Mefloquine-resistant strains of Plasmodium falciparum in Madagascar: impact on tourists and public health.

Although the national policy for malaria control in Madagascar is to use chloroquine as the first line of treatment, mefloquine has been and is recommended to travellers to the country, both for malaria prevention and cure. The in-vitro susceptibility of Plasmodium falciparum to mefloquine was therefore assessed during a prospective surveillance study in various areas in Madagascar, including the tourist sites of Nosy-be and Sainte Marie. Of the 254 isolates of P. falciparum successfully tested, 232 (90.9%) were sensitive to mefloquine, 12 (4.7%) showed decreased susceptibility (40 nM < IC50 < 50 nM), and 10 (3.9%) were resistant (IC50 > 50 nM). Five (50%) of the resistant strains and nine (75%) of those with decreased susceptibility were from coastal areas or the two tourist sites. The drug pressure that could have induced the resistance observed could therefore be related to the donation of antimalarials, such as mefloquine, by tourists to local populations. The residents of the coastal areas take any donated drugs as self-medication, ignoring recommended doses and durations of treatment. This situation has two main consequences: (1) there is an urgent need to control the abusive and incorrect use of antimalarial drugs in Madagascar, to safeguard the effectiveness of chemotherapy in the future; and (2) these increases in resistance compromise the efficiency of the antimalarial chemoprophylaxis currently recommended to tourists. The use of mefloquine can no longer be considered as a guarantee of protection against malaria in coastal areas and other sites frequented by tourists.

[Drug resistance of Plasmodium falciparum along the borders of the highlands in Madagascar: outlook for a national control program]. / Chimioresistance de Plasmodium falciparum sur les marges des hautes terres malgaches: perspectives pour le programme national de lutte.

Resistance of Plasmodium falciparum to chloroquine was first suspected in Madagascar in 1975 and later confirmed in vivo and in vitro. During the period from 1985 and 1990, the network of public health monitoring stations reported that 1% of the population living on the central Highlands of Madagascar died of malaria. Thereafter the National Malaria Control Program achieved good success by spraying homes with insecticide and reorganizing distribution of chloroquine in all villages. However data recorded between 1996 and 1998 indicates that, after four years of widespread chloroquine use, resistance to amino-4-quinolones is progressing in Madagascar. The tests described in this report were performed on patients with documented malaria included in cohorts and followed year round by a physician. The three villages studied were located along the borders of the highlands between the plateaus and coastal areas. In vivo tests showed that the incidence of chloroquine resistance was 0% in Mahakary, 32% in Ankazobe and 30% in Saharivo. Clinically, however, treatment was unsuccessful in only 16% and 8% of cases respectively. In vitro tests demonstrated chloroquine sensitivity in 79% of the 153 strains tested. No resistance to quinine or halofantrine was observed. In vitro tests indicated an onset of resistance to mefloquine. Although the success rate of chloroquine treatment is nearly 80%, spread of strongly chloroquine-resistant strains is a risk especially in subjects with mild immunity to malaria.

In vitro and in vivo chloroquine-potentiating action of Strychnos myrtoides alkaloids against chloroquine-resistant strains of Plasmodium malaria.

Crude alkaloids of Strychnos myrtoides Gilg & Busse, empirically used as an adjuvant to chloroquine (CQ) in Malagasy herbal remedies, were practically devoid of intrinsic in vitro and in vivo antimalarial activity. However, when combined with CQ at a dose level much lower than their IC50 value, they markedly enhanced in vitro the effectiveness of the synthetic drug against a CQ-resistant strain of Plasmodium falciparum. They also enhanced in vivo CQ activity against a resistant strain of Plasmodium yoelii. By counter-current distribution (CCD) separation of the crude alkaloid extract, the two major alkaloids strychnobrasiline (1) and malagashanine (2), together with four minor alkaloids, were isolated. Strychnobrasiline and malagashanine were devoid of both intrinsic antimalarial activity and cytotoxicity effect, but exhibited significant CQ-potentiating actions. These findings could account for the above-mentioned empirical use of S. myrtoides. The present state of research on antimalarial drug from Strychnos genus is also discussed.

In vitro antimalarial activity and chloroquine potentiating action of two bisbenzylisoquinoline enantiomer alkaloids isolated from Strychnopsis thouarsii and Spirospermum penduliflorum.

The bisbenzylisoquinolines 7-O-demethyltetrandrine and limacine, respectively, isolated from Strychnopsis thouarsii Baill. and Spirospermum penduliflorum Thou. were evaluated for their intrinsic antimalarial activity in vitro and chloroquine potentiating action against the chloroquine-resistant Plasmodium falciparum FCM 29 originating from Cameroon. They both showed significant antiplasmodial potency in vitro with very similar IC50 values of respectively, 740 nM and 789 nM (IC50 = 214 nM for chloroquine used as standard drug), which demonstrated that the stereochemistry of the C-1 and C-1' configuration likely plays a role in the chloroquine potentiating effect of these drugs. If confirmed in vivo, these results may account for the traditional use of the two plants as antimalarials and adjuvant to chloroquine in Madagascan folklore remedies.