High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury.

PURPOSE: Lung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury. METHODS: We retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions. RESULTS: AKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06-2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02-3.77), infection (OR 2.48; 95% CI 1.31-4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16-4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%. CONCLUSIONS: After lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation. What is known about this subject? • Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality. • To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated. • The immunosuppressant tacrolimus is difficult to dose, especially in the unstable clinical setting, and is nephrotoxic. WHAT THIS STUDY ADDS: • For the first time, supra-therapeutic whole-blood tacrolimus trough concentrations are related to the emergence of acute kidney injury in the first days after lung transplantation. • Supra-therapeutic whole-blood tacrolimus trough concentrations often occur early after lung transplantation. • AKI after lung transplantation shows low recovery rates.

Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation.

Annually, about 8000 heart and lung transplantations are successfully performed worldwide. However, morbidity and mortality still pose a major concern. Renal failure in heart and lung transplant recipients is an essential adverse cause of morbidity and mortality, often originating in the early postoperative phase. At this time of clinical instability, the kidneys are exposed to numerous nephrotoxic stimuli. Among these, tacrolimus toxicity plays an important role, and its pharmacokinetics may be significantly altered in this critical phase by fluctuating drug absorption, changed protein metabolism, anemia and (multi-) organ failure. Limited understanding of tacrolimus pharmacokinetics in these circumstances is hampering daily practice. Tacrolimus dose adjustments are generally based on whole blood trough levels, which widely vary early after transplantation. Moreover, whole blood trough levels are difficult to predict and are poorly related to the area under the concentration-time curve. Even within the therapeutic range, toxicity may occur. These shortcomings of tacrolimus monitoring may not hold for the unbound tacrolimus plasma concentrations, which may better reflect tacrolimus toxicity. This review focuses on posttransplant tacrolimus pharmacokinetics, discusses relevant factors influencing the unbound tacrolimus concentrations and tacrolimus (nephro-) toxicity in heart and lung transplantation patients.

Clinical pharmacology of exogenously administered alkaline phosphatase.

PURPOSE: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). METHODS: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg(-1) 24 h(-1)) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. RESULTS: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. CONCLUSIONS: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis.

[Intoxication with magnesium, a 'forgotten' electrolyte]. / Intoxicatie met magnesium, een 'vergeten' elektrolyt.

Magnesium salts are widely used and are usually regarded as rather harmless. Magnesium intoxication, however, can be lethal. Recently, severe magnesium intoxication was identified in 3 patients, one woman aged 68 and 2 men aged 19 and 26 years respectively, who required treatment in an Intensive Care setting. Initial symptoms of magnesium intoxication went unnoticed due to sedation or paraplegia. Only after developing severe neurological symptoms, respiratory or circulatory failure, magnesium intoxication was diagnosed. Plasma magnesium levels exceeded 6 mmol/l (reference value: 0.70-1.00). Therapy consisted of cessation of magnesium therapy, administration of calcium and enhanced elimination of magnesium by haemodialysis. All patients survived the intoxication. Magnesium intoxication may develop unnoticed when the initial signs and symptoms are masked by clinical conditions. Especially patients with renal failure, inflammatory bowel disease, sedation and paraplegia need careful monitoring when magnesium is administered.

Effects of sub-chronic nitrate exposure on the thyroidal function in humans.

No experimental data exist on the thyroid toxicity of nitrate among humans. We aimed to show that no significant antithyroid effect could be observed after exposure to a three times the acceptable daily intake of nitrate in humans. In a randomized controlled non-inferiority trial, 10 volunteers received 15 mg/kg sodium nitrate during 28 days whereas 10 control participants received distilled water. We performed 5- and 24-h measurements of thyroidal (131)I uptake (RAIU) before and at the end of the exposure period. Thyroid hormone plasma concentrations of T3, rT3, T4, TSH were also measured prior to and after exposure. Differences in RAIU between the intervention and the control groups at 4 weeks were 3.4% (95% confidence interval -0.5 to 7.3, and 4.8% (95% confidence interval -1.4 to 11.0, respectively, for the 5- and 24-h RAIU measurement. Plasma concentrations of thyroid hormones stayed normal. In conclusion, no significant effects on thyroidal (131)I uptake and thyroid hormones plasma concentrations were observed after sub-chronic exposition to 15 mg/kg sodium nitrate among humans.

[The effects of blue algae on health]. / Gezondheidseffecten van blauwalgen.

Cyanobacteria (blue algae) regularly cause recreational waters to become murky and smelly. Skin irritation and mild gastrointestinal disorders have regularly been reported following recreational activities in water suspected of being contaminated with cyanobacteria. The exact cause of these effects on health is not clear. Severe effects are not to be expected from recreational exposure to water contaminated with cyanobacteria. Cyanobacteria can produce hepatotoxins, neurotoxins, cytotoxins and irritants. In Brazil lethal intoxications have occurred due to the occurrence of toxins in drinking water and in dialysis fluid. The Dutch policy is based on the Commissie Integraal Waterbeheer (Commission Integral Water Management) guidelines for recreational waters. It is not clear to what extent the other cyanotoxins occur in the Netherlands. However, several genera ofcyanobacteria capable of producing these other cyanotoxins have been found in the Netherlands. For a good risk assessment in the Netherlands, more information is needed on the effects on health of cyanobacteria. There is also a need for more data on the prevalence of different cyanobacteria and toxins in Dutch recreational waters.

Practical recommendations for calcium channel antagonist poisoning.

Calcium channel antagonists (CCAs) are widely used for different cardiovascular disorders. At therapeutic doses, CCAs have a favourable side effect profile. However, in overdose, CCAs can cause serious complications, such as severe hypotension and bradycardia. Patients in whom a moderate to severe intoxication is anticipated should be observed in a monitored setting for at least 12 hours if an immediate-release formulation is ingested, and at least 24 hours when a sustained-release formulation (or amlodipine) is involved, even if the patient is asymptomatic. Initial treatment is aimed at gastrointestinal decontamination and general supportive care, i.e., fluid resuscitation and correction of metabolic acidosis and electrolyte disturbances. In moderate to severe CCA poisoning, a combined medical strategy might be indispensable, such as administration of vasopressors, intravenous calcium and hyperinsulinaemia/euglycaemia therapy. Especially hyperinsulinaemia/euglycaemia therapy is an important first-line treatment in CCA-overdosed patients in whom a large ingestion is suspected. High-dose insulin, in combination with glucose, seems to be most effective when used early in the intoxication phase, even when the patient shows hardly any haemodynamic instability. Intravenous lipid emulsion therapy should only be considered in patients with life-threatening cardiovascular toxicity, such as refractory shock, which is unresponsive to conventional therapies. When supportive and specific pharmacological measures fail to adequately reverse refractory conditions in CCA overdose, the use of extracorporeal life support should be considered. The efficacy of these pharmacological and non-pharmacological interventions generally advocated in CCA poisoning needs further in-depth mechanistic foundation, in order to improve individualised treatment of CCA-overdosed patients.

Neurotoxicity screening of (illicit) drugs using novel methods for analysis of microelectrode array (MEA) recordings.

Annual prevalence of the use of common illicit drugs and new psychoactive substances (NPS) is high, despite the often limited knowledge on the health risks of these substances. Recently, cortical cultures grown on multi-well microelectrode arrays (mwMEAs) have been used for neurotoxicity screening of chemicals, pharmaceuticals, and toxins with a high sensitivity and specificity. However, the use of mwMEAs to investigate the effects of illicit drugs on neuronal activity is largely unexplored. We therefore first characterised the cortical cultures using immunocytochemistry and show the presence of astrocytes, glutamatergic and GABAergic neurons. Neuronal activity is concentration-dependently affected following exposure to six neurotransmitters (glutamate, GABA, serotonin, dopamine, acetylcholine and nicotine). Most neurotransmitters inhibit neuronal activity, although glutamate and acetylcholine transiently increase activity at specific concentrations. These transient effects are not detected when activity is determined during the entire 30min exposure window, potentially resulting in false-negative results. As expected, exposure to the GABAA-receptor antagonist bicuculline increases neuronal activity. Exposure to a positive allosteric modulator of the GABAA-receptor (diazepam) or to glutamate receptor antagonists (CNQX and MK-801) reduces neuronal activity. Further, we demonstrate that exposure to common drugs (3,4-methylenedioxymethamphetamine (MDMA) and amphetamine) and NPS (1-(3-chlorophenyl)piperazine (mCPP), 4-fluoroamphetamine (4-FA) and methoxetamine (MXE)) decreases neuronal activity. MXE most potently inhibits neuronal activity with an IC50 of 0.5µM, whereas 4-FA is least potent with an IC50 of 113µM. Our data demonstrate the importance of analysing neuronal activity within different time windows during exposure to prevent false-negative results. We also show that cortical cultures grown on mwMEAs can successfully be applied to investigate the effects of different (illicit) drugs on neuronal activity. Compared to investigating multiple single endpoints for neurotoxicity or neuromodulation, such as receptor activation or calcium channel function, mwMEAs can provide information on integrated aspects of drug-induced neurotoxicity more rapidly. Therefore, this approach could contribute to a faster insight in possible health risks and shorten the regulation process.

[Toxicity of dioxins in humans]. / Toxiciteit van dioxinen voor de mens.

Dioxins are produced as pollutants in industrial production processes and during incineration (e.g. of waste). Thanks to their highly lipophilic nature and long half-life in fat tissue, they accumulate in the food chain. One of the most important initial steps in the toxicity of dioxins is the activation of a cytosol receptor. This induces the production of a number of proteins, including cytochrome P450 CYP1A1. Our knowledge about the effects of dioxins in humans is based primarily on long-term epidemiological studies of people who were exposed to high concentrations of dioxins, either occupationally or as the result of an accident. The best known and most definitely established effect of exposure to dioxins is chloracne. Whether there is a relation between exposure to dioxins and other diseases, such as cancer, is uncertain.

[Measures to reduce absorption in the treatment of intoxications]. / Absorptieverminderende maatregelen bij de behandeling van vergiftigingen.

New guidelines on gastrointestinal decontamination in overdose situations have been published. In cases of serious and potentially life-threatening intoxication, gastric lavage can be performed up to 1 hour after ingestion. It should not be considered as routine treatment. If a patient has ingested a potentially toxic amount of a poison which is known to be absorbed by charcoal, single-dose activated charcoal in powder form may be considered up to 1 hour after ingestion. After ingestion of a potentially lethal amount of a toxin that is travelling through the enterohepatic or entero-enteral circulation, multiple-dose activated charcoal can be considered. The efficacy of carbamazepine, theophylline, quinine, dapsone and phenobarbital has been proven. In the treatment of potentially life-threatening intoxications with sustained-release preparations or drug-filled packages, particularly after ingestion of substances that do not bind to activated charcoal, whole bowel irrigation can be considered. Only ifdefaecation is insufficient should administration of a laxative together with activated charcoal be considered.

Evaluation of three physiologically based pharmacokinetic (PBPK) modeling tools for emergency risk assessment after acute dichloromethane exposure.

INTRODUCTION: Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen). MATERIALS AND METHODS: We assessed the accuracy of the models' predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated. RESULTS: With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52-4.19mg/L with the Bos model, 1.42-4.04mg/L with the Mumtaz model, and 1.81-4.31mg/L with the Jongeneelen model compared to 0.27-5.44mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4-2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels. CONCLUSIONS: The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment.

Occupational exposure during nitric oxide inhalational therapy in a pediatric intensive care setting.

OBJECTIVE: To determine the amount of occupational exposure to nitric oxide (NO) and nitrogen dioxide (NO2) during NO inhalational therapy. DESIGN: In a standard pediatric intensive care room, 800 ppm NO was delivered to a high-frequency oscillator and mixed with 100% O2 to obtain 20 ppm NO in the inspiratory gas flow. NO and NO2 concentrations in room air were measured using a chemiluminescence analyzer. Air samples were taken from a height of 150 cm at a horizontal distance of 65 cm from the ventilator in a nonventilated and in a well-ventilated room with and without an expiratory gas exhaust under normal intensive care environmental conditions. SETTING: Pediatric intensive care unit in a university children's hospital. MEASUREMENTS AND RESULTS: Maximal concentrations of NO and NO2 were reached after 4 h NO use. Without exhaust, in a nonventilated room, environmental NO and NO2 concentration rose to a maximum of 0.462 and 0.064 ppm, respectively. With the use of an expiratory gas exhaust, NO and NO2 concentrations were 0.176 and 0.042 ppm, respectively. With normal air-conditioning, these values were 0.075 and 0.034 ppm, respectively, without the use of an expiratory gas exhaust. With expiratory gas exhaust added to normal air-conditioning, values for NO and NO2 were 0.035 and 0.030 ppm, respectively. CONCLUSIONS: The use of 20 ppm NO, even under minimal room ventilation conditions, did not lead to room air levels of NO or NO2 that should be considered toxic to adjacent intensive care patients or staff. Slight increases in NO and NO2 concentrations were measurable but remained within occupational safety limits. The use of an exhaust system and normal room ventilation lowers NO and NO2 concentrations further to almost background levels.

Skin lesions due to exposure to methyl bromide.

Six patients were occupationally exposed to high concentrations of methyl bromide during a fumigation procedure using adequate airway protection. Within a few hours all patients developed skin lesions, consisting of sharply demarcated erythema with multiple vesicles and large bullae. There was a striking predisposition for parts of the skin that were relatively moist or subject to mechanical pressure, such as axillae, groin, and abdomen. Microscopically, early skin lesions revealed necrosis of keratinocytes, severe edema of the upper dermis, subepidermal blistering, and diffuse infiltration of neutrophils and, to a lesser degree, eosinophils. Two patients developed an urticarial rash approximately one week after the exposure. On histologic examination, these late lesions showed combined features of a spongiotic dermatitis and urticaria. No immunopathologic manifestations were observed. In all patients, the skin returned to normal after four weeks, except for some residual hyperpigmentation. Plasma bromide levels after exposure strongly suggested percutaneous absorption of methyl bromide.

A new physiological biomarker for nitrate exposure in humans.

After toxicological studies with nitrate/nitrite in rats it was observed with nuclear magnetic resonance that N-methylnicotinamide (NMN), a metabolite of tryptophan was increased. The use of NMN as a biomarker for nitrate/nitrite exposure was investigated further in additional experiments with rats and in a human study with volunteers. Rats have been exposed to 36 mmol KCl, KNO2 or KNO3 per 1 tap water for 13 weeks. In general, the animals receiving KNO2 showed a statistically significant (P < 0.01) 2-fold increase in NMN compared with the KCl group. This increase was observed after a relatively high exposure (about 800 mg/kg body wt./day). It was also noticed that the initial increase in urinary NMN concentrations decreased after prolonged exposure for 12 weeks. To investigate the induction of urinary NMN in humans, an experiment has been performed in which 8 volunteers received a single oral dose of sodium nitrate, corresponding with 10 mg NaNO3/kg body wt./day (2 times the acceptable daily intake for nitrate). A rapid increase of urinary NMN (up to 6-fold) was observed in 4 volunteers. In the other 4 volunteers the urinary NMN concentration did hardly react. When the experiment was repeated with the same volunteers, it was remarkable to see that in this experiment all volunteers showed the same individual response on urinary NMN as in the first experiment. It is concluded that NMN can possibly be a good biomarker for the internal nitrite exposure of humans, but further studies are necessary to assess its value.

Healthy volunteer studies in toxicology.

In the future there will be an increasing need for quantitative human risk assessment in order to develop soundly-based risk level regulations. Human volunteer studies can contribute to gain essential data needed for this risk assessment. Volunteer studies are especially relevant to study the biokinetics and metabolism of a compound. Comparison of these data with those of laboratory animals can increase the accuracy in extrapolation study results from animals to man. Furthermore, the results of volunteer studies can be used to fill in the gaps of knowledge which cannot be solved with in vitro or animal studies in order to develop adequate physiologically-based biokinetic or biodynamic models for human risk assessment.

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

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 rat's 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.

Acute nitrous oxide intoxication: clinical symptoms, pathophysiology and treatment.

Nitrogen dioxide is a representative of the group of compounds which may cause pulmonary symptoms after a symptom free interval. Even when there are no symptoms immediately following exposure to nitrogen dioxide, clinical observation is advisable, because severe pulmonary involvement can be the result. The present paper discusses the clinical symptoms which are observed in man after acute exposure to nitrogen dioxide, as well as the pathophysiological mechanisms involved. Practical therapeutic guidelines are given for dealing with the diagnostic difficulties concerning this type of intoxication.

Renal failure associated with the use of dextran-40.

A typical case of dextran-40 associated acute renal failure is presented. In this patient a single plasma exchange was successful in considerably lowering the plasma dextran concentration. At the same time the elevated plasma oncotic pressure was reduced to normal values. Diuresis returned within 12 h. Several possible explanations of the mechanism of renal failure associated with the use of dextran-40 are discussed. While the mechanism of dextran-associated renal failure remains unsolved, plasma exchange seems to be effective therapy.

Mercury kinetics in a case of severe mercuric chloride poisoning treated with dimercapto-1-propane sulphonate (DMPS).

A case of severe mercuric chloride poisoning with clinical signs of mucosal damage of the gastrointestinal tract and anuric renal failure, is presented. The initial whole blood mercury concentration was 14,300 micrograms l-1. This concentration is supposed to be associated with fatal outcome due to multiple organ failure. Because of anuric renal failure, haemodialysis was necessary. Kidney function returned to normal within 10 days. Haemodialysis proved to be ineffective with regard to total mercury elimination. Treatment with DMPS was started because of very severe poisoning, anuric renal failure and optimistic reports on the "new" chelating agent 2,3-dimercapto-1 propanesulphonic acid (DMPS) in mercury poisoning. DMPS was administered by parenteral route initially and was continued thereafter by oral route, until whole blood and urine mercury concentrations had decreased below a level considered as toxic. Except for a temporary pruritic erythema of the skin, no side effects of DMPS treatment were observed. The clinical course was mild, despite continuing high whole blood mercury concentrations. Recovery was uneventful and complete. DMPS treatment, administered by intravenous and oral route, was shown to be an effective alternative for BAL in life-threatening mercuric chloride intoxication. The pharmacokinetic data presented in this case report suggest that non-renal mercury clearance may considerably exceed renal mercury clearance.

No beneficial effect of N-acetylcysteine treatment on broncho-alveolar lavage fluid variables in acute nitrogen dioxide intoxicated rats.

1. In previous studies a rat inhalation model was developed to investigate the efficacy of treatment in acute NO2 intoxication. 2. N-acetylcysteine (NAC) was administered intravenously to study its effect on biochemical variables in broncho-alveolar lavage fluid in acute NO2 intoxicated rats. It was decided to start the intravenous administration of NAC 24 h before the exposure to NO2 to induce higher intracellular glutathione (GSH) levels in lung cells of NAC-treated rats compared to not NAC-treated rats. Because, on theoretical grounds, the therapeutic effect of NAC may be expected to be especially marked during the first 24 h after exposure, the rats were observed for a period of 24 h and were then killed for investigation. A loading dose of 85 mg kg-1 h-1 or 170 mg kg-1 h-1 was followed by a continuous infusion (until autopsy) with a dose of 225 mg kg-1 24 h-1 or 450 mg kg-1 24 h-1 respectively. 3. Twenty four hours after exposure to 175 ppm NO2 (1 ppm is 1.88 mg m-3) for 10 min, NAC did not reduce the increase of variables in broncho-alveolar lavage fluid which reflect the severity of lung damage. 4. The protein and albumin concentration and the activities of angiotensin converting enzyme and alkaline phosphatase in broncho-alveolar lavage fluid after NO2 exposure were even more increased in the NAC-treated than in the saline-treated rats, but none of the differences was statistically significant. 5. In sham exposed rats no effect of NAC was observed.