HK1173995B - Use of ferroquine in the treatment of malaria - Google Patents

Description

The present invention relates to the implementation of active substances useful for the prevention and/or treatment of infections with the parasite Plasmodium vivax and, more generally, with a parasite of the genus Plasmodium, whose life cycle includes a hepatic latency phase in the human host.

Specifically, the present invention concerns the implementation of ferroquin or its N-demethylated metabolite for this purpose.

Malaria is one of the world's leading infectious causes of death, affecting more than 5,000,000 people each year, of whom 3,000,000 die each year.

The disease is most prevalent in sub-Saharan Africa, Southeast Asia, and Latin America.

There are generally four main species of Plasmodium responsible for transmitting malaria: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae, the first two being the most common.

P. falciparum and P. vivax parasites differ in geographical coverage and developmental cycle in the human host.

P. vivax is the most widespread plasmodium species on all continents except in sub-Saharan Africa where P. falciparum predominates, despite the presence of P. malariae which can sometimes cause up to 1/3 of malaria cases and P. ovale, which is nevertheless more rare (Mendis K. et al., The Neglected Burden of Plasmodium vivax Malaria, Am. J. Trop. Med. Hyg., 2001, 64 (1-2 suppl) : 97-106).

Specifically, the P. vivax parasite is found mainly in Southeast Asia and the Pacific where it is thought to be responsible for 49% of malaria cases, but also to a lesser extent in the territories of East and South Africa. It is actually present in Afro-Asian populations, particularly in Kenya, Tanzania and the islands of the Indian Ocean, such as Madagascar.

Estimates of the geographical prevalence of this parasite vary according to the methodology used, but one thing is certain: the importance of this parasite has been largely underestimated.

The parasite is transmitted by a bite of a female anopheles mosquito. Once in the human host, the parasite enters the liver cells, undergoes an asexual replication phase and leads to the formation of vesicles, the schizophrenia. The vesicles thus formed are released into the hepatic sinuses to then join the bloodstream and spread there a flood of young pre-erythrocytic merozoites ready to infect the red blood cells. After the pre-erythrocytic merozoites enter the red blood cells and begin the erythrocytic cycle, the successive divisions of the erythrocytic cycles or erythrocyte cells in the bloodstream cause the formation of new erythrocyte cells.

It should also be noted that for species other than P. falciparum, some pre-erythrocyte merozoites do not directly access the blood but attack new hepatocytes.

These hepatic forms, called hypnozoites, will remain in the latent state for a specific time period depending on the strain and its environment. They will maintain the parasitosis in the liver for 2 to 3 years for P. ovale, 3 to 5 years or more for P. vivax and for life for P. malariae, before reactivating in successive waves, causing a high fever, also called third-line fever, one of the forms of malaria still called malaria.

In view of this specificity, it is clear that drugs which are effective in treating infections caused by P. falciparum are generally inadequate in terms of their effectiveness against infections caused by these other species, since they are limited to eliminating circulating forms of the parasite and have no effect on quiescent forms stored in human hepatocytes.

However, the conventional antimalarial treatments available to treat all parasitic infections of the genus Plasmodium are treatments that have been substantially validated for efficacy only in P. falciparum.

Err1:Expecting ',' delimiter: line 1 column 346 (char 345)

However, the phenomena of resistance of P. vivax to chloroquine make this active substance less and less effective against this parasite.

As regards primaquine, it presents significant toxicity concerns and increases the risk of hemolysis in subjects with a glucose-6-phosphate-dehydrogenase deficiency, often from Africa, the Middle East, India, the Mediterranean basin or South-East Asia.

Other compounds, such as quinine, chloroquine, mefloquine, and artemisinin derivatives have little or no effect on the liver form of the parasite.

Antifolates and atovaquone, initially used in combination to treat the parasite in its circulating phase, have also been recognized as active on hepatocytes, but many resistance to these agents have emerged.

As for ART (Artemisinin-based-Combination Therapy), very few studies have so far been conducted on its effectiveness in P. vivax.

Therefore, there are no effective treatments to date to treat and prevent P. vivax infections and more generally to treat latent hepatic hypnozoic forms characteristic of relapses.

Therefore, there remains a need for specific preventive and curative treatment of infections caused by a parasite of the genus Plasmodium, whose life cycle includes a hepatic latency phase in the human host.

Thus, the present invention describes the use of ferroquin or its pharmaceutically acceptable N-demethylated metabolite or one of its salts for the treatment and/or prevention of infections caused by a parasite of the genus Plasmodium, whose life cycle includes a hepatic dormant phase in the human host.

Infections are caused mainly by P. vivax, P. ovale or P. malariae and more specifically by P. vivax.

The present invention therefore describes ferroquin or its N-demethylated metabolite or one of its pharmaceutically acceptable salts for use in the treatment and/or prevention of infections of blood and/or liver cells infected with a parasite of the genus Plasmodium, in particular P. vivax, P. ovale or P. malariae, and in particular P. vivax.

The present invention concerns ferroquin or one of its pharmaceutically acceptable salts for use in the treatment of blood cell infections caused by Plasmodium vivax at the stages of ring parasitic and mature trophozoite development.

The present invention also describes ferroquin or its pharmaceutically acceptable N-demethylated metabolite or one of its salts for use in the treatment, prevention and elimination of quiescent hypnozoite forms stored in human hepatocytes, including those resulting from infections caused by a parasite of the genus Plasmodium, in particular P. vivax, P. ovale or P. malariae, and in particular P. vivax.

The present invention also describes ferroquine or its N-demethylated metabolite or one of their pharmaceutically acceptable salts, for use in the prevention of relapses due to infection by the P. vivax parasite.

The present invention also describes ferroquine or its N-demethylated metabolite or one of their pharmaceutically acceptable salts for use in the treatment and/or prevention of benign tertiary fevers due to infection by P. vivax.

The present invention also covers ferroquine or one of its pharmaceutically acceptable salts for use in the treatment of infections caused by P. vivax in patients with glucose-6-phosphate dehydrogenase deficiency.

This ferroquin and other related derivatives which differ from it in the substituents on the quinoline cycle are described in WO 96/35698.

Structurally, it is the result of the insertion of a ferrocene group inside a chloroquine molecule and corresponds to a compound of the following structure: - What?

Its metabolite (N) -demethylated corresponds to a compound of the following structure: - What?

The parasitic strains specifically referred to in WO 96/35698 are P. falciparum strains, since the development of such complexes is based precisely on the affinity of the parasite for the iron in the blood vessels it infects.

Err1:Expecting ',' delimiter: line 1 column 203 (char 202)

Err1:Expecting ',' delimiter: line 1 column 227 (char 226)

The present application demonstrates that ferroquine is particularly effective in the treatment of P. vivax infections. Unlike chloroquine, and quite unexpectedly, it not only eliminates the parasite in its circulatory phase at the level of blood cells, but it does so with equal effectiveness on the immature ( ring stage) and mature trophozoite forms of P. vivax.

The active substances of the present invention may be in the form of a free base, but also in the form of a salt, hydrate or solvate (the latter being defined as combinations or combinations of ferroquin with one or more water or solvent molecules, respectively).

It is advantageous to use ferroquin in the free base form.

The invention relates to a pharmaceutical composition containing as active ingredients ferroquin or its N-demethylated metabolite or one of their pharmaceutically acceptable salts, for use in the treatment of P. vivax infections.

Such a pharmaceutical formulation shall contain therapeutically effective doses of ferroquine or its (N) -demethylated metabolite, or any of their pharmaceutically acceptable salts, their hydrates or ferroquine solvates, and at least one pharmaceutically acceptable excipient, selected according to the pharmaceutical form and intended route of administration from among the usual excipients known to the professional.

Suitable unit forms of administration include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous, rectal and implant forms. For topical application, the compounds of the invention may be used in creams, gels, ointments or lotions.

The preferred routes of administration are oral, rectal and injectable.

For example, when preparing a solid composition in the form of tablets, the active ingredients are mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hydroxypropyl-methyl cellulose, croscarmellose, magnesium stearate, hypromellose, or analogues.

A capsule preparation can also be obtained by mixing the active ingredients with a diluent and pouring the resulting mixture into soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile solutions for injection containing dispersion agents and/ or pharmacologically compatible wetting agents, e.g. propylene glycol or butylene glycol, are used.

There may be special cases where higher or lower doses are appropriate; such doses are not outside the scope of the invention.

For example, a unit form of administration of ferroquine in tablet form may include the following components: Ferroquine 50 mgMannitol 224 mgSodium croscaramellose 6 mgMais amide 15 mgHydroxypropyl methyl cellulose 2 mgMagnesium stearate 3 mg The total amount of ferroquine administered to the population was approximately 50 mg.

In vitro evaluation of the efficacy of ferroquine against other reference antimalarials in P. vivax-infected blood isolates

The following test is performed on 110 P. vivax isolates collected in North-West Thailand (Tak Province) from willing, P. vivax infected patients in the acute phase of infection who came to the Shoklo Malaria Research Unit (SMRU).

Samples are collected 5 hours after arrival and placed in heparinated 5 ml tubes at room temperature.

The parasitemia of the isolates collected is about 4432 parasites/μl. 99 isolates were finally successfully cultured and only those with more than 80% trophozoites were selected.

Platelets and leukocytes are removed from these isolates, by analogy with the method described in Kanlaya et al., Malaria Journal, 2009, 8:115.

Around 60 samples are finally selected and about 10 isolates per plate or per experiment are tested in duplicate.

The activity of the different agents is tested in pre-drilled wells, by analogy with the method described in Barends et al., Malaria Journal 2007,6:81 and Brice et al., Antimicrobial agents and chemotherapy, Jan 2003, pp 170-173. Figure 1 showing a dose-response diagram shows the EC50 (effective concentration 50) results obtained for ferroquine and reference antimalarials, chloroquine, mefloquine and piperaquine.Figure 2 showing a dose-response diagram shows the CI50 (inhibitory concentration 50) results obtained for ferroquine and chloroquine.

As shown in Figure 1 above, the lowest EC50 of the order of 6 nM is that of ferroquin, demonstrating its increased efficacy compared to conventional antimalarials.

Err1:Expecting ',' delimiter: line 1 column 200 (char 199)

Claims (2)

1. Ferroquine or a pharmaceutically acceptable salt thereof, for use in the treatment of infections of blood cells caused by Plasmodium vivax at the parasitic growth stages of the immature trophozoite "ring stage" and of the mature trophozoite.
2. Ferroquine or a pharmaceutically acceptable salt thereof for use according to Claim 1, characterized in that the treatment is the treatment of infections in patients deficient in glucose-6-phosphate dehydrogenase.