halofantrine

Halofantrine
Systematic (IUPAC) name
	3-dibutylamino-1-[1,3-dichloro-6-(trifluoromethyl); phenanthren-9-yl]-propan-1-ol
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a603030
Routes of; administration	Oral
Pharmacokinetic data
Protein binding	60 to 70%
Metabolism	Hepatic (CYP3A4-mediated)
Biological half-life	6 to 10 days
Identifiers
CAS Number	69756-53-2
ATC code	P01BX01 (WHO)
PubChem	CID 37393
DrugBank	DB01218
ChemSpider	34303
UNII	Q2OS4303HZ
ChEMBL	CHEMBL1107
Chemical data
Formula	C26H30Cl2F3NO
Molar mass	500.423 g/mol
	SMILES FC(F)(F)c3ccc2c(cc1c(Cl)cc(Cl)cc1c2c3)C(O)CCN(CCCC)CCCC ;
	InChI InChI=1S/C26H30Cl2F3NO/c1-3-5-10-32(11-6-4-2)12-9-25(33)23-16-22-21(14-18(27)15-24(22)28)20-13-17(26(29,30)31)7-8-19(20)23/h7-8,13-16,25,33H,3-6,9-12H2,1-2H3 ; Key:FOHHNHSLJDZUGQ-UHFFFAOYSA-N ;
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Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/05/03 12:37:17」(JST)

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Halofantrine is a drug used to treat malaria. Halofantrine's structure contains a substituted phenanthrene, and is related to the antimalarial drugs quinine and lumefantrine. Marketed as Halfan, halofantrine is never used to prevent malaria and its mode of action is unknown, although a crystallographic study showed that it binds to hematin in vitro, suggesting a possible mechanism of action.^[1] Halofantrine has also been shown to bind to plasmpesin, a haemoglobin degrading enzyme unique to the malarial parasites.^[2]

Halofantrine was developed at SRI International for the Walter Reed Army Institute of Research from 1965 to 1975 by a team led by medicinal chemist William Colwell.^[3]

Adverse reactions

Halofantrine can cause abdominal pain, diarrhoea, vomiting, rash, headache, itching and elevated liver enzymes.

It can be associated with cardiotoxicity.^[4] The most dangerous side effect is cardiac arrhythmias: halofantrine causes significant QT prolongation,^[5] and this effect is seen even at standard doses. The drug should therefore not be given to patients with cardiac conduction defects and should not be combined with mefloquine. A survey from 2009 suggests that the drug is safe when correctly administered ^[6]it

Other adverse reactions

Consumption of grapefruit combined with certain medications can cause serious side effects, even death. Halofantrine combined with this fruit or grapefruit juice is dangerous. The mechanism of action is inhibition of CYP3A4, which is necessary to metabolize the drug and eliminate it from the body. Without CYP3A4, levels of the drug will become toxic in the body.

Pharmacology

The mechanism of action of halofantrine is unknown. The absorption of halofantrine is erratic, but is increased when taken with fatty food. Because of fears of toxicity due to increased halofantrine blood levels, halofantrine should be taken on an empty stomach.

Plasma levels peak at 16 hours and the half-life of the drug is about 4 days.

Uses

Halofantrine is only used to treat malaria. It is not used to prevent malaria (prophylaxis) because of the risk of toxicity and unreliable absorption.

Dosing

Adult dose: Three doses of 500 mg six hours apart. Halofantrine should be taken on an empty stomach.

Manufacturing information and availability

Halfan (GlaxoSmithKline) is available as 250 mg tablets. A full treatment cost (6 tablets) costs US$1.40 in the developing world. Halofantrine is not available in the UK or U.S.

References

^ de Villiers KA, Marques HM, Egan TJ (2008). "The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials". J. Inorg. Chem. 102 (8): 1660–7. doi:10.1016/j.jinorgbio.2008.04.001. PMID 18508124.
^ Friedman R, Caflisch A (2009). "Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring". ChemMedChem 4 (8): 1317–26. doi:10.1002/cmdc.200900078. PMID 19472268.
^ Nielson, Donald (2006). A Heritage of Innovation: SRI's First Half Century. Menlo Park, California: SRI International. pp. 10–3 – 10–5. ISBN 978-0974520810.
^ Wesche DL, Schuster BG, Wang WX, Woosley RL (May 2000). "Mechanism of cardiotoxicity of halofantrine". Clin. Pharmacol. Ther. 67 (5): 521–9. doi:10.1067/mcp.2000.106127. PMID 10824631.
^ Sánchez-Chapula JA, Navarro-Polanco RA, Sanguinetti MC (2004). "Block of wild-type and inactivation-deficient human ether-a-go-go-related gene K+ channels by halofantrine". Naunyn Schmiedebergs Arch. Pharmacol. 370 (6): 484–91. doi:10.1007/s00210-004-0995-5. PMID 15558243.
^ Bouchaud O, Imbert P, Touze JE, Dodoo AN, Danis M, Legros F (2009). "Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base". Malaria J. 8: 289. doi:10.1186/1475-2875-8-289. PMC 2801676. PMID 20003315.

UpToDate Contents

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1. 抗マラリア剤：概要 antimalarial drugs an overview
2. アフリカ・トリパノソーマ症の臨床症状、診断、および治療 clinical manifestations diagnosis and treatment of african trypanosomiasis
3. 合併症のない熱帯熱マラリアの治療 treatment of uncomplicated falciparum malaria
4. 妊娠中のマラリアの予防および治療 prevention and treatment of malaria in pregnant women
5. 旅行者におけるマラリア感染の予防 prevention of malaria infection in travelers

English Journal

A mouse model to evaluate the impact of species, sex, and lipid load on lymphatic drug transport.

Trevaskis NL, Caliph SM, Nguyen G, Tso P, Charman WN, Porter CJ.Author information Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria, Australia, 3052, Natalie.Trevaskis@monash.edu.AbstractPURPOSE: To establish a lymph-cannulated mouse model, and use the model to investigate the impact of lipid dose on exogenous and endogenous lipid recruitment, and drug transport, into the lymph of males versus females. Finally, lymphatic transport and drug absorption in the mouse were compared to other pre-clinical models (rats/dogs).
Pharmaceutical research.Pharm Res.2013 Dec;30(12):3254-70. doi: 10.1007/s11095-013-1000-0. Epub 2013 Feb 21.
PURPOSE: To establish a lymph-cannulated mouse model, and use the model to investigate the impact of lipid dose on exogenous and endogenous lipid recruitment, and drug transport, into the lymph of males versus females. Finally, lymphatic transport and drug absorption in the mouse were compared to ot
PMID 23430484

[Treatment of severe and uncomplicated falciparum malaria in children in France].

Pull L, Bellettre X, Michel JF, Bouchaud O, Siriez JY.Author information Service d'accueil des urgences pédiatriques, hôpital Robert-Debré, AP-HP, 48, boulevard Sérurier, 75019 Paris, France. Electronic address: lauren.pull@rdb.aphp.fr.AbstractQuinine was the main treatment for malaria between 1630 and the beginning of the XXth century. In the 1940s, the synthesis of chloroquine gave rise to the hope of eliminating this plague. Falciparum resistance to chloroquine, first observed in Asia then in sub-Saharan Africa, lead researchers to discover halofantrine, mefloquine, atovaquone-proguanil and artemisinin combined therapies. There is no ideal treatment for uncomplicated imported malaria in children. Medical teams have to develop a protocol according to available drugs and their personal experience, with a special attention to follow-up at days 3-4 and day 28. From now on, severe malaria must be treated with intravenous artesunate, a more effective therapy than quinine.
Archives de pédiatrie : organe officiel de la Sociéte française de pédiatrie.Arch Pediatr.2013 Nov;20(11):1260-4. doi: 10.1016/j.arcped.2013.08.002. Epub 2013 Oct 2.
Quinine was the main treatment for malaria between 1630 and the beginning of the XXth century. In the 1940s, the synthesis of chloroquine gave rise to the hope of eliminating this plague. Falciparum resistance to chloroquine, first observed in Asia then in sub-Saharan Africa, lead researchers to dis
PMID 24094758

Characterization of Polymer Adsorption onto Drug Nanoparticles Using Depletion Measurements and Small-Angle Neutron Scattering.

Goodwin DJ, Sepassi S, King SM, Holland SJ, Martini LG, Lawrence MJ.Author information Institute of Pharmaceutical Science, King's College London , Stamford Street, London SE1 9NH, United Kingdom.AbstractProduction of polymer and/or surfactant-coated crystalline nanoparticles of water-insoluble drugs (nanosuspensions) using wet bead milling is an important formulation approach to improve the bioavailability of said compounds. Despite the fact that there are a number of nanosuspensions on the market, there is still a deficiency in the characterization of these nanoparticles where further understanding may lead to the rational selection of polymer/surfactant. To this end small-angle neutron scattering (SANS) measurements were performed on drug nanoparticles milled in the presence of a range of polymers of varying molecular weight. Isotopic substitution of the aqueous solvent to match the scattering length density of the drug nanoparticles (i.e., the technique of contrast matching) meant that neutron scattering resulted only from the adsorbed polymer layer. The layer thickness and amount of hydroxypropylcellulose adsorbed on nabumetone nanoparticles derived from fitting the SANS data to both model-independent and model dependent volume fraction profiles were insensitive to polymer molecular weight over the range Mv = 47-112 kg/mol, indicating that the adsorbed layer is relatively flat but with tails extending up to approximately 23 nm. The constancy of the absorbed amount is in agreement with the adsorption isotherm determined by measuring polymer depletion from solution in the presence of the nanoparticles. Insensitivity to polymer molecular weight was similarly determined using SANS measurements of nabumetone or halofantrine nanoparticles stabilized with hydroxypropylmethylcellulose or poly(vinylpyrrolidone). Additionally SANS studies revealed the amount adsorbed, and the thickness of the polymer layer was dependent on both the nature of the polymer and drug particle surface. The insensitivity of the adsorbed polymer layer to polymer molecular weight has important implications for the production of nanoparticles, suggesting that lower molecular weight polymers should be used when preparing nanoparticles by wet bead milling since nanoparticle formation is more rapid but with no likely consequence on the resultant physical stability of the nanoparticles.
Molecular pharmaceutics.Mol Pharm.2013 Oct 22. [Epub ahead of print]
Production of polymer and/or surfactant-coated crystalline nanoparticles of water-insoluble drugs (nanosuspensions) using wet bead milling is an important formulation approach to improve the bioavailability of said compounds. Despite the fact that there are a number of nanosuspensions on the market,
PMID 24074034

Japanese Journal

PRESCRIPTION PATTERNS OF ANTIMALARIAL DRUGS AMONG MEDICAL PRACTITIONERS IN OSOGBO METROPOLIS. SOUTH-WEST NIGERIA.

Tropical Medicine and Health 33(4), 201-208, 2005
NAID 130002056132

Interaction of the Antimalarial Agents Halofantrine and Lumefantrine with Lipid Bilayers

Chemical & pharmaceutical bulletin 51(3), 241-246, 2003-03-01
NAID 110003615277

Halofantrine-Phospholipid Interactions : Monolayer Studies

Chemical & pharmaceutical bulletin 49(7), 871-876, 2001-07-01
NAID 110003616008

Related Pictures

[pmid18508124-1] Villiers KA, Marques HM, Egan TJ (2008). "The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials". J. Inorg. Chem. 102 (8): 1660–7. doi:10.1016/j.jinorgbio.2008.04.001. PMID 18508124.

[pmid19472268-2] Friedman R, Caflisch A (2009). "Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring". ChemMedChem 4 (8): 1317–26. doi:10.1002/cmdc.200900078. PMID 19472268.

[3] Nielson, Donald (2006). A Heritage of Innovation: SRI's First Half Century. Menlo Park, California: SRI International. pp. 10–3 – 10–5. ISBN 978-0974520810.

[pmid10824631-4] Wesche DL, Schuster BG, Wang WX, Woosley RL (May 2000). "Mechanism of cardiotoxicity of halofantrine". Clin. Pharmacol. Ther. 67 (5): 521–9. doi:10.1067/mcp.2000.106127. PMID 10824631.

[pmid15558243-5] Sánchez-Chapula JA, Navarro-Polanco RA, Sanguinetti MC (2004). "Block of wild-type and inactivation-deficient human ether-a-go-go-related gene K+ channels by halofantrine". Naunyn Schmiedebergs Arch. Pharmacol. 370 (6): 484–91. doi:10.1007/s00210-004-0995-5. PMID 15558243.

[pmid20003315-6] Bouchaud O, Imbert P, Touze JE, Dodoo AN, Danis M, Legros F (2009). "Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base". Malaria J. 8: 289. doi:10.1186/1475-2875-8-289. PMC 2801676. PMID 20003315.

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