Primaquine overdose in a toddler.

Antimalarial medications carry a risk of rare, but serious side effects. Primaquine in particular is known to cause methemoglobinemia and hemolytic anemia. In patients with underlying glucose-6-phosphate dehydrogenase (G6PD) deficiency, these side effects become amplified and can be life-threatening. This can complicate treatment plans as the recommended first-line management of severe methemoglobinemia, methylene blue, may cause or worsen hemolytic anemia in G6PD deficient patients. We present a case of a toddler with an accidental primaquine overdose who had undiagnosed G6PD deficiency. Over the 2 days following his ingestion he developed severe methemoglobinemia and hemolytic anemia toxicity. He was initially treated with a dose of methylene blue prior to learning of his G6PD deficiency. He was subsequently given additional doses of ascorbic acid and a blood transfusion. His condition gradually improved and he was ultimately discharged in good condition. To our knowledge, this case represents a unique presentation of mixed methemoglobinemia and hemolytic toxicity due to an accidental primaquine overdose in a G6PD deficient pediatric patient. Though cases remain relatively rare, pediatric patients represent the vast majority of known primaquine overdoses. Their diagnosis and treatment require maintaining a high index of suspicion and a good working knowledge of antimalarial toxicities and management options.

Concentration-dependent mortality of chloroquine in overdose.

Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1-17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.

Hydroxychloroquine and chloroquine are closely-related drugs used for the treatment of malaria and rheumatological conditions, such as lupus. Laboratory tests have indicated that these drugs could also be used against the virus that causes COVID-19. Given the urgent need, these drugs have been fast-tracked into large-scale clinical trials, bypassing the usual stages that would provide estimates for suitable dosage. The dosage is a critical factor in a clinical trial: too low and the drug will not have an effect, too high and the side effects may counteract any potential benefits. Laboratory tests suggest that higher doses of chloroquine or hydroxychloroquine are needed for treating COVID-19 compared to malaria or lupus. However, there are concerns about the high doses used in some trials, as the drugs can have lethal side effects. Indeed, chloroquine has been used extensively in suicide attempts, particularly in France. To address these concerns, Watson et al. set out to determine the highest dosage of chloroquine (and thus of hydroxychloroquine, approximately) that does not cause unacceptable side effects. First, data was analysed regarding the concentration of chloroquine in the blood of 302 patients who had intentionally overdosed on the drug, since this concentration is tightly correlated with their risk of death. Watson et al. used a statistical model to calculate the maximal chloroquine concentration in a person's blood associated with a one per cent risk of death. This is taken to be the threshold above which any potential benefit of chloroquine treatment would be outweighed by the possibility of lethal toxicity. Watson et al. also estimated the relationship between chloroquine concentrations and changes in electrocardiogram patterns, which record the electrical activity of the heart. This makes it possible to determine whether a high dose of chloroquine has led to dangerous levels in the blood. Using a mathematical model of how chloroquine is metabolised, Watson et al. predicted that most of the trials that tested chloroquine as a treatment for COVID-19 did not reach the calculated threshold concentration. An exception was the CloroCovid-19 trial in Brazil, which was stopped early because people in the higher dosage group suffered more heart problems and died in greater numbers than those in the lower dosage group. Two large randomised trials, RECOVERY and SOLIDARITY, have shown no benefit of hydroxychloroquine or chloroquine in the treatment of COVID-19, changing clinical practice worldwide. Both of these trials used high doses resulting in higher hydroxychloroquine or chloroquine concentrations than normally observed in the treatment of malaria or rheumatological conditions. The results from Watson et al demonstrate that the lack of benefit seen in these two large clinical trials is not due to the drug dosage being too high.

Toxicokinetics of hydroxychloroquine following a massive overdose.

BACKGROUND: We report a patient with a massive hydroxychloroquine overdose manifested by profound hypokalemia and ventricular dysrhythmias and describe hydroxychloroquine toxicokinetics. CASE REPORT: A 20-year-old woman (60 kg) presented 1 h after ingesting 36 g of hydroxychloroquine. Vital signs were: BP, 66 mmHg/palpation; heart rate, 115/min; respirations 18/min; oxygen saturation, 100% on room air. She was immediately given intravenous fluids and intubated. Infusions of diazepam and epinephrine were started. Activated charcoal was administered. Her initial serum potassium of 5.3 mEq/L decreased to 2.1 mEq/L 1 h later. The presenting electrocardiogram (ECG) showed sinus tachycardia at 119 beats/min with a QRS duration of 146 ms, and a QT interval of 400 ms (Bazett's QTc 563 ms). She had four episodes of ventricular tachydysrhythmias requiring cardioversion, electrolyte repletion, and lidocaine infusion. Her blood hydroxychloroquine concentration peaked at 28,000 ng/mL (therapeutic range 500-2000 ng/mL). Serial concentrations demonstrated apparent first-order elimination with a half-life of 11.6 h. She was extubated on hospital day three and had a full recovery. CONCLUSION: We present a massive hydroxychloroquine overdose treated with early intubation, activated charcoal, epinephrine, high dose diazepam, aggressive electrolyte repletion, and lidocaine. The apparent 11.6 hour half-life of hydroxychloroquine was shorter than previously described.

Use of hyperbaric oxygen therapy in quinine-associated visual disturbances.

INTRODUCTION: Hyperbaric oxygen (HBO2 ) therapy is infrequently reported as a treatment for poison-induced retinal damage. We describe a case in which HBO2 therapy was used to treat suspected retinal toxicity induced by quinine. CASE REPORT: We present a case in which HBO2 was used to treat visual disturbances thought to be caused by quinine-induced retinal damage. The patient intentionally ingested undisclosed amounts of citalopram and quinine. Following a complicated hospital course, including profound shock requiring treatment with four vasopressors and a peripheral left-ventricular assist device, the patient, once extubated, reported visual abnormalities consistent with those described from quinine-induced retinal toxicity. Visual disturbances seemed to show improvement following HBO2 treatment. Several months following hospitalization visual defects continued to be present on examination. However, with corrective lenses the patient's visual acuity was normal. No adverse events were attributed to the use of HBO2. DISCUSSION: HBO2 for treatment of quinine-induced retinal damage is infrequently reported or studied. In the reported case, use of HBO2 appeared to be associated with substantial improvement in visual disturbances occurring in the setting of an overdose of quinine. The patient's improvement is remarkable, given her retinas were also jeopardized by her profound shock. Additional data are needed to understand the risks and benefits of this procedure, but due to limited treatment options for poison-induced retinal toxicity and the low likelihood for implementation of a controlled randomized trial of HBO2 in this population, the procedure may be considered in quinine-induced retinal toxicity.

A Literature Review of the Use of Sodium Bicarbonate for the Treatment of QRS Widening.

Sodium bicarbonate is a well-known antidote for tricyclic antidepressant (TCA) poisoning. It has been used for over half a century to treat toxin-induced sodium channel blockade as evidenced by QRS widening on the electrocardiogram (ECG). The purpose of this review is to describe the literature regarding electrophysiological mechanisms and clinical use of this antidote after poisoning by tricyclic antidepressants and other agents. This article will also address the literature supporting an increased serum sodium concentration, alkalemia, or the combination of both as the responsible mechanism(s) for sodium bicarbonate's antidotal properties. While sodium bicarbonate has been used as a treatment for cardiac sodium channel blockade for multiple other agents including citalopram, cocaine, flecainide, diphenhydramine, propoxyphene, and lamotrigine, it has uncertain efficacy with bupropion, propranolol, and taxine-containing plants.

Development, validation and clinical application of a LC-MS/MS method for the simultaneous quantification of hydroxychloroquine and its active metabolites in human whole blood.

A rapid, sensitive and specific method using liquid chromatography coupled to tandem mass spectrometry was developed for the simultaneous quantification of hydroxychloroquine (HCQ) and its three major metabolites in human whole blood. The assay, using a sample volume of 100µL, was linear in a dynamic 25-2000ng/mL range (R(2)>0.99) for all four compounds and suitable for the determination of elevated HCQ concentrations up to 20,000ng/mL, after appropriate sample dilution. Inter- and intra-assay precisions were <18.2% and accuracies were between 84% and 113% for any analyte. No matrix effects were observed. The assay was successfully applied to a blood sample obtained from one poisoned patient following a massive HCQ self-ingestion resulting in an estimated concentration of 19,500ng/mL on hospital admission. In this patient, HCQ metabolites were identified and quantified at 1123, 465 and 91ng/mL for monodesethylhydroxychloroquine, desethylchloroquine and bisdesethylchloroquine, respectively. Further investigations are still required to assess the usefulness of the simultaneous measurement of blood concentrations of HCQ and its three active metabolites for monitoring HCQ treatment and managing HCQ poisoning.

A simple qualitive procedure for the detection of chloroquine in urine for use in clinical analytical toxicology in resource poor settings.

Objective: To develop and validate a simple procedure for the qualitative determination of chloroquine in urine with potential for use in developing countries lacking sophisticated analytical equipment and expensive reagents. Design: This was a laboratory based study making use of which combines a colorimetric test, Dill-Glazko's test, and UV/Visible absorbance spectrometry to confirm the presence of chloroquine. The spectrophotometric method was cross validated with the standard Baselt's method for quantification of chloroquine in biological fluids. Setting: Pharmacology laboratory at the Department of Clinical Pharmacology, College of Health Sciences, University of Zimbabwe. Main Outcome Measures: Recovery of the methods was assessed by comparing the peak absorbances and the resolution of the peaks at 329nm and 343nm. Sensitivity and specificity was determined by analysing in a blinded manner. The limits of detection of both the Dill-Glazko's test and the confirmatory test was determined. Results: In the prevalidation procedures increasing the volume of the ethylacetate and the volume of the lower aqueous layer extracted was found to increase the recovery of the confirmatory test. There was a significant difference between both the peak absorbances and the peak resolution for the two methods (p<0.0001). The confirmatory test had a sensitivity of 90% and a specificity of 100%, whereas the Baselt's method had a sensitivity of 83.3% and a specificity of 96.7%. The limit of detection of the Dill-Glazko's test was 15mg/Land that of the confirmatory test was 5mg/L. Conclusions: The confirmatory test had better recovery and was more sensitivity compared with the Baselt's method. The limit of detection of the combination method (Dill-Glazko's plus confirmatory test) was 15mg/L. The combination test showed appreciable sensitivity to be suitable for application to clinical toxicology.

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 E(max) 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.

Small dose... big poison.

BACKGROUND: It is not possible to identify all toxic substances in a single journal article. However, there are some exposures that in small doses are potentially fatal. Many of these exposures are particularly toxic to children. Using data from poison control centres, it is possible to recognise this group of exposures. OBJECTIVE: This article provides information to assist the general practitioner to identify potential toxic substance exposures in children. DISCUSSION: In this article the authors report the signs and symptoms of toxic exposures and identify the time of onset. Where clear recommendations on the period of observation and known fatal dose are available, these are provided. We do not discuss management or disposition, and advise readers to contact the Poison Information Service or a toxicologist for this advice.

Immunohistochemical demonstration of the distribution of chloroquine (CQ) and its metabolites in CQ-poisoned mice.

Chloroquine (CQ) distribution in tissues of acutely poisoned mice was demonstrated by immunohistochemistry using anti-CQ polyclonal antibodies (PAC). PAC recognized 4-amino-7-chloro-quinoline structure and sufficiently reacted with CQ and CQ's metabolite bisdesethyl-chloroquine. In the brain, CQ and its metabolites (CQs) localized in the region of the choroids plexus, indicating an important role in the blood-cerebrospinal barrier system. In the heart, most regions showed diffused positive staining, and relatively strong reaction was observed in Purkinje cells, indicating an important role in acute CQ toxicity. In the lungs, CQs were observed in the bronchial epithelium, type II pneumocytes, and on the surface of alveolar walls. It was suggested that CQs were excreted to the alveolar wall with surfactant phospholipids, which are produced by type II pneumocytes. In the liver, CQs were concentrated in the centrolobular area rather than in the periportal area, in agreement with CQ's metabolic pathway. In the kidneys, tubular cells were strongly stained compared to glomerular capsules, and the distal part of renal tubules was better stained than the proximal tubules. These findings suggested that CQs were predominantly excreted or reabsorbed through the distal tubules and the collecting duct. Distribution of CQs in tissues presented here were mostly consistent with the physico-chemical properties of CQ and its metabolites. However, the elucidation of CQs' localization in Purkinje cells remains open. Further experimental studies at the level of microorganella will be needed to clarify the present result.

[Acute chloroquine intoxication--rare, but always serious: case reports and literature review]. / Ostre zatrucie chlorochina--rzadkie, ale zawsze powazne: opis przypadków i przeglad literatury.

Chloroquine is a derivative of 4-aminoquinoline, which is used in the malaria prophylaxis and treatment and the therapy of some connective tissue diseases. Its narrow therapeutic index causes that the medicine is relatively toxic, especially in the case of an overdose or an acute intoxication. In the recent study two cases of the acute chloroquine poisoning, hospitalized in the Toxicology Department in Kraków, were described and one of them was fatal. The first case was 16-year-old girl who ingested 5 g of chloroquine phosphate in the suicidal attempt. After about 2 hours general seizures appeared followed by ventricular fibrillation and cardiac arrest. After near 2-hour-lasted reanimation procedures she was resuscitated, but 14 hours later another cardiac arrest appeared because of the bradyasystole. Despite the institution of advanced reanimation methods including external pacemaker and electrostimulation, spontaneous circulation did not return and the patient was declared dead. Postmortem toxicological examination of blood, vitreous humour, bile and liver revealed extremely high concentrations of chloroquine (252.15 mg/l in blood). The second case was the 15-year-old girl who ingested 7.5 g of chloroquine phosphate. She developed significant hypotension requiring intravenous infusions of fluids and catecholamines and respiratory distress positively treated with endotracheal intubation and mechanical ventilation. In both cases a considerable hypokalemia and prolonged QTc interval were observed. According to the literature, a clinical picture, diagnosis and recommended therapy of an acute chloroquine poisoning were reviewed.

[Acute hydroxychloroquine poisoning. The danger of rapid or excessive correction of initial hypokalemia]. / Intoxication aiguë à l'hydroxychloroquine. Danger d'une correction exagérée ou rapide de l'hypokaliémia initiale.

INTRODUCTION: Toxic effects of hydroxychloroquine, like chloroquine, include membrane stabilization and hypokalemia, which is correlated with the severity of the overdose. Correction of hypokalemia can expose patients to the risk of ventricular arrhythmia. CASE: A 19-year-old woman who had ingested 6 grams of hydroxychloroquine was admitted to intensive care with severe hypokalemia (1.5 mmol/L on admission). Thirty-six hours after correction of the hypokalemia, circulatory arrest followed ventricular fibrillation. Her potassium level at that time was 5.8 mmol/L. Outcome was favorable after it returned to normal. DISCUSSION: Because its pathogenesis remains debatable, the hypokalemia following hydroxychloroquine poisoning must be corrected with care, even when severe. This correction is difficult, and extracellular transfer of the excess potassium after elimination of the toxin exposes the patient to the risk of ventricular arrhythmia.

HPLC analysis of anti-malaria agent, chloroquine in blood and tissue from forensic autopsy cases in Tanzania.

HPLC analysis of anti-malaria agent, chloroquine (CQ) in blood and tissues with a simple HCl back extraction method was applied to three forensic autopsy cases in Dar es Salaam, Tanzania. CQ concentrations in femoral vein blood were 8.5, 48.4 and 43.8 microg/ml in three cases, respectively, which were high enough to attribute the cause of deaths to an acute CQ poisoning. There were great site dependent variations in blood CQ levels. The right heart blood samples were very high, which may be explained by incomplete distribution of the drug before death or postmortem diffusion from liver and its surrounding blood, as high CQ levels were remarkable in the liver. Suicidal and accidental CQ poisonings are very common and CQ is a very important chemical in the field of forensic toxicology in Tanzania.

One pill can kill: assessing the potential for fatal poisonings in children.

Antimalarials, camphor, clonidine, methyl salicylates, and sulfonylureas all may result in serious poisonings and are potentially fatal in small doses in toddlers. Early recognition and appropriate management, including antidotal and supportive care, may prevent poor outcomes in these patients.

Chloroquine gestational use in systemic lupus erythematosus: assessing the risk of child ototoxicity by pure tone audiometry.

The objective of this study was to assess child chloroquine ototoxicity after its use during the gestational period in systemic lupus erythematosus (SLE). Nineteen children over four years old were evaluated: nine were exposed to chloroquine diphosphate (CDP) during gestation and 10 were born from mothers that did not take this drug before conception or anytime during pregnancy (CONTROL). Pure tone audiometry was performed in all children and high and low frequency threshold means were compared to evaluate the hearing status. All nine mothers taking CDP were exposed to this drug at least during the first trimester of pregnancy (56% during the whole gestational period) and the mean time of CDP use was 6.1 +/- 2.9 months. No significant difference was found in children of CDP and CONTROL groups regarding age (7.6 +/- 4.4 versus 12.3 +/- 7.2 years; P = 0.10, respectively) and gender (P = 0.65). Pure tone high frequency thresholds, which are the first to be affected by ototoxic drugs, presented within normal limits in children exposed or not to CDP (8.5 +/- 5.0 versus 7.4 +/- 3.6 dBHL; P = 0.55, respectively). Likewise, the mean hearing thresholds at low frequencies were also similar in both groups (11.4 +/- 4.5 versus 11.9 +/- 3.0 dBHL; P = 0.66). In conclusion, child in utero exposure to chloroquine diphosphate does not seem to induce hearing impairment as measured by pure tone audiometry, reinforcing its safe use during pregnancy of lupus patients.