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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Drugbox |
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| verifiedrevid = 407971997 |
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| verifiedrevid = 457118423 |
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| IUPAC_name = (''Z'')-5-furan-2-ylidene]pentanoic acid |
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| image = Prostacyclin-2D-skeletal.png |
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| image = Prostacyclin.svg |
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| width = 200px |
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| width = 275 |
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| image2 = Prostacyclin spacefill.png |
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| image2 = Prostacyclin spacefill.png |
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<!--Clinical data--> |
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<!-- Clinical data --> |
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| tradename = |
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| pronounce = |
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| tradename = Flolan, Veletri |
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| Drugs.com = {{drugs.com|monograph|iloprost}} |
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| Drugs.com = {{drugs.com|monograph|epoprostenol-sodium}} |
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| pregnancy_category = |
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| legal_status = |
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| MedlinePlus = |
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| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) --> |
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| routes_of_administration = |
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| licence_EU = <!-- EMA uses INN (or special INN_EMA) --> |
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| DailyMedID = Epoprostenol_sodium |
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| licence_US = <!-- FDA may use generic or brand name (generic name preferred) --> |
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| pregnancy_AU = B1 |
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| pregnancy_AU_comment = |
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| pregnancy_US = B |
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| pregnancy_US_comment = (Veletri); N (Flolan) |
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| pregnancy_category= |
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| dependency_liability = |
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| addiction_liability = |
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| routes_of_administration = |
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| class = |
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| ATCvet = |
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| ATC_prefix = B01 |
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| ATC_suffix = AC09 |
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| ATC_supplemental = |
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<!--Pharmacokinetic data--> |
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<!-- Legal status --> |
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| legal_AU = S4 |
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| bioavailability = |
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| protein_bound = |
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| legal_AU_comment = |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| metabolism = |
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| legal_BR_comment = |
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| elimination_half-life = |
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| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA_comment = |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> |
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| legal_UK_comment = |
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| legal_US = Rx-only |
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| legal_US_comment = |
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| legal_EU = |
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| legal_EU_comment = |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = <!-- For countries not listed above --> |
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<!-- Pharmacokinetic data --> |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| metabolites = |
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| onset = |
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| elimination_half-life = 42 seconds |
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| duration_of_action = |
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| excretion = |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| index2_label = as salt |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| IUPHAR_ligand = 1915 |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 35121-78-9 |
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| CAS_number = 35121-78-9 |
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| ATC_prefix = B01 |
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| PubChem = 5282411 |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| ATC_suffix = AC09 |
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| DrugBank = DB01240 |
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| ATC_supplemental = |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| PubChem = 114805 |
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| ChemSpiderID = 102770 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| DrugBank = <!-- blanked - oldvalue: APRD00949 --> |
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| UNII = DCR9Z582X0 |
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| KEGG = D00106 |
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| KEGG2 = D01337 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = <!-- blanked - oldvalue: 962 --> |
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| ChEMBL = 1139 |
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| C=20 | H=32 | O=5 |
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<!--Chemical data--> |
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| molecular_weight = 352.465 g/mol |
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| IUPAC_name = (''Z'')-5-furan-2-ylidene]pentanoic acid |
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| C=20 | H=32 | O=5 |
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| smiles = OC(=O)CCC\C=C1\C2(/C=C/(O)CCCCC)(O)C2O1 |
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| smiles = OC(=O)CCC\C=C1\C2(/C=C/(O)CCCCC)(O)C2O1 |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI = 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 |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = KAQKFAOMNZTLHT-OZUDYXHBSA-N |
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}} |
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}} |
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'''Prostacyclin''' (or '''PGI<sub>2</sub>''') is a member of the family of ] ]s known as ]. |
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'''Prostacyclin''' (also called '''prostaglandin I<sub>2</sub>''' or '''PGI<sub>2</sub>''') is a ] member of the ] family of ] ]s. It inhibits platelet activation and is also an effective vasodilator. |
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As a drug, it is also known as "epoprostenol".<ref>{{DorlandsDict|three/000036426|epoprostenol}}</ref> The terms are sometimes used interchangeably.<ref name="pmid1883670">{{cite journal |author=Kermode J, Butt W, Shann F |title=Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery |journal=British heart journal |volume=66 |issue=2 |pages=175–8 |year=1991 |month=August |pmid=1883670 |pmc=1024613 |doi= 10.1136/hrt.66.2.175|url=http://heart.bmj.com/cgi/pmidlookup?view=long&pmid=1883670}}</ref> |
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When used as a drug, it is also known as '''epoprostenol'''.<ref>{{DorlandsDict|three/000036426|epoprostenol}}</ref> The terms are sometimes used interchangeably.<ref name="pmid1883670">{{cite journal | vauthors = Kermode J, Butt W, Shann F | title = Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery | journal = British Heart Journal | volume = 66 | issue = 2 | pages = 175–178 | date = August 1991 | pmid = 1883670 | pmc = 1024613 | doi = 10.1136/hrt.66.2.175 }}</ref> |
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==History== |
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During the 1960s, a U.K. research team, headed by Professor ], began to explore the role of ]s in anaphylaxis and respiratory diseases. Working with a team from the Royal College of Surgeons, Sir John 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. |
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== Function == |
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Sir John and a team from the Wellcome Foundation, had identified a lipid mediator they called “PG-X,” which inhibits platelet aggregation. PG-X, which later would become known as prostacyclin, is 30 times more potent than any other then-known anti-aggregatory agent. |
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Prostacyclin chiefly prevents formation of the ] involved in primary ] (a part of ] formation). It does this by inhibiting platelet activation.<ref>''Pathologic Basis of Disease'', Robbins and Cotran, 8th ed. Saunders Philadelphia 2010</ref> It is also an effective ]. Prostacyclin's interactions contrast with those of ] (TXA<sub>2</sub>), another eicosanoid. Both molecules are derived from ], and work together with opposite platelet aggregatory effects. These strongly suggest a mechanism of cardiovascular ] between these two hormones in relation to ] damage. |
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==Medical uses== |
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By 1976, Sir John and fellow researchers ], ] and ] published the first paper on prostacyclin, in the scientific journal Nature. The collaboration produced a synthesized molecule, which was given the name epoprostenol. But, as with native prostacyclin, the structure of the epoprostenol molecule proved to be unstable in solution, prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications. |
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It is used to treat ] (PAH),<ref name="Ruopp 2022">{{cite journal | vauthors = Ruopp NF, Cockrill BA | title = Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review | journal = JAMA | volume = 327 | issue = 14 | pages = 1379–1391 | date = April 2022 | pmid = 35412560 | doi = 10.1001/jama.2022.4402 }}</ref><ref>{{cite web | title=Epoprostenol Sodium Monograph for Professionals | website=Drugs.com | publisher=AHFS | date=6 April 2020 | url=https://www.drugs.com/monograph/epoprostenol-sodium.html | access-date=22 October 2020}}</ref><ref>{{cite web | title=Flolan- epoprostenol sodium injection, powder, lyophilized, for solution Diluent- water solution | website=DailyMed | date=15 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8e4b636e-ee9c-4111-779d-28c8369d283b | access-date=22 October 2020}}</ref> ],<ref name = "Stitham_2011">{{cite journal | vauthors = Stitham J, Midgett C, Martin KA, Hwa J | title = Prostacyclin: an inflammatory paradox | journal = Frontiers in Pharmacology | volume = 2 | pages = 24 | date = 13 May 2011 | pmid = 21687516 | pmc = 3108482 | doi = 10.3389/fphar.2011.00024 | publisher = Frontiers Media S.A. | doi-access = free }}</ref> as well as ].<ref name = "Stitham_2011" /> Prostacyclins are given to people with class III or class IV PAH.<ref name="Hassoun 2021">{{cite journal | vauthors = Hassoun PM | title = Pulmonary Arterial Hypertension | journal = The New England Journal of Medicine | volume = 385 | issue = 25 | pages = 2361–2376 | date = December 2021 | pmid = 34910865 | doi = 10.1056/NEJMra2000348 }}</ref> |
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To overcome this challenge, the research team that discovered prostacyclin was determined to continue the research in an attempt to build upon the success they had seen with the prototype molecule. The research team synthesized nearly 1,000 analogues. |
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Through innovative work done by researcher ], ] has demonstrated a unique effect on ] gamma, a ] important in vascular pathogenesis as a mediator of proliferation, ], and ]. Through a complementary, yet ], treprostinil activates PPARs , another mechanism that contributes to the anti-growth benefits of the prostacyclin class. |
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==Production== |
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] Prostacyclin is produced in ] ]s from ] (PGH<sub>2</sub>) by the action of the ] ]. Although prostacyclin is considered an independent mediator, it is called '''PGI<sub>2</sub>''' (prostaglandin I<sub>2</sub>) in eicosanoid nomenclature, and is a member of the ]s (together with the ]s and ]). |
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The series-3 prostaglandin PGH<sub>3</sub> also follows the prostacyclin synthase pathway, yielding another prostacyclin, '''PGI<sub>3</sub>'''.<ref>{{cite journal |author=Fischer S, Weber PC |title=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 |journal=Biomed. Mass Spectrom. |volume=12 |issue=9 |pages=470–6 |year=1985 |pmid=2996649 |doi=10.1002/bms.1200120905}}</ref> The unqualified term 'prostacyclin' usually refers to PGI<sub>2</sub>. PGI<sub>2</sub> is derived from the ω-6 ]. PGI<sub>3</sub> is derived from the ω-3 ]. |
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==Function== |
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Prostacyclin (PGI<sub>2</sub>) chiefly prevents formation of the ] plug involved in primary ] (a part of ] formation). It does this by inhibiting platelet activation.<ref>''Pathologic Basis of Disease'', Robbins and Cotran, 8th ed. Saunders Philadelphia 2010</ref> It is also an effective ]. Prostacyclin's interactions in contrast to ] (TXA<sub>2</sub>), another eicosanoid, strongly suggest a mechanism of cardiovascular ] between the two hormones in relation to ] damage. |
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==Degradation== |
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==Degradation== |
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Prostacyclin, which has a ] of 42 seconds<ref>Cawello W, Schweer H, Muller R, et al. Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects. Eur J Clin Pharmacol 1994;46:275-7</ref>, is broken down into 6-keto-PGF<sub>1</sub>, which is a much weaker vasodilator. |
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Prostacyclin, which has a ] of 42 seconds,<ref name="pmid8070511">{{cite journal | vauthors = Cawello W, Schweer H, Müller R, Bonn R, Seyberth HW | title = Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects | journal = European Journal of Clinical Pharmacology | volume = 46 | issue = 3 | pages = 275–277 | year = 1994 | pmid = 8070511 | doi = 10.1007/BF00192562 | s2cid = 25410558 }}</ref> is broken down into 6-keto-PGF<sub>1</sub>, which is a much weaker vasodilator. |
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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 ].<ref name="pmid6354353">{{cite journal | vauthors = Lewis PJ, Dollery CT | title = Clinical pharmacology and potential of prostacyclin | journal = British Medical Bulletin | volume = 39 | issue = 3 | pages = 281–4 | date = July 1983 | pmid = 6354353 | doi = 10.1093/oxfordjournals.bmb.a071834 }}</ref> |
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==Mode of action== |
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==Mechanism== |
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:{| class=wikitable |
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!Cellular response |
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!Cellular response |
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|rowspan=3|Classical<br>functions |
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| rowspan=3|Classical<br />functions |
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|Vessel tone |
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| Vessel tone |
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|↑cAMP, ↓ET-1<br>↓Ca<sup>2+</sup>, ↑K<sup>+</sup> |
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|↑cAMP, ↓ET-1<br />↓Ca<sup>2+</sup>, ↑K<sup>+</sup> |
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|↓SMC proliferation<br>↑Vasodilation |
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|↓SMC proliferation<br />↑Vasodilation |
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|Antiproliferative |
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| Antiproliferative |
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|↑cAMP<br /> ↑PPARgamma |
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|↑cAMP<br>&earr;PPAR |
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|↓Fibroblast growth<br>↑Apoptosis |
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|↓Fibroblast growth<br />↑Apoptosis |
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|Antithrombotic |
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| Antithrombotic |
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|↓Thromboxane-A2<br>↓PDGF |
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|↓Thromboxane-A2<br />↓PDGF |
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|↓Platelet aggregation<br>↓Platelet adherence to vessel wall |
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|↓Platelet aggregation<br />↓Platelet adherence to vessel wall |
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|rowspan=2|Novel<br>functions |
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| rowspan=2|Novel<br />functions |
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|Antiinflammatory |
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| Antiinflammatory |
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|↓IL-1, IL-6<br>↑IL-10 |
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|↓IL-1, IL-6<br />↑IL-10 |
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|↓Proinflammatory cytokines<br>↑Antiinflammatory cytokines |
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|↓Proinflammatory cytokines<br />↑Antiinflammatory cytokines |
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|Antimitogenic |
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| Antimitogenic |
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|↓VEGF<br>↓TGF-β |
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|↓VEGF<br />↓TGF-β |
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|↓Angiogenesis<br>↑ECM remodeling |
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|↓Angiogenesis<br />↑ECM remodeling |
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As mentioned above, prostacyclin (PGI<sub>2</sub>) is released by healthy endothelial cells and performs its function through a ] signaling cascade that involves ]s on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor (]) is activated when it binds to PGI<sub>2</sub>. This activation, in turn, signals adenylyl cyclase to produce ]. 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 ] (TXA<sub>2</sub>) binding (leading to platelet activation and subsequent ]). PGI<sub>2</sub> also binds to endothelial ]s, and in the same manner, raises cAMP levels in the cytosol. This cAMP then goes on to activate ] (PKA). PKA then continues the cascade by promoting the phosphorylation of the ], which inhibits it and leads to ] relaxation and ]. It can be noted that PGI<sub>2</sub> and TXA<sub>2</sub> work as physiological antagonists. |
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Prostacyclin (PGI<sub>2</sub>) is released by healthy endothelial cells and performs its function through a ] signaling cascade that involves ]s on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor (]) is activated when it binds to PGI<sub>2</sub>. This activation, in turn, signals adenylyl cyclase to produce ]. 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 ] (TXA<sub>2</sub>) binding (leading to platelet activation and subsequent ]). PGI<sub>2</sub> also binds to endothelial ]s and in the same manner raise cAMP levels in the cytosol. This cAMP then goes on to activate ] (PKA). PKA then continues the cascade by phosphorylating and inhibiting ], which leads to ] relaxation and ]. It can be noted that PGI<sub>2</sub> and TXA<sub>2</sub> work as physiological antagonists. |
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==Members<ref>^ REM_RefGuideWC_AUG07v.1</ref>== |
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==Members<ref>^ REM_RefGuideWC_AUG07v.1</ref>== |
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{| class="wikitable" border="1" |
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! PROSTACYCLINS |
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! PROSTACYCLINS |
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| Flolan<br>(epoprostenol sodium)<br>for Injection |
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| Flolan<br />(epoprostenol sodium)<br />for Injection |
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| Continuously infused |
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| Continuously infused |
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| 2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achieved |
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| 2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achieved |
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| Class III<br>Class IV |
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| Class III<br />Class IV |
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| <br>(epoprostenol)<br>for Injection |
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| <br />(epoprostenol)<br />for Injection |
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| Continuously infused |
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| Continuously infused |
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| 2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achieved |
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| 2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achieved |
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| Class III<br>Class IV |
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| Class III<br />Class IV |
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| Remodulin SC§<br>(treprostinil sodium)<br>Injection |
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| Remodulin SC§<br />(] sodium)<br />Injection |
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| Continuously infused |
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| Continuously infused |
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| 1.25 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 |
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| 1.25 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 achieved |
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| Class II<br />Class III<br />Class IV |
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suitable efficacy/tolerability balance is achieved |
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| Class II<br>Class III<br>Class IV |
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| <br>(iloprost)<br>Inhalation Solution |
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| <br />(])<br />Inhalation Solution |
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| Inhaled 6–9 times daily |
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| Inhaled 6–9 times daily |
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| 2.5 mcg 6–9 times daily to start, increased to 5.0 mcg 6–9 times daily if well tolerated |
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| 2.5 μg 6–9 times daily to start, increased to 5.0 μg 6–9 times daily if well tolerated |
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| Class III<br>Class IV |
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| Class III<br />Class IV |
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* in primary pulmonary hypertension (PPH) |
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* in primary pulmonary hypertension (PPH) |
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Its production is inhibited indirectly by ], which inhibit the ] enzymes COX1 and COX2. These convert ] to ] (PGH<sub>2</sub>), the immediate precursor of prostacyclin. Since thromboxane (an ] 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, TXA<sub>2</sub> and PGI<sub>2</sub>. Since PGI<sub>2</sub> 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 ] the formation of PGI<sub>2</sub>. In contrast, TXA<sub>2</sub> is released primarily by anucleated platelets, which are unable to respond to NSAID COX inhibition with additional ] of the COX gene because they lack ] material necessary to perform such a task. This allows NSAIDs to result in PGI<sub>2</sub> dominance that promotes circulation and retards ]. |
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The production of prostacyclin is inhibited by the action of ] on ] enzymes COX1 and COX2. These convert ] to ] (PGH<sub>2</sub>), the immediate precursor of prostacyclin. Since thromboxane (an ] 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, TXA<sub>2</sub> and PGI<sub>2</sub>. Since PGI<sub>2</sub> 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 ] the formation of PGI<sub>2</sub>. In contrast, TXA<sub>2</sub> is released primarily by anucleated platelets, which are unable to respond to NSAID COX inhibition with additional ] of the COX gene because they lack ] material necessary to perform such a task. This allows NSAIDs to result in PGI<sub>2</sub> dominance that promotes circulation and retards ]. |
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In patients with ], inhaled epoprostenol reduces pulmonary pressure, and improves right ventricular ] 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 ] dysfunction or an increase in surgical bleeding after administration of inhaled epoprostenol has been found.<ref>Haché M, Denault A, et al. Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery. J Thorac Cardiovasc Surg 2003;125:642-649</ref> |
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In patients with ], inhaled epoprostenol reduces pulmonary pressure, and improves right ventricular ] 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 ] dysfunction or an increase in surgical bleeding after administration of inhaled epoprostenol has been found.<ref name="pmid12658208">{{cite journal | vauthors = Haché M, Denault A, Bélisle S, Robitaille D, Couture P, Sheridan P, Pellerin M, Babin D, Noël N, Guertin MC, Martineau R, Dupuis J | display-authors = 6 | title = Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery | journal = The Journal of Thoracic and Cardiovascular Surgery | volume = 125 | issue = 3 | pages = 642–649 | date = March 2003 | pmid = 12658208 | doi = 10.1067/mtc.2003.107 | doi-access = free }}</ref> The drug has been known to cause flushing, headaches and hypotension.<ref> |
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Nickson, C. (2015, October 28). Prostacyclin or Epoprostenol. Retrieved November 16, 2015, from http://lifeinthefastlane.com/ccc/prostacyclin-or-epoprostenol/</ref> |
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==See also== |
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==Synthesis== |
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===Biosynthesis=== |
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] Prostacyclin is produced in ] ]s, which line the walls of arteries and veins,<ref>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</ref> from ] (PGH<sub>2</sub>) by the action of the ] ]. Although prostacyclin is considered an independent mediator, it is called '''PGI<sub>2</sub>''' (prostaglandin I<sub>2</sub>) in eicosanoid nomenclature, and is a member of the ]s (together with the ]s and ]). PGI<sub>2</sub>, 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.<ref>{{cite journal | vauthors = Kirkby NS, Lundberg MH, Harrington LS, Leadbeater PD, Milne GL, Potter CM, Al-Yamani M, Adeyemi O, Warner TD, Mitchell JA | display-authors = 6 | title = Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 43 | pages = 17597–17602 | date = October 2012 | pmid = 23045674 | pmc = 3491520 | doi = 10.1073/pnas.1209192109 | doi-access = free | bibcode = 2012PNAS..10917597K }}</ref> |
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The series-3 prostaglandin PGH<sub>3</sub> also follows the prostacyclin synthase pathway, yielding another prostacyclin, '''PGI<sub>3</sub>'''.<ref>{{cite journal | vauthors = Fischer S, Weber PC | title = 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 | journal = Biomedical Mass Spectrometry | volume = 12 | issue = 9 | pages = 470–476 | date = September 1985 | pmid = 2996649 | doi = 10.1002/bms.1200120905 }}</ref> The unqualified term 'prostacyclin' usually refers to PGI<sub>2</sub>. PGI<sub>2</sub> is derived from the ω-6 ]. PGI<sub>3</sub> is derived from the ω-3 ]. |
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==References== |
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===Artificial synthesis=== |
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Prostacyclin can be ] from the ] ] of ].<ref>{{cite journal | vauthors = Johnson RA, Lincoln FH, Nidy EG, Schneider WP, Thompson JL, Axen U |doi=10.1021/ja00492a043|title=Synthesis and characterization of prostacyclin, 6-ketoprostaglandin F1.alpha., prostaglandin I1, and prostaglandin I3|journal=Journal of the American Chemical Society|volume=100|issue=24|pages=7690–7705|year=1978 }}</ref> After its synthesis, the drug is reconstituted in saline and glycerin.<ref> |
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{{cite web | vauthors = Nickson C | date = 15 October 2015 | title = Prostacyclin or Epoprostenol | access-date = 16 November 2015 | url = http://lifeinthefastlane.com/ccc/prostacyclin-or-epoprostenol/ | archive-url = https://web.archive.org/web/20150328235845/http://lifeinthefastlane.com/ccc/prostacyclin-or-epoprostenol/ | archive-date = 28 March 2015 | work = Life in the Fast Lane }}</ref> |
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Because prostacyclin is so chemically labile, quantitation of their inactive metabolites, rather than the active compounds, is used to assess their rate of synthesis.<ref>{{cite journal|doi=10.1021/cr00020a007|title=Synthesis of therapeutically useful prostaglandin and prostacyclin analogs| journal = Chemical Reviews | volume = 03|issue=4|pages=1533–1564|year=1993| vauthors = Collins PW, Djuric SW }}</ref> |
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==History== |
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<!-- this section is repeated (with minor changes) in ] --> |
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During the 1960s, a UK research team, headed by Professor ], began to explore the role of ]s in anaphylaxis and respiratory diseases. Working with a team from the ], 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. |
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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, ]<ref name="pmid7840052">{{cite journal | vauthors = Kermode J, Butt W, Shann F | title = Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery | journal = British Heart Journal | volume = 66 | issue = 2 | pages = 175–178 | date = August 1991 | pmid = 1883670 | doi = 10.1016/s0002-9149(99)80377-4 | pmc = 1024613 }}</ref> |
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In 1976, Vane and fellow researchers ], ], and ] published the first paper on prostacyclin in ''Nature''.<ref>{{cite journal | vauthors = Moncada S, Gryglewski R, Bunting S, Vane JR | title = An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation | journal = Nature | volume = 263 | issue = 5579 | pages = 663–665 | date = October 1976 | pmid = 802670 | doi = 10.1038/263663a0 | s2cid = 4279030 | bibcode = 1976Natur.263..663M }}</ref> 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|date=December 2015}} This presented a challenge for both in vitro experiments and clinical applications. |
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To overcome this challenge, the research team that discovered prostacyclin continued the research. The research team synthesized nearly 1,000 analogues.{{citation needed|date=December 2015}} |
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== References == |
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{{reflist}} |
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{{reflist}} |
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== External links == |
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* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/epoprostenol | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Epoprostenol }} |
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* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/epoprostenol%20sodium | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Epoprostenol sodium }} |
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