Tafenoquin

Structural formula
	Simplified structural formula without stereochemistry - mixture of substances
General
Non-proprietary name	Tafenoquin
other names	( RS ) - N -4- (2,6-Dimethoxy-4-methyl-5 - ((3-trifluoromethyl) phenoxy) -8-quinolinyl) -1,4-pentanediamine ( IUPAC ) ; (±) - N -4- (2,6-Dimethoxy-4-methyl-5 - ((3-trifluoromethyl) phenoxy) -8-quinolinyl) -1,4-pentanediamine;
Molecular formula	C 24 H 28 F 3 N 3 O 3 (tafenoquine) ; C 24 H 28 F 3 N 3 O 3 · C 4 H 6 O 4 (tafenoquine · succinate ) ;
External identifiers / databases
PubChem	115358
ChemSpider	103196
DrugBank	DB06608
Wikidata	Q2387553
Drug information
Drug class	Antiprotozoic
properties
Molar mass	463.49 g · mol -1 (tafenoquine)
Physical state	firmly
Melting point	146–149 ° C (tafenoquine succinate)
safety instructions
GHS hazard labeling ; no classification available
GHS hazard labeling ; no classification available
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Tafenoquine (WR-238605) is an anti- malarial drug . It is a further development of the 8-aminoquinoline primaquine by the Walter Reed Army Institute of Research (WRAIR) of the United States Army . The drug has a comparatively long plasma half-life . Tafenoquine is effective against tissue and blood schizonts . For these reasons, it is suitable for malaria prophylaxis and for the treatment of recurrences caused by Malaria Tertiana. Several tafenoquin products received marketing approval between July and September 2018 in the United States and Australia. On the other hand, according to the German Society for Tropical Medicine and International Health e. V. not to be expected for the time being.

controversy

Because of the potential neurotoxicity of 8-aminoquinolines, the approval of tafenoquine is controversial. The need for particularly careful testing before a possible introduction of the drug was emphasized. However, research close to the manufacturers and the US Army doubts the neurotoxicity of tafenoquine in the approved dose.

In Australia, studies on tafenoquine and mefloquine that were carried out on members of the Australian armed forces have received massive criticism in the media for ethical reasons since 2015 . The Australian Senate launched an investigation into the health issues reported by participants in 2018. The final report, published in December of the same year, found that her symptoms were authentic, with no clear explanation of the cause. Veterans were mostly disappointed about this in the press.

Since tafenoquine is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), restrictions on the practical use of the drug for malaria prophylaxis are also being discussed.

Stereochemistry

Tafenoquine contains a stereocenter and consists of two enantiomers. This is a 1: 1 mixture ( racemate ) of ( R ) - and ( S ) -form:

Enantiomers of tafenoquine
( R ) shape	( S ) shape

literature

GD Shanks, AJ Oloo, GM Aleman et al: A New Primaquine Analogue, Tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria. In: Clin Infect Dis . 33, 2001, pp. 1968-1974, PMID 11700577 .
B. Lell, JF Faucher, MA Missinou et al: Malaria chemoprophylaxis with tafenoquine: a randomized study. In: The Lancet . 355 (9220), 2000, pp. 2041-2045, PMID 10885356 .
JM Karle, R. Olmeda: Rapid and sensitive quantitative analysis of the new antimalarial N4- [2,6-dimethoxy-4-methyl-5 - [(3-trifluoromethyl) phenoxy] -8-quinolinyl] -1,4-pentanediamine in plasma by liquid chromatography and electrochemical detection. In: Journal of Chromatography. 424, 1988, pp. 347-356, PMID 3372627 .

Individual evidence

^ The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 14th edition. Merck, Whitehouse Station, NJ, USA, 2006, ISBN 0-911910-00-X , p. 1551.
↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
↑ Single-dose Tafenoquine 300 mg for Radical Cure of Plasmodium vivax Malaria. GlaxoSmithKline , July 12, 2018.
↑ US FDA approves Krintafel (tafenoquine) for the radical cure of P. vivax malaria. Press release. GlaxoSmithkline. 20th July 2018.
↑ First Preventative Antimalarial In Almost 2 Decades Gets FDA Approval. In: Pharmacy Times. August 9, 2018.
↑ Kozenis (tafenoquine) approved by the Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria. Press release. Medicines for Malaria Venture. September 21, 2018.
↑ KODATEF® (tafenoquine) approved in Australia; first malaria prevention drug in more than two decades. Press release. 60 Degrees Pharmaceuticals. 18th September 2018.
↑ Malaria prophylaxis - recommendations of the Standing Committee on Travel Medicine (StAR) of the DTG. (PDF) German Society for Tropical Medicine and International Health e. V., June 2019.
↑ RL Nevin: Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine. In: International Journal for Parasitology: Drugs and Drug Resistance . Volume 4, Number 2, August 2014, pp. 118–125, doi: 10.1016 / j.ijpddr.2014.03.002 . PMID 25057461 , PMC 4095041 (free full text).
^ RL Nevin, AM Croft: Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. In: Malaria journal. Volume 15, 2016, p. 332, doi: 10.1186 / s12936-016-1391-6 . PMID 27335053 , PMC 4918116 (free full text) (review).
↑ J. Berman, T. Brown, G. Dow, S. Toovey: Tafenoquine and primaquine do not exhibit clinical neurologic signs associated with central nervous system lesions in the same manner as earlier 8-aminoquinolines. In: Malaria journal , 17, 2018, p. 407, PMC 6219089 (free full text).
^ JK Baird: Tafenoquine for travelers' malaria: evidence, rationale and recommendations. In: J Travel Med. , 25 (1), 1 Jan 2018. doi: 10.1093 / jtm / tay110 , PMC 6243017 (free full text).
^ J. Berman: Approval of Tafenoquine for Malaria Chemoprophylaxis. In: Am J Trop Med Hyg. 2019 Mar 18. doi: 10.4269 / ajtmh.19-0001 , PMID 30887947 .
^ Paul Cleary: Drug trial a test of ethics. In: The Australian. September 11, 2015.
↑ Mandie Sami: Defense Force accused of 'massive cover-up' over anti-malarial drug. In: ABC News. 4th December 2015.
^ Jesse Dorsett: Former soldiers, families face military officials in Townsville over anti-malaria drug side effects. In: ABC News. March 14, 2016.
↑ Henry Belot: Therapeutic Goods Administration warned military doctors before using experimental drug on soldiers. In: Sydney Morning Herald. April 29, 2016.
↑ Senate Foreign Affairs Defense and Trade References Committee: Use of the Quinoline anti-malarial drugs Mefloquine and Tafenoquine in the Australian Defense Force. Australian Parliament website. June 2018.
↑ Michael Atkin: It's destroyed my life: Hopes inquiry will back veterans claims anti-malaria drug caused illness. In: ABC News. July 31, 2018.
↑ Senate Foreign Affairs Defense and Trade References Committee: Use of the Quinoline anti-malarial drugs Mefloquine and Tafenoquine in the Australian Defense Force. Executive summary. Australian Parliament website. December 2018. Quote: "The committee needs to state that it is not comprised of medical professionals or health experts and so cannot make any findings or rulings in relation to the medical causes for health issues. However, it notes that the weight of prevailing medical evidence provided to the committee in response to these claims is that long term problems as a result of taking mefloquine are rare and there is no compelling evidence that tafenoquine causes long term effects. To be clear, there has always been recognition by Defense that mefloquine, like any drug, has side effects and this has been taken into consideration in the development of its health policy. "
↑ Rachel Eddie: 'Disheartening': Veterans 'let down' by inquiry into anti-malarial drug trials. In: The New Daily. 5th December 2018.
^ DO Freedman: Tafenoquine: integrating a new drug for malaria prophylaxis into travel medicine practice. In: J Travel Med. 29 Nov 2018, doi: 10.1093 / jtm / tay140 .
↑ , M. Grobusch A. Rodriguez-Morales, P. Schlagenhauf: The primaquine problem - solution and the? Point of care G6PDd diagnostics. In: Clin Infect Dis. 2019 Feb 13. doi: 10.1093 / cid / ciz124 . PMID 30783651 .

[MERCK_Index-1] The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 14th edition. Merck, Whitehouse Station, NJ, USA, 2006, ISBN 0-911910-00-X , p. 1551.

[NV-2] This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.

[3] Single-dose Tafenoquine 300 mg for Radical Cure of Plasmodium vivax Malaria. GlaxoSmithKline , July 12, 2018.

[4] US FDA approves Krintafel (tafenoquine) for the radical cure of P. vivax malaria. Press release. GlaxoSmithkline. 20th July 2018.

[5] First Preventative Antimalarial In Almost 2 Decades Gets FDA Approval. In: Pharmacy Times. August 9, 2018.

[6] Kozenis (tafenoquine) approved by the Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria. Press release. Medicines for Malaria Venture. September 21, 2018.

[7] KODATEF® (tafenoquine) approved in Australia; first malaria prevention drug in more than two decades. Press release. 60 Degrees Pharmaceuticals. 18th September 2018.

[8] Malaria prophylaxis - recommendations of the Standing Committee on Travel Medicine (StAR) of the DTG. (PDF) German Society for Tropical Medicine and International Health e. V., June 2019.

[9] RL Nevin: Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine. In: International Journal for Parasitology: Drugs and Drug Resistance . Volume 4, Number 2, August 2014, pp. 118–125, doi: 10.1016 / j.ijpddr.2014.03.002 . PMID 25057461 , PMC 4095041 (free full text).

[10] RL Nevin, AM Croft: Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. In: Malaria journal. Volume 15, 2016, p. 332, doi: 10.1186 / s12936-016-1391-6 . PMID 27335053 , PMC 4918116 (free full text) (review).

[11] J. Berman, T. Brown, G. Dow, S. Toovey: Tafenoquine and primaquine do not exhibit clinical neurologic signs associated with central nervous system lesions in the same manner as earlier 8-aminoquinolines. In: Malaria journal , 17, 2018, p. 407, PMC 6219089 (free full text).

[12] JK Baird: Tafenoquine for travelers' malaria: evidence, rationale and recommendations. In: J Travel Med. , 25 (1), 1 Jan 2018. doi: 10.1093 / jtm / tay110 , PMC 6243017 (free full text).

[13] J. Berman: Approval of Tafenoquine for Malaria Chemoprophylaxis. In: Am J Trop Med Hyg. 2019 Mar 18. doi: 10.4269 / ajtmh.19-0001 , PMID 30887947 .

[14] Paul Cleary: Drug trial a test of ethics. In: The Australian. September 11, 2015.

[15] Mandie Sami: Defense Force accused of 'massive cover-up' over anti-malarial drug. In: ABC News. 4th December 2015.

[16] Jesse Dorsett: Former soldiers, families face military officials in Townsville over anti-malaria drug side effects. In: ABC News. March 14, 2016.

[17] Henry Belot: Therapeutic Goods Administration warned military doctors before using experimental drug on soldiers. In: Sydney Morning Herald. April 29, 2016.

[18] Senate Foreign Affairs Defense and Trade References Committee: Use of the Quinoline anti-malarial drugs Mefloquine and Tafenoquine in the Australian Defense Force. Australian Parliament website. June 2018.

[19] Michael Atkin: It's destroyed my life: Hopes inquiry will back veterans claims anti-malaria drug caused illness. In: ABC News. July 31, 2018.

[20] Senate Foreign Affairs Defense and Trade References Committee: Use of the Quinoline anti-malarial drugs Mefloquine and Tafenoquine in the Australian Defense Force. Executive summary. Australian Parliament website. December 2018. Quote: "The committee needs to state that it is not comprised of medical professionals or health experts and so cannot make any findings or rulings in relation to the medical causes for health issues. However, it notes that the weight of prevailing medical evidence provided to the committee in response to these claims is that long term problems as a result of taking mefloquine are rare and there is no compelling evidence that tafenoquine causes long term effects. To be clear, there has always been recognition by Defense that mefloquine, like any drug, has side effects and this has been taken into consideration in the development of its health policy. "

[21] Rachel Eddie: 'Disheartening': Veterans 'let down' by inquiry into anti-malarial drug trials. In: The New Daily. 5th December 2018.

[22] DO Freedman: Tafenoquine: integrating a new drug for malaria prophylaxis into travel medicine practice. In: J Travel Med. 29 Nov 2018, doi: 10.1093 / jtm / tay140 .

[23] , M. Grobusch A. Rodriguez-Morales, P. Schlagenhauf: The primaquine problem - solution and the? Point of care G6PDd diagnostics. In: Clin Infect Dis. 2019 Feb 13. doi: 10.1093 / cid / ciz124 . PMID 30783651 .