Pyrimethamine Mefloquine

Chloroquine-resistant Quinine Artemisinin derivatives Atovaquone-proguanil Mefloquine Pyrimethamine-sulfadoxine Antibacterials (e.g., clindamycin, doxycycline, sulfamethoxazole, or tetracycline] ... 

The chemotherapeutic response of Plasmodium berghei to various combinations of mefloquine with other drugs (sulfadoxine + pyrimethamine, primaquine, floxacrine) have shown that the desired effects are purely additive (SEDA-13, 809), so the adverse effects too are probably only those of the individual compounds. Adverse reactions occurred in 46% of 400 patients treated with Fanimef (mefloquine + pyrimethamine + sulfadoxine) (SEDA-12, 693). Of note were dizziness (29%), nausea (9.5%), vomiting (7.3%), weakness/lassitude (5.8%), abdominal discomfort or pain (5.5%), diarrhea (3.8%), pruritus (3.0%), insomnia (2.0%), and headache (2.0%). 

Extracted metabolites, chloroquine, monodesethylchloroquine, nordiazepam Simultaneous epinephrine, mefloquine, pyrimethamine, quinine, sulfadoxine... 

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. 

ACTs are currently recommended artemether-lume-fantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine [1, 5]. In areas with amodiaquine and sulfadoxine-pyrimethamine resistance exceeding 20%, i.e., SE Asia, artesunate + mefloquine or artemether-lumefantrine should be used [1,5]. 

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. 

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. 

Chloroquine, quinine, mefloquine, halofantrine, proguanil, pyrimethamine, and tetracyclines blood schizontocides) kill these asexual forms. Drugs which act on this stage in the cycle of the parasite may be used for ... 

Mefloquine, chloroquine, proguanil, and pyrimethamine plus dapsone (Maloprim), alone or in combination are most commonly advised for prophylaxis regimens and doxycycline for special cases (drug resistance or intolerance) primaquine is being re-evaluated. 

Single-dose pyrimethamine + sulfadoxine (25 mg/kg n = 54) has been compared with mefloquine (15 mg/kg n = 48) in the treatment of uncomplicated P. falciparum malaria in an unblinded, randomized study in 102 Malawi children (10). Immediate vomiting was more common in those who took mefloquine (eight cases) than in those who took pyrimethamine + sulfadoxine (one case), with comparable parasite failure rates at 14 days (20 and 22% respectively). 

Instances of mefloquine resistance were reported in Tanzania in 1983, in Thailand in 1989, and in Africa (Malawi) in 1991. Resistance to combinations of mefloquine with sulfadoxine and pyrimethamine was reported in 1985 (SEDA-13, 808) (40 4). The possibility of crossresistance between mefloquine and halofantrine was raised in 1990 (SEDA-13, 808) (45). Currently there are extensive areas, including Thailand, Cambodia, Laos, Papua New Guinea, and Myanmar, where P. falciparum... 

A review of the use of mefloquine in pregnancy (47) did not suggest that mefloquine has a worse effect in pregnancy than other antimalarial drugs, such as chloroquine and pyrimethamine + sulfadoxine. 

MacArthur J, Stennies GM, Macheso A, Kolczak MS, Green MD, Ali D, Barat LM, Kazembe PN, Ruebush TK 2nd. Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998. Am J Trop Med Hyg 2001 65(6) 679-84. 

Hoffman SL, Rustama D, Dimpudus AJ, Punjabi NH, Campbell JR, Oetomo HS, Marwoto HA, Harun S, Sukri N, Heizmann P, Laughlin LW. Rll and Rill type resistance of Plasmodium falciparum to combination of mefloquine and sulfadoxine/pyrimethamine in Indonesia. Lancet 1985 2 1039 0. 

Pyrimethamine (25 mg), sulfadoxine (500 mg), and mefloquine (250 mg) are available in the combination formulation known as Fansimef. The adverse effects characteristic of aU three components can be expected. 

WR-243251 is a floxacrine analogue, a dihydroacridine-dione. It is active in vitro against chloroquine-resistant, mefloquine-resistant, and pyrimethamine-resistant strains of malaria (1). By analogy to quinacrine and floxacrine, there is concern about possible dermatological, cardiac, and neuropsychiatric toxicity and vascular adverse effects. 

Drugs used to treat an acute attack. Blood schizonticides are used to suppress an acute attack, and the various drugs used include oral chloroquine, mefloquine or quinine plus pyrimethamine or doxycycline or halofantrine. 

Drugs used in prophylaxis. These block a stage in the life cycle, e.g. chloroquine, dapsone, doxycycline, mefloquine, proguanil and pyrimethamine, and often in combinations. 

Mefloquine is a long-acting blood schizontocide with high efficacy against malarial parasites resistant to quinine, chloroquine and sulphonamide-pyrimethamine combinations [124-129], A single oral dose of the drug of 15 mg/kg (with a maximum of 750-1000 mg/adult) produces cure rates above 90%, Detailed clinical trials carried out in Zimbabwe, Thailand, Burma, Brazil and Europe have established mefloquine as an effective drug both for prophylaxis and treatment of vi-vax and falciparum malaria [125-130],... 

In P. falciparum (chloroquine-resistant) infections, a dose of 750 mg mefloquine followed by 500 mg 12 hours later is recommended. The pediatric dose of mefloquine is 15 mg/kg (<45 kg) followed by 10 mg/kg 8 to 12 hours later.Intravenous quinidine gluconate followed by oral quinine should be administered for severe illness, as already indicated.A second drug needs to be administered in chloroquine-resistant P. falciparum, and this second drug should follow the oral quinidine regimen either a single dose of three tablets of pyrimethamine-sulfadoxine (Fansidar) on the last day of intravenous quinidine or clindamycin 900 mg three times daily for 3 to 5 days. An alternative oral treatment for chloroquine-resistant P falciparum infection in adults, especially in those with a history of seizures or psychiatric disorders, is the combination of atovaquone 250 mg and proguanil 100 mg (Malarone) (4 tablets daily... 

Synthetic antimalarials developed fiom herbals include chloroquine, primaquine, proguanil, pyrimethamine and mefloquine. Botanicals represent a diverse arsenal of molecules that could constitute lead compounds for new antimalarial dmgs, such as artemisinin, isolated from Artemisia annuaSeveral studies have been undertaken to evaluate the inhibitory effects of various plants extracts on P. falciparum in culture. The in vivo antiplasmodial effects of several plant extracts have been studied on Plasmodium berghei and P. yoelii The majority of the plants that we screened for antimalarial activities had similar ethnopharmacological use among different Kenyan ethnic groups. ... 

In the last few years, variations on the basic stracmre have been launched in combination with other antimalarials (usually variations on the chloroquine structure) such as dihydroartemismin and piperaquine phosphate (Artekin), artemether and lumefantrine (Coartem), artesunate/mefloquine (Artequin) and artesunate, sulfamethoxypyrazine, and pyrimethamine (Co-Arinate). Currently, there is another fixed dose combination with an artemisinin derivative in clinical trials, pyronaridine/artesunate (Pyramax in Phase III). However, the tri-oxo scaffold system in artemisinins has led to the synthesis of not only artemisinin variations but to totally synthetic molecules with the trioxane moiety included, such as arterolane tosylate (81). This compound is in Phase II trials as a single agent under Ranbaxy and is in Phase I trials in combination with piperaquine phosphate, also under Ranbaxy. 

---