Single-dose chloroquine therapy for Plasmodium falciparum in children in Togo, West Africa

Chloroquine, in a single dose of 10 mg of base/kg, was given orally to Togolese children less than 5 years of age as primary therapy for Plasmodium falciparum malaria. A simplified World Health Organization in vivo method was used, as was a sequential analysis procedure for determining if the drug trial was a success or failure. A total of 178 children in 3 regions were treated; 174 (98%) responded successfully, which required a greater than or equal to 75% reduction in parasites by day 2 and elimination of parasites by day 7. All 4 failures had low blood levels of chloroquine and desethylchloroquine at day 7. A single dose of chloroquine for treating malaria can be considered for those areas of Africa where the efficacy of such therapy is documented, and where an antimalarial drug sensitivity monitoring system is operating.     

Susceptibility of Plasmodium falciparum to chloroquine in Liberia, West Africa: in vitro tests for 24 and 48 hours

In vitro tests of Plasmodium falciparum susceptibility to chloroquine were performed in May 1982 in Yekepa area, northern Liberia where several previous in vivo investigations had shown full susceptibility. The isolates from 19 subjects were studied. 18 Rieckmann 24-h micro tests were successful. Effective chloroquine concentrations by probit analysis were 0.3 microM for 50% inhibition (EC50) and 1.2 microM for 99% inhibition (EC99). 18 of the 48-h tests were successful. 10 isolates were inhibited by 0.75 microM chloroquine and another 8 by 2.5 microM.     

RII-RIII chloroquine resistant Plasmodium falciparum malaria from East Africa: studies of the in vivo and in vitro response to chloroquine

A case is reported of Plasmodium falciparum malaria from East Africa resistant to chloroquine in the in vivo test at the RII level. Serum chloroquine concentrations and the in vitro test indicated RIII resistance. The need for further comparative studies of parasitaemia, serum chloroquine concentration and in vitro chloroquine sensitivity assessment is emphasized.     

Changing response of Plasmodium falciparum to chloroquine in West Bengal during 1980-1988

A total of 314 cases of Plasmodium falciparum malaria studied during 1980-88 in nine times monitoring revealed three RIII foci i.e. two in Jalpaiguri and one in Purulia districts. The studies showed a parasite clearance of 40 per cent and 32 per cent of P. falciparum cases within seventh day in Purulia and Jalpaiguri districts respectively, with a dosage of 25 mg per kg body weight, spread over three days in divided doses. Increase in transmission potential and prolonged drug pressure with single drug have been noted in association with development of resistance. Malaria parasite clearance time (MPCT) value of sensitive and resistant cases reach parallelism and malaria parasite recrudescence time (MPRT) value starts declining, giving an indication of stabilisation of genetic change in the parasite.     

In vitro and in vivo susceptibility of Plasmodium falciparum isolates from Liberia to pyrimethamine, cycloguanil and chlorcycloguanil

In vivo susceptibility of Plasmodium falciparum to chlorproguanil and in vitro susceptibility to pyrimethamine, cycloguanil and chlorcycloguanil were studied in 38 children from two Liberian villages. Children in one village (Lagbala) had received monthly chemosuppression with chlorproguanil from 1976-1985, and children in the other village (JDF) had received fortnightly chlorproguanil from 1981-1985. The highest and lowest IC100 for pyrimethamine differed by a factor of 10(5), but they differed only by a factor of 10(3) for chlorcycloguanil. The mean IC100 for chlorcycloguanil was significantly lower (P less than 0.0001) than the mean IC100 for pyrimethamine and cycloguanil, and the IC100 for the samples most resistant to chlorcycloguanil (10(-8) M) was still well below peak blood concentrations after chlorproguanil administration. Resistance could be defined as IC100 greater than or equal to 10(-6) M for pyrimethamine and IC100 greater than or equal to 10(-8) M for chlorcycloguanil. The isolates most resistant or most sensitive to pyrimethamine were also the most resistant or most sensitive to chlorcycloguanil, indicating partial cross-resistance between the two drugs. The in vivo response to chlorproguanil 1.5 mg kg-1 in Lagbala was equal to the response in 1983. Chlorproguanil 1.5 mg kg-1 resulted in lower parasite rates on day 3 and 7, but did not prevent 60% of the children requiring treatment with chloroquine during the four weeks' follow-up after chlorproguanil administration.     

In vivo efficacy of chloroquine treatment for Plasmodium falciparum in Malawian children under five years of age

In 1984 the government of Malawi instituted a program to reduce malaria mortality and morbidity in children less than 5 years of age as a part of the Combatting Childhood Communicable Diseases (CCCD) program. To define the appropriate malaria therapy regimen, investigators used a quality assurance design in a simplified 7-day in vivo drug response study with follow-up observations on day 2 (D2), D3, and D7 after the initial day of the study (D0). The efficacy of oral chloroquine was assessed in 224 children who were enrolled at 6 sites, 2 in each of the 3 administrative regions of Malawi. Parasitological failure, defined as failure of parasitemia to decrease by 75% of the value by D3 or presence of any detectable parasitemia on D7, ranged from 41%-65% following administration of chloroquine 25 mg (base)/kg. However, only 8% of children who were parasitemic on D7 were febrile or judged to be ill. Considering these therapeutic results and the higher cost and limited availability of alternative therapies, chloroquine 25 mg/kg therapy was adopted as the primary therapy for malaria.     

In vitro chemosensitivity of Plasmodium falciparum to four chloroquine derivatives

The antimalarial activity of four chloroquine derivatives has been assessed in vitro by the Trager and Jensen technique against the strain of Plasmodium falciparum FCC, 2spp. Monodesethyl-chloroquine possessed a significant activity, reducing the parasitaemia to 5% with 2 nM ml-1 (base). The hydroxy-metabolite showed a slight activity, reducing the parasitaemia to 39.5% with 2 nM ml-1 (base). No activity was found with the amino-metabolite and the pyrrolidinyl chemical derivative. The anti-malarial activity of monodesethyl-chloroquine should be considered for pharmacokinetics and for optimizing chloroquine treatments.     

Susceptibility of Plasmodium falciparum to chloroquine in northern Liberia after 20 years of chemosuppression and therapy

The in vivo and in vitro susceptibility of Plasmodium falciparum to chloroquine was investigated in northern Liberia after 20 years of continuous chemosuppression and therapy with 4-aminoquinolines. In all patients studied (n = 53) parasitaemias were cleared within four days. There were no recrudescences in 16 patients followed-up for 28 days. All isolates of P. falciparum tested in vitro (n = 26) showed sensitive patterns. Schizont maturation was inhibited by a chloroquine concentration of between 0.25 and 0.75 mumol-1. In this area of Liberia no resistance to chloroquine was found in spite of extensive use of 4-aminoquinolines. This may support the view that importation of at least partially resistant strains, rather than local mutation of P. falciparum, precedes selection of resistant strains. Hence, we conclude that regular intake of chloroquine by groups at risk is justified if it is combined with regular monitoring of drug susceptibility.     

间日疟原虫对氯喹敏感性的体内监测

目的了解广东省间日疟原虫对氯喹敏感性变化,以指导合理用药.方法采用WHO体内现场试验(7d)法和扩展试验(28d)法,在广东省东、中、西、北部选点进行敏感性监测.结果1996-2000年共观察157例,平均退热时间为22.2h±10.2h;无性体平均转阴时间为38.1h±12.6h;复燃率为0.结论广东省间日疟原虫对氯喹仍然敏感.     

Treatment of children with Plasmodium falciparum malaria with chloroquine in Guinea-Bissau

Children with symptomatic malaria in Bissau, Guinea-Bissau were randomly assigned to treatment with a 25 mg/kg total dose of chloroquine as recommended by the National Malaria Program or with a higher total dose of 50 mg/kg. Sixty-seven and 62 children, respectively, completed the treatment and were then followed once a week for five weeks. Treatment with a dose of 50 mg/kg was significantly more effective than treatment with 25 mg/kg in preventing recrudescence. The cumulative relative risk (95% confidence interval) of having parasitemia in the low-dose group during follow-up was 0.20 (0.08-0.52) on day 21, 0.38 (0.17-0.86) on day 28, and 0.48 (0.23-0.98) on day 35. Few adverse events were reported, although more children complained of vomiting and diarrhea on day 2 in the high-dose group compared with those in the low-dose group. However, this difference was not statistically significant. We conclude that a dose of 50 mg/kg of chloroquine could be recommended for treatment of Plasmodium falciparum malaria in Bissau. To minimize the risk of side effects, this higher dose should be given divided into two daily doses over a three-day period.     

云南东南部地区恶性疟原虫对氯喹敏感性纵向观察

目的了解恶性疟原虫对氯喹的敏感性变化趋势,指导合理用药。方法采用WHO推荐的恶性疟原虫对抗疟药敏感性体内临床观察法,进行纵向监测。结果1981～1983年共观察恶性疟病人78例,其中对氯喹敏感(S)2例,抗性(R)76例,包括Ⅰ级抗性(RⅠ)34例、Ⅱ级抗性(RⅡ)12例、Ⅲ级抗性(RⅢ)30例,抗性率为97.44%。2005～2006年共观察32例,其中S19例,S或RⅠ2例,抗性11例(RⅠ8例、RⅡ1例、RⅢ2例),抗性率为36.67%(11/30)。两组病例对氯喹的抗性率和抗性程度差异均有统计学意义(P<0.01)。结论云南省南部地区恶性疟原虫对氯喹的抗性较1983年明显下降,但仍有34.38%(11/32)的抗性病例,且存在着RⅢ抗性病例,提示当前氯喹仍不能用于当地恶性疟现症病人的治疗。     

The in vivo sensitivity of Plasmodium falciparum to chloroquine in the Red River basin, Yunnan, China

The sensitivity of Plasmodium falciparum to chloroquine in vivo was examined out in a small town in the Red River basin from 1995 to 1996. forty cases were recruited into the present study, 32 cases were completely followed-up. The results of the in vivo study revealed that only 3 (9%) cases were sensitive to chloroquine, 29 (90.6%) showed resistance to chloroquine, among whom 7 cases (22%) showed resistance at RI, 12 cases (38%) at RII, and 10 cases (31%) at RIII. It is suggested that P. falciparum endemic areas should stop using chloroquine and other 4-aminoquinolines in the Red River basin now. Qinhaosu and pyronaridine were recommended to use as the first line antimalarial drugs of P. falciparum infection in the basin.     

恶性疟原虫氯喹敏感株与抗性株对青蒿素类药物体外敏感性的研究

目的 测定恶性疟原虫氯喹敏感株与抗性株对青蒿素类药物的体外敏感性. 方法 运用体外微量法与酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)测定青蒿琥酯、蒿甲醚及双氢青蒿素等3种青蒿素类抗疟药物对体外培养的恶性疟原虫氯喹敏感株与氯喹抗性株的体外敏感性,并比较两种方法测定的IC50值. 结果 体外微量法测定的3种药物对恶性疟原虫氯喹敏感株的IC50值依次为3.12 nmol/L、4.30 nmol/L、2.18 nmol/L,对恶性疟原虫氯喹抗性株的IC50值依次为4.31nmol/L、3.90 nmol/L、3.17 nmol/L;同时,将体外微量法与ELISA法所获的结果进行相关性分析,两种方法结果基本一致(r2=0.93,P＜0.001). 结论 恶性疟原虫氯喹抗性株对青蒿素类药物无明显的交叉抗性;ELISA法可用于恶性疟原虫对抗疟药物的体外敏感性检测.     

In vivo efficacy of quinine treatment for Plasmodium falciparum malaria in Malawian children

Twenty-five Malwaian children with Plasmodium falciparum infection were studied for response to quinine in an eight-hourly dosage of 10 mg salt kg-1 body weight. The mean parasite clearance time, defined as the time after initiation of treatment when the first of two consecutive 12-hourly smears was negative for P. falciparum parasites, was 67 hours. The mean fever clearance time, defined as the time after initiation of treatment when the axillary temperature first fell below 37.5 degrees C and remained below this level for 48 hours, was 36 hours. Twenty-four hours after the first dose of quinine, the geometric mean parasite density among the children studied had decreased by 84%, from 41 357-6586 parasites mm-3, and all children cleared their parasitaemia within 108 hours. Results of this study confirm that quinine remains effective in rapidly controlling P. falciparum parasitaemias in Malawi, where resistance to the 4-aminoquinolines is highly prevalent.     

In vitro reversal of chloroquine resistance in Plasmodium falciparum with dihydroethanoanthracene derivatives

The effects of combining four dihydroethanoanthracenic (DEA) derivatives and chloroquine were assessed in vitro against Plasmodium falciparum chloroquine resistant parasites W2, Palo Alto, FCR3, and Bres1. Like verapamil or promethazine, the four dihydroethanoanthracenic derivatives tested can be added to the growing list of agents that show capability in enhancing the activity of chloroquine against resistant parasites. The structurally related tricyclic antihistaminic compounds examined in this study exerted different intrinsic antimalarial activity, but the same chloroquine-potentiating activity as verapamil or promethazine. They may act both on the rate of chloroquine accumulation and on its access to ferriprotoporphyrin IX. The reversal mechanism would be assumed to result from competition between DEA derivatives and chloroquine for efflux translocation sites, thus causing an increase in steady-state accumulation of chloroquine and a return to susceptibility. Restoration of therapeutic efficacy of chloroquine against resistant parasites by the administration of an additional drug available at relatively low cost may be a more effective strategy than the introduction of another antimalarial drug at the national level.     

Response of Plasmodium falciparum in Sudan to oral chloroquine.

The chloroquine sensitivity of Plasmodium falciparum was studied in two areas of Sudan. In the Gezira, 99.2% of the patients tested responded completely to the drug. Two patients (0.4%) and one patient (0.2%) showed, respectively, RI and RII responses. However, in those showing RI response reinfection could not be excluded. In an area of southern Sudan patients could only be followed-up for 7 days; nevertheless, this was sufficient to exclude the presence of RII and RIII responses there. This study also showed that malaria is a common cause of fever in Sudan, as over 90% of fever cases tested in the Gezira were positive for malaria and P. falciparum was the predominant species in these cases.