Chloroquine-resistant parasites

Amodiaquine (Camoquin) is another 4-aminoquinoline derivative whose antimalarial spectrum and adverse reactions are similar to those of chloroquine, although chloroquine-resistant parasites may not be amodi-aquine-resistant to the same degree. Prolonged treatment with amodiaquine may result in pigmentation of the palate, nail beds, and skin. There is a 1 2000 risk of agranulocytosis and hepatocellular dysfunction when the drug is used prophylactically. 

ANTIPARASITIC ACTIVITY Extensive structure-activity studies have confirmed the requirement for an endoperoxide moiety for antimalarial activity. These drugs act rapidly against the asexual erythrocytic stages of P. vivax and P. falciparum. Their potency in vivo is 10- to 100-fold greater than that of other antimalarials. They are not cross-resistant with other drugs indeed, sensitivity to the artemisinins may be increased in chloroquine-resistant parasites. When used alone, the artemisinins are associated with a high level of parasite recrudescence, which may be related to their rapid metabolism. They have gametocytocidal activity but do not affect either primary or... 

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. 

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. 

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 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. 

Quinine sulfate is appropriate first-line therapy for uncomplicated falciparum malaria except when the infection was transmitted in an area without documented chloroquine-resistant malaria. Quinine is commonly used with a second drug (most often doxycycline or, in children, clindamycin) to shorten quinine s duration of use (usually to 3 days) and limit toxicity. Quinine is less effective than chloroquine against other human malarias and is more toxic. Therefore, it is not used to treat infections with these parasites. 

In order to determine the significance of the 1,5-H shift and the secondary radical species for antimalarial activity, the trioxanes 22a—c were synthesized and tested18. The diastereomeric trioxanes 22a and 22b possessed very different antimalarial activity against both chloroquine-resistant and chloroquine-sensitive strains of the parasite the 4-/3 isomer was approximately twice as active as artemisinin while the 4-a isomer and the disubsti-tuted trioxane were more than sixty times less potent. The authors proposed that the (y-substitucnt prevented the suprafacial 1,5-H shift and therefore suppressed the activity of these compounds. 

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. 

The activity of selected experimental agents against parasite clones of chloroquine-susceptible malaria strains, Sierra Leone, D6, and chloroquine-resistant malaria strain, Indochina, W2, was determined using the method of Desjardins (1). Testing results are provided in Table 2. 

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