In vitro susceptibility of Plasmodium falciparum to amodiaquine, mefloquine, quinine and chloroquine in Liberia, West Africa

The in vitro susceptibility of seven Plasmodium falciparum isolates to four schizonticidal drugs was studied in Yekepa area, northern Liberia, by the Rieckmann 24-hour micro method. The seven patients were successfully treated with the standard chloroquine regimen. The results of the individual in vitro tests all indicated full susceptibility to the four drugs. By probit analysis, the drug concentrations achieving 50% (EC 50) and 99% (EC 99) inhibition, respectively, were 0.2 and 0.7 microM chloroquine, 0.04 and 0.2 microM amodiaquine, 0.01 and 0.07 microM mefloquine and 1.4 and 3.0 microM quinine.     

The relationship between the in vitro response of Plasmodium falciparum to chloroquine, quinine and mefloquine

We have measured the in vitro response of several isolates of Plasmodium falciparum to chloroquine, quinine and mefloquine. We show that parasites which are resistant to chloroquine also have a reduced sensitivity to quinine. However, there appears to be no correlation between chloroquine resistance and reduced sensitivity to mefloquine. We conclude that the emergence and spread of chloroquine resistance could also be establishing a population of parasites with a reduced sensitivity to quinine which may provide the basis for the eventual emergence of quinine resistance.     

Sensitivity to quinine and mefloquine of Plasmodium falciparum in Thailand

Between 1982 and 1984 a regimen consisting of quinine and tetracycline was routinely used in Thailand to treat outpatients with microscopically confirmed falciparum malaria. Due to compliance problems associated with the 7-day multiple-dose regimen, there was a recrudescence rate of approximately 30%. Studies carried out in 1982 and 1984 in four areas of Thailand indicated that there was a significant decrease in the sensitivity of Plasmodium falciparum to quinine. A significant, though less marked, reduction in the sensitivity of P. falciparum to the structurally related drug mefloquine was also observed, although this compound was not operationally deployed in Thailand before 1985. These findings emphasize the need to replace the long multiple-dose quinine regimen by an effective, acceptable, single-dose treatment.     

Assessment of susceptibility of Plasmodium falciparum to chloroquine, quinine, mefloquine, sulfadoxine-pyrimethamine and artemisinin in southern Viet Nam.

Resistance to antimalarial chemotherapy is a major concern for malaria control in Viet Nam. In this study undertaken in 1998, 65 patients with uncomplicated Plasmodium falciparum malaria were monitored for 28 days after completion of a 5-day treatment course with artemisinin. Overall 36.9% (24/65) of patients had recurrent parasitaemia during the surveillance period. P. falciparum isolates were tested for sensitivity in vitro to chloroquine, mefloquine, quinine, sulfadoxine-pyrimethamine and results were compared to those from a similar study in 1995. Increased parasite sensitivity to sulfadoxine-pyrimethamine, chloroquine and quinine was demonstrated, with significantly lower mean EC50 and EC99 values in 1998 compared to 1995. Parasite sensitivity to mefloquine did not differ significantly in the 2 surveys. Isolates were also tested for sensitivity in vitro to artemisinin in the 1998 survey. The mean EC50 was 0.03 mumol/L and the EC99 was 0.94 mumol/L. Parasite sensitivity to artemisinin will need to be monitored in view of its increasing use in Viet Nam.     

The sensitivity of Plasmodium falciparum to chloroquine and amodiaquine in Ibadan, Nigeria

An extended in vivo test of the sensitivity of Plasmodium falciparum to antimalarial drugs in Nigerian children showed no evidence of resistance to chloroquine and amodiaquine. However, the results of a small number of in vitro tests suggest a decreased sensitivity of the parasite to chloroquine when compared with the results of earlier studies in the same locality.     

Susceptibility of Plasmodium falciparum strains to chloroquine and mefloquine in the Amazonas Federal Territory of Venezuela

The susceptibilities of 27 Plasmodium falciparum strains to chloroquine and mefloquine were studied in the area of Puerto Ayacucho, Amazonas Federal Territory of Venezuela, to determine their levels of resistance in vivo and in vitro. 50% of these strains showed chloroquine resistance in vivo. No grade III chloroquine resistance was found. 25% of the strains were resistant to chloroquine in vitro and 9% were resistant to mefloquine in vitro. Preliminary results suggest that strains resistant to Fansidar may also be found.     

Plasmodium falciparum: modulation by calcium antagonists of resistance to chloroquine, desethylchloroquine, quinine, and quinidine in vitro

Intrinsic interactions of calcium antagonists (broadly defined) and quinoline-containing antimalarial drugs were evaluated against chloroquine-sensitive and chloroquine-resistant clones of Plasmodium falciparum in vitro. Verapamil, D-600 (methoxyverapamil), Ro 11-2933/001 (tiapamil analogue), chlorpromazine, SKF 21133-A (chlorpromazine analogue), and diltiazem each potentiated the efficacy of the quinoline-containing antimalarials chloroquine, desethylchloroquine, and quinine with a chloroquine-resistant clone of P. falciparum, but did not affect the response of the quinoline-susceptible clone. Similar concentrations of either chlorpromazine or Ro 11-2933/001 lowered the IC50 of the resistant clone to approximately the same level as that observed for the sensitive clone for each of the quinolines tested. This reversal of resistance by many of the same calcium antagonists underscores the similarities in one mechanism of multi-drug resistance in neoplastic cells and quinoline-resistance in P. falciparum.     

In vitro assessment of sensitivity of Plasmodium falciparum to chloroquine and mefloquine in Ghana

An in vitro study of sensitivity of Plasmodium falciparum to chloroquine and mefloquine in Ghana is described. Results of 60 short-term cultures from 36 patients are evaluated. No sign of chloroquine resistance was found as all microtests showed complete inhibition of maturation at a level of 0.8 X 10(-6) M. For mefloquine schizont maturation was seen at higher levels of the drug. However, the estimated EC99, with 2.2830 X 10(-6) M is probably within the range of sensitivity.     

In-vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, dihydroartemisinin and quinine in an area of high chloroquine resistance in Rwanda

Plasmodium falciparum in-vitro susceptibility to chloroquine (CQ), monodesethylamodiaquine, quinine and dihydroartemisinin was investigated in Rwandan patients with a parasitaemia of at least >or=4000/microl. The study was carried out in November-December 2003. Dihydroartemisinin was the most potent (GM IC(50)=2.6nmol/l, 95% CI 2.2-3.2) among the drugs tested. Resistance to chloroquine was 45% (33/74) and that to monodesethylamodiaquine 7% (5/74). All the tested isolates were susceptible to quinine. The mean IC(50) of monodesethylamodiaquine, quinine and dihydroartemisinin was significantly higher for chloroquine-resistant than for chloroquine-sensitive strains (P<0.05). The IC(50) of each drug was significantly and positively correlated to that of the other three drugs (P<0.005), and this correlation was higher between CQ and monodesethylamodiaquine (r=0.8). In-vitro CQ resistance is linked to that of the other drugs tested. Most worrying is the positive correlation between the IC(50) of dihydroartemisinin and the other drugs, more particularly with CQ, suggesting an increased tolerance of the parasites to all drugs.     

Low resistance of Plasmodium falciparum to mefloquine in Tanga region, Tanzania

Studies were undertaken in the towns of Muheza, Korogwe and Tanga in Tanga region, north-eastern Tanzania in 1986 to assess the sensitivity of Plasmodium falciparum to mefloquine using an in vitro microtechnique. Successful tests were achieved on 29, 40 and 118 isolates from Korogwe, Muheza and Tanga respectively. The mean minimum inhibitory concentrations (logometric) were 0.52, 0.50 and 0.59 mumol per litre of blood for Korogwe, Muheza and Tanga respectively. Six isolates, 2 from Muheza and 4 from Tanga, showed resistance to mefloquine, having minimum inhibitory concentrations greater than 3.2 mumol per litre of blood. The chloroquine and mefloquine sensitivities of the isolates which showed mefloquine resistance were determined.     

Plasmodium falciparum: mefloquine resistance produced in vitro

Camp and Smith strains of the human malaria parasite Plasmodium falciparum became resistant to mefloquine after continuous cultivation in the presence of the drug. The 50% inhibitory dose (ID₅₀) values for mefloquine, as assessed by [³H]hypoxanthine incorporation, were found to have increased 4-fold, from 3 μg/l to 12 μg/l. The ID₅₀ values obtained by morphological examination of the cultures increased 10-fold. Resistance was stable in both strains either when grown in a drug-free medium or when kept frozen in liquid nitrogen. The mefloquine-resistant Camp strain remained sensitive to chloroquine and amodiaquine, and became slightly more resistant to quinine; there was increased sensitivity to pyrimethamine. The mefloquine-resistant Smith strain remained sensitive to amodiaquine and resistant to pyrimethamine; there was increased resistance to quinine, and an increase in sensitivity to chloroquine.     

Susceptibility of Plasmodium falciparum in vitro to chloroquine, mefloquine, quinine and sulfadoxine/pyrimethamine in Somalia: relationships between the responses to the different drugs.

The susceptibilities of Plasmodium falciparum to chloroquine, mefloquine, quinine and sulfadoxine/pyrimethamine were investigated in Mogadishu in 1988, after chloroquine resistance had spread widely in Somalia. Possible correlations of the responses to these drugs were also investigated. Standard World Health Organization in vitro micro-tests were performed. Of 76 isolates tested for chloroquine susceptibility, 58 (76%) were resistant to the drug with mean EC50 and EC99 values of 1.06 x 10(-6) mol/litre and 10.44 x 10(-6) mol/litre of blood, respectively, indicating a high prevalence and degree of resistance. In contrast, all isolates tested were inhibited by mefloquine 3.2 x 10(-6) mol/litre of blood, quinine at 2.56 x (-6) mol/litre of blood-medium mixture, and sulfadoxine/pyrimethamine at 6.0/0.075 x 10(-6) mol/litre of blood-medium mixture, indicating full sensitivity to these 3 drugs. However, a significant positive correlation was found between responses to quinine and chloroquine and between those to quinine and mefloquine; the responses to chloroquine and mefloquine were not correlated. The results may suggest that sites responsible for the correlation are shared between quinine and chloroquine but not essentially between chloroquine and mefloquine. Thus the evolution of chloroquine resistance together with increased use of quinine treatment of P. falciparum may increase the risks of development of quinine resistance, whereas the development of mefloquine resistance would not be triggered by chloroquine resistance.     

Susceptibility of Plasmodium falciparum strains to mefloquine in an urban area in Senegal.

A total of 47 nonimmune febrile patients from Pikine, Senegal, with greater than 1,000 Plasmodium falciparum asexual forms per microliter whole blood were given 12.5 mg per kg body weight of mefloquine in a single oral dose and were followed up daily until day 7 and also on day 14 of the study. Seven of the patients who vomited, four who had 4-aminoquinolines in their blood, and five dropouts were excluded. Fever and parasitaemia were suppressed within four days until day fourteen in 29 of the 31 remaining patients, including 10 with P. falciparum strains that had a low sensitivity to mefloquine. Two failures were due to poor absorption of mefloquine. The presence of P. falciparum strains with low in vitro susceptibility to mefloquine did not affect, within 14 days, the clinical and parasitological efficacy of a single oral dose mefloquine regimen in patients who had received no previous antimalarial treatment and who did not have partial immune protection.     

Efficacy of chloroquine, sulfadoxine-pyrimethamine and amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria among children under five in Bongor and Koumra, Chad

We report two 28-day in-vivo antimalarial efficacy studies carried out in the urban centres of Bongor and Koumra, southern Chad. We assess chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) to treat Plasmodium falciparum uncomplicated malaria. Methods and outcome classification complied with latest WHO guidelines. Out of the 301 and 318 children aged 6-59 months included in Bongor and Koumra, respectively, 246 (81.7%) and 257 (80.8%) were eligible for analysis. In Bongor and Koumra, the 28-day PCR-adjusted failure rates for CQ were 23.7% (95% CI 14.7-34.8%) and 32.9% (95% CI 22.1-45.1%), respectively, and those for SP were 16.3% (95% CI 9.4-25.5%) and 4.3% (95% CI 1.2-10.5%). AQ failure rates were 6.4% (95% CI 2.1-14.3%) and 2.2% (95% CI 0.3-7.6%). The current use of CQ in Bongor and Koumra is questionable, and a more efficacious treatment is needed. Considering the reduced efficacy of SP in Bongor, AQ seems to be the best option for the time being. Following WHO recommendations that prioritize the use of artemisinin-based combinations, artesunate plus amodiaquine could be a potential first-line treatment. Nevertheless, the efficacy of this combination should be evaluated and the change carefully prepared, implemented and monitored.