[Cannabinoids and emesis: new evidences, new questions].
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Antiemetics↗
Biomedical subjects
Magí Farré
Publications and source records attributed to Magí Farré.
Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA.
The aim of this study was to model the in vivo kinetic consequences of mechanism-based inhibition (MBI) of CYP2D6 by 3,4 methylenedioxymethamphetamine (MDMA, ecstasy). A model with physiologically-based components of drug metabolism was developed, taking account of change in the hepatic content of active CYP2D6 due to MBI by MDMA. Based on the in vitro information, plasma concentration time profiles of MDMA after various doses were computed and compared with reported observations. The analysis suggested that a typical recreational MDMA dose could inactivate most hepatic CYP2D6 within an hour, and the return to a basal level of CYP2D6 could take at least 10 days. Thus, the genetic polymorphism of CYP2D6 and coadministration of CYP2D6 inhibitors may have less impact on MDMA pharmacokinetics and the risk of acute toxicity than previously thought. This is consistent with clinical observations that indicate no obvious link between inherited CYP2D6 deficiency and acute MDMA intoxication.
Algorithms↗
Is dopamine behind the health benefits of red wine?
BACKGROUND: The contribution of biologically active non-nutrient chemicals to the health benefits of the Mediterranean diet is controversial because of their low dietary concentrations. Hydroxytyrosol is a dopamine metabolite, and also a very active naturally occurring phenol compound in olive oil. AIM OF THE STUDY: To examine the disposition of hydroxytyrosol in humans, given that we discovered its presence in red wine in the frame of the study. METHODS: The pharmacokinetics of hydroxytyrosol from two clinical trials, designed to assess the short-term and postprandial effects of moderate doses of wine and olive oil in healthy volunteers, were compared. RESULTS: Despite a five-fold difference in the doses of hydroxytyrosol administered (0.35 mg for red wine and 1.7 mg for olive oil), urinary recoveries of hydroxytyrosol were higher after red wine administration. An interaction between ethanol and dopamine after red wine ingestion leading to the formation of hydroxytyrosol was observed. CONCLUSIONS: Biological effects after red wine ingestion should be re-examined on the basis of combined hydroxytyrosol concentrations from red wine and dopamine turnover.
Adolescent↗
A meta-analysis of the placebo response in acute migraine and how this response may be influenced by some of the characteristics of clinical trials.
Migraine is the most common cause of vascular headache and a highly prevalent illness. In the last 20 years, the discovery of new agents has increased clinical research on migraine. In most of clinical trials that have been conducted, the efficacy was established using a placebo as a control treatment. The objective of the study reported here was to analyse the response rate in patients who received a placebo as well as to determine how a number of the methodological factors may affect the effect of the placebo in clinical trials of acute migraine. Computer-based information searches were conducted on the Medline database. Data analysis included the outcomes 'pain relief', 'pain-free', 'associated symptoms', 'recurrence', 'patients' opinion' about pain relief and 'adverse events'. Administration route, study design and country in which the study was carried out were the methodological factors that were analyzed. Meta-analysis was computed using Mantel-Haenszel, and a total of 98 papers were considered in the final analysis. After 2 h, 28.6% of the patients of the placebo group improved and 8.8% were pain-free. The percentage of pain-free patients was the highest in the placebo and active drug groups in which the placebo or drug had been administered subcutaneously, in parallel design studies (vs. cross-over trials) and in studies performed in Europe (vs. North America). Adverse events in the placebo group were significantly higher in studies performed in North America. These data reinforce the need for knowing the magnitude of the placebo response in each specific situation during the planning of clinical trials on acute migraine.
Acute Disease↗
Assessment of chronic exposure to MDMA in a group of consumers by segmental hair analysis.
The suitability of segmental hair analysis of MDMA to monitor past chronic exposure to the drug was investigated in a follow-up study of ecstasy consumers. The purpose, among others, was to look for an objective biomarker of the history of drug consumption. Thirteen naturally colored hair samples were used to assess possible association between hair concentration of MDMA in 1-, 5-, and 9-cm segments and self-reported use in the last 1, 6, and 12 months. Agreement between the self-reported data given by the subjects on their "ecstasy" use in the previous month and MDMA hair concentration was good (r = 0.92) in all the examined subjects, with the exception of 2 individuals who declared a high consumption of the drug (12 tablets in the last month). When comparing the subjects' declaration of tablets consumed per month within the last 6 months, concordance with the hair MDMA values decreased and no correlation seemed to exist between the mean number of tablets consumed in the last 12 months and the concentration of MDMA in hair. However, when grouping subjects with a similar level of declared drug use (independently of whether in the previous month, last 6 months and last 12 months) and comparing the data with the mean MDMA concentrations found in the corresponding hair segments, an excellent level of agreement was found in groups of subjects consuming <5 tablets of MDMA per month (r = 0.93). Although the present findings were obtained from a small group of individuals and are intended as preliminary results, we can conclude that a cutoff of 0.5 ng MDMA per mg hair seems reasonable to assess drug consumption, unless the level of consumption was once per month in the last 12 months. Doubling the monthly consumption increases hair MDMA by around 1 ng/mg hair up to a level of 4 consumed tablets a month. It does not seem possible to draw definitive conclusions from higher concentrations in hair samples.
Adolescent↗
Evaluation of RNA isolation procedures from human blood and its application for gene expression studies (Sod-1, Sod-2).
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Adult↗
MDMA (ecstasy) pharmacokinetics in a CYP2D6 poor metaboliser and in nine CYP2D6 extensive metabolisers.
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Area Under Curve↗
Quantification of the plant-derived hallucinogen Salvinorin A in conventional and non-conventional biological fluids by gas chromatography/mass spectrometry after Salvia divinorum smoking.
A gas chromatography method with mass spectrometric detection is described for the determination of Salvinorin A, the main active ingredient of the hallucinogenic mint Salvia divinorum. The method was validated in plasma, urine, saliva and sweat using 17-alpha-methyltestosterone as internal standard. The analytes were extracted from biological matrices with chloroform/isopropanol (9:1, v/v). Chromatography was performed on a 5% phenyl methyl silicone capillary column and analytes were determined in the selected ion monitoring mode. The method was validated over the concentration range 0.015-5 microg/mL plasma, urine and saliva and 0.01-5 microg/patch in the case of sweat. Mean recoveries ranged between 77.1 and 92.7% for Salvinorin A in different biological matrices, with precision and accuracy always better than 15%. The method was applied to the analysis of urine, saliva and sweat from two consumers after smoking 75 mg plant leaves to verify the presence of the active ingredient of S. divinorum in human biological fluids as a biomarker of plant consumption. Salvinorin A was detected in urine (2.4 and 10.9 ng/mL) and saliva (11.1 and 25.0 ng/mL), but not in sweat patches from consumers.
Body Fluids↗
Prevalence and risk of gingival overgrowth in patients treated with diltiazem or verapamil.
OBJECTIVES: This study was conducted to determine the prevalence and risk factors for gingival enlargement in patients treated with diltiazem or verapamil. MATERIAL AND METHODS: A cross-sectional study was conducted and data from 46 patients actually taking diltiazem or verapamil were compared with 49 cardiovascular controls that never received any of these drugs. All patients were examined for the presence of gingival enlargement using two different indices, the vertical gingival overgrowth (GO) index, and horizontal Miranda & Brunet (MB) index in the inter-dental area. Gingival index, plaque index, and probing depth were also evaluated. RESULTS: The total study population was 95:32 diltiazem-treated, 14 verapamil-treated and 49 cardiovascular control subjects. Gingival enlargement occurred in 31% (GO index) and 50% (MB index) of the patients taking diltiazem. Gingival enlargement in the verapamil-treated group was 21% for the GO index and 36% for the MB index. The prevalence of gingival enlargement was higher in the diltiazem- and verapamil-treated patients than in controls for both indices. The difference between the diltiazem-treated group and control was statistically significant (p=0.022 for GO and p=0.001 for MB), while the difference between the verapamil-treated group and controls was not significant. The risk of gingival enlargement (OR--Odds Ratio) associated with diltiazem therapy was 4.0 (1.2-13.1) for the GO index and of 6.0 (2.1-17.3) for the MB index. When the OR were adjusted for gingival index (GI) values, the risk of gingival enlargement was 3.5 (1.0-12.4) for the GO index and 6.2 (1.9-20.0) for the MB index. In the verapamil-treated group the OR values were not significant. The level of concordance between GO and MB indices in all three groups showed a kappa-value of 0.72 (p<0.001). CONCLUSION: Patients taking diltiazem are at high risk for gingival enlargement and gingivitis has a stronger effect than the drug treatment on gingival enlargement risk.
Aged↗
Contribution of cytochrome P450 2D6 to 3,4-methylenedioxymethamphetamine disposition in humans: use of paroxetine as a metabolic inhibitor probe.
BACKGROUND: 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. 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 20 mg. On the third day, a single oral dose of MDMA 100 mg was administered in both paroxetine and placebo conditions. 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). RESULTS: Paroxetine given before MDMA resulted in significant increases of MDMA area under the plasma concentration-time curve from 0 to 27 hours (AUC(27)) [23%], AUC from zero to infinity (AUC(infinity)) [27%] and maximum plasma concentration (C(max)) [17%], without significant differences in MDMA time to reach C(max) (t(max)). MDMA elimination-related pharmacokinetic parameters showed a significant reduction of MDMA elimination rate constant (K(e)) [-14%] and plasmatic clearance (CL(P)) [-29%]. In the case of 3,4-dihydroxymethamphetamine (HHMA), a 21% decrease in C(max) with no significant differences in AUC(27), AUC(infinity), K(e) and elimination half-life) were found. 4-Hydroxy-3-methoxymethamphetamine (HMMA) showed a decrease in plasma concentrations with a reduction in AUC(27) (-28%), AUC(infinity) (-20%) and C(max) (-46%). In the case of 3,4-methylenedioxyamphetamine (MDA) an increase in C(max) (17%) and AUC(27) (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 C(max) values of paroxetine and its metabolite on days 1 and 3 showed a 3-fold reduction, with no differences in t(max). 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.
Adult↗
Efficacy of antidepressants in substance use disorders with and without comorbid depression. A systematic review and meta-analysis.
Antidepressants are commonly used in substance abusers due to the potential effect on some underlying mechanisms involved in drug use disorders and to treat comorbid depression. A systematic review of the literature of the efficacy of antidepressant drugs in subjects with drug abuse disorders, including alcohol, cocaine, nicotine and opioid, with and without comorbid depression was performed. Only randomised, double-blind, controlled trials have been evaluated. A meta-analysis was done with the included studies that used common evaluation procedures in alcohol, cocaine and opioid dependence. Based on the present review some recommendations may be proposed. The prescription of antidepressants for drug abuse seems only clear for nicotine dependence with or without previous comorbid depression (bupropion and nortryptiline). In alcohol dependence without comorbid depression, the use of any antidepressant seems not justified, while in cocaine dependence has to be clarified. The use of antidepressants in alcohol, cocaine or opioid dependence with comorbid depression needs more studies in well-defined samples, adequate doses and duration of treatment to be really conclusive. Interestingly, SSRIs do not seem to offer significant advantages compared with tricyclic drugs in substance abuse disorders. Differences both related to individual characteristics and specific antidepressant drugs need to be clarified in future studies.
Antidepressive Agents↗
[Club drugs: old medicines as new party drugs].
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.
Designer Drugs↗
[Nocebo effect: the other side of placebo].
Administration of drugs is often followed by beneficial (placebo effects) and harmful (nocebo effects) effects that are not always related to their mechanism of action. Nocebo effects are rather unknown even when may be the source of many adverse reactions which could be erroneously attributed to drug therapy. Some mechanisms have been postulated which might be associated with the development of nocebo effects. Expectancy, learning and classical conditioning are probably important in the psychological domain. The neuropharmacological substrate is much less known yet an opioid peptide-cholecystokinin interaction has been suggested. At the clinical setting, a nocebo effect should be suspected in those patients who present common unspecific symptoms after drug administration and have a tendency to somatize. An early detection of these patients may contribute to the prevention of the nocebo effect.
Clinical Trials as Topic↗
Reversible coma secondary to cefepime neurotoxicity.
OBJECTIVE: To describe a case of cefepime neurotoxicity associated with acute renal failure that resulted in nonconvulsive status epilepticus. CASE SUMMARY: A 66-year-old woman with acute myeloid leukemia had fever on the third day of the initial chemotherapy cycle. Empiric antibiotic treatment with cefepime 2 g every 8 hours was started; fluconazole and vancomycin were subsequently added due to the persistence of fever. Ten days after initiation of cefepime, the patient developed acute renal failure followed by altered consciousness (Glasgow coma scale 6) associated with nonconvulsive status epilepticus. Cefepime was discontinued. Epileptiform activity in the electroencephalogram disappeared with clonazepam, and the patient regained consciousness 48 hours after cefepime withdrawal. DISCUSSION: Acute renal impairment combined with the use of cefepime may account for nonconvulsive status epilepticus. An objective causality assessment revealed that the adverse event was probably due to cefepime. Cefepime's neurotoxic effects derive from high serum concentrations resulting from decreased renal clearance, increased unbound antibiotic, and blood-brain barrier dysfunction during uremia. CONCLUSIONS: The combination of cefepime treatment and acute renal failure may induce drug-related neurotoxicity. Nonconvulsive status epilepticus frequently passes unnoticed in severely ill patients without a history of epilepsy. This disorder should be included in the list of potential causes of coma. In this patient, early detection of nonconvulsive status epilepticus and withdrawal of the antibiotic resulted in full recovery.
Acute Kidney Injury↗
Paroxetine inhibits acute effects of 3,4-methylenedioxymethamphetamine on the immune system in humans.
The effect of pretreatment with paroxetine on cell-mediated immune response and release of cytokines after the administration of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") was investigated in a double-blind, randomized, crossover, controlled clinical trial in which 12 healthy male recreational users of MDMA participated. Subjects received 20 mg/day paroxetine (or placebo) for the 3 days before MDMA challenge (100 mg). Acute MDMA administration produced a time-dependent decrease in CD4 T-helper cells, a decrease in the functional responsiveness of lymphocytes to mitogenic stimulation, a simultaneous increase in natural killer (NK) cells as well as cortisol and prolactin stimulation kinetics. A high increase in the release of anti-inflammatory cytokines (transforming growth factor-beta and interleukin-10) with a simultaneous decrease of anti-inflammatory response (interleukin-2) was also observed. Pretreatment with paroxetine partially reduced MDMA effects on CD4 T and NK cells, whereas totally inhibiting the suppression of the immune response to mitogens and alterations in cytokines release. MDMA-induced alterations in the immune system as well as antagonistic effects mediated by paroxetine show a trend toward baseline levels at 24 h. These findings suggest that acute effects of MDMA on immune system are mainly mediated by its interaction with the serotonin transporter and subsequent serotonin release with a possible participation of other neuroendocrine regulatory systems.
Adult↗
Effects of differing phenolic content in dietary olive oils on lipids and LDL oxidation--a randomized controlled trial.
BACKGROUND: Evidence from in vitro studies suggests that antioxidant olive oil phenolic compounds can prevent LDL oxidation. However, in vivo evidence in support of this hypothesis is sparse. AIM OF THE STUDY: to establish the antioxidant effect of olive oils with differences in their phenolic compounds content in humans METHODS: A controlled, double blind, cross-over, randomized, clinical trial using three similar olive oils with increasing phenolic concentration (from 0 to 150 mg/Kg) was conducted in 30 healthy volunteers. Olive oils were administered over three periods of 3 weeks preceded by two-week washout periods. RESULTS: Urinary tyrosol and hydroxytyrosol increased (p < 0.020), in vivo plasma oxidized LDL decreased (p = 0.006), and ex vivo resistance of LDL to oxidation increased (p = 0.012) with the phenolic content of the olive oil administered. After virgin olive oil administration, an increase (p = 0.029) was observed in HDL cholesterol levels. CONCLUSIONS: Sustained consumption of virgin olive oil with the high phenolic content was more effective in protecting LDL from oxidation and in rising HDL cholesterol levels than that of other type of olive oils. Dose-dependent changes in oxidative stress markers, and phenolic compounds in urine, were observed with the phenolic content of the olive oil administered. Our results support the hypothesis that virgin olive oil consumption could provide benefits in the prevention of oxidative processes.
Antioxidants↗
Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans.
Several studies suggest that MDMA-induced acute toxicity and long-term neurotoxicity is dependent on the metabolic disposition of MDMA. Differences in MDMA metabolism among animal species might therefore account for different sensitivities to its neurotoxic effects. The kinetic parameters of enzymes that regulate the formation of neurotoxic metabolites of MDMA differ among species, as does the ability of MDMA to self-inhibit these enzymes and the degree of genetic polymorphisms exhibited by these enzymes. Such features limit allometric scaling across animal models.
Animals↗
Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition.
MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is a widely misused psychostimulant drug abused among large segments of the young population. Pharmacologically it displays effects related to amphetamine-type drugs and a set of distinctive effects (closeness to others, facilitation to interpersonal relationship, and empathy) that have been named by some authors "entactogen" properties. MDMA is a potent releaser and/or reuptake inhibitor of presynaptic serotonin (5-HT), dopamine (DA), and norepinephrine (NE). These actions result from the interaction of MDMA with the membrane transporters involved in neurotransmitter reuptake and vesicular storage systems. The most frequent effects after MDMA/ecstasy administration are euphoria, well-being, happiness, stimulation, increased energy, extroversion, feeling close to others, increased empathy, increased sociability, enhanced mood, mild perceptual disturbances, changed perception of colors and sounds, somatic symptoms related to its cardiovascular and autonomic effects (blood pressure and heart rate increase, mydriasis), and moderate derealization but not hallucinations. Acute toxic effects are related to its pharmacologic actions. The serotonin syndrome (increased muscle rigidity, hyperreflexia, and hyperthermia), among others, is characteristic of acute toxicity episodes. MDMA metabolism is rather complex and includes 2 main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The fact that the polymorphic enzyme CYP2D6 partially regulates the O-demethylenation pathway prompted some expectations that subjects displaying the poor metabolizer phenotype may be at higher risk of acute toxicity episodes. In this metabolic pathway a mechanism-based inhibition of the enzyme operates because the formation of an enzyme-metabolite complex that renders all subjects, independently of genotype, phenotypically poor metabolizers after the administration of 2 consecutive doses. Therefore, the impact of CYP2D6 pharmacogenetics on acute toxicity is limited. One of the interesting features of MDMA metabolism is its potential involvement in the development of mid- to long-term neurotoxic effects as a result of progressive neurodegeneration of the serotonergic neurotransmission system.
Adrenergic Uptake Inhibitors↗