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Mefloquine for preventing malaria in non-immune adult travellers.

OBJECTIVES: Mefloquine has now largely replaced earlier malaria prophylaxis drugs which are no longer considered to be effective against all Plasmodium species, due to parasite resistance. However mefloquine may be associated with neuropsychological harmful effects. The objective of this review was to assess the effects of mefloquine in adult travellers. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, Medline, Embase, Lilacs, Science Citation Index and reference lists of articles. We contacted researchers in the subject of malaria chemoprophylaxis, and drug companies. SELECTION CRITERIA: Randomised trials comparing mefloquine with other standard prophylaxis or placebo in non-immune adult travellers. DATA COLLECTION AND ANALYSIS: The two reviewers independently assessed trial quality and extracted data. Study authors were also contacted. MAIN RESULTS: Ten trials involving 2750 non-immune adult travellers were included. One trial comparing mefloquine with placebo showed mefloquine prevented malaria episodes in an area of drug resistance (odds ratio 0.04, 95% confidence interval 0.02 to 0.08). Withdrawals in the mefloquine group were consistently higher in four placebo controlled trials (odds ratio 3. 56, 95% confidence interval 1.67 to 7.60). In five trials comparing mefloquine with other chemoprophylaxis, no difference in tolerability was detected. REVIEWER'S CONCLUSIONS: Mefloquine prevents malaria, but there is not enough evidence to evaluate its tolerability and toxicity, particularly for general travellers.

Adult↗

Mefloquine resistance reversal action of ketoconazole - a cytochrome P450 inhibitor, against mefloquine-resistant malaria.

Plasmodium knowlesi (W1) shows a high level of innate resistance to mefloquine as shown by recrudescence of blood-induced infection in rhesus monkeys, following oral mefloquine treatment with up to 80-160 mg/kg total dose over 3-4 days. Ketoconazole, at a dose of 75 mg/kg/day x 10 days given orally to P. knowlesi-infected rhesus monkeys, exerted a suppressive antimalarial effect in 1 of the 2 monkeys as evidenced by a delayed recrudescence (on day 30) and curative action in case of the other monkey, whereas a lower dose of ketoconazole (25 mg/kg/day x 10 days) failed to suppress infection effectively. When ketoconazole at a low dose (25 mg/kg/day x 10 days) treatment was combined with mefloquine (20 mg/kg/ day x 4), 1 of the 2 infected monkeys was cured, while the combination of a higher dose of ketoconazole (75 mg/kg/day x 10 days) with mefloquine (20 mg/kg/day x 4), had a complete curative effect on P. knowlesi infection in all the treated monkeys (7/7). Besides exerting direct antimalarial action against a mefloquine-resistant P. knowlesi, ketoconazole also acts as an inhibitor of hepatic microsomal CYP4503A, which regulates and slows down mefloquine biotransformation to carboxymefloquine, resulting in a possible elevation of the effective plasma drug level, which seems to be responsible for elimination of the resistant P. knowlesi. The study shows a resistance reversal effect of a ketoconazole - mefloquine combination that could be exploited for the control of mefloquine-resistant malaria infection. The study shows that ketoconazole can reverse mefloquine resistance of P. knowlesi. These findings can also be applied to reverse mefloquine resistance of P.falciparum in areas where mefloquine resistance is already established. The precise role of parasite CYP450 in mefloquine resistance and its possible role, if any, in expelling the intracellular mefloquine from the resistant plasmodia still remains to be elucidated.

Animals↗

Artesunate plus mefloquine versus mefloquine for treating uncomplicated malaria.

BACKGROUND: Multiple-drug-resistant malaria is widespread, and in South-East Asia resistance is high against nearly all single therapy antimalarial drugs. Here, and in other areas with low malaria transmission, the combination of artesunate and mefloquine may provide an effective alternative. OBJECTIVES: To compare artesunate plus mefloquine with mefloquine alone for treating uncomplicated Plasmodium falciparum malaria. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (May 2005), CENTRAL (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to May 2005), EMBASE (1988 to May 2005), LILACS (May 2005), BIOSIS (1985 to June 2005), conference proceedings, and reference lists. We also contacted researchers, organizations, and pharmaceutical companies. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing artesunate plus mefloquine with mefloquine alone for treating uncomplicated malaria. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria, extracted data, and assessed methodological quality. The primary outcome was treatment failure by day 28, defined as evidence of parasitaemia with or without clinical failure between days zero (start of treatment) and 28. For dichotomous data we calculated relative risks (RR) and 95% confidence intervals (CI). MAIN RESULTS: Eight trials involving 1996 participants met the inclusion criteria. All were conducted in areas with low malaria transmission, seven in South-East Asia and one in the Peruvian Amazon. The doses and dosing regimens of artesunate and mefloquine varied across trials. The trials using a total dose of 25 mg/kg mefloquine and 10 mg artesunate reported fewer treatment failures with the combination at all time points: day 28 (RR 0.17, 95% CI 0.06 to 0.47; 824 participants, 4 trials), day 42 (RR 0.23, 95% CI 0.14 to 0.39; 298 participants, 1 trial), and day 63 (RR 0.26, 95% CI 0.09 to 0.77; 501 participants, 2 trials). The results for parasitaemia showed a similar trend. Trials using a lower dose of artesunate tended to favour the artesunate plus mefloquine combination. Overall, adverse events were similar across treatment arms. AUTHORS' CONCLUSIONS: Artesunate plus mefloquine performs better than mefloquine alone for treating uncomplicated falciparum malaria in areas with low malaria transmission. A total dose of 25 mg/kg mefloquine and at least 10 mg artesunate leads to higher cure rates. Better reporting of methods and standardisation of outcomes would help the interpretation of future trials.

Antimalarials↗

Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study.

BACKGROUND: Worsening drug resistance in Plasmodium falciparum malaria is a major threat to health in tropical countries. We did a prospective study of malaria incidence and treatment in an area of highly multidrug-resistant P. falciparum malaria. METHODS: We assessed incidence of P. falciparum malaria and the in-vivo responses to mefloquine treatment over 13 years in two large camps for displaced Karen people on the northwest border of Thailand. During this time, the standard mefloquine dose was first increased, and then combined artesunate and mefloquine was introduced as first-line treatment for uncomplicated P. falciparum malaria. FINDINGS: Early detection and treatment controlled P. falciparum malaria initially while mefloquine was effective (cure rate with mefloquine [15 mg/kg] and sulphadoxine-pyrimethamine in 1985, 98% [95% CI 97-100]), but as mefloquine resistance developed, the cure rate fell (71% [67-77] in 1990). A similar pattern was seen for high-dose (25 mg/kg) mefloquine monotherapy from 1990-94. Since the general deployment of the artesunate-mefloquine combination in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of P. falciparum malaria in the study area. In-vitro susceptibility of P. falciparum to mefloquine has improved significantly (p=0.003). INTERPRETATION: In this area of low malaria transmission, early diagnosis and treatment with combined artesunate and mefloquine has reduced the incidence of P. falciparum malaria and halted the progression of mefloquine resistance. We recommend that antimalarial drugs should be combined with artemisinin or a derivative to protect them against resistance.

Animals↗

Randomized trial of mefloquine alone and artesunate followed by mefloquine for the treatment of acute uncomplicated falciparum malaria.

Mefloquine is the main antimalarial used for treatment of falciparum malaria patients at the malaria clinics in Thailand. However, the cure rate with mefloquine alone has declined seriously in recent years. The efficacy and tolerability of a sequential treatment of artesunate followed by mefloquine was therefore compared with those of mefloquine alone, in a randomized therapeutic trial involving 125 patients with acute uncomplicated falciparum malaria. Sixty-three patients received mefloquine alone (750 mg given immediately, followed by 500 mg 6 h later) and 62 each received 800 mg artesunate over 2 days (200 mg every 12 h) followed 6 h later by a single, 750-mg dose of mefloquine. All patients were admitted to the hospital in Bangkok for 28 days to exclude re-infection. Most patients (107) completed the study; 18 left the hospital prior to completion of follow-up for reasons unrelated to their treatment. Cure rates for the two groups were 74% (42/57) for mefloquine alone and 92% (46/50) for artesunate followed by mefloquine. The mean parasite clearance time was significantly shorter (P < 0.001) in the group treated with the sequential combination than in the group treated with mefloquine alone, but the mean fever clearance times were not significantly different (P = 0.26). Most patients responded well to the treatment regimens and none suffered from serious toxic adverse reactions. Only four patients who were treated with mefloquine alone had parasitaemia persisting to day 7 (RII), thus requiring alternative follow-up treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Efficacies of mefloquine alone and of artesunate followed by mefloquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan.

In late 2003, the efficacies of mefloquine monotherapy and of an artesunate-mefloquine combination, for the oral treatment of uncomplicated, Plasmodium falciparum malaria, were investigated and compared in New Halfa, in eastern Sudan. Of the patients who completed the 28 days of follow-up, 40 were treated only with single-dose mefloquine (at a dose of 25 mg/kg), and 38 with artesunate (at 4 mg/kg. day) for 3 days followed by single-dose mefloquine (at 15 mg/kg), given on the third day. Compared with those given the combination, the patients given mefloquine alone were more likely to suffer nausea, vomiting and dizziness (25.0% v. 2.6%; P=0.005) and to be found gametocytaemic (12.5% v. 0%; P=0.02) after treatment, and more likely to be found febrile (i.e. with a temperature >37.5 degrees C) on day 2 (25.0% v. 2.6%; P=0.005), although no patients were found febrile on day 3. Six of the patients--three (7.5%) of those given mefloquine only and three (7.9%) of those given the combination (P>0.05)--appeared to be treatment failures. Parasite genotyping indicated, however, that, although five of these six patients had true recrudescences, one (who had been treated with the combination) had been re-infected during the follow-up. The true frequencies of cure were therefore 92.5% after mefloquine alone and 94.7% after the combination (P>0.05). Thus, although the treatments appeared equally effective in clearing parasitaemias, the combination was better at clearing gametocytaemias and was less likely to cause adverse side-effects. It remains unclear why mefloquine given alone was almost 10-fold more likely to trigger adverse effects than treatment with a combination that contained the same drug. This may be a reflection of the different mefloquine doses and, for the patients given the combination, of the use of artesunate before the mefloquine treatment.

Administration, Oral↗

Trials of mefloquine in vivax and of mefloquine plus 'fansidar' in falciparum malaria.

Two randomised double-blind trials were conducted to examine the activity and tolerability of mefloquine alone and in combination with sulfadoxine/pyrimethamine (MSP). In one trial mefloquine was compared with chloroquine in 40 patients with Plasmodium vivax malaria and in the other one mefloquine was compared with MSP in 40 patients with P falciparum malaria. The former trial showed that both a single oral dose of 250 mg mefloquine and a single oral dose of 450 mg chloroquine (base) were highly effective in relieving symptoms of malaria and in clearing P vivax parasitaemia. No side-effects and no changes in laboratory variables attributable to the test drugs were observed. The other trial showed that a single oral dose of 750 mg mefloquine and a single oral dose of MSP (750 mg mefloquine plus 3 tablets of 'Fansidar', were equally effective in the treatment of falciparum malaria. 2/4 treatment failures in the mefloquine group and 2/3 treatment failures in the MSP group were due to low plasma drug levels resulting from vomiting soon after ingestion of the tablets. Gametocytes of P falciparum were unaffected by either mefloquine or MSP. 5 patients in each group had side-effects such as vomiting, skin rash, diarrhoea, and transient mental confusion. Mefloquine was well tolerated by patients with glucose-6-phosphate dehydrogenase deficiency or heterozygous haemoglobin E.

Adolescent↗

Plasma and whole blood mefloquine concentrations during treatment of chloroquine-resistant falciparum malaria with the combination mefloquine-sulphadoxine-pyrimethamine.

Mefloquine-sulphadoxine-pyrimethamine (MSP) in combination has proved effective against multiple-drug-resistant falciparum malaria, but nothing is known about mefloquine absorption when it is given in this formulation. Nine Thai patients, aged 15-51 years with uncomplicated chloroquine-resistant falciparum malaria, took 11.2-16.7 mg of mefloquine base per kilogram bodyweight as MSP tablets. All patients responded to treatment with fever and parasite clearance times of 61 +/- 29 h (mean +/- s.d.) and 52 +/- 24 h, respectively. The mean apparent absorption half-time (t1/2abs) of mefloquine was 4.89 h (range 2.25-9.72) and mean peak plasma concentration was 1815 ng ml-1 (range 725-3368). Peak plasma mefloquine concentrations in three patients who vomited within 2 h of treatment were 725, 956 and 1972 ng ml-1. There was no significant difference between plasma and whole blood mefloquine concentrations during the first 48 h of treatment. Based on the elimination of parasitaemia, the plasma mefloquine concentrations are adequate for therapy of uncomplicated falciparum malaria although the relationship between plasma concentrations and therapeutic efficacy of mefloquine requires further study.

Adolescent↗

In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003.

OBJECTIVE: To monitor the efficacy of anti-malarial treatments in Thailand. METHOD: A 28-day in vivo study in nine provinces along international borders in 2003. The first group comprised 164 patients from four provinces: Mae Hong Son, Chiang Mai, Ratchaburi and Ubon Ratchathani. These patients received 15 mg/kg mefloquine as a single dose. The second group, 58 patients from Kanchanaburi, were treated with 15 mg/kg mefloquine plus artesunate (12 mg/kg). The third group, 196 patients from provinces with high-level mefloquine resistance (Tak, Ranong, Chanthaburi and Trat), received 25 mg/kg of mefloquine plus 12 mg/kg artesunate. In all arms, follow-up blood smears were scheduled for days 1, 2, 3, 7, 14, 21 and 28. All patients tolerated the regimens well. RESULTS: The percentage of adequate clinical and parasitological response to mefloquine monotherapy was 62.0% in Mae Hong Son, 75.0% in Chiang Mai, 94.0% in Ratchaburi and 89.7% in Ubon Ratchathani. In Kanchanaburi, the percentage of adequate clinical and parasitological response to the artesunate-mefloquine combination was 94.2%. In the third group, this response exceeded 90%, except in Trat, where it was only 78.6% (44 patients). CONCLUSION: Mefloquine monotherapy must urgently be replaced in Mae Hong Son and Chiang Mai. The markedly reduced efficacy of the artesunate-mefloquine combination used in Trat raises questions about the future of this therapy on the southeastern border of Thailand with Cambodia. It is very worrying because no practical and affordable alternative is yet available.

Administration, Oral↗

Mefloquine-halofantrine cross-resistance in Plasmodium falciparum induced by intermittent mefloquine pressure.

The study was designed to evaluate how exposure of Plasmodium falciparum to mefloquine modifies the sensitivity of the parasite to four major antimalarial drugs. A recently culture-adapted strain of P. falciparum was subjected to intermittent drug pressure at three different mefloquine concentrations (2.34, 4.68, and 9.37 ng/ml). Growth was monitored by daily evaluation of parasitemia on thin smears. Drug sensitivity tests were done weekly, using a radioisotope microdilution method. Mefloquine was removed from culture media when decreasing parasitemia was observed, and reintroduced when multiplication reoccurred. Parasite survival was inversely proportional to drug concentrations. The parasites tolerated progressively higher concentrations of mefloquine with prolonged exposure to the drug. Throughout this adaptation, the 50% inhibitory concentration for chloroquine and quinine showed no modification, but it increased considerably for mefloquine, exceeding known levels of resistance. Furthermore, a parallel increased resistance to halofantrine was observed, surpassing the normal range of sensitivity. Cross-resistance between mefloquine and halofantrine shown in this study has now been confirmed by epidemiologic in vitro surveys and clone analysis. These findings may have important in vivo consequences and eventually affect the choice of antimalarial therapy.

Animals↗

Mefloquine sulfadoxine pyrimethamine (MSP) combination delays in vitro emergence of mefloquine resistance in multiple drug resistant Plasmodium falciparum.

Sulfadoxine-pyrimethamine-resistant and chloroquine resistant, but mefloquine sensitive (MIC 5 x 10(-9] isolates of Plasmodium falciparum were used to study the emergence of mefloquine resistance. The continuously cultured isolates which were exposed intermittantly to varying concentrations of mefloquine alone became insensitive to the drug at 1 x 10(-7) M after 12 months, whereas the culture line exposed to the combination of mefloquine, sulfadoxine and pyrimethamine became only slightly insensitive to mefloquine (MIC 2 x 10(-8]. Thus, the efficacy of mefloquine may be prolonged through use in combination with sulfadoxine-pyrimethamine.

Animals↗

Single dose artemisinin-mefloquine versus mefloquine alone for uncomplicated falciparum malaria.

The efficacy of the combination of a single oral dose of 500 mg artemisinin with a single 500 mg oral dose of mefloquine (AM) in the treatment of uncomplicated falciparum malaria was compared to mefloquine therapy alone (M) in a double-'blind' randomized study in an endemic area in the south of Viet Nam where single low dose treatment was employed and where mefloquine had been recently introduced. 231 patients, 117 AM and 114 M, were studied. Failure of therapy occurred in 1 AM patient and in 3 M patients. The radical cure rate was 84% for the AM regimen and 65% for the M regimen (P = 0.002). Recrudescence (including an unknown percentage of reinfections) occurred in 15% of AM patients and in 30% of M patients (P = 0.01). The mean parasite clearance time was 40 h (SD = 16) for AM and 60 h (SD = 27) for the M regimen (P = 0.0001). No effect of artemisinin was noted on gametocytes present on admission, but new gametocytes developed less frequently in the AM group. The addition of a single dose of 500 mg artemisinin to 500 mg mefloquine increased the efficacy and reduced the rate of recrudescence, but this regimen was not adequate and, for short course regimens, more doses of artemisinin as well as higher, doses of mefloquine should be studied.

Adolescent↗

The pharmacokinetics of mefloquine in man: lack of effect of mefloquine on antipyrine metabolism.

A method is described for the determination of the new antimalarial agent, mefloquine, in plasma and urine. After oral administration of 750 mg mefloquine to six volunteers, absorption, was apparently slow, with plasma mefloquine concentrations at 24 h (559 +/- 181 ng ml-1; mean +/- s.d.) higher than at 6 h (459 +/- 166 ng ml-1). The elimination half-life was 373 +/- 249 h, oral clearance was 5.09 +/- 2.7 1 h-1, and apparent volume of distribution was 35.7 +/- 30.7 l kg-1 (assuming 100% bioavailability). Mefloquine (750 mg) had no significant effect on salivary kinetics of antipyrine or on the metabolic clearance of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine, when antipyrine was administered either 2 h or 2 weeks after dosing with mefloquine.

Adult↗

Mefloquine-pyrimethamine-sulfadoxine combination delays emergence of mefloquine resistant Plasmodium falciparum in continuous culture.

The efficacy of mefloquine against Plasmodium falciparum in continuous culture was studied. The development of mefloquine resistance in P. falciparum was significantly inhibited by a combination of mefloquine, pyrimethamine and sulfadoxine. By contrast, more resistant variants were selected in continuous culture without drug pressure or with pyrimethamine-sulfadoxine pressure. The most mefloquine resistant variants were selected by step-wise increases in mefloquine pressure.

Animals↗

Mefloquine levels in patients with mefloquine resistant Plasmodium falciparum in the eastern part of Thailand.

A total of 99 patients with uncomplicated falciparum malaria who attended the malaria clinic in Bo Rai, Trat Province were treated with a single oral dose of MSP 3 tablets (Fansimef; equivalent to 750 mg of mefloquine) concurrently with primaquine (30 mg). The aim of the study was to detect RII and RIII types of response with 3 tablets of MSP. Seven (8.1%) and 22 patients (25.3%) had RII and RIII types of response, respectively, and 58 (66.8%) had no parasitemia on Day-7 (S or RI response). Mefloquine concentrations on Day-3 after treatment in patients in the S/RI group were significantly higher than those with early treatment failure (RII, RIII), with the respective mean (SD) values of 1,959 (696) and 1,622 (863) ng/ml. The mean concentrations of mefloquine in these patients with RII and RIII types of response were higher than those with a sensitive response in a previous study. The result suggests that Plasmodium falciparum strains in this part of the country are highly resistant to mefloquine and that blood levels of mefloquine on Day-3 may also be a good indicator of treatment outcome in this particular area.

Adolescent↗

Comparison of chloroquine, sulfadoxine/pyrimethamine, mefloquine and mefloquine-artesunate for the treatment of falciparum malaria in Kachin State, North Myanmar.

Multi-drug resistant falciparum malaria is widespread in Asia. In Thailand, Cambodia and Vietnam the national protocols have changed largely to artesunate combined treatment regimens but elsewhere in East and South Asia chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) are still widely recommended by national malaria control programmes. In Kachin State, northern Myanmar, an area of low seasonal malaria transmission, the efficacy of CQ (25 mg base/kg) and SP (1.25/25 mg/kg), the nationally recommended treatments at the time, were compared with mefloquine alone (M; 15 mg base/kg) and mefloquine combined with artesunate (MA; 15:4 mg/kg). An open randomized controlled trial enrolled 316 patients with uncomplicated Plasmodium falciparum malaria, stratified prospectively into three age-groups. Early treatment failures (ETF) occurred in 41% (32/78) of CQ treated patients and in 24% of patients treated with SP (18/75). In young children the ETF rates were 87% after CQ and 35% after SP. Four children (two CQ, two SP) developed symptoms of cerebral malaria within 3 days after treatment. By day 42, failure rates (uncorrected for reinfections) had increased to 79% for CQ and 81% for SP. ETF rates were 2.5% after treatment with M and 3.9% after treatment with MA (P > 0.2). Overall uncorrected treatment failure rates at day 42 following M and MA were 23% and 21%, respectively. Chloroquine and SP are completely ineffective for the treatment of falciparum malaria in northern Myanmar. Mefloquine treatment is much more effective, but three day combination regimens with artesunate will be needed for optimum efficacy and protection against resistance.

Adolescent↗

Efficacy of mefloquine and mefloquine-artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon region of Bolivia.

We assessed the efficacy of mefloquine monotherapy and mefloquine-artesunate (MQ-AS) combination therapy for the treatment of Plasmodium falciparum malaria at four sites in the Bolivian Amazon region. Patients with uncomplicated P. falciparum infections between 5 and 60 years of age were randomly assigned to be treated with either MQ (15 mg/kg in a single oral dose) or MQ (15 mg/kg) plus AS (4 mg/kg daily for 3 days). A total of 143 patients were enrolled and followed for 28 days. None of the 73 patients who received MQ alone or the 70 patients who received MQ-AS combination therapy had recurrences of parasitaemia during the 28-day follow-up period. Asexual parasite densities fell significantly more rapidly and the proportion of patients with gametocytes was significantly lower on days 7-28 in patients treated with MQ-AS than in those treated with MQ alone. All patients tolerated the medications well. After this study, the Bolivian Ministry of Public Health changed its treatment policy for uncomplicated P. falciparum malaria in the Amazon region to combination therapy with MQ-AS to slow or prevent the development of resistance.

Adolescent↗

Sensitivity of Plasmodium falciparum to mefloquine-sulphadoxine-pyrimethamine (Fansimef) in vivo and to mefloquine alone in vitro in Nigeria.

In Nigeria chloroquine remains the drug of choice for the treatment of falciparum malaria, since chloroquine resistance is not yet a problem. Nevertheless, in view of the rapid spread of multi-resistant Plasmodium falciparum in Africa it is desirable to test alternative drugs for efficacy and safety. To this end, we undertook a comparative controlled trial of the new triple combination, mefloquine-sulphadoxine-pyrimethamine (MSP, Fansimef) with chloroquine in a group of Nigerian children with symptomatic falciparum malaria. Our results showed that Fansimef was an effective blood schizontocide against the Nigerian strain of P. falciparum and was well tolerated. In particular, sinus bradycardia, which was frequently observed with Fanismef in the trials conducted in Zambia, was not seen in any of the Nigerian patients. In vitro sensitivity tests done on 26 P. falciparum isolates showed that all isolates were susceptible to complete inhibition by mefloquine, but the minimum concentration which produced complete inhibition in some isolates was higher than expected for fully sensitive parasites.

Animals↗