Chloroquine-resistant malari

Mostly for chloroquine-resistant malarial infections. Extensively transformed before excretion. 

Then we evaluated the viability of this approach in controlling chloroquine-resistant P. berghei infections in mice (23). The results of these studies revealed that liposomized chloroquine was very effective in suppressing the disease both in terms of reduction in parasitemia and prolongation in the survival times of the liposome-treated mice, as compared to the appropriate control mice (23). It was also reported that liposomization of chloroquine increased its maximal tolerable dose as well as efficiency against chloroquine-resistant malarial infection (24). 

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. 

Areas without known chloroquine-resistant P falciparum are Central America west of the Panama Canal, Haiti, Dominican Republic, Egypt, and most malarious countries of the Middle East. Malarone or mefloquine are currently recommended for other malarious areas except for border areas of Thailand, where doxycycline is recommended. 

Mefloquine is effective in prophylaxis against most strains of P falciparum and probably all other human malarial species. Mefloquine is therefore among the drugs recommended by the CDC for chemoprophylaxis in all malarious areas except for those with no chloroquine resistance (where chloroquine is preferred) and some rural areas of Southeast Asia with a high prevalence of mefloquine resistance. As with chloroquine, eradication of P vivax and P ovale requires a course of primaquine. 

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. 

Mefloquine (t) 21 d) is similar in several respects to quinine although it does not intercalate with plasmodial DNA. It is used for malaria chemoprophylaxis, to treat uncomplicated Plasmodium falciparum (both chloroquine-sensitive and chloroquine resistant) and chloroquine-resistant Plasmodium vivax malaria. Mefloquine is rapidly absorbed from the gastrointestinal tract and its action is terminated by metabolism. When used for prophylaxis, 250 mg (base)/week should be taken, commencing 1-3 weeks before entering and continued for 4 weeks after leaving a malarious area. It should not be given to patients with hepatic or renal impairment. 

Cimanga et al (17) assessed the anti-plasmodial (anti-malarial) activity of three different extracts and four alkaloids from the root back of C. sanguinolenta in vitro against P. falciparum D-6 (chloroquine-sensitive strain), K-1, and W-2 (chloroquine-resistant strains). 

The membrane of the food vacuole has other transporter proteins associated with it. One such protein, encoded by the pfmdrl gene, shows structural similarity to the human PGP that was discussed earlier in this chapter. This malaria protein has a molecular weight of 162 kD, and is an ABC transporter with 12 transmembrane domains and two ATP binding folds. The mammalian PGP pumps drug out of the cell but the malarial MDRl actually pumps drugs into the food vacuole. Although this protein can add to the resistance associated with K76T mutation of the CRT protein, by itself it does not provide a chloroquine resistant... 

Sulfadoxine (1500 mg) and pyrimethamine (75 mg) orally as a single dosage is indicated for the treatment of P. falciparum malaria in patients in whom chloroquine resistance is suspected. However, chloroquine remains the drug of choice for travelers to malarious areas, hi addition, sulfadoxine-pyrimethamine has been used as a prophylactic agent for the prevention of Pneumocystis carinii pneumonia in patients with AIDS, usually as a second-tine agent. 

Clinical use Recommended by the CDC for prophylaxis in all malarious areas except those with no chloroquine resistance. 

The 4-substituted quinolines are referred to as rapidly acting blood schizonticides, with activity against plasmodium in the erythrocytic stage. Chloroquine is the drug of choice, but unfortunately, the incidence of chloroquine-resistance infections are extremely common today. The spread of chloroquine resistance has reached almost all malarious areas of the world. In addition, multidrug-... 

Ward SA. Mechanisms of chloroquine resistance in malarial chemotherapy. Trends Pharmacol Sci 1988 9 241-246. 

It was found inactive against breast and pancreatic cancer ous cells and normal human embryonic cells (HEK) at the tested concentration (40 pM). While it was active against chloroquine resistant strain of the malarial parasite Plasmodium falciparum at 20 pM (50% inhibition ) and against chloroquine-sensitive strain at 20 pM (70% inhibition) [68]. Biosynthesis of kororamide A (141) is not reported in literature. 

---