Malaria causes an estimated 247 million human infections per year among the 3.3 billion individuals at risk. Although millions are infected only a small proportion of individuals progress to severe and cerebral forms of the disease which account for the majority of the 1 million annual deaths from malaria. Most of these deaths occur in children under 5 years of age, although travelers to malariaendemic regions are also susceptible to this form of malaria due to their lack of immunity to the disease.

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Malaria causes an estimated 247 million human infections per year among the 3.3 billion individuals at risk. Although millions are infected only a small proportion of individuals progress to severe and cerebral forms of the disease which account for the majority of the 1 million annual deaths from malaria. Most of these deaths occur in children under 5 years of age, although travelers to malariaendemic regions are also susceptible to this form of malaria due to their lack of immunity to the disease. There are currently no simple laboratory tests to determine the severity of infection and to identify individuals at risk for developing cerebral malaria. Current diagnostic methods for cerebral malaria are based on clinical presentation and are unable to accurately differentiate cerebral malaria from neurological conditions or other infectious diseases. Furthermore, these methods cannot predict which patients presenting with uncomplicated malaria will go on to develop the cerebral form of the disease. A better diagnostic for cerebral malaria would allow greater accuracy in choice of treatment. A prognostic method for cerebral malaria would allow limited intensive therapeutic resources to be appropriately allocated to the small proportion of infected individuals who are at risk of developing severe and potentially deadly forms of the disease. This selective intervention has the potential to maximize the impact and effectiveness of limited health resources and to greatly reduce malaria deaths. We have identified novel serum protein based biomarkers (ANG-1 and ANG-2) that correlate with disease severity and have shown high specificity and sensitivity for diagnosis of cerebral malaria (as high as 100%). These biomarkers can be measured with simple antibody based blood tests or other methods. Validation studies of these markers for prognosis of severe and cerebral malaria in large banked sample sets are underway.

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Quinolines (mefloquine, quinine, quinidine etc.) are amongst the most commonly used antimalarials; however, all suffer from increasing drug resistance. Resistance to these agents is accomplished by the activity of a drug efflux pump. Toronto researchers have discovered potent inhibitors of these pumps, thus restoring the anti-malarial activity of quinoline drugs including activity against P. falciparum (the most deadly form of human malaria).

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Quinolines (mefloquine, quinine, quinidine etc.) are amongst the most commonly used antimalarials; however, all suffer from increasing drug resistance. Resistance to these agents is accomplished by the activity of a drug efflux pump. Toronto researchers have discovered potent inhibitors of these pumps, thus restoring the anti-malarial activity of quinoline drugs including activity against P. falciparum (the most deadly form of human malaria). These inhibitors are very inexpensive, nontoxic and stable at room temperatures, and thus could be easily incorporated into quinoline formulations Preliminary toxicology studies indicate that these surfactants are very well tolerated in rodents and that effective doses can be achieved in vivo. Malaria produces an estimated 247 million cases per year among 3.3 billion at risk and results in nearly one million deaths, mostly in children under five years of age. Increasing resistance to current anti-malarials has created a critical need for either new, low-cost, effective anti-malarials or resistance reversal technologies for existing therapies.

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Malaria produces an estimated 247 million cases per year among 3.3 billion individuals at risk of the disease and results in nearly one million deaths – mostly in children under five years of age. Increasing resistance to current anti-malarials has created a critical need for new, low-cost, effective anti-malarials for the developing world. A new, effective and well-tolerated anti-malarial would also have a significant competitive advantage in the profitable military and travelers’ use markets due to undesirable side-effects of therapeutics currently sold for these markets.

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Malaria produces an estimated 247 million cases per year among 3.3 billion individuals at risk of the disease and results in nearly one million deaths – mostly in children under five years of age. Increasing resistance to current anti-malarials has created a critical need for new, low-cost, effective anti-malarials for the developing world. A new, effective and well-tolerated anti-malarial would also have a significant competitive advantage in the profitable military and travelers’ use markets due to undesirable side-effects of therapeutics currently sold for these markets. Researchers at UHN have developed a novel family of small molecule malaria therapeutics that exploit a key metabolic difference in the nucleotide synthesis pathway between the malaria plasmodium and mammals. This is a previously unexploited target for malaria therapeutic development allowing for the creation of first-in-class therapeutics. The current lead compound has demonstrated activity against several drug-resistant P. falciparum (the most deadly form of human malaria) isolates in the nanomolar range and has good selectivity. This class of compounds can be synthesized rapidly, are stable and can easily cross membranes. No cross resistance with current anti-malarials has been observed which is consistent with their novel mechanism of action. Animal testing of this class of compounds has indicated that they are both bioavailable and well-tolerated. Promising preliminary data has also been obtained showing inhibition of P. falcaparim malaria in a Nodscid mouse model.

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Malaria produces an estimated 247 million cases per year among 3.3 billion individuals at risk of the disease and results in nearly one million deaths, mostly in children under five years of age. A large majority of these deaths are due to the cerebral form of the disease which has a 15% or greater fatality rate and typically occurs in nonimmune individuals such as young children living in malarious areas and travelers (who are visiting these regions in increasing numbers). Dr. Kain has developed a novel approach to prevent and treat severe and cerebral malaria that utilizes existing medications.

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Malaria produces an estimated 247 million cases per year among 3.3 billion individuals at risk of the disease and results in nearly one million deaths, mostly in children under five years of age. A large majority of these deaths are due to the cerebral form of the disease which has a 15% or greater fatality rate and typically occurs in nonimmune individuals such as young children living in malarious areas and travelers (who are visiting these regions in increasing numbers). Dr. Kain has developed a novel approach to prevent and treat severe and cerebral malaria that utilizes existing medications. Dr. Kain’s studies demonstrate that stimulating expression of the CD36 receptor (the major receptor mediating clearance of malaria in nonimmune individuals) increases clearance of malaria and decreases the excessive pro-inflammatory responses that have been linked to severe and cerebral malaria. This novel therapeutic strategy relies on stimulating the CD36 gene promoter with PPARgamma RXR agonists drugs which are currently on the market for the treatment of other indications. A Phase I clinical trial of this technology has been successfully completed.

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