Jan Meulenbelt

Health implications of exposure to environmental nitrogenous compounds.

All living systems need nitrogen for the production of complex organic molecules, such as proteins, nucleic acids, vitamins, hormones and enzymes. Due to the intense use of synthetic nitrogen fertilisers and livestock manure in modern day agriculture, food (particularly vegetables) and drinking water may contain higher concentrations of nitrate than in the past. The mean intake of nitrate per person in Europe is about 50–140 mg/ day and in the US about 40–100 mg/day. In the proximal small intestine, nitrate is rapidly and almost completely absorbed (bioavailability at least 92%). In humans, approximately, 25% of the nitrate ingested is secreted in saliva, where some 20% (about 5–8% of the nitrate intake) is converted to nitrite by commensal bacteria. The nitrite so formed is then absorbed primarily in the small intestine.Nitrate may also be synthesised endogenously from nitric oxide (especially in case of inflammation), which reacts to form nitrite. Normal healthy adults excrete in the urine approximately 62mg nitrate ion/day from endogenous synthesis. Thus, when nitrate intake is low and there are no additional exogenous sources (e.g. gastrointestinal infections), the endogenous production of nitrate is more important than exogenous sources.Nitrate itself is generally regarded nontoxic. Toxicity is usually the result of the conversion of nitrate into the more toxic nitrite. There are two major toxicological concerns regarding nitrite. First, nitrite may induce methaemoglobinaemia, which can result in tissue hypoxia, and possibly death. Secondly, nitrite may interact with secondary or N-alkyl-amides to form N-nitroso carcinogens. However, epidemiological investigations and human toxicological studies have not shown an unequivocal relationship between nitrate intake and the risk of cancer.The Joint Expert Committee of the Food and Agriculture Organization of the United Nations/World Health Organization (JECFA) and the European Commission’s Scientific Committee on Food have set an acceptable daily intake (ADI) for nitrate of 0–3.7mg nitrate ion/kg bodyweight; this appears to be safe for healthy neonates, children and adults. The same is also true of the US Environmental Protection Agency (EPA) Reference Dose (RfD) for nitrate of 1.6mg nitrate nitrogen/kg bodyweight per day (equivalent to about 7.0mg nitrate ion/kg bodyweight per day). This opinion is supported by a recent human volunteer study in which a single dose of nitrite, equivalent to 15–20 times the ADI for nitrate, led to only mild methaemoglobinaemia (up to 12.2%), without other serious adverse effects.The JECFA has proposed an ADI for nitrite of 0–0.07mg nitrite ion/kg bodyweight and the EPA has set an RfD of 0.1mg nitrite nitrogen/kg bodyweight per day (equivalent to 0.33mg nitrite ion/kg bodyweight per day). These values are again supported by human volunteer studies.

THE PHARMACOKINETICS OF GLYCYRRHIZIC ACID EVALUATED BY PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING

Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. In addition, it is of clinical interest for possible treatment of chronic hepatitis C. In some highly exposed subjects, side effects such as hypertension and symptoms associated with electrolyte disturbances have been reported. To analyze the relationship between the pharmacokinetics of glycyrrhizic acid in its toxicity, the kinetics of glycyrrhizic acid and its biologically active metabolite glycyrrhetic acid were evaluated. Glycyrrhizic acid is mainly absorbed after presystemic hydrolysis as glycyrrhetic acid. Because glycyrrhetic acid is a 200–1000 times more potent inhibitor of 11-β-hydroxysteroid dehydrogenase compared to glycyrrhizic acid, the kinetics of glycyrrhetic acid are relevant in a toxicological perspective. Once absorbed, glycyrrhetic acid is transported, mainly taken up into the liver by capacity-limited carriers, where it is metabolized into glucuronide and sulfate conjugates. These conjugates are transported efficiently into the bile. After outflow of the bile into the duodenum, the conjugates are hydrolyzed to glycyrrhetic acid by commensal bacteria; glycyrrhetic acid is subsequently reabsorbed, causing a pronounced delay in the terminal plasma clearance. Physiologically based pharmacokinetic modeling indicated that, in humans, the transit rate of gastrointestinal contents through the small and large intestines predominantly determines to what extent glycyrrhetic acid conjugates will be reabsorbed. This parameter, which can be estimated noninvasively, may serve as a useful risk estimator for glycyrrhizic-acid-induced adverse effects, because in subjects with prolonged gastrointestinal transit times, glycyrrhetic acid might accumulate after repeated intake.

The oral bioavailability of nitrate from nitrate-rich vegetables in humans

High dietary nitrate intake may pose a risk to human health. Since up to 80-85% of dietary nitrate intake comes from vegetables, the aim of this study was to determine the absolute bioavailability of nitrate from three nitrate-rich vegetables. In an open, four-way cross-over, single dose study, 12 human subjects underwent the following treatments: (1) intravenous infusion of 500mg sodium nitrate, (2) oral administration of 300g cooked spinach, (3) oral administration of 300g raw lettuce, and (4) oral administration of 300g cooked beetroot. The wash-out period between treatments was at least 6 days. Plasma samples were analysed to assess the nitrate and nitrite concentrations, and pharmacokinetic parameters were calculated. The bioavailability of nitrate was 98+/-12% from cooked spinach, 114+/-14% from raw lettuce and 106+/-15% from cooked beetroot. There was no significant increase in plasma nitrite concentrations. This study shows that nitrate from vegetables, whether cooked or uncooked, is absorbed very effectively, resulting in an absolute nitrate bioavailability of around 100%. Thus, reducing the amount of nitrate in vegetables can be an effective measure to lower the systemic nitrate exposure of the general population. However, other aspects, such as the costs to produce vegetables with a low nitrate content and the possible beneficial effects of nitrate in vegetables, need to be considered when evaluating the usefulness of such a measure.

Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration

ObjectiveTo study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CVVHF). DesignProspective, open-labeled study. SettingMedical intensive care unit of the University Medical Center Utrecht. PatientsFive critically ill patients receiving CVVHF for acute renal failure treated with meropenem for documented or suspected bacterial infection. InterventionAll patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval. Measurements and ResultsMean age and body weight of the patients studied were 46.6 yrs (range, 28–61 yrs) and 85.8 kg (range, 70–100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 ± 7.2 mg/L, mean trough plasma concentration was 3.0 ± 0.9 mg/L, mean terminal elimination half-life was 6.37 ± 1.96 hrs, mean total plasma clearance was 4.57 ± 0.89 L/hr, mean CVVHF clearance was 1.03 ± 0.42 L/hr, mean nonrenal clearance was 3.54 ± 1.06 L/hr, and mean volume of distribution was 0.37 ± 0.15 L/kg. ConclusionIn critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CVVHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CVVHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.

Extracorporeal membrane oxygenation in the treatment of poisoned patients

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

Bioavailability of sodium nitrite from an aqueous solution in healthy adults.

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.

Effect of nitrite on blood pressure in anaesthetized and free-moving rats

Nitrate intake in humans is high through intake of vegetables such as beets, lettuce, and spinach. Nitrate itself is a compound of low toxicity but its metabolite, nitrite, formed by bacteria in the oral cavity and gastrointestinal tract, has been suspected of potential carcinogenic effects. Nitrite can induce systemic toxicity only after having been absorbed from the gastrointestinal tract. The aim of this study was to determine the absolute bioavailability of nitrite following oral administration in humans. In an open, three-way cross-over study, nine subjects received two single oral doses of sodium nitrite (0.12 and 0.06 mmol NaNO(2)/mmol Hb) and one intravenous sodium nitrite dose (0.12 mmol NaNO(2)/mmol Hb). Plasma samples were analysed to assess the nitrite levels, and pharmacokinetic parameters were calculated. Nitrate and methaemoglobin levels in plasma were also measured as oxidation of nitrite results in the formation of these two compounds. Absolute bioavailability of nitrite was 98% after oral administration of 0.12 mmol NaNO(2)/mmol Hb, and 95% after oral administration of 0.06 mmol NaNO(2)/mmol Hb. Minor adverse effects were observed after the 0.12 mmol NaNO(2)/mmol Hb oral dose. In conclusion, nitrite in solution is highly absorbed from the gastrointestinal tract and the first pass effect in the liver is low.

A human physiologically-based model for glycyrrhzic acid, a compound subject to presystemic metabolism and enterohepatic cycling.

The effect of nitrite on blood pressure and heart rate was studied in anaesthetized (non-telemetric method) and free-moving rats (biotelemetry system). In anaesthetized rats, NaNO2 (10-1000 mumol/kg), infused over 5 min, induced a dose-related decrease in blood pressure. The maximal decrease in mean arterial blood pressure (MAP), caused by 1000 mumol/kg NaNO2 and measured 15 min after infusion was 55.9 +/- 3.2% (n = 3). After NaNO2 infusion, in the plasma, rapid conversion of nitrite into nitrate was observed. However, sodium nitrate (NaNO3, 100 mumol/kg) did not decrease blood pressure and there was no conversion of nitrate into nitrite. Free-moving rats received KNO2 which was added to drinking water (36 mmol/litre) for a period of 3 days. KNO2 decreased the MAP and increased the heart rate during the rats activity phase at night but not during their resting phase in the day. An equal concentration of potassium (KCl, 36 mmol/litre added to drinking water) for 3 days did not decrease blood pressure. It is concluded that nitrite decreases blood pressure in rats, which probably induces, by renin-angiotensin system activation, hypertrophy of the adrenal zona glomerulosa.

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

AbstractPurpose. To analyze the role of the kinetics of glycyrrhizic acid (GD) in its toxicity. A physiologically-based pharmacokinetic (PBPK) model that has been developed for humans. Methods. The kinetics of GD, which is absorbed as glycyrrhetic acid (GA), were described by a human PBPK model, which is based on a rat model. After rat to human extrapolation, the model was validated on plasma concentration data after ingestion of GA and GD solutions or licorice confectionery, and an additional data derived from the literature. Observed interindividual variability in kinetics was quantified by deriving an optimal set of parameters for each individual. Results. The a-priori defined model successfully forecasted GA kinetics in humans, which is characterized by a second absorption peak in the terminal elimination phase. This peak is subscribed to enterohepatic cycling of GA metabolites. The optimized model explained most of the interindividual variance, observed in the clinical study, and adequately described data from the literature. Conclusions. Preclinical information on GD kinetics could be incorporated in the human PBPK model. Model simulations demonstrate that especially in subjects with prolonged gastrointestinal residence times, GA may accumulate after repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.

Do corticosteroids have a role in preventing or reducing acute toxic lung injury caused by inhalation of chemical agents

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-HT2A 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.