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

{{short description|Antibiotic}}

| Watchedfields = changed

| verifiedrevid = 470618270

| IUPAC_name = 7-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-[1,8] naphthyridine-3-carboxylic acid

| image = Trovafloxacin.svg

| width = 220

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 9763

| C=20 | H=15 | F=3 | N=4 | O=3

'''Trovafloxacin''' (sold as '''Trovan''' by [[Pfizer]] and '''Turvel''' by [[Laboratorios Almirall]]) is a broad spectrum [[antibiotic]] that inhibits the uncoiling of [[supercoiling|supercoiled]] [[DNA]] in various [[bacteria]] by blocking the activity of [[DNA gyrase]] and [[topoisomerase]] IV.<ref>{{cite journal | vauthors = Gootz TD, Zaniewski R, Haskell S, Schmieder B, Tankovic J, Girard D, Courvalin P, Polzer RJ | display-authors = 6 | title = Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyrase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro | journal = Antimicrobial Agents and Chemotherapy | volume = 40 | issue = 12 | pages = 2691–2697 | date = December 1996 | pmid = 9124824 | pmc = 163605 | doi = 10.1128/AAC.40.12.2691 }}</ref> It was withdrawn from the market due to the risk of [[hepatotoxicity]]. It had better [[Gram-positive]] bacterial coverage but less [[Gram-negative]] coverage than the previous [[fluoroquinolones]].

==Adverse reactions==

Trovafloxacin use is significantly restricted due to its high potential for inducing serious and sometimes fatal liver damage.<ref>{{cite journal |title=Acute liver failure due to trovafloxacin: CT findings |journal=Emergency Radiology |volume=8 |issue=2 |pages=108–110 |doi=10.1007/PL00011876 |year=2001 | vauthors = Pannu HK, Gottlieb L, Fishman EK |s2cid=43307678 }}</ref> Currently, the drug is not approved for use in the U.S. or the European Union due to association with cases of acute liver failure and death.

==Manufacturing==

[[File:Trovafloxacin synthesis.svg|thumb|center|700px|Trovafloxacin synthesis: K. E. Brighty, {{US patent|5164402}} (1992 to Pfizer).]]

The key reaction in building the ring consists of [[1,3-Dipolar cycloaddition]] of [[ethyl diazoacetate]] to N-Cbz-[[3-pyrroline]] to afford the [[pyrrazolidine]] ('''3'''). [[Pyrolysis]] results in loss of nitrogen and formation of the cyclopropylpyrrolidine ring. The stereochemistry of the ring simply reflects the thermodynamics, since ''cis'' ring fusion is by far the most stable arrangement, as is the ''cis'' configuration of the ester group. The ester is then saponified to the corresponding carboxylic acid ('''5'''). The acid undergoes a version of the [[Curtius rearrangement]] when treated with [[diphenylphosphoryl azide]] (DPPA) to afford the transient isocyanate ('''6'''). The reactive function adds [[t-BuOH]] from the reaction medium to afford the product as its [[tert-Butyloxycarbonyl protecting group]] derivative ('''7'''). [[Catalytic hydrogenation]] then removes the [[carbobenzyloxy]] [[protecting group]] to afford the secondary amine ('''8'''). In a standard [[quinoline]] reaction, this amine is then used to displace the more reactive fluorine at the 7-position in Ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate ('''9''').<ref>D. Lednicer, ''The organic chemistry of Drug Synthesis'', '''Vol. 5''', p 123 (1995).</ref>

== Society and culture ==

=== Legal status ===

The U.S. Food and Drug Administration approved trovafloxacin for therapeutic use in December 1997 for use in patients aged 18 years and older.<ref>{{Cite web|title=Trovafloxacin – Approval Letter & Printed Labelling|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020760a_appltr_prntlbl.pdf|website=[[Food and Drug Administration]]}}</ref> In June 1999, the agency advised doctors to limit the prescription of trovafloxacin due to adverse events associated with the drug (over 100 cases of acute liver injury reported to FDA). In May 2000, the FDA withdrew marketing authorisation for trovafloxacin.

Trovafloxacin received marketing authorisation in the European Union in October 1998.<ref name=":0">{{Cite web|title=Public statement on Trovan / Trovan IV / Turvel / Turvel IV: Withdrawal of the marketing authorisations|url=https://www.ema.europa.eu/en/documents/public-statement/public-statement-trovan/trovan-iv/turvel/turvel-iv-withdrawal-marketing-authorisations_en.pdf|website=[[European Medicines Agency]]}}</ref> In June 1999, in view of reported adverse events, the [[Committee for Proprietary Medicinal Products]] recommended suspension of the marketing authorisation for a year.<ref name="NYT3">{{cite news| vauthors = Petersen M |date=August 27, 2000|title=Unforeseen Side Effects Ruined One Blockbuster|page=3.11|work=[[The New York Times]]|url=https://www.nytimes.com/2000/08/27/business/unforeseen-side-effects-ruined-one-blockbuster.html}}</ref><ref name="NYT2">{{cite news|date=June 12, 1999|title=Suspension of Trovan Drug in Europe Is Urged|page=C.3|work=[[The New York Times]]|url=https://www.nytimes.com/1999/06/12/business/company-news-suspension-of-trovan-drug-in-europe-is-urged.html}}</ref> The suspension took effect in August 1999 and was renewed in September 2000.<ref name=":0" /> In October 2000, Pfizer notified the European Commission of its decision to voluntarily withdraw the marketing authorisation which was approved by EMA in March 2001.<ref name=":0" />

=== Economics ===

Trovan sales during its first full year on the market contributed US$160 million of Pfizer's total revenue of US$12.6 billion. Investors expected it to eventually bring in US$1 billion per year.<ref name="NYT3" />

=== Nigerian clinical trial controversy ===

{{main|Kano Trovafloxacin trial litigation}}

In 1996, during a [[meningitis]] [[epidemic]] in [[Kano (city)|Kano]], [[Nigeria]], the drug was administered to approximately 200<ref>{{cite book | vauthors = Oldani M |title=The SAGE Encyclopedia of Pharmacology and Society|date=2016|pages=1444–1447|chapter=Trovafloxacin (Trovan) Controversy|chapter-url=http://sk.sagepub.com/reference/the-sage-encyclopedia-of-pharmacology-and-society/i11727.xml|publisher=SAGE Publications, Inc.|doi=10.4135/9781483349985.n409|isbn=9781483350004|access-date=2019-01-21}}</ref><ref>{{citation|title=Report of the Investigation Committee on the Clinical Trial of Trovafloxacin (Trovan) by Pfizer, Kano, 1996.|url=https://www.washingtonpost.com/wp-srv/world/documents/Clinical_Trial_Report.pdf|publisher=Federal Ministry of Health, Nigeria}}</ref> infected children. Eleven children died in the trial: five after taking Trovan and six after taking an older antibiotic used for comparison in the clinical trial. Others suffered blindness, deafness and brain damage, common consequences of meningitis that have not been seen in patients treated with trovafloxacin for other infection types.<ref>{{cite journal | vauthors = Williams D, Hopkins S | title = Safety of trovafloxacin in treatment of lower respiratory tract infections | journal = European Journal of Clinical Microbiology & Infectious Diseases | volume = 17 | issue = 6 | pages = 454–458 | date = June 1998 | pmid = 9758292 | doi = 10.1007/bf01691582 | s2cid = 1325773 }}</ref><ref>{{cite journal | vauthors = Lipsky BA, Baker CA | title = Fluoroquinolone toxicity profiles: a review focusing on newer agents | journal = Clinical Infectious Diseases | volume = 28 | issue = 2 | pages = 352–364 | date = February 1999 | pmid = 10064255 | doi = 10.1086/515104 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sabatini C, Bosis S, Semino M, Senatore L, Principi N, Esposito S | title = Clinical presentation of meningococcal disease in childhood | journal = Journal of Preventive Medicine and Hygiene | volume = 53 | issue = 2 | pages = 116–119 | date = June 2012 | pmid = 23240173 }}</ref> An investigation by the Washington Post concluded that [[Pfizer]] had administered the drug as part of an illegal [[clinical trial]] without authorization from the [[Government of Nigeria|Nigerian government]] or [[consent]] from the children's parents.<ref name="WP">{{cite news| vauthors = Stephens J |date=May 7, 2006|title=Panel Faults Pfizer in '96 Clinical Trial In Nigeria|page=A01|newspaper=[[The Washington Post]]|url=https://www.washingtonpost.com/wp-dyn/content/article/2006/05/06/AR2006050601338.html|access-date=2006-08-28}}</ref> The case came to light in December 2000 as the result of an investigation by ''[[The Washington Post]]'', and sparked significant public outcry. The most serious error was the falsification and backdating of an ethics approval letter by the lead investigator of the trial, Dr. Abdulhamid Isa Dutse. Dr. Dutse is now the chief medical officer of Aminu Kano Teaching Hospital. The result of the trial was that children treated with oral trovafloxacin had a 5% (5/100) mortality rate compared to a 6% (6/100) mortality rate with intramuscular ceftriaxone.

Between 2002 and 2005 the victims of the Trovan tests in Nigeria filed a [[Kano Trovafloxacin trial litigation|series of unsuccessful lawsuits]] in the United States. However, in January 2009, the United States Court of Appeals for the Second Circuit [[Ius cogens#Ethics|ruled]] that the Nigerian victims and their families were entitled to bring suit against [[Pfizer]] in the United States under the [[Alien Tort Statute]]. A US$75 million settlement with the State of Kano was reached on July 30, 2009.<ref name="washingtonpost">{{cite news| vauthors = Stephens J |date=July 31, 2009|title=Pfizer to Pay $75 Million to Settle Nigerian Trovan Drug-Testing Suit|newspaper=The Washington Post|url=https://www.washingtonpost.com/wp-dyn/content/article/2009/07/30/AR2009073001847.html|access-date=May 26, 2010}}</ref>

Additionally two lawsuits also remain pending in New York, United States.<ref name="washingtonpost" /> According to Wikileaked US embassy cables, Pfizer's country manager admitted that "Pfizer had hired investigators to uncover corruption links to federal attorney general Michael Aondoakaa to expose him and put pressure on him to drop the federal cases."<ref>{{cite news| vauthors = Boseley S |date=9 December 2010|title=WikiLeaks cables: Pfizer 'used dirty tricks to avoid clinical trial payout'|work=The Guardian|url=https://www.theguardian.com/business/2010/dec/09/wikileaks-cables-pfizer-nigeria}}</ref>

== See also ==

*[[Alatrofloxacin]], a [[prodrug]] of trovafloxacin for intravenous administration

*[[Quinolone antibiotic|Quinolone]]

== References ==

{{reflist}}

== External links ==

*[http://www.ca2.uscourts.gov/decisions/isysquery/45aeb87b-d8dc-494e-bfea-bc363bc36660/6/doc/05-4863-cv_opn.pdf#xml=http://www.ca2.uscourts.gov/decisions/isysquery/45aeb87b-d8dc-494e-bfea-bc363bc36660/6/hilite/ Abdullahi v Pfizer. US Court of Appeals 2d Cir 30 Jan 2009] {{Webarchive|url=https://web.archive.org/web/20110613165526/http://www.ca2.uscourts.gov/decisions/isysquery/45aeb87b-d8dc-494e-bfea-bc363bc36660/6/doc/05-4863-cv_opn.pdf#xml=http://www.ca2.uscourts.gov/decisions/isysquery/45aeb87b-d8dc-494e-bfea-bc363bc36660/6/hilite/ |date=13 June 2011 }}

{{QuinoloneAntiBiotics}}

[[Category:Fluoroquinolone antibiotics]]

[[Category:Hepatotoxins]]

[[Category:Withdrawn drugs]]

[[Category:Naphthyridines]]

[[Category:Alpha-keto acids]]

[[Category:Aromatic ketones]]

[[Category:Nitrogen heterocycles]]

[[Category:Heterocyclic compounds with 2 rings]]

[[Category:Cyclopropanes]]

[[Category:Amines]]

[[Category:Fluorobenzene derivatives]]