Mefloquine Artemether

In a study in patients with acute uncomplicated falciparum malaria 15 patients were given a single 300-mg dose of artemether, with a single 750-mg dose of mefloquine 24 hours later. The AUC of mefloquine in these patients was found to be 27% lower than the AUC of 7 patients receiving mefloquine alone. However, the addition of artemether improved the rate of parasite clearance, and cure rates were similar between the groups. For discussion of a study that found mefloquine pharmacokinetics did not appear to be altered when artemether/lumefantrine was given 12 hours after mefloquine treatment, see Co-artemether + Mefloquine , p.224. Note that co-artemether (artemether with lumefantrine) is one of the recommended treatment options in the WHO guidelines for the treatment of uncomplicated falciparum malaria. ... 

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]. 

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. 

For uncomplicated falciparum malaria there are several options (with the major drawback in brackets) halofantrine (arrhytmia), mefloquine (neurotoxicity), quinine (vomiting, tinnitus), artemether (recrudescence), atovaquone-proguanil (possible fast development of resistance). 

Three currently-used artemisinin based combination therapies (ACT) artesunate-mefloquine, artemether-lumefantrine and dihydroartemisinin-piperaquine, have been proven highly simple, safe and effective in the treatment of multidrug resistant P. falciparum malaria. 

Severe or complicated infections with P falciparum3 Artesunate, 2.4 mg/kg IV, every 12 hours for 1 day, then daily for two additional days follow with 7 day oral course of doxycycline or clindamycin or full treatment course of mefloquine or Malarone Artemether, 3.2 mg/kg IM, then 1.6 mg/kg/d IM follow with oral therapy as for artesunate... 

ANTIHISTAMINES-terfenadine, hydroxyzine, mizolastine 8. ANTI-M ALARIALS - artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine... 

PROPAFENONE I. ANTIARRHYTHMICS - disopyra-mide, procainamide 2. ANTIBIOTICS - macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS -arsenic trioxide 4. ANTIDEPRESSANTS - TCAs, venlafaxine 5. ANTIEMETICS-dolasetron 6. ANTIFUNGALS-fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES - terfenadine, hydroxyzine, mizolastine 8. ANTI-M ALARIALS - artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS - pentamidine isetionate 10. ANTIPSYCHOTICS-atypicals, phenothiazines, pimozide II. BETA-BLOCKERS - sotalol 12. BRONCHODILATORS -parenteral bronchodilators 13. CNS STIMULANTS - atomoxetine Risk of ventricular arrhythmias, particularly torsades de pointes Additive effect these drugs prolong the Q-T interval. Also, amitriptyline, clomipramine and desipramine levels may be t by propafenone. Amitriptyline and clomipramine may t propafenone levels. Propafenone and these TCAs inhibit CYP2D6-mediated metabolism of each other Avoid co-administration... 

ANTIMALARIALS - artemether with lume-fantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS -pentamidine isetionate 10. ANTI-PSYCHOTICS - atypicals, phenothiazines, pimozide 11. BETA-BLOCKERS - sotalol 12. BRONCHODILATORS-parenteral bronchodilators 13. CNS STIMULANTS -atomoxetine... 

Quinine, mefloquine, chloroquine, artesunate, artemether and primaquine (gametocytocides) act on sexual forms and prevent transmission of the infection because the patient becomes noninfective and the parasite fails to develop in the mosquito (site 4). 

A large trial of the first fixed-dose combination of an artemisinin derivative likely to be licensed (artemether + benflumetol) had disappointing relapse rates compared with mefloquine monotherapy (6). In the 126 patients who took artemether + benflumetol there were no adverse effects attributed to drug treatment. However, less than 70% of patients were cured at 28 days. Benflumetol may be more effective at higher concentrations (12) but toxicity studies are lacking. 

Artemisinin derivatives (artesunate and artemether) for the treatment of multidrug-resistant Plasmodium falciparum malaria have been evaluated in 83 Karen pregnant women in Thailand 55 women were treated for recrudescent infection after quinine or mefloquine, 12 for uncomplicated hyperparasitemic episodes, and 16 had not declared their pregnancy when treated (32). 

Looareesuwan S, Wilairatana P, Chokejindachai W, Chalermrut K, Wernsdorfer W, Gemperli B, Gathmann I, Royce C. A randomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand Am J Trop Med Hyg 1999 60(2) 238 3. 

Lumefantrine is a synthetic aminoalcohol fluorene derivative, related to halofantrine and mefloquine (1). It was highly effective in uncomplicated chloroquine-resistant malaria tropica in an open, non-comparative trial in 102 patients in China when given in four oral doses over 48 hours (2). No significant adverse effects have been reported. It has also been marketed in a combination of artemether (20 mg) plus lumefantrine (120 mg). 

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. 

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. 

ANTIDEPRESSANTS - TCAs, venlafaxine 5. ANTIEMETICS-dolasetron 6. ANTIFUNGALS-fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES-terfenadine, hydroxyzine, mizolas-tine 8. ANTIMALARIALS -artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPRO-TOZOALS - pentamidine isetionate... 

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