Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Terfenadine: Difference between pages

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc}}

| Watchedfields = changed

| verifiedrevid = 470602363

| width = 250px

| tradename = Seldane, Triludan, Teldane

| pregnancy_US = C

| routes_of_administration = [[Oral administration|By mouth]]

| bioavailability =

| metabolism = [[Liver|Hepatic]] ([[CYP3A4]])

| metabolites = [[Fexofenadine]]

| IUPHAR_ligand = 2608

| synonyms =

| C=32 | H=41 | N=1 | O=2

| SMILES = OC(c1ccccc1)(c2ccccc2)C4CCN(CCCC(O)c3ccc(cc3)C(C)(C)C)CC4

| StdInChI = 1S/C32H41NO2/c1-31(2,3)26-18-16-25(17-19-26)30(34)15-10-22-33-23-20-29 (21-24-33)32(35,27-11-6-4-7-12-27)28-13-8-5-9-14-28/ h4-9,11-14,16-19,29-30,34-35H,10,15,20-24H2,1-3H3

| chirality = [[Racemic mixture]]

'''Terfenadine''' is an [[antihistamine]] formerly used for the treatment of [[allergy|allergic]] conditions. It was brought to market by [[Hoechst Marion Roussel]] (now [[Sanofi]]) and was marketed under various brand names, including '''Seldane''' in the [[United States]], '''Triludan''' in the [[United Kingdom]], and '''Teldane''' in [[Australia]].<ref name="jama96"/> It was superseded by [[fexofenadine]] in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart (specifically [[Cardiac dysrhythmia|cardiac arrhythmia]] caused by [[QT interval]] prolongation) and has been withdrawn from markets worldwide.<ref>{{cite book | vauthors = Horak F | chapter = Antialergic and Vasoactive Drugs for Allergic Rhinitis Chapter 4 | title = Allergy Frontiers:Therapy and Prevention | volume = 5 | veditors = Pawankar R, Holgate ST, Rosenwasser LJ | publisher = Springer Science & Business Media | date = 2010 | isbn = 978-4-431-99362-9 }}</ref>{{rp|53}}

==Pharmacology==

Terfenadine acts as a [[peripherally-selective drug|peripherally-selective]] [[antihistamine]], or [[receptor antagonist|antagonist]] of the [[histamine]] [[H1 receptor|H₁ receptor]].<ref name="Sneader2005">{{cite book | author = Walter Sneader | date = 31 October 2005 | title = Drug Discovery: A History | publisher = John Wiley & Sons | pages = 406– | isbn = 978-0-470-01552-0 | url = https://books.google.com/books?id=jglFsz5EJR8C&pg=PA406}}</ref> It is a [[prodrug]], generally completely [[metabolism|metabolized]] to the active form [[fexofenadine]] in the [[liver]] by the [[enzyme]] [[cytochrome P450 3A4]]. Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally is not measurable in the plasma. Terfenadine itself, however, is [[cardiotoxic]] at higher doses, while its major [[active metabolite]] is not. Terfenadine, in addition to its antihistamine effects, also acts as a [[potassium channel blocker]] (K_v11.1 encoded by the gene ''[[hERG]]''). Since its active metabolite is not a potassium channel blocker, no cardiotoxicity is associated with [[fexofenadine]].<ref name="Cir1996"/> Sudden toxicity is possible even after years of use without problems as a result of an interaction with other medications such as [[erythromycin]], or foods such as [[List of drugs affected by grapefruit|grapefruit]]. The addition of, or a dosage increase in, these CYP3A4 inhibitors makes it harder for the body to metabolize and remove terfenadine. In larger plasma concentrations, it may lead to toxic effects on the heart's rhythm (e.g. [[ventricular tachycardia]] and ''[[torsades de pointes]]'').

==History==

Terfenadine was synthesized by chemists at [[Marion Merrell Dow#Richardson-Merrell|Richardson–Merrell]] in 1973 as a potential [[tranquilizer]].<ref name="Sneader2005" /> However, it was found to be inactive for such purposes as it did not cross the [[blood–brain barrier]] or enter the [[central nervous system]].<ref name="Sneader2005" /> Pharmacologist Richard Kinsolving noticed that terfenadine showed a structural resemblance to the antihistamine [[diphenhydramine]], so terfenadine was tested as an antihistamine.<ref name="Sneader2005" /> It was found to be a non-sedating antihistamine and was the first such drug to be discovered.<ref name="Sneader2005" />

In the United States, terfenadine as Seldane was brought to market in 1985 as the first [[non-sedating antihistamines|non-sedating antihistamine]] for the treatment of [[allergic rhinitis]].<ref name="jama96"/><ref name="ladainews"/> In June 1990, evidence of serious [[ventricular arrhythmia]]s among those taking Seldane prompted the FDA to issue a report on the [[risk factor]]s associated with [[wikt:concomitant|concomitant]] use of the drug with [[macrolide]] antibiotics and [[ketoconazole]].<ref name="jama96"/> Two months later, the FDA required the manufacturer to send a letter to all physicians, alerting them to the problem; in July 1992, the existing precautions were elevated to a [[black box warning]]<ref name="jama96"/> and the issue attracted mass media attention in reports that people with liver disease or who took ketoconazole, an antifungal agent, or the antibiotic [[erythromycin]], could suffer [[cardiac dysrhythmia|cardiac arrhythmia]] if they also took Seldane.<ref name="ladainews"/>

In January 1997, the same month when the U.S. [[Food and Drug Administration]] (FDA) had earlier approved a generic version of Seldane made by [[Ivax Corporation|IVAX Corporation]] of Miami, the FDA recommended terfenadine-containing drugs be removed from the market and physicians consider alternative medications for their patients.<ref name="ladainews"/> Seldane (and Seldane-D, terfenadine combined with the decongestant [[pseudoephedrine]]) were removed from the U.S. market by their manufacturer in late 1997 after the FDA approval of Allegra-D (fexofenadine/pseudoephedrine).<ref>{{cite web| title= FDA Approves Allegra-D, Manufacturer To Withdraw Seldane From Marketplace | publisher= [[Food and Drug Administration]] | url= https://www.fda.gov/bbs/topics/ANSWERS/ANS00843.html | archive-url= https://web.archive.org/web/20080223144824/https://www.fda.gov/bbs/topics/ANSWERS/ANS00843.html | archive-date= 2008-02-23 | access-date=2010-11-11}}</ref> Terfenadine-containing drugs were subsequently removed from the Canadian market in 1999,<ref>{{cite web | url = http://www.hc-sc.gc.ca/dhp-mps/medeff/advers-react-neg/fs-if/terfenadine_e.html | title = Status of Terfenadine-Containing Drugs in Canada | archive-url = https://web.archive.org/web/20060713234226/http://www.hc-sc.gc.ca/dhp-mps/medeff/advers-react-neg/fs-if/terfenadine_e.html | archive-date= 13 July 2006 | work = [[Health Canada]] | date = 23 April 2004 }}</ref> and are no longer available for prescription in the UK.<ref>{{cite web | url = http://www.gpnotebook.com/simplepage.cfm?ID=-1603600346 | title = Terfenadine - General Practice notebook | work = GPnotebook.co.uk | publisher = Oxbridge Solutions Lt }}</ref>

==References==

{{Reflist|refs=

<ref name="jama96">{{cite journal | vauthors = Thompson D, Oster G | title = Use of terfenadine and contraindicated drugs | journal = JAMA | volume = 275 | issue = 17 | pages = 1339–41 | date = May 1996 | pmid = 8614120 | doi = 10.1001/jama.1996.03530410053033 | publisher = [[American Medical Association]] }}</ref>

<ref name="ladainews">{{cite web | title= FDA May Pull Plug on Seldane | url= http://www.thefreelibrary.com/FDA+MAY+PULL+PLUG+ON+SELDANE-a083851730 | date= January 14, 1997 | vauthors= Rosenthal | via= [[Associated Press|AP]] | work= [[Los Angeles Daily News]] | publisher= [[TheFreeLibrary.com]] | access-date= 2010-11-11 | archive-date= 2012-10-21 | archive-url= https://web.archive.org/web/20121021205439/http://www.thefreelibrary.com/FDA+MAY+PULL+PLUG+ON+SELDANE-a083851730 | url-status= dead }}</ref>

<ref name="Cir1996">{{cite journal | vauthors = Roy M, Dumaine R, Brown AM | title = HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine | journal = Circulation | volume = 94 | issue = 4 | pages = 817–23 | date = August 1996 | pmid = 8772706 | doi = 10.1161/01.cir.94.4.817 | publisher = [[American Heart Association]] }}</ref>

}}

{{Antihistamines}}

{{Histamine receptor modulators}}

{{PAF receptor modulators}}

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