Search

One thousand and twenty six P. falciparum strains isolated from cases imported in France and field surveys in four regions of Africa and Madagascar were studied in vitro against chloroquine, monodesethylamodiaquine, quinine and mefloquine, 917 in vivo tests were performed during field studies with chloroquine (10 and 25 mg/kg) and amodiaquine (10, 25, 35 mg/kg). In Madagascar, the chemoresistance remained low and stable during the study period, concerning mostly chloroquine (11% in vitro and in vivo) without obvious geographical variation. 25 mg/kg chloroquine or amodiaquine were satisfactory as respectively first and second line therapeutic regimen. In Central Africa, chemoresistance emerged with an epidemic profile and increased dramatically in disseminated urban focus. High level and prevalence of chloroquine resistance and multiresistance were observed few months after the index cases in these foci. In South West Cameroon, amodiaquine remained efficient as curative treatment but only at a dose of 35 mg/kg/5 days. Decrease of in vitro sensitivity and in vivo efficacy of quinine is a matter of concern. Given the heterogeneous and evolutive situation of drug resistance, the need for epidemiological surveillance and monitoring of P. falciparum drug sensitivity in Africa is obvious to adjust therapeutic regimen.

The sensitivity of I. F. A. T. was compared with E. L. I. S. A. using the first method with cross-sections of adult Schistosoma mansoni (A. S. M.), and the second with ovular S. mansoni soluble extract (O. S. M.), the test sera from 86 schistosomiasis patients (32 with S. mansoni and 54 with S.haematobium) and 100 control sera. Despite the better response of S. mansoni sera in both methods, the significant level of antibody detection (maximum sensitivity for minimum non specificity) was higher for E. L. I. S. A., O. S. M. than for I. F. A. T., A. S. M., especially for urinary schistosomiasis.

We present two cases of Plasmodium falciparum malaria contracted in Douala despite adequate prophylaxis by Fansidar for one and by chloroquine for the other. Failure of curative treatment by Fansidar for the first case (in vitro chloroquine-resistant strain) and by amodiaquine plus erythromycin for the second. After these therapeutic failures, both patients presented without fever, but with splenomegaly and anaemia. The successful therapeutic was mefloquine.

The authors report a case of malaria from Burundi, due to chloroquine resistant Plasmodium falciparum. It is the second case of chloroquine resistance, confirmed by in vitro tests, in this country. Decreased sensitivity to quinine is demonstrated by in vivo study, and quinine assay. The isolate was sensitive to amodiaquine and mefloquine in vitro.

The authors report two additional cases of malaria due to chloroquine-resistant Plasmodium falciparum, one from Tanzania, the other from Kenya. In addition to the in vivo observations, these strains were thoroughly investigated by chloroquine assay and evaluation of ED50 using an original method (in vitro semi-microtest).

34 case-reports of type RI resistance of P. falciparum to chloroquine published between 1975 and 1982 are reviewed. The patients were non-immune travellers infected in East Africa and in the neighbouring islands, especially Tanzania, Kenya and Madagascar. The increase in number and level of resistance might be a problem in Africa. A monitoring system of the patient and in the field is proposed and the possibilities of prevention and control are discussed.

24 cases of Plasmodium falciparum malaria in a group of 73 non-immune subjects coming mostly from central Africa have been tested in vitro for chloroquine sensitivity: 5 are sensitive, 19 are resistant among whom one is also quinine-resistant. The comparison of the major clinical and biological features in the two groups by methods of statistical calculation shows that the parasitological diagnosis is retarded and that hemolysis is more frequent in the strains of Plasmodium falciparum resistant to chloroquine. Thrombopenia is more frequent with chemosensitives strains. In any case, the delay between the first symptoms and the parasitological diagnosis is increased with an average of 17 days in comparison to what was observed in the 1970's. Under the influence of several complex factors including human ones, the clinical aspects are changed in comparison to forms usually observed. In this context of an extension of the emergence of the chemoresistance and in the aim of efficiency, only the quinine I.V., with an average dose of 16.5 mg/kg per day of quinine-base, has been chosen as a curative treatment during 5 days allowing a rapid recovery without after-effects for all the cases.

Between April and June 1984, eight chloroquine-resistant P. falciparum malaria cases were observed in non-immune patients after their emergency sanitary return from NE Mozambique. In vivo resistance to amodiaquine and pyrimethamine were demonstrated from two isolates. Radical cure was obtained with mefloquine in all cases. These patients came from an expatriate community of 35 adult men among which six other chloroquine-resistant malarial cases were probable. The epidemic pattern of this chloroquine-resistant focus is underlined.

563 cases of Falciparum malaria were detected in 1984 and 1985 in 7 malarial zones covering 3 climatic regions in Madagascar. All subjects underwent a therapeutic test; 175 strains of Plasmodium falciparum were isolated for in vitro drug sensitivity studies. 28 strains which were moderately chloroquine resistant in vitro were identified in 1983 in these various zones. However, 16% strains studied in 1984 in Alatsinainy (plateaux area), were chloroquine-resistant in vitro. The in vitro sensitivity to the other amino-4-quinolines seemed to be retained. In vivo, 7% of resistance type RI or RII were noted with 25 mg/kg of chloroquine but none with 25 mg/kg of amodiaquine. The usual therapeutic schedule for partially immune subjects (10 mg/kg in one dose) was ineffective on day 7 in 34% of the cases with chloroquine and 5% of the cases with amodiaquine. In conclusion to this study, we recommend that chemoprophylaxis should be stopped in schools in Madagascar and that presumed malarial attacks should be treated with a minimum dose of 25 mg/kg of chloroquine in 3 days. We suggest that amodiaquine should be used in cases of therapeutic failure with chloroquine.

Halofantrine is a 9-phenanthrene-methanol effective against multiresistant strains of Plasmodium falciparum. It is extremely effective and well-tolerated in treating cases of malaria imported into France. 1,500 mg in 3 doses at 8 hour intervals produced 100% cure rate in semi-immune patients. This dosage could be repeated after 14 days in order to obtain the same cure rate in non-immune patients. Side-effects are minor and include epigastric pain, nausea and one case of skin rash.

One hundred and ten patients with severe falciparum malaria have been admitted between 1985 and 1987. All had received quinine to the same protocol: 8.3 mg base/kg infused intravenously over 3 hours every eight hours. A systematic glycaemic supervision by capillary glycaemia every eight hours has been employed. Hypoglycaemia occurred in 17 patients (15.5%). Despite an early injection of glucose, recurrent hypoglycaemia was almost constant (16 over 17). The mortality of the group with hypoglycaemia is significantly higher (41% to 25%; 00.5 less than p less than 0.1). We have not found any connection between the risk of hypoglycaemia and elements of gravity of the access. If the part of the patient (age, pregnancy), high parasitemia and impaired hepatic gluconeogenesis have been finding, our results suggest than quinine-induced insulin secretion is the principal mechanism of this hypoglycaemia. Its high incidence and its severity impose preventive measures.

The sulfadoxine-pyrimethamine combination has not been recommended for the prophylaxis of malaria since 1985 following serious accidents in the USA. However, this drug is worth considering for treatment since it has the advantage over mefloquine of being cheaper, having fewer side effects and it avoids using mefloquine. A study of Plasmodium falciparum resistance to Fansidar should be carried out on cases imported to France to determine an adapted utilisation of this drug. This would be an appreciable advantage for tropical Africa.

The in vitro susceptibility of various Plasmodium falciparum isolates obtained from patients infected in French Guiana was tested in a semi-microtest, using four antimalarial drugs. 90.6% of 32 isolates were resistant to chloroquine, 40% to amodiaquine and 17% to quinine. All the 17 isolates were susceptible to mefloquine.

In vitro testing of P. falciparum chemosensitivity was assessed from 2 severe malaria cases in which the parasite was thought to be resistant to chloroquine. The 3 following methods were compared in both cases. 1.--Maturation test, carried out before and from the outset of treatment, is a rapid and simple method. Primary efficiency of therapeutic procedures can be estimate and the eventually adjust. 2.--Rieckmann test, on patient blood, measure chemosensitivity of host strain modulated by hosts factors. Initially proposed for epidemiological trials, this method is of interest for the choice of treatment at the end of acute phase in individuals cases. 3.--Strain chemosensitivity measurement, require one or more weeks of Plasmodium cultivation. This value will be very helpful to estimate the sensitivity level of P. falciparum to chloroquine in the outcoming strain area.

Among 172 strains collected in Yaoundé 60% are chloroquine-resistant, 37% are amodiaquine-resistant, instead of quinine and mefloquine which are completely efficient. Among 30 strains collected at a rural health center (where self treatment decreases), 27% are chloroquine-resistant. New therapeutic schemes for first and second line treatment in endemic areas must be evaluated.

The study by an isotopic semi-microtest of the sensitivity of 44 P. falciparum strains isolated from Congolese children living in Pointe-Noire demonstrated a high prevalence of chloroquine resistance and partial cross resistance to monodesethylamodiaquine. The sensitivity to quinine was high except for 3 isolates. The assay of amino-4-quinolines by H. P. L. C. on 37 subjects revealed the extent of self-treatment and drug-pressure in this population. A 3-day treatment with 25 mg/kg of chloroquine or amodiaquine in 24 subjects resulted in the disappearance of clinical symptoms in all patients and a parasitological cure on day 7 in 75%. The partial maintenance of efficacy of amino-4-quinolines in this chloroquine-resistant region implies that chloroquine and amodiaquine can be used as first choice drugs for uncomplicated acute malaria, but on condition that the levels of resistance and transmission are monitored.

Spreading of chemoresistance from East Africa to Central Africa is a very worrying problem for Western Africa. In fact, chemotherapy of febrile attacks is at present admitted as malaria control strategy in the framework of Primary Health Care. This new strategy is based on the fact that commonly used antimalarial drugs as chloroquine are surely efficacious. Thus, the surveillance of chemosensitivity of Plasmodium falciparum local strains becomes a priority. From studies carried out in Burkina Faso during many years, Centre Muraz of O.C.C.G.E. has organized a surveillance system with several levels: a Reference Center, a National Center for each country and sentinel centers located in the different epidemiological features of the countries. This surveillance concerning many states can allow to detect more quickly some possible problems in relation with chemoresistance and to take measures to limit its impact.

The kindling effect is an experimental model of epilepsy which results from an intermittent application of focal electrical stimulations to certain regions of the brain. Generalized seizures are usually obtained after about fifteen stimulations of amygdala in the rat. We studied the kindling effect in hyperbaric-hyperoxic conditions. Eleven Wistar rats were stimulated daily in a caisson and all stimulations were delivered after 30 min of diving at 3 ATA of air. Diving inhibited kindling in half animals. In the others, which all presented generalised convulsions, diving produced a reduction in seizure duration, especially during the generalisation phase.

Seventy-nine French residents in Dar-es-Salaam, Tanzania, on 3 chemoprophylactic regimens, were included in a prospective study for a mean time of 10.8 +/- 3 months. No malaria attack was observed in the group (n = 32) taking chlorproguanil and chloroquine for chemoprophylaxis. Two attacks were reported in the group (n = 29) using chlorproguanil alone and 5 attacks in the group (n = 20) that was not taking antimalarial chemoprophylaxis. The blood concentration of chlorproguanil and chlorcycloguanil, the active metabolite, were measured, 3 hours (II3), 3 days (D3), and 7 days (D7) after the weekly dose. The urine concentration was measured at D7. The prophylaxis failure with chlorproguanil can be explained either by irregular use of the drug, or insufficiently lasting plasma concentration of chlorcyloguanil, or existence of parasite resistance to dihydrofolate reductase inhibitors.

A death from chloroquinoresistant falciparum malaria contracted by a traveller under chloroquine chemoprophylaxis during a stay in the Cameroon provides the authors with an opportunity to analyze the extension of chloroquinoresistance in Africa. Having appeared there about 10 years ago, it remained for a long time localized in East Africa. In recent years, it has moved West. Today, 17 countries located from the North to the South between Sudan and Mozambique, and from East to West between Kenya and the Cameroon are affected, as are the Malagasy Republic, the Comores and Zanzibar. The strains resistant to chloroquine are still sensitive to amodiaquine. In certain regions which are widespread in the continent, resistance to pyrimethamine has become evident in the last 30 years; resistance to pyrimethamine-sulfadoxine and pyrimethamine-dapsone has appeared in the last 3 years in East Africa. In the light of the complexity of the problem of malaria chemoprophylaxis, the authors emphasize the necessity of resensitizing the public at large with respect to personal protection against biting anopheline mosquitos, especially during the hours of darkness. The medical profession should equally be made aware of these new problems. Three types of chemoprophylaxis in relation to the areas visited are proposed: the first for West Africa; the second for Central Africa, neighbouring regions and the Malagasy Republic and the Comores; the third for the 3 East Africa countries the most affected, which are Kenya, Burundi and Tanzania.