Blood Chloroquine Concentrations Research Articles

The antiviral mechanisms, effects, safety and adverse effects of chloroquine.

Chloroquine, a 4-aminoquinoline derivative, was initially used to treat malaria. It was later found to have immunomodulating, anti-infective, anti-thrombotic, anti-tumor, and metabolic effects. Recently, many studies have focused on the application of chloroquine in viral infections. Most in vitro studies suggested that chloroquine exerted some benefit in infections from viruses. However, animal experiment and clinical trials that attempted to use chloroquine in prevention or treatment of viral infections have reported disappointing results. It might be attributable to inadequate steady-state whole blood chloroquineconcentration necessary for exerting its antiviral effects. A 16 μM/Lsteady-state whole blood concentration of chloroquineshould suffice in antiviral treatment with minimal toxicity. Furthermore, chloroquine has both acute and cumulative toxicity. Hence, not only the appropriate treatment dose is crucial, the occurrence of adverse reactions should also be closely monitored and treated in time. Herein, we report the antiviral mechanisms, effects, safety and adverse effects of chloroquine.

English

The blood schizontocidal chloroquine (CQ) and the tissue schizontocidal and gametocytocidal primaquine (PQ) remain the mainstay treatment of Plasmodium vivax and Plasmodium ovale infections for more than six decades. The review focuses on the clinical pharmacokinetic studies of both drugs in Thai population that have provided useful information for clinical application in the treatment of malaria.  There appears to be no major differences in the pharmacokinetics of both drugs with respect to the influences of ethinicity, acute phase malaria infection, and G6PD status. The increase in systemic exposure of CQ and/or its metabolite mono-desethylchlorooquine (DECQ) following oral administration could be due to change in the absorption kinetics during acute phase infection. The high clinical efficacy of CQ for treatment of P. vivax infection in Thailand supports this benefitial pharmacokinetic change. Transiently high and toxic plasma/whole blood concentrations of CQ following intravenous infusion at high rate is explained by the pharmacokinetic characteristics of CQ.  Pharmacokinetics of PQ following repeated dosing in most studies appears to be similar to that following a single dosing. This suggests that auto-inhibition of PQ metabolism during multiple dosing is unlikely. Co-administration of CQ, dihydroartemisinin-piperaquine (DHA-PIP), and pyronaridine-artesunate (PYR-ARS) significantly altered the pharmacokinetics of PQ. In the presence of these drugs, PQ exposure was significantly increased. The apparent volume of distribution of PQ was reduced when co-administered with PYR-ARS. In addition, plasma concentrations of CPQ were significantly increased in the presence of CQ.  Clinical relevance of these interactions needs to be confirmed. Key words: Malaria, pharmacokinetics, chloroquine, primaquine, Thai population.

Evaluation of the paediatric dose of chloroquine in the treatment of Plasmodium vivax malaria.

BackgroundChloroquine (CQ) continues to be the first-line medication used worldwide in the treatment of Plasmodium vivax malaria. The dose recommended by the World Health Organization is 25 mg/kg independently of the age of the subject. Nonetheless, the pharmacokinetics and pharmacodynamics of drugs in children are different from those in adults and may influence the drug concentrations in blood and become risk factors for therapeutic failure and/o resistance to CQ.MethodsThis study is a secondary analysis of the data from a clinical trial in which children over 5 years of age were administered 25 mg/kg of CQ, and CQ concentrations in blood were measured at day 7 of follow-up. Models of regression and comparison were used to evaluate and compare the CQ dose taken per kg/body weight, the CQ dose calculated based on body surface area, CQ levels in blood on day 7 and the age of the population.ResultsThe younger the study population the greater the difference between the dose per kg/body weight (real dose) and that calculated according to the BSA (theoretical dose). The difference between the two doses was −181.206 mg in the 5–9 years of age group (CI 95 % −195.39; −167.02 mg) and −71.39 mg (CI 95 % −118.61; −23.99 mg) in the 10–14-year-old group. The CQ concentrations in blood on day 7 differed in patients over and under 15 years (p = 0.008). A negative correlation was found between the real and theoretical dose (difference in dose) and the age in years (R2 = 0.529, p = 0.001). A negative correlation was also found between the difference in dose (mg) and CQ concentrations on day 7 (ng/ml) (r = −0.337, p = 0.001). Children under 15 years were found to have a higher rate of therapeutic failure than those over 15 (28 vs 4.2 %, respectively) (Kaplan–Meier p = 0.005).ConclusionsA CQ dose of 25 mg/kg for the treatment of P. vivax malaria may be too low in children as demonstrated by the reduction in CQ concentrations in blood at day 7 of follow-up. This under-dosage is probably associated with the higher rate of therapeutic failure found in children under 15 years (28 vs 4.3 %). These results suggest the need to review the paediatric doses of CQ currently used.

Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border.

BackgroundA three-day course of chloroquine remains a standard treatment of Plasmodium vivax infection in Thailand with satisfactory clinical efficacy and tolerability although a continuous decline in in vitro parasite sensitivity has been reported. Information on the pharmacokinetics of chloroquine and its active metabolite desethylchloroquine are required for optimization of treatment to attain therapeutic exposure and thus prevent drug resistance development.MethodsThe study was conducted at Mae Tao Clinic for migrant worker, Tak province, Thailand. Blood samples were collected from a total of 75 (8 Thais and 67 Burmeses; 36 males and 39 females; aged 17–52 years) patients with mono-infection with P. vivax malaria [median (95 % CI) admission parasitaemia 4898 (1206–29,480)/µL] following treatment with a three-day course of chloroquine (25 mg/kg body weight chloroquine phosphate over 3 days). Whole blood concentrations of chloroquine and desethylchloroquine were measured using high performance liquid chromatography with UV detection. Concentration–time profiles of both compounds were analysed using a population-based pharmacokinetic approach.ResultsAll patients showed satisfactory response to standard treatment with a three-day course of chloroquine with 100 % cure rate within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred. A total of 1045 observations from 75 participants were included in the pharmacokinetic analysis. Chloroquine disposition was most adequately described by the two-compartment model with one transit compartment absorption model into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. First-order elimination from the central compartment of chloroquine and desethylchloroquine was assumed. The model exhibited a strong predictive ability and the pharmacokinetic parameters were estimated with adequate precision.ConclusionThe developed population-based pharmacokinetic model could be applied for future prediction of optimal dosage regimen of chloroquine in patients with P. vivax infection.

Chloroquine Is Grossly Under Dosed in Young Children with Malaria: Implications for Drug Resistance

Background Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations.Methods and FindingsDay 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m2 were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10–14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662–988) and 758 (95% CI 640–876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10–14 taking 50 mg/kg and children aged 0–2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent.ConclusionsCQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10–14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.

Tissue and blood concentrations of chloroquine following chronic administration in the rat.

The antimalarial drug, chloroquine, is extensively distributed in tissue and slowly eliminated such that after a single dose, a plasma half-life of 3-5 days has been found (McChesney & McAuliff 1961; McChesney et al 1967). A peak tissue/plasma concentration ratio greater than 300 is obtained in many tissues and after a single dose the drug can be found in the liver and urine for up to five years (Gaudette & Coatney 1961; Rubin et al 1963; Zvaifler et al 1963). Chronic administration of chloroquine for the treatment of rheumatoid arthritis has revealed an ocular toxicity due to accumulation of the drug in the pigmented layers of the eye, particularly the choroid (Fuld & Horwish 1958; Fuld 1959). A more recent indication for chronic administration of chloroquine is in the prophylaxis of malaria, for which the drug is administered at a dose of 300-600 mg weekly to adults. The long term toxic effects of chloroquine when administered in this way are unknown but no ocular toxicity has been reported even after five years of such use. Since tissue toxicity and other untoward effects are largely determined by tissue stores (Fuld & Horwish 1958; Fuld 1959) and blood levels (Laaksonen et al 1974; Frisk-Holmberg et al 1979) of the drug, it is useful to know the changes occurring in tissue and plasma concentrations during chronic administration. Previous studies in animals have given conflicting results. McChesney et al (1965) found a steady increase in the tissue and plasma concentrations in rats throughout a 3-month period although the increase was fastest in the first month. Grundmann et al (1972) found that most rat tissues were saturated with chloroquine between the 10th and the 16th weeks. Plasma concentrations were not measured hence the effect of tissue saturation on blood levels was not determined, yet saturation of tissue stores would be expected to lead to a rapid increase in plasma concentration that could affect the pattern and incidence of adverse reactions to the drug. We have reinvestigated the uptake of chloroquine by rat tissues during chronic administration of the drug and in particular to relate the tissue levels to plasma concentrations.

Blood concentrations are better predictors of chioroquine poisoning severity than plasma concentrations: a prospective study with modeling of the concentration/effect relationships

Introduction. Chloroquine causes rare but life-threatening toxicity. The prognostic value of plasma chloroquine concentrations in acute poisonings remains poorly investigated. We investigated the hypothesis that blood chloroquine concentrations better predicted chloroquine poisoning severity than plasma concentrations. Methods. A prospective study of consecutive chloroquine poisonings admitted to an intensive care unit from 2003 to 2007 was performed with simultaneous measurements of blood and plasma chloroquine (chloroquine and desethylchloroquine) concentrations. A population pharmacokinetic–pharmacodynamic model described epinephrine infusion rate, our surrogate marker of cardiovascular toxicity, as function of blood or plasma chloroquine concentrations. Results. Forty-four patients [29F/15M, 33 years (25–41), median (25–75th percentile), 34% with cardiac arrest] were included. Management included mechanical ventilation (80%), 8.4% sodium bicarbonate (66%), epinephrine [73%, maximal rate: 2.8 mg/h (0.8–5.0)], and extracorporeal life support (16%). Seven patients died. Blood [6.7 mg/L (4.0–13.0)] and plasma [1.5 mg/L (1.2–2.9)] chloroquine concentrations were weakly, although significantly correlated (r = 0.66, p < 0.0001, Spearman test). Admission chloroquine concentrations correlated with the reported ingested dose (r = 0.70 for blood vs. 0.48 for plasma), QRS duration (r = 0.82 vs. 0.64), lactate concentrations (r = 0.63 vs. 0.47), and epinephrine infusion rates (r = 0.70 vs. 0.62). Chloroquine concentrations differed significantly between patients with and without cardiac arrest (p = 0.0002 for blood vs. 0.02 for plasma). A one-compartment pharmacokinetic (PK) model adequately described blood chloroquine concentrations. An effect compartment linked to the blood compartment adequately described plasma chloroquine concentrations. Using a sigmoidal Emax pharmacodynamic (PD) model, epinephrine infusion rate was better predicted with blood than plasma concentrations (p < 0.01), suggesting that time-course of blood concentrations is a better prognostic value than plasma concentrations. Conclusion. Immediate and serial measurements of blood chloroquine concentrations are better than plasma for predicting cardiovascular severity of chloroquine poisonings.

Chloroquine Is Grossly Overdosed and Overused but Well Tolerated in Guinea-Bissau

High chloroquine doses are commonly prescribed in Guinea-Bissau. Double-dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed, and it was not known if the high doses prescribed in Guinea-Bissau were taken or whether they caused adverse effects. We aimed to determine the dosage of chloroquine commonly prescribed, the doses commonly taken, and whether concentration-dependent adverse events occurred in routine practice. Chloroquine prescriptions by eight physicians and chloroquine intake by 102 children were recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations in whole blood were measured. The median total chloroquine dose prescribed and that reportedly taken were 81 and 77 mg kg(-1), respectively. The total dose was usually split into two to three daily doses of 6.6 mg kg(-1) each. These were taken unsupervised for a median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50 mg kg(-1)) of chloroquine was taken. Only 3/102 children had Plasmodium falciparum in the blood at the time of diagnosis and treatment. No severe adverse events were reported. No adverse events were associated with higher chloroquine concentrations. High doses of chloroquine are commonly taken and well tolerated in Guinea-Bissau. Malaria diagnostics are poor, and chloroquine is commonly prescribed to children without parasitemia. Use of high-dose chloroquine is concurrent with an exceptionally low prevalence of chloroquine-resistant P. falciparum.

Pretreatment Blood Concentrations of Chloroquine in Patients with Malaria Infection: Relation to Response to Treatment

Resistance of Plasmodium falciparum to chloroquine has been reported in many areas in Ghana. Most of these reports, which are from hospital-based studies, indicate RI and RII rather than RIII type of resistance. Since high pretreatment levels of chloroquine have also been measured in patients with malaria infection in Ghana, we hypothesized that the 'added effect' of the pretreatment ingested drug to the full dose given at the hospital may be responsible for the low proportion of RIII type of resistance observed. To ascertain this, pretreatment blood levels of chloroquine were correlated with treatment outcomes in 231 paediatric malaria patients, referred to a major hospital in Ghana. The rate of parasite clearance and prevalence of recrudescence, 14 days post-treatment, were determined for each patient. Results from this study showed no correlation between pretreatment chloroquine levels and day 0 parasitaemia. Two hundred and seven patients (89.6 per cent) had parasites that were sensitive to chloroquine whilst 24 (10.4 per cent) had resistant parasites. Of the latter group 17, six, and one patients had P. falciparum parasites, which were resistant at RI, RII and RIII levels, respectively. Seventy-five per cent of the patients without any detectable pretreatment blood chloroquine had parasites that were sensitive to chloroquine whilst 89.8 per cent, 98 per cent, and 100 per cent with pretreatment blood chloroquine concentration ranges of 0.5--100.5 ng/ml, 100.5--200 ng/ml, and >200 ng/ml, respectively, had chloroquine-sensitive parasites. An inverse relationship was thus observed between pretreatment blood chloroquine concentration and the degree of resistance in this study. We conclude that pre-hospital treatment ingested chloroquine contributes significantly to the resolution of malaria in children in Ghana, in the presence of chloroquine resistance.

MULTI-DRUG RESISTANT PLASMODIUM FALCIPARUM MALARIA IN ASSAM, INDIA: TIMING OF RECURRENCE AND ANTI-MALARIAL DRUG CONCENTRATIONS IN WHOLE BLOOD

The susceptibility of 23 cases of Plasmodium falciparum malaria from the Sonapur primary health center in the Kamrup district of Assam, India to different antimalarials was investigated using the 28-day World Health Organization in vivo test. Whole blood concentrations of chloroquine, sulfadoxine, and quinine were determined at different intervals and at the time of parasites recrudescence after completion of treatment with the respective drugs to confirm the status of drug sensitivity. A case of multi-drug resistant P. falciparum malaria was found where recrudescence occurred, despite standard oral treatment with chloroquine, sulfadoxine/pyrimethamine, and quinine sequentially. Whole blood concentrations of chloroquine, sulfadoxine, and quinine at the time of recrudescence were 0.35 microg/ml (day 7), 18 microg/ml (day 14), and 0.009 microg/ml (day 14), respectively. Therefore, monitoring of drug-resistant P. falciparum malaria and its proper treatment should be intensified to check the spread of multi-drug resistant strains in other parts of the country.

Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha-thalassaemic children.

Alpha-thalassaemia is common in malaria-endemic regions and is considered to confer protection from clinical disease due to infection with Plasmodium falciparum. In vitro, sensitivity to chloroquine (CQ) of P. falciparum infecting alpha-thalassaemic erythrocytes is reduced. We examined, in a cross-sectional study of 405 Nigerian children, associations between alpha-globin genotypes, blood concentrations of CQ, and P. falciparum parasitaemia. Of the children, 44% were alpha+-thalassaemic (36.8% heterozygous, 7.6% homozygous). CQ in blood and P. falciparum-infection were observed in 52 and 80%, respectively. CQ was more frequently found in homozygous alpha+-thalassaemic (71%) than in non-thalassaemic children (50%; odds ratio, 2.42; 95% confidence interval, 1.01-5.8). Among children with CQ in blood and despite similar drug concentrations, alpha+-thalassaemic individuals had fewer infections below the threshold of microscopy which were detectable by PCR only, and they had a higher prevalence of elevated parasitaemia than non-thalassaemic children. No such differences were discernible among drug-free children. CQ displays a lowered efficacy in the suppression of P. falciparum parasitaemia in alpha+-thalassaemic children; hence protection against malaria due to alpha+-thalassaemia may be obscured in areas of intense CQ usage. Moreover, alpha+-thalassaemia may contribute to the expansion of CQ resistance.

Chloroquine-Chlorpheniramine Interaction In Human Malaria

The purpose of this study was to examine the effect of chloroquine-chlorpheniramine (CQ-CP) combination therapy on the efficacy and disposition of chloroquine (CQ) in acute uncomplicated malaria. A 3-day standard treatment with 25 mg CQ base per kilogram body weight alone or in combination with chlorpheniramine (CP) was orally administered to 17 semi-immune Nigerian children with Plasmodium falciparum parasitemia, attending the Massey Street Children's Hospital, Lagos, Nigeria. Parasitemia was determined on thick blood films stained with Giemsa, and treatment failures were established following the WHO classification for CQ resistance. Whole blood CQ concentrations were monitored at pre-determined intervals during the 28 days of follow-up using blood dried on filter-paper. Treatment with CQ-CP combination resulted in a shorter parasite clearance time (2.0 ± 0.5 d) & a higher cure rate (87.5%) compared to treatment with CQ alone (3.5 ± 0.5 d; 66.7%). CQ pharmacokinetic parameters: maximum drug concentration (Cmax) and the area under the first-moment drug-concentration-time curve (AUMC) were significantly increased (p < 0.01; p < 0.001 respectively) by CP administration while the time to achieve the peak was reduced in the presence of CP. We conclude that administration of CP increased CQ uptake as judged by an increase in the maximum concentration (Cmax) and a decrease in the time to attain the concentration (Tmax), as well as an increase in the area under the curve, which signifies increased systemic availability of CQ in the presence of CP. Nigerian Quarterly Journal of Hospital Medicine Vol.9, No.3 (1999) pp. 225-230

Plasma chloroquine concentrations in young and older malaria patients treated with chloroquine

Plasma chloroquine (CQ) concentrations were measured by bioassay in young (0–4 years, n=9) and older (5–60 years, n=21) patients from Vanuatu infected with malaria following treatment with 25 mg/kg CQ over 3 days. CQ concentrations in young children tended to be lower than in older patients at days 2, 3, 4 and 7 after onset of treatment, with no drug present in two young children on day 3 and in one child on day 7. The greater difficulty experienced by young children to ingest all of their prescribed medication could have contributed to the lower CQ concentrations observed in the younger age group. The possibility that sub-therapeutic CQ concentrations are responsible for treatment failures in young children should be considered in areas where a high degree of CQ resistance has not yet been established. In such areas, the presence or prevalence of CQ-resistant infections should not be based on treatment failures observed in young children unless it can be confirmed that adequate blood CQ concentrations were achieved after treatment.

Chloroquine blood concentrations and malaria prophylaxis in Tanzanian women during the second and third trimesters of pregnancy.

Routine malaria prophylaxis with chloroquine (CQ) is recommended to pregnant semi-immune women in several countries in Africa. The dosage is empirically based. We investigated whether blood CQ concentrations and apparent oral blood clearance (CL/F) change during the course of pregnancy. We also studied whether malaria parasites could be detected together with low CQ blood levels. Forty nine semi-immune Tanzanian women were recruited in the 16th week of pregnancy. They were given 310 mg oral CQ base once per week as prophylaxis during the whole pregnancy. Capillary blood samples were taken for analysis of CQ before treatment and at weeks 26 and 36. Blood samples were dried on filter paper and analysed by HPLC. Blood was also drawn to detect occurrence of malaria parasites. A total of 25 women fulfilled the sampling schedule. CL/F increased significantly from 160 ml.min-1 at week 26 to 180 ml.min-1 at week 36. In 7 of 25 women, CL/F increased > 20%. Trough blood CQ concentrations, determined on four occasions at week 26 and at week 36 varied between 200 and 900 nmol.l-1. No statistically significant differences between occasions were seen. Malaria parasites were seen in two individuals early in pregnancy. Blood CQ CL/F showed a small increase during the course of pregnancy. The estimated mean blood CL/F values of 160 and 180 ml.min-1 (week 26 and 36, respectively) were higher than the mean CL/F of 125 ml.min-1 in non-pregnant individuals, published previously. Efficacy of higher dosages of CQ in malaria prophylaxis in pregnant women could, therefore, be evaluated in controlled trials in high-risk malaria areas.

Determination of Chloroquine and Desethylchloroquine in Biological Samples Using Perfusion Chromatography and Fluorescence Detection

A high-speed reversed phase HPLC method for the determination of chloroquine and desethylchloroquine in biological samples is presented. Perfusion chromatography, based on the use of flow-through particles made of cross-linked polystyrene/divinylbenzene, allowed to increase the flow-rate of the mobile phase to 4 mL/min, resulting in base-line separation of bis-desethylchloroquine, desethylchloroquine, chloroquine, and the internal standard in less than 3 minutes. As the column material withstands prolonged exposure to high pH conditions, the pH of the mobile phase could be adjusted to 9.5, enabling direct determination of chloroquine and desethylchloroquine by fluorescence detection after elution; therefore, no post-column alkalinization to obtain the pH of optimal fluorescence was required. Interday as well as intraday reproducibility for chloroquine concentrations ranging from 31.3 to 500 ng/mL in plasma was lower than 7%. The applicability of the method is illustrated by measuring blood concentrations of chloroquine and desethylchloroquine in blood during 1 week after oral intake of 500 mg chloroquine.

Treatment of acute chloroquine poisoning: a 5-year experience.

To describe various aspects of prognostic and therapeutic importance in patients treated for acute chloroquine poisoning. Retrospective study. Toxicology intensive care unit (ICU) of a university hospital. None. One hundred sixty-seven consecutive patients with acute chloroquine overdose admitted to our toxicology ICU. The mean amount ingested by history was 4.5 +2- 2.8 g. and 43 (26%) of 167 patients ingested > 5 g. The mean blood chloroquine concentration on admission was 20.5 +/- 13.4 mumol/L The majority (87%) of our patients received at least one arm of a combination therapy regimen (epinephrine, mechanical ventilation, diazepam). cardiac arrest occurred in 25 patients before hospital arrival; In seven of these patients, cardiac arrest occurred immediately after injection of thiopental. The mortality rate was 8.4% overall, and was 9.3% in patients with massive ingestions (NS vs. the group as a whole). We did not find a meaningful correlation between the amount ingested as estimated by history and the peak blood chloroquine concentration; the latter was highly correlated with the mortality rate. The mortality rate in patients with acute chloroquine poisoning, including those patients sick enough to be referred to a specialty unit such as ours, can be limited to < or = 10%. This finding appears to be true even in patients with massive ingestions. We were not able to correlate mortality with amount ingested by history, although the mortality rate does correlate with blood chloroquine concentration. While early use of diazepam, epinephrine, and mechanical ventilation in most of our patients may have contributed to the excellent overall results, these elements, either singly or in combination, do not appear to have a truly antidotal effect in acute chloroquine poisoning. Thiopental, on the other hand, should be used with great caution, if at all, in such cases.

Chloroquine-Resistant Plasmodium vivax Malaria in Borneo.

Chloroquine-resistant Plasmodium vivax infection has been reported from Myanmar (Burma),’ the island of Nias, Indonesia,‘ Papua New Guinea,”‘ and Irian Jaya (Indonesian New Guinea).’.” We describe a case of chloroquine-resistant I? vivux infection acquired in Sabah, Borneo. A 58-year-old Swedish man was admitted to our department in June 1993 with intermittent high fever, malaise, and headache. Nine days before adnlission, the patient had returned from a 4-week period of work within a forest research project outside Tawau in Sabah, Borneo. From the date of arrival in Borneo until admission, he had taken chloroquine (300 mg base weekly) as prophylaxis. On adniission, I? vivax trophozoites and gametocytes were found in thick and thin bloodfilms. Blood concentrations of chloroquine and desetylchloroquine, 2 days after the last dose, were 540 nmol/L and 170 nmol/L, respectively, in a sample. After treatment with mefloquine (total dose 1500 mg), the patient recovered uneventfully.To prevent further relapse, primaquine 22.5 mg base daily for 14 days was given. Nevertheless, during the following 6 months the patient experienced two relapses of I? vivux infection.The first was in September 1993; the patient fell ill when returning from a 6-day stay without malaria prophylaxis in an urban area ofKota Kmabalu in Sabah,Borneo.This was his only visit to an endemic area afier the initial hospitalization. I? vivux was again demonstrated, and treatment with quinine 700 mg t.i.d. for 1 day and thereafter 600 mg t.i.d. for 3 days was given, followed by primaquine 22.5 mg base per day for 14 days.The patient recovered and, on a follow-up in October 1993, no malaria plasmodies were found in blood smears. The second relapse occurred in January 1994. I! vivax rings, gametocytes, and trophozoites were again found in blood smears.The patient was only treated with mefloquine (total dose of 1500 mg) and recovered. Strong evidence indicates that the present I? vivux strain was chloroquine resistant. The patient developed symptomatic infection in spite of having putatively protective whole blood levels of chloroquine.’ Furthermore, despite two courses of primaquine treatment, he had two verified relapses of I? vivax infection.This implies that the strain probably also was resistant to primaquine, which is well-known in the area. Compliance was, however, not controlled by analyses of blood concentrations of priniaquine. Reinfection with I? vivax during the second brief visit to Borneo seems highly unlikely, as symptoms appeared within 6 days after arrival in Borneo and he stayed in an urban area with limited risk of malaria transmission. This is, to our knowledge, the first report of a chloroquine-resistant Z? vivax infection acquired in Borneo. Although the magnitude of the problem is not known, our report supports further geographical spread of chloroquine-resistant vivax strains in the region.

Hypokalaemia related to acute chloroquine ingestion

Summary Large doses of chloroquine can cause poisoning. Our aim was to determine the possible relation between the plasma potassium concentration on admission with the severity of acute chloroquine poisoning and to assess the mechanism of chloroquine-induced hypokalaemia. We conducted a retrospective study of 191 consecutive cases. The main data included the occurrence of vomiting before admission, plasma, and urinary potassium concentration at admission, whole blood chloroquine concentration on admission, haemodynamic parameters and ECG, administration of catecholamines and outcome. Mean blood chloroquine level was 20·1 μmol/L (SD 14·3) (therapeutic level ≤6 μmol/L). Mean plasma potassium concentration was 3·0 mmol/L (0·8) and was lower in the subjects who died than in those who survived (p=0·0003). Plasma potassium varied directly with the systolic blood pressure and inversely with the QRS and QT. Plasma potassium varied inversely with the blood chloroquine (p=0·0001; τ=-0·42). Acute chloroquine intoxication is responsible for a hypokalaemia which correlates with the gravity of the intoxication and may be due to a transport-dependent mechanism. Plasma potassium concentrations should be carefully observed, particularly among patients who also receive catecholamine infusions. We should keep in mind, however, that overzealous repletion invokes the risk of subsequent hyperkalaemia and thus should be avoided.

Clinical response and susceptibility in vitro of Plasmodium vivax to the standard regimen of chloroquine in Thailand

The clinical effectiveness of the standard regimen of chloroquine (CQ) (a total dose of 1500 mg, given over 48 h at 0, 6, 24 and 48 h) for the treatment of Plasmodium vivax malaria in Thailand was investigated in 57 patients in an endemic area of Thailand (Chantaburi Province, eastern Thailand). For radical treatment, an additional course of a tissue schizontocidal agent, primaquine, was given following the complete course of CQ. With this regimen, satisfactory whole blood concentration-time profiles of CQ and its major metabolite desethylchloroquine (DECQ) were achieved. Mean whole blood levels of CQ and DECQ always much exceeded the reported therapeutic level of CQ (90 ng/mL) during the first 7 d of treatment. All patients responded well to the treatment; in most cases, complete and rapid clearance of parasitaemia was observed within the first 48 h. No reappearance of the parasitaemia was detected in peripheral blood films of any patient within 14 d of the evaluation period. In 6 patients, however, reappearance of P. vivax parasitaemia was observed after 30 d; 2 of them had not completed the course of primaquine. There was no difference in whole blood concentrations of CQ and DECQ, admission parasitaemia, susceptibility of the isolates to chloroquine in vitro, and parasite clearance time between patients with or without reappearance of parasitaemia. A prominent trend of deteriorating sensitivity of the parasite to the drug was, however, suggested.

In vivo sensitivity of Plasmodium falciparum to chloroquine in rural areas of Côte d'Ivoire

In vivo testing of Plasmodium falciparum sensitivity to chloroquine was carried out in four rural sites of differing socio-geographical environment in Côte d'Ivoire. Of a total of 1282 patients of all ages with fever or previous history of fever, 649 were slide positive, with 435 patients with a pure P. falciparum infection; 191 fulfilled all the criteria for inclusion in this study, and 113 completed it. Treatment failure rates ranged from 9.7% (Djébonoua) to 38.1% (Tiéviéssou), and were most often associated with higher degrees of resistance (RII = 54.2%; RIII = 37.5%). Blood chloroquine levels measured by ELISA test suggest that many people take chloroquine routinely; furthermore 37.5% of resistance cases occurred in subjects who had high blood chloroquine concentrations on day 0. Twenty-three out of 24 cases of resistance were found in children under 7 years of age. Nearly all children with persisting parasitaemia were afebrile on day 7, even those ( 7 8 ) with RIII resistance. Children aged <7 years represent the best sentinel group for monitoring P. falciparum sensitivity to chloroquine in Côte d'Ivoire.