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PubMed1999

Atovaquone-proguanil compared with chloroquine and chloroquine-sulfadoxine-pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines.

This randomized, open-label clinical trial compared a fixed-dose combination of atovaquone and proguanil (n=55) with chloroquine (n=23) or a combination of chloroquine, sulfadoxine, and pyrimethamine (n=32) for treatment of acute falciparum malaria in the Philippines. Patients were hospitalized for 28 days to ensure medication compliance and prevent reinfection. Atovaquone-proguanil produced a significantly higher cure rate (100%) compared with that for chloroquine (30.4%; P<.0001) or chloroquine-sulfadoxine-pyrimethamine (87.5%; P<.05). Treatments did not differ significantly with respect to parasite clearance time (mean: 46.7 h for atovaquone-proguanil, 60.0 h for chloroquine, and 42.8 h for chloroquine-sulfadoxine-pyrimethamine) or fever clearance time (mean, 38.8, 46.8, and 34.5 h, respectively). Adverse events were typical of malaria symptoms; the most frequently reported events were vomiting (18% for atovaquone-proguanil, 17% for chloroquine, and 9% for chloroquine-sulfadoxine-pyrimethamine), abdominal pain (15%, 17%, and 3%, respectively), anorexia (11%, 13%, and 0%, respectively), and headache (6%, 17%, and 3%, respectively). Atovaquone-proguanil was well tolerated and more effective than chloroquine or chloroquine-sulfadoxine-pyrimethamine for treatment of multidrug-resistant falciparum malaria in the Philippines.

Antimalarials↗
PubMed1974

Chloroquine-resistant Plasmodium falciparum: effect of substrate on chloroquine and amodiaquin accumulation.

Glucose stimulates the high-affinity processes of chloroquine and amodiaquin accumulation in owl monkey erythrocytes infected with a chloroquine-susceptible strain of Plasmodium falciparum. Although these erythrocytes have greater ability to accumulate amodiaquin than chloroquine, glucose has relatively less effect on amodiaquin accumulation than on chloroquine accumulation. In contrast to these findings with chloroquine-susceptible P. falciparum, glucose stimulates amodiaquin but not chloroquine accumulation in erythrocytes infected with chloroquine-resistant P. falciparum. This lack of function of a substrate-dependent component of chloroquine accumulation distinguishes chloroquine-resistant from chloroquine-susceptible P. falciparum.

Amodiaquine↗
PubMed1997

Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood chloroquine levels.

To develop criteria for the diagnosis of resistance to chloroquine using an in vivo test, we examined published records of early clinical trials of quinine and chloroquine against Plasmodium vivax. These data established the timing of relapse by tropical P. vivax relative to therapy by these drugs. The first relapse occurred 17 days after initiating and three days after terminating quinine therapy. The median day of relapse was day 23, and 59% of the patients had relapsed by day 30 (n = 333). In contrast, no relapse occurred until day 36 following chloroquine treatment (n = 256). Data from our laboratory may help explain this difference; among 91 Indonesian patients with malaria, the mean whole blood levels of chloroquine (CQ) and desethylchloroquine (DCQ) were 141 ng/ml (95% confidence interval = 115-167) on day 28 after initiating standard therapy (25 mg base/kg in three doses over a 48-hr period). This exceeds the estimated minimal effective concentration of chloroquine (100 ng/ml of whole blood). Thus, chloroquine lingering in the blood for at least 28 days after starting standard therapy was sufficient to eliminate or at least suppress chloroquine-sensitive tropical P. vivax. We conclude that a parasitemia by P. vivax recurring in the 28 days after full compliance to standard chloroquine therapy demonstrates resistance. If the recurrence appears before day 16, it is almost certainly a recrudescence and between days 17 and 28 it may be either a recrudescence or a relapse by chloroquine-resistant parasites. Recurrences beyond day 28 could be relapse by chloroquine-sensitive P. vivax.

Animals↗
PubMed1991

Comparison of mefloquine, chloroquine plus pyrimethamine-sulfadoxine (Fansidar), and chloroquine as malarial prophylaxis in eastern Thailand.

From July 1983 to March 1984 a randomized double blind prophylactic trial in Thai gem miners working across the border in Cambodia was conducted to determine the prophylactic efficacy of 3 drug regimens against P. falciparum and P. vivax malaria along the Thai-Cambodian border. Gem miners have a high incidence of malaria. Maximum duration of individual participation was 14 weeks. Of 334 participants in this study who were seen every 2 weeks, 145 received mefloquine 500 mg fortnightly, 112 received chloroquine 300 mg base weekly plus Fansidar (1000 mg sulfadoxine and 50 mg pyrimethamine) fortnightly and 77 received chloroquine as 300 mg base weekly. The significant reduction of vivax malaria in study subjects (compared to background incidence) implied good compliance with self administration of chloroquine in the intervening weeks between scheduled appointments. The attack rate in each prophylactic regimen was 2188 cases/1000/year with mefloquine, 8338 cases/1000/year with chloroquine-Fansidar and 10,207 cases/1000/year receiving chloroquine alone. There was a 79% prophylactic efficacy for mefloquine and 18% efficacy for the chloroquine plus Fansidar regimen compared to chloroquine. Using life table analysis, 56% of the mefloquine group, 6% of the chloroquine-Fansidar group and 4% of the chloroquine group were malaria free at the end of the 14 weeks study. The chloroquine plus sulfadoxine-pyrimethamine regimen prescribed for prophylaxis is no longer effective for multidrug resistant strains of P. falciparum in the study area. This study also seriously questions the efficacy of mefloquine prophylaxis.

Adolescent↗
PubMed1992

Energy dependence of chloroquine accumulation and chloroquine efflux in Plasmodium falciparum.

Chloroquine inhibits the growth of susceptible malaria parasites at low (nanomolar) concentrations because of an energy-requiring drug-concentrating mechanism in the parasite secondary lysosome (food vacuole) which is dependent on the acidification of that vesicle. Chloroquine resistance results from another energy-requiring process: efflux of chloroquine from the resistant parasite with a half-time of 2 min. Chloroquine efflux is inhibited reversibly by the removal of metabolizable substrate (glucose); it is also reduced by the ATPase inhibitor vanadate. These results suggest that chloroquine efflux is an energy-requiring process dependent on the generation and hydrolysis of ATP. Chloroquine efflux cannot be explained by differences in drug accumulation between chloroquine-susceptible and -resistant parasites because the 40-50-fold difference in initial efflux rates between -susceptible and -resistant parasites is unchanged when both parasites contain the same amount of chloroquine. Although chloroquine efflux is phenotypically similar to the efflux of anticancer drugs from multidrug-resistant (mdr) mammalian cells, it is not linked to either of the mdr-like genes of the parasite.

Adenosine Triphosphatases↗
PubMed2005

Primaquine synergises the activity of chloroquine against chloroquine-resistant P. falciparum.

In recent years, resistance to the antimalarial drug, chloroquine, has become widespread. It is, therefore, imperative to find compounds that could replace chloroquine or work synergistically with this drug to overcome chloroquine resistance. We have examined the interaction between chloroquine, a 4-aminoquinoline, and a number of 8-aminoquinolines, including primaquine, a drug that is widely used to treat Plasmodium vivax infections. We find that primaquine is a potent synergiser of the activity of chloroquine against chloroquine-resistant Plasmodium falciparum. Analysis of matched transfectants expressing mutant and wild-type alleles of the P. falciparum chloroquine resistance transporter (PfCRT) indicate that primaquine exerts its activity by blocking PfCRT, and thus enhancing chloroquine accumulation. Our data suggest that a novel formulation of two antimalarial drugs already licensed for use in humans could be used to treat chloroquine-resistant parasites.

Animals↗
PubMed2004

Endogenous opioids, mu-opiate receptors and chloroquine-induced pruritus: a double-blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine-induced itching.

AIMS: Chloroquine induces a severe generalized pruritus, in predisposed Black African patients, during treatment of malaria fever, and also in some Caucasian patients treated for rheumatological diseases. We have previously shown that chloroquine may release endogenous opioids and/or interact with micro-opiate receptors in rats, and that both histamine and malaria parasite blood density, contribute to the itching severity in malaria fever in humans. The aim of our present study was to assess and compare the antipruritic efficacy of the micro-opiate receptor antagonist, naltrexone, and the antihistamine, promethazine, in chloroquine treated patients with malaria fever. METHODS: A double-blind, randomized, parallel group comparison of the chloroquine-induced pruritus intensity and time profile in patients with parasitologically proven malaria fever, who were pretreated with a single dose of either naltrexone 50 mg or promethazine 25 mg orally (six patients each). All patients had an established history of severe pruritus following chloroquine treatment of malaria fever. A self-assessed itching severity score was undertaken at 0, 6, 12, 24, 48 and 72 h after initial chloroquine dosing, and the areas under the pruritus-intensity time curve AUCP0-72 h was determined in each patient and correlated to the malaria parasite density in blood. RESULTS: Both naltrexone and promethazine subjectively reduced itching severity compared with prior historical experience. One patient on naltrexone and two on promethazine never experienced any itching. There was no statistically significant treatment effect, but a significant time effect (P = 0.001, F = 4.77 d.f. 5) by two-way repeated measures ANOVA. The AUCP for naltrexone was 82 +/- 25 units/h, and 57 +/- 34 units/h for promethazine [95% confidence interval for the difference being -73 to 123]. However, the malaria parasite density in the naltrexone group (740 +/- 178 microl(-1)) tended to be higher than in the promethazine group 314 +/- 69 microl(-1) (P = 0.056, 95% confidence interval for the difference being -15 to 866 microl(-1)). Correction of the AUCP for malaria parasite density (parasite pruritogenic index, AUCP. units/h/parasites/microl blood) tended to be lower with naltrexone 9.1 +/- 2.6 than with promethazine 12.2 +/- 7.0 There was a highly significant and positive correlation between the malaria parasite density and the AUCP0-72 h, on naltrexone (r2 = 0.78, P = 0.040) and promethazine (r2 = 0.93, P = 0.008). However, comparison of regressions revealed that the slope of the regression was significantly steeper with promethazine 0.48 than naltrexone 0.12 (P = 0.006, t = 4.2), with the intercepts showing a trend to a difference (P = 0.086). CONCLUSION: Naltrexone exerted an antipruritic action, at least to a similar extent to promethazine in patients with chloroquine-induced itching in malaria fever. However, the relationship between parasite density and resultant pruritus was significantly different between naltrexone and promethazine. Thus, micro-opiate receptors/and or endogenous opioids may contribute to chloroquine itching in malaria fever, in humans, in accord with animal experimental findings. Malaria parasite density in blood is a strong determinant of itching severity in patients predisposed to chloroquine-induced pruritus.

Administration, Oral↗
PubMed1988

Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine.

As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 male and 351 female; 384 taking chloroquine phosphate with proguanil hydrochloride and 383 taking chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking chloroquine with proguanil hydrochloride and three taking chloroquine with sulfadoxine-pyrimethamine developed falciparum malaria, which was verified microscopically. Side effects were reported by 36 subjects taking chloroquine phosphate with proguanil hydrochloride and 55 taking the other regimen (p = 0.043). The side effects of both regimens were generally mild, but the combination of chloroquine phosphate with proguanil hydrochloride is recommended because it results in fewer side effects. As breakthroughs of malaria occurred at the earliest after seven weeks self treatment should not be recommended for travellers staying only a short time. Thick blood films are useful for diagnosis of suspected cases of malaria, can be prepared by non-specialists in Africa, and can be analysed successfully after long delays.

Adult↗
PubMedDate not supplied

Antenatal chloroquine chemoprophylaxis in Malawi: chloroquine resistance, compliance, protective efficacy and cost.

The roles of Plasmodium falciparum resistance to chloroquine and compliance in the protective efficacy of the antenatal chloroquine prophylaxis programme in Malawi were evaluated by interviewing pregnant women attending antenatal clinics and examining them for P. falciparum parasites in thick smears and chloroquine metabolites in urine. 36% of 642 women had urine chloroquine metabolite levels compatible with regular compliance to the weekly chloroquine dosage schedule. Among a subgroup of 288 pregnant women who were provided weekly prophylaxis under supervision for 4 consecutive weeks, P. falciparum infection rates were 37%, representing the failure of chloroquine to eliminate P. falciparum in Malawi. Among pregnant women not taking prophylaxis, the P. falciparum infection rate was 48%. Based on the P. falciparum infection rates among these 2 groups of women, the protective efficacy of CQ chloroquine was estimated as 23%. If the 36% of pregnant women who had chloroquine in their urines accurately estimates the proportion of women who comply with the prophylaxis programme in Malawi, the actual protective efficacy of the programme would be 8%. The cost of preventing one P. falciparum infection among pregnant women in the Malawi programme is estimated at US$ 10.87. This is an unacceptably high cost in much of Africa, and research is required to define more cost-effective interventions, including more effective drugs, and health education programmes to improve compliance among pregnant women.

Animals↗
PubMed1998

Direct binding of chloroquine to the multidrug resistance protein (MRP): possible role for MRP in chloroquine drug transport and resistance in tumor cells.

Multidrug resistance protein (MRP) transports a range of compounds that include glutathione S-conjugates, amphiphilic anionic drugs, and natural-product toxins. However, the mechanism of MRP drug binding and transport is presently unclear. We recently demonstrated the direct binding of a quinoline-based photoactive drug, N-[4-[1-hydroxy-2-(dibutylamino)ethyl]quinolin-8-yl]-4-az idosalicylamide (IAAQ), to MRP at a biologically relevant site [Vezmar et al., Biochem Biophys Res Commun 241: 104-111, 1997]. In the present report, we demonstrated that the lysosomotropic or antimalarial drug chloroquine is a substrate for MRP. Specifically, our results showed that chloroquine, similar to leukotriene C4 (LTC4) and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl-phenyl)((3-(dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (MK 571), inhibits the photoaffinity labeling of MRP by IAAQ. Furthermore, cell growth assays showed MRP-expressing multidrug-resistant cells (H69/AR and HL60/AR) to be more resistant to chloroquine than their parental cells (i.e., IC50 of 121 microM versus 28 microM chloroquine for H69/AR and H69, respectively). Moreover, MK 571, an LTD4 receptor antagonist, reversed the resistance of H69/AR cells to chloroquine. Drug transport studies using [14C]chloroquine demonstrated that MRP-expressing cells accumulate less drug than the parental drug-sensitive cells. The reduced accumulation of [14C]chloroquine in resistant cells was ATP dependent and was due to enhanced drug efflux. Taken together, the results of this study show that MRP modulates the transport of chloroquine by direct binding.

ATP-Binding Cassette Transporters↗
PubMed1987

Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance.

Chloroquine-resistant Plasmodium falciparum accumulate significantly less chloroquine than susceptible parasites, and this is thought to be the basis of their resistance. However, the reason for the lower accumulation of chloroquine was unknown. The resistant parasite has now been found to release chloroquine 40 to 50 times more rapidly than the susceptible parasite, although their initial rates of chloroquine accumulation are the same. Verapamil and two other calcium channel blockers, as well as vinblastine and daunomycin, each slowed the release and increased the accumulation of chloroquine by resistant (but not susceptible) Plasmodium falciparum. These results suggest that a higher rate of chloroquine release explains the lower chloroquine accumulation, and thus the resistance observed in resistant Plasmodium falciparum.

Animals↗
PubMed1995

Chloroquine encapsulated in malaria-infected erythrocyte-specific antibody-bearing liposomes effectively controls chloroquine-resistant Plasmodium berghei infections in mice.

The suitability of liposomes as drug carriers in the treatment of drug-resistant rodent malaria was examined after covalently attaching F(ab')2 fragments of a mouse monoclonal antibody (MAb), MAb F10, raised against the host cell membranes isolated from the Plasmodium berghei-infected mouse erythrocytes, to the liposome surface. The antibody-bearing liposomes thus formed specifically recognized the P. berghei-infected mouse erythrocytes under both in vitro and in vivo conditions. No such specific binding of the liposomes with the infected cells was observed when MAb F10 was replaced by another mouse monoclonal antibody, MAb D2. Upon loading with the antimalarial drug chloroquine, the MAb F10-bearing liposomes effectively controlled not only the chloroquine-susceptible but also the chloroquine-resistant P. berghei infections in mice. The chloroquine delivered in these liposomes intravenously at a dosage of 5 mg/kg of body weight per day on days 4 and 6 postinfection completely cured the animals (75 to 90%) of chloroquine-resistant P. berghei infections. These results indicate that selective homing of chloroquine to malaria-infected erythrocytes may help to cure the chloroquine-resistant malarial infections with low doses of chloroquine.

Animals↗
PubMed1996

4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum.

We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.

Aminoquinolines↗
PubMed1991

Chloroquine-induced pruritus: its impact on chloroquine utilization in malaria control in Dar es Salaam.

To confirm reports that chloroquine-induced pruritus might have a negative impact on chloroquine utilization on malaria control in Dar es Salaam, a precoded questionnaire was administered to 300 malaria patients and the respondents were then followed up at their homes during the period of their malaria treatment. It was found that 45% of the study population had suffered from chloroquine-induced pruritus at some time in their life and 27% complained of it during the study. Chloroquine-induced pruritus was found to have a significant negative impact on chloroquine utilization on malaria control in Dar es Salaam, Tanzania (P less than 0.001). The defaulting rate attributable to chloroquine-induced pruritus was 64%. The high defaulting rate (91%) among the patients with chloroquine-induced pruritus is suspected to be among the factors that contribute to the emergence and spread of resistant malaria parasites in Dar es Salaam. However, studies are needed to confirm this point. Studies are also needed to determine if there may be familial predisposition to chloroquine-induced pruritus as hypothesized in this study.

Chloroquine↗
PubMed1990

Efficacies of chloroquine and pyrimethamine-sulphadoxine in a Nigerian population with chloroquine resistant P. falciparum malaria.

A modification of the standard World Health Organisation 7--day in vivo test was used to assess the parasitologic and, to limited extent, the clinical response of children less than 5 years of age to defined oral dosages of chloroquine and pyrimethamine-sulphadoxine during the 14 days following the initiation of treatment. The study took place in Jato-Aka, a rural community in Benue State of Nigeria. 471 children were screened and 271 (59%) of these had plasmodium parasites thus showing a high transmission rate at a time of the year with scarce rainfall. Of the 42 children on chloroquine and who were followed up to day 2, 4 or 9.5% of them were parasitologic failures while none of the 45 children on pyrimethamine-sulphadoxine (P-S) failed parasitologically. By day 7, 21 (50%) of the children on chloroquine and 4 or 8.9% of those on P-S. had become parasitologic failures. The total number of parasitologic failures on day 14 were 21 (50%) and 4(8.9%) for chloroquine and P-S groups respectively. Chloroquine improved the clinical state of the patients better than P-S. However, P-S appears superior in clearing the parasites. These results confirm the existence of both chloroquine and pyrimethamine-sulphadoxine resistant strains of P. falciparum in some regions of Nigeria. The routine chloroquine chemoprophylaxis of children under 5 years of age should be discontinued so as not to hasten the intensification of chloroquine resistance and because of its probable marginal efficacy at chemoprophylaxis dosages. There is also need for a national policy on pyrimethamine-sulphadoxine usage in order not to hasten its resistance to P. falciparum.

Animals↗
PubMed1989

Antagonism of serum of mice infected with chloroquine-resistant 'NS' line to the antimalarial action of chloroquine.

Chloroquine (CQ) solution was separately mixed with the serum of mice infected with chloroquine-resistant 'NS' line (SMNS), the serum of mice infected with chloroquine-sensitive Plasmodium berghei ANKA strain (SMCS), and the serum of normal mice (SM). These mixtures were then used in treating mice inoculated with P. berghei ANKA strain. The results obtained on d 5 after drug-serum administration showed that the erythrocyte infection rates in the SMNS + CQ, SMCS + CQ, and SM + CQ groups were 32, 16, and 14% respectively. There were significant differences with respect to parasitemia between the SMNS + CQ group and the SMCS + CQ or SM + CQ group (P less than 0.05), suggesting that SMNS may be antagonistic to the antimalarial action of chloroquine. Further study showed that when the 'NS' line lost resistance to chloroquine, the antagonism of SMNS to chloroquine disappeared. The antagonism rates of SMNS to chloroquine, piperaquine, hydroxypiperaquine and pyronaridine were 75, 56, -5, and -17% respectively, a trend similar to that of the results from cross-resistance tests on chloroquine-resistant P. berghei ANKA strain. The results indicate that drug-resistant malaria parasites may produce and release a certain 'specific anti-drug substance'.

Animals↗
PubMedDate not supplied

Lack of effect of desipramine on the response to chloroquine of patients with chloroquine-resistant falciparum malaria.

The potential of desipramine to improve the efficacy of chloroquine against chloroquine-resistant Plasmodium falciparum in vivo in man was investigated. Fifty-three malaria patients were selected according to the criteria for the standard World Health Organization (WHO) in vivo test and were randomly divided in 2 groups. One group (n = 27) was given standard therapeutic doses of chloroquine (25 mg/kg body weight of base) and the other (n = 26) was given standard doses of chloroquine, as above, in combination with desipramine (1.3-2.8 mg/kg body weight) daily for 3 consecutive days. Standard WHO in vitro micro-tests were performed in parallel with the tests in vivo to provide chloroquine sensitivity patterns of the P. falciparum parasites. The results in vitro from both groups did not differ with regard to chloroquine sensitivity and the means of the pre-treatment parasite densities were similar. There was no apparent difference in parasite clearance in vivo between the 2 groups. This study provided no evidence for enhanced chloroquine efficacy in vivo through the use of desipramine in doses corresponding to the usual therapeutic range.

Animals↗