Esther Papaseit

Determination of maternal-fetal biomarkers of prenatal exposure to ethanol: A review

The deleterious effects exerted by prenatal ethanol exposure include physical, mental, behavioural and/or learning disabilities that are included in the term fetal alcohol spectrum disorder (FASD). Objective assessment of exposure to ethanol at both prenatal and postnatal stages is essential for early prevention and intervention. Since pregnant women tend to underreport alcohol drinking by questionnaires, a number of biological markers have been proposed and evaluated for their capability to highlight gestational drinking behaviour. These biomarkers include classical biomarkers (albeit indirect) of alcohol-induced pathology (mean corpuscular volume (MCV), gamma glutamyltransferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) acetaldehyde-derived conjugates, and finally derivatives of non-oxidative ethanol metabolism (fatty acid ethyl esters (FAEEs), ethyl glucuronide (EtG), ethyl sulphate (EtS) and phosphaditylethanol (PEth)). Since ethanol itself and acetaldehyde are only measured few hours after ethanol intake in conventional matrices such as blood, urine and sweat, they are only useful to detect recent ethanol exposure. In the past few years, the non-oxidative ethanol metabolites have received increasing attention because of their specificity and in some case wide time-window of detection in non-conventional matrices from the pregnant mother (oral fluid and hair) and fetus-newborn (neonatal hair, meconium, placenta and umbilical cord). This article reviews bioanalytical procedures for the determination of these markers of ethanol consumption during pregnancy and related prenatal exposure. In addition, clinical toxicological applications of these procedures are presented and discussed.

Biological matrices for the evaluation of exposure to environmental tobacco smoke during prenatal life and childhood

The measurement of nicotine and its major metabolites cotinine and trans-3´-hydroxicotinine together with other minor metabolites (e.g., cotinine N-oxide, cotinine, and trans-3´-hydroxicotinine glucuronides) in conventional and nonconventional biological matrices has been used as a biomarker to assess the exposure to environmental tobacco smoke during childhood. The determination of these substances in matrices such as amniotic fluid, meconium, and fetal hair accounts for prenatal exposure to cigarette smoking at different stages of pregnancy. Nicotine and its metabolites in cord blood, neonatal urine, and breast milk are useful for determining acute exposure to drugs of abuse in the period immediately before and after delivery. Cotinine measurement in children’s blood and urine and nicotine and cotinine measurements in children’s hair constitute objective indexes of acute and chronic exposure during infancy, respectively. However, for monitoring and categorizing cumulative exposure to environmental tobacco smoke during the entire childhood, including the prenatal period, the assessment of nicotine in teeth has been proposed as a promising noninvasive tool. This article reviews the usefulness of measurement of nicotine and its metabolites in different fetal and pediatric biological matrices in light of noninvasive collection, time window of exposure detection, and finally clinical application in pediatrics.

Emerging drugs in Europe.

Purpose of review New psychoactive substances refer to emerging substances that have appeared on the market and are not under international control. NPS have been categorized in different main groups (e.g. synthetic cannabinoids, synthetic cathinones, phenethylamines, piperazines, ketamine and phencyclidine-type substances, tryptamines). This article reviews the recent literature regarding emerging trends of NPS in Europe. Recent findings According to the last report of the European Union Early warning system (EWS), 73 NPS were officially identified for the first time. The more frequent NPS self-reported or detected are synthetic cannabinoids and cathinones. A combination of different NPS and also mixed with other drugs, mainly cannabis and ecstasy, is usual among experienced drug users. Acute NPS toxicity includes significant psychoactive and sympathomimetic effects. Summary This article summarizes new European epidemiological and clinical data published between January and December 2013 on NPS. In the last few years, there has been a rapid increase in the number of NPS launched on the European drugs market. The presence of some of these new substances has been detected through surveys/questionnaires, studies in drug samples and biological fluids, and case reports and NPS-induced fatalities.

Pharmacokinetics and therapeutic drug monitoring of psychotropic drugs in pediatrics.

Therapeutic drug monitoring (TDM) in pediatrics (0-14 years) is especially important because the absorption, distribution, metabolism, and excretion of drugs and drug pharmacokinetic profiles can be different from that of the adult population. In this context, several parameters like half-life of drug elimination from the body (t½), peak plasma concentration (Cmax), area under the curve, clearance (CL), Tmax, and dose/concentration relationship in children may differ from adults. Hence, the knowledge of pharmacokinetic parameters and therapeutic and toxic ranges of drug concentrations may help the clinicians to optimize drug treatment regimens in the pediatric population. TDM of psychotropic drugs requires particular attention for the pharmacological and clinical consequences of nonadequate dose use, lack in the compliance, and overdoses with possible toxic effects. Psychoactive drugs such as benzodiazepines, antiepileptic drugs, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotic drugs, psychostimulants (attention-deficit hyperactivity disorder drugs), opioid analgesics, and antimigraine drugs are a heterogeneous group. These drugs are subject to interindividual variability, and therefore, the usefulness of TDM for these drugs has to be assessed individually. Because of the occurrence of comorbid pathologies, including psychiatric disorders, the use of combined pharmacotherapy is not uncommon. As a consequence, these patients may be at risk from a number of potential drug-drug interactions. The implementation of TDM in pediatric population is more difficult than in adults because some sampling procedures are invasive and cause discomfort in children, and additionally, they require the cooperation of the patient. Several examples will be provided where the use of alternative matrices, such as saliva, is proposed to minimize inconvenience and patient discomfort.

Unsuspected exposure to cocaine in preschool children from a Mediterranean city detected by hair analysis.

We used hair testing to investigate the prevalence of unsuspected exposure to cocaine in a group of preschool children presenting to an urban pediatric emergency department without signs or symptoms suggestive of exposure. Hair samples were obtained from 90 children between 18 months and 5 years of age attending the emergency room of Hospital del Mar in Barcelona, Spain. In 85 cases, hair samples from the accompanying parent were also provided. The samples were analyzed for the presence of cocaine and benzoylecgonine by gas chromatography-mass spectrometry, which also determined opiates and amphetamines. Parental sociodemographics, possible drug history, and information on the childs features were recorded. Hair samples from 21 children (23.3%) were positive for cocaine (concentration range 0.3-5.96 ng/mg of hair) with 1 sample also positive for 3,4-methylenedioxymethamphetamine and another for opiates. In 88% of the positive cases, cocaine was also found in the hair of the accompanying parent (15 of 17 matched parent-child hair samples). Parental sociodemographics were associated neither with childrens exposure to cocaine nor with somatometry of children at birth. However, the behavioral patterns with potential harmful effects for the childs health (eg, tobacco smoking, cannabis, benzodiazepines and/or antidepressants use, and shorter breast-feeding time) were significantly higher in the parents of exposed children. A statistically higher percentage of exposed children were in the lower weight percentile group compared with the nonexposed children. In the light of these results, we advocate general hair screening to disclose exposure to cocaine and other drugs of abuse in children from risky environments, which could provide the basis for specific social and health interventions.

Mass spectrometric evaluation of mephedrone in vivo human metabolism: identification of phase I and phase II metabolites, including a novel succinyl conjugate.

In recent years, many new designer drugs have emerged, including the group of cathinone derivatives. One frequently occurring drug is mephedrone; although mephedrone was originally considered as a “legal high” product, it is currently banned in most Western countries. Despite the banning, abuse of the drug and seizures are continuously reported. Although the metabolism of mephedrone has been studied in rats or in vitro using human liver microsomes, to the best of our knowledge, no dedicated study with human volunteers has been performed for studying the in vivo metabolism of mephedrone in humans. Therefore, the aim of this study was to establish the actual human metabolism of mephedrone and to compare it with other models. For this purpose, urine samples of two healthy volunteers, who ingested 200 mg mephedrone orally, were taken before administration and 4 hours after substance intake. The discovery and identification of the phase I and phase II metabolites of mephedrone were based on ultra-high-performance liquid chromatography coupled to hybrid quadrupole time-of-flight mass spectrometry, operating in the so-called MSE mode. Six phase I metabolites and four phase II metabolites were identified, four of them not previously reported in the literature. The structure of four of the detected metabolites was confirmed by synthesis of the suggested compounds. Remarkably, a mephedrone metabolite conjugated with succinic acid has been identified and confirmed by synthesis. According to the reviewed literature, this is the first time that this type of conjugate is reported for human metabolism.

Human Pharmacology of Mephedrone in Comparison with MDMA.

Mephedrone (4-methylmethcathinone) is a novel psychoactive substance popular among drug users because it displays similar effects to MDMA (3,4-methylenedioxymethamphetamine, ecstasy). Mephedrone consumption has been associated with undesirable effects and fatal intoxications. At present, there is no research available on its pharmacological effects in humans under controlled and experimental administration. This study aims to evaluate the clinical pharmacology of mephedrone and its relative abuse liability compared with MDMA. Twelve male volunteers participated in a randomized, double-blind, crossover, and placebo-controlled trial. The single oral dose conditions were: mephedrone 200 mg, MDMA 100 mg, and placebo. Outcome variables included physiological, subjective, and psychomotor effects, and pharmacokinetic parameters. The protocol was registered in ClinicalTrials.gov (NCT02232789). Mephedrone produced a significant increase in systolic and diastolic blood pressure, heart rate, and pupillary diameter. It elicited stimulant-like effects, euphoria, and well-being, and induced mild changes in perceptions with similar ratings to those observed after MDMA administration although effects peaked earlier and were shorter in duration. Maximal plasma concentration values for mephedrone and MDMA peaked at 1.25 h and 2.00 h, respectively. The elimination half-life for mephedrone was 2.15 h and 7.89 h for MDMA. In a similar manner to MDMA, mephedrone exhibits high abuse liability. Its earlier onset and shorter duration of effects, probably related to its short elimination half-life, could explain a more compulsive pattern of use as described by the users.

Assessment of prenatal exposure to tobacco smoke by cotinine in cord blood for the evaluation of smoking control policies in Spain

BackgroundOver the last few years a decreasing trend in smoking has occurred not only in the general population but also during pregnancy. Several countries have implemented laws requiring all enclosed workplace and public places to be free of second hand smoke (SHS). In Spain, legislation to reduce SHS was implemented in 2005. The present study examines the possible effect of this legislation on prenatal SHS exposure.MethodsMothers and newborns were recruited from 3 independent studies performed in Hospital del Mar (Barcelona) and approved by the local Ethics Committee: 415 participated in a study in 1996-1998, 283 in 2002-2004 and 207 in 2008. A standard questionnaire, including neonatal and sociodemographic variables,tobacco use and exposure during pregnancy, was completed at delivery for all the participants in the three study groups. Fetal exposure to tobacco was studied by measuring cotinine in cord blood by radioimmunoassay (RIA).Results32.8% of the pregnant women reported to smoke during pregnancy in 1996-1998, 25.9% in 2002-2004 and 34.1% in 2008. In the most recent group, the percentage of no prenatal SHS exposure (cord blood cotinine 0.2-1 ng/mL) showed an increase compared to the previous groups while the percentages of both: low (1.1-14 ng/mL) and very high (> 100 ng/mL) prenatal SHS exposure showed a decrease.DiscussionThe results of the three study periods (1996-2008) demonstrated a significant increase in the percentage of newborns free from SHS exposure and a decrease in the percentage of newborns exposed to SHS during pregnancy, especially at the very high levels of exposure. A significant maternal smoking habit was noted in this geographical area with particular emphasis on immigrant pregnant smoking women.ConclusionsOur study indicates that there is a significant maternal smoking habit in this geographical area. Our recommendation is that campaigns against smoking should be directed more specifically towards pregnant women with particular emphasis on non-native pregnant smokers due to the highest prevalence of tobacco consumption in the immigrant women.

Bilastine vs. hydroxyzine: occupation of brain histamine H1‐receptors evaluated by positron emission tomography in healthy volunteers

Aim A close correlation exists between positron emission tomography (PET)-determined histamine H1-receptor occupancy (H1RO) and the incidence of sedation. Antihistamines with H1RO <20% are classified as non-sedating. The objective was to compare the H1RO of bilastine, a second generation antihistamine, with that of hydroxyzine. Methods This randomized, double-blind, crossover study used PET imaging with [11C]-doxepin to evaluate H1RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated. Results The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H1RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine. Conclusions A single oral dose of bilastine 20 mg had minimal H1RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.

Moderate consumption of wine, through both its phenolic compounds and alcohol content, promotes hydroxytyrosol endogenous generation in humans. A randomized controlled trial

In humans, urinary hydroxytyrosol (OHTyr) concentrations have been associated to alcohol and wine consumption. To explore the role of wine components on promoting an endogenous OHTyr generation we performed a cross-over, double-blind, randomized controlled clinical trial (n = 28 healthy volunteers). Ethanol (wine and vodka), dealcoholized wine, and placebo were administered. Alcohol, dealcoholized wine, and particularly wine promoted a de novo OHTyr generation in vivo in humans. Potential OHTyr precursors (tyrosine, tyrosol, tyramine) were investigated in rats. Tyrosol was metabolized to OHTyr. Collating both studies, it is postulated that an increased Tyr bioavailability, a shift to a reductive pathway in dopamine and tyramine oxidative metabolism, and the biotransformation of Tyr to OHTyr were mechanisms involved in the OHTyr endogenous generation.