Pharmacodynamics of mefloquine and praziquantel combination therapy in mice harbouring juvenile and adult Schistosoma mansoni

Praziquantel (PZQ) is currently the only drug widely used for the treatment of schistosomiasis, but the antimalarial drug mefloquine (Mef) possesses interesting antischistosomal properties. Combination therapy with these two drugs has been suggested as a strategy for transmission control, as PZQ is active against adult worms and Mef is active against schistosomula. To examine the efficacy of combination therapy, Schistosoma mansoni-reinfected mice were separated into seven groups: untreated (I), treated with PZQ in doses of 200 mg/kg (II) or 1,000 mg/kg (III), treated with Mef in doses of 200 mg/kg (IV) or 400 mg/kg (V); each dose was divided equally and given on two consecutive days. Group VI was treated with doses of PZQ + Mef as in groups II and IV, respectively, while group VII was treated with PZQ + Mef as in groups III and V, respectively. PZQ + Mef at the reduced doses of 200 mg/kg each enhanced the therapeutic efficacy over the reduced PZQ dose alone as shown by a very high reduction in the total numbers of mature worms (95 percent vs. 49 percent), immature worms (96 percent vs. 29 percent) and the complete eradication of immature females, mature females and immature eggs. The reduction in worm burden was associated with the healing of hepatic granulomatous lesions and the normalisation of all liver enzymes. Therefore, the use of Mef with PZQ is more effective than PZQ alone and should be considered for clinical trials in humans as a potential treatment regimen to prevent treatment failures in areas with high rates of schistosomiasis.

Efficacy of Artequick versus artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand.

To determine the efficacy, safety and tolerability of an alternative short-course, artemisinin-based combination therapy for acute uncomplicated Plasmodium falciparum malaria, we compared Artequick--a fixed-dosed combination of artemisinin (80 mg), piperaquine (400 mg), and primaquine (4 mg), per tablet--with a standard regimen of artesunate-mefloquine. A total of 130 patients were randomly assigned to treatment with an orally administered, once-daily, 3-day regimen of either Artequick (Group A: 3.2 mg/Kg/day of artemisinin, 16 mg/Kg/day of piperaquine, and 0.16 mg/Kg/day of primaquine) or artesunate-mefloquine (Group B: artesunate, 4 mg/Kg/day, with mefloquine, 8 mg/Kg/day). Patients receiving each regimen had a rapid clinical and parasitological response. All treatments were well tolerated, and no serious adverse effects occurred. No significant differences were found in fever- and parasite-clearance times between the two study groups. The 28-day cure rates were similarly high, at 98.5% and 100%, in groups A and B, respectively. We conclude that Artequick was as effective and well tolerated as artesunate-mefloquine and could be used as an alternative treatment for multidrug-resistant Plasmodium falciparum malaria in Southeast Asia.

Pharmacokinetics of mefloquine with dihydroartemisinin as 2-day regimens in patients with uncomplicated falciparum malaria.

The objective of this study was to investigate the pharmacokinetics of mefloquine (MQ) when given as 750 mg at two different times in combination regimens with dihydroartemisinin (DHA) in patients with acute uncomplicated falciparum malaria. A total of 12 Vietnamese patients (6 in each group) were randomized to receive two MQ-DHA regimens as follows: regimen-A: an initial oral dose of 300 mg DHA, followed by 750 mg MQ and 300 DHA 6 and 24 hours later; regimen-B: an initial dose of 300 mg DHA, followed by 300 mg DHA and 750 mg MQ at 24 hours. Both combination regimens were well tolerated. All patients responded well to treatment with no recrudescence during a 42 day follow-up period. The pharmacokinetics of MQ following both regimens were similar but pooled data from both groups suggest that the kinetics of MQ was different from that observed in Vietnamese healthy subjects reported in a previous study. The median (95% CI) time period for maintenance of whole blood MQ concentrations above 500 ng/ml was 16 (0-24) days. It was concluded that since no pharmacokinetic drug interaction was observed, MQ dose given 24 hours after an initial dose of DHA is a preferable combination treatment regimen with regard to patient compliance.

An in vivo test to assess mefloquine 25 mg/kg for the treatment of uncomplicated falciparum malaria in Rondônia, Brazil

Drug-resistant Plasmodium falciparum is undermining malaria control efforts worldwide. In Brazil, mefloquine (MQ) at a dose of 15 mg/kg body weight is used to treat P. falciparum. At this dose, MQ resistance developed rapidly in Thailand. Use of a higher MQ dose may retard the development of resistance. We treated 50 patients aged one to 67 years who had acute, uncomplicated P falciparum malaria using MQ 25 mg/kg. There were no serious adverse events. Two patients complained of dizziness and insomnia. Assessing evaluable patients, the day 42 cure rate was 40/42 [95.2 percent (95 percent confidence interval 83.8 to 99.4 percent)]. Mefloquine was efficacious and well tolerated in this small cohort from the state of Rôndonia.

El citocromo P-450 y la respuesta terapéutica a los antimaláricos / Cytochrome P-450 and the response to antimalarial drugs

OBJETIVOS: Evaluar la relación entre los factores genéticos y fenotípicos del sistema enzimático del citocromo P-450 y la respuesta terapéutica antimalárica a la cloroquina, la amodiaquina, la mefloquina y el proguanil, así como determinar la influencia de algunos factores biológicos y sociales del hospedero en el comportamiento de este complejo enzimático. MÉTODOS: Revisión sistemática de las bases de literatura biomédica PubMed, Excerpta Medica, LILACS y SciELO mediante descriptores en español e inglés. Se usaron los siguientes descriptores: "CYP-450" y "citocromo P-450" y sus combinaciones con "proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "farmacocinética de proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "resistencia a proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "metabolismo", "farmacogenética", "enfermedad", "inflamación", "infección", "enfermedad hepática", "malaria", "nutrición" y "desnutrición". Estos mismos términos se usaron en inglés. La búsqueda se limitó a los artículos publicados en español, inglés y portugués hasta el 30 de junio de 2005 y a cuatro medicamentos antimaláricos: amodiaquina, cloroquina, mefloquina y proguanil. RESULTADOS: Algunos factores genéticos del citocromo P-450 humano (principalmente su polimorfismo), así como otros de tipo biológico y social (la propia presencia de enfermedad, inflamación o infección, la administración de medicamentos antimaláricos y su combinación, y el estado nutricional del paciente), influyen en la actividad de ese complejo enzimático. Solo en la última década se ha abordado el estudio de las bases genéticas de los citocromos y se han podido dilucidar los mecanismos de algunas interacciones entre fármacos y del metabolismo de estos, lo que ha permitido caracterizar el proceso de biotransformación de la amodiaquina y de la cloroquina. Se espera que nuevas investigaciones permitan responder a las interrogantes que aún subsisten, entre ellas cuál es la ruta metabólica de otros medicamentos antimaláricos, la distribución en la población de los alelos de las enzimas que participan en su metabolismo, y la contribución de tales mutaciones al fracaso terapéutico, y predecir la respuesta a los tratamientos antimaláricos...

An open randomized clinical trial of Artekin vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria.

Malaria remains a major cause of morbidity and mortality in tropical countries and subtropical regions in the world. Southeast Asia has the most resistant malaria parasites in the world, which has limited treatment options in this region. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The combination of dihydroartemisinin (DHA) and piperaquine (PQP) in the form of Artekin has been developed as an alternative to established combinations, such as artesunate-mefloquine, primarily to reduce treatment costs and toxicity. We conducted a study comparing a standard treatment for acute uncomplicated falciparum malaria (artesunate 4 mg/kg/day together with mefloquine 8 mg/kg/day oral route once a day for 3 days) (Group A) and a combination of dihydroartemisinin 40 mg and piperaquine 320 mg in the form of Artekin given once a day for 3 days (Group B) to determine safety, efficacy, and tolerability. One hundred and eighty patients were randomly enrolled at the ratio of 1:2 into groups A:B. All patients had rapid initial clinical and parasitological responses. There were no significant differences in fever clearance time or parasite clearance time between both groups. The 28-day cure rates were high, at 100% and 99%, in groups A and B, respectively. We conclude that Artekin was as effective and well-tolerated as artesunate-mefloquine, and can be used alternatively as the current treatment for multidrug-resistant P. falciparum malaria.

An open, randomized trial of three-day treatment with artesunate combined with a standard dose of mefloquine divided over either two or three days, for acute, uncomplicated falciparum malaria.

The combination of artesunate and mefloquine is currently one of the most effective treatments for multidrug-resistant Plasmodium falciparum malaria. Simultaneous, rather than sequential treatment with the two drugs, would allow better patient compliance. We therefore evaluated three-day treatment with artesunate combined with either 2 or 3 days of mefloquine co-administered once a day with artesunate. The study was an open, randomized trial for acute, uncomplicated falciparum malaria and was conducted at the Bangkok Hospital for Tropical Diseases. One hundred and twenty adult patients were randomized to two treatment groups. Group 1 patients received 4 mg/kg/day of artesunate for 3 days and 3 daily doses of 8.0 mg/kg/day mefloquine given with artesunate. Group 2 patients received the same dose of artesunate and the same total dose of mefloquine (25 mg/kg). However, the mefloquine was given as 15 mg/kg on the first day and 10 mg/kg/ on the second day, again with artesunate. The baseline demographic and clinical characteristics of the patients in the two groups were similar. The cure rates for the 3-day and 2-day mefloquine regimens were 100% and 99%, respectively. There were no significant differences in either median fever clearance times (group 1=32 hours; group 2=33 hours) or mean parasite clearance times (group 1=42.3 hours; group 2=43.3 hours). Both regimens were well tolerated and there were no significant differences in the incidence of adverse effects. Nausea or vomiting occurred in 3.8% of patients in both groups and transient dizziness occurred in 4% of group 1 and 9% of group 2 patients. These results suggest that a 3-day regimen of mefloquine administered with artesunate is effective and well tolerated. This practical regimen could improve patient compliance.

Life-saving rectal artesunate for complicated malaria in children.

We report the effectiveness of two regimens of rectal artesunate formulation in treating 13 Thai children with cerebral/complicated falciparum malaria. The drug was given at an initial dose of 40 mg/kg bodyweight, in 3 or 4 divided doses in the first 24 hours, followed by 10 mg/kg bodyweight once daily for three consecutive days. Mefloquine, at a dose of 15 mg/kg bodyweight was given orally at 72 hours after the initial dose of artesunate, followed by 10 mg/kg bodyweight 6 hours later. Three cases with cerebral malaria gained consciousness within 20 hours of artesunate administration. The median time required for reduction of parasitemia by 90% of the initial value (P90) in 13 children was 11.2 hours. No recrudescence was observed in any of the patients during the 28-day follow-up period. Plasma concentrations of artesunate and dihydroartemisinin (active plasma metabolite of artesunate) measured in two patients who received the high initial dose regimen (20 mg/ kg bodyweight) suggested rapid absorption and adequate plasma concentrations of both compounds following the administration of artesunate via the rectal route. Further studies for the optimized regimen of rectal artesunate in the treatment of cerebral/complicated childhood falciparum malaria in areas of multidrug resistance are warranted.

Investigation of bioavailability, pharmacokinetics and safety of new pediatric formulations of artesunate and mefloquine.

The bioavailability/pharmacokinetics of dihydroartemisinin and mefloquine following the oral doses of 4 mg/kg body weight artesunate (Cambodian Pharmaceutical Enterprise) given concurrently with 10 mg/kg body weight oral mefloquine artesunate (Cambodian Pharmaceutical Enterprise) were investigated in 15 healthy Cambodian male volunteers. Both formulations were generally well tolerated. Both produced satisfactory plasma/blood concentration-time profiles. Oral artesunate and mefloquine were rapidly absorbed from gastrointestinal tract with marked inter-individual variation. For the dihydroartemisinin, the median (95% Cl) Cmax of 748 (304-1,470) ng/ml was observed at 1.5 (0.3-3.0) hours (tmax) after drug administration. The median (95% CI) values for AUC0-infinity, lambda(z) and tl/2z were 1.673 (1.08-2.88) microg.h/ml, 0.54(0.24-1.1)/hour and 1.3 (0.6-2.9) hours, respectively. For mefloquine, a median (95% Cl) Cmax of 1,000 (591-1,500) ng/ml was observed at 4 (2-6) hours (tmax) after drug administration. The median (95% CI) value for AUC0-168h was 3.92 (2.88-7.02) microg.h/ml.

Pharmacokinetics of the four combination regimens of dihydroartemisinin/mefloquine in acute uncomplicated falciparum malaria.

The pharmacokinetics of oral dihydroartemisinin and mefloquine were investigated in 40 patients (aged 16-30 y, weighing 45-60 kg) with acute uncomplicated falciparum malaria following the four combination regimens of dihydroartemisinin/ mefloquine [regimen-I: 300 mg dihydroartemisinin (h-0) plus 750 mg mefloquine (h-0); regimen-II: 300 mg dihydroartemisinin (h-0) plus 750 mg mefloquine (h-24); regimen-III: 300 mg dihydroartemisinin (h-0) plus 750 and 500 mg mefloquine (h-24 and 30); regimen-IV: 300 mg dihydroartemisinin (h-0) plus 750 and 500 mg mefloquine (h-0, 24)]. The four combination regimens were well tolerated. Patients in all treatment groups had a rapid initial response. However, 9 patients (4, 4, and 1 cases in regimens-I, II, and IV) had reappearance of parasitemia during the follow-up period. Significant changes in the pharmacokinetic parameters of both mefloquine and dihydroartemisinin were observed in patients with malaria compared with healthy subjects reported in a paralleled study. For mefloquine, Cmax (mg per dose), AUC0-day1 (mg per dose), and AUC0-day7 (mg per dose) were significantly higher in patients. Furthermore, tmax, was prolonged while V/F contracted and tl/2,z, MRT shortened in patients with malaria. For dihydroartemisinin, Cmax AUC, tmax and Vz/F were changed in the same direction as mefloquine, whereas t1/2z and MRT were prolonged. CL/F was also significantly reduced in patients with malaria. Absorption/disposition kinetics of oral dihydroartemisinin were similar among the various regimens. On the other hand, AUC0-day1 (mg per dose) of mefloquine after regimen-III was significantly higher than the other three regimens. Combination regimens with two divided doses of mefloquine (regimens-III and IV) resulted in a significantly delayed tmax (especially regimens-IV) compared with those with single dose regimens (regimens-I and II).

Monitoring the therapeutic efficacy of antimalarials against uncomplicated falciparum malaria in Thailand.

Increasing antimalarial drug-resistance is an important problem in Thailand. The results of monitoring the antimalarial efficacy are used in decision-making about using antimalarials to treat uncomplicated falciparum malaria in Thailand. In 2002, 552 patients with uncomplicated malaria were treated according to the Thai National Drug Policy, with mefloquine 25 mg/kg plus artesunate 12 mg/kg and primaquine 30 mg in divided doses for 2 days in high-mefloquine-resistant areas; mefloquine 15 mg/kg plus primaquine 30 mg in non- or low-mefloquine-resistant areas; mefloquine 15 mg/kg plus artesunate 12 mg/kg and primaquine 30 mg in divided doses for 2 days or Coartem (6-dose regimen for adult contains 480 mg artemether and 2880 mg lumefantrine) plus primaquine 30 mg given over 3 days in moderate-mefloquine-resistant areas. The study shows that mefloquine, artesunate plus mefloquine, and artemether plus lumefantrine are effective in the treatment of uncomplicated malaria in most areas of Thailand except for Ranong and Kanchanaburi, where the first-line treatment regimen should be revised.

Randomized trial of artesunate and mefloquine in comparison with quinine sulfate to treat P. falciparum malaria pregnant women.

To compare the effectiveness and safety of quinine sulfate and artesunate with mefloquine for treating second trimester pregnancy in women who suffered from Plasmodium falciparum malaria. The prospective study was done in Srisangwal Hospital, Mae Hong Son, Thailand. Sixty, second to third trimester pregnant patients with P. falciparum infection, were recruited at random. They received either quinine sulfate 10 mg/kg/day for at least 7 days, 29 women (group I), or oral artesunate 2 mg/kg as the first dose, 1 mg/kg every 12 hours orally for at least 5 days together with split doses of mefloquine, 15 mg/kg and 6 hours later 10 mg/kg orally 1 day after artesunate was stopped, 28 women (group II). Three cases (5%) were lost to follow-up before delivery, one case in group I and two cases in group II. After treatment, the mean hematocrit of group I was significantly less than group II (p = 0.000). The PCT (parasite clearance time) and FCT (fever clearance time) of group II were significantly shorter than group I (p = 0.000). None of the patients in both groups had recrudescences within 28 days. Group I had more adverse effects than group II. No adverse neurological effects in pregnancy were found in both groups. The calcification of placenta and IUGR (Intrauterine growth retard) were not different between the two groups (p = 0.964, 0.363 respectively). The PCT was not different between the calcified placenta group and normal placenta group (p = 0.058), but the TTPP (Total time of parasite presentation) was (p = 0.000). TTPP related to low birth weight and low apgar score at 1 minute might be the cause (p = 0.000, 0.000 F = 5.261, 21.627 respectively). TTPP and PCT related to neonatal blood pH and caused low neonatal blood pH (p = 0.000, 0.001 F = 24.351, 11.162 respectively). The physical and neurological development of the babies at 2, 4, 6 and 12 months follow-up, were normal and there were no congenital abnormalities in either group. TTPP relating to fetal outcome, the longer the TTPP, the worse the fetal outcome, so we should diagnose early and treat P. falciparum malaria in pregnancy to prevent fetal jeopardy. Artesunate with mefloquine could shorten the PCT more than quinine sulfate in pregnancy, so the fetal outcome was better than that of quinine sulfate. In cases of prolonged infection before treatment, artesunate might be the alternative treatment of P. falciparum malaria in pregnancy. However, its safety should be carefully studied further with a larger sample size.

Resistência à mefloquina do tipo RIII em crianças com malária falciparum em Manaus, AM, Brasil / RIII mefloquine resistance in children with falciparum malaria in Manaus, AM, Brazil

Relata-se a ocorrência de resistência à mefloquina administrada na dose de 20mg/kg em 51 crianças com malária falciparum atendidas em centro de referência em Manaus, Brasil, no período de outubro a novembro de 1997. Todas as crianças foram avaliadas nos dias 3, 5, 7, 14, 21, 28 e 35 do tratamento, segundo critérios clínico e parasitológico. Foi encontrada uma incidência de resistência RIII de 5,9 por cento (IC 95 por cento variando de 1,5 a 17,2), a razäo cura/resistência calculada foi 20:1 e cura/gravidade 62:1. Os dados chamam a atençäo para a importância da resistência à mefloquina nesse grupo de crianças

Efectos de la Mefloquina sobre la leishmaniasis visceral en ratones

Evaluamos el efecto de la administración oral de mefloquina sobre leishmaniasis visceral experimental en ratones inoculados con Leishmania (Leishmania) donovani. Los ratones que recibieron mefloquina oral a una dosis de 75 mg/kg por dos días antes de ser infectados, mostraron una reducción del 50 por ciento del número de parásitos en el hígado. Sin embargo, la administración de la misma dosis por dos días después de la infección no tuvo efecto terapéutico tal como la eliminación de parásitos en el hígado de los ratones infectados.

Antimalarial drug susceptibility testing of Plasmodium falciparum in Brazil using a radioisotope method

From March 1996 to August 1997, a study was carried out in a malaria endemic area of the Brazilian Amazon region. In vivo sensitivity evaluation to antimalarial drugs was performed in 129 patients. Blood samples (0.5 ml) were drawn from each patient and cryopreserved to proceed to in vitro studies. In vitro sensitivity evaluation performed using a radioisotope method was carried out with the cryopreserved samples from September to December 1997. Thirty-one samples were tested for chloroquine, mefloquine, halofantrine, quinine, arteether and atovaquone. Resistance was evidenced in 96.6 percent (29/30) of the samples tested for chloroquine, 3.3 percent (1/30) for quinine, none (0/30) for mefloquine and none for halofantrine (0/30). Overall low sensitivity was evidenced in 10 percent of the samples tested for quinine, 22.5 percent tested for halofantrine and in 20 percent tested for mefloquine. Means of IC 50 values were 132.2 (SD: 46.5) ng/ml for chloroquine, 130.6 (SD: 49.6) ng/ml for quinine, 3.4 (SD: 1.3) ng/ml for mefloquine, 0.7 (SD: 0.3) ng/ml for halofantrine, 1 (SD: 0.6) ng/ml for arteether and 0.4 (SD: 0.2) ng/ml for atovaquone. Means of chloroquine IC 50 of the tested samples were comparable to that of the chloroquine-resistant strain W2 (137.57 ng/ml) and nearly nine times higher than that of the chloroquine-sensitive strain D6 (15.09 ng/ml). Means of quinine IC 50 of the tested samples were 1.7 times higher than that of the low sensitivity strain W2 (74.84 ng/ml) and nearly five times higher than that of the quinine-sensitive strain D6 (27.53 ng/ml). These results disclose in vitro high resistance levels to chloroquine, low sensitivity to quinine and evidence of decreasing sensitivity to mefloquine and halofantrine in the area under evaluation

Mefloquine in treatment of cutaneous leishmaniasis

Três casos de leishmaniose tegumentar em pacientes internados no Hospital Escola da Faculdade de Medicina do Triângulo Mineiro, Uberaba, MG, foram tratados com mefloquina, na dose de 4,2mg/kg/dia por via oral, durante seis dias. Nova série foi repetida três semanas após. Nenhum dos três pacientes foi curado

Two doses of artemether/mefloquine or artesunate/mefloquine combination for multidrug resistant falciparum Malaria.

Plasmodium falciparum in Southeast Asia is highly resistant to chloroquine, sulfadoxine/ pyrimethamine, quinine and even mefloquine. The use of two doses of short course artemether/mefloquine combination has been shown to be effective in a recent study. In the present study, we have assessed the efficacy of short course treatment with artesunate/mefloquine, in comparison with artemether/mefloquine in patients with multidrug resistant falciparum malaria. Ninety-nine Thai male patients who sought consultation at Makham Malaria Clinic, Chantaburi (eastern part of Thailand), were randomized to receive either the combination of artemether (150 and 100 mg; group A) or artesunate (150 and 100 mg; group B) with mefloquine (750 and 500 mg) at 24 hours apart. The follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Patients in both groups showed a rapid initial response to treatment; fever and parasite were cleared within 48 hours in 100 and 100% vs 91.8 and 96%, for group A vs B, respectively. All patients in group A had completed the 42 day-follow up; however, two patients in group B did not finish the 42-day follow-up. The cure rate was 100% in either group. No serious adverse effects were found. Artemether or artesunate with mefloquine given two doses at 24 hours apart can be used as effective alternative treatment regimens for multidrug resistant falciparum malaria.

Estudo da eficácia e tolerância do artesunato oral isolado e em associaçäo com mefloquina, no tratamento da malária falciparum näo complicada em área endêmica do Pará, Brasil / An efficacy and tolerant study of oral artesunate alone and in combination with mefloquine in the treatment of uncomplicated falciparum malaria in an endemic area of Pará, Brazil

Com o objetivo de avaliar a eficácia e tolerância do artesunato no tratamento da malária falciparum nao complicada em área endêmica do Estado do Pará, 153 pacientes foram randomizados e estudados em três grupos, distribuídos por esquema terapêutico (I recebeu mefloquina l000mg; II utilizou artesunato l000mg; III usou a combinaçao de 600mg de artesunato seguida de 500 de mefloquina). A avaliaçao constou de exame clínico e parasitológico diariamente nos primeiros 7 dias e semanalmente até o 35§ dia do acompanhamento e de análise bioquímica e hematológica realizada antes e no 7§ dia, visando o controle de cura e a identificaçao de possíveis efeitos associados à administraçao das drogas. Os grupos estudados foram homogêneos quanto ao sexo, parasitemia e presença de febre. O tempo para desaparecimento da parasitemia foi mais curto nos grupos II e III, respectivamente, cujos esquemas terapêuticos empregaram artesunato. O desaparecimento da febre foi mais rápido no grupo tratado com a combinaçao das drogas. Alteraçoes clínicas e bioquímicas associadas a administraçao das drogas nao mostraram diferenças significativas entre os grupos estudados. O desaparecimento precoce da febre e parasitemia, e a ausência de importantes efeitos indesejáveis, sugerem que artesunato administrado isoladamente ou em combinaçao com mefloquina constituem medidas terapêuticas capazes de contribuir para o controle da doença na regiao.

Quinine toxicity when given with doxycycline and mefloquine.

The pharmacokinetic and dynamic interactions among 3 antimalarials, ie quinine, doxycycline and mefloquine was observed in a 26-year-old Thai male patient with falciparum malaria. During the acute episode of the infection, the patient was treated with an intravenous dose of quinine hydrochloride at 600 mg qid, together with an oral dose of doxycycline 100 mg bid. Due to nausea, tinnitus and the persistence of parasitemia in peripheral blood smears, the dose of quinine was reduced 2 days after the first treatment to 300 mg; concurrently oral mefloquine 750 mg was given as 2 divided doses at 24 hours apart. During the course of treatment, the patient developed hearing loss; deafness of the right ear lasted for one week after stopping quinine administration. Higher plasma quinine and lower whole blood mefloquine concentrations than would be expected from the simulation profiles were detected 4 days after the first treatment. However, the concentration of mefloquine was increased upon the cessation of quinine treatment.