+

WO2013071365A1 - Procédé de traitement et de prophylaxie, et compositions utiles associées - Google Patents

Procédé de traitement et de prophylaxie, et compositions utiles associées Download PDF

Info

Publication number
WO2013071365A1
WO2013071365A1 PCT/AU2012/001422 AU2012001422W WO2013071365A1 WO 2013071365 A1 WO2013071365 A1 WO 2013071365A1 AU 2012001422 W AU2012001422 W AU 2012001422W WO 2013071365 A1 WO2013071365 A1 WO 2013071365A1
Authority
WO
WIPO (PCT)
Prior art keywords
griseofulvin
plasmodium
nmpp
effective amount
subject
Prior art date
Application number
PCT/AU2012/001422
Other languages
English (en)
Inventor
Simon James Foote
Brendan John MCMORRAN
Clare Margaret SMITH
Original Assignee
Macquarie University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Macquarie University filed Critical Macquarie University
Publication of WO2013071365A1 publication Critical patent/WO2013071365A1/fr

Links

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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • 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 disclosure teaches the treatment and prophylaxis of infection of subjects by members of Phylum Apicomplexa, including species of Plasmodium and compositions useful therefore.
  • Sporozoites are transmitted to a human host by infected mosquitoes when they take a blood meal. Sporozoites pass rapidly in the blood stream to the liver where they invade hepatocytes and proliferate and differentiate into merozoites. Merozoites break out of hepatocytes into the blood stream where they invade red blood cells. There, they differentiate through various forms and proliferate clonally to produce more merozoites which emerge and invade uninfected red cells establishing an unremitting cycle of escalating infection. Sexual forms (gametocytes) are also produced and if these are taken up by a mosquito they will undergo genetic exchange.
  • the waves of fever that are characteristic of malarial infection are caused by the cycle of intraerythrocytic merozoites bursting out of old red blood cells and invading new red blood cells. If this prol i ferative cycle continues, the infected subject may rapidly (within days) become comatose and die.
  • Vector control is one form of malaria prevention and insecticide-treated bed nets (mostly using pyrethroidal insecticides) have been useful, in reducing deaths in endemic countries.
  • insecticide resistance There is, however, currently no effective vaccine against malaria.
  • Chemotherapy has also been successfully used. Chloroquine was the mainstay of antimalarial chemotherapy for fifty years but chloroquine resistance strains are now widespread.
  • artemisinin-based combination therapy is recommended although artemisinin resistance has already been observed. Resistance appears to occur through (i ) mutations that reduce the ability of the drug to bind to its parasite target: or ( ii ) the development of parasite membrane transporters able to transport drugs away from the parasite.
  • the established ability of Plasmodium sp. to develop drug resistance means that current anti-plasmodium drugs have to be considered as relatively short-term solutions.
  • the present disclosure is instructional for a method for the treatment or prophylaxis of infection in a subject by a member of Phylum Apicomplexa, the method comprising administering to the subject an effective amount of griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof.
  • the subject may have an infection, or has had exposure to infection or may have exposure to infection.
  • the Phylum Apicomplexa member is a species of Plasmodium.
  • Plasmodium falciparum An example of a Plasmodium species is Plasmodium falciparum.
  • Taught herein is the treatment or prevention of infection by a species of Plasmodium in a subject by providing the subject with griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof prior to, during or following infection or exposure to the Plasmodium sp.
  • Griseofulvin is able to inhibit the erythrocytic heme biosynthetic enzyme errochelatase (FECH) which is shown to be an essential host factor for malarial parasite growth.
  • FECH erythrocytic heme biosynthetic enzyme
  • FECH catalyses the conversion of its substrate protoporphyrin IX (PPIX) and is the terminal enzyme in the heme biosynthetic pathway which pathway is present in mammalian hosts of apicomplaxal parasites and in apicomplexal parasites such as plasmodium.
  • PPIX substrate protoporphyrin IX
  • the anti-FECH activities of both the clinically approved antifungal agent, griseofulvin, and N-methyl protoporphyrin which is a metabolic product of griseofulvin (via a cytochrome-dependent process) and also a FECH substrate analogue, are demonstrated herein to reduce the growth and development of intraerythrocytic (red blood cell) stages of Plasmodium sp. Importantly.
  • FECH inhibition was shown to be effective in reducing parasite growth in chloroquine resistant and multidrug resistant strains as well as chloroquine sensitive strain of . falciparium (which causes the most acute forms of malaria).
  • the subject or population of subjects is (i) tested for infection with a member of Phylum Apicomplexa and then (ii) administered a composition comprising griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoform or enantiomer thereof if the subject or population of subjects tests positive for infection by or prior exposure to or potential exposure to an Apicomplexa member.
  • the subject is (i) tested for infection with Plasmodium sp. and (ii) administered griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoform or enantiomer thereof if the subject tests positive for infection by or prior exposure to or potential exposure to Plasmodium sp.
  • MRD minimal residual disease
  • a member of Phylum Apicomplexa such as a Plasmodium sp. after administration of griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoform or enantiomer thereof.
  • composition comprising griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof.
  • the composition comprises a pharmaceutically or physiologically acceptable carrier, diluent or excipient.
  • the composition may also comprise another active agent which directly or indirectly targets the Apicomplexa parasite or facilitates ameliorating the symptoms of infection therewith.
  • griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof for use in the treatment or prophylaxis of infection by a member of Phylum Apicomplexa.
  • griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof is used in the treatment or prophylaxis of malaria caused by Plasmodium sp.
  • the present disclosure enables the use of griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof in. or in the manufacture of, a medicament for the treatment or prevention of infection by a member of Phylum Apicomplexa.
  • This aspect includes the treatment of malaria.
  • the composition is generally administered for a time and under conditions sufficient to treat the infection, or reduce the risk of onset of severe infection or to reduce the level of parasite in the subject or population for at least minimal residual disease levels.
  • This aspect includes the treatment, prevention or amelioration of symptoms of malaria.
  • griseofulvin or N- methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof inhibits a host and/or parasite ferrochelatase.
  • administration is in combination or conjunction with one or more further anti-Apicomplexa agents including antimalaria agents.
  • Taught herein is a kit comprising griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoform or enantiomer thereof for use in the treatment or prophylaxis of infection by a member of phylum Apicomplexa such as infection by Plasmodium sp.
  • the kit includes instructions for use in the treatment or prophylaxis of malaria and may also include one or more other active agents such as another anti-Apicomplexa agent or an anti-malaria agent.
  • anti-malaria agent includes an agent that targets the parasite such as the intraerythrocytic life-cycle stages of the parasite as well as an agent which ameliorates the symptoms of malaria.
  • a drug-screening method comprising (i) testing or selecting or designing a drug for its ability to inhibit ferrochelatase or another enzyme in the heme biosynthetic pathway or a precursor thereof and (ii) if a ferrochelatase inhibitor or another inhibitor of another enzyme in the heme biosynthetic pathway or a precursor thereof is identified, testing the drug, for anti-Apicomplexa activity in vitro or in vivo.
  • a screening assay for an anti-malaria drug is provided herein comprising screening for a compound which inhibits ferrochelatase and then testing the drug for its ability to inhibit growth or development of a malarial parasite.
  • An isolated enzyme in the heme biosynthetic pathway for use in screening for a medicament for the treatment of malaria is also contemplated.
  • the Apicomplexa is Plasmodium
  • the enzyme is host ferrochelatase. In an embodiment, the enzyme is a parasite ferrochelatase.
  • parasite is meant the Apicomplexa including Plasmodium sp.
  • the drug is sub-licensed for use in drug testing.
  • Figure 1 is a photographic representation of data showing that host ferrochelatase (Fech) is present in uninfected RBCs (uiRBC) and compartmentalised inside the parasite.
  • Fech host ferrochelatase
  • a and B Western blot analyses of protein samples prepared from uiRBC and purified P. falciparum parasites (free of red blood cell membrane and cytosol ). Proteins were separated on denaturing SDS polyacrylamidc gels, transferred to nitrocellulose membranes and immuno-blotted with anti-human Fech antibody (A) and anti-human hexokinase antibody (B). A band corresponding to the predicted size of human Fech (43 kD) is present in both the red cell and parasite samples.
  • C-G Images showing P. falciparum infected red blood cells immuno-stained with anti-human FECH and anti-EXP2 antibodies, and stained with the DNA-specific dye DAPI (to detect parasite nuclei). Anti-EXP2 was used to detect the parasitophorous vacuole membrane.
  • FIG. 2 is a graphical representation of data showing parasitological kinetics and survival curves of mice infected with P. chabaudi.
  • the mouse strains (on a C57BL/6 genetic background) used were Fech+/+ (WT), Fech+/- (Het) and Fech-/- (Mut).
  • WT Fech+/+
  • Het Fech+/-
  • Fech-/- Fech-/-
  • Figure 3 is a graphical representation of data showing that P. falciparum growth is impaired when cultured in blood from individuals with Fech deficiencies (erythropoietic protoporphyria. EPP). Proportions of cells infected with parasites (% parasitemia) were determined a different time points after in vitro infection of red blood cells purified from blood samples collected from three different individuals w ith EPP (A- C) or a normal individual (D). Data represent the mean of triplicate cultures at each time point; at least 500 cells were counted for each replicate. Error bars indicate SEM.
  • Figure 4 is a graphical representation of data described in Example 3 showing the anti-plasmodial effect of NMPP (a specific Fech inhibitor) and griseofulvin.
  • A Growth inhibition of P. falciparum cultured in the presence of different concentrations of NMPP (relative to an imtreated culture).
  • B Growth inhibition of P. falciparum in cultured in red blood cells that were treated prior to infection with various concentrations of griseofulvin. Red blood cells were treated with griseofulvin for 3 days, with the medium replaced each day; griseofulvin was also included in the parasite cultures.
  • FIG. 5 is a graphical representation of data described in Example 4 showing that administration of griseofulvin to human subjects results in red cells unable to support parasite growth ex vivo. In all experiments isolated red cells were used. They were prepared by centrifugation and washing (in phosphate-buffered saline) the blood sample to remove contaminating white blood cells and platelets.
  • A Percentage of parasite-infected cells (% parasitemia) in blood collected before (untreated) and follow ing a 7 day course of griseofulvin (treated; 500mg/day taken orally).
  • Purified red blood cells (untreated and treated) were prepared and infected with P. falciparum strain 3D7 at the same day.
  • the mean (SD) initial percentage of infected cells was 1 .01 % (0.34).
  • Parasite cultures were smeared after 24 hours, stained with Giemsa stain and numbers of infected cells enumerated using light microscopy. Seven different individuals were tested. For all the individuals tested, parasite growth was significantly impaired in blood after 7 days of griseofulvin treatment (p ⁇ 0.01 ).
  • B Parasite growth in blood collected each day from one individual taking a daily 500mg/day course of griseofulvin for five days. Growth (determined as described in A) was compared as a proportion with cultures using untreated blood. The proportion of growth in the treated blood is significantly less that untreated after four and five days of griseofulvin (pO.01 ).
  • C Levels of griseofulvin measured in blood during a five day course of griseofulvin (500mg/day taken orally ; same individual as in B).
  • Levels were determined by HPLC-coupled MS-MS analysis in conjunction with a griseofulvin standard concentration curve.
  • D Parasite growth in blood collected from one individual at indicated time points after taking one single dose (2 g) of griseofulvin. Growth is compared as a proportion with cultures using untreated blood. The proportion of growth in the treated blood is significantly less that untreated 8, 24 and 48 hours after taking the drug (pO.O l ). Data points represent the mean of 3 replicate cultures. At least 1000 cells were counted per replicate. Error bars indicate SEM.
  • E Levels of griseofulvin measured in blood after a single dose of griseofulvin (2000mg taken orally; same individual as in D).
  • FIG. 6 is a graphical illustration of results, wherein P. falciparum is grown in red cells from individuals with erythropoietic protoporphyria (EPF) and X-linked dominant protoporphyria (XLDPP). Results are shown as a percentage of parasitemia of test blood relative to normal red cells. In all experiments, infection was initiated by the addition of purified trophozoite-stage infected cells (grown in normal cells) to the test blood (EPP. XLDPP or normal) to a final concentration of 1 %. Relative parasitemias were determined at the times indicated.
  • EPF erythropoietic protoporphyria
  • XLDPP X-linked dominant protoporphyria
  • Average percentages ( ⁇ SD) of infected cells measured in the normal blood were, 0 hr, 1 .1 ( ⁇ 0.9); 24 hr. 2.0 ( ⁇ 1. 1 ); 48 hr. 3.2 ( ⁇ 1.3); 72 hr. 6. 1 ( ⁇ 1 .7).
  • Figure 7 provides a graphical illustration of results described in Example 5 extending the results provided in Example 3 and Figure 4 showing pharmacological inhibition of FECH using griseofulvin and NMPP and growth inhibition of P. falciparum infected human red cells.
  • Parasite growth inhibition (relative to untreated control) with increasing concentrations of NMPP (0. 1 to 100000 iiM NMPP) (A) and griseofulvin (0.08 to 250 ⁇ griseofulvin) (B).
  • Assays were conducted using P. falciparum 3D7. l and W2mef strain parasites and growth was determined after 48 h incubation. Data ( ⁇ SEM) represent the mean of two independent assays (each concentration assayed in triplicate).
  • Figure 8 illustrates the results described in Example 6 wherein griseofulvin treated human red blood cells are unable to support parasite growth ex vivo
  • Panel A shows the percentage of parasite growth in red cells collected from seven individuals taking griseofulvin (500 mg/day) after seven days: (panel B) or each day for five days; (panel C) or at eight hours and (panel D) at indicated time points after a single dose of 2000 mg-. All assays were conducted by inoculating red cells (with purified trophozoite-stage infected cells (mean parasitaemia, 1 ⁇ 0.5%). Growth was determined relative to an untreated control after 24 hours incubation Data ( ⁇ SEM) represent the mean of 3 replicate cultures. * * p ⁇ 0.01 and * * * * p ⁇ 0.001 compared to untreated cells.
  • Figure 9 provides an illustration of the results of ultra performance liquid chromatography-mass spectrometry (UPLC-MS) analysis of griseofulvin in red cells from individuals taking griseofulvin for five days (500 mg/day) (A) or once (2000 mg) (B), respectively. Blood samples were collected and analysed at the indicated times, and quantified by comparison to a stEindard curve of known griseofulvin amounts. Data ( ⁇ SEM) represent the mean of three independent assays.
  • UPLC-MS ultra performance liquid chromatography-mass spectrometry
  • Figure 10 provides an illustration of the results of ultra performance liquid chromatography-mass spectrometry (UPLC-MS) analysis of griseofulvin in red cells treated with 10 ⁇ griseofulvin for up to five - days, and sampled every 24 hours. Griseofulvin-containing medium was replaced every 24 hours. Griseofulvin levels were quantified by comparison to a standard curve of known griseofulvin amounts. Data ( ⁇ SEM) represent the mean of three independent assays.
  • UPLC-MS ultra performance liquid chromatography-mass spectrometry
  • the present disclosure teaches the use of griseofulvin or N-methyl protoporphyrin or a salt, homOlog, analog, isoform or enantiomer thereof to specifically inhibit growth and development of a member of Phylum Apicomplexa thereby being useful in the treatment or prophylaxis of infection in a subject by the member. Further taught herein is the amelioration of symptoms of disease caused by the infection.
  • griseofulvin includes its salts, homolog, analog, isoforms and enantiomers.
  • Functional equivalent forms of griseofulvin are also contemplated herein.
  • a functional equivalent includes a molecule sterically similar to griseofulvin and having the same ability to inhibit a host cell ferrochelatase and/or inhibit development of a stage of the parasite life-cycle.
  • An example of a functional equivalent includes the change or modification of a substituent on the griseofulvin molecule, selecting a particular isoform, natural ly occurring or prepared by physical or chemical manipulation and selecting a molecule with the same physical or chemical properties as griseofulvin.
  • Griseofulvin administrations results in pharmacological inhibition of Fech leading to reduced parasite growth and/or death of intraerythrocytic li fe cycle stages.
  • N- methy protoporphyrin is produced from griseofulvin in the host via a cytochrome- dependent mechanism and shares the chemical property of griseofulvin as a FECH inhibitor by competing with PPIX for ferrochelatase.
  • N-methyl protoporphyrin has the chemical formula C35H36N404 and its structure is set forth in Formula (II)
  • N-methyl protoporphyrin also referred to as NMPP
  • NMPP N-methyl protoporphyrin
  • Functional equivalent forms of N-methyl protoporphyrin arc also contemplated herein.
  • a functional equivalent includes a molecule sterically similar to N- methyl protoporphyrin and having at least the same ability to inhibit ferrochelatase and/or inhibit development of a stage of the parasite life-cycle.
  • An example of a functional equivalent includes the change or modification of a substituent on the N- methylprotoporphyrin molecule, selecting a particular active form, natural ly occurring or prepared by physical or chemical manipulation and selecting a molecule with the same desirable physical or chemical properties as N-methyl protoporphyrin.
  • a method for the treatment or prophylaxis of a subject infection with or who has or who may have exposure to a member of Phylum Apicomplexa the method comprising administering to the subject an effective amount of griseofulvin or N-methyl protoporphyrin or its salt, homolog, analog, isoform or enantionmer.
  • the griseofulvin or N-methyl protoporphyrin may also be given in a composition.
  • a method for the treatment or prophylaxis of a subject infected with or who has or who may have or who had exposure to a member of Phylum Apicomplexa comprising administering to the subject an effective amount of a composition comprising griseofulvin or N-methyl protoporphyrin or its salt, homolog. analog, isoform or enantiomer.
  • the composition may further comprise one or more pharmaceutically acceptable carriers, di luents or excipients.
  • composition may also contain another active agent such as another anti-Apicomplexa agent or anti-malarial agent or an agent which ameliorates symptoms of an infection by a member of Phylum Apicomplexa.
  • agent may also specifically target a ferrochelatase produced by a host cell or by the parasite or both.
  • an example of a Apicomplexa member is a species of Plasmodium (Plasmodium sp.).
  • Plasmodium sp. include Plasmodium falciparum, Plasmodium virax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi.
  • the present specification is instructional for the treatment or prophylaxis of a subject for infection with or who has or who may have exposure to Plasmodium sp.. the method comprising administering to the subject an effective amount of griseofulvin or N-methyl protoporphyrin or its salt, homolog, analog, isoform or enantiomer.
  • a related embodiment taught herein is a method for the treatment or prophylaxis of a subject for infection with or who has or who may have exposure to Plasmodium sp., the method comprising administering to the subject an effective amount of a composition comprising griseofulvin or N-methyl protoporphyrin or its salt, homolog, analog, isoform or enantiomer.
  • the composition may further comprise one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the composition may also contain another active agent such as another anti-Apicomplexa agent or an agent which ameliorates symptoms of an infection by Plasmodium sp.
  • the Plasmodium sp. is selected from the list consisting of P. falciparum, P. virax, P. ovale, P. malariae and P. knowlesi.
  • the present specification is instructional for the treatment or prophylaxis of a subject for infection with or who has or who may have exposure to Plasmodium sp. selected from the list consisting of P. falciparum, P. virax, P. ovale, P. malariae and P. knowlesi, the method comprising administering to the subject an effective amount of griseofulvin or N-mcthyl protoporphyrin or its salt, homolog, analog, isoform or enantiomer.
  • a related embodiment taught herein is a method for the treatment or prophylaxis of a subject for infection with or who has or who may have exposure to Plasmodium sp. selected from the list consisting of P. falciparum, P. virax, P. ovale, P. malariae and P. knowlesi, the method comprising administering to the subject an effective amount of a composition comprising griseofulvin or N-methyl protoporphyrin or its salt, homolog, analog, isoform or enantiomer.
  • the composition may further comprise one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the composition may also contain another active agent such as another anti-Apicomplexa agent or an agent which ameliorates symptoms of an infection by Plasmodium sp.
  • the Plasmodium sp. is P. falciparum.
  • the present specification is instructional for the treatment or prophylaxis of a subject for infection with or who has or who may have exposure to P. falciparum, the method comprising administering to the subject an effective amount of griseofulvin or N- methyl protoporphyrin or its salt, homolog, analog, isoform or enantiomer.
  • a related embodiment taught herein is a method for the treatment or prophylaxis of a subject for infection with or who has or who may have exposure to P. falciparum, the method comprising administering to the subject an effective amount of a composition comprising griseofulvin or N-methyl protoporphyrin or its salt, homolog, analog, isoform or enantiomer.
  • the composition may further comprise one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the composition may also contain another active agent such as another anti-Apicomplexa agent or an agent which ameliorates symptoms of an infection by Plasmodium sp.
  • the subject is in need of treatment or prophylaxis for malaria.
  • the subject may be infected with Plasmodium sp. or is at risk of becoming infected.
  • administration is prior exposure to Plasmodium sp.
  • a subject or population of subjects is (i) tested for infection with a member of Phylum Apicomplexa and (ii ) administered a composition comprising griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoform or enantiomer thereof if the subject or population of subjects tests positive for infection by a member of Apicomplexa.
  • the subject is (i) tested for infection with Plasmodium sp. and (ii) administered a composition comprising griseofulvin or N-methyl protoporphyrin if the subject tests positive for Plasmodium sp.
  • the subject is tested for infection or infection levels with Plasmodium sp. after administration of griseofulvin.
  • the subject is treated after exposure to Plasmodium sp.
  • compositions are conveniently prepared according to conventional pharmaceutical compounding techniques. See, for example. Remington's Pharmaceutical Sciences. 18th Ed., ( 1990) Mack Publishing, Company. Faston, PA. U.S.A. These compositions may comprise, in addition to griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoi rm or enantiomer thereof, a pharmaceutically acceptable excipient, carrier, diluent or which includes a buffer, stabilizer or other material well known in the art. Such materials are generally non-toxic and do not interfere with the efficacy of the active ingredient.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. intravenous, oral, parenteral or topical.
  • the present disclosure is also directed griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof for use in the treatment or prophylaxis of infection by a member of Phylum Apicomplexa.
  • This aspect includes the use of griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoform or enantiomer thereof in. or in the manufacture of a medicament for, the treatment or prevention of infection of a member of Phylum Apicomplexa.
  • the present disclosure is also directed to griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof for use in the treatment or prophylaxis of infection by Plasmodium sp.
  • This aspect includes the use of griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof in, or in the manufacture of a medicament for, the treatment or prevention of infection Plasmodium sp.
  • the present disclosure is also directed griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof for use in the treatment or prophylaxis of malaria.
  • This aspect includes the use of griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof in, or in the manufacture of a medicament for, the treatment or prevention of malaria.
  • Griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoform or enantiomer thereof or a composition comprising same is generally administered for a time and under conditions sufficient to inhibit infection or attenuate or reduce the ability for parasite or life-cycle stages thereof to cause an adverse infection.
  • griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof or a composition comprising same is administered for a time and under conditions sufficient to ameliorate by symptoms of malaria or reduce the risk of onset of a severe from of malaria.
  • the griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof is administered for a time and under conditions sufficient to inhibit a host and/or parasite, ferrochelatase.
  • the terms "effective amount” includes “therapeutically effective amount” and “prophylactically effective amount” and means a sufficient amount of a composition comprising griseofulvin or N-methyl protoporphyrin or a salt, homolog. analog, isoform or enantiomer thereof either in a single dose or as part of a series or slow release system which provides the desired therapeutic, preventative, epidemiological or physiological effect in some subjects.
  • Undesirable effects e.g. side effects, may sometimes manifest along with the desired therapeutic effect: hence, a practitioner balances the potential benefits against the potential risks in determining an appropriate "effective amount”.
  • compositions required will vary from subject to subject, depending on the species, age, and sex general condition of the subject, mode of administration and the like. Thus, it may not be possible to specify an exact "effective amount”. However, an appropriate "effective amount” in any individual case may be determined by one of ordinary skill in the art using routine skills or experimentation. One of ordinary skill in the art would be able to determine the required amounts based on such factors as prior administration of the compositions or other agents, the subject's size and age, the severity of a subject's symptoms or the severity of symptoms in an infected population, member of Phylum Apicomplexa, species of Plasmodium, and the particular composition or route of administration selected.
  • an effective amount includes plasma concentration levels of griseofulvin from about 0 ⁇ g/ml blood to about 20 ⁇ g/ml blood including about 1 , 2, 3. 4, 5, 6, 7, 8, 9, 10, I I , 12, 13, 14, 15, 16, 17. 18, 19 and 20 ⁇ g/ml blood.
  • a single or multiple doses may be administered such as hourly, daily, weekly, monthly or yearly.
  • a dose of from 100-2000mg e.g.. 500mg or 2000mg
  • the effective amount may also be determined on the minimal amount to inhibit or reduce activity of host and/or parasite ferrochelatasc.
  • the effective amount may also be determined on the minimal amount to inhibit or reduce inraerythrocytic malarial parasite growth or development.
  • the IC50 of griseofulvin was found to be about 10 ⁇ to 50 ⁇ .
  • NMPP effective amounts sufficient to reduce parasite growth in red cells are in the 25nM range (See Figure 4A) or at least in the l OnM to ⁇ ⁇ range (see Figure 7A).
  • l OOOOOnM NMPP was effective in completely inhibiting parasite growth ( 100% inhibition) in three different P. faciparum strains.
  • treatment refers to any measurable or statistically significant amelioration in at least some subjects in one or more symptoms of infection or a disease caused thereby such as malaria or in the risk of developing severe symptoms of or the risk of transmitting the disease.
  • treatment also includes a measurable decrease in host and/or parasite ferrochelatase.
  • prevention and “prophylaxis” and the like are used interchangeably and include administration of griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof or a composition comprising same to a subject not known to be infected with a member of Apicomplexa for the purpose of prevention or reducing the risk of becoming infected or reducing the severity or onset of a disease caused or exacerbated by infection by Apicomplexa sp.
  • the member is Plasmodium sp. and the disease is malaria.
  • a composition comprising griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof is provided to a subject either before the onset of infection (so as to prevent or attenuate an anticipated infection) or after the initiation of an infection to treat the infection or a disease caused thereby, such as malaria.
  • a composition is provided to a subject before or after onset of infection, to reduce transmission of infectious agents between subjects.
  • compositions taught herein can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent Apicomplexa infection or symptoms associated with Apicomplexa infection.
  • agents include, but are not limited to, host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma.
  • CpG oligonucleotides and the like in the case of Plasmodium sp. infection anti-malarial compounds/agents such as artemether, artemisinin, artemotil and artesunate. quinine, alone or in further combination with one or more of lumefantrine, malarone, chloraquine. mefloquine, ⁇ pyronaridine, amodiaquine, piperaquine, sulphadoxine-pyrimethamine. clindamycin, doxycycline, dihydroartemisinin.
  • Plasmodium sp. infection anti-malarial compounds/agents such as artemether, artemisinin, artemotil and artesunate. quinine, alone or in further combination with one or more of lumefantrine, malarone, chloraquine. mefloquine, ⁇ pyronaridine, amodiaquine, piperaquine, sulphadoxine-pyrimeth
  • primaquine and the like: antibodies or antigen-binding portions that directly or indirectly inhibit or reduce infection; compounds that enhance the development of an effective antibody and/or T cell response; interfering RNA; anti-sense RNA; vaccines comprising malaria antigens or antigen adjuvant combinations directed against Apicomplexa member such as Plasmodium sp.
  • Administration is generally for a time and under conditions sufficient to elicit the desired response. Administration may be parenteral or non-parenteral, systemic or local. Other contemplated routes of administration are by patch, cellular transfer, implant, sublingually, intraocularly, topically, orally, rectally, vaginally, nasally or transdermal ly. Griseofulvin or N-methyl protoporphyrin may be administered orally, as known in the art.
  • Taught here is a kit comprising griseofulvin or N-methyl protoporphyrin or a salt, homolog, analog, isoform or enantiomer thereof and optionally one or more further agents.
  • the kit includes instructions for use in the treatment or prophylaxis of infection by a member of Phylum Apicomplexa such as Plasmodium sp. including those which cause malaria.
  • the kit may contain an anti-malaria agent.
  • anti-malaria agent includes an agent which targets the parasite or a life-cycle form of the parasite as well as an agent which ameliorates the symptoms of malaria or which targets host or parasite ferrochelatase activity or expression.
  • a drug-screening method comprising (i) testing or selecting or designing a drug for its ability to inhibit ferrochelatase or another enzyme in the heme biosynthetic pathway or a precursor thereof and (ii) if an inhibitor is identified, testing the drug, for anti-Apicomplexa activity in vitro or in vivo.
  • a screening assay for an anti-malaria drug is provided herein comprising screening for a compound which inhibits ferrochelatase and then testing the drug for its ability to inhibit growth or development of a malarial parasite.
  • the Apicomplexa is Plasmodium sp.
  • the enzyme is ferrochelatase.
  • the enzyme is a host heme synthetic enzyme.
  • the enzyme is a host ferrochelatase.
  • the enzyme is a parasite ferrochelatase.
  • parasite is meant the Apicomplexa species or genera, including Plasmodium sp.
  • a screening assay is enabled for an anti-malaria drug, the assay comprising screening a compound which inhibits human ferrochelatase and the testing the drug for its ability to inhibit growth or development of Plasmodium sp. such as P. falciparum.
  • treating and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms of an infection, elimination of the infection and/or improvement or remediation or amelioration of a disease condition following infection by the Apicomplexa member.
  • treatment may involve actively treating a disease arising from or exacerbated by the infection treatment or treating the infection.
  • Treating" a subject may involve prevention or reduction in extent of development of infection or a condition arising therefrom as well as treatment of a clinically symptomatic individual by ameliorating the symptoms of the infection or treating as a symptomatic subject exposed to potential infection.
  • the infection is by a Plasmodium sp. such as a Plasmodium sp. selected from the list consisting of human infective species, P. falciparum. . virax, . ovale, P. malariae and P. knowlesi.
  • Also enabled herein is a method for the treatment or prophylaxis of a subject with, suspected of having or previously exposed to malaria, the method comprising administering to the subject an effective amount of griseofulvin or N-methyl protoporphyrin or its salt, homolog. analog, isoform or enantiomer.
  • a method for the treatment or prophylaxis of a subject with, suspected of having or previously exposed to malaria comprising administering to the subject an effective amount of a composition comprising griseofulvin or N-methyl protoporphyrin or its salt, homolog. analog, isoform or enantiomer.
  • a "subject" as used herein refers to an animal, such as a mammal including a human who can benefit from the pharmaceutical agents and formulations and methods of the present disclosure. Animal models arc encompassed. A subject regardless of w hether a human or non-human animal may also be referred to as an individual, patient, animal, host or recipient.
  • P. falciparum culture P. falciparum strains 3D7, l and W2mef were maintained at between 0.5 and 10% parasitemia in purified AB+ human erythrocytes in a 1 % 02/5% C02 atmosphere according to the method of Trager and Jensen (Trager et al.. (1976)).
  • the cell culture medium comprised of RPMI 1640 supplemented with I X Glutamax, 0.2% Albumax (all from Gibco), 4% pooled AB+ human serum (Invitrogen), 10 mM D-glucose, 25 ng/ml gentamycin, 6 mM HEPES and 0.2 mM hypoxanthine (al l from Sigma).
  • PPIX was added in varying concentrations to RBCS with either 50 ⁇ NMPP, 250 ⁇ griseofulvin (as pre-incubated above) or PPIX alone and incubated for 48 h prior to analysis.
  • PPIX was added in varying concentrations to RBCS with either 50 ⁇ NMPP, 250 ⁇ griseofulvin (as pre-incubated above) or PPIX alone and incubated for 48 h prior to analysis.
  • parasites grown in normal untreated blood were harvested by Percoll density gradient centrifugation or MACS column (Rivadeneira et al.. ( 1983); Ribaut el al., (2008)) and then added to the test blood at a final percentage parasitemia of approximately 0.5%.
  • Thin-blood smears were obtained after incubation of the parasites for up to 72 hours, stained with 10% Giemsa stain and the percentage of infected parasites (% parasitemia) was determined by counting cells under a light microscope. At least 1000 cells were counted on each slide. In some experiments parasite growth was also quantified by flow cytometry analysis using YOYO- 1 dye (Li el al.. (2007)). Percentage parasite growth and percentage growth inhibition were determined by comparison of growth in cultures treated without drug, or in blood from normal, untreated individuals.
  • Blood stage parasitemia (% infected red blood cells) for each mouse during infection was determined by counting cells on Giemsa-stained thin blood smears taken from mice during the course of infection. Percentage parasitemia was calculated by counting at least 500 cells per slide.
  • UPLC-MS analysis of griscofulvin levels in blood Quantification of griseofulvin in blood from griseofulvin treated volunteers or griscofulvin pre-incubated red cells was analysed by UPLC-MS using a Waters Acquity H-series UPLC coupled to a Waters Xevo triple quadrupole mass spectrometer as described previously (Mensch el al., (2007)).
  • Late-stage parasitized cells trophozoites and schizonts were harvested from P. falciparum cultures (at approximately - 10% parasitemia) using Percoll density gradient centrifugation (Rivadeneira el al., ( 1983)); 80-90% of the harvested cells were infected.
  • the harvested parasites were treated with 10 volumes of saponin (0.1 5 % w/v) for 1 0 minutes on ice.
  • the resulting supernatant (containing the hemoglobin, red cell cylosol components and plasma membranes of uninfected cells) was removed and the parasite pellet was washed with RPM1 and then resuspended in PBS containing protease inhibitors (Complete® protease cocktail from Roche). The parasites were then subjected to sonication (3 x 30 sec) and protein quantified using a Bradford protein assay. Puri fied parasites and equivalent numbers of uninfected red blood cells were lysed in equal volume of 2x SDS loading buffer (containing 0.5 % ⁇ -mercaptoefhanol), heated at 95 °C for 5 min.
  • 2x SDS loading buffer containing 0.5 % ⁇ -mercaptoefhanol
  • Slides were then incubated in the following primary antibodies (overnight at 4 °C, diluted in PBT); mouse monoclonal anti-human FECH and rabbit anti-/ 5 EXP2, and after washing, incubated in donkey anti-mouse Alexa Fluor® 488 ( 1 : 1000) or goat anti-rabbit Alexa Fluor® 594 ( 1 : 1000; both from Invitrogen) for 90 min at room temperature in the dark. Slides were counter-stained with DAPI ( 1 :5000), washed and mounted in Slowiade Gold (Invitrogen). Slides were viewed on a Nikon inverted microscope at 60x magnification with a water immersion lens at room temperature. Images were obtained using an Evolve camera and NIS-Elements software.
  • EXAMPLE 1 Detection of host ferrochelatase in malarial parasites
  • EXAMPLE 2 A deficiency in host ferrochelatase is detrimental to parasite growth
  • EPP erythrocytes contain elevated levels of the FECFI substrate, protoporphyrin IX (PPIX) (Table 1 ). PPIX is known to be toxic at elevated concentrations (Holme et al., (2007)). To exclude the possibility that PPIX was the cause of impaired parasite growth in EPP cells, the growth of parasites in erythrocytes from patients with X- linked dominant protoporphryia was tested (XLDPP; MIM 300752).
  • FECH activity is normal in these cells. But they contain elevated levels of PPIX due to a mutation in the gene encoding aminolevulinate synthase-2.
  • the mutant enzyme upregulates the entry of succinyl-CoA and glycine precursors into the heme synthesis pathway, resulting in substrate buildup at the next rate limiting step (FECH) (Whatley et ai, (2008)).
  • Parasite growth was identical between XLDPP and normal erythrocytes ( Figure 6), excluding a growth-inhibitory effect of PPIX. Instead the data indicate, as before, that erythrocytic FECH is required for growth (increasing parasitaemia) of stasis of intraerythrocylic P. falciparum parasites.
  • mice In the second approach, mice ( isogenic to a C57BL/6 background) with a genetically induced deficiency in murine Fech were infected with a rodent malarial parasite ⁇ Plasmodium chahaudi) and its resulting parasitaemia and survival was monitored.
  • This model of malaria infection is comparable with human P. falciparum infections, as the P. chahaudi parasites infect mouse red cells and infected mice eventually succumb to hyper-parasitemia and severe anemia.
  • the Fech-deficient strain called Fe ch m 1 Pd ⁇ contains a single nucleotide mutation in the murine Fech gene. Mice homozygous for the mutation express a mutant Fech enzyme with only 5% of normal Fech activity (Lyoumi er ai . (2007)), while heterozygotes have 45-65% activity compared to wild type mice.
  • N-methylprotoporphyrin is a FF,CH substrate analogue and a potent competitive inhibitor of the enzyme (Km - 10 nM) (Shi and Ferreira (2006) Biochem J., 399:21 -28). Increasing concentrations of NMPP are tested for their ability to inhibit the growth of P. falciparum under culture conditions. NMPP is observed to have potent anti- plasmodial activity with an 1C50 of 25nM ( Figure 4A).
  • griseofuivin has an anti- Fech activity that is a side-effect to its normal anti-fungal activity.
  • Griseofuivin concentrates in skin cells, binding to fungal microtubules, making keratin precursor cells resistant to fungal infection. It has the reported additional effect of inhibiting FECH. which manifests in susceptible humans and mice as porphyria.
  • FECH erythrocytes
  • Intra-erythropoietic griseofuivin inhibits parasite growth 48 hours after the addition of parasites to pre-treated uninfected erythrocytes with an IC50 of 10-50 ⁇ ( Figure 4B).
  • the numbers of parasites measured in cultures using the seven-day griseofulvin-treatment samples are less than the numbers added at the start of the infection. This indicates that the parasites are killed and are not just growth retarded.
  • the anti-plasrhodial effect of the treatment is pronounced as early as 4 days of griseofulvin treatment, but effects are negligible at earlier collection time points (Figure 5B). This observation coincides with an observed time- dependent accumulation of griseofulvin in the red blood cells.
  • Samples of the purified red cells are analyzed for levels of griseofulvin using HPLC-coupled MS-MS analysis. Griseofulvin levels increased steadily during the first few days of treatment and reached a steady-state maximum after four days (Figure 5C).
  • griseofulvin if given in sufficient amounts is effective in preventing parasite growth in an ex vivo setting and is, therefore, a useful therapeutic agent to treat malaria.
  • Griseofulvin may be used alone or in conjunction with other antimalarial drugs. Its use alone could be valuable in areas where other drugs are compromised by underlying parasite drug resistance.
  • the anti-plasmodial activity of griseofulvin is related to its rates of accumulation in red blood cells.
  • EXAMPLE 5 NMPP and griseofulvin inhibit parasite growth by specifically targeting FECH
  • N-methylprotoporphyrin is a FECH substrate analogue and a potent competitive inhibitor of the enzyme (Km - 10 nM) (Shi et ai, (2006)) P. falciparum parasites cultured with NMPP were highly sensitive to the compound with IC50 values of around 25nM ( Figure 4A). The action of N MPP was found to be independent of the drug resistance status of the parasite ( Figure 7A).
  • NMPP has nM activity, its IC50 is similar to antimalarial drugs and it acts rapidly. ⁇
  • the antifungal drug, griseofulvin is reported to have an anti-FECH activity (Bellingham et ai , ( 1995); Holley et ai, ( 1991 )). It is commonly used to treat human dermatophyte fungal infections. It accumulates in dermatophytes and binds to fungal microtubules, preventing fungal growth (Develoux (2001 )). Griseofulvin is also metabolized by a cytochrome-dependent mechanism that results in the alkylation of protoporphyrin rings and the formation of NMPP (Bellingham el ai, ( 1995)). Griseofulvin was therefore tested to determine if it could inhibit growth of P. falciparum parasites.
  • FECH is essential for intraerythrocytic parasite growth and blood stage malarial infection.
  • Cells and animals in which FECH activity was reduced through genetic changes additionally suggest the parasite has a high reliance for the host version of the enzyme. This supports other observations that host erythrocyte FECH is imported by the parasite and is functionally active (Varadharajan et ai , (2004)).
  • a total absence of FECI I is lethal and it is therefore relevant to test the involvement of partial mutants of the parasite enzyme.
  • EPP individuals retain at least 1 0% FECI I activity (Gouya et ai , (2006)); this is likely to be surpassed by NMPP and griseofulvin mediated inhibition of FECH and may explain the differences between the genetic and pharmacologic effects.
  • NMPP and griseofulvin may be targeting both host and Plasmodium FECH. and any such treatments may be vulnerable to drug resistance.
  • resistance would require the unlikely simultaneous mutations in the parasite that both reduce the enzyme's affinity for the NMPP substrate analog (without affecting catalysis of PPI X to heme) and up-regulate expression to compensate for the lack of active host FECH.
  • Griseofulvin (0 I 19

Landscapes

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

Abstract

La présente invention concerne un procédé de traitement ou de prophylaxie pour un sujet infecté par un membre du phylum des Apicomplexa ou un sujet qui a été exposé au dit membre, ledit procédé comprenant l'administration au dit sujet d'une quantité efficace de griséofulvine ou de N-méthyl protoporphyrine (NMPP).
PCT/AU2012/001422 2011-11-16 2012-11-16 Procédé de traitement et de prophylaxie, et compositions utiles associées WO2013071365A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161560497P 2011-11-16 2011-11-16
US61/560,497 2011-11-16

Publications (1)

Publication Number Publication Date
WO2013071365A1 true WO2013071365A1 (fr) 2013-05-23

Family

ID=48428845

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2012/001422 WO2013071365A1 (fr) 2011-11-16 2012-11-16 Procédé de traitement et de prophylaxie, et compositions utiles associées

Country Status (1)

Country Link
WO (1) WO2013071365A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022107161A1 (fr) * 2020-11-23 2022-05-27 Institute Of Life Sciences Griséofulvine utilisée comme médicament d'appoint pour le traitement des paludismes cérébral et grave
US20220218242A1 (en) * 2019-05-29 2022-07-14 Ohio State Innovation Foundation Methods and apparatus for making a determination about a presence or an absence of a parasite in a blood sample

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004233565B2 (en) * 2003-05-02 2009-10-01 Makhteshim Chemical Works Ltd. Active substance combinations that have nematicidal, insecticidal, and fungicidal properties and are based on trifluorobutenyl compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004233565B2 (en) * 2003-05-02 2009-10-01 Makhteshim Chemical Works Ltd. Active substance combinations that have nematicidal, insecticidal, and fungicidal properties and are based on trifluorobutenyl compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAGARAJ V. ET AL.: "Mitochondrial localization of functional ferrochelatase from Plasmodium falciparum", MOLECULAR AND BIOCHEMICAL PARASITOLOGY, vol. 168, 2009, pages 109 - 112, XP026496717 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220218242A1 (en) * 2019-05-29 2022-07-14 Ohio State Innovation Foundation Methods and apparatus for making a determination about a presence or an absence of a parasite in a blood sample
WO2022107161A1 (fr) * 2020-11-23 2022-05-27 Institute Of Life Sciences Griséofulvine utilisée comme médicament d'appoint pour le traitement des paludismes cérébral et grave
GB2616213A (en) * 2020-11-23 2023-08-30 Inst Of Life Sciences Griseofulvin as an adjunct drug for the treatment of cerebral and severe malaria
GB2616213B (en) * 2020-11-23 2025-01-08 Inst Of Life Sciences Griseofulvin as an adjunct drug for the treatment of cerebral and severe malaria

Similar Documents

Publication Publication Date Title
Pradel et al. Antibiotics in malaria therapy and their effect on the parasite apicoplast
CN1809382A (zh) 通过肝细胞生长因子拮抗物预防人的疟疾感染的方法
Grewal Pharmacology of 8-aminoquinolines
Chandana et al. Malaria parasite heme biosynthesis promotes and griseofulvin protects against cerebral malaria in mice
Sudhakar et al. Bazedoxifene, a postmenopausal drug, acts as an antimalarial and inhibits hemozoin formation
Mukherjee et al. A phosphoinositide-binding protein acts in the trafficking pathway of hemoglobin in the malaria parasite Plasmodium falciparum
Tripathi et al. Current status of malaria control
WO2007023370A1 (fr) Compositions et methodes permettant de traiter le paludisme
Pradines et al. Chemosensitizers in drug transport mechanisms involved in protozoan resistance
WO2013071365A1 (fr) Procédé de traitement et de prophylaxie, et compositions utiles associées
Renar et al. Understanding malarial toxins
US6194421B1 (en) Inhibitors of metazoan parasite proteases
Yamamoto et al. Antimalarial activity of vitamin D3 (VD3) does not result from VD3-induced antimicrobial agents including nitric oxide or cathelicidin
Anand et al. Significance of Plasmodium berghei amino acid transporter 1 in food vacuole functionality and its association with cerebral pathogenesis
US20110124723A1 (en) Compounds for Preventing and Treating Plasmodium Infections
US20110223179A1 (en) Methods and compositions for malaria prophylaxis
Sowunmi et al. Early changes in Plasmodium falciparum asexual and sexual populations in children with acute infections following treatment with artemisinin-based combination drugs
US20080119483A1 (en) Compositions and methods for inhibiting protozoan growth
US5863716A (en) Treatment of plasmodium
US11485714B2 (en) Hydroxyethylamine-based piperazine compounds, and methods of producing and using the same for treating disease
WO1996009405A1 (fr) Traitement contre les parasites du genre plasmodium
US20240009165A1 (en) Griseofulvin as an adjunct drug for the treatment of cerebral and severe malaria
Linares et al. Oxidative stress and protein carbonylation in malaria
Tarimo Oxidative stree management is essential for anopheles mosquito survival post plasmodium infected blood meal ingestion
WO2008147826A1 (fr) Médicaments contre la malaria en phase hépatique

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12849725

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WPC Withdrawal of priority claims after completion of the technical preparations for international publication

Ref document number: 61/560,497

Country of ref document: US

Date of ref document: 20140508

Free format text: WITHDRAWN AFTER TECHNICAL PREPARATION FINISHED

122 Ep: pct application non-entry in european phase

Ref document number: 12849725

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载