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It is with interest that we read the recent paper “Immunosuppressive drug therapy – biopharmaceutical challenges and remedies” by Kahn and co-workers.[1] We support the importance of the improvemen...

Context. Acute chemical incidents can have substantial public health consequences in terms of morbidity and mortality. Objective. We aimed to characterize acute chemical incidents and near-misses in the Netherlands and compare the results with previous studies. This review is a first step in evaluating whether Physiologically Based Pharmacokinetic (PBPK) models can be of value in acute chemical incidents. Material and methods. Government, regional, municipal and University Hospital Institutes involved in the management of acute chemical incidents in the Netherlands were contacted, and they provided data between 2008 and 2010 on the characteristics and consequences of the incidents. The study is a retrospective epidemiological study based on data from five institutes. Incidents involving biological agents or radiation were excluded. Results. A total of 764 reports were available which involved 722 incidents after cross-matching the different sources of data. Forty incidents were excluded, leaving 682 incidents for which information was available in accordance with the inclusion criteria. Of the 682 incidents included in this study, most occurred in non-industrial buildings (37%) or industrial sites (34%). The most frequently observed event types were loss of containment (60%) and fire (36%), leading to gas emission (54%), followed by spill of liquid or solid chemicals (36%). The chemicals involved were most often products of combustion (e.g. smoke, soot, particles, 25%) and volatile organic compounds (e.g. solvents, styrene, xylene, 23%), followed by inorganic gases (e.g. carbon monoxide, hydrogen, hydrogen sulphide, 13%). A minimum of 847 people experienced adverse health effects following exposure during a chemical incident, and 10 fatalities were reported. The most frequently reported symptoms were respiratory (27%), due to irritant chemicals. The number of incidents related to fire and the number of injured people were higher in this study than in previous studies; 49% of the injured were transported to hospital. Discussion. This study helps to identify which chemicals are frequently involved in acute chemical incidents in the Netherlands. The results will be used in future to assess whether PBPK models may be useful for risk assessment of chemicals often involved in acute chemical incidents and for which human toxicological and kinetic data are scarce.

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-β 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.

Introduction No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69 mg THC). Methods Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3 mg, 49.1 mg, and 69.4 mg THC. Blood samples were collected over a period of 0–8 h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were Cmax = 175 ng/mL, Tmax = 14 min, and AUC0–8h = 8150 ng × min/mL for the 69.4 mg THC dose. Median model results show an almost linear dose response relation for Cmax/Dose = 2.8 × 10− 6/mL and AUC0–8h/Dose = 136 × 10− 6 min/mL. However, for increasing dose level, there was a clear decreasing trend: Cmax/Dose = 3.4, 2.6 and 2.5 × 10− 6/mL and AUC0–8h/Dose = 157, 133 and 117 × 10− 6 min/mL for the 29.3, 49.1 and 69.4 mg dose, respectively. Within the restriction of 8 h of observation, the apparent terminal half life of THC was 150 min. Conclusion The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8 h after smoking cannabis with a high THC content (up to 23%).

Rapid administration of stable iodine is essential for the saturation and subsequent protection of the thyroid gland against the potential harm caused by radioiodines. This paper proposes the Dutch risk analysis that uses an atmospheric dispersion model to calculate the size of the zones around nuclear power plants where radiological thyroid doses for children might be sufficiently high to warrant iodine administration. Dose calculations for possible releases from the nuclear power plants of Borssele (The Netherlands), Doel (Belgium) and Emsland (Germany) are based on two scenarios in combination with a 1-y set of authentic, high-resolution meteorological data. The dimensions of the circular zones were defined for each nuclear power plant. In these zones, with a radius up to 50 km, distribution of stable iodine tablets is advised.

Background: Encephalopathy associated with metronidazole is rare and, in most cases, reversible following discontinuation. Objective: We describe a case of fatal encephalopathy after treatment with high-dose intravenous metronidazole and the potential causes of the irreversibility. Case summary: A 38-year-old white woman (weight, 45 kg) received metronidazole among other medications to treat osteomyelitis for 74 days after surgery to correct a spinal neuroarthropathy. An initial dose of 500 mg IV QID was administered. After 6 weeks, the patient was discharged and the dose was changed to 1500 mg IV administered once dally (over 90 minutes) by a visiting nurse. Other treatments included teicoplanin 400 mg once dally and trimethoprim-sulfamethoxazole 480 mg BID for the infection, baclofen 25 mg TID for pain associated with a congenital spinal cord lesion with paraplegia, and omeprazole 20 mg once daily for pyrosis. Tell weeks after the start of metronidazole, the patient developed somnolence and dysarthria, changing to encephalopathy with coma on admission 2 weeks later. Despite discontinuation of all medication, including metronidazole, 2 days after admission, the patient's condition appeared to be irreversible. After 8 weeks, her coma was considered permanent, mechanical ventilation was discontinued, and she died. Evaluating all medicines administered, metronidazole, with a Naranjo adverse drug reaction score of 5 (probable), was the most plausible cause of the encephalopathy. The other medicines, including baclofen, had a negative score of -3 to -2 (doubtful). All tests on infections, metabolic disorders, or interactions between medications were negative. Conclusion: This patient had a fatal encephalopathy, probably associated with long-standing exposure to high plasma concentration peaks of metronidazole, due to a once-dally dose of 1500 ing IV over several weeks. (Clin Ther. 2010;32:60-64) (C) 2010 Excerpta Medica Inc.

Baclofen has been increasingly used in the treatment of alcohol withdrawal syndrome (AWS). We present a patient with AWS and psychiatric comorbidity who ingested 700 mg of baclofen. ICU admission was necessary for ventilatory support and symptomatic treatment. The patient was dismissed without sequelae.

Treatment of paracetamol intoxication consists of administration of N-acetylcysteine, preferably shortly after paracetamol ingestion. In most countries, the decision to treat patients with N-acetylcysteine depends on the paracetamol plasma concentration. In the literature, different arguments are given regarding when to treat paracetamol overdose. Some authors do not recommend treatment with N-acetylcysteine at low paracetamol plasma concentrations since unnecessary adverse effects may be induced. But no treatment with N-acetylcysteine at higher paracetamol plasma concentrations may lead to unnecessary severe morbidity and mortality. In this review, we provide an overview on the severity and prevalence of adverse side effects after N-acetylcysteine administration and the consequences these side effects may have for the treatment of paracetamol intoxication. The final conclusion is to continue using the guidelines of the Dutch National Poisons Information Centre for N-acetylcysteine administration in paracetamol intoxication.

Many drugs can significantly influence cardiac repolarisation causing an increased duration of this repolarisation phase, challenging the repolarisation reserve. This may set the stage for life-threatening ventricular arrhythmias such as torsades de pointes (TdP). TdP generally occurs in conjunction with a prolonged QT interval (QT) on the electrocardiogram. The Dutch Poisons Information Centre (NVIC) often receives information requests about drugs that can influence the QT already at therapeutic dosages. Drug-induced QT prolongation is dose dependent and hence can be particularly pronounced in overdose situations. Also, additional risk factors for the development of life-threatening arrhythmias are often present in intoxicated patients. This review focuses on identification and management of drug-intoxicated patients who are at risk for a reduction in their repolarisation reserve, measured by their QT interval. The QT interval is strongly dependent on heart rate, which has led to the introduction of different methods to adjust the QT interval, i.e. the QTc. Bazett's formula, which has been used for decades, lacks accuracy concerning QTc calculation at higher and lower heart rates, situations often relevant when dealing with intoxicated patients. Additionally, we highlight drugs with QT-prolonging potential that are commonly associated with an overdose setting in the Netherlands. Finally, standard treatment options specifically pointed toward the intoxicated patient at risk of QT prolongation and TdP will be discussed.

Tijdens de nucleaire top van begin vorige week hebben de wereldleiders zich gebogen over het borgen van nucleaire veiligheid. Maar wat als er toch iets misgaat? Wat is het medische antwoord op radioactieve besmetting? Een overzicht.

Ethylene glycol (EG) and methanol poisoning can cause life-threatening complications. Toxicity of EG and methanol is related to the production of toxic metabolites by the enzyme alcohol dehydrogenase (ADH), which can lead to metabolic acidosis, renal failure (in EG poisoning), blindness (in methanol poisoning) and death. Therapy consists of general supportive care (e.g. intravenous fluids, correction of electrolytes and acidaemia), the use of antidotes and haemodialysis. Haemodialysis is considered a key element in the treatment of severe EG and methanol intoxication and is aimed at removing both the parent compound and its toxic metabolites, reducing the duration of antidotal treatment and shortening the hospital observation period. Currently, there are two antidotes used to block ADH-mediated metabolism of EG and methanol: ethanol and fomepizole. In this review, the advantages and disadvantages of both antidotes in terms of efficacy, safety and costs are discussed in order to help the physician to decide which antidote is appropriate in a specific clinical setting.

Many drugs can significantly inf luence cardiac repolarisation causing an increased duration of this repolarisation phase, challenging the repolarisation reserve. This may set the stage for life-threatening ventricular arrhythmias such as torsades de pointes (TdP). TdP generally occurs in conjunction with a prolonged QT interval (QT) on the electrocardiogram. The Dutch Poisons Information Centre (NVIC) often receives information requests about drugs that can influence the QT already at therapeutic dosages. Drug-induced QT prolongation is dose dependent and hence can be particularly pronounced in overdose situations. Also, additional risk factors for the development of life-threatening arrhythmias are often present in intoxicated patients. This review focuses on identification and management of drug-intoxicated patients who are at risk for a reduction in their repolarisation reserve, measured by their QT interval. The QT interval is strongly dependent on heart rate, which has led to the introduction of different methods to adjust the QT interval, i.e. the QTc. Bazett's formula, which has been used for decades, lacks accuracy concerning QTc calculation at higher and lower heart rates, situations often relevant when dealing with intoxicated patients. Additionally, we highlight drugs with QT-prolonging potential that are commonly associated with an overdose setting in Netherlands. Finally, standard treatment options specifically pointed toward the intoxicated patient at risk of QT prolongation and TdP will be discussed.

Ethylene glycol (EG) and methanol poisoning can cause life-threatening complications. Toxicity of EG and methanol is related to the production of toxic metabolites by the enzyme alcohol dehydrogenase (ADH), which can lead to metabolic acidosis, renal failure (in EG poisoning), blindness (in methanol poisoning) and death. Therapy consists of general supportive care (e.g. intravenous fluids, correction of electrolytes and acidaemia), the use of antidotes and haemodialysis. Haemodialysis is considered a key element in the treatment of severe EG and methanol intoxication and is aimed at removing both the parent compound and its toxic metabolites, reducing the duration of antidotal treatment and shortening the hospital observation period. Currently, there are two antidotes used to block ADH-mediated metabolism of EG and methanol: ethanol and fomepizole. In this review, the advantages and disadvantages of both antidotes in terms of efficacy, safety and costs are discussed in order to help the physician to decide which antidote is appropriate in a specific clinical setting.

CONTEXT : Although extracorporeal membrane oxygenation (ECMO) was used in many patients following its introduction in 1972, most hospitals had abandoned this experimental treatment for adult patients. Recently, improvements in the ECMO circuitry rendered it more biocompatible. The surprisingly low mortality in patients with severe acute respiratory distress syndrome who were treated with ECMO in the influenza A/H1N1 pandemic of 2009 resurrected interest in ECMO in many intensive care units around the world. OBJECTIVES: This article reviews the different techniques of ECMO, the indications, contraindications and complications of its use, its role in poisoned patients and the ethics of its use. METHODS: We searched Pubmed, Toxnet, Cochrane database and Embase from 1966 to September 2012 using the search terms (''extracorporeal membrane oxygenation'', 'extracorporeal life support', 'ECMO', 'ECLS', 'assist-device', and 'intox*' or 'poison*'). These searches identified 242 papers of which 116 described ECMO in conditions other than intoxications or were reviews. In total 46 publications selected for this manuscript were case reports or case series involving poisoned patients. ECMO TECHNIQUES: Two types of ECMO are used: veno-venous ECMO (VV-ECMO) or veno-arterial ECMO (VA-ECMO). VV-ECMO is used for patients with severe ARDS to secure adequate oxygenation of the organs while protecting the lungs from harmful ventilation pressures or prolonged inspiratory fraction of oxygen. VA-ECMO can be used whenever the patient remains in shock despite adequate fluid resuscitation and is refractory to administration of inotropes and vasopressors. INDICATIONS: The organ support that can be applied with ECMO makes it especially useful in patients with severe poisoning as the clinical impact of the intoxication is often temporary; ECMO can be used as a 'bridge to recovery'. CONTRAINDICATIONS: Absolute contraindications are uncontrolled coagulopathy and severe intracranial bleeding, which precludes the use of anticoagulation therapy. Relative contraindications to ECMO include advanced age, severe irreversible brain injury, untreatable metastatic cancer, severe organ dysfunction (some suggest a Sequential Organ Failure Assessment (SOFA) score > 15), and high pressure positive pressure ventilation for more than 7 days. COMPLICATIONS: The most common complication of ECMO is either bleeding at the cannulation site (in VV-ECMO) or bleeding at the surgical entry site (in VA-ECMO). Overall bleeding complications currently occur in 10-36% patients, and intracranial haemorrhage is seen in up to 6% of patients. ECMO should be reserved, therefore, for the most severely ill poisoned patients with a high risk of death. ECMO in poisoned patients. There are no randomised trials of ECMO in poisoned patients with refractory shock or who have ARDS caused by an intoxication. VV-ECMO can be considered in patients with type l and ll respiratory failure. In patients with life-threatening haemodynamic instability, VA-ECMO can be considered when shock persists despite volume administration, inotropes and vasoconstrictors, and (sometimes) intra-aortic balloon counterpulsation. Typical examples include poisoning due to calcium channel antagonists, beta-blockers, tricyclic antidepressants, chloroquine and colchicine. ETHICS OF ECMO USE: It is only ethical to use such a costly intervention (£19,252 and US$ 31,000 per quality-adjusted life year) if the treatment has a real purpose such as a 'bridge to recovery', a 'bridge to transplant', or a 'bridge to permanent assist device' (in the case of persistent cardiac failure). CONCLUSIONS: In the last decade, ECMO equipment has improved considerably, rendering it more biocompatible, and it has been used more frequently as an assist device for patients needing oxygenation as well as circulatory support. ECMO is considered a good salvage therapy for patients who are severely poisoned with ARDS or refractory circulatory shock.