Ana M. Peiró

Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics

Rationale3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is increasingly used by young people for its euphoric and empathic effects. MDMA presents non-linear pharmacokinetics, probably by inhibition of cytochrome P450 isoform 2D6. Users are known to often take more than one dose per session. This practice could have serious implications for the toxicity of MDMA.ObjectiveTo evaluate the pharmacological effects and pharmacokinetics of MDMA following the administration of two repeated doses of MDMA (24xa0h apart).MethodsA randomised, double-blind, cross-over, placebo controlled trial was conducted in nine healthy male subjects. Variables included physiological, psychomotor performance, subjective effects, endocrine response and pharmacokinetics. MDMA 100xa0mg or placebo was administered in two successive doses separated by an interval of 24xa0h.ResultsMDMA produced the prototypical effects of the drug. Following a second dose, plasma concentrations of MDMA increased (AUC 77% and Cmax 29%) in comparison with the first. The increase is greater than those expected by simple accumulation and indicates metabolic inhibition. The pharmacological effects after the second dose were slightly higher than those observed after the first in the majority of variables including blood pressure, heart rate, most subjective effects and cortisol concentrations. The effects were similar in the case of pupil diameter, esophoria and prolactin.ConclusionsPharmacological effects after the second administration were higher than those following the first but lower than expected. A disproportionate increase in plasma concentrations in MDMA and MDA was observed most likely due to metabolic inhibition. This inhibition lasts at least 24xa0h. Further experiments need to be conducted to evaluate its duration.

Pharmacological Interaction between 3,4-Methylenedioxymethamphetamine (Ecstasy) and Paroxetine: Pharmacological Effects and Pharmacokinetics

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is increasingly used by young people for its euphoric and empathic effects. MDMA can be used in combination with other drugs such as selective serotonin reuptake inhibitors. A clinical trial was designed where subjects pretreated with paroxetine, one of the most potent inhibitors of both 5-hydroxytryptamine reuptake and CYP2D6 activity, were challenged with a single dose of MDMA. The aim of the study was to evaluate the pharmacodynamic and pharmacokinetic interaction between paroxetine and MDMA in humans. A randomized, double-blind, crossover, placebo-controlled trial was conducted in 12 healthy male subjects. Variables included physiological parameters, psychomotor performance, subjective effects, and pharmacokinetics. Subjects received 20 mg/day paroxetine (or placebo) orally for the 3 days before MDMA challenge (100 mg oral). MDMA alone produced the prototypical effects of the drug. Pretreatment with paroxetine was associated with marked decreases of both physiological and subjective effects of MDMA, despite a 30% increase in MDMA plasma concentrations. The decreases of 3-methoxy-4-hydroxymethamphetamine plasma concentrations suggest a metabolic interaction of paroxetine and MDMA. These data show that pretreatment with paroxetine significantly attenuates MDMA-related physiological and psychological effects. It seems that paroxetine could interact with MDMA at pharmacodynamic (serotonin transporter) and pharmacokinetic (CYP2D6 metabolism) levels. Marked decrease in the effects of MDMA could lead users to take higher doses of MDMA and to produce potential life-threatening toxic effects.

Contribution of cytochrome P450 2D6 to 3,4- methylenedioxymethamphetamine disposition in humans : Use of paroxetine as a metabolic inhibitor probe

AbstractBackground: 3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative typically used for recreational purposes. The participation of cytochrome P450 (CYP) 2D6 in the oxidative metabolism of MDMA may suggest an increased risk of acute toxicity in CYP2D6 poor metabolisers. This study was aimed at assessing the contribution of CYP2D6 to MDMA disposition in vivo using paroxetine as a metabolic probe inhibitor. Paroxetine, a CYP2D6 inhibitor, was repeatedly administered before MDMA administration.n Study design: This was a randomised, double-blind, crossover, placebo-controlled trial conducted in seven healthy male volunteers who were CYP2D6 extensive metabolisers. Treatment conditions (paroxetine/MDMA and placebo/ MDMA) were randomly assigned. Each volunteer participated in two 3-day sessions. On days 1, 2 and 3 subjects received a single oral dose of paroxetine or placebo 20mg. On the third day, a single oral dose of MDMA 100mg was administered in both paroxetine and placebo conditions.n Methods: Plasma concentration-time profiles and urinary recoveries of MDMA and its metabolites were measured, as well as plasma concentrations of paroxetine, (3S,4R)-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine, and (3S,4R)-4-(4-fluorophenyl)-3-(3-methoxy-4-hydroxyphenoxymethyl)-piperidine (HM-paroxetine).n Results: Paroxetine given before MDMA resulted in significant increases of MDMA area under the plasma concentration-time curve from 0 to 27 hours (AUC27) [23%], AUC from zero to infinity (AUC∞) [27%] and maximum plasma concentration (Cmax) [17%], without significant differences in MDMA time to reach Cmax (tmax). MDMA elimination-related pharmacokinetic parameters showed a significant reduction of MDMA elimination rate constant (Ke) [−14%] and plasmatic clearance (CLP) [−29%]. In the case of 3,4-dihydroxymethamphetamine (HHMA), a 21% decrease in Cmax with no significant differences in AUC27, AUC∞, Ke and elimination half-life) were found. 4-Hydroxy-3-methoxymethamphetamine (HMMA) showed a decrease in plasma concentrations with a reduction in AUC27 (−28%), AUC∞ (−20%) and Cmax (−46%). In the case of 3,4-methylenedioxyamphetamine (MDA) an increase in Cmax (17%) and AUC27 (16%) was found. Following paroxetine pretreatment, the urinary recovery (0–45 hours) of MDMA increased by 11%; HHMA and HMMA urinary recoveries were 27% and 16% lower, respectively compared with placebo. The ratio of Cmax values of paroxetine and its metabolite on days 1 and 3 showed a 3-fold reduction, with no differences in tmax.n Discussion and conclusion: The contribution of CYP2D6 to MDMA metabolism in humans is not >30%, therefore other CYP isoenzymes may contribute to O-demethylenation of MDMA. Accordingly, the relevance of genetic polymorphism in CYP2D6 activity on MDMA effects and MDMA-induced acute toxicity should be examined as well as the interactions of other CYP2D6 substrates with MDMA, once the enzyme is inhibited. The pharmacokinetics of HM-paroxetine in humans after the administration of repeated doses is reported for the first time in this study.

Club drugs: los viejos fármacos son las nuevas drogas de la fiesta

During the last few years the term club drugs has been used for defining an heterogeneous group of chemical substances in permanent evolution, that are consumed for recreational purposes. These substances have been extensively used, firstly by the Rave culture and later by the so called Club culture. These movements are characterized by the search of amplified sensations, by means of the combination of electronic music, marathon dancing and substance abuse. After years with a predominating consumption of designer amphetamines in these groups, it seems that the use of another type of substances is increasing, fundamentally drugs with hallucinogenic effects. This review focus in four of these substances; ketamine, dextromethorphan, nitrous oxide and gamma-hydroxybutyric acid (GHB, liquid ecstasy), and includes a discussion of their pharmacology, recreational use, adverse effects and patient management. These drugs are, at he same time, drugs of abuse and medicines with concrete indications in therapeutics, with an important increase of their consumption in the last few years. The Rave and Club cultures are also described.

The relationship of salivary testosterone and male sexual dysfunction in opioid-associated androgen deficiency (OPIAD)

Abstract Background: Opioids are an effective treatment for chronic non-malignant pain (CNP). Long-term use risks and side effects such as opioid-induced androgen deficiency (OPIAD) exist. This could be measured by saliva testosterone (Sal-T). Objectives: To evaluate OPIAD in long-term opioid use in CNP patients. Methods: A cross-sectional study included CNP male outpatients under opioid treatment. Total-Testosterone (Total-T), Free-Testosterone (Free-T), Bio-Testosterone (Bio-T) and Sal-T were measured. Correlations were calculated by Spearman’s rho (SPSS 20). Results: From 2012 to 2014, 134 from 249 (54%) consecutive male outpatients reported erectile dysfunction (ED), 37% of them related to opioids and 19% evidenced OPIAD. A total of 120 subjects (94 cases and 26 matched-controls) were included. A significantly lower luteinizing hormone, Total-T and Free-T were found, as well as, a significant correlation between Sal-T and Total-T (ru2009=u20090.234, pu2009=u20090.039), Bio-T (ru2009=u20090.241, pu2009=u20090.039), IIEF (ru2009=u20090.363, pu2009=u20090.003) and HAD-anxiety (r =u2009−0.414, pu2009=u20090.012) in OPIAD patients. Sal-T levels were significantly lower in patients with severe–moderate ED versus mild ED (pu2009=u20090.045) and in patients with severe ED versus moderate–mild ED (pu2009=u20090.036). Conclusions: These data demonstrate the high prevalence of ED in long-term use of opioids, part of this is associated to OPIAD, which can be tested by Sal-T as a non-invasive approach.

Pharmacogenomics in pain treatment

Abstract The experience of chronic pain is one of the commonest reasons for seeking medical attention, being a major issue in clinical practice. While pain is a universal experience, only a small proportion of people who felt pain develop pain syndromes. In addition, painkillers are associated with wide inter-individual variability in the analgesic response. This may be partly explained by the presence of single nucleotide polymorphisms in genes encoding molecular entities involved in pharmacodynamics and pharmacokinetics. However, uptake of this information has been slow due in large part to the lack of robust evidences demonstrating clinical utility. Furthermore, novel therapies, including targeting of epigenetic changes and gene therapy-based approaches are further broadening future options for the treatment of chronic pain. The aim of this article is to review the evidences behind pharmacogenetics (PGx) to individualize therapy (boosting the efficacy and minimizing potential toxicity) and genes implicated in pain medicine, in two parts: (i) genetic variability with pain sensitivity and analgesic response; and (ii) pharmacological concepts applied on PGx.

What is the future of pharmacogenomics in pain management

How can an individual have a sensory experience, very different of another person, receiving a similar sensory input? Developing an understanding of such differences and the mechanisms that support them is the base to optimize pain treatment on an individual-byindividual focus [1]. However, the scenario of chronic pain management is unsatisfactory, with many patients suffering from pain up to their maximum tolerance level, high rates of patient dissatisfaction, huge impact on their own quality of life and a large variability of pharmacological combinations used to treat it [2]. Chronic pain is an unpleasant sensory and emotional experience, without apparent biological value, that persists beyond normal tissue healing [3]. New opioid analgesic drugs appear to benefit from classical ones, in terms of efficacy and tolerability, but studies in ‘real world’ remain scarce, without any predictable biomarker of analgesic response [4]. The concept that ‘one size fits all’ has been replaced by the idea of patient-tailored healthcare prevention and therapy. This is the base of personalized medicine, which foresees the use of molecular data to better classify disease, to facilitate the development and validation of new targeted therapies, to treat patients with more specificity and efficacy but fewer adverse events and towards more accurately disease predis position. So hopefully, patients with an unsatisfactory response to analgesic treatment will have a ray of hope [5]. Discovery efforts in pharmacogenomics (PGx) have been assisted by robust, nationally accessible reference databases which classify and annotate genomic variation, for example, single nucleotide polymorphism database/genomic structural variation database, ClinVar and Online Mendelian Inheritance in Man (OMIM) [6]. Genes can affect pharmaco dynamics based on variations in drug target receptors and downstream signal transduction (i.e. OPRM1, COMT ). On the other hand, genes affecting pharmacokinetics that affect drug metabolism and/or elimination (i.e. CYP450 family of enzymes, enzymes responsible for glucuronidation, drug transporter proteins and COX enzymes) altering the relationship between drug dose and steady-state serum drug concentrations [7,8]. In musculoskeletal chronic pain, the contribution from the catecholaminergic system, represented by COMT and adrenoceptor β 2 (ADRB2), is seconded by the involvement of the serotonergic system, exemplified by associations between serotonin transporter (SLC6A4) and serotonin receptor 2A (HTR2A) [9]. Complementary nociceptive and inhibitory systems are implicated in postoperative pain studies: as the association between variant in GTP hydrolase, GCH1 (a regulator in the dopamine, serotonin and nitric oxide biosynthesis pathway) and postoperative pain [10] where OPRM1 genotypes could predict the extent of chronic post operative pain, similarly as variants in What is the future of pharmacogenomics in pain management?

Cost and effectiveness of lung lobectomy by video-assisted thoracic surgery for lung cancer

BACKGROUNDnVideo-assisted thoracic surgery (VATS) emerged as a minimally invasive surgery for diseases in the field of thoracic surgery. We herein reviewed our experience on thoracoscopic lobectomy for early lung cancer and evaluated Health System use.nnnMETHODSnA cost-effectiveness study was performed comparing VATS vs. open thoracic surgery (OPEN) for lung cancer patients. Demographic data, tumor localization, dynamic pulmonary function tests [forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusion capacity (DLCO) and maximal oxygen uptake (VO2max)], surgical approach, postoperative details, and complications were recorded and analyzed.nnnRESULTSnOne hundred seventeen patients underwent lung resection by VATS (n=42, 36%; age: 63±9 years old, 57% males) or OPEN (n=75, 64%; age: 61±11 years old, 73% males). Pulmonary function tests decreased just after surgery with a parallel increasing tendency during first 12 months. VATS group tended to recover FEV1 and FVC quicker with significantly less clinical and post-surgical complications (31% vs. 53%, P=0.015). Costs including surgery and associated hospital stay, complications and costs in the 12 months after surgery were significantly lower for VATS (P<0.05).nnnCONCLUSIONSnThe VATS approach surgery allowed earlier recovery at a lower cost than OPEN with a better cost-effectiveness profile.

β2‑adrenergic receptor functionality and genotype in two different models of chronic inflammatory disease: Liver cirrhosis and osteoarthritis

The present study was designed to investigate the functional status of β2 adrenoceptors (β2AR) in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthritis (OA). The β2AR gene contains three single nucleotide polymorphisms at amino acid positions 16, 27 and 164. The aim of the present study was to investigate the potential influence of lymphocyte β2AR receptor functionality and genotype in LC and OA patients. Blood samples from cirrhotic patients (n=52, hepatic venous pressure gradient 13±4xa0mmHg, CHILD 7±2 and MELD 11±4 scores), OA patients (n=30, 84% Kellgren‑Lawrence severity 4 grade, 14% knee replacement joint) and healthy volunteers as control group (n=26) were analyzed. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and basal and isoproterenol induced adenylate cyclase activity (isoproterenol stimulus from 10‑9 to 10‑4xa0mM), and β2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. β2AR functionality was decreased in the two different models of chronic inflammatory disease studied, OA (50% vs. control) and LC (85% vs. control). In these patients, the strength of the β2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the β2AR stimulus is decreased in chronic inflammatory processes including LC and OA, suggesting that the adrenergic system may be important in the development of these processes.

OPRM1 influence on and effectiveness of an individualized treatment plan for prescription opioid use disorder patients

Screening for opioid use disorder should be considered in chronic non‐cancer pain (CNCP) patients with long‐term use of opioids. The aim of our study was to assess the effectiveness of an individualized treatment plan (ITP) for prescription opioid dependence that included screening of pharmacogenetic markers. An observational prospective study was performed using prescription opioid‐dependent CNCP outpatients (n = 88). Patients were divided into nonresponders, responders, or high responders according to their response to the ITP. Genotyping of OPRM1 (A118G), OPRD1 (T921C), COMT (G472A), ABCB1 (C3435T), and ARRB2 (C8622T) was performed by real‐time PCR. Our ITP achieved a significant reduction of the morphine equivalent daily dose (MEDD) in 64% of responders, including 33% of high responders. Nonopioid medication or buprenorphine use was significantly higher at final versus basal visit. 118‐AA OPRM1 patients required significantly lower MEDD at basal and final visits. Our ITP showed effectiveness and security in reducing MEDD in opioid‐dependent patients, with good conversion to buprenorphine that was more pronounced in 118‐AA OPRM1 patients.