Resistance to chloroquine

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. 

Acute P. falciparum malaria resistant to chloroquine should be treated with intravenous quinidine via central venous catheter and fluid status and the electrocardiogram (ECG) should be monitored closely. 

There remains an urgent need for new effective antiparasitic agents, an area of drug development that has languished because of poor economic return. The spread of resistance to chloroquine (an antimalaria treatment) is one reason for attention to be paid to this area, as well as the sheer numbers of people affected. Antimony compounds (43) and (44) (Figure 20) are used to treat... 

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 By 1959 it was superseded by other drugs, especially chloroquine.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. 

Once the primary therapeutic objective has been achieved, attention can be focused on such additional considerations as elimination of the gametocytes and the tissue forms of the parasite. Success in these areas would help to ensure that relapses do not occur. Since no latent liver forms are associated with mosquito-induced, drug-sensitive P. falciparum malaria, administration of chloroquine for up to 3 months after the patient leaves a malarious area will usually bring about a complete or radical cure unless the organism is resistant to chloroquine. 

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. 

Malawne is indicated for uncomplicated infections resistant to chloroquine. For severe infections, parenteral administration of quinidine is indicated with hourly monitoring of serum glucose levels. 

Resistance to chloroquine is now very common among strains of P falciparum and uncommon but increasing for P vivax. In P falciparum, mutations in a putative transporter, PfCRT, have been correlated with resistance. Chloroquine resistance can be reversed by certain agents, including verapamil, desipramine, and chlorpheniramine, but the clinical value of resistance-reversing drugs is not established. 

Sporadic resistance to mefloquine has been reported from many areas. At present, resistance appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand). Mefloquine resistance appears to be associated with resistance to quinine and halofantrine but not with resistance to chloroquine. 

The mechanism by which PfCRT confers resistance to chloroquine is still under discussion [75], The first aspect concerns the nature of the protein whether PfCRT, postulated to possess ten transmembrane helices, is considered as a member of the drug-metabolite transporter family of proteins [55, 76-78], Some authors discuss about the channel nature of the protein [79, 80], It has been suggested that the change of the charged lysine to uncharged threonine affects the electrostatic interaction with the diprotonated CQ [81]. In the mutated forms, the absence of electrostatic interactions allows the drug to cross the channel (Fig. 6). This results in the efflux of the drug out of the DV [81]. Note here that the reduced accumulation can be partially reversed by verapamil, a lipophilic compound (Fig. 5). 

In addition, the Plasmodium parasite became resistant to chloroquine, the mainstay of drug therapy (National Institute of Allergy and Infectious Diseases, 2002). 

Over decades of sublethal exposure the resistance of all types of malaria has increased to a point where chloroquine no longer offers certain protection (217). With the partial exception of quinine and dihydroquinine (218), resistance to antimalarials had reached the stage at the time of the Vietnam war where more research was required. The development of mefloquine (164) was a continuation of the World War II effort, with a gap of about 20 years. Resistance to chloroquine had developed widely during that period, but surprisingly less so to quinine, given the obvious similarities in structure. This observation stimulated a reappraisal of quinolines, known as quinoline methanols, which bear a hydroxy group on the a-carbon of a substituent at-... 

Amodiaquine is a Mannich base derivative related to chloroquine. While it is generally considered equivalent to chloroquine, more recent studies have shown that amodiaquine is superior to chloroquine in tackling resistant strains of Plasmodium falciparum, although there may be cross-resistance to chloroquine (SEDA-20, 260). 

Amopyroquine is a 4-aminoquinoline, structurally related to amodiaquine. It is not a new compound, but it is of renewed interest as a result of the extensive occurrence of resistance to chloroquine and the adverse effects of prophylactic amodiaquine. In a study in 152 patients with malaria, the efficacy of a 12 mg/kg, given as two intramuscular injections of 6 mg/kg 24 hours apart, was described as good (1). AU the patients became apyrexial and there was clearance of parasites on day 7 in 143 cases the nine who retained a low level of parasitemia were all children. In 50% of the cases, the parasite had been chloroquine-resistant. The drug was well tolerated, and there were no major adverse effects. 

Verapamil completely reversed pre-existing in vitro resistance to chloroquine to below the cut-off point of 70 nmoVl (48). 

The increasing prevalence of strains of P. falciparum that are resistant to chloroquine (CQ), a blood schizontocide which had been efficacious, safe, accessible and affordable, poses a serious problem for malaria control, predisposing Afiica to an unprecedented situation since the only affordable treatment options are rapidly losing therapeutic efficacy. Drug-resistant strains of P. falciparum are endemic in many areas of the world and the majority of conventional antimalarial drugs have been associated with treatment failure. These developments and the difficulty of creating efficient vaccines, coupled with adverse reactions to chemotherapy, underline the urgent need for novel, cheap, safe and... 

Repeat the above treatment several times until it becomes resistant to chloroquine (50 mg/kg x 4 d intraperitoneally) (see Notes 21-24). 

P. falciparum is resistant to chloroquine in most parts of the world. This appears to be due to decreased uptake and/or increased removal of the dmg from the parasite. Quinine is now the main dmg used against P. falciparum malaria. Chloroquine is still effective against other forms of malaria. 

Halofantrine is another antimalarial dmg that is being used more now that resistance to chloroquine and quinine has developed. Its mode of action is not known. 

Resistance to Chloroquine Another Membrane-bound Transporter Protein... 

Ethers, esters and carbonates of dihydroartemisinin have been prepared to obtain novel and more active derivatives [45]. After examination of the ethers, including the epimers at position 10, artemether (31 2, R = CH3) and arteether (31 3, R = CH2CH3), they were found to be about twice as active as artemisinin, but less active than dihydroartemisinin. Artemether has been isolated as a natural constituent of A. annua. Arteether was found to be 34 times more active than chloroquine against the W-2 (Indochina) clone of P. falciparum (normally resistant to chloroquine) and three times less active against the D-6 (Sierra Leone) clone (normally resistant to mefloquine). Artemether was two times more active and eight times more active than mefloquine against the W-2 and D-6 clones, respectively. Both artemether and arteether are more oil soluble than artemisinin and are currently in clinical trials. 

MECHANISMS OF ANTIMALARIAL ACTION AND RESISTANCE TO CHLOROQUINE AND OTHER ANTIMALARIAL QUINOLINES... 

Clinical use The main use of quinine is in P falciparum infections resistant to chloroquine. Quinine is sometimes used with doxycycline to shorten the duration of therapy and limit toxicity. Quinidine, the dextrorotatory stereoisomer of quinine, is used intravenously in the USA for treatment of severe falciparum malaria. To delay emergence of resistance, the drugs should not be used routinely for prophylaxis. 

Resistance to proguanil, pyrimethamine, sulphonamides, and sulphones, is readily produced in the laboratory and the field, and has seriously compromised the use of these drugs, particularly proguanil which has been withdrawn from the U.S. Pharmacopoeia [16, 324, 330]. Resistance to chloroquine, quinacrine, and quinine, is more difficult to produce both in the laboratory and the field, but it is rapidly becoming a serious problem in the therapy and prophylaxis of falciparum malaria [16, 324, 325]. It is evident that all four... 

Deficiencies of chloroquine binding by infected erythrocytes have been implicated in the development of resistance to chloroquine, but it is likely that they are not related to binding to haemoglobin degradation products. 

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