AU614515B2 - A pharmaceutical combination for the prophylaxis and therapy of malaria - Google Patents
A pharmaceutical combination for the prophylaxis and therapy of malaria Download PDFInfo
- Publication number
- AU614515B2 AU614515B2 AU15675/88A AU1567588A AU614515B2 AU 614515 B2 AU614515 B2 AU 614515B2 AU 15675/88 A AU15675/88 A AU 15675/88A AU 1567588 A AU1567588 A AU 1567588A AU 614515 B2 AU614515 B2 AU 614515B2
- Authority
- AU
- Australia
- Prior art keywords
- group
- arteether
- pharmaceutical combination
- dihydroartemisinine
- chloroquine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 201000004792 malaria Diseases 0.000 title claims description 15
- 238000002560 therapeutic procedure Methods 0.000 title description 5
- 238000011321 prophylaxis Methods 0.000 title description 4
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 35
- 229960003677 chloroquine Drugs 0.000 claims description 35
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 35
- 229960002970 artemotil Drugs 0.000 claims description 34
- NLYNIRQVMRLPIQ-XQLAAWPRSA-N artemotil Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-XQLAAWPRSA-N 0.000 claims description 34
- 229960002521 artenimol Drugs 0.000 claims description 28
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 claims description 28
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 claims description 21
- 229960000611 pyrimethamine Drugs 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 claims description 9
- 229960001962 mefloquine Drugs 0.000 claims description 9
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 8
- 230000002195 synergetic effect Effects 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 claims description 4
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 4
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 claims description 4
- 229960001444 amodiaquine Drugs 0.000 claims description 4
- 229960004991 artesunate Drugs 0.000 claims description 4
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 claims description 4
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 4
- 229960005179 primaquine Drugs 0.000 claims description 4
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 claims description 4
- 229960000948 quinine Drugs 0.000 claims description 4
- 229960004673 sulfadoxine Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229950002996 floxacrine Drugs 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000003981 vehicle Substances 0.000 claims description 2
- 235000009917 Crataegus X brevipes Nutrition 0.000 claims 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims 1
- 235000009685 Crataegus X maligna Nutrition 0.000 claims 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims 1
- 235000009486 Crataegus bullatus Nutrition 0.000 claims 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims 1
- 235000009682 Crataegus limnophila Nutrition 0.000 claims 1
- 235000004423 Crataegus monogyna Nutrition 0.000 claims 1
- 240000000171 Crataegus monogyna Species 0.000 claims 1
- 235000002313 Crataegus paludosa Nutrition 0.000 claims 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 210000002837 heart atrium Anatomy 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 31
- 229960004191 artemisinin Drugs 0.000 description 30
- 241000699670 Mus sp. Species 0.000 description 12
- 241000224017 Plasmodium berghei Species 0.000 description 11
- 239000000126 substance Substances 0.000 description 8
- 239000003430 antimalarial agent Substances 0.000 description 7
- 229940033495 antimalarials Drugs 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 244000045947 parasite Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 241000223960 Plasmodium falciparum Species 0.000 description 3
- 230000000078 anti-malarial effect Effects 0.000 description 3
- 229960000981 artemether Drugs 0.000 description 3
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- -1 10-0methylfloxacrine Chemical compound 0.000 description 2
- ZGJHFPBCIVRXAQ-UHFFFAOYSA-N 7-(hydroxymethyl)-2,3-dihydropyrrolizin-1-one Chemical compound C1CC(=O)C2=C(CO)C=CN21 ZGJHFPBCIVRXAQ-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001445 schizonticidal effect Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- AWHZKKVSUJJVNL-UHFFFAOYSA-N 7-chloro-10-hydroxy-3-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2h-acridine-1,9-dione Chemical compound C1C(=O)C=2C(=O)C3=CC(Cl)=CC=C3N(O)C=2CC1C1=CC=C(C(F)(F)F)C=C1 AWHZKKVSUJJVNL-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000003826 Artemisia Nutrition 0.000 description 1
- 240000006891 Artemisia vulgaris Species 0.000 description 1
- 235000003261 Artemisia vulgaris Nutrition 0.000 description 1
- 208000002476 Falciparum Malaria Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000224453 Mycoplasma coccoides Species 0.000 description 1
- 206010035500 Plasmodium falciparum infection Diseases 0.000 description 1
- 201000011336 Plasmodium falciparum malaria Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000009052 artemisia Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000008303 genetic mechanism Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- ILSQBBRAYMWZLQ-UHFFFAOYSA-N n-(1,3-benzothiazol-2-ylsulfanyl)-n-propan-2-ylpropan-2-amine Chemical compound C1=CC=C2SC(SN(C(C)C)C(C)C)=NC2=C1 ILSQBBRAYMWZLQ-UHFFFAOYSA-N 0.000 description 1
- 231100000706 no observed effect level Toxicity 0.000 description 1
- 229940058924 other antimalarials in atc Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000037972 tropical disease Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- A61K31/49—Cinchonan derivatives, e.g. quinine
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
6 4 5rm10 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class Int. Class Application Number: Lodged: C C I 54 4 Conplete Specification Lodged: i Accepted: C Published: 44 4 Priority o o Related Art: c t c e4 4 4 4 Name of Applicant: o aE AdWdess of Applicant: Actual Inventor: Address for Service: HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany DIPAK KUMAR CHATTERJEE, BINDUMADHAVAN VENUGOPALAN, BANSI LAL, NOEL JOHN DE SOUZA and RICHARD HELMUT RUPP EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: A PHARMACEUTICAL COMBINATION FOR THE PROPHYLAXIS AND THERAPY OF MALARIA Thi following statement is a full description of this invention, including the best method of performing it known to Us 1 >6; I HOECHST AKTIENGESELLSCHAFT HOE 87/F 135 Dr.WN/rh a c S10 e C C C S0 C coe o e 0 a oe c a c ac c c t C CE C C C O0 0 0000 Specification A pharmaceutical combination for the prophylaxis and therapy of malaria The present invention relates to a combination of the malaria therapeutics artemisinine and its derivatives, for example dihydroartemisinine, arteether, artemether or artesunate, with one or more of the antimalarials chloroquine, 10-0-methylfloxacrine, quinine, mefloquine, amodiaquine, pyrimethamine, sulfadoxine, primaquine and the pharmaceutically utilizable salts thereof, for potentiating the action, and to dosage methods for these combinations of active substances.
The generic names used here and elsewhere in the text are taken from "Tropical Diseases Research, Seventh Programme Report", chapter 2; Malaria, UNDP/WORLD BANK/WHO, published by the WHO in 1985; 10-O-methylfloxacrine is a derivative of the antimalarial floxacrine and has been described in German Patent Application P 36 24 778.2.
Malaria which is resistant to medicaments represents a serious problem for clinical care and public health. The malaria parasite PLasmodium falciparum has developed a versatile ability to elude the action of a medicament by either genetic mechanisms or non-genetic (adaptive) methods. It has been demonstrated that the chloroquine resistance of malaria parasites takes the form of a stable genetically determined property (Warhurst, D.C. Pharmaceut.
J. Nov. 23 (1985) 689-692). The spread of PLasmodium falciparum resistant to chloroquine and other antimalarials presents the public health programs in tropical and subtropical countries with a difficult task (Suphat et al., Trans. R. Soc. Trop. Med. and Hyg. (1983) 73 338-340).
The use of combinations of various antimalariaLs in the 4> 2 chemotherapy of malaria is known. Thus, for example, a combination of amodiaquine and tetracycline and a combination of pyrimethamine and sulfadoxine, which is known under the name Fansidar has been used in clinical care (Suphat et al. cit.). More recently, clinical studies have been started on another antimalarial combination, Fansimef (mefloquine, pyrimethamine and sulfadoxine) (WHO Loc. cit.).
o 10 Peters has reported (Peters et al., Ann. Trop. Med. and 000 o Parasit. 71 (1977), 407-418) that the development of resistance can be slowed down in an animal study if one o 09 "o I. antimalarial is administered in combination with certain o 00 So° other antimalarials. Peters Peters, Bull. W.H.O. 51 000 0 0,0Q t5 (1974), 379-383 and W. Peters, Handbook of Experimental 0 0 Pharmacology 68/11 (1984) Springer Verlag Berlin, Heidelberg, New York, Editors: W. Peters and 0 00 o oo W.H.G. Richards) has also drawn attention to the use of o0o o appropriate medicament combinations for the treatment of 0 00 20 malaria in humans, these not only being able to delay the o oo00 oo 0° development of resistance but also improving the success of treatment. Thus, for example, it has been demonstrated that a .riple combination of mefloquine, sulfadoxine and 0 00 0"o 0 pyrimethamine delayed the development of resistance of Plasmodium berghei (Merkli et al., Ann. Trop. Med. and Parasit. (1980), 4 1-9).
Artemisinine and derivatives have Likewise already been disclosed as antimalarials. Artemisinine was isolated from Artemisia annual subsequently synthesized and used for the treatment of P. falciparum malaria Koch, Pharm. Int. (1981), 184-185; L.J. Bruce-Chwatt, British Med. J. 284 (1982), 767-768). It has also proved to be effective against chloroquine-resistant strains of P. falciparum in humans. Dihydroartemisinine, arteether, artemether and artesunate, for example, are semisynthetic derivatives of artemisinine, and the action thereof against malaria has been described in various reports Report of the Scientific Working Group on the ]1 3 Chemotherapy of Malaria, PDR/ChemaL 3rd Review, 85.3, Geneva, June 3-5, 1985, and references contained therein).
Artemisinine and its derivatives are represented by formuLa I 0 0 0 00 0 a 00 0 C 0O 00 0000 02 5 0 0 00 0 000 0 00 0 0 0 00 00 0 a 0000 H3C R R
I
with R and R 1 together denoting oxygen (artemisinine), or R denoting in each case hydrogen, and R 1 denoting OH (dihydroartemisinine), -O-C 1
-C
6 -alkyl, -O-C 2
-C
6 -aLkenyl, -0-C1-C 6 -alkanoyL, -0-C 1
-C
6 -carboxyalkanoyL, -0-cyclohexyLcarbonyL, -O-benzoyl or -O-naphthoyL, as well as the corresponding pharmacoLogically tolerated salts.
The compound of the formula I with R H and R 1
-O-CH
3 is called artemether, that with R H and R 2 -0-C 2
H
is called arteether, and that with R H and R 1
-O-COCH
2
CH
2
CO
2 Na is called artesunate.
It has now been found, surprisingly, that combinations of artemisinine and/or its abovementioned derivatives with the known malaria therapeutics chloroquine, 10-0-methylfloxacrine, quinine, mefLoquine, amodiaquine, pyrimethamine, sulfadoxine, primaquine and the pharmaceutically utilizable salts thereof show a synergistic action.
The clinical importance of the present improved compositions for malaria therapy is reflected by relevant animal experiments. The specific examples which follow contain typical test protocols used to examine the ability of the test substance to be an effective antimalarial b:: 1 i 3' i
D
_i
F:
4 even for medicament-resistant strains of P. berghei.
The present combination of antimaLarials which is described in more detail hereinafter permits the desired malaria treatment, specifically both for prophylaxis and for therapy, and prevents or delays the development OT resistance.
Artemisinine or one of its abovementioned derivatives is administered to mammals in general in the range 0.125-10 mg/kg in a single dose each day for 5 days. The other antimalarial which has already been mentioned hereinbefore in this specification chloroquine, 10-0methylfloxacrine, quinine, pyrimethamine, mefloquine, .oo .15 amodiaquine, sulfadoxine and primaquine) can be administered separately; in this case, the latter is administered in an amount within the (although usually C 00 C, lower) dose range and in accordance with the treatment regimens (frequency, dosage form and compositions) as are specified for the use thereof in publications to date, for example in the references cited above or further in the said references.
It is advantageous and more convenient to administer artemisinine or one of its derivatives and further antimalarials of the invention in a single combined composition. This can be a form suitable for parenteral administration, but a form suitable for oral administration is to be preferred. The proportion of each medicament in the proposed combined dosage form corresponds to the proportion of the total daily dose of each medicament when it is administered alone. The combined medicaments can be administered in single or divided doses.
In the preferred oral administration, the amount of artemisinine for an average adult patient will in general be in the range 0.2-2 g in combination with 200-400 mg of chloroquine or with 200-400 mg of 10-0-methylfloxacrine as initial dose; the 2nd dose can be administered 6 hours -5 5 later in the range 0.2-2 g of artemisinine in combination with 100-200 mg of chloroquine or with 100-200 mg of 10-0-methylfloxacrine. The dose administered at the second intake can be maintained for a further 3 days, with a single dose being administered each day.
Combinations of artemisinine or one of its derivatives with other antimalarials of the second group can be administered in a similar manner. In general, a combination of dihydroartemisinine (range 0.2-1.5 g) with chLoroquine (range 200-400 mg) or with 10-0-methylfloxacrine (range 200-400 mg) can be administered to an adult patient, with administration 6 hours later of a second dose of 0.2-1.5 g of dihydroartemisinine in combination with 100-200 mg of chLoroquine or with 100-200 mg of 0Q 10-0-methyLfloxacrine. The amount administered as the 2nd dose can in general be administered as a single dose oo 0 each day for a further 3 days.
It is also possible to administer to an adult patient a c combination of arteether (range 0.2-1.5 g) together with chloroquine or with 10-0-methylfloxacrine (range 200-400 mg). The 2nd dose can be administered 6 hours a 0a oe. after the 1st dose and can contain 0.2-1.5 g of arteether plus 100-200 mg of chloroquine or 10-0-methylfloxacrine.
The amount aai.inistered with the 2nd dose can in general be given as a single dose each day for a further 3 days.
The combined substances are administered, both orally and parenterally, alone or in a further combination with pharmaceutically utilizable vehicles. On oral administration, the suitable pharmaceutical vehicles include inert diluents or extenders used for the preparation of tablets, powders, capsules or the like. These pharmaceutical combinations can, if this is desired, contain additional ingredients such as flavorings, binders, corrigents or the like. For example, tablets which contain various corrigents such as sodium citrate, together with various soluble substances such as starch, alginates and ~Li_ 6 certain complex silicates and binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic, are used.
In addition, lubricants such as magnesium stearate, sodium LauryL sulfate and talc are often suitable for the preparation of tablets. Solid compositions of a similar nature are also used as fillers in filled soft and hard gelatin capsules. Accordingly, the preferred materials include lactose and polyethylene glycols of high molecular weight.
The present invention is illustrated by the examples which follow. However, it ought to be pointed out that the invention is not confined to the specific details of the examples.
5 Example 1 Synergistic therapeutic actions of subcurative doses of artemisinine, dihydroartemisinine and arteether in combination with subcurative doses of chloroquine, 10-0-methylfloxacrine, mefloquine or pyrimethamine against chloroquine-sensitive Plasmodium berghei infection in Swiss mice.
Methodology of the biological evaluation: "e.O The assessment of the schizontocidal action in the blood from the "28-day test" described by Raether and Fink (Ann.
Trop. Med. and Parasit., 73 (1979), 503-526) was used for this.
Mice: all the experiments were carried out with randomly bred male and female Swiss mice which originated from the rearing unit of Hoechst India Limited in Muland, Bombay.
The animals were free of Eperythrozoon coccoides. The animals received dry feed and water ad Lib. and were housed at a room temperature of 22-25 0
C.
Parasite: the London School of Hygiene and Tropical Medicine supplied the strain Plasmodium berghei K-173 which is sensitive to medicaments, and P. berghei (NS) which is moderately resistant to chloroquine. The strains 7 elicit, after they have been inocuLated intraperitorn ally, a lethal infection with 1 x 107 parasite-infected erythrocytes per mouse.
Administration of the substances: the substances were administered oraLLy or subcutaneously by the methods described by Raether and Fink (Loc. cit.). Artemisinine, dihydroartemisinine and arteether were homogenized in doubLy refined corn oil and used as suspensions for the subcutaneous inoculation of mice. The medicaments were administered for 5 days. The 1st dose was given within 2 hours after the infection followed by D+1, D+2, D+3 and D+4 (intervals of 1 day each).
Observation of the treated mice: from 0+4 to D+28 blood smears were prepared at various intervals. The blood smears were obtained from the distal end of the tail and *were stained with Giemsa solution. The mice were free of P. berghei on D+28 and were regarded as completely cured. At least 12 mice were investigated for each dose.
The synergistic therapeutic action of subcurative doses of artemisinine, dihydroartemisinine and arteether, each in combination with subcurative doses of chloroquine, mefloquine, pyrimethamine or 10-0-methylfloxacrine, on mice infected with chloroquine-sensitive P. berghei is shown in Table I for oral, and in Table II for subcutaneous, administration of the substances. As shown by these data, subcurative doses of artemisinine, dihydroartemisinine and arteether, each in combination with subcurative doses of chloroquine, 10-0-methylfloxacrine or pyrimethamine, completely cure mice infected with chloroquine-sensitive P. berghei when the substances are administered either orally or subcutaneously.
1: -8 TabLe I Compos it ion Oral dose mg /k g x5 M ic e pe r gr o up 25 27 12 ChLoroquine (curative dose) ChLoroquine (subcurative dose) 10-0-Methytfioxacrine (curative dose) 10-0--MethyL fLoxac rifle (cubcurative dose) MefLoquine (curative dose) MefLoquine (subcurative dose) Pyrimethamine (curative dose) Pyrimethamine (subcurative d ose) Artemisinine (curative dose) Artemisinine (subcurative Dihydroartemisinine (curative do se) Dihydroartemisinine (subcurative dose) Arteether (curative dose) cc Arteether (subcurative dose) Artemisinine chioroquine Dihydroartemisinine chLoroqu ine Arteether chLoroquine Artemisinine 10-0-methylfLoxacrine Arteether 10-0-methylfloxacrine Dihydroartemisii~ine 10-0methyLfioxacrine Arteether mefLoquine Arteether pyrimethamine 12.5 10 10 infected an im a Ls cu re d 100 100 100 6 100 18 "t00 7. 5 2.5 7.5 1 .25 200 100 100 12 100 100 50 10+ 10 5+5 7.5+5 20+5 91 100 100 100 100 10+5 10+5 12 100 12 100 10+2.5 10+1 }4 9- TabLe Il Compos it ion S u bcu t aneous dlo se mg /k gx M ic e pe r gr ou p i' .fectedl a n im aLs c u redc ChLoroquinine (curative dose) Chioroquine (subcurative dose) 10-0-MethyLfLoxacrine (curative dose) 10-0-MethyLfLoxacrime (subcurative dose) Pyrimethamine (curative dose) Pyrirnethamine (subcurative dlo se) Artemisinine (curative dose) Artemisinine (subcurative d(je) Dihydroartemisinine (curative do se) Arteether (curative dose) Arteether (subcurative dose) Dihydroartemisinine (subcurative dose) Arteether (curative dose) Arteether (subcurative dose) Artemisinine chLoroquine Dihydroartemisinine c h Loroqu ine Arteether chLoroquine Artemisinine 10-0-methylf Lox ac r ine Dihydroartemisinine 10-0methyLfLoxacrine Arteether 10-0-methyLfLoxacrine Arteether pyrimethamine 2.5 6 2.5 20 1.0 100 100 84 100 66 100 12 100 1 2 1 10+2.5 2.5+2.5 12 100 5+2.5 14 100 1 2 5 1 2 j 1.2+1 2~22 100 10 Example 2 Synergistic action of subcurative doses of artemisinine or artemisinine deri atives in combination with subcurative doses of chloroquine, 10-0-methylfLoxacrine or pyrimethamine for chLoroquine-resistant strains of Plasmodium berghei (NS) in infected Swiss mice.
The schizontocidaL actions in the blood were assessed by the procedure described in Example 1 using the chloroquine-resistant strains of P. berghei.
The synergistic therapeutic action of subcurative doses of artemisinine, dihydroartemisinine or arteether in combination with subcurative doses of chloroquine or of 15 10-0-methylfloxacrine or pyrimethamine for infection of Swiss mice with PLasmodium berghei (NS) is shown in Table III for oral and subcutaneous administration. As shown by these data, the mice infected with chloroquineresistant P. berghei are completely cured with subcurative doses of artemisinine, dihydroartemisinine or arteether in combination with subcurative doses of chloroquine or 10-0-methylfLoxacrine or pyrimethamine when the substances are administered either orally or subcutaneously.
I
i ~.1 11 Table III Composition Route Dose m g/k g x5) Chioroquine (subcurative dose) 10-0-MethyLfLoxacrine (subcurative dose) Pyr imethamine (curative dose) Pyrimethamine (subcurative dose) Artemisinine (subcurative dose) Dihydroartemisinine 0 (subcurative dose) Ar teether (subcurative dose) Artemisinine chLoroquine Dihydroartemisinine c h 10roqu ine Arteether chioroquine Artemisinine 10-0methyifLoxacrine Dihydroartemisinine 10-0-methy Lf Lox ac r i n e Arteether 10-0methylfioxacrine Arteether py rime tham ine o ra L s .c o ra L s o ra L s c.
o ra L s c.
o ra L s c.
o ra L s c.
o ra l s c.
o ra L s c.
o ra L s c.
o ra L s .c o ra L s c.
o ra L s c.
o ra L s .c o ra L s c.
40 20 10 2.5 5.0 1 .25 0.31 1 .25 200 20 100 5 100 10 25+15 10+15 15+15 5+ 15 10+15 5+15 15+5 10+2.5 15+5 2. 5+2. 5 10+7.5 5+2.5 20+0.31 5+0.31 M ic e pe r g r oup 24 24 17 15 16 20 40 16 12 12 12 12 12 15 12 15 12 15 12 15 16 16 20 16 infected an im a Ls cu re d 52 ?3 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
Claims (12)
1. A pharmaceutical combination with a synergistic action against malaria, which, besides customary auxiliaries and vehicles, contains one or more compounds of the formula Ci 13C 3R 1 I 1 la l 4 4 1 l oo o0 o a Q 0 6 S a0 in which R in each case denotes hydrogen, and R i denotes OH, -0-C -C -alkyl, except O-methyl, -0-C -C -alkenyl, -O-C -C alkanoyl, -0-C 1 -C -carboxyalkanoyl, -O-cyclonexylcarbonyl, -O-benzoyl or -O-naphthoyl, as well as the pharmacologically tolerated salts thereof (group and one or more compounds from the group comprising chloroquine, 10-0-methyl- floxacrine, quinine, mefloquine, amodiaquine, pyrimethamine, sulfadoxine, primaquine and the pharmaceutically effective salts thereof.
2. A pharmaceutical combination as claimed in claim 1, which contains one or more compounds from the group comprising dihydroartemisinine, arteether and artesunate and one or more compounds from group
3. A pharmaceutical combination as claimed in claim 1, which contains in each case one compound from group and one or more compounds from group Mn lb Disk 10/1.62 MG 1 1 r. A I_ -13-
4. A pharmaceutical combination as claimed in claim 1, which contains one compound from group and one from group A pharmaceutical combination as claimed in claim 1, which contains dihydroartemisinine and chloroquine.
6. A pharmaceutical combination as claimed in claim 1, which contains dihydroartemisinine and 10-0-methylfloxa- crine. 0 o 7. A pharmaceutical combination as claimed in claim .o 1, which contains dihydroartemisinine and pyrimethamine. o o ooo 8. A pharmaceutical combination as claimed in claim 1, S e which contains arteether and chloroquine.
9. A pharmaceutical combination as claimed in claim 1, which contains arteether and 10-0-methylfloxacrine. .,ao 10. A pharmaceutical combination as claimed in claim 1, o which contains arteether and pyrimethamine. i0 11. A method of preparation of pharmaceuticals having a l E synergistic action against malaria comprising combining compounds of group and as claimed in claim 1 in a pharmacologically acceptable ratio with pharmaceutically acceptable carriers and excipients.
12. A method as claimed in claim 11 comprising combining in each case, one compound from group and one or more from group
13. A method as claimed in claim 11 comprising combining dihydroartemisinine and chloroquine. Melb Disk 10/1.62 MG
14. A method as claimed in claim 11 comprising combining dihydroartemisinine and 10-0-methylfloxacrine. A method as claimed in claim 11 comprising combining dihydroartemisinine and pyrimethamine.
16. A method as combining arteether and
17. A method as combining arteether and
18. A method as combining arteether and claimed in claim 11 comprising chloroquine. claimed in claim 11 comprising l0-O-methylfloxacrine. claimed in claim 11 comprising pyrimethamine. o 00 So0 0 0 oo 0 0 0 000 0 00 00 0 0Q0 0 0 o C C DATED this 27th day of May 1991. HOECHST AKTIENGESELLSCHAFT 0 c WATERMARK PATENT ATTORNEYS 2ND FLOOR "THE ATRIUM", 290 BURWOOD ROAD, HAWTHORN, VIC. 3122. AUSTRALIA i: 'i T.i 1 Melb Disk 10/1.62 MG f'y
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873715378 DE3715378A1 (en) | 1987-05-08 | 1987-05-08 | COMBINATION OF MEDICINES ON PROPHYLAXIS AND THERAPY FROM MALARIA |
| DE3715378 | 1987-05-08 |
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| Publication Number | Publication Date |
|---|---|
| AU1567588A AU1567588A (en) | 1988-11-10 |
| AU614515B2 true AU614515B2 (en) | 1991-09-05 |
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| AU15675/88A Ceased AU614515B2 (en) | 1987-05-08 | 1988-05-06 | A pharmaceutical combination for the prophylaxis and therapy of malaria |
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|---|---|
| EP (1) | EP0290959A3 (en) |
| JP (1) | JPS6452714A (en) |
| KR (1) | KR880013558A (en) |
| AU (1) | AU614515B2 (en) |
| DE (1) | DE3715378A1 (en) |
| DK (1) | DK249688A (en) |
| HU (1) | HU200688B (en) |
| IL (1) | IL86302A0 (en) |
| IN (1) | IN166154B (en) |
| PT (1) | PT87427B (en) |
| ZA (1) | ZA883209B (en) |
Families Citing this family (15)
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|---|---|---|---|---|
| US4916204A (en) * | 1987-07-31 | 1990-04-10 | Massachusetts Institute Of Technology | Pure polyanhydride from dicarboxylic acid and coupling agent |
| NZ228748A (en) * | 1988-04-20 | 1991-07-26 | Merrell Dow Pharma | Treating drug-resistant protozoal infections with a tricyclic compound and an antiprotozoal agent: composition and kit therefor |
| EP0362810B1 (en) * | 1988-10-07 | 1993-05-05 | Hoechst Aktiengesellschaft | Antimalarial compositions using quinidine, artemisinine and its derivatives |
| EP0535719A3 (en) * | 1988-12-06 | 1993-04-14 | Dermatologic Research Corporation | Treatment of hemorrhoids with artemisinin and derivates |
| EP0464233A1 (en) * | 1990-07-02 | 1992-01-08 | Hoechst Aktiengesellschaft | Pharmaceutical combinations against malaria |
| NZ246606A (en) * | 1992-02-07 | 1995-09-26 | Ciba Geigy Ag | Antimalarial compostions containing a synergistic combination of benflumetol and quinine or a derivative thereof |
| GB9622427D0 (en) * | 1996-10-28 | 1997-01-08 | Pharma Mar Sa | Antimalarial drugs |
| US6160004A (en) * | 1997-12-30 | 2000-12-12 | Hauser, Inc. | C-10 carbon-substituted artemisinin-like trioxane compounds having antimalarial, antiproliferative and antitumor activities |
| IN191696B (en) * | 1999-02-12 | 2003-12-20 | Council Scient Ind Res | |
| WO2001072304A1 (en) * | 2000-03-28 | 2001-10-04 | Council Of Scientific And Industrial Research | A novel anti-microbial composition and method for producing the same |
| AU2001295979A1 (en) * | 2000-10-20 | 2002-04-29 | Ajinomoto Co., Inc. | Medicinal compositions, dose and method for treating malaria |
| CN1255106C (en) | 2003-09-26 | 2006-05-10 | 李国桥 | Complex artemisia apiacea extract |
| WO2006070393A1 (en) * | 2004-12-28 | 2006-07-06 | Council Of Scientific And Industrial Research | SYNERGISTIC COMBINATION KIT OF α,ß-ARTEETHER, SULFADOXIN AND PYMETHAMINE FOR TREATMENT OF SEVERE/MULTI-DRUG RESISTANT CEREBRAL MALARIA |
| FR2884715B1 (en) * | 2005-04-20 | 2007-06-15 | Sanofi Aventis Sa | ASSOCIATION BETWEEN FERROQUIN AND AN ARTEMISININE DERIVATIVE FOR THE TREATMENT OF MALARIA |
| WO2007043061A1 (en) * | 2005-10-11 | 2007-04-19 | Ipca Laboratories Ltd. | Anti-malarial combination and methods of formulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3302389A (en) * | 1988-04-20 | 1989-10-26 | Merrell Dow Pharmaceuticals Inc. | N-alkylamino derivatives of aromatic, tricyclic compounds in the treatment of drug-resistant protozoal infections |
| AU4263789A (en) * | 1988-10-07 | 1990-04-12 | Hoechst Aktiengesellschaft | Antimalarial compositions and methods of treatment using quinidine, artemisinine and its derivatives |
-
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- 1987-01-29 IN IN26/BOM/87A patent/IN166154B/en unknown
- 1987-05-08 DE DE19873715378 patent/DE3715378A1/en not_active Withdrawn
-
1988
- 1988-05-05 EP EP88107223A patent/EP0290959A3/en not_active Withdrawn
- 1988-05-05 ZA ZA883209A patent/ZA883209B/en unknown
- 1988-05-06 JP JP63109239A patent/JPS6452714A/en active Pending
- 1988-05-06 HU HU882314A patent/HU200688B/en not_active IP Right Cessation
- 1988-05-06 DK DK249688A patent/DK249688A/en unknown
- 1988-05-06 AU AU15675/88A patent/AU614515B2/en not_active Ceased
- 1988-05-06 PT PT87427A patent/PT87427B/en not_active IP Right Cessation
- 1988-05-06 IL IL86302A patent/IL86302A0/en unknown
- 1988-05-07 KR KR1019880005305A patent/KR880013558A/en not_active Ceased
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3302389A (en) * | 1988-04-20 | 1989-10-26 | Merrell Dow Pharmaceuticals Inc. | N-alkylamino derivatives of aromatic, tricyclic compounds in the treatment of drug-resistant protozoal infections |
| AU4263789A (en) * | 1988-10-07 | 1990-04-12 | Hoechst Aktiengesellschaft | Antimalarial compositions and methods of treatment using quinidine, artemisinine and its derivatives |
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| ZA883209B (en) | 1988-11-08 |
| PT87427A (en) | 1989-05-31 |
| IN166154B (en) | 1990-03-24 |
| DK249688A (en) | 1988-11-09 |
| EP0290959A3 (en) | 1990-03-07 |
| PT87427B (en) | 1992-09-30 |
| EP0290959A2 (en) | 1988-11-17 |
| IL86302A0 (en) | 1988-11-15 |
| JPS6452714A (en) | 1989-02-28 |
| AU1567588A (en) | 1988-11-10 |
| DE3715378A1 (en) | 1988-11-24 |
| DK249688D0 (en) | 1988-05-06 |
| HU200688B (en) | 1990-08-28 |
| KR880013558A (en) | 1988-12-21 |
| HUT47846A (en) | 1989-04-28 |
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