Chloroquine Base Research Articles

British Association of Dermatologists guidelines for the management of people with cutaneous lupus erythematosus 2021.

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of cutaneous lupus erythematosus (CLE) in the presence or absence of systemic lupus erythematosus (SLE) in adults, young people and children. The document aims to: offer an appraisal of all relevant literature up to December 2020, focusing on any key developments address important, practical clinical questions relating to the primary guideline objective. provide guideline recommendations and if appropriate research recommendations.

Heterologous protection against malaria by a simple chemoattenuated PfSPZ vaccine regimen in a randomized trial

Immunization with Plasmodium falciparum (Pf) sporozoites under chemoprophylaxis (PfSPZ-CVac) is the most efficacious approach to malaria vaccination. Implementation is hampered by a complex chemoprophylaxis regimen and missing evidence for efficacy against heterologous infection. We report the results of a double-blinded, randomized, placebo-controlled trial of a simplified, condensed immunization regimen in malaria-naive volunteers (EudraCT-Nr: 2018-004523-36). Participants are immunized by direct venous inoculation of 1.1 × 105 aseptic, purified, cryopreserved PfSPZ (PfSPZ Challenge) of the PfNF54 strain or normal saline (placebo) on days 1, 6 and 29, with simultaneous oral administration of 10 mg/kg chloroquine base. Primary endpoints are vaccine efficacy tested by controlled human malaria infection (CHMI) using the highly divergent, heterologous strain Pf7G8 and safety. Twelve weeks following immunization, 10/13 participants in the vaccine group are sterilely protected against heterologous CHMI, while (5/5) participants receiving placebo develop parasitemia (risk difference: 77%, p = 0.004, Boschloo’s test). Immunization is well tolerated with self-limiting grade 1–2 headaches, pyrexia and fatigue that diminish with each vaccination. Immunization induces 18-fold higher anti-Pf circumsporozoite protein (PfCSP) antibody levels in protected than in unprotected vaccinees (p = 0.028). In addition anti-PfMSP2 antibodies are strongly protection-associated by protein microarray assessment. This PfSPZ-CVac regimen is highly efficacious, simple, safe, well tolerated and highly immunogenic.

Chloroquine Dosing Recommendations for Pediatric COVID-19 Supported by Modeling and Simulation.

As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control coronavirus disease 2019 (COVID‐19) experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing World Health Organization (WHO) dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best‐evidence to inform pediatric CHQ doses for children infected with COVID‐19. A previously developed physiologically‐based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID‐19 recommended adult dosage regimen of 44 mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in area under the concentration‐time curve from zero to 70 hours (AUC0–70h) the optimal CHQ dose was determined in children of different ages compared with adults. Revised doses were re‐introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body‐weight based dose is given. As such, we propose the following total cumulative doses: 35 mg/kg (CHQ base) for children 0–1 month, 47 mg/kg for 1–6 months, 55 mg/kg for 6 months–12 years, and 44 mg/kg for adolescents and adults, not to exceed 3,300 mg in any patient. Our study supports age‐adjusted CHQ dosing in children with COVID‐19 in order to avoid suboptimal or toxic doses. The knowledge‐driven, model‐informed dose selection paradigm can serve as a science‐based alternative to recommend pediatric dosing when pediatric clinical trial data is absent.

Antimalarial Activities of Hydromethanolic Crude Extract and Chloroform Fraction of Gardenia ternifolia Leaves in Plasmodium berghei Infected Mice.

Background Gardenia ternifolia is utilized in traditional medicine of Ethiopia for malaria treatment and possessing in vitro antimalarial activity. However, no in vivo study was conducted to substantiate the claim. The aim of this study was to judge the antimalarial activity of Gardenia ternifolia extract in vivo in Plasmodium berghei-infected mice. Methods Plasmodium berghei was inoculated to healthy mice, and hydromethanolic crude extract and chloroform fraction of G. ternifolia leaves at 100 mg/kg/day, 200 mg/kg/day, and 400 mg/kg/day were administered. Percent parasitemia inhibition, percent change in bodyweight, hemoglobin level, and mean survival time were determined. Data were analyzed using one-way ANOVA followed by post hoc Tukey HSD test with IBM SPSS software version 20.0 statistical package and P < 0.05 considered as statistically significant. Results The chemosuppressive test of hydromethanolic crude extract at 100 mg/kg/day, 200 mg/kg/day, and 400 mg/kg/day ranged from 27.09% to 67.72%, and chloroform fraction had 35.21%–78.19% parasitemia suppression, respectively. For curative test on day 5, hydromethanolic crude extract at 100 mg/kg/day, 200 mg/kg/day, and 400 mg/kg/day ranged from 25.58% to 48.76%, chloroform fraction at 100 mg/kg/day, 200 mg/kg/day, and 400 mg/kg/day and chloroquine base at 10 mg/kg showed 46.36%–74.42% and 92.87% percent parasitemia inhibition, respectively, and also the results to both tests were highly significant (P < 0.001) compared to the negative control. Maximum effects on chemosuppressive, curative, prevention of weight loss, and reduction in hemoglobin were observed at higher doses of the hydromethanolic crude extract and chloroform fraction. Conclusion From this study, hydromethanolic crude extract and chloroform fraction of G. ternifolia leaves have shown promising antimalarial activity. The findings support the traditional claim of G. ternifolia leaves for malaria treatment; however, species variation could also limit such a straightforward extrapolation of the findings of this study in humans.

Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial

SummaryBackgroundSickle-cell disease increases the risk of malnutrition. Low arginine and nitric oxide bioavailability are implicated in morbidity related to sickle-cell disease. Simple interventions are required, especially in low-income settings. We aimed to test the hypotheses that: (1) supplementary arginine, citrulline, and daily chloroquine increase bioavailable arginine and flow-mediated dilatation (FMD; maximal diameter change; FMDmax%), a measure of nitric oxide-dependent endothelial function; and (2) protein energy supplementation in the form of ready-to-use supplementary food (RUSF) improves the height-for-age and body-mass index-for-age Z-scores in children with sickle-cell disease.MethodsWe performed a double-blind, random order crossover trial with two 4-month intervention periods (each followed by 4-month washout periods) in Muhimbili National Hospital in Dar-es-Salaam, Tanzania. We enrolled 119 children from the Muhimbili Sickle Cohort who were aged 8–12 years, naive to hydroxyurea, and had documented HbSS phenotype. Two formulations of RUSF (providing 500 kcal/day) were tested: basic (RUSF-b), with which children also received weekly chloroquine (150 mg or 225 mg chloroquine base, dependent on bodyweight); and vascular (RUSF-v), which was fortified with arginine and citrulline (designed to achieve mean intakes of 0·2 g/kg per day of arginine and 0·1 g/kg per day of citrulline), and with which children received daily chloroquine (maximum 3 mg chloroquine base/kg per day). Children were randomly allocated to receive either RUSF-b first or RUSF-v first and, after a washout period, were then given the other treatment. The primary outcomes in comparing the two RUSF formulations were mean plasma arginine, arginine to ornithine ratio, and arginine to asymmetric dimethylarginine ratio, and mean FMDmax%. The primary outcomes of the combined effect of both RUSF interventions were mean height-for-age Z-score and body-mass index-for-age Z-score. Analyses were done on the eligible intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01718054; and with ISRCTN74331412.FindingsBetween Aug 9, 2012, and Feb 26, 2014, 145 children were randomised (71 children to RUSF-v first and 74 children to RUSF-b first) and 119 children were treated, of whom 114 children yielded complete data for all reported endpoints. The ratio of arginine to ornithine (mean of individual differences −8·67%, 95% CI −19·55 to 2·20; p=0·12) and the mean FMDmax% (1·00, −0·47 to 2·47; p=0·18) did not significantly differ between the RUSF-b and RUSF-v treatments. However, the arginine to asymmetric dimethylarginine ratio was significantly increased by RUSF-v compared with RUSF-b (56·26%, 31·13 to 81·38; p<0·0001). In planned analyses that used mixed effects models to estimate the effect of each intervention compared with the participants at baseline or during washout periods, the arginine to asymmetric dimethylarginine ratio increased following both RUSF-v treatment (86%; p<0·0001) and RUSF-b treatment (40%; p<0·0001). However, FMDmax% was higher after treatment with RUSF-v (0·92; p<0·0001) but not RUSF-b (0·39; p=0·22). Following either intervention (RUSF-b and RUSF-v, pooled) body-mass index-for-age Z-score (0·091; p=0·001) and height-for-age Z-score (0·013; p=0·081) increased compared with baseline and washout timepoints. In 83 participants in the treated population, there were 71 adverse events during the intervention, of which 21 (30%) were serious, and 81 adverse events during the washout periods, of which 26 (32%) were serious (p=0·31), including one patient who died in the second washout period.InterpretationRUSF providing 500 kcal/day results in small weight gains in children with sickle-cell disease. However, even without arginine and citrulline fortification, RUSF seems to ameliorate arginine dysregulation and might improve endothelial function. Long-term studies are required to assess whether these physiological effects translate to improved clinical outcomes and better growth and development in patients with sickle-cell disease.FundingWellcome Trust.

A randomized, double-blind, active-control trial to evaluate the efficacy and safety of a three day course of tafenoquine monotherapy for the treatment of Plasmodium vivax malaria.

BackgroundTafenoquine is an investigational 8-aminoquinoline for the prevention of Plasmodium vivax relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the currently recommended 14-day primaquine regimen.MethodsThis randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed P. vivax were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120.ResultsDay 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83–98%) with tafenoquine, and 100% (22/22) (90%CI 87–100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92–100%), and 95% (19/20) (90%CI 78–100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4–25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5–5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient.DiscussionAlthough there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of P. vivax malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing.Trial registrationClinicaltrials.gov NCT01290601

Relative Bioavailability of a Fixed-Combination Tablet Formulation of Azithromycin and Chloroquine in Healthy Adult Subjects

A fixed-dose combination of azithromycin and chloroquine (AZCQ) is in development for intermittent preventive treatment of malaria in pregnant women (IPTp). The combination has demonstrated synergistic activity against chloroquine-resistant strains of Plasmodium falciparum in vitro and in vivo and efficacy in Phase 2 and 3 treatment studies in patients with symptomatic uncomplicated P. falciparum malaria. This was an open-label, randomized, single-dose, parallel-group study to estimate the relative bioavailability of two AZCQ tablets, each containing azithromycin base 250 mg and chloroquine base 155 mg (test treatment), compared with the coadministration of commercially available individual tablets of azithromycin base 500 mg and chloroquine base 300 mg (reference treatment) in 40 healthy male and female subjects (aged 18-55 years; body weight >50.0 kg). Fasting subjects were randomized 1:1 to receive either test or reference treatment. Blood samples for the determination of serum azithromycin and plasma chloroquine concentrations were collected at specified time points pre- and post-dose for noncompartmental pharmacokinetic analyses. Safety evaluations included monitoring adverse events and vital signs as well as performing clinical laboratory tests. All subjects completed the study. Area under the concentration– time curve from time zero to time of last measurable concentration (AUClast) of azithromycin and chloroquine for the two AZCQ tablets was comparable to the reference treatment. The relative bioavailability as measured by AUClast ratio of adjusted geometric means (90% confidence interval) for the two AZCQ tablets was 101% (85.4%, 119%) for azithromycin and 99.1% (84.0%, 117%) for chloroquine compared with the reference treatment. Maximum concentration values for the two AZCQ tablets were approximately 13.0% higher for azithromycin and 11.0% lower for chloroquine compared with reference treatment. Both treatments were well tolerated. This AZCQ tablet formulation is currently being evaluated in Phase 3 clinical trials for IPTp.

CHLOROQUINE-RESISTANT PLASMODIUM FALCIPARUM

Objective: The study was conducted to determine the frequency of Chloroquine-resistant Plasmodium falciparum. Subjects&amp; Methods: This was a descriptive case series study conducted at Muhammad Medical College Mirpurkhas &amp; Liaquat University HospitalHyderabad/ Jamshoro, from January 2007 to December 2007. Total 160 patients with acute attack of fever were selected &amp; studied who fulfilledthe inclusion criteria. The WHO extended test was done by giving 25 mg/kg body weight of Chloroquine base over 3 days. The interpretationof the test was done as per criteria laid down by WHO. Results: Out of one hundred sixty, 110 (68.75%) were males and 50 (31.25%) werefemales with ratio of 2.2:1. The age range 16-45 years with mean 28±12 years. Seventy one patients (44.375%) were Chloroquine sensitive.Chloroquine-resistance (CQR) Rl, Rll &amp; both Rl Rll noted were 28.125%, 15.645% &amp; 43.75% respectively. The CQR- R III was not observedin our study. Conclusions: In view of this situation, more organized and thorough studies must be conducted to elucidate the epidemiology,geographic-distribution &amp; degree of Chloroquine resistance. And the local strategies be made to overcome this problem and to assess the needfor changing the first line drug.

Evaluation of chloroquine therapy for vivax and falciparum malaria in southern Sumatra, western Indonesia

BackgroundChloroquine was used as first-line treatment for Plasmodium falciparum or Plasmodium vivax in Indonesia before the initial launch of artemisinin combination therapy in 2004. A study to evaluate efficacies of chloroquine against P. falciparum and P. vivax was undertaken at Lampung in southern Sumatra, western Indonesia in 2002.MethodsPatients infected by P. falciparum or P. vivax were treated with 25 mg/kg chloroquine base in three daily doses over 48 hr. Finger prick blood was collected on Days 0, 2, 3, 7, 14, 21 and 28 after starting drug administration. Whole blood chloroquine and its desethyl metabolite were measured on Days-0, -3 and -28, or on the day of recurrent parasitaemia.Results42 patients infected by P. falciparum were enrolled, and 38 fullfilled criteria for per protocol analysis. Only six of 38 (16%) showed a response consistent with senstivity to chloroquine. 25 of 32 failures were confirmed resistant by demonstrating chloroquine levels on day of recurrence exceeding the minimally effective concentration (200 ng/mL whole blood). The 28-day cumulative incidence of resistance in P. falciparum was 68% (95% CI: 0.5260 - 0.8306). Thirty one patients infected by P. vivax were enrolled, and 23 were evaluable for per protocol analysis. 15 out of 23 (65%) subjects had persistent or recurrent parasitaemia. Measurement of chloroquine levels confirmed all treatment failures prior to Day-15 as resistant. Beyond Day-15, 4 of 7 recurrences also had drug levels above 100 ng/mL and were classified as resistant. The 28-day cumulative incidence of chloroquine resistance in P. vivax was 43% (95% CI: 0.2715 - 0.6384).ConclusionThese findings confirm persistantly high levels of resistance to chloroquine by P. falciparum in southern Sumatra, and suggest that high-grade and frequent resistance to chloroquine by P. vivax may be spreading westward in the Indonesia archipelago.

Chloroquine excretion in semen following antimalarial-drug administration.

The study described here was carried out to establish whether or not chloroquine was excreted in semen. Chloroquine was assayed in the semen of eight male volunteers (aged between 19 and 45 years) by a fluorimetric method before and after taking a total dose of 1.500 mg chloroquine base corresponding to the accepted dosage of the drug in malarial chemotherapy. Mean pre- and post-drug administration levels of 0.7 +/- 0.2 microM and 5.7 +/- 0.6 microM were obtained respectively, indicating a significant excretion of chloroquine in semen.

Synthesis, characterization and antimalarial activity of new iridium–chloroquine complexes

Chloroquine base (CQ) reacts with [Ir(COD)Cl]2 and IrCl3·3H2O to yield of Ir(CQ)Cl(COD) (1) and Ir2Cl6(CQ)·3H2O (2), respectively. Reaction of [Ir(COD)Cl]2 with CQ in the presence of NH4PF6 leaded to [Ir(CQ)(Solv)2]PF6 (3). The three new iridium–CQ complexes were characterized by a combination of elemental analysis, IR and NMR spectroscopies and evaluated in vitro against Plasmodium beghei. Comparison of the IC50 values obtained with the experimental compounds with that determined for chloroquine diphosphate indicated a higher activity for complex 2, while complexes 1 and 3 showed a similar and lower activity, respectively.

Quantitative assessment of seminal vesicle and prostate drug concentrations by use of a noninvasive method

The male genital tract is a complex collection of anatomically and biochemically distinct compartments that contribute to the ejaculate. Understanding the pharmacokinetics in these compartments should inform rational therapeutics involving these glands. Nineteen men were administered a single dose of 600 mg chloroquine (base) and 975 mg aspirin before providing a semen sample by masturbation with fractionation into a 5-compartment collection device. Fractions were assayed for fructose (unique seminal vesicle marker), prostate-specific antigen (unique prostate marker), salicylate, and chloroquine. Seminal vesicle and prostate concentrations of salicylate and chloroquine were estimated via a novel analytic method involving a multilevel latent-variable model implemented by use of Bayesian methods. The geometric mean chloroquine semen/blood ratio was 4.02 (95% confidence interval [CI], 2.36-6.86); for salicylate, the primary metabolite of aspirin, the semen/blood ratio was 0.10 (95% CI, 0.08-0.14). The estimated mean prostate/seminal vesicle ratio for salicylate, 0.38 (95% CI by Bayesian methods, 0.12-0.73), was consistent with our hypothesis that salicylate would achieve higher concentrations in the seminal vesicle than in the prostate. Chloroquine, however, did not demonstrate a statistically significant seminal vesicle/prostate difference (4.41; 95% CI by Bayesian methods, 0.14-30.52). We successfully demonstrated the quantitative, noninvasive estimation of drug concentrations in the prostate gland fluid distinct from the seminal vesicle fluid using our optimized method of split-ejaculate collection and a novel mixed-effects model with Bayesian estimation. Our methods can be applied to gland-specific quantitation of drugs and other substances of interest, thus enabling pharmacokinetic, pharmacodynamic, and pathophysiologic studies to inform rational therapeutics within different glands of the male genital tract.

Chloroquine administration for malaria suppression after abdominal surgery.

Administration of chloroquine after major surgery is indicated in malaria endemic areas. In emergencies it is commonly administered parenterally after the operation. The present study, undertaken at St. Francis Hospital, Ifakara (Kilombero District), Tanzania, compared plasma chloroquine levels after oral and subcutaneous administration of 300 mg of chloroquine base in 14 patients after abdominal, non-bowel-resective surgery and in 12 controls. There were no significant differences in the plasma chloroquine levels of all groups, and the chloroquine concentrations reached suppressive levels for at least 3 days (greater than 0.1 nmol/ml). Oral administration was well tolerated in both patients and controls. In all areas where the Plasmodium strains are still sensitive to chloroquine and where parenteral chloroquine may not be easily available, oral chloroquine represents a cheap, easy and safe alternative for postoperative prophylactic malaria suppression. It can be applied after abdominal non-bowel-resective emergency surgery.

Are 1–2 dangerous? Chloroquine and hydroxychloroquine exposure in toddlers

Ingestion of 1–2 tablets of chloroquine or hydroxylchloroquine is thought to predispose children under 6 years of age to serious morbidity and mortality. The actual risk to the toddler and appropriate guidelines for care remain unclear at a time when both medications are therapeutically utilized as anti-inflammatory agents in addition to their main use as anti-parasitics. A review of the literature and data from the American Association of Poison Control Centers reveals instances where exposure to as little as 1–2 tablets of chloroquine resulted in serious consequences. Based on these findings, ingestions of greater than 10 mg/kg of chloroquine base or unknown amounts require triage to the nearest health care facility for 4–6 h of observation. There is very limited data on pediatric hydroxychloroquine overdoses and no reports of toxicity from 1–2 pills, but given its similarity to chloroquine, it also should be considered potentially toxic at small doses. Thus, similar recommendations should be followed for triage after accidental hydroxychloroquine overdose.

No benefits from combining chloroquine with artesunate for three days for treatment of Plasmodium falciparum in Guinea-Bissau

The use of a combination of chloroquine and artesunate has been suggested for treatment of malaria in Africa. We used concomitant as well as sequential medication with these 2 drugs in relation to each drug separately for children infected with Plasmodium falciparum in Guinea-Bissau from March 2000 to November 2001. By block-randomization, 474 children with symptomatic malaria were divided into 4 groups and given either a total of 8 mg artesunate per kg bodyweight for 3 d, a total of 25 mg chloroquine base per kg bodyweight for 3 d, both drugs concomitantly for 3 d, or both drugs in sequence. All children were followed weekly for 5 weeks. On day 28, parasites had been detected in 40% of the children who were treated with artesunate only compared with 21% treated with chloroquine, 20% treated with artesunate in combination with chloroquine, and 16% treated with artesunate and chloroquine in sequence; on day 35 the corresponding percentages were 48%, 29%, 27%, and 24%, respectively. The outcome of the combination of chloroquine and artesunate in the doses studied was similar to the outcome of chloroquine monotherapy regardless of whether the 2 drugs are given concomitantly (relative risk [RR] = 0.93, 95% CI 0.56-1.53, P= 0.76) or in sequence (RR = 0.78, 95% CI 0.47–1.28, P = 0.32). Thus, neither an antagonistic, an additive, or a synergistic effect of the 2 drugs was indicated.

Treatment of uncomplicated malaria in children in Guinea-Bissau with chloroquine, quinine, and sulfadoxine-pyrimethamine

With the increasing resistance to commonly used antimalarial drugs, different untested ‘local’ treatment regimens for malaria will arise. We compared commonly used treatment regimens for children in Guinea-Bissau. Symptomatic children with Plasmodium falciparum mono-infection were allocated at random to one of 4 treatments: 15 mg/kg quinine twice a day for 3 d (group 1); 10 mg/kg quinine twice a day for 3 d followed by a total dose of 25 mg chloroquine base given over 3 d (group 2); a total dose of 50 mg/kg chloroquine base given in 2 daily doses for 3 d (group 3), or sulfadoxine-pyrimethamine (group 4). On day 28 more children from group 1 (33%; relative risk [RR]= 2·9, 95% confidence interval [CI]1·5–5·7) and group 2 (26%; RR = 2·1, CI 1·0–4·3) had had parasitaemia than in group 4 (12%), whereas no significant difference was found between group 3 (17%; RR = 1·3, CI 0·6–2·2) and group 4. No severe adverse reaction was observed in any of the groups. Chloroquine is still effective in Guinea-Bissau at an increased dose of 50 mg/kg, which appears safe when given orally in 2 daily doses for 3 d. Sulfadoxine-pyrimethamine could serve as an efficient, cheap and easy to administer second-line drug, leaving quinine to be used for third-line treatment. Quinine should not be used in short courses, nor does the combination of quinine and chloroquine have any advantage.

PLASMA TOTAL CHLOROQUINE LEVEL IN RELATION TO PLASMODIUM FALCIPARUM DENSITY IN ADULT MALARIA PATIENTS IN CALABAR

Quantification of plasma total chloroquine level was carried out in relation to Plasmodium falciparum density in 80 adult malaria patients in Calabar. The WHO in Vivo seven-day test was used with follow-up on days 1, 2, 3 and 7 after treatment with 25mg chloroquine base per kilogram body weight. Clinical and parasitological evaluations were performed. Detectable residual plasma total chloroquine level was found in the blood of 32 percent of the patients. There was no significant difference in the means of total chloroquine levels in plasma for both sensitive and resistant infections on days 3 and 7. Clinical successes of 94 percent was recorded in the study. Chloroquine treatment in vivo resulted in 90 percent parasite clearance within 7 days (sensitive responses). Seven cases of early recrudescence (R1) and one case of R11 were recorded in the study. On the basis of our findings Chloroquine is recommended for the treatment of malaria in Calabar if taken in prescribed dosages. Key Words: Plasma, Total chloroquine, Malaria, Plasmodium Falciparum. (Global J Med Sci: 2002 1(1): 41-47)

Standardization of the Physicochemical Parameters to Assess in Vitro the β-Hematin Inhibitory Activity of Antimalarial Drugs

Parapini, S., Basilico, N., Pasini, E., Egan, T. J., Olliaro, P., Taramelli, D., and Monti, D. 2000. Standardization of the physicochemical parameters to assess in vitro the β-Hematin inhibitory activity of antimalarial drugs. Experimental Parasitology96, 249–256. Intraerythrocytic plasmodia form hemozoin as a detoxification product of hemoglobin-derived heme. An identical substance, β-hematin (BH), can be obtained in vitro from hematin at acidic pH. Quinoline-antimalarials inhibit BH formation. Standardization of test conditions is essential for studying the interaction of compounds with this process and screening potential inhibitors. A spectrophotometric microassay of heme polymerization inhibitory activity (HPIA) (Basilico et al., Journal of Antimicrobial Chemotherapy42, 55–60, 1998) previously reported was used to investigate the effect of pH and salt concentration on BH formation. The yield of BH formation decreased with pH. Moreover, under conditions used in the above HPIA assay (18 h, 37°C, pH = 2.7), several salts including chloride and phosphate inhibited the process. Aminoquinoline drugs formulated as salts (chloroquine—phosphate, primaquine—diphosphate), but not chloroquine—base, also inhibited the reaction. Interference by salts was highest at low pH and decreased at higher pH (pH 4). Here, we describe different assay conditions that eliminate these problems (BHIA, β-hematin inhibitory activity). By replacing hematin with hemin as the porphyrin and NaOH solution with DMSO as solvent, the formation of BH was independent of pH up to pH 5.1. No interference by salts was observed over the pH range 2.7–5.1. Dose-dependent inhibition of BH formation was obtained with chloroquine—base, chloroquine—phosphate, and chloroquine—sulfate at pH 5.1. Primaquine was not inhibitory. The final product, characterized by solubility in DMSO, consists of pure BH by FT-IR spectroscopy. The BHIA assay (hemin in DMSO, acetate buffer pH 5 ± 0.1, 18 h at 37°C) is designed to screen for those molecules forming π—π interactions with hematin and thus inhibiting β-hematin formation.

MALARIA CONTROL AMONGST TROOPS INVOLVED IN COUNTER INSURGENCY OPERATION IN RESISTANT PLASMODIUM FALCIPARUM AREAS

Incidence of malaria in troops carrying out counter-insurgency operation in thick jungles in North East region was compared for the year 1995 and 1996. Since troops were on constant move in thick jungles in hostile environment and they have to sleep and rest outdoor, use of mosquito net was not feasible in both years. Counter-insurgency operation lasted for two and half months in both the years from last week of March - 1st week of June. Inspite of troops being on 300mg chloroquine (base) per week as chemoprophylaxis, 40 cases (5%) of malaria were observed in troops in the year 1995. During the year 1996 troops were advised to take 600mg chloroquine (base) per week as chemoprophylaxis. Three cases (0.40%) of malaria were observed during the year 1996. Difference was found to be statistically significant.

Suicidal Chloroquine Poisoning: Clinical Course, Autopsy Findings, and Chemical Analysis

Suicidal overdose of chloroquine is rare. We present a 14-year-old girl who was admitted to our Emergency Department after intentional ingestion of 7.5 g of chloroquine base followed by cardiac and respiratory arrest. Despite early mechanical ventilation, cardiac support, and treatment with high doses of diazepam, the patient died. Laboratory investigation indicated disseminated intravascular coagulation confirmed by petechial hemorrhages in the leptomeninges at autopsy, a finding that has not previously been described. Postmortem tissue analysis demonstrated early drug distribution to the medulla oblongata and cerebellum.