WO2015041722A1 - Traitement combiné amélioré à base d'artémisinine permettant de traiter une maladie à médiation par des parasites - Google Patents

Traitement combiné amélioré à base d'artémisinine permettant de traiter une maladie à médiation par des parasites Download PDF

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WO2015041722A1
WO2015041722A1 PCT/US2014/033555 US2014033555W WO2015041722A1 WO 2015041722 A1 WO2015041722 A1 WO 2015041722A1 US 2014033555 W US2014033555 W US 2014033555W WO 2015041722 A1 WO2015041722 A1 WO 2015041722A1
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individual
composition
treating
malaria
individual suffering
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PCT/US2014/033555
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English (en)
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Robert Lewis STEELE
Anthony Fedele MUSSO
David D. Mundschenk
Russell Van De Casteele
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Kryptonite Group, Ltd
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Priority claimed from US14/201,749 external-priority patent/US20140256762A1/en
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Publication of WO2015041722A1 publication Critical patent/WO2015041722A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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 microbial therapies, and particularly to a method of treating individuals suffering from a parasitic related disease using an improved Artemisinin based therapy, to a method of treating an individual suffering from malaria using an improved Artemisinin Combination Therapy (ACT) ; and more particularly to an enhanced method of treating an individual suffering from all forms of malaria from multiple parasite species using an improved Artemisinin Combination Therapy (ACT) adapted to prevent reoccurrence and minimize transmission stemming from untreated gametocytes in the liver.
  • ACT Artemisinin Combination Therapy
  • Malaria is a serious and complex tropical parasitic disease spread by several species of mosquito. It is caused by a parasite from the Plasmodium genus, particularly Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae , and Plasmodium knowlesi.
  • the symptoms of malaria include fever, headaches, and vomiting usually after 10-15 days post mosquito bite. Left untreated, it may quickly develop into life-threatening complications.
  • the Plasmodium parasites undergo complex life cycles once inside their human host. The life cycle starts with the mosquito bite of an infected female Anopheles mosquito. As a result of the bite, sporozoites are injected into the bloodstream, eventually reaching the liver.
  • the sporozoites multiply and release merozoites into the bloodstream where they invade the erythrocytes.
  • many parasites remain dormant in the liver.
  • Those parasites in the liver can be reactivated, ultimately causing relapse.
  • many parasites can live and remain dormant in the gastrointestinal tract.
  • Malaria is a world wide problem with an estimated 500+ million cases in 2010 . It is estimated that over 1 . 5 million people die every year from malaria, with most patients being children under the age of 5 .
  • a number of drugs ranging from natural drugs such as artemisinin and quinine, to synthetic drugs such as chloroquine, mefloquine, primaquine, halofantrine, amodiaquine, proguanil, and maloprim, have been developed to treat malaria.
  • natural drugs such as artemisinin and quinine
  • synthetic drugs such as chloroquine, mefloquine, primaquine, halofantrine, amodiaquine, proguanil, and maloprim
  • anti-malarial drugs the number of infections and deaths related to the infection continue to rise.
  • One factor resulting in the large number of malaria-related mortalities is the fact that Plasmodium falciparum, the deadliest malaria parasite, has acquired resistance against many available anti ⁇ malarial drugs.
  • the World Health Organization now prohibit
  • the method of treating individuals suffering from a parasitic mediated disease such as malaria must be capable of treating all forms of the disease (uncomplicated, complicated and cerebral), must account for the multiple parasites species causing the disease, and must prevent relapse or reoccurrence.
  • the treatment When used for malaria, the treatment must be able to treat all forms of malaria without the need to identify which species specific disease type, must not have any side effects, and must clear gametocytes to prevent reoccurrence of the disease .
  • the present invention describes a therapy for individuals suffering from a parasitic infection based on an enhanced Artemisinin Combination Therapy (ACT) .
  • ACT Artemisinin Combination Therapy
  • the present invention describes a method which uses a combination of four drugs.
  • the method includes administering to an individual a first composition.
  • the first composition comprises a therapeutically effective amount of an artemisinin derivate or its salt, such as an artemether spray delivered sublingually .
  • the individual is then administered a second composition.
  • the second composition comprises of a therapeutically effective amount of a second artemisinin derivate or its salt.
  • the second artemisinin derivate differs from the first composition and is preferably artesunate.
  • a third anti-microbial composition is then administered to the individual.
  • the third composition comprises of an effective amount of berberine, or its pharmaceutically acceptable derivatives or salts.
  • the second and third compositions are administered to the individual for additional periods, such as for two or three days.
  • a fourth anti-malarial composition is then administered to the individual.
  • the fourth composition should be a compound that eliminates tissue infection (exo- erythrocytic, preferably in the liver) and therefore, prevents the development of blood (erythrocytic) forms of the parasite which are responsible for relapses in malaria.
  • the fourth composition comprises of an effective amount of Primaquine, or its pharmaceutically acceptable derivatives or salts.
  • the fourth composition may be given to individuals on Day 4 as a one time dosage administration, or may be administered for a pre-determined period, up to for example 14 days, and preferably for 14 days.
  • the novel combination therapy in accordance with the present invention may be referred to generally as TriAct Plus therapy.
  • the treatment is administered to an individual suffering from a disease transmitted by an arthropod, such as a mosquito or tick.
  • the treatment is administered to an individual suffering from a disease mediated by a eukaryotic protist of the genus Plasmodium .
  • the treatment is administered to an individual suffering from a disease mediated by Plasmodium falciparum , Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi .
  • the treatment is administered to an individual suffering from a disease mediated by a combination of one or more of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi .
  • the treatment is administered to an individual suffering from malaria. In an alternative embodiment, the treatment is administered to an individual suffering from cerebral malaria .
  • the treatment is administered to an individual in order to prevent relapse or reoccurrence of a disease mediated by one or more of Plasmodium falciparum , Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi.
  • the TriAct Plus therapy can 1) be used as a universal treatment to cure for all four (4) Plasmodia species (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae) , 2) facilitates early administration of the treatment not requiring specie identification, thus preventing eventual complications of delayed treatment, 3) uses a delivery method for artemether via sublingual (spray) to treat complicated and severe forms of Malaria especially in the absence of parenteral forms and may serve as a treatment option regardless of the level of consciousness of the patient (cerebral malaria) , even when treatment is critical in the most remote areas.
  • Plasmodia species Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae
  • 3) uses a delivery method for artemether via sublingual (spray) to treat complicated and severe forms of Malaria especially in the absence of parenteral forms and may serve as a treatment option regardless of the level of
  • the TriAct Plus therapy was shown to be effective in the reduction of fever and headaches, elimination all forms of parasites within two (2) days, and promotion of needle-free treatment.
  • the TriAct Plus therapy demonstrated no incidence of recurrence, recrudescence, or relapse.
  • the subjects receiving the study drugs did not experience any adverse reactions like hypoglycemia, palpitations and tinnitus which are typically observed with quinine use or its derivatives.
  • the present invention further describes an improved artemether based supplement and/or pharmaceutical composition which is administered as a sublingual spray.
  • the supplement and/or pharmaceutical composition contains an Artemisinin derivative, an allergenic minimizing carrier, and a mucosal absorption enhancer.
  • the present invention further relates to a method of manufacturing the artemether based supplement and/or pharmaceutical composition and the uses thereof for delivery to an individual in need thereof.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier, “general refers to organic or inorganic materials, non ⁇ toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which cannot react with active ingredients.
  • the excipients include but are not limited to sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose , and cellulose acetate; powered tragacanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; cocoa butter and suppository waxes; vegetable oils, such as peanut oil, cotton seed oil, seasame oil, olive oil, corn oil and oil of theobroma; esters such as but not limited to, ethyl oleate and ethyl laurate; polyols such as propylene glycol, glycerine, sorbitol, mannitol and polyethylene glycol; agar; alginic acids; buffering agents such as but not limited to, magnesium hydroxide and aluminum hydroxide; pyrogen-free water; isotonic sa
  • wetting agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, flavoring agents, sweetening agents, lubricants, releasing agents, perfuming agents, carriers, tabletting agents, stabilizers, antioxidants and preservatives can also be present .
  • “Pharmaceutically-acceptable salt” refers to salts which retain the biological effectiveness and properties of compounds which are not biologically or otherwise undesirable.
  • Pharmaceutically-acceptable salts refer to pharmaceutically-acceptable salts of the compounds, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • the term "therapeutically effective amount” generally refers to an amount of an agent, for example the amount of a compound as an active ingredient, that is sufficient to effect treatment as defined herein when administered to an individual, such as a mammal, preferably a human in need of such treatment.
  • a therapeutically effective amount of a compound, salt, analog, or derivative of the present invention will depend on a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician.
  • the term “treat”, “treating” or “treatment” refers to the administration of therapy to a subject, particularly a mammal, more particularly a human, who already manifests at least one symptom of a disease to obtain a desired pharmacological and physiological effect.
  • a subject includes an individual who is diagnosed as having a disease.
  • the term may also include preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • Figure 1 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of positive malarial smear;
  • Figure 2 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of abnormal platelet count;
  • Figure 3 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of abnormal hemoglobin levels;
  • Figure 4 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of abnormal WBC count;
  • Figure 5 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of tacypnea;
  • Figure 6 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of hypotension;
  • Figure 7 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of altered sensorium;
  • Figure 8 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of abdominal pain
  • Figure 9 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of vomiting;
  • Figure 10 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of nausea;
  • Figure 11 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of myalgia;
  • Figure 12 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of anorexia;
  • Figure 13 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days of fever;
  • Figure 14 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days with a headache;
  • Figure 15 is a graph comparing individuals diagnosed with malaria and treated with the TriAct Plus therapy versus individuals diagnosed with malaria and treated using standard care protocol with respect to the number of days with reported chills.
  • the present invention describes a novel combination therapy for the treatment of microbial infections, such as parasitic infections.
  • the present invention may be useful in treating diseases mediated by arthropods and/or a Plasmodium based parasites causing malaria.
  • the combination therapy in accordance with the present invention is based on Artemisinin Combination Therapy (ACT) .
  • ACT Artemisinin Combination Therapy
  • WHO World Health Organization
  • the present invention uses a quad-therapy modality, using a unique combination of four compositions: artemether, artesunate, berberine, and primaquine.
  • the quad-therapy may allow for killing of the parasites in the blood (artemesinin derivatives) , the digestive tract (berberine) , and the liver (primaquine) .
  • the quad-therapy in accordance with the present invention allows for quick administration to patients suffering cerebral malaria.
  • the novel combination therapy may be referred to generally as TriAct Plus therapy, for the triple components plus primaquine that make up combination therapy.
  • the quad-therapy in accordance with the present invention may allow for treating individuals suffering from malaria caused by one or more of Plasmodium falciparum , Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae, and possibly Plasmodium knowlesi.
  • Administering the first composition by a sublingual spray not only allows the drug to enter the patient's body rapidly, but allows delivery to patients who may not be able to receive dosages via pills and eliminates any problems associated with using needles (i.e. safety, disposal) .
  • Follow up doses of the second and third compositions ensure that the parasites are killed both in the blood and the digestive tract, thereby eliminating re-occurrence.
  • Doses of the fourth composition ensure that the parasites are killed in the liver, thereby eliminating re-occurrence.
  • Artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. This peroxide is believed to be responsible for the drug's mechanism of action. Few other natural compounds with such a peroxide bridge are known, see Artemisinin and a new generation of antimalarial drugs". Education in Chemistry. July 2006. http: / /www. sc . org/Education/EiC/issues/2006July/
  • Artemisini . asp It is widely used for the treatment of malaria, particularly in combination with other drugs such as mefloquine (ASMQ) , lumefantrine (such as sold under the trade name Coartem) , amodiaquine (such as sold under the trade names Camoquin, Flavoquine, ASAQ) , piperaquine (such as sold under the trade name Duo-Cotecxin) , artemisinin and pyronaridine (such as sold under the trade name Pyramax) .
  • Artemisinin derivatives are typically used as prodrugs of the biologically active metabolite dihydroartemisinin, which is active during the stage when the parasite is located inside red blood cells.
  • compositions may include free-radical production in the parasite food vacuole and inhibition of a parasite calcium ATPase.
  • a key advantage of artemisinins is rapid action against all of the erythrocytic stages of the parasite, including transmissible gametocytes, resulting in a rapid clinical benefit and decreased transmission of malaria, see Rosenthal, Artesunate for Treatment of Severe Falciparum Malaria, N. Engl J Med 2008, 358 : 1829-1836.
  • artemisinin is its poor physical properties resulting in poor bioavailability, limiting its effectiveness.
  • the compound is sparingly soluble in either water or oils and thus not readily absorbable by the gastrointestinal tract.
  • artesunate water-soluble: for oral, rectal, intramuscular, or intravenous use
  • artemether 1 ipid-soluble : for oral, rectal or intramuscular use
  • dihydroartemisinin artelinic acid
  • artenimol and artemotil artemotil.
  • the Artemisinin derivatives include but are not limited to artesunate, dihydroartemisinin, dihydroartemisinin hemisuccinate, dihydrodroartemisinin succinate, sodium artesunate, stabilized forms of artesunate, stabilized forms of sodium artesunate, dihydroartemisitene dimers as described in U.S. Patent 7,098,242, amino-functionalized 1 , 2 , 4-trioxanes as described in U.S. Patent 7,071,226, artemisinin endoperoxides as described in U.S. Patent 6,984,640, spiro and dispiro 1, 2, 4-trioxolane anti-malarials as described in U.S.
  • Patent 6,906,205 mixed steroidal 1,2,4,5- tetraoxane compounds as described in U.S. Patent 6,906,098, arteether as described in U.S. Patent 6,750,356, substituted 1, 2, 4-trioxanes as described in U.S. Patent 6,737,438, Artemisia annua extracts as described in U.S. Patent 6,685,972, artemether as described in U.S. Patent 6,683,193, trioxane derivatives based on artemisinin as described in U.S. Patent 6,649,647, trioxane dimer compounds as described in U.S. RE38,117, conjugates of artelinic acid as described in U.S.
  • Patent 6,461,603 arteethers from dihydroartemisinin as described in U.S. Patent 6,346,631, artemisinine or artemisinene derivatives as described in U.S. Patent 6,306,896, C-10 carbon substituted artemisinin-like trioxane compounds as described in U.S. Patent 6,160,004, water-soluble trioxanes as described in U.S. Patent 6,136,847, alpha arteether as described in U.S. Patent 6,127,405, artemisinin dimers as described in U.S. Patent 5,856,351, ( + ) -deoxoarteminisinin and analogs of (+) -deoxoartemisinin as described in U.S.
  • Artemether is a methyl-ether derivative of dihydroartemisinin derived from artemisinin.
  • Artemether is known to be effective against blood schizots of several malaria causing parasites, and is used as an ACT drug .
  • Artesunate also known as dihydroartemisinin hemisuccinate and its salts, has a IUPAUC chemical name of 3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR) -Decahydro-3 , 6, 9-trimethyl- 3 , 12-epoxy-12H-pyrano ( 4 , 3- j ) -1 , 2benzodioxepin-10-ol
  • the oral dosage range for artemisinin, artemisinin salts and derivatives is between about 1 mg to about 1,500 mg per dose administered one to three times daily. More preferably, the oral dosage range for Artemisinin, Artemisinin salts and derivatives is between about 20 mg to about 250 mg per dose if taken one to three times daily. Most preferably, the oral dosage ranges for artemisinin, artemisinin salts and derivatives is between about 40 mg to about 100 mg per dose taken one to three times daily.
  • Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It has a IUPAC name of (5, 6-Dihydro-9, 10-dimethoxybenzo [g] -1, 3- benzodioxolo [ 5 , 6-a ] quinolizinium) , with a chemical formula of:
  • Berberis e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris (Barberry) , and Berberis aristata (Tree Turmeric)
  • other plant families including but not limited to Hydrastis canadensis (Goldenseal), Phellodendron amurense (Amur Cork Tree, Huang Bai, Huang Po, Po Mu) and Coptis chinensis (Chinese Goldthread, Huang-Lian, Huang-Lien) , and Tinospora cordifolia, and to a smaller extent in Argemone mexicana (Prickly Poppy) and Eschscholzia californica (Californian Poppy) , Rhizoma coptidis Huanglian Jiedu decoction, San-Huang-Xie-Xin-Tang, Xietianwu, Gegen Quinlian, and Shizhu.
  • Berberine is primarily isolated from the roots, rhizomes, stems, and bark. Berberine has been used for medical use in both Ayurvedic and Chinese medicines, and recently has been tested for antibacterial activity and use in diarrhea, prostate cancer and diabetes. It is generally considered to be non-toxic and shows no genotoxic activity.
  • berberine, berberine derivatives, or its salts may include, but not limited to, berberine alkaloid, berberine base, j er&erir!ehydrochloride , berberine, berberrubine, coreximine, tetrahydropalmatine, j atrorrhi zine , 13- hydroxyberberine chloride, coralyne, coralyne chloride, 7 , 8-dihydro-13-methylberberine, berberine acetone, 13- allylberberine , palmatine, 13-benzylberberine, t etrahydroberber ine , tetrahydroprotoberberine
  • the oral dosage range of berberine is from about 50 mg to about 1, 500 mg administered in a single dose two to three times daily, not to exceed 4, 500 mg per day. More preferably, the dose of berberine is about 100 mg to about 1, 000 mg in a single human dose not to exceed 3,000 mg per day, taken one to three times daily. The most preferable dosage range for a single dose of berberine is about 200 to about 500 mg taken one to three times daily.
  • Primaquine is an 8-aminoquinoline anti-protozoal agent which is highly active against exo-erythrocytic stages of Plasmodium vivax, Plasmodium ovale and against the primary exo-erythrocytic stages of Plasmodium falciparum. Primaquine is also highly active against gametocytes of Plasmodia, especially Plasmodium falciparum. It has the chemical formula of:
  • Primaquine is readily absorbed from the gastro-intestinal tract and extensively distributed into body tissues. Peak plasma concentration occurs about 1 to 3 hours after a dose is taken and then rapidly diminishes with a reported elimination half life of 3 to 6 hours. Primaquine is rapidly metabolized in the liver, its principal metabolite being carboxyprimaquine .
  • the preferred form of the composition is its salt derivative, preferably the phosphate salt, primaquine phosphate. Primaquine phosphate may be given at orally as a tablet in dosages of 0.5-0.75 mg-base per kilogram if based on weight.
  • Primaquine phosphate may be given at daily dosages of 15-45 mg as a single dosage administration and 7.5 to 15 mg/day for 14 days if based on age. Dosages and administration of primaguine phosphate can vary depending on the desired treatment needed as a result of the type of Plasmodium species.
  • Table 1 Delivery Schedule for Uncomplicated Malaria (P. falciparum/P. malariae) : Primaquine phosphate 15mg/tablet .
  • the present invention is further described by the following non-limiting examples.
  • the following examples illustrate embodiments, albeit preferred embodiments, of routes of administration and forms of the compositions. While the preferred forms and/or routes are described, other forms, such as but not limited to tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration.
  • compositions may also be developed for inhalational, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, intravenous or any other route of administration .
  • the dosage form of the present invention may include either immediate or controlled release forms.
  • Each composition can be formulated and manufactured by procedures known to one of skill in the art, and may include 100% composition or a mixture of one or more pharmaceutically acceptable excipients or pharmaceutically acceptable carriers.
  • liquid artemether can be prepared as a spray form using, for example, microfluidization process as described in U.S. Patent 6,861,066.
  • the artemether spray can be prepared as a sublingual nano-spray.
  • the present invention further describes an alternative sublingual spray, artemether based supplement and/or pharmaceutical composition, a method of manufacturing the improved artemether based supplement and/or pharmaceutical composition, and the use thereof for delivery to an individual in need thereof.
  • the supplement and/or pharmaceutical composition contains an active compound such as an Artemisinin derivative, a carrier which reduces the risk of an allergic reaction when administered to an individual, and a mucosal absorption enhancer.
  • the sublingual spray supplement and/or pharmaceutical composition includes artemether, a phci ⁇ 3ceut ically ⁇ llergenic acceptable carrier, such as neutral oil, including but not limited to olive oil (obtained from the fruit of Olea europaea) . , and a quaternary ammonium salt such as Benzalkonium Chloride which acts as a mucosal absorption enhancer.
  • the present invention includes an improved artemether supplement and/or pharmaceutical composition utilizing a carrier which reduces the risk of an allergic reaction when administered to an individual susceptible to food based allergies.
  • Artemisinin and Artemisinin derivatives for use in the treatment of malaria is known in the art, such compositions are prepared using arachis (peanut) oil.
  • arachis (peanut) oil The use of such oil presents a problem for any supplement or pharmacological routes of administration that require delivery within the oral cavity, such as the mouth whereby the active ingredient is required to diffuse into the circulatory system through tissues under the tongue.
  • peanut oil as a carrier for sublingual sprays increases the risk of severe injury and even fatalities.
  • the supplement and/or pharmaceutical composition in accordance with the present invention uses olive oil as a carrier for the Artemether as there is no known cases of hypersensitivity to olive oil when taken by mouth.
  • Quaternary ammonium salts may be used to form the supplement and/or pharmaceutical composition.
  • Such quaternary ammonium salts include those commonly used and considered as safe for human use.
  • Such compounds are typically tetrasubstituted ammonium salts in which the substituent groups are preferably hydrocarbon compounds attached to the nitrogen by an —C bond, and selected from the group consisting of substituted and unsubstituted, saturated and unsaturated, aliphatic and aromatic, and branched and normal chain groups.
  • the nitrogen atom is pentavalent and is in the positively charged portion of the molecule, thus quaternary ammonium salts are cationic electrolytes.
  • the mucosal absorption enhancer of this invention is benzalkonium chloride, also known as alkyl dimethylbenzyl ammonium chloride, alkyldimethyl
  • Benzalkonium chloride has a chemical formula of:
  • Benzalkonium chloride is commercially available in suitable form from a number of sources, including Sigma Aldrich Chemical Co. Benzalkonium chloride used in an amount effective to serve as a membrane enhance as well as a preservative. The Benzalkonium chloride may be used at a final concentration of between about 0.001% and about 0.1%, by weight, and preferably between about 0.005% and about 0.05%, based on the weight of the composition, and more preferably at 0.007% based on the weight of the composition . Tables 5-9 provide various illustrative examples of the spray arteraether supplement and/or pharmaceutical composition in accordance with the present invention.
  • the artemether solution described above is packaged in a single dose delivery system.
  • a single dose delivery system such as an atomizing spray pump as described in U.S. Patent No. 6,126,038, where the patient can simply spray the composition to the desired place, i.e. under the tongue, until the bottle is completely discharged.
  • Example 1 Method of treating an individual suffering from a disease mediated by a parasite.
  • a method of treating an individual suffering from disease mediated by a parasite, preferably plasmodial parasites which cause malaria comprises the steps of (1) administering to a mammal, preferably a human, a first composition, the first composition comprising a therapeutically effective amount of an artemisinin derivative, preferably artemether at 50-80 mg per dose, preferably 60 mg (2) administering to the mammal a second composition, the second composition comprising a therapeutically effective amount of a second artemisinin derivate, the second artemisinin derivate differing from the first composition, and preferably being artesunate or its pharmaceutically acceptable derivatives at 1 mg-1500 mg per individual dose, preferably about 20 mg to about 250 mg per dose, administered three times daily, and most preferably about 40 mg to about 100 mg per dose administered three times daily; and (3) administering to a mammal a third composition, the third composition comprising a therapeutically effective amount of berberine, or its pharmaceutically acceptable derivatives at lmg to about 1500 mg per individual
  • Delivery of primaquine tablets, according to user age or weight, administration may be on Day 5 only or daily for a period of 14 days.
  • Example 2 Treatment for adult humans over 165 pounds (75 Kg) having a parasitic infection using sublingual delivery of an artemether solution: Malaria.
  • a method of treating an individual suffering from malaria comprises the steps of (1) administering to an adult mammal, preferably a human, a first composition, the first composition comprising a therapeutically effective amount of artemether; (2) administering to the adult mammal a second composition, the second composition comprising a therapeutically effective amount of artesunate or its pharmaceutically acceptable derivatives; (3) administering to the adult mammal a third composition, the third composition comprising a therapeutically effective amount of berberine, or its pharmaceutically acceptable derivatives; and (4) administering to the adult mammal a fourth composition, the fourth composition comprising a therapeutically effective amount of primaquine, or its pharmaceutically acceptable derivatives or salts.
  • the method of treatment can be facilitated by the use of a kit comprising a sublingual spray containing artemether solution as a single dosage unit spray bottle, a first packet containing artesunate tablets, a second packet containing berberine tablets, and a third packet containing primaquine, or its pharmaceutically acceptable derivatives or salts.
  • a kit comprising a sublingual spray containing artemether solution as a single dosage unit spray bottle, a first packet containing artesunate tablets, a second packet containing berberine tablets, and a third packet containing primaquine, or its pharmaceutically acceptable derivatives or salts.
  • An adult human, over 165 pounds (75 Kg) suffering from malaria, including acute, chronic, or cerebral malaria begins the method in accordance with the present invention by administering the first loading dose of the artemether.
  • the artemether is delivered to the individual using a sublingual spray bottle containing 60 mg of artemether solution per bottle.
  • a spray offers advantages over injectable form by providing a method of delivery that is easy to administer, does not require trained medical professionals such as a doctor or nurse, and avoids the problems associated with needles, such as fear of spreading disease such as HIV or Hepatitis C and proper disposal.
  • sublingual drug delivery, particularly sprays allows the active ingredients improved absorption and enhanced bioavailability.
  • the user simply removes the bottle from the transportation/delivery packaging and displaces any safety features, such as any tamper proofing outside wrapping, secured to the bottle.
  • any safety features such as any tamper proofing outside wrapping
  • the adult individual lifts his/her tongue and pumps the spray bottle with artemether solution into the mouth so the solution is delivered to the area under the tongue.
  • the bottle remains in that position until the contents of the bottle are fully delivered to the area under the tongue.
  • the liquid is preferably held under the tongue for a predetermined time period, preferably 30 seconds. Any liquid remaining in the user's mouth is then swallowed.
  • the user After waiting for a predetermined time period, such as 1 minute to 1 hour, and more preferably 30 minutes the user administers the second composition comprising a dosage of artesunate, such as 3 X 50 mg tablets for the first 12 hours, followed by a repeat dosage the next 12 hours (300 mg per day) . The user then takes 2 tablets every 24 hours (100 mg) for 3 additional days.
  • the user administers the third composition comprising a dosage of berberine, such as 2 X 400 mg tablets for the first 12 hours followed by a repeat dosage the next 12 hours (1600 mg per day) . The user then takes 2 tablets every 24 hours (800 mg) for 3 additional days.
  • the second and third compositions can be administered simultaneously with the first composition.
  • the user also administers the fourth composition comprising a dosage of primaquine, or its pharmaceutically acceptable derivatives or salts, preferably primaquine phosphate.
  • administration of primaquine, or its pharmaceutically acceptable derivatives or salts is performed on Day 4 of the treatment and given as a single dose, according to the following, primaquine, administered to a patient by weight of 0.75 mg base per kilogram single dose as 1 one day administration. If the weight of the individual is unknown, primaquine tablets of 15 mg/tablet is administered based on an age based dosage. For individuals 12 years old or older, 3 primaquine tablets are given as a single dose administration.
  • multiple dosages may be given to the individual from Day 4 to Day 17, for a total of 14 days.
  • primaquine for administration of primaquine for a period of 14 days, if the weight if the individual is known, primaquine is administered using 0.5 mg base per kilogram body weight for 14 days. If the weight of the individual is unknown, primaquine tablets, 15mg/tablet, is administered based on an age based dosage. For individuals 12 years old or older, 1 primaquine tablet is administered daily for 14 days .
  • the method of treating an individual suffering from malaria is performed by a procedure in which the first, second, third and fourth compositions are delivered to the infected individual without identifying the Plasmodium species affecting said individual.
  • the method of treating an individual suffering from malaria includes the step of the combined drugs clearing all forms of the Plasmodium from the patient.
  • Example 3 Treatment for adult human 66 (30 kg) -165 pounds (75 Kg) suffering a parasitic infection using sublingual delivery of an artemether solution: Malaria.
  • the method of treatment can be facilitated by the use of a kit comprising a sublingual spray containing artemether solution as a single dosage unit spray bottle, a first packet containing artesunate tablets, and a second packet containing berberine tablets.
  • a kit comprising a sublingual spray containing artemether solution as a single dosage unit spray bottle, a first packet containing artesunate tablets, and a second packet containing berberine tablets.
  • An adult human 66 (30 kg) -165 pounds (75 Kg) suffering from malaria, including acute, chronic, or cerebral malaria begins the method in accordance with the present invention by administering the first loading dose of artemether.
  • the artemether is delivered to the individual using a sublingual spray bottle containing 60 mg artemether solution per bottle. The user simply removes the bottle from the transportation/delivery packaging and displaces any safety features, such as outside wrapping to indicate tampering, secured to the bottle.
  • the adult individual After removing the seal from the spray bottle, the adult individual lifts his/her tongue and pumps the spray bottle with artemether solution into the mouth so the solution is delivered to the area under the tongue.
  • the bottle remains in that position until the contents of the bottle are fully delivered to the area under the tongue.
  • the liquid is preferably held under the tongue for a predetermined time period, preferably 30 seconds. Any liquid remaining in the user's mouth is then swallowed.
  • the user administers the second composition comprising a dosage of artesunate, such as 2 x 50 mg tablets for the first 12 hours, followed by a repeat dosage the next 12 hours (200 mg per day) .
  • the second and third compositions can be administered simultaneously with the first composition.
  • the user also administers the fourth composition comprising a dosage of primaquine, or its derivatives or salts, preferably primaquine phosphate.
  • administration of primaquine is performed on Day 4 of the treatment and given as a single dose, according to the following, primaquine administered to a patient by weight of 0.75 mg base per kilogram single dose as 1 one day administration. If the weight of the individual is unknown, primaquine tablets of 15 mg/tablet is administered based on an age based dosage. For individuals 12 years old or older, 3 primaquine tablets are given as a single dose administration. Depending on the need and/or type of Plasmodium species, multiple dosages may be given to the individual from Day 4 to Day 17, for a total of 14 days. For administration of primaquine for a period of 14 days, if the weight if the individual is known, primaquine is administered using 0.5 mg base per kilogram body weight for 14 days.
  • primaquine tablets 15mg/tablet
  • 1 primaquine tablet is administered daily for 14 days.
  • the method of treating an individual suffering from malaria is performed by a procedure in which the first, second, third and fourth compositions are delivered to the infected individual without identifying the Plasmodium species affecting said individual.
  • the method of treating an individual suffering from malaria includes the step of the combined drugs clearing all forms of the Plasmodium from the patient.
  • Example 4 Treatment for human child 33 pounds (15 kg) -66 pounds ( 30 Kg) suffering a parasitic infection using sublingual delivery of an artemether solution: Malaria.
  • the treatment is the same as described in Example 3 for compositions 1- 3 .
  • the user also administers the fourth composition comprising a dosage of primaguine, or its derivatives or salts, preferably primaquine phosphate.
  • administration of primaquine is performed on Day 4 of the treatment and given as a single dose, according to the following, primaquine administered to a patient by weight of 0.75 mg base per kilogram single dose as 1 one day administration. If the weight of the individual is unknown, primaquine tablets of 15 mg/tablet is administered based on an age based dosage.
  • primaquine tablets are given as a single dose administration.
  • 1 primaquine tablets are given as a single dose administration.
  • multiple dosages may be given to the individual from Day 4 to Day 17, for a total of 14 days.
  • primaquine is administered using 0.5 mg base per kilogram body weight for 14 days. If the weight of the individual is unknown, primaquine tablets, 15mg/tablet, is administered based on an age based dosage.
  • primaquine tablets 15mg/tablet, is administered based on an age based dosage.
  • 3/4 of the primaquine tablet is administered daily for 14 days.
  • 1/2 of the primaquine tablet is administered daily for 14 days.
  • the method of treating an individual suffering from malaria is performed by a procedure in which the first, second, third and fourth compositions are delivered to the infected individual without identifying the Plasmodium species affecting said individual.
  • the method of treating an individual suffering from malaria includes the step of the combined drugs clearing all forms of the Plasmodium from the patient.
  • Example 5 Treatment for infants and toddlers 33 pounds up to 3 years old (under 15 kg) suffering a parasitic infection using sublingual delivery of an artemether solution: Malaria.
  • the dosage delivered to the user includes artemether delivered using a sublingual spray bottle containing 60 mg artemether solution per bottle, 25 mg artesunate per dosage, 1 dose every 12 hours for the first day (50 mg total per day) followed by 1 dose (25 mg) every day for three days, and 1 X 200 mg berberine dose every 12 hours for the first day (400 mg total per day) followed by 1 dose (200 rag) every day for three days.
  • the tablets can be ground up and mixed with liquids that allow delivery to the user, such as milk, juice, and syrups.
  • the user also administers the fourth composition comprising a dosage of primaquine, or its derivatives or salts, preferably primaquine phosphate.
  • administration of primaquine is performed on Day 4 of the treatment and given as a single dose, according to the following, primaquine administered to a patient by weight of 0.75 mg base per kilogram single dose as 1 one day administration. If the weight of the individual is unknown, primaquine tablets of 15 mg/tablet is administered based on an age based dosage. For individuals between 1 years old and 3 years old, 1/2 of a primaquine tablet is given as a single dose administration.
  • multiple dosages may be given to the individual from Day 4 to Day 17, for a total of 14 days.
  • primaquine For administration of primaquine for a period of 14 days, if the weight if the individual is known, primaquine is administered using 0.5 mg base per kilogram body weight for 14 days. If the weight of the individual is unknown, primaquine tablets, 15mg/tablet, is administered based on an age based dosage. For individuals between 1 years old and 3 years old, 1/2 of the primaquine tablet is administered daily for 14 days.
  • the method of treating an individual suffering from a malaria is performed by a procedure in which the first, second, third and fourth compositions are delivered to the infected individual without identifying the Plasmodium species affecting said individual.
  • the method of treating an individual suffering from malaria includes the step of the combined drugs clearing all forms of the Plasmodium from the patient.
  • Example 6 Treatment for individuals suffering a parasitic infection using injectable delivery of artemether solution an artemether solution: Malaria.
  • a method of treating an individual suffering from malaria comprises the steps of (1) administering to a mammal, preferably a human, a first composition, the first composition comprising a therapeutically effective amount of artemether; (2) administering to the mammal a second composition, the second composition comprising a therapeutically effective amount of a artesunate or its pharmaceutically acceptable derivatives; (3) administering to the mammal a third composition, the third composition comprising a therapeutically effective amount of berberine, or its pharmaceutically acceptable derivatives; and (4) and administering to the mammal a fourth composition, the fourth composition comprising a therapeutically effective amount of primaquine, or its pharmaceutically acceptable derivatives or salts, preferably primaquine phosphate.
  • the method of treating an individual suffering from malaria is performed by a procedure in which the first, second, third and fourth compositions are delivered to the infected individual without identifying the Plasmodium species affecting said individual.
  • the method of treating an individual suffering from malaria includes the step of the combined drugs clearing all forms of the Plasmodium from the patient.
  • the study carried out was a prospective, randomized, controlled multi-center study enrolling two hundred twenty (220) subjects stratified into two treatment groups, Group A, WHO Standard Malaria Treatment and Group B, TriAct Plus therapy in several health facilities in the Philippines. Subjects included individuals of ages 5 years to 65 years old. Such individuals were diagnosed cases of malaria (from all four types Plasmodium species), screened by careful history and physical examination complying with the inclusion criteria. All of the subjects were positive for malarial parasites by direct microscopy.
  • the method of treating an individual suffering from malaria was performed by a procedure in which the first, second, third and fourth compositions were delivered to the infected individual without identifying the Plasmodium species affecting said individual.
  • BSMP Blood smears for malarial parasites
  • TriAct Plus therapy was show to be comparable to the WHO Standards of Care illustrating that the therapy was effective Current treatment modalities for malaria are effective only if the proper drugs are administered for the specific Plasmodia species infecting the patient. The most common infections are with P. falciparum , P. vivax, P. malariae , P. ovale and mixed infections with P. falciparum and P. vivax. Correct species identification required when using the standard of care is problematic and time consuming. This is especially true in endemic areas where the diagnostic tests are not available. This makes the choice of treatment difficult in situations where immediate treatment is urgently needed. The TriAct Plus therapy is not dependent on proper species identification and can be administered immediately when the first clinical symptoms appear including patients suffering from fever of unknown origin.
  • a delivery for artemether via a sublingual (spray) mechanism allows for the treatment of complicated and severe forms of Malaria especially in the absence of parenteral forms.
  • Such form may further serve as a treatment option regardless of the level of consciousness of the patient (cerebral malaria) , even when treatment is critical in the most remote areas.
  • Such treatment options are lacking using current stand of care protocols.
  • Applicant's method eliminates the first pass effect (the drug bypasses the liver, thereby reaching the systemic circulation immediately) without sacrificing the serum concentration.
  • the treatment using the TriAct Plus therapy is needle free and can be used anywhere in the world.
  • TriAct Plus therapy did not experience any adverse reactions like hypoglycemia, palpitations and cinchonism which are typically observed with quinine use or its derivatives. Other known side effects using traditional treatments were not observed as well.
  • TriAct Plus therapy was as effective as standard WHO Standard of Care treatments when species identification (required in standard of care) was correct and the proper drugs were used.
  • the advantage of the TriAct Plus therapy is that such protocol is the only known universal therapy in that it does not require the identification of the specific Plasmodium species which cause the disease. As such, whatever species the individual is infected with, the current TriAct Plus protocol was shown to be effective. This is important in areas where rapid species identification is not available or may come too late, thereby delaying treatment and risking death. It is known that treatment with the current standard of care protocols have many severe side effects in complicated cases, especially with the use of quinine. The TriAct Plus therapy demonstrated no incidence of recurrence, recrudescence, and relapse. Finally, the present protocol resulted in the clearance of gametocytes. None of the subjects came back with any symptoms within a month period.
  • the method of treatment can be facilitated by the use of a kit including any component as described throughout the specification.
  • the method of treatment can be facilitated by the use of a kit comprising an injectable artemether solution as a single dosage unit contained in an ampoule, injection vial, or as an individual single, preloaded injection syringe with needle, a first packet containing artesunate tablets, a second packet containing berberine tablets, and a third packet containing primaquine, or its derivatives or salts, preferably primaquine phosphate.
  • An individual begins the method in accordance with the present invention by administering the first loading dose of the artemether.
  • the artemether is delivered to the individual as an injection, via IV or IM route of administration, or preferably by a sublingual spray.
  • the second, third, and fourth compositions are delivered as previously described in Examples 2-5, depending on the weight and age of the individual user.
  • the components of the present invention can be supplied in a kit to aid. in delivery and use in areas where distribution channels and/or medical communities are not easily accessible or established.
  • the kit may include a secure delivery package in the form of a self sealing blister pack, zip lock packs, standup pouches, foil pouches which include the single use spray bottle and one day, two day, three day, four day, five plus day packs of the artesunate and berberine, and one day and fourteen day packs of primaquine. If injectable artemether is used, needles, syringes, injection bottles, or pre-loaded syringes with capped needles may be included.
  • the kit preferably contains directions and/or any other instructions for the proper use and storage of the components of the kit.

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Abstract

La présente invention concerne une méthode de traitement de sujets souffrant d'infections microbiennes et, notamment, d'une maladie parasitaire telle que le paludisme, en utilisant un traitement combiné amélioré à base d'artémisinine (ACT), connu sous le nom de ActRx Tri-ACT Plus. Ledit traitement ACT amélioré implique l'administration d'une combinaison de quatre médicaments. Selon un mode de réalisation de la présente invention, la méthode implique l'administration à un sujet d'une première composition contenant une quantité thérapeutiquement efficace d'artéméther par pulvérisation sublinguale. Le sujet se voit ensuite administrer une deuxième composition contenant une quantité thérapeutiquement efficace d'artésunate. Une troisième composition contenant une quantité efficace de berbérine, ou de dérivés ou sels pharmaceutiquement acceptables de celle-ci, est ensuite administrée au sujet. Enfin, une quatrième composition, contenant une quantité efficace de primaquine, ou de dérivés ou sels pharmaceutiquement acceptables de celle-ci, est administrée au sujet.
PCT/US2014/033555 2013-09-17 2014-04-09 Traitement combiné amélioré à base d'artémisinine permettant de traiter une maladie à médiation par des parasites WO2015041722A1 (fr)

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US14/201,749 US20140256762A1 (en) 2012-07-06 2014-03-07 Artemisinin-based combination therapy for treating viral mediated disease

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KR20210103962A (ko) 2020-02-14 2021-08-24 충북대학교 산학협력단 B세포 성숙화 항원을 표적으로 하는 키메라 항원 수용체 및 이의 용도
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WO2022128920A3 (fr) * 2020-12-14 2022-07-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de médicaments qui rigidifient des gamétocytes matures pour bloquer la transmission de parasites de plasmodium

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