Mefloquine antimalarial

Antimalarials Mefloquine is a major drug for malaria, in particular, for chloroquine-resistant malaria." However, some cases of neuropsychiatric adverse events and the apparition of resistance tend to limit its use. Metabolism into inactive and phototoxic 1 -7/-2-oxoquinoline is blocked by the presence of the CF3 group." Instead of performing the resolution of enantiomers at the end of the synthesis," the asymmetric reduction of the carbonyl group in the presence of ruthenium catalyst and a chiral diphosphine provided mefloquine with an excellent enantiomeric excess (Figure 8.25). °... 

In parallel, extensive studies on P. falciparum field isolates in Gabon [140-142], Senegal [143], Cambodia [118, 119, 144], and the Thailand Burmese border [145] corroborated the efficacy of FQ on the parasite whatever its resistance level to chloroquine or to other commonly used antimalarials mefloquine, quinine, halofantrine, and artemisinin derivatives [146, 147]. The cross reactivity observed in some studies with CQ was limited and it was demonstrated that it was caused by differences in initial parasitemia among isolates at the start of the assays [141]. Independance of susceptibility of P. falciparum with phenotypic variation of pfcrt gene, responsible for CQ resistance, could be suspected from these results, but this was demonstrated at the molecular level on Cambodia isolates [148] and extended further on other genes currently involved in resistance to aminoquinoline antimalarials [89, 90]. 

CALCIUM CHANNEL BLOCKERS ANTIMALARIALS -MEFLOQUINE Risk of bradycardia Additive bradycardic effect mefloquine can cause cardiac conduction disorders, e.g. bradycardia. Also a theoretical risk of Q-T prolongation with co-administration of mefloquine and calcium channel blockers Monitor PR closely... 

CHLOROQUINE ANTIMALARIALS -MEFLOQUINE Risk of seizures Additive effect Warn patient of the risk patients should be advised to avoid driving while taking these drugs in combination... 

The effects of solution acidity and basicity on luminescence spectra result from the dissociation of acidic functional groups or protonation of basic functional groups associated with the aromatic portions of fluorescing and phosphorescing molecules. Protonation or dissociation can alter the natures and rates of non-radiative processes competing with luminescence and, thereby, affect the quantum yields of emission. For example, the antimalarial mefloquine fluoresces very weakly but phosphoresces well in neutral aqueous media. However, at pH < 1, its protonated form fluoresces intensely, and its phosphorescence is very weak. 

Ridtitid W, Wongnawa M, Mahatthanatrakul W, Raungsri N, Sunbhanich M. Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers. J Clin Pharm Ther (2005) 30, 285-90. 

Of industrial significance are ethyl 4,4,4-trifluoroacetoacetate [372-31-6] methyl 4,4,4-trifluoroacetoacetate, and isopropyl 4,4,4-trifluoroacetoacetate for the production of herbicides (eg, Monsanto s Dimension) and antimalarial agents such as Roche s Mefloquin [51773-92-3] as weU as ethyl 4,4,4-trichloroacetoacetate [3702-98-5] for the production of pharmaceuticals. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Quinacrine (49) is an acridine that was used extensively from the mid-1920s to the end of World War 11. It acts much like chloroquine and is reasonably effective. Because it causes the skin to turn yellow and, in high doses, causes yellow vision, the dmg is no longer in use as an antimalarial. Pyronaridine (77), a 1-azaacridine developed in China, appears to be effective against mefloquine-resistant, but not entirely against chloroquine-resistant, strains of P falciparum. 

The E-state indices may define chemical spaces that are relevant in similarity/ diversity search in chemical databases. This similarity search is based on atom-type E-state indices computed for the query molecule [55]. Each E-state index is converted to a z score, Z =(% -p )/0 , where is the ith E-state atomic index, p is its mean and O is its standard deviation in the entire database. The similarity was computed with the EucHdean distance and with the cosine index and the database used was the Pomona MedChem database, which contains 21000 chemicals. Tests performed for the antiinflamatory drug prednisone and the antimalarial dmg mefloquine as query molecules demonstrated that the chemicals space defined by E-state indices is efficient in identifying similar compounds from drug and drug-tike databases. 

The Plasmodium falciparum malaria PD model successfully described the antimalarial effect of artemisinin, mefloquine, and a combination of the two drugs... 

Antimalarial drugs are designed to prevent or treat malaria. Antimalarial drugs currently used for treatment for prophylaxis are mefloquine, primaquine, chloroquine, pyrimethamine, amodiaquin, quinine/quinidine, chloroguanide. 

VI.a.2.1. AminoquinoUnes. The aminoquinolines currently used as antimalarials include the 4-amino-quinolines chloroquine and mefloquine and the 8-aminoquinoline primaquine. 

VLa.2,6. Other antimalarials. Doxycydine (see Section ILb) is a useful and effective short-term prophylactic agent for travellers to chloroquine-resistant areas and can be used as an alternative when mefloquine or proguanil is unavailable or mefloquine is contraindicated. In combination with quinine also tetracycline is used as an antimalarial. 

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

There is very limited evidence available on the effectiveness of the drugs in pregnant women. A possible increase in risk of stillbirth with the use of mefloquine in pregnancy has been reported. Standard adult dose of antimalarial drugs recommended for 2nd and 3rd trimester pregnancy did not cause harm or congenital abnormalities. Evidence on the safety of all recommended antimalarial drugs in the 1st trimester is still unclear. 

Mefloquine is effective in treating most falciparum malaria. The drug is not appropriate for treating individuals with severe or complicated malaria, since quinine, quinidine, and artemisinins are more rapidly active, and since drug resistance is less likely with those agents. The combination of artesunate plus mefloquine showed excellent antimalarial efficacy in regions of Southeast Asia with some resistance to mefloquine, and this regimen is now one of the combination therapies recommended by the WHO for the treatment of uncomplicated falciparum malaria (Table 52-4). Artesunate-mefloquine is the first-line therapy for uncomplicated malaria in a number of countries in Asia and South America. 

Weekly dosing with mefloquine for chemoprophylaxis may cause nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness. Neuropsychiatric toxicities have received a good deal of publicity, but despite frequent anecdotal reports of seizures and psychosis, a number of controlled studies have found the frequency of serious adverse effects from mefloquine to be no higher than that with other common antimalarial chemoprophylactic regimens. Leukocytosis, thrombocytopenia, and aminotransferase elevations have been reported. 

Clinical Use. Mefloquine (Lariam) has emerged as one of the most important antimalarial agents.61 This drug is especially important in the prevention and treatment of malaria that is resistant to traditional antimalarial drugs such as chloroquine and quinine.50 Mefloquine is often the drug of choice for antimalarial prophylaxis, especially in areas of the world where chloroquine-resistant strains of malaria are common.23 Mefloquine can be used alone, but combining this... 

Mechanism of Action. Although the drug s exact mechanism of action is unknown, mefloquine may exert antimalarial effects similar to chloroquine that is, these drugs inhibit hemoglobin digestion in malarial parasites, thus causing heme by-products to accumulate within the protozoa and cause toxicity and death of this parasite.65... 

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