Plasmodium falciparum chloroquine resistance

How the parasite removes chloroquine from the food vacuole appears to be related to mutations of a specific gene, named pfcrt for plasmodium falciparum chloroquine resistance transporter. The protein product of this gene (CRT) is a 49 kD transmembrane protein that has a predicted 10 transmembrane domains. The key mutation seems to be K76T since no chloroquine resistant isolate carries the wild type lysine at position 76. It should be noted that usually a number of other mutations are noted in chloroquine resistant malaria, but only the K76T amino acid switch is seen consistently in the chloroquine resistant malaria. 

VI.a.2.3. Quinine alkaloids. The quinine alkaloids include quinine and quinidine. Quinidine, the dextrorotatory diastereoisomer of quinine, is mainly used for the parenteral treatment of cardiac arrhythmias but it can be an alternative antimalarial in regions where Plasmodium falciparum is resistant to both chloroquine and antifolate-sulfonamide combinations. 

Trioxaquines have modular structures linking two different moieties. A study of the relation between the structure of the trioxaquines and their antiplasmodial activities in vitro and in vivo was done. All the trioxaquines tested in vitro present interesting antimalarial properties on strains of Plasmodium falciparum chloroquine-sensitive and chloroquine-resistant with ICso inferior to 100 nM and around 10 nM for the best trioxaquines 41). 

Malaria (doxycycline only) Prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. 

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

Malaria is the cause for approximately 20% of child deaths in Africa and for more than 1 million deaths around the world each year. The appearance and spread of drug resistance of the Plasmodium falciparum parasites to common antimalarial drugs, such as chloroquine and hydroxychloroquine, have posed the urgent challenge of developing effective, safe and affordable antimalarial drugs. 

Chloroquine is a rapidly acting blood schizonti-cide with some gametocytocidal activity. It is used with primaquine for Plasmodium vivax and Plasmodium ovale infections. It has been widely used prophylactically by traveler s to endemic areas. Its mechanism of action is unclear. It is believed to hinder the metabolism of hemoglobin in the parasite. Presumably chloroquine prevents the formation in the plasmodia of polymers out of free heme which then builds up and becomes toxic. Resistance occurs as a consequence of the expression of a membrane phospho-glycoprotein pump in the plasmodia which is able to expel chloroquine from the parasite. Plasmodium falciparum is the most likely to become resistant. 

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. 

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... 

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. 

Artemisia annua L. A. apiacea Hance ex Walpers Qing Guo (Stinking artemisia) (aerial part) Dihydroartemisinin, artesunate, artemisinin, chloroquine, flavonoids, sesquiterpene.33-269-476 This herb is mildly toxic. A schizonticidal agent, antimalarial, treat infections of multidrug-resistant strains of Plasmodium falciparum, the cause of human malignant cerebral malaria. 

High-level Chloroquine Resistance in Sudanese Isolates of Plasmodium Falciparum is... 

The benzo-l,5-naphthyridine (168) has shown significant activity against chloroquine-resistant strains of Plasmodium falciparum. 24 Oxo derivatives... 

Following the development of synthetic antimalarial agents, such as chloroquine and mefloquine, the use of Cinchona alkaloid quinine declined. However, with the emergence of chloroquine-resistant and multiple-drug-resistant strains of malarial parasites, its use has become firmly reestablished. Quinine is the drug of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum. In the U.S., the related alkaloid quinidine is recommended because of its wide availability and use as an antiarrhythmic agent. In many clinics in the tropics, quinine is the only effective treatment for severe malaria unfortunately, decreasing sensitivity of P. falciparum to quinine has already been reported from Southeast Asia. 

Chloroquine destroys schizonts in erythrocytes by interfering with DNA synthesis. The phosphate salts are active orally, whereas the hydrochloride salt is used for intravenous purposes. It accumulates in normal and parasitized erythrocytes. Overdosage has caused reversible corneal damage and permanent retinal damage. In toxic doses, chloroquine causes visual disturbances, hyperexcitability, convulsions, and heart block. It is an antimalarial of choice in all cases except chloroquine-resistant Plasmodium falciparum. In addition, it has a certain degree of effectiveness in amebiasis and in the late stages of rheumatoid arthritis. 

Quinine is a naturally occurring alkaloid obtained from Cinchona bark, with a mechanism of action similar to that of chloroquine. Quinine is very useful in treating chloroquine-resistant Plasmodium falciparum. In toxic doses, it may cause cinchonism characterized by tinnitus, headache, nausea, and visual disturbances. 

Pyrimethamine is a fohc acid antagonist (antifol) with pharmacological actions similar to chlorguanide, methotrexate, and trimethoprim. Pyrimethamine may be used in combination with sulfadoxine for suppression and sulfadiazine for treatment of chloroquine-resistant Plasmodium falciparum. 

The sulfones and sulfonamides synergize with the inhibitors of dihydrofolate reductase, and the combinations have been effective in controlling malaria, toxoplasmosis, and coccidiosis. Fansidar, a combination of sulfadoxine and pyrimethamine, has been successful in controlling some strains of chloroquine-resistant Plasmodium falciparum malaria (see Chapter 53 Antiprotozoal Drugs). However, reports of Fansidar resistance have increased in recent years. New inhibitors effective against the sulfonamide-resistant 7,8-dihydropteroate synthase are needed. 

Krogstad DJ, Gluzman IY, Kyle DE et al (1987) Efflux of chloroquine from Plasmodium falciparum mechanism of chloroquine resistance. Science 238 1283-1285... 

Plasmodium falciparum, responsibleforthe most dangerous form of malaria, is particularly prone to develop drug resistance. The prevalence of resistant strains rises with increasing frequency of drug use. Resistance has been reported for chloroquine and also the combination pyrimethamine/sulfadoxine. 

Artemisinin (quinghaosu) (3,12-peroxyC60 ] C50L ( C6 ) from Artemisia annua (Asteraceae) is of major importance as an antimalarial because of extensive resistance of Plasmodium falciparum to antimalarials such as chloroquine. Artemisinin in has a 3,12-peroxy (-0—0—) substituent spanning the C60 ring. Artemisinin alkylates and inhibits glutathione S-transferase. 

Asteraceae) important antimalarial source after post-Vietnam War rise of chloroquine-resistant malaria-causing Plasmodium falciparum... 

Chemosensitizing agents prepared by Lin (6) consisting of phenothiazine derivatives, (V), were effective against chloroquine-resistant Plasmodium falciparum. 

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