Resistance malaria parasite

HaUett RL, Sutherland CJ, Alexander N, Ord R, Jawara M, Drakeley CJ, Pinder M, Walraven G, Target GA, Alloueche A. Combination therapy counteracts the enhanced transmission of drug-resistant malaria parasites to mosquitoes. Antimicrob Agents Chemother 2004 48(10) 3940-3. 

Artemisinin (Fig. 1), isolated in 1972 from Chinese medicinal plant Artemisia annua L, is a novel antimalarial drug with a sesquiterpene lactone structure containing an internal endoperoxide linkage which is essential for the drug s activity. Artemisinin and its derivatitives form a series of antimalarial compounds with activity against chloroquine-resistant malaria parasites. In contrast to chloroquine, artemisinin penetrates the blood brain barrier, which makes it especially valuable for the treatment of cerebral malaria. ... 

Rhaphidophora decursiva Schott (Araceae). It is active against the chloroquine-resistant malaria parasite Plasmodium falciparum. For this reason, such compounds are currently of high mteest in pharmacy. The structural analogue serotobenine has been synthesized using the same strategy. For further synthesis studies, see Ref. [50]. 

White NJ, Pongtavompinyo W. (2003) The de-novo selection of drug resistance in malaria parasites. Philos Trans R Soc LondBBiol Sci 270 545-554. 

Malaria parasite has developed resistance to many of these so-called quinoline antimalarials rendering them completely obsolete. This situation has forced the use of combination regimens that consists of a mixture of two or more antimalarial active ingredients this approach has proven to work better than monotherapies, but often is only a temporary soulu-tion. Nevertheless, quinine remains a very effective drug, with only few treatment failures or resistance reported around the globe. 

In light of the growing problem of multidrug resistance in malaria parasites in the 1970s, several well known anthraquinone antibiotics... 

Afonso A, Hunt P, Cheesman S, Alves AC, Cunha CV, do Rosario V, Cravo P. (2006) Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (encoding the sarcoplasmic and endoplasmic reticulum Ca " ATPase), tctp, mdrl, and cglO. Antimicrob Agents Chemother 50 480 89. 

Artemisinin ( qinghaosu ) (18), a sesquiterpene lactone antimalarial compound with an endoperoxide group, discovered in the Peoples Republic of China as a constituent of Artemisia annua L., has created great interest in the biomedical community, owing to its unique mechanism of action on the heme complex. Artemisinin serves as an option for the treatment of chloroquine (4l)-resistant malaria and is used in some Asian countries as an antimalarial. However, the use of artemisinin as a single agent anti-malarial is a potential risk since the malaria parasite may become resistant to this compound class. 

It now appears certain that destruction of malaria parasites in vivo depends in part, if not wholly, upon the presence of humoral antibodies, and this must explain the success achieved with the passive transfer experiments. The exact role of the T and B lymphocytes in immunity in malaria infection in man still needs clarification. In rats the ability to resist P. berghei infection seems to be thymus dependent, and higher parasitemias were encountered in the thymectomized rats, which also developed severe anemia (B6). 

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). 

Many Inherited blood diseases show this geographic distribution, possibly because the altered RBC physiology confers resistance to the malaria parasite, which infects normal, HbA-bearing RBCs. 

Mefloquine is also a 4-aminoquinoline. It is a blood schizonticide active against the asexual stages of all malaria parasites. Mefloquine is currently the prophylactic agent of choice for short-term travellers. Resistance of P. falciparum against mefloquine has occurred in South-East Asia. Only an oral... 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

Two major diseases, malaria and AIDS, are still out of control vaccines are not available, while the malaria parasite and the HIV virus, responsible for AIDS, have developed resistance to current dmgs. Variability of the agent, lack of commercial interest, and perhaps also unconfessed political plans at population growth control, have been an obstacle to active immunization against malaria. The hope for an HIV vaccine is now from the engagement of Merck Co (Conference 2001). 

There are some who have argued that without the use of Cinchona extracts, and later synthetic quinine analogues, world history over the past two centuries would have taken a very different course. It is argued that the use of quinine to treat malaria (and to a lesser extent yellow fever) facilitated colonialisation by western European countries of territories that would have been too hostile for foreigners with little natural resistance to parasitic-induced fevers. For example, the Panama Canal might not have been built without access to quinine. The outcome of the American Civil War has even been speculated upon because the successful blockade of the Confederate ports caused severe shortages of quinine so the Confederate Armies were debilitated by fevers. 

Chloroquine has been the drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s, but its usefulness against P falciparum has been seriously compromised by drug resistance. It remains the drug of choice in the treatment of sensitive P falciparum and other species of human malaria parasites. 

Increasing in vitro resistance of parasites from a number of areas suggests that quinine resistance will be an increasing problem. Resistance to quinine is already common in some areas of Southeast Asia, especially border areas of Thailand, where the drug may fail if used alone to treat falciparum malaria. However, quinine still provides at least a partial therapeutic effect in most patients. 

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. 

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