Falciparum

Malaria is transmitted by the bite of an infected female Anopheles mosquito, one of the few species of the insect capable of carrying the human malaria parasite. The responsible protozoa ate from the genus P/asmodium of which only four of some 100 species can cause the disease in humans. The remaining species affect rodents, reptiles, monkeys, birds, and Hvestock. The species that infect humans are P/asmodium falciparum Plasmodium vivax Plasmodium malariae and Plasmodium ovale. Note that concomitant multiple malaria infections are commonly seen in endemic areas, a phenomenon that further compHcates choice of treatment. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Quinacrine (49) is an acridine that was used extensively from the mid-1920s to the end of World War 11. It acts much like chloroquine and is reasonably effective. Because it causes the skin to turn yellow and, in high doses, causes yellow vision, the dmg is no longer in use as an antimalarial. Pyronaridine (77), a 1-azaacridine developed in China, appears to be effective against mefloquine-resistant, but not entirely against chloroquine-resistant, strains of P falciparum. 

Four different protozoa of the genus Plasmodium -P. falciparum, P. vivax, P. ovale and P malariae - can cause malaria. P. falciparum is the most virulent, being responsible for virtually all fatal malaria cases. Humans are infected by a feeding female Anopheles mosquito (Fig. 2). The clinical symptoms of malaria are associated with the development of the parasite within human red blood cells, while the liver stages remain asymptomatic. The following dtugs (in alphabetical order) are currently in use for the treatment of malaria [5]. 

Malaria remains a major public health problem in many parts of the world, including Southeast Asia, sub-Saharan Africa and Latin America where an estimated 300-500 million people are infected. 1-3 million die of malaria every year. The etiologic agents of malaria are protozoan parasites of the genus Plasmodium. Of the four pathogens that can cause malaria in humans (Plasmodium falciparum, P. vivax, P. ovale,... 

P. malariae), P. falciparum is responsible for the most severe form. At particular risk of developing severe malaria-associated pathology are the non-immune, including tourists and, in endemic areas, children and pregnant women during first pregnancy. 

Malaria is transmitted from person to person by a certain species of the Anopheles mosquito. The four different protozoans causing malaria are Plasmodium falciparum, P. malariae, P. ovale, and P. vivax. Drugp used to treat or prevent malaria are called anti malarial drags. Three antimalarial drugs are discussed in the chapter chloroquine, doxycycline, and quinine sulfate. Other examples of antimalarial drugs in use today are listed in the Summary Drug Table Antimalarial Drugs. 

Inhibitors for proteases plasmepsin I and II of the malaria parasite Plasmodium falciparum, with a good plasmepsin/human protease cathepsin D selectivity, have been identified via library construction involving rapid microwave-accelerated Suzuki reactions [57]. The phenyl ring of the biphenyl unit in the lead compound M-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-phenyl-benzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methylpropyl)pyridine-2-carboxamide has been altered by performing Suzuki reactions on N-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-bromobenzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methyl-propyl)pyridine-2-carboxamide (Scheme 37). In particular, a 2-benzofuryl moiety proved to be interesting since a Ki value of 13 nM for plasmepsin I and... 

Plasmodium falciparum DHFR inhibitor, Ki = 0.9 jxM, Ki vs. different resistant strains = 0.6-2.1 xM... 

Toyoda T, Brobey RKB, Sano G, Horii T, Tomioka N, Itai Akiko. Lead discovery of inhibitors of the dihydrofolate reductase domain of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase. Biochem Biophys Res Commun 1997 235 515-19. 

Rastelli G, Pacchioni S, Sirawaraporn W, Sirawaraporn R, Parenti MD, Ferrari AM. Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors. J Med Chem 2003 46 2834-45. 

Bfx and Fx derivatives have been evaluated against the parasites Trypanosoma cruzi (T. cruzi), which is responsible for American Trypanosomiasis and Plasmodium falciparum (P. falciparum) responsible for Malaria. 

Fig. 11 Sulfonyl Fxs and its deoxygenated analogues evaluated as anti-P. falciparum agents...

Narum, D. L., Welling, G. W., and Thomas, A. W., Ion-exchange-immuno-affinity purification of a recombinant baculovirus Plasmodium falciparum apical membrane antigen, PF83/AMA-1, /. Chromatogr. A, 657, 357, 1993. 

Falciparum malaria must be considered a life-threatening medical emergency. 

Complications of falciparum malaria include hypoglycemia, acute renal failure, pulmonary edema, seizure, and coma. 

Malaria is transmitted by the bites of the Anopheles mosquitoes which introduce into the bloodstream one of four species of sporozoites of the plasmodia (Plasmodium falciparum, P. ovale, P. vivax or P. malariae). Initial symptoms of malaria are nonspecific and may resemble influenza and include chills, headache, fatigue, muscle pain, rigors, and nausea. The onset of the symptoms is between 1 to 3 weeks following exposure. Fever may appear 2 to 3 days after initial symptoms and may follow a pattern and occur every 2 or 3 days (P. vivax, P. ovale and P. malariae). Fever with P. falciparum can be erratic and may not follow specific patterns. It is not unusual for patients to have concomitant infections with P. vivax and P. falciparum. Falciparum malaria must always be regarded as a life-threatening medical emergency. 

The distribution of the various species of malaria is not well defined but P. vivax is reported to be prevalent in the Indian subcontinent, Central America, North Africa, and the Middle East, whereas P. falciparum is predominantly in Africa (including sub-Saharan Africa), both East and West Africa, Haiti, the Dominican Republic, the Amazon region of South America, Southeast Asia, and New Guinea. Most P. ovale infections occur in Africa, while the distribution of P. malariae is worldwide.7 Most infections in the United States are reported in American travelers, recent immigrants, or immigrants who have visited... 

P. falciparum malaria is a life-threatening emergency. Complications include hypoglycemia, acute renal failure, pulmonary edema, severe anemia (high parasitism), thrombocytopenia, heart failure, cerebral congestion, seizures, coma, and adult respiratory distress syndrome. 

In an uncomplicated attack of malaria (for all plasmodia except chloroquine-resistant P. falciparum and P. vivax), the recommended regimen is chloroquine 600 mg (base) initially, followed by 300 mg (base) 6 hours later, and then 300 mg (base) daily for 2 days.3 In severe illness or falciparum malaria, patients should be admitted to an acute care unit and quinidine gluconate 10 mgsalt/kg... 

Alternatives Doxycycline (oral) 1 00 mg daily Greater than or equal to 8 years of age 2 mg/kg (maximum 100 mg) Effective for mefloquine-resistant P. falciparum Start 1-2 days before departure, continue through stay in endemic area, and continue regimen for 4 weeks after returning... 

Following treatment of falciparum malaria, TW has remained well for 2 months. However, 2 days ago, he started developing fever and chills, nausea, and abdominal pain. When seen in the emergency department he has a fever of 38.4°C and complains of severe headache. Examinations of a thick and thin blood smear of the patient s blood identified P. vivax infection. TW received a course of chloroquine and primaquine. In a follow-up 2 weeks later, a repeat blood smear was negative for parasites and the patient was asymptomatic. 

Exchange transfusion that may be required in patients with P. falciparum malaria in whom parasitemia may be between 5% and 15% remains a questionable modality. Either peritoneal or hemodialysis may be indicated in renal failure. 

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