10/21/2008

Malaria

Overview

 

Emerging and reemerging diseases caused by intracellular pathogens, such as malaria and tuberculosis are major causes of morbidity and mortality globally.

 

Malaria continues to be a major health problem in many parts of the world, causing 300-500 million new infections and 1-2 million deaths each year, mainly due to the widespread presence of drug-resistant strains of the parasite, resulting in a dramatically decreased efficacy of available antimalarial drugs.

 

The appearance of drug-resistant strains of pathogens underlies the need for the development of new medicines, including those capable of boosting the host immune response.

 

This is important in infections by intracellular pathogens since conventional vaccines and antibody-based therapies are often totally or partially ineffective against intracellular pathogens.

 

Compounds developed in relatively recent times, and recognized as having immunomodulatory activity, such as Interferons ( mainly IFN-alfa and IFN-gamma), have turned out to be of limited usefulness, due to factors such as toxicity and high treatment cost, which restrict their use to a few applications.

 

Although immune-based therapy with Interferons, mainly by administration of exogenous interferon-gamma, is a promising path to treating infectious diseases caused by intracellular pathogens, including leishmaniasis and malaria, it still features serious problems and dilemmas, as cited.

 

In view of this, an innovative approach for treating these diseases is to administer agents such as immune response modifiers--immunomodulators that enhance production of physiological amounts of interferon-gamma through an immunoregulatory mechanism.

 

The immunomodulator P-MAPA is a strong candidate for the role, as explained below.

 

Rationale for use of P-MAPA in diseases caused by intracellular pathogens

 

In malaria, including pregnancy associated-malaria (PAM) there is strong evidence of a correlation between interferon-gamma levels and resistance to re-infection.

 

Extensive studies in animal models for the study of infectious diseases and cancer, have shown that P-MAPA induces proliferation of lymphocyte T, increases cytokine production, mainly Interferon-gamma and Interleukin-2, increases NK cell activity and stimulate NO release by macrophages.

 

Because these are key components and substances in the body´s defense mechanisms against infectious diseases caused by intracellular pathogens, such as malaria and others caused by bacteria and virus, it is reasonable to hypothesize that P-MAPA is applicable to them as well.

 

The results on Plasmodium yoelii and Plasmodium chabaudi infection model systems are described below.

 

P-MAPA activity in Plasmodium yoelii -infected mice

 

Study design:

 

The efficacy of P-MAPA against infection by P. yoelii was assessed in 7-week-old female C57BL/6 mice (SPF-- specific pathogen free) injected i.p. with 1 x 10⁶ P. yoelii infected erythrocytes.

 

Mice (n=5-7/group) were treated daily with P-MAPA (0.5, 5 or 50 mg/kg/d, i.p.) for 8 days (day 0-7) starting 1 h p.i., or with a single dose of P-MAPA (100 mg/kg, i.p.) given 24 h p.i., when detectable levels of parasitemia were observed.

 

Infected mice treated with saline (vehicle) showed maximum parasitemia (60.4%, group mean of 49.1 ± 7.1%) on the sixth day p.i.

 

The inhibition of parasitemia was expressed as a percentage relative to the saline-treated group ± SD.

 

The results of the P-MAPA-treated and saline-treated mice were compared by one-way ANOVA.

 

Results:

 

Results showed that daily doses of 5 mg/kg of P-MAPA inhibited parasitemia levels up to 50% on day 5 post-infection.

 

Notably, a single dose administered 24 h p.i. also inhibited parasite burden up to 50% compared to saline-treated animals.

 

P-MAPA activity in Plasmodium chabaudi-infected mice

 

Study design:

 

The P-MAPA activity against malaria was evaluated in groups of 7-10 C57BL/6 female mice, 5-8 week-old and pathogen-free.

 

Upon infection with lethal cells of Plasmodium chabaudi AJ, P-MAPA was administrated in one, unique, dose of 100 mg/kg one day after infection, and in diary doses of 50 and 5 mg/kg/day - 1 h upon infection.

 

The results of the P-MAPA-treated and saline-treated mice were compared by one-way ANOVA

 

Results:

 

P-MAPA inhibited the parasitemia up to 100 % with only one dose of 100 mg/kg during six days of the infection, while the control survival was only 50 %.

 

With administration of 5 mg/kg per day, 90 % of animals survived during nine days, meanwhile 60 % of the control animals died.

 

Bibliografic reference : Tasic L. - 2nd World Conference on Magic Bullets - Ehrlich II - Nürnberg -Germany 2008

 

Conclusions 

 

The experiments in animal models of protozoan infections warrant the development of the immunomodulator P-MAPA as a potential treatment for those diseases, including malaria.

 

There are strong evidences from preclinical studies that P-MAPA is a safe drug. It has not shown any significant toxic effects on mice, rats, and monkeys and furthermore, it has not shown any teratogenic effects either in vitro or in vivo  studies, which may allow its use for the treatment of Pregnancy associated-malaria (PAM), that is one of the severe forms of malaria leading to poor outcomes to the mother and fetus. 

 

Because the action of P-MAPA is on the immune system rather than against the pathogens themselves, it is unlikely that it will cause the emergence of resistant varieties of parasites.

 

Further studies are in progress in appropriate animal models to evaluate its use in conjunction with current antimicrobials.

 

Such studies may pave the way to clinical trials of P-MAPA as adjuvant in the treatment of infectious diseases including malaria, increasing the effectiveness of therapies now in use.