Sulfadoxine Mefloquine

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]. 

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

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. 

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%). 

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. 

Quinine, chloroquine, amodiaquine, amopyroquine, hydroxychloroquine, primaquine, mefloquine, proguanil, chlorproguanil, cycloguanil, sulfadiazine, sulfalene, sulfadoxine, dap... 

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... 

Pyrimethamine-sulfadoxine or, plus Tetracycline or, plus Clindamycin Mefloquine Halofantrine... 

Note Fansimef is a combination of mefloquine with Fan-sidar (pyrimethamine and sulfadoxine, q.q.v.). 

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

Chloroquine-resistant P falciparum is endemic in many regions of Africa, including Kenya, and the prophylactic use of chloroquine as a sole agent will not prevent infection. While pyrimethamine-sulfadoxine has been used prophylactically. it is not the drug of choice. Weekly doses of mefloquine one week before entering an endemic area, during the sojourn, and for 4 weeks after leaving, is the preferred method. 

Pyrimethamine/sulfadoxine and tetracycline have been shown to increase halofantrine levels, and may therefore increase its toxicity. Diltiazem, erythromycin, ketoconazole, mefloquine, quinine, and quinidine might also increase the toxicity of halofantrine because they have been shown to inhibit its metabolism in vitro. The manufacturer has therefore recommended caution with the concurrent use of potent CYP3A4 inhibitors. Fatty food markedly increases halofantrine levels, consequently it is recommended that halofantrine is taken on an empty stomach. Grapefruit juice has a similar effect Note that halofantrine is no longer widely marketed. 

Karbwang J, Back DJ, Bunnag D, Breckenridge AM. Pharmacokinetics of mefloquine inccm-bination with sulfadoxine-pyrimediamine and primaquine in male Thai patients wifli Mci-parum malaria. Bull WHO ( 990) 68, 633-8. 

Sulfadoxine/pyrimethamine caused a modest increase in exposure to mefloquine in healthy subjects, but not in a study in patients. Any changes seem unlikely to be clinically relevant... 

These studies suggest that, at the most, a small increase in exposure to mefloquine may occur when it is given with sulfadoxine/pyrimethamine. It would seem that this is unlikely to be clinically relevant, especially in view of the inter-individual variability in mefloquine pharmacokinetics. No special precautions appear to be needed. 

Hydroxychloroquine may reduce insulin requirements by about 25%, and a case of hypoglycaemia has been reported. Similarly, hypoglycaemia has occurred in a patient taking chloroquine and insulin. Reduced glucose levels or hypoglycaemia have been reported with mefloquine, quinidine, quinine, and sulfadoxine-py-rimethamine. Note that falciparum malaria per se can result in severe hypoglycaemia, and quinine in particular may contribute to this. 

The half-life of mefloquine in the human body averages 15 days. Unlike quinine, it has a very high therapeutic index. Intensive clinical studies have shown it to be safe and effective in curing both falciparum and vivax types of malaria, regardless of whether these are resistant to chloroquine. Fears that resistance to mefloquine would be initiated by indiscriminate use of this drug are limiting its curative use to areas where chloroquine-resistant strains of Plasmodium flourish. Yor prophylactic use in such areas, it is combined with the pyrimethamine-sulfadoxine pair to decrease likelihood of resistance developing, in accord with principles discussed in Section 6.5. For clinical details, see Schmidt et al. (1978) for the overall picture on mefloquine, see WHO (1983). 

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