Paracetamol In Neonates Research Articles

Long-Term Safety of Prenatal and Neonatal Exposure to Paracetamol: A Systematic Review

Introduction: Paracetamol is the most commonly used antipyretic and analgesic in pregnancy. It is also increasingly used off-label in the neonatal intensive care unit. Despite the frequent use of paracetamol, concerns have been raised regarding the high variability in neonatal dosing regimens and the long-term safety of early life exposure. Objective: To investigate the available evidence on the long-term safety of prenatal and neonatal paracetamol exposure. Methods: We conducted a systematic search of the electronic databases Ovid Medline, Ovid Embase and Web of Science from inception to August 2021 for original research studies of any design that described the use of paracetamol in the prenatal or neonatal (within the first four weeks of life) periods and examined the occurrence of neurodevelopmental, atopic or reproductive adverse outcomes at or beyond birth. Results: We identified 1313 unique articles and included 30 studies in the final review. Of all studies, 27 (90%), two (7%) and one (3%) were on the long-term safety of prenatal, neonatal and both prenatal and neonatal exposure, respectively. Thirteen (46%), 11 (39%) and four (15%) studies examined neurodevelopmental, atopic and reproductive outcomes. Eleven (100%), 11 (100%), and three (27%) studies on prenatal exposure reported adverse neurodevelopmental, atopic and reproductive outcomes. Only one study found a possible correlation between neonatal paracetamol exposure and long-term adverse outcomes. Conclusions: The available evidence, although limited, suggests a possible association between prenatal paracetamol exposure and an increased risk of neurodevelopmental, atopic and reproductive adverse outcomes. There is an immediate need for robust data on the long-term safety of paracetamol exposure in the prenatal and neonatal periods.

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

Long-term safety of prenatal and neonatal exposure to paracetamol: a protocol for a systematic review

IntroductionA surge in the use of paracetamol in neonates has resulted in growing concerns about its potential long-term adverse events. In this study, we conduct a systematic review of the...

Population Pharmacokinetic Modeling in the Presence of Missing Time-Dependent Covariates: Impact of Body Weight on Pharmacokinetics of Paracetamol in Neonates.

Body weight is the primary covariate in pharmacokinetics of many drugs and dramatically changes during the first weeks of life of neonates. The objective of this study is to determine if missing body weights in preterm and term neonates affect estimates of model parameters and which methods can be used to improve performance of a population pharmacokinetic model of paracetamol. Data for our analysis were obtained from previously published studies on the pharmacokinetics of intravenous paracetamol in neonates. We adopted a population model of body weight change in neonates to implement three previously introduced methods of handling missing covariates based on data imputation, likelihood function modification, and full random effects modeling. All models were implemented in NONMEM 7.4, and population parameters were estimated using the FOCE method. Our major finding was that missing body weights minimally affect population estimates of pharmacokinetic parameters but do affect the covariate relationship parameters, particularly the one describing dependence of clearance on body weight. None of the tested methods changed estimates of between-subject variability nor impacted the predictive performance of the model. Our analysis shows that a modeling approach towards handling missing covariates allows borrowing information gathered in various studies as long as they target the same population. This approach is particularly useful for handling time-dependent missing covariates.

A case of accidental neonatal paracetamol overdose with prolonged half-life and measured metabolites

Introduction: Limited data exist regarding paracetamol metabolism after overdose in the neonate. We report a case of repeated supratherapeutic overdose in a neonate with paracetamol metabolite concentrations.Case report: A 10-day-old male neonate presented to hospital after repeated supratherapeutic dosing of paracetamol. Paracetamol concentration 19.5 h post-last dose was 381 μmol/L and 236 μmol/L, 9 h later. Initial alanine aminotransferase (ALT) was normal (18 IU/L) and total bilirubin was 262 μmol/L (N < 300). Acetylcysteine infusion was commenced and ceased 27 h later, when serum paracetamol was undetectable and alanine aminotransferase remained normal.Initial paracetamol elimination half-life was 14.5 h. Analysis of serum paracetamol metabolites showed paracetamol-glucuronide was the major metabolite on presentation (64%). After acetylcysteine was commenced, paracetamol concentration fell, serum bilirubin increased, and paracetamol-sulfate represented a larger proportion of total metabolites (72%). Notably, paracetamol cytochrome (CYP450), cysteine- and mercapturate-conjugates, represented 21% of total measured metabolites on presentation.Conclusion: Repeated supratherapeutic ingestion of paracetamol in the neonate was associated with prolonged elimination half-life. Of note, this was in the presence of unconjugated hyperbilirubinaemia. CYP450 metabolism of paracetamol did not appear to be reduced in this neonate when compared to paracetamol metabolite ratios in older age groups.

Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study

IntroductionAnticipated or actual pain in neonates results in use of paracetamol for prolonged pain relief in many neonatal intensive care units. Clinical trials examining safety of paracetamol exposure in neonates...

PP-17 Intravenous paracetamol in neonates: safety, ethanol-drug interactions and efficacy – protocol of the parashute trial

Introduction A chart-review of 200 neonates randomly selected from the Neonatal Intensive Care Unit (NICU) of the university hospital in Copenhagen revealed that ap-proximately 10% received intravenous (i.v.) paracetamol≥4 days (unpublished data). Paracetamol (acetaminophen) is commonly used to control mild-to-moderate pain or to reduce opioid exposure either by oral, rectal or intrave-nous route. The newborn population includes a hetero-geneous group with substantial differences in their drug disposition characteristics. Hence, reflecting their degree of immaturity, organ dysfunction, as well as genetic vari-ation in drug metabolising enzymes and potential drug interactions. Different types of pain and pain assessment tools are used in neonatology. The pharmacokinetics and metabolism of i.v. paracetamol have been extensively published but there is very limited data on the pharma-codynamics (PD) and safety of this drug. The PARASHUTE trial will explore intravenous paracetamol in neonates in relation to: Primary objective: Safety of prolonged use (>72 hours); Secondary key objectives: Analgesic effect (PD) in neonates with chest tubes. Drug-excipient interaction with ethanol containing drugs (CYP2E1) Endpoints Primary endpoints: To described the concentration-time data of plasma paracetamol (APAP), APAP-sulphate, APAP-glucuronide, oxidative metabolites and liver bio-markers (ALAT, PP, bilirubin) in neonates treated with i.v. paracetamol every sixth hour. Secondary endpoints: Pain scores (COMFORTneo pain scale) combined with paracetamol concentrations and cumulative rescue dosages of morphine.Levels of oxida-tive metabolites of paracetamol and levels of p-ethanol in patients receiving one or more ethanol containing drugs. Design A multicenter phase IV safety trial on prolonged i.v paracetamol administration in neonates combined with a randomised placebo controlled trial assessing ef-fect on pain. Participants Neonates at any gestational age at birth for the safety and excipient study. However, for the for the PD study patients with chest tube due to pneumothorax or pleural effusion without prior operation are eligible for inclusion. For the PD and drug-excipient study the patient must weigh >1 kg. Sample size Safety and excipient trial: 60; PD trial: 48:29 (unequal allocation) Intervention The safety trial will follow clinical practice and i.v. paracetamol (10 mg/kg) will be administered. Plasma samples will be collected through an arterial line if present for clinical reasons. In neonates without arteri-al access, two heel pricks are necessary (start and end of trial) to collect blood. Additional plasma samples will only be collected when venipuncture is performed for clinical indications i.e. opportunistically. Patients with chest tubes are, after bolus morphine and insertion of tube, unequally allocated to i.v. paracetamol + rescue morphine or i.v. saline + res-cue morphine. In addition to COMFORTneo pain scores and p-paracetamol, safety parameters will be gathered. Study duration September 2017 – January 2019 (PD tri-al will end in summer 2019) Key references Allegaert et al. Paediatr Anaesth 2013: Cook et al. Clin Pharmacokinet 2016; van Ganzewinkel et al. Acta Paediatr 2014; Palmer et al. Br J Anaesth 2008 Trial registration The trial will be registered in EudraCT before the ESDPPP congress. Funding Funded by Department of Clinical Pharmacolo-gy and non-profit grants.

Comparison of epidural versus systemic analgesia for major surgeries in neonates and infants

Background and Aims: Postoperative analgesia in neonate reduces acute behavioral responses to pain. It also protects the developing nervous system from persistent sensitization of pain pathway and potential damaging effects of altered neural activity on central nervous system development. We compared the effectiveness of epidural versus systemic modes of analgesia for major surgeries in neonates and infants. Materials and Methods: This randomized, single center, prospective, controlled study was conducted in sixty patients, aged 1 day to 6 months, weighing 2–5 kg belonging to the American Society of Anesthesiology physical Grade II to IV, posted for major thoracic and abdominal surgery. After general anesthesia, in Group A, the epidural catheter was inserted through standard caudal epidural technique. Initial bolus of 0.125% bupivacaine (0.75 ml/kg) and postoperatively caudal infusion of 0.0625% bupivacaine (0.1 ml/kg/h) was given. Intraoperatively Group B received fentanyl (1–2 μg/kg) and paracetamol (10 mg/kg) intravenously and postoperatively paracetamol (10 mg/kg)/intravenous (IV) six hourly or pain score > 4. Postoperative pain was assessed using face, legs, activity, cry, and consolability pain scale and sedation score was assessed by using four-point sedation score for 48 h. Results: Patients in Group A remained hemodynamically stable except occasional bradycardia below 100 which was successfully managed with anticholinergics. There was less requirement of sevoflurane in the intraoperative period and good quality of analgesia. While in Group B, multiple and regular dosage of IV paracetamol was required to maintain adequate analgesia. Conclusion: Very efficient postoperative analgesia can be achieved via caudal epidural catheter in combination with general anesthesia compared to IV paracetamol in neonates and infants.

Neonatal paracetamol treatment reduces long-term nociceptive behaviour after neonatal procedural pain in rats.

Pain from skin penetrating procedures (procedural pain) during infancy in the neonatal intensive care unit (NICU) may result in changes of nociceptive sensitivity in later life. This supports the need for pain management during such vulnerable periods in life. This study, therefore, analyses the short- and long-term consequences of neonatal paracetamol (acetaminophen) treatment on pain behaviour in an experimental rat model of neonatal procedural pain. A repetitive needle-prick model was used, in which neonatal rats received four needle pricks into the left hind paw per day from postnatal day 0 to day 7 (P0-P7). Paracetamol (50mg/kg/day s.c.) was administered daily (P0-P7), and sensitivity to mechanical stimuli was compared with a needle-prick/saline-treated group and to a tactile control group. At 8weeks of age, all animals underwent an ipsilateral paw-incision, modelling postoperative pain, and the duration of hypersensitivity was assessed. Neonatal paracetamol administration had no effect upon short-term mechanical hypersensitivity during the first postnatal week or upon long-term baseline sensitivity from 3 to 8weeks. However, neonatal paracetamol administration significantly reduced the postoperative mechanical hypersensitivity in young adults, caused by repetitive needle pricking. Paracetamol administration during neonatal procedural pain does not alter short-term or long-term effects on mechanical sensitivity, but does reduce the duration of increased postoperative mechanical hypersensitivity in a clinically relevant neonatal procedural pain model. Paracetamol can be used safely in neonatal rats. Neonatal paracetamol treatment had no effect upon short-term mechanical hypersensitivity during the first postnatal week, nor upon long-term baseline sensitivity from 3 to 8weeks. Paracetamol treatment during the first postnatal week significantly reduced the postoperative mechanical hypersensitivity in young adult rats.

Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants

The therapeutic options available to treat neonatal pain are limited, and one alternative for nonopioid systemic treatment is paracetamol. However, pharmacokinetic data from prolonged administration of intravenous paracetamol in neonates are limited. The aim of this study was to present pharmacokinetics after multiple dose of intravenous paracetamol in very preterm infants of <32weeks' gestation. Fifteen very preterm infants received five, six-hourly doses of intravenous paracetamol (7.5mg/kg). Blood samples were taken to measure paracetamol, glutathione and hepatic function, together with urine samples for paracetamol metabolites. A two-compartment pharmacokinetic model gave the best fit for all individual patients and resulted in a predictable pharmacokinetic profile. The estimated pharmacokinetic population parameters were volume of distribution 0.764±0.225L/kg, elimination rate constant (ke ) 0.117±0.091/h and intercompartment rate constants k12 0.607±0.734/h and k21 1.105±0.762/h. Our study found that multiple doses of intravenous paracetamol resulted in a predictable pharmacokinetic profile in very preterm infants. Increases in postmenstrual age and weight were associated with increased clearance. No evidence of hepatotoxicity was found.

Paracetamol (Acetaminophen) Administration During Neonatal Brain Development Affects Cognitive Function and Alters Its Analgesic and Anxiolytic Response in Adult Male Mice

Paracetamol (acetaminophen) is one of the most commonly used drugs for the treatment of pain and fever in children, both at home and in the clinic, and is now also found in the environment. Paracetamol is known to act on the endocannabinoid system, involved in normal development of the brain. We examined if neonatal paracetamol exposure could affect the development of the brain, manifested as adult behavior and cognitive deficits, as well as changes in the response to paracetamol. Ten-day-old mice were administered a single dose of paracetamol (30 mg/kg body weight) or repeated doses of paracetamol (30 + 30 mg/kg body weight, 4h apart). Concentrations of paracetamol and brain-derived neurotrophic factor (BDNF) were measured in the neonatal brain, and behavioral testing was done when animals reached adulthood. This study shows that acute neonatal exposure to paracetamol (2 × 30 mg) results in altered locomotor activity on exposure to a novel home cage arena and a failure to acquire spatial learning in adulthood, without affecting thermal nociceptive responding or anxiety-related behavior. However, mice neonatally exposed to paracetamol (2 × 30 mg) fail to exhibit paracetamol-induced antinociceptive and anxiogenic-like behavior in adulthood. Behavioral alterations in adulthood may, in part, be due to paracetamol-induced changes in BDNF levels in key brain regions at a critical time during development. This indicates that exposure to and presence of paracetamol during a critical period of brain development can induce long-lasting effects on cognitive function and alter the adult response to paracetamol in mice.

Prenatal and perinatal analgesic exposure and autism: an ecological link.

BackgroundAutism and Autism Spectrum Disorder (ASD) are complex neurodevelopmental disorders. Susceptibility is believed to be the interaction of genetic heritability and environmental factors. The synchronous rises in autism/ASD prevalence and paracetamol (acetaminophen) use, as well as biologic plausibility have led to the hypothesis that paracetamol exposure may increase autism/ASD risk.MethodsTo explore the relationship of antenatal paracetamol exposure to ASD, population weighted average autism prevalence rates and paracetamol usage rates were compared. To explore the relationship of early neonatal paracetamol exposure to autism/ASD, population weighted average male autism prevalence rates for all available countries and U.S. states were compared to male circumcision rates – a procedure for which paracetamol has been widely prescribed since the mid-1990s. Prevalence studies were extracted from the U.S. Centers for Disease Control and Prevention Summary of Autism/ASD Prevalence Studies database. Maternal paracetamol usage and circumcision rates were identified by searches on Pub Med.ResultsUsing all available country-level data (n = 8) for the period 1984 to 2005, prenatal use of paracetamol was correlated with autism/ASD prevalence (r = 0.80). For studies including boys born after 1995, there was a strong correlation between country-level (n = 9) autism/ASD prevalence in males and a country’s circumcision rate (r = 0.98). A very similar pattern was seen among U.S. states and when comparing the 3 main racial/ethnic groups in the U.S. The country-level correlation between autism/ASD prevalence in males and paracetamol was considerably weaker before 1995 when the drug became widely used during circumcision.ConclusionsThis ecological analysis identified country-level correlations between indicators of prenatal and perinatal paracetamol exposure and autism/ASD. State level correlation was also identified for the indicator of perinatal paracetamol exposure and autism/ASD. Like all ecological analyses, these data cannot provide strong evidence of causality. However, biologic plausibility is provided by a growing body of experimental and clinical evidence linking paracetamol metabolism to pathways shown to be important in autism and related developmental abnormalities. Taken together, these ecological findings and mechanistic evidence suggest the need for formal study of the role of paracetamol in autism.

Biochemical tolerance during low dose propylene glycol exposure in neonates: A formulation-controlled evaluation

Background and purpose of the studyPropylene glycol (PG) is a frequently co-administered solvent in formulations administered to neonates, but reports on its (in)tolerance are limited. We aimed to report on renal, metabolic and hepatic tolerance before, during and following intravenous (iv) PG-paracetamol exposure and compared these data with similar datasets reported in literature on neonates exposed to PG without paracetamol or paracetamol without PG.MethodsRenal (diuresis, creatinemia, sodium), metabolic (Base Excess, Anion Gap, lactate, bicarbonate) and hepatic (liver enzymes, bilirubinemia) indicators before, during and following iv paracetamol-PG exposure in neonates as included in the PARANEO (paracetamol in neonates) study (intra-individual trends, ANOVA) were collected and analysed. Comparison with observations collected in cases exposed to either iv phenobarbital-PG or iv paracetamol-mannitol (inter-individual comparison, Mann Whitney-U test) were made.ResultsPG exposure (median 34.1 mg/kg/24 h) did not affect postnatal renal, metabolic and hepatic adaptations in 60 cases exposed to paracetamol-PG. These indicators were similar when compared to 29 cases exposed to phenobarbital-PG or 172 cases exposed to paracetamol-mannitol.Major conclusionBased on observations in 89 neonates, low dose PG exposure was tolerated well. Studies on PG pharmacokinetics and its covariates are needed to estimate the upper level of PG tolerance in neonates.

The pharmacokinetics of intravenous paracetamol in neonates: size matters most

BackgroundThe aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates.MethodsA population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27–45...

Haemodynamics of intravenous paracetamol in neonates

Reports on the haemodynamics of intravenous (iv) paracetamol in adult intensive care were recently published. We therefore wanted to explore the haemodynamics of iv paracetamol in neonates. Retrospective, pooled analysis of heart rate (bpm) and blood pressure (mean, systolic, diastolic) observations collected during iv paracetamol pharmacokinetic studies in neonates. Heart rate and blood pressure were recorded just before and 30, 60, 120, 180, 240, 300 and 360 min after iv paracetamol (paired, ANOVA). Clinical characteristics in hypotensive (mean mmHg < gestational age, weeks) cases were compared with controls (Mann-Whitney U test). Based on observations in 72 neonates, heart rate decreased from 145 (SD 20) to 138 (21), 141 (20), 137 (20), 137 (22), 140 (20), 139 (20) and 140 (21) bpm (paired p < 0.05, ANOVA p = 0.36). There were no changes in systolic and diastolic pressure, but mean arterial pressure decreased from 46 (7) to 43 (8) mmHg at 60 min (paired p < 0.05, ANOVA p = 0.75). Eight neonates developed hypotension. These patients had lower pre-administration arterial pressure (38 vs 47 mmHg, p < 0.05). In a setting of open label administration to alleviate (procedural) pain, haemodynamic effects of iv paracetamol in neonates remained modest. We suggest considering impaired haemodynamics to be a relative contra-indication for iv paracetamol in neonates.

Clinical Pharmacology of Intravenous Paracetamol in Neonates

Effective analgesia in neonates is still hampered due to the lack of data on pharmacokinetics and –dynamics of analgesics in this specific population. To a certain extent, this is even true for paracetamol. An intravenous formulation might improve prediction of concentration and consequent effect compared to enteral administration. In this review, we summarize the consecutive steps reported in literature to document the pharmacokinetics, metabolism and hepatic tolerance of intravenous paracetamol in neonates.

Single center study on trends in hepatic enzymes during repeated intravenous administration of paracetamol in neonates

Single center study on trends in hepatic enzymes during repeated intravenous administration of paracetamol in neonates

Hepatic tolerance of repeated intravenous paracetamol administration in neonates

An intravenous (i.v.) formulation of paracetamol is available, but reports on its hepatic tolerance in neonates are limited. We therefore assessed hepatic tolerance of i.v. paracetamol in neonates. In a single centre retrospective study, clinical data and hepatic enzyme profiles (ALT, AST, gammaGT) were collected in neonates treated with i.v. paracetamol between January 1, 2006 and October 1, 2007. Hepatic enzyme profiles were retrieved from 2 days before until 2 days after i.v. paracetamol administration. Mann-Whitney U-test was used to compare hepatic enzymes before, during, and after i.v. treatment. Correlations (Spearman rank) of hepatic enzymes with duration of treatment during i.v. administration were investigated. In 189 cases, 2360 administrations {postmenstrual age 38 (range 30-55) weeks, postnatal age 5 (1-182) days} were documented and 1132 hepatic enzyme observations were available in 149/189 cases. There was no significant increase in ALT, AST, or gammaGT when pretreatment observations (n = 310) were compared with observations during (n = 649) or during with after (n = 173) treatment, nor was there a significant increase during administration. This retrospective study on hepatic tolerance provides evidence on safety aspects of i.v. paracetamol in neonates. Future studies should focus on dose-findings and pharmacodynamics of this formulation in neonates.

Single-centre audit on the use of intravenous paracetamol in neonates

An intravenous formulation of paracetamol is available, but remains off-label in patients below 10 kg although pharmacokinetics during repeated intravenous administration were documented and dosing regimes suggested [1,2]. We therefore retrospectively evaluated aspects of the administration of intravenous paracetamol in neonates.

Sinister choices

<h3>Introduction</h3> A chart-review of 200 neonates randomly selected from the Neonatal Intensive Care Unit (NICU) of the university hospital in Copenhagen revealed that ap-proximately 10% received intravenous (i.v.) paracetamol≥4 days (unpublished data). Paracetamol (acetaminophen) is commonly used to control mild-to-moderate pain or to reduce opioid exposure either by oral, rectal or intrave-nous route. The newborn population includes a hetero-geneous group with substantial differences in their drug disposition characteristics. Hence, reflecting their degree of immaturity, organ dysfunction, as well as genetic vari-ation in drug metabolising enzymes and potential drug interactions. Different types of pain and pain assessment tools are used in neonatology. The pharmacokinetics and metabolism of i.v. paracetamol have been extensively published but there is very limited data on the pharma-codynamics (PD) and safety of this drug. The PARASHUTE trial will explore intravenous paracetamol in neonates in relation to: Primary objective: Safety of prolonged use (&gt;72 hours); Secondary key objectives: Analgesic effect (PD) in neonates with chest tubes. Drug-excipient interaction with ethanol containing drugs (CYP2E1) <h3>Endpoints</h3> Primary endpoints: To described the concentration-time data of plasma paracetamol (APAP), APAP-sulphate, APAP-glucuronide, oxidative metabolites and liver bio-markers (ALAT, PP, bilirubin) in neonates treated with i.v. paracetamol every sixth hour. Secondary endpoints: Pain scores (COMFORTneo pain scale) combined with paracetamol concentrations and cumulative rescue dosages of morphine.Levels of oxida-tive metabolites of paracetamol and levels of p-ethanol in patients receiving one or more ethanol containing drugs. <h3>Design</h3> A multicenter phase IV safety trial on prolonged i.v paracetamol administration in neonates combined with a randomised placebo controlled trial assessing ef-fect on pain. <h3>Participants</h3> Neonates at any gestational age at birth for the safety and excipient study. However, for the for the PD study patients with chest tube due to pneumothorax or pleural effusion without prior operation are eligible for inclusion. For the PD and drug-excipient study the patient must weigh &gt;1 kg. <h3>Sample size</h3> Safety and excipient trial: 60; PD trial: 48:29 (unequal allocation) <h3>Intervention</h3> The safety trial will follow clinical practice and i.v. paracetamol (10 mg/kg) will be administered. Plasma samples will be collected through an arterial line if present for clinical reasons. In neonates without arteri-al access, two heel pricks are necessary (start and end of trial) to collect blood. Additional plasma samples will only be collected when venipuncture is performed for clinical indications i.e. opportunistically. Patients with chest tubes are, after bolus morphine and insertion of tube, unequally allocated to i.v. paracetamol + rescue morphine or i.v. saline + res-cue morphine. In addition to COMFORTneo pain scores and p-paracetamol, safety parameters will be gathered. <h3>Study duration</h3> September 2017 – January 2019 (PD tri-al will end in summer 2019) <h3>Key references</h3> Allegaert et al. Paediatr Anaesth 2013: Cook et al. Clin Pharmacokinet 2016; van Ganzewinkel et al. Acta Paediatr 2014; Palmer et al. Br J Anaesth 2008 <h3>Trial registration</h3> The trial will be registered in EudraCT before the ESDPPP congress. <h3>Funding</h3> Funded by Department of Clinical Pharmacolo-gy and non-profit grants.