Modeling the effect of succimer (DMSA; dimercaptosuccinic acid) chelation therapy in patients poisoned by lead.

CONTEXT: Kinetic models could assist clinicians potentially in managing cases of lead poisoning. Several models exist that can simulate lead kinetics but none of them can predict the effect of chelation in lead poisoning. Our aim was to devise a model to predict the effect of succimer (dimercaptosuccinic acid; DMSA) chelation therapy on blood lead concentrations. MATERIALS AND METHODS: We integrated a two-compartment kinetic succimer model into an existing PBPK lead model and produced a Chelation Lead Therapy (CLT) model. The accuracy of the model's predictions was assessed by simulating clinical observations in patients poisoned by lead and treated with succimer. The CLT model calculates blood lead concentrations as the sum of the background exposure and the acute or chronic lead poisoning. The latter was due either to ingestion of traditional remedies or occupational exposure to lead-polluted ambient air. The exposure duration was known. The blood lead concentrations predicted by the CLT model were compared to the measured blood lead concentrations. RESULTS: Pre-chelation blood lead concentrations ranged between 99 and 150 µg/dL. The model was able to simulate accurately the blood lead concentrations during and after succimer treatment. The pattern of urine lead excretion was successfully predicted in some patients, while poorly predicted in others. CONCLUSIONS: Our model is able to predict blood lead concentrations after succimer therapy, at least, in situations where the duration of lead exposure is known.

The need for ICU admission in intoxicated patients: a prediction model.

CONTEXT: Intoxicated patients are frequently admitted from the emergency room to the ICU for observational reasons. The question is whether these admissions are indeed necessary. OBJECTIVE: The aim of this study was to develop a model that predicts the need of ICU treatment (receiving mechanical ventilation and/or vasopressors <24 h of the ICU admission and/or in-hospital mortality). MATERIALS AND METHODS: We performed a retrospective cohort study from a national ICU-registry, including 86 Dutch ICUs. We aimed to include only observational admissions and therefore excluded admissions with treatment, at the start of the admission that can only be applied on the ICU (mechanical ventilation or CPR before admission). First, a generalized linear mixed-effects model with binominal link function and a random intercept per hospital was developed, based on covariates available in the first hour of ICU admission. Second, the selected covariates were used to develop a prediction model based on a practical point system. To determine the performance of the prediction model, the sensitivity, specificity, positive, and negative predictive value of several cut-off points based on the assigned number of points were assessed. RESULTS: 9679 admissions between January 2010 until January 2015 were included for analysis. In total, 632 (6.5%) of the patients admitted to the ICU eventually turned out to actually need ICU treatment. The strongest predictors for ICU treatment were respiratory insufficiency, age >55 and a GCS <6. Alcohol and "other poisonings" (e.g., carbonmonoxide, arsenic, cyanide) as intoxication type and a systolic blood pressure ≥130 mmHg were indicators that ICU treatment was likely unnecessary. The prediction model had high sensitivity (93.4%) and a high negative predictive value (98.7%). DISCUSSION AND CONCLUSION: Clinical use of the prediction model, with a high negative predictive value (98.7%), would result in 34.3% less observational admissions.

Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans.

CONTEXT: No kinetic models presently exist which simulate the effect of chelation therapy on lead blood concentrations in lead poisoning. OBJECTIVE: Our aim was to develop a kinetic model that describes the kinetics of dimercaptosuccinic acid (DMSA; succimer), a commonly used chelating agent, that could be used in developing a lead chelating model. MATERIAL AND METHODS: This was a kinetic modelling study. We used a two-compartment model, with a non-systemic gastrointestinal compartment (gut lumen) and the whole body as one systemic compartment. The only data available from the literature were used to calibrate the unknown model parameters. The calibrated model was then validated by comparing its predictions with measured data from three different experimental human studies. RESULTS: The model predicted total DMSA plasma and urine concentrations measured in three healthy volunteers after ingestion of DMSA 10 mg/kg. The model was then validated by using data from three other published studies; it predicted concentrations within a factor of two, representing inter-human variability. CONCLUSIONS: A simple kinetic model simulating the kinetics of DMSA in humans has been developed and validated. The interest of this model lies in the future potential to use it to predict blood lead concentrations in lead-poisoned patients treated with DMSA.

Clinical presentation and management of an Aruban rattlesnake bite in the Netherlands.

Bites by Aruban Rattlesnake (Crotalus durissus unicolor) are rare and not known to induce severe envenomations. Here, we present a case of a 57 year-old man bitten by his pet Aruban Rattlesnake (Crotalus durissus unicolor). He was admitted to hospital within 15 min. Three and a half hours later his fibrinogen concentration decreased to 0.6 g/L (normal: 2.0-4.0). Nine hours post-bite, he was treated with polyvalent snake antivenom covering Crotalus durissus. Three hours later his fibrinogen became undetectable while at that time clotting times were prolonged (PT 38.7 s (normal: 12.5-14.5) and aPTT 40 s (normal: 25-35)). His platelet count remained within normal limits. Creatine kinase (CK) concentrations reached a maximum of 1868 U/L (normal: <200) 16 h post-bite. After a second antivenom dose, 10.5 h after the first antivenom administration, clotting times returned to normal. Fibrinogen was restored to normal within three days. He was discharged from hospital on day five. In conclusion, administration of polyvalent snake antivenom covering Crotalus durissus snakebites shows cross-neutralization and is effective in the treatment of patients bitten by Crotalus durissus unicolor.

Structure-dependent inhibition of the human α1ß2γ2 GABAA receptor by piperazine derivatives: A novel mode of action.

Piperazine derivatives are a class of psychoactive substances applied in prescription medicines like antidepressants as well as in drugs of abuse. They are known to increase brain levels of catecholamines, likely via reversal of reuptake transporters. However, other mechanisms could also contribute to increased neurotransmitter levels, e.g., reduced inhibitory inputs on catecholaminergic neurons. Inhibition of the main inhibitory input in the brain, the GABAergic system, by piperazine derivatives could contribute to increased neurotransmitter levels. Our previous studies support this by demonstrating that 1-(3-chlorophenyl)piperazine (3CPP/mCPP) is an antagonist of the human α1ß2γ2 GABAA receptor (GABAA-R). We therefore investigated the effect of 12 additional piperazine derivatives on the function of the human α1ß2γ2 GABAA-R expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. Tested derivatives included benzylpiperazine (BZP), methylbenzylpiperazines (2/3MBP), phenylpiperazine (PP), methoxyphenylpiperazines (2/3/4MPP/MeOPP), chlorophenylpiperazines (2/4CPP) and fluorophenylpiperazines (4FPP/TFMPP). All derivatives concentration-dependently inhibited the GABA-evoked ion current. Chlorophenylpiperazines were the most potent GABAA-R antagonists; the IC20 value for 1-(2-chlorophenyl)piperazine (2CPP) was 46µM and 2CPP induced a maximum inhibition of ∼ 90% at 1mM. Derivatives can be ranked as follows from highest to lowest potency based on IC20 values: 2CPP>3MPP>4CPP>4MPP>2MBP>3CPP>PP>4FPP>2MPP>TFMPP>3MBP>BZP. This study demonstrates a novel mode of action of piperazine derivatives, i.e., antagonism of the GABAA-R. This mechanism can result in increased catecholamine levels that indirectly contribute to toxicity, e.g., adverse effects during overdoses. Therefore, this important mode of action is not only relevant for therapeutic psychiatric interventions, but could also proof valuable for therapeutic interventions in intoxications.

The etiology and outcome of non-traumatic coma in critical care: a systematic review.

BACKGROUND: Non-traumatic coma (NTC) is a serious condition requiring swift medical or surgical decision making upon arrival at the emergency department. Knowledge of the most frequent etiologies of NTC and associated mortality might improve the management of these patients. Here, we present the results of a systematic literature search on the etiologies and prognosis of NTC. METHODS: Two reviewers independently performed a systematic literature search in the Pubmed, Embase and Cochrane databases with subsequent reference and citation checking. Inclusion criteria were retrospective or prospective observational studies on NTC, which reported on etiologies and prognostic information of patients admitted to the emergency department or intensive care unit. RESULTS: Eventually, 14 studies with enough data on NTC, were selected for this systematic literature review. The most common causes of NTC were stroke (6-54%), post-anoxic coma (3-42%), poisoning (<1-39%) and metabolic causes (1-29%). NTC was also often caused by infections, especially in African studies affecting 10-51% of patients. The NTC mortality rate ranged from 25 to 87% and the mortality rate continued to increase long after the event had occurred. Also, 5-25% of patients remained moderately-severely disabled or in permanent vegetative state. The mortality was highest for stroke (60-95%) and post-anoxic coma (54-89%) and lowest for poisoning (0-39%) and epilepsy (0-10%). CONCLUSION: NTC represents a challenge to the emergency and the critical care physicians with an important mortality and moderate-severe disability rate. Even though, included studies were very heterogeneous, the most common causes of NTC are stroke, post anoxic, poisoning and various metabolic etiologies. The best outcome is achieved for patients with poisoning and epilepsy, while the worst outcome was seen in patients with stroke and post-anoxic coma. Adequate knowledge of the most common causes of NTC and prioritizing the causes by mortality ensures a swift and adequate work-up in diagnosis of NTC and may improve outcome.

Evaluation of semi-generic PBTK modeling for emergency risk assessment after acute inhalation exposure to volatile hazardous chemicals.

BACKGROUND: Physiologically Based Toxicokinetic Models (PBTK) may facilitate emergency risk assessment after chemical incidents with inhalation exposure, but they are rarely used due to their relative complexity and skill requirements. We aimed to tackle this problem by evaluating a semi-generic PBTK model built in MS Excel for nine chemicals that are widely-used and often released in a chemical incident. MATERIAL & METHODS: The semi-generic PBTK model was used to predict blood concentration-time curves using inhalation exposure scenarios from human volunteer studies, case reports and hypothetical exposures at Emergency Response Planning Guideline, Level 3 (ERPG-3) levels.(2) Predictions using this model were compared with measured blood concentrations from volunteer studies or case reports, as well as blood concentrations predicted by chemical-specific models. The performances of the semi-generic model were evaluated on biological rationale, accuracy, and ease of use and range of application. RESULTS: Our results indicate that the semi-generic model can be easily used to predict blood levels for eight out of nine parent chemicals (dichloromethane, benzene, xylene, styrene, toluene, isopropanol trichloroethylene and tetrachloroethylene). However, for methanol, 2-propanol and dichloromethane the semi-generic model could not cope with the endogenous production of methanol and of acetone (being a metabolite of 2-propanol) nor could it simulate the formation of HbCO, which is one of the toxic end-points of dichloromethane. The model is easy and intuitive to use by people who are not so familiar with toxicokinetic models. CONCLUSION: A semi-generic PBTK modeling approach can be used as a 'quick-and-dirty' method to get a crude estimate of the exposure dose.

Methylphenidate intoxications in children and adults: exposure circumstances and evidence-based dose threshold for pre-hospital triage.

CONTEXT: Methylphenidate intoxications mostly have a relatively mild course, although serious complications can occur. OBJECTIVE: We aimed to characterize methylphenidate exposures and reassess our current dose threshold for hospital referral (2 mg/kg). METHODS: In a prospective follow-up study, we analysed 364 consecutive methylphenidate exposures that were reported to the Dutch Poisons Information Center. Patients and/or physicians were surveyed by telephone using standardized questionnaires. Three physicians independently scored the observed severity of the intoxication of each patient as 'no/mild' (observation at home) or 'moderate/severe' (hospital referral necessary). RESULTS: Unintentional exposures (40%) mostly occurred at home involving the patients' own medication or those from a family member. Compared to unintentionally exposed patients, intentionally exposed patients were exposed to relatively high methylphenidate doses (3.1 vs 1.6 mg/kg), more often used immediate release methylphenidate formulations (62 vs 34%) and more frequently had concomitant exposures (71 vs 17%). Severe symptoms like convulsions or coma were reported only in patients with concomitant exposures. Following exposure to methylphenidate only (i.e. no concomitant exposures), the most commonly reported symptoms were dry mucosa, headache, agitation, sleepiness and tachycardia. Our results show that the reported methylphenidate dose is predictive of the observed severity of the intoxication and can therefore aid in pre-hospital triage. CONCLUSION: We increased our current dose threshold for hospital referral from 2 to 3 mg/kg. In addition, we will refer patients at lower doses when clinical symptoms indicate the need for hospital referral. Application of this new dose threshold optimizes triage, thereby reducing unnecessary hospital referral and thus costs, without jeopardising patient safety.

Rhabdomyolysis in Clozapine Overdose.

CONTEXT: Clozapine is used for decennia for the treatment of schizophrenia. Agranulocytosis, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis are well-known adverse effects of clozapine, which are sometimes life threatening. Here we report a case of rhabdomyolysis upon an acute overdose of clozapine. CASE: A male patient, 36 years, with elevated creatinine kinase levels (9899 U/l), developed rhabdomyolysis afterafter admission to the emergency department. Approximately 2-4 h earlier he had intoxicated himself with his maintenance oral medication clozapine 125 mg, temazepam 20 mg and lorazepam 1.5 mg. Co-medications, and physical and laboratory examinations did not reveal other risk factors for rhabdomyolysis. According to the Naranjo probability scale there was a probable relation between clozapine dose and symptoms, that developed approximately 2-4 h after the auto-intoxication of 125 mg tablets. At day 5 of hospitalization, clozapine and creatinine kinase levels returned to normal and the patient was discharged with no somatic sequelae. CONCLUSIONS: Elevated creatinine kinase levels in acute clozapine intoxication may be an indicator that rhabdomyolysis may be involved.

Acute subjective effects after smoking joints containing up to 69 mg Δ9-tetrahydrocannabinol in recreational users: a randomized, crossover clinical trial.

RATIONALE: An increase in the potency of the cannabis cigarettes has been observed over the past three decades. OBJECTIVES: In this study, we aimed to establish the impact of Δ9-tetrahydrocannabinol (THC) on the rating of subjective effects (intensity and duration of the effects), up to 23 % THC potency (69 mg THC) among recreational users. METHODS: Recreational users (N = 24) smoked cannabis cigarettes with four doses of THC (placebo 29, 49 and 69 mg of THC) on four separate test days in a randomized, double-blind, placebo-controlled, crossover study. The participants filled in three different questionnaires measuring subjective effects during the exposure up to 8 h post-smoking. The 'high' feeling, heart rate, blood pressure and THC serum concentrations were also regularly recorded during these 8 h. RESULTS: THC significantly increased the high feeling, dizziness, dry-mouthed feeling, palpitations, impaired memory and concentration, and 'down', 'sedated' and 'anxious' feelings. In addition, THC significantly decreased alertness, contentment and calmness. A cubic relationship was observed between 'feeling the drug' and 'wanting more'. The THC-induced decrease in 'feeling stimulated' and increase in anxiety lasted up to 8 h post-smoking. Sedation at 8 h post-smoking was increased by a factor of 5.7 with the highest THC dose, compared to the placebo. CONCLUSIONS: This study shows a strong effect of cannabis containing high percentages of THC on the rating of subjective effects. Regular users and forensic toxicologists should be aware that the THC-induced increase in 'feeling sedated' continues longer with a 69 mg THC dose than with a 29 mg THC dose.

In-hospital mortality and long-term survival of patients with acute intoxication admitted to the ICU.

OBJECTIVE: To assess in-hospital and long-term mortality of Dutch ICU patients admitted with an acute intoxication. DESIGN: Cohort of ICU admissions from a national ICU registry linked to records from an insurance claims database. SETTING: Eighty-one ICUs (85% of all Dutch ICUs). PATIENTS: Seven thousand three hundred thirty-one admissions between January 1, 2008, and October 1, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Kaplan-Meier curves were used to compare the unadjusted mortality of the total intoxicated population and for specific intoxication subgroups based on the Acute Physiology and Chronic Health Evaluation IV reasons for admission: 1) alcohol(s), 2) analgesics, 3) antidepressants, 4) street drugs, 5) sedatives, 6) poisoning (carbon monoxide, arsenic, or cyanide), 7) other toxins, and 8) combinations. The case-mix adjusted mortality was assessed by the odds ratio adjusted for age, gender, severity of illness, intubation status, recurrent intoxication, and several comorbidities. The ICU mortality was 1.2%, and the in-hospital mortality was 2.1%. The mortality 1, 3, 6, 12, and 24 months after ICU admission was 2.8%, 4.1%, 5.2%, 6.5%, and 9.3%, respectively. Street drugs had the highest mortality 2 years after ICU admission (12.3%); a combination of different intoxications had the lowest (6.3%). The adjusted observed mortality showed that intoxications with street drugs and "other toxins" have a significant higher mortality 1 month after ICU admission (odds ratioadj = 1.63 and odds ratioadj= 1.73, respectively). Intoxications with alcohol or antidepressants have a significant lower mortality 1 month after ICU admission (odds ratioadj = 0.50 and odds ratioadj = 0.46, respectively). These differences were not found in the adjusted mortality 3 months upward of ICU admission. CONCLUSIONS: Overall, the mortality 2 years after ICU admission is relatively low compared with other ICU admissions. The first 3 months after ICU admission there is a difference in mortality between the subgroups, not thereafter. Still, the difference between the in-hospital mortality and the mortality after 2 years is substantial.

Additive inhibition of human α1ß2γ2 GABAA receptors by mixtures of commonly used drugs of abuse.

Yearly, exposure to drugs of abuse results in ∼1 million emergency department visits in the US. In ∼50% of the visits, stimulant drugs like cocaine and amphetamine-like substances (e.g. 3,4-methylenedioxymethamphetamine (MDMA, the main active ingredient of ecstasy)) are involved, whereas in ∼60% multiple drugs are involved. These drugs induce higher dopamine and serotonin levels resulting in drug-induced toxicity. Since GABA receptors (GABA-R) provide the main inhibitory input on dopaminergic and serotonergic neurons, drug-induced inhibition of GABA-R could contribute to higher neurotransmitter levels and thus toxicity. We therefore investigated the effects of combinations of commonly abused stimulant drugs (cocaine, MDMA, 3,4-methylenedioxyamphetamine (MDA) and meta-chlorophenylpiperazine (mCPP)) on the function of the human α1ß2γ2 GABAA receptor (hGABAA-R), expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. These drugs concentration-dependently inhibited the GABA-evoked current (mCPP>cocaine>MDMA>MDA). Most drug combinations decreased the GABA-evoked current stronger than the single drug. Additivity was observed during combined exposure to low concentrations of cocaine and mCPP as well as during combined exposure to MDA with cocaine or mCPP. However, combinations containing MDMA mainly resulted in sub-additivity or no additivity. At drug concentrations relevant for clinical toxicology, co-exposure to ≥2 drugs can decrease the GABA-evoked current in an additive manner. Thus, in patients exposed to multiple drugs, inhibitory GABA-ergic input is reduced more prominently, likely resulting in higher brain dopamine levels. As this will increase the risk for drug-induced toxicity, treatment of drug-intoxicated patients with drugs that enhance GABA-ergic input should be further optimized.

[Cobalt poisoning due to metal-on-metal hip implants]. / Kobaltvergiftiging door metaal-op-metaalheupprothese.

Since 2011, cobalt and chromium blood levels are measured in patients with a metal-on-metal hip implant (MoM prosthesis). In this article we discuss the health risks that are related to chronically elevated blood cobalt concentrations induced by abnormal wear and corrosion of the MoM prosthesis. Only a few patients who have systemic symptoms of poisoning, besides local symptoms around the failing MoM prosthesis, have been described in the literature. Toxic blood cobalt concentrations may be accompanied by hypothyroidism, polyneuropathy, impairment of cranial nerves II and VIII and cardiomyopathy. Treatment consists of removal of the prosthesis. In patients with a normal kidney function, the cobalt blood levels rapidly decrease and symptoms of cobalt intoxication subside. Chelation therapy should be restricted to those patients who are unable to undergo removal of the prosthesis immediately due to their medical condition. This can for example be because of a severe cobalt-induced cardiomyopathy.

Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions.

Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or α-ß adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.

Methamphetamine, amphetamine, MDMA ('ecstasy'), MDA and mCPP modulate electrical and cholinergic input in PC12 cells.

Reversal of the dopamine (DA) membrane transporter is the main mechanism through which many drugs of abuse increase DA levels. However, drug-induced modulation of exocytotic DA release by electrical (depolarization) and neurochemical inputs (e.g., acetylcholine (ACh)) may also contribute. We therefore investigated effects of methamphetamine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and meta-chlorophenylpiperazine (mCPP) (1-1000 µM) on these inputs by measuring drug-induced changes in basal, depolarization- and ACh-evoked intracellular calcium concentrations ([Ca(2+)](i)) using a dopaminergic model (PC12 cells) and Fura 2 calcium imaging. The strongest drug-induced effects were observed on cholinergic input. At 0.1mM all drugs inhibited the ACh-evoked [Ca(2+)](i) increases by 40-75%, whereas ACh-evoked [Ca(2+)](i) increases were nearly abolished following higher drug exposure (1mM, 80-97% inhibition). Additionally, high MDMA and mCPP concentrations increased basal [Ca(2+)](i), but only following prior stimulation with ACh. Interestingly, low concentrations of methamphetamine or amphetamine (10 µM) potentiated ACh-evoked [Ca(2+)](i) increases. Depolarization-evoked [Ca(2+)](i) increases were also inhibited following exposure to high drug concentrations, although drugs were less potent on this endpoint. Our data demonstrate that at high drug concentrations all tested drugs reduce stimulation-evoked increases in [Ca(2+)](i), thereby probably reducing dopaminergic output through inhibition of electrical and cholinergic input. Furthermore, the increases in basal [Ca(2+)](i) at high concentrations of MDMA and mCPP likely increases dopaminergic output. Similarly, the increases in ACh-evoked [Ca(2+)](i) upon cholinergic stimulation following exposure to low concentrations of amphetamines can contribute to drug-induced increases in DA levels observed in vivo. Finally, this study shows that mCPP, which is regularly found in ecstasy tablets, is the most potent drug regarding the investigated endpoints.