WO2010004573A1 - Composition pharmaceutique synergiste antipaludique - Google Patents

Composition pharmaceutique synergiste antipaludique Download PDF

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Publication number
WO2010004573A1
WO2010004573A1 PCT/IN2008/000543 IN2008000543W WO2010004573A1 WO 2010004573 A1 WO2010004573 A1 WO 2010004573A1 IN 2008000543 W IN2008000543 W IN 2008000543W WO 2010004573 A1 WO2010004573 A1 WO 2010004573A1
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Prior art keywords
arteether
oral
combination
artemotil
pharmaceutical composition
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PCT/IN2008/000543
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English (en)
Inventor
Anil Pareek
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Ipca Laboratories Limited
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Publication of WO2010004573A1 publication Critical patent/WO2010004573A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a pharmaceutical formulation comprising of oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) in a fixed dose combination with other antimalarials including piperaquine, lumefantrine, curcumin useful for treating falciparum malaria, including drug resistant falciparum malaria.
  • oral arteether ⁇ arteether (artemotil) or ⁇ / ⁇ arteether
  • other antimalarials including piperaquine, lumefantrine, curcumin useful for treating falciparum malaria, including drug resistant falciparum malaria.
  • Malaria the most important parasitic disease of humans, remains a major health and economic burden in most tropical countries. Malaria is a major cause of death equal with HIV/ AIDS and tuberculosis. The mortality and morbidity associated with malaria have a crippling effect on the economies of endemic countries. It afflicts more than 500 million people, causing from 1.7 million to 2.5 million deaths each year. (Goodman & Gilman 's - The Pharmacological Basis of Therapeutics, 10 th Ed., 2001, p. 1069)
  • the main obstacle to malaria control is the emergence of drug resistant strains of Plasmodium falciparum. Emergence of resistance in P. falciparum to antimalarial drugs increases malaria morbidity, mortality and treatment cost. P. falciparum has developed resistance to nearly all antimalarials in current use, although the geographical distribution of resistance to any single antimalarial drug varies greatly. Chloroquine resistance is a major contributor to the increasing malaria-related morbidity and mortality. Resistance has been seen even with sulfadoxine-pyrimethamine, quinine and mefloquine, though it is not as prevalent as chloroquine resistance.
  • artemisinins are the only group of antimalarial drugs to which resistance to P. falciparum has not yet developed in the field.
  • ⁇ arteether is the ⁇ -ethyl ether derivative of artemisinin. It is a blood schizonticide active against all stages of P. falciparum, including the very early ring forms. It is an effective and rapidly acting drug for the treatment of falciparum malaria. No serious or inconvenient side effects have been reported with ⁇ arteether (artemotil).
  • Arteether is also available as an anomeric mixture of ⁇ / ⁇ arteether (30:70), which has been developed by CDRI.
  • EP 0330520 discloses a process of epimerization for conversion of the alpha -epimer of arteether to the beta -epimer (ethyletherartemisininelactol) or preparation of arteether by subjecting the alpha -epimer to an acid catalysed isomerization reaction. It further discloses a pharmaceutical composition comprising arteether can be administered as intramuscular or oral administration when combined with a pharmaceutically-acceptable carriers, medium, diluents or excipients
  • US 6326023 disclose a formulation comprising .alpha./.beta. arteether and a neutralized refined vegetable oil in respective amounts effective to provide for rectal absorption in treating a multi-drug resistant malarial infection in the patient. It further discloses the formulation is administered to the patient in the form of a rectal formulation, rectal suppository or an oral gelatin capsule.
  • EP 0464233 discloses a pharmaceutical combination with a synergistic action against malaria, which besides customary auxiliaries and/or vehicles contains Arteether and Quinine or Arteether and Quinine with Mefloquine.
  • US 6214864 disclose a sterile synergistic formulation useful for the control of wide spectrum of malarial infections, which consists essentially of a pharmaceutically effective amount of dihydroartemisinin and a sterilized neutral refined vegetable oil. Further it disclose the artemisinin derivatives, selected from artemether and arteether and the formulation is administered through intramuscular injection to treat severe complicated/cerebral malaria and multi-drug resistant malaria infections
  • WO 2007017646 describes an antimalarial composition comprising artisunate and lumefantrine in a single pharmaceutical dosage unit.
  • WO2008001294 disclose high dose oral pharmaceutical compositions of arteemether with lumefantrine. Delayed release antimalarial composition comprising pharmaceutically effective amounts of antimalarial agent selected from artemisinin group such as alpha or beta arteether or artisunate is disclosed in WO2007036947.
  • compositions used for Anti malarial activity comprising both.alpha./.beta. arteether for rectal use, synergistic combination of arteether with quinine or arteether with quinine and Mefloquine and a sterile synergistic injection formulation of artemisinin derivatives, selected from artemether and arteether with neutral refined vegetable oil.
  • the injectable routes and rectal routes are painful when administered.
  • the current invention aims to provide a potential successor in the field of antimalarial, which comprises the composition comprising oral formulation of arteether like ⁇ arteether (artemotil) or ⁇ / ⁇ arteether in combination with other antimalarials selected from the group consisting of piperaquine, lumefanfrine and curcumin, which works synergistically against drug resistant falciparum malaria.
  • arteether like ⁇ arteether (artemotil) or ⁇ / ⁇ arteether in combination with other antimalarials selected from the group consisting of piperaquine, lumefanfrine and curcumin, which works synergistically against drug resistant falciparum malaria.
  • artemisinin derivative with mefloquine, lumefantrine, amodiaquine and sulphadoxine-pyrimethamine is currently being used.
  • arteether ⁇ arteether (artemotil) or ⁇ / ⁇ arteether
  • other antimalarials as setout herein below.
  • Piperaquine is a bisquinoline antimalarial drug, which is effective against P. vivax and P. falciparum, including strains of P. falciparum resistant to chloroquine. It has favourable safety and toxicity profile. A number of Chinese research groups documented that it was at least as effective as and better tolerated than chloroquine against falciparum and vivax malaria. Piperaquine's tolerability, effectiveness, pharmacokinetic profile and low cost make it a promising partner drug for use as part of short course artemisinin combination therapy.
  • Curcumin is the major yellow pigment of turmeric, the common curry powder, derived from the rhizome of the herb Curcuma longa. It has demonstrated antimalarial activity in vitro and in experimental animals. It was found to be potent against both chloroquine- sensitive and -resistant P. falciparum strains.
  • Curcumin is tolerated at very high doses, and as much as 8 g/day has been given for 3 months to cancer patients on trial without toxic side effects. (Adv Exp Med Biol 2007;595:471-80) Thus the safety of curcumin is well established.
  • lumefantrine is available in fixed dose combination with artemether.
  • the combination combines the fast onset of action of artemether (an artemisinin derivative) in terms of parasite clearance with the high cure rate of lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria.
  • the combination therapy will be safe and effective for falciparum malaria, including drug resistant falciparum malaria, ⁇ arteether (artemotil) or ⁇ / ⁇ arteether, with its quick onset of action, will rapidly reduce parasite biomass and quickly resolves clinical symptoms, whilst the long- acting activity of antimalarials such as piperaquine, curcumin or lumefantrine is thought to prevent recrudescence thus giving synergy to the combinations of the present invention.. This dual effect also appears to reduce the selective pressure on the parasite to develop resistance.
  • beta arteether artificial beta arteether
  • ⁇ / ⁇ arteether a formulation comprising of oral beta arteether (artemotil) or ⁇ / ⁇ arteether) in a fixed dose synergistic combination with other antimalarials including piperaquine, curcumin and lumefantrine for falciparum malaria, including drug resistant falciparum malaria.
  • This fixed dose combination will be an effective alternative for drug resistant falciparum malaria.
  • the present invention discloses a pharmaceutical formulation comprising of oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) in a fixed dose combination with other antimalarials including piperaquine, curcumin and lumefantrine, which works synergistically against drug resistant falciparum malaria.
  • oral arteether ⁇ arteether (artemotil) or ⁇ / ⁇ arteether
  • other antimalarials including piperaquine, curcumin and lumefantrine
  • composition of the present invention comprises of oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) formulation in a fixed dose combination with other antimalarials including piperaquine, curcumin, lumefantrine etc which works synergistically against drug resistant falciparum malaria
  • the said formulation comprises therapeutically effective amount of oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) with other antimalarials such as piperaquine, curcumin, lumefantrine for treatment of falciparum malaria, including drug resistant falciparum malaria.
  • oral arteether ⁇ arteether (artemotil) or ⁇ / ⁇ arteether
  • other antimalarials such as piperaquine, curcumin, lumefantrine for treatment of falciparum malaria, including drug resistant falciparum malaria.
  • arteether ⁇ arteether (artemotil) or ⁇ / ⁇ arteether
  • ⁇ arteether ⁇ / ⁇ arteether
  • Other antimalarials such as piperaquine, curcumin, lumefantrine etc. make a promising partner drug for use as part of short course artemisinin combination therapy.
  • Fixed dose combination of arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) with these antimalarials will thus be safe and effective combination therapy for falciparum malaria, including drug resistant falciparum malaria. It will reduce the duration of antimalarial treatment while at the same time enhance efficacy and reducing the likelihood of resistance development.
  • the inventor has conducted a comparative, open label pre-clinical (animal) study to evaluate the efficacy in terms of potency of ⁇ -arteether alone and in combination with antimalarials like piperaquine, lumefantrine and curcumin.
  • Arteether is generally administered in mammal in the range of 0.125 to lOmg/kg for 5 days as a single dose.
  • the anti malarial, piperaquine is normally administered in the range of 500 to 2000mg.
  • inventive composition of the present invention for oral administration comprising arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) and piperaquine that can be administered in a fixed dosage form for an average adult, wherein oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) may be in the range of 25 to 200mg and piperaquine may be in the range of 50 mg to 2000mg.
  • the fixed dose combination of oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) with piperaquine can be administered once or twice daily for 3 - 7 days to a patient infected with falciparum malaria.
  • the amount of curcumin for an average adult patient may generally be in the range of 100 mg to 2000mg in a fixed dose combination, wherein oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) may be in the range of 25 mg to 200 mg.
  • the fixed dose combination of oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) with curcumin can be administered once or twice daily for 3 - 7 days.
  • the invention encompasses various formulations of curcumin, including those where bioenhancers or absorption enhancers are incorporated in curcumin to increase absorption of curcumin or nano particles of curcumin
  • Lumefantrine is normally administered in a mammal along with other antimalarial such as ⁇ -artemether in an amount of 720mg to 3000mg as daily dose for 3 to 5 days.
  • lumefantrine can be administered along with oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) in an amount of 50mg to lOOOmg.
  • the fixed dose combination of oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) with lumefantrine can be administered once or twice daily for 3 - 7 days to an infected patient.
  • the fixed dose composition of oral arteether ( ⁇ arteether (artemotil) or ⁇ / ⁇ arteether) along with other antimalarials selected from piperaquine, curcumin and lumefantrine can be administered in combination with pharmaceutical carriers or diluents orally.
  • suitable pharmaceutical carriers include inert diluents or fillers thereby forming oral dosage forms such as tablets, powders, capsules, syrups or suspensions and the like.
  • tablets containing variety of excipients such as disintegrants such as starch, complex silicates together with binding agents such as poly vinyl pyrrolidone, sucrose, gelatin and acacia.
  • Lubricants such as magnesium silicate, sodium lauryl sulfate and talc are often used in tabletting purposes.
  • Solid compositions of the present invention can also be filled into soft and hard gelatin capsules.
  • the composition may be solubilized in suitable vegetable or edible oil such as sunflower oil, corn oil, peanut oil or any other suitable oil.
  • mice ( ⁇ 30g) infected with P. berghei for 72hr were given 3 oral doses of ⁇ -arteether (1.5mg/mouse) with or without piperaquine (5mg/mouse). 5 animals were used in each group.
  • the combination gave 80% protection to mice against P. berghei as compared to individual drugs, ⁇ -arteether and piperaquine, which gave 40% protection individually.
  • the combination was found to have synergistic action against malaria, giving high cure rate.
  • mice 5 2 0 0 0 0
  • mice ( ⁇ 30g) infected with P.berghei for 72hr were given 3 oral doses of ⁇ -arteether (AE, 1.5mg/mouse) with or without piperaquine (PQ, 5mg/mouse) as described below. 5 animals were used in each group. Survival of mice was used as the end point. 10 animals were used in each group. All infected animals in Control group, to which no drug was administered died by the 7 th day. 80% of the animals treated with the combination drug survived till Day 40, whereas only 40% of the animals treated with monotherapy survived till Day 40.
  • AE ⁇ -arteether
  • PQ piperaquine
  • AE at 1.5mg/mouse (3 doses) is partially protective (40%).
  • PQ at 5mg/mouse (3 doses) is partially protective (40%).
  • AE + PQ (3 doses) gives 80% protection.
  • mice ⁇ 30g were infected with P.berghei and after 48 or 72hr, the animals received ⁇ arteether (oral), 1 or 3 doses, with or without curcumin (oral) as indicated.
  • DMSO was used as the solvent.
  • the animals were given the drugs at 24hr intervals. Survival of mice was used as the end point. 10 animals were used in each group. All infected animals (control) died by the 7 th day.
  • mice infected with P.berghei were partially protected (40-50%) when given ⁇ arteether orally at 1.5mg/mouse in 3 doses at 24hr intervals.
  • a combination of ⁇ arteether with 3 oral doses of curcumin gave 90-100% protection, ⁇ arteether by itself was able to provide 100% protection when given at 3mg/mouse in 3 oral doses at 24hr interval.
  • the dose of ⁇ arteether can be reduced to 1.5mg/mouse and still get 100% protection.
  • the combination was found to have synergistic action against malaria, giving high cure rate.
  • mice ⁇ 30g were infected with P.berghei and after 48 or 72hr, the animals received ⁇ - arteether (AE, oral), 1 or 3 doses, with or without curcumin (oral) as indicated. DMSO was used as the solvent. The animals were given the drugs at 24hr intervals. Survival of mice was used as the end point. 10 animals were used in each group. All infected animals in the Control group, to whom no drug was administered died by the 7 l day. Partial protection (40-50%) were obtained when the drug was given as monotherapy, whereas 90-100% protection was obtained when the drug was given in combination with curcumin.
  • Partial protection 40-50%) were obtained when the drug was given as monotherapy, whereas 90-100% protection was obtained when the drug was given in combination with curcumin.
  • mice infected with P.berghei were partially protected (40-50%) when given ⁇ -arteether orally at 1.5mg/mouse in 3 doses at 24hr intervals.
  • a combination with 3 oral doses of curcumin gave 90-100% protection
  • ⁇ -arteether by itself was able to provide 100% protection when given at 3mg/mouse in 3 oral doses at 24hr interval.
  • the results obtained with mice infected for 48 or 72hr is similar.
  • the said formulation is for oral administration in the solid dosage form preferably in the form of tablets or capsules.
  • Example 3 i. Each tablet/capsule contains: ⁇ arteether (artemotil) or ⁇ / ⁇ arteether 25mg to 200mg
  • Each tablet/capsule contains: ⁇ arteether (artemotil) or ⁇ / ⁇ arteether ....25mg to 200mg
  • curcumin variant formulations of curcumin, including those where bioenhancers or absorption enhancers are incorporated in curcumin to increase absorption of curcumin or nano particles of curcumin
  • Example 5 iii Each tablet/capsule contains: ⁇ arteether (artemotil) or ⁇ / ⁇ arteether 25mg to 200mg
  • Lumefantrine .... 50mg to lOOOmg

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur de nouvelles compositions pharmaceutiques synergistes comprenant des dérivés d'artémisinine oraux, de préférence un β-arté éther (artémotil) ou alpha/β-arté éther dans une combinaison à dose fixe avec d'autres antipaludéens choisis dans le groupe constitué par la pipéraquine et la luméfantrine conjointement avec des excipients/supports pharmaceutiques utiles pour le traitement du paludisme à plasmodium Falciparum résistant aux médicaments.
PCT/IN2008/000543 2008-07-07 2008-08-27 Composition pharmaceutique synergiste antipaludique WO2010004573A1 (fr)

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IN1416MU2008 2008-07-07

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2404601A1 (fr) * 2010-07-06 2012-01-11 BioAgency AG Nouvelles combinaisons de médicaments pour le traitement du paludisme
WO2023004427A1 (fr) * 2021-07-23 2023-01-26 University of Sassari Traitement du paludisme grave et non compliqué

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002217A1 (fr) * 1990-08-08 1992-02-20 Ciba-Geigy Ag Compositions antipaludeennes
WO1993007126A1 (fr) * 1991-10-03 1993-04-15 Board Of Regents Of The University Of Nebraska Bisquinolines anti-malariques
WO2003035651A2 (fr) * 2001-10-26 2003-05-01 Centre National De La Recherche Scientifique Derives de l'artemisinine, et leurs utilisations dans le traitement du paludisme
EP1702616A1 (fr) * 2003-09-26 2006-09-20 Guoqiao Li Compose a base d'artemisinine
WO2007017646A2 (fr) * 2005-08-05 2007-02-15 Cipla Limited Composition antimalarienne
WO2007132438A2 (fr) * 2006-05-17 2007-11-22 Ranbaxy Laboratories Limited Traitement antipaludéen faisant appel à une combinaison d'un dérivé d'artémisinine synthétique et d'un dérivé de bisquinoline
WO2008001294A2 (fr) * 2006-06-26 2008-01-03 Ranbaxy Laboratories Limited Compositions pharmaceutiques pour l'administration orale à des doses élévées d'arteméther et de luméfantrine
CN101199489A (zh) * 2006-12-15 2008-06-18 珠海华澳进出口有限公司 双氢青蒿素呱喹片及其制备方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002217A1 (fr) * 1990-08-08 1992-02-20 Ciba-Geigy Ag Compositions antipaludeennes
WO1993007126A1 (fr) * 1991-10-03 1993-04-15 Board Of Regents Of The University Of Nebraska Bisquinolines anti-malariques
WO2003035651A2 (fr) * 2001-10-26 2003-05-01 Centre National De La Recherche Scientifique Derives de l'artemisinine, et leurs utilisations dans le traitement du paludisme
EP1702616A1 (fr) * 2003-09-26 2006-09-20 Guoqiao Li Compose a base d'artemisinine
WO2007017646A2 (fr) * 2005-08-05 2007-02-15 Cipla Limited Composition antimalarienne
WO2007132438A2 (fr) * 2006-05-17 2007-11-22 Ranbaxy Laboratories Limited Traitement antipaludéen faisant appel à une combinaison d'un dérivé d'artémisinine synthétique et d'un dérivé de bisquinoline
WO2008001294A2 (fr) * 2006-06-26 2008-01-03 Ranbaxy Laboratories Limited Compositions pharmaceutiques pour l'administration orale à des doses élévées d'arteméther et de luméfantrine
CN101199489A (zh) * 2006-12-15 2008-06-18 珠海华澳进出口有限公司 双氢青蒿素呱喹片及其制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2404601A1 (fr) * 2010-07-06 2012-01-11 BioAgency AG Nouvelles combinaisons de médicaments pour le traitement du paludisme
WO2012004324A1 (fr) * 2010-07-06 2012-01-12 Bioagency Ag Nouvelles combinaisons thérapeutiques dans le traitement du paludisme
CN103079568A (zh) * 2010-07-06 2013-05-01 生物机构股份公司 用于疟疾治疗的新药物组合
WO2023004427A1 (fr) * 2021-07-23 2023-01-26 University of Sassari Traitement du paludisme grave et non compliqué

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