Chloroquine-resistance

The sulfas also remain clinically useful in the treatment of chancroid, lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and the fungus-related nocardiosis (7). In combination with pyrimethamine, they are recommended for toxoplasmosis (8) and have been used for chloroquine-resistant falciparium malaria (4,9). There has also been some use of sulfas for the prophylaxis of rheumatic fever. The sulfone, dapsone, remains an accepted treatment for all forms of leprosy (4). 

Plasmodium vivax, responsible for the most prevalent form of malaria (benign tertian), has an incubation period of 8—27 days (14 average). A variety seen in northern and northeastern Europe has an incubation period as long as 8—10 months. The disease can cause splenic mpture and anemia. Relapses (renewed manifestations of erythrocytic infection) can occur with this type of malaria. Overall, P. vivax is stiU susceptible to chloroquine however, resistant strains have been reported from Papua New Guinea and parts of Indonesia. Plasmodium malariae the cause of quartan malaria, has an incubation period of 15—30 days and its asexual cycle is 72 hours. This mildest form of malaria can cause nephritis in addition to the usual symptoms. It is a nonrelapsing type of malaria but the ted blood ceU infection can last for many years. No resistance to chloroquine by this plasmodium has been reported. Plasmodium ovale responsible for ovale tertian malaria, has an incubation period of 9—17 days (15 average). Relapses can occur in people infected with this plasmodium. No chloroquine resistance has been reported for this parasite. 

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. 

The best example of the class of phenanthrene-methanols is halofantrine (66, Halfan [36167-63-2]) a dmg that is effective against chloroquine-resistant malaria and is now being evaluated in Africa. It produces temporary gastrointestinal disturbances. 

Quinones and naphthoquinones were explored during the World War 11 Antimalarial Dmg Program. Now that chloroquine resistance is a serious problem, compounds of this group such as menoctone (76) are being reinvestigated. 

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. 

Phosphorus ylides C-substituted and stabifized by elements of group 16 are often used for the synthesis of natural substances. For example, the synthesis of simpHfied analogs of artemisinin, used against chloroquine-resistant malaria, has been recently described from methoxymethylphosphonium yhde 120 [127,128]. The later is able to convert afiphatic nitriles into a-functionafized ketones 122 which are the precursors of the target compounds. Starting from the aromatic ni-... 

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... 

When advising potential travelers on prophylaxis for malaria, be aware of the incidence of chloroquine-resistant P. falciparum malaria and the countries where it is prevalent. In patients who have P. vivax or P. ovale malaria (note that some patients can have P. falciparum and one of these species), following the treatment of the acute phase of malaria and screening for glucose-6-phosphate dehydrogenase deficiency, patients should receive a regimen of primaquine for 14 days to ensure eradication of the hypnozoite stage of P. vivax or P. ovale. For detailed recommendations for prevention of malaria go to www.cdc.gov/travel/. 

Since that time, artemisinin has been used successfully in many thousand malaria patients throughout the world including those infected with both cldoroquine-sensitive and chloroquine-resistant strains of P falciparum. Artemisinin has progressively estabhshed itself as one of the most potent and effective antimalarial dmg, and is primarily recommended in the treatment of multidrug-resistant strains of P. falciparum. However, the therapeutic... 

Chalcones are one of the classes of flavonoids well known for their antiplasmodial properties. Licochalcone A (65), isolated from Chinese licorice roots, was shown to display strong in vitro activity against both chloroquine-susceptible (3D7) and chloroquine-resistant (Dd2) P. falciparum strains it also displayed a strong in vivo acitivity in mice infected with P. yoelii, when administered intraperitoneally or orally for 3 to 6 days. The compound appeared to inhibit the growth of the parasites at all stages (rings, trophozoites, and schizonts). Although licochalcone and some derivatives interred the clinical trials as anti-malarials, none of them have ever made it to the market due to severe toxicity observed in phase II clinical trials. 

Upon oral administration, quinine effectively acts in combination with pyrimethamine, sulfadiazine, and/or tetracycline for treating uncomplicated incidents of chloroquine-resistant forms of P. falciparum. Because of the many associated side effects, its use is extremely limited. Currently, the only indication for use is for forms of malaria that are resistant to other synthetic drugs. Synonyms of this drug are bronchopulmin, nicopriv, quinnam, and others. 

A combination of pyrimethamine, sulfonamide, and qninine is the dmg of choice for acute attacks of malaria and its chloroquine-resistant forms. 

As adjunctive therapy because of chloroquine-resistant strains of Plasmodium falciparum. 

In 1999, Rickards et al. reported the isolation of calothrixins A (377) and B (378) from photoautrophic cultures of Calothrix cyanobacteria (345). These two, novel, pentacyclic carbazole alkaloids contain a quinolino[4,3-fc]carbazole-l,4-quinone framework. Calothrixins A and B inhibit the growth of a chloroquin-resistant strain of the malaria parasite P. falciparum and human HeLa cancer cells (345). 

The use of the long-acting sulfonamides such as sulfadimethoxine and sulfadoxine is limited because of a high rate of hypersensitivity reactions. Sulfadoxine in combination with pyrimethamine is indicated for chloroquine-resistant falciparum malaria. 

VI.a.2.2. Biguanides. Proguanil is a dihydrofolate reductase inhibitor. It is a slow acting blood schizonticide and not effective on its own. It has also a marked effect on the primary tissue stages of Plasmodium falciparum. It is used in combination with chloroquine for the prophylaxis of chloroquine-resistant Plasmodium falciparum. 

Quinine is the principal alkaloid derived from the bark of the cinchona tree. It has been used for malaria suppression for over 300 years. By 1959 it was superseded by other drugs, especially chloroquine. After widespread resistance to chloroquine became manifest quinine again became an important antimalarial. Its main uses are for the oral treatment of chloroquine-resistant falciparum malaria and for parenteral treatment of severe attacks of falciparum malaria. Quinine is a blood schizonticide with some gametocytocidal activity. It has no exoerythrocytic activity. Its mechanism of action is not well understood. It can interact with DNA, inhibiting strand separation and ultimately protein synthesis. Resistance of quinine has been increasing in South-East Asia. 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

VLa.2,6. Other antimalarials. Doxycydine (see Section ILb) is a useful and effective short-term prophylactic agent for travellers to chloroquine-resistant areas and can be used as an alternative when mefloquine or proguanil is unavailable or mefloquine is contraindicated. In combination with quinine also tetracycline is used as an antimalarial. 

Halofantrine, a 9-phenanthrenemethanol derivative, is a blood schizonticide and is active against Plasmodium vivax and chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum. As no parenteral preparation is available it cannot be used for severely ill patients. Oral absorption is slow and incomplete and is increased by a fatty meal. 

Non-falciparum malaria (like P. vivax) can still be treated with chloroquine although chloroquine resistant P. vivax has been reported from Irian Jaya and Papua New Guinea. In those areas treatment with mefloquine is recommended. To treat the liverstages an additional 2-3 weeks treatment with primaquine is given. It appears that tafenoquine (dosed once a week), a new 8-aminoquinoline, would be a better replacement for primaquine in preventing relapses in P. vivax malaria. 

Sulfonamides, such as sulfadiazine, in combination with pyrimethamine, are considered the treatment of choice of symptomatic toxoplasmosis. Patients should be well hydrated to prevent crystalluria this problem may be reduced with the use of triple sulfas (trisulfapyrimidine). Some regimens have included a sulfonamide (sul-fadoxine) in combination with pyrimethamine (Fansidar) for the treatment of chloroquine-resistant malaria caused by P. falciparum. 

The emergence of parasites resistant to chloroquine is an increasingly important problem. Several strains of chloroquine-resistant P. falciparum have been identified. This resistance would lead to the reappearance of overt symptoms of P. falciparum malaria. 

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