGI2 is derived from the ω-6 arachidonic acid. PGI3 is derived from the ω-3 EPA.

Artificial synthesis

Prostacyclin can be synthesized from the methyl ester of prostaglandin F2α. [15] After its synthesis, the drug is reconstituted in saline and glycerin. [16]

Because prostacyclin is so chemically labile, quantitation of their inactive metabolites, rather than the active compounds, is used to assess their rate of synthesis. [17]

History

During the 1960s, a UK research team, headed by Professor John Vane, began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Working with a team from the Royal College of Surgeons, Vane discovered that aspirin and other oral anti-inflammatory drugs work by inhibiting the synthesis of prostaglandins. This critical finding opened the door to a broader understanding of the role of prostaglandins in the body.

A team at The Wellcome Foundation led by Salvador Moncada had identified a lipid mediator they called "PG-X," which inhibits platelet aggregation. PG-X, later known as prostacyclin, is 30 times more potent than any other then-known anti-aggregatory agent. They did this while searching for an enzyme that generates a fellow unstable prostanoid, Thromboxane A2 [18]

In 1976, Vane and fellow researchers Salvador Moncada, Ryszard Gryglewski, and Stuart Bunting published the first paper on prostacyclin in Nature. [19] The collaboration produced a synthesized molecule, which was named epoprostenol. But, as with native prostacyclin, the epoprostenol molecule is unstable in solution and prone to rapid degradation.[ citation needed ] This presented a challenge for both in vitro experiments and clinical applications.

To overcome this challenge, the research team that discovered prostacyclin continued the research. The research team synthesized nearly 1,000 analogues.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Prostaglandin</span> Group of physiologically active lipid compounds

Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.

An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation where classical Vitamin K antagonist anticoagulants have minimal effect.

<span class="mw-page-title-main">Cyclooxygenase</span> Class of enzymes

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Eicosanoids may also act as endocrine agents to control the function of distant cells.

<span class="mw-page-title-main">Thromboxane</span> Group of lipids

Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.

Prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins, the thromboxanes, and the prostacyclins. Prostanoids are seen to target NSAIDS which allow for therapeutic potential. Prostanoids are present within areas of the body such as the gastrointestinal tract, urinary tract, respiratory and cardiology systems, reproductive tract and vascular system. Prostanoids can even be seen with aid to the water and ion transportation within cells. Prostanoids help release prostaglandins upon activation, receptors may open possibilities for treatments within different systems.

<span class="mw-page-title-main">Essential fatty acid interactions</span>

There are many fatty acids found in nature. Two types of fatty acids considered essential for human health are the omega-3 and omega-6 types. These two essential fatty acids are necessary for some cellular signalling pathways and are involved in mediating inflammation, protein synthesis, and metabolic pathways in the human body.

<span class="mw-page-title-main">Thromboxane receptor</span> Mammalian protein found in Homo sapiens

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

<span class="mw-page-title-main">Treprostinil</span> Chemical compound

Treprostinil, sold under the brand names Remodulin for infusion, Orenitram for oral, and Tyvaso for inhalation, is a vasodilator that is used for the treatment of pulmonary arterial hypertension. Treprostinil is a synthetic analog of prostacyclin (PGI2).

A prostaglandin antagonist is a hormone antagonist acting upon one or more prostaglandins, a subclass of eicosanoid compounds which function as signaling molecules in numerous types of animal tissues.

<span class="mw-page-title-main">Prostacyclin synthase</span>

Prostaglandin-I synthase also known as prostaglandin I2 (prostacyclin) synthase (PTGIS) or CYP8A1 is an enzyme involved in prostanoid biosynthesis that in humans is encoded by the PTGIS gene. This enzyme belongs to the family of cytochrome P450 isomerases.

<span class="mw-page-title-main">Thromboxane A2</span> Chemical compound

Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by activating the thromboxane receptor, which results in platelet-shape change, inside-out activation of integrins, and degranulation. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot. Thromboxane A2 is also a known vasoconstrictor and is especially important during tissue injury and inflammation. It is also regarded as responsible for Prinzmetal's angina.

<span class="mw-page-title-main">Prostaglandin-endoperoxide synthase 2</span> Human enzyme involved in inflammation

Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the PTGS2 gene. In humans it is one of two cyclooxygenases. It is involved in the conversion of arachidonic acid to prostaglandin H2, an important precursor of prostacyclin, which is expressed in inflammation.

<span class="mw-page-title-main">PTGS1</span>

Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the PTGS1 gene. In humans it is one of two cyclooxygenases.

<span class="mw-page-title-main">Prostacyclin receptor</span> Mammalian protein found in Homo sapiens

The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.

<span class="mw-page-title-main">Mechanism of action of aspirin</span>

Aspirin causes several different effects in the body, mainly the reduction of inflammation, analgesia, the prevention of clotting, and the reduction of fever. Much of this is believed to be due to decreased production of prostaglandins and TXA2. Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs, which are reversible inhibitors; aspirin creates an allosteric change in the structure of the COX enzyme. However, other effects of aspirin, such as uncoupling oxidative phosphorylation in mitochondria, and the modulation of signaling through NF-κB, are also being investigated. Some of its effects are like those of salicylic acid, which is not an acetylating agent.

Cyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane(s). Their main role is to catalyze the transformation of arachidonic acid into the intermediate prostaglandin H2, which is the precursor of a variety of prostanoids with diverse and potent biological actions. Cyclooxygenases have two main isoforms that are called COX-1 and COX-2. COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system. Prostaglandin synthesis in these sites is a key factor in the development of inflammation and hyperalgesia. COX-2 inhibitors have analgesic and anti-inflammatory activity by blocking the transformation of arachidonic acid into prostaglandin H2 selectively.

<span class="mw-page-title-main">12-Hydroxyheptadecatrienoic acid</span> Chemical compound

12-Hydroxyheptadecatrienoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was discovered and structurally defined in 1973 by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg, as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.

Prostaglandin inhibitors are drugs that inhibit the synthesis of prostaglandin in human body. There are various types of prostaglandins responsible for different physiological reactions such as maintaining the blood flow in stomach and kidney, regulating the contraction of involuntary muscles and blood vessels, and act as a mediator of inflammation and pain. Cyclooxygenase (COX) and Phospholipase A2 are the major enzymes involved in prostaglandin production, and they are the drug targets for prostaglandin inhibitors. There are mainly 2 classes of prostaglandin inhibitors, namely non- steroidal anti- inflammatory drugs (NSAIDs) and glucocorticoids. In the following sections, the medical uses, side effects, contraindications, toxicity and the pharmacology of these prostaglandin inhibitors will be discussed.

<span class="mw-page-title-main">Furegrelate</span> Chemical compound

Furegrelate, also known as 5-(3-pyridinylmethyl)benzofurancarboxylic acid, is a chemical compound with thromboxane enzyme inhibiting properties that was originally developed by Pharmacia Corporation as a drug to treat arrhythmias, ischaemic heart disorders, and thrombosis but was discontinued. It is commercially available in the form furegrelate sodium salt.

References

  1. ↑ " epoprostenol " at Dorland's Medical Dictionary
  2. ↑ Kermode J, Butt W, Shann F (August 1991). "Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery". British Heart Journal. 66 (2): 175–178. doi:10.1136/hrt.66.2.175. PMC   1024613 . PMID   1883670.
  3. ↑ Pathologic Basis of Disease, Robbins and Cotran, 8th ed. Saunders Philadelphia 2010
  4. ↑ "Epoprostenol Sodium Monograph for Professionals". Drugs.com. AHFS. 6 April 2020. Retrieved 22 October 2020.
  5. ↑ "Flolan- epoprostenol sodium injection, powder, lyophilized, for solution Diluent- water solution". DailyMed. 15 November 2019. Retrieved 22 October 2020.
  6. 1 2 Stitham J, Midgett C, Martin KA, Hwa J (13 May 2011). "Prostacyclin: an inflammatory paradox". Frontiers in Pharmacology. Frontiers Media S.A. 2: 24. doi: 10.3389/fphar.2011.00024 . PMC   3108482 . PMID   21687516.
  7. ↑ Cawello W, Schweer H, Müller R, Bonn R, Seyberth HW (1994). "Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects". European Journal of Clinical Pharmacology. 46 (3): 275–277. doi:10.1007/BF00192562. PMID   8070511. S2CID   25410558.
  8. ↑ Lewis PJ, Dollery CT (July 1983). "Clinical pharmacology and potential of prostacyclin". British Medical Bulletin. 39 (3): 281–4. doi:10.1093/oxfordjournals.bmb.a071834. PMID   6354353.
  9. ↑ ^ REM_RefGuideWC_AUG07v.1
  10. ↑ Haché M, Denault A, Bélisle S, Robitaille D, Couture P, Sheridan P, et al. (March 2003). "Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery". The Journal of Thoracic and Cardiovascular Surgery. 125 (3): 642–649. doi: 10.1067/mtc.2003.107 . PMID   12658208.
  11. ↑ Nickson, C. (2015, October 28). Prostacyclin or Epoprostenol. Retrieved November 16, 2015, from http://lifeinthefastlane.com/ccc/prostacyclin-or-epoprostenol/
  12. ↑ prostacyclin. (n.d.) Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health, Seventh Edition. (2003). Retrieved November 17, 2015 from http://medical-dictionary.thefreedictionary.com/prostacyclin
  13. ↑ Kirkby NS, Lundberg MH, Harrington LS, Leadbeater PD, Milne GL, Potter CM, et al. (October 2012). "Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system". Proceedings of the National Academy of Sciences of the United States of America. 109 (43): 17597–17602. Bibcode:2012PNAS..10917597K. doi: 10.1073/pnas.1209192109 . PMC   3491520 . PMID   23045674.
  14. ↑ Fischer S, Weber PC (September 1985). "Thromboxane (TX)A3 and prostaglandin (PG)I3 are formed in man after dietary eicosapentaenoic acid: identification and quantification by capillary gas chromatography-electron impact mass spectrometry". Biomedical Mass Spectrometry. 12 (9): 470–476. doi:10.1002/bms.1200120905. PMID   2996649.
  15. ↑ Johnson RA, Lincoln FH, Nidy EG, Schneider WP, Thompson JL, Axen U (1978). "Synthesis and characterization of prostacyclin, 6-ketoprostaglandin F1.alpha., prostaglandin I1, and prostaglandin I3". Journal of the American Chemical Society. 100 (24): 7690–7705. doi:10.1021/ja00492a043.
  16. ↑ Nickson C (15 October 2015). "Prostacyclin or Epoprostenol". Life in the Fast Lane. Archived from the original on 28 March 2015. Retrieved 16 November 2015.
  17. ↑ Collins PW, Djuric SW (1993). "Synthesis of therapeutically useful prostaglandin and prostacyclin analogs". Chemical Reviews. 03 (4): 1533–1564. doi:10.1021/cr00020a007.
  18. ↑ Kermode J, Butt W, Shann F (August 1991). "Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery". British Heart Journal. 66 (2): 175–178. doi:10.1016/s0002-9149(99)80377-4. PMC   1024613 . PMID   1883670.
  19. ↑ Moncada S, Gryglewski R, Bunting S, Vane JR (October 1976). "An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation". Nature. 263 (5579): 663–665. Bibcode:1976Natur.263..663M. doi:10.1038/263663a0. PMID   802670. S2CID   4279030.
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