Publications by authors named "Jordi Ortuno"

28 Publications

  • Page 1 of 1

Rapid tannin profiling of tree fodders using untargeted mid-infrared spectroscopy and partial least squares regression.

Plant Methods 2021 Feb 6;17(1):14. Epub 2021 Feb 6.

Institute for Global Food Security, Queen's University Belfast, Belfast, BT9 5DL, Northern Ireland, UK.

Background: The presence of condensed tannins (CT) in tree fodders entails a series of productive, health and ecological benefits for ruminant nutrition. Current wet analytical methods employed for full CT characterisation are time and resource-consuming, thus limiting its applicability for silvopastoral systems. The development of quick, safe and robust analytical techniques to monitor CT's full profile is crucial to suitably understand CT variability and biological activity, which would help to develop efficient evidence-based decision-making to maximise CT-derived benefits. The present study investigates the suitability of Fourier-transformed mid-infrared spectroscopy (MIR: 4000-550 cm) combined with multivariate analysis to determine CT concentration and structure (mean degree of polymerization-mDP, procyanidins:prodelphidins ratio-PC:PD and cis:trans ratio) in oak, field maple and goat willow foliage, using HCl:Butanol:Acetone:Iron (HBAI) and thiolysis-HPLC as reference methods.

Results: The MIR spectra obtained were explored firstly using Principal Component Analysis, whereas multivariate calibration models were developed based on partial least-squares regression. MIR showed an excellent prediction capacity for the determination of PC:PD [coefficient of determination for prediction (RP) = 0.96; ratio of prediction to deviation (RPD) = 5.26, range error ratio (RER) = 14.1] and cis:trans ratio (RP = 0.95; RPD = 4.24; RER = 13.3); modest for CT quantification (HBAI: RP = 0.92; RPD = 3.71; RER = 13.1; Thiolysis: RP = 0.88; RPD = 2.80; RER = 11.5); and weak for mDP (RP = 0.66; RPD = 1.86; RER = 7.16).

Conclusions: MIR combined with chemometrics allowed to characterize the full CT profile of tree foliage rapidly, which would help to assess better plant ecology variability and to improve the nutritional management of ruminant livestock.
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http://dx.doi.org/10.1186/s13007-021-00715-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866629PMC
February 2021

The Effect of Ensiling on the Nutritional Composition and Fermentation Characteristics of Brown Seaweeds as a Ruminant Feed Ingredient.

Animals (Basel) 2020 Jun 11;10(6). Epub 2020 Jun 11.

Institute for Global Food Security, Queen's University Belfast, Belfast BT9 5DL, Northern Ireland, UK.

Ensiling could be an effective method to preserve seaweeds for animal feed applications, however, there is limited scientific knowledge in this area. Seaweeds are a promising ruminant feed ingredient, in part due to the content of phenolic compounds, which are receiving considerable interest as alternative antimicrobial agents in feed. The aim of the study was to compare the effect of ensiling on the nutritional composition and fermentation characteristics of two brown seaweed species, FV and (SL) with or without the use of a (LAB) inoculant. The effect of ensiling on the stability of phlorotannin was also investigated using nuclear magnetic resonance (NMR). After harvesting, the seaweeds were wilted for 24 h and subsequently ensiled in laboratory-scaled silos for 90 days. SL silage showed a stronger fermentation pattern (pH < 4), dominated by lactic acid (50-60 g/kg Dry Matter (DM)), and a slightly higher acetic acid content compared to FV silages ( < 0.05). The fermentability of FV was limited (pH > 4.8) with low lactic acid production (<5 g/kg DM). The addition of the LAB inoculant showed no effect on the fermentation process but a modest effect on the chemical composition of both species was observed after the 90-day ensiling period. The results showed no losses in the nutrient content of FV after ensiling, however losses in the Crude Protein (CP, -32%), ash (-36%), Neutral Detergent Fibre (NDF, -77%) and Acid Detergent Fibre (ADF, -58%) content of SL were observed. The ensiling process had a limited effect on the in vitro true dry matter digestibility and phenolic content of either species. Therefore, ensilage may be a suitable preservation method for the use of brown seaweeds as a ruminant feed; however, species-specific differences were observed.
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http://dx.doi.org/10.3390/ani10061019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341188PMC
June 2020

Impact of Thermal and High-Pressure Treatments on the Microbiological Quality and Digestibility of Black Soldier Fly () Larvae.

Animals (Basel) 2020 Apr 14;10(4). Epub 2020 Apr 14.

Institute for Global Food Security, Queen's University Belfast, Belfast BT9 5AJ, Northern Ireland, UK.

Black soldier fly larvae (BSFL) are gaining importance in animal feeding due to their ability to upcycle low-value agroindustry by-products into high-protein biomass. The present study evaluated the nutritional composition of BSFL reared on brewer's by-product (BBP) and the impact of thermal (90 °C for 10/15 min) and high-pressure processing (HPP; 400/600MPa for 1.5/10 min) treatments on the microbial levels and digestibility in both ruminant and monogastric models. BBP-reared BSFL contained a high level of protein, amino acids, lauric acid, and calcium, and high counts of total viable counts (TVC; 7.97), Enterobacteriaceae (7.65), lactic acid bacteria (LAB; 6.50), and yeasts and moulds (YM; 5.07). Thermal processing was more effective ( < 0.05) than any of the HPP treatments in reducing TVC. Both temperature of 90 °C and pressure of 600 MPa reduced the levels of Enterobacteriaceae, LAB, and YM below the detection limit. In contrast, the application of the 400 MPa showed a reduced inactivation ( < 0.05) potential. Heat-treated samples did not result in any significant changes ( > 0.05) on any of the digestibility models, whereas HPP showed increased and decreased ruminal and monogastric digestibility, respectively. HPP did not seem to be a suitable, cost-effective method as an alternative to heat-processing for the large-scale treatment of BSFL.
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http://dx.doi.org/10.3390/ani10040682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222827PMC
April 2020

Effects of sage distillation by-product (Salvia lavandulifolia Vahl.) dietary supplementation in light lambs fed on concentrates on meat shelf life and fatty acid composition.

Meat Sci 2017 Dec 10;134:44-53. Epub 2017 Jul 10.

Department of Food Science and Technology and Nutrition, Faculty of Veterinary Science, University of Murcia, Campus Espinardo, 30071 Murcia, Spain; Department of Animal Production, Faculty of Veterinary Science, University of Murcia, Campus Espinardo, 30071 Murcia, Spain. Electronic address:

Sage distillation by-product (SDB) was tested as dietary supplement in lambs for its effects on the lipid profile and meat stability. Segureño lambs from two different rearing systems (ewes grazing Mediterranean shrubland vs. ewes fed indoors on barley/lucerne) were weaned at 13kg live weight and given a basal diet (concentrate) or the SDB diet (concentrate with 100gSDBkg feed) until they reached 25kg. Intramuscular fat composition and meat stability were determined. SDB increased n-3 PUFA and polyphenol intake. It was necessary to provide an n-3 PUFA-promoting diet to both ewes (by grazing) and lambs (SDB) to increase the proportions of total PUFAs, n-3 PUFAs and CLA in meat. SDB had no antioxidant or antimicrobial effects; on the contrary, lipid oxidation, rancidity and lean discoloration were higher in retailed meat with high PUFA levels. Thus, the SDB-based diet used needs to be readjusted to ensure that meat quality is improved irrespective of the diet provided to ewes.
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http://dx.doi.org/10.1016/j.meatsci.2017.07.007DOI Listing
December 2017

Incorporating rosemary diterpenes in lamb diet to improve microbial quality of meat packed in different environments.

Anim Sci J 2017 Sep 31;88(9):1436-1445. Epub 2017 Jan 31.

Department of Food Science and Technology and Nutrition, Faculty of Veterinary Science, University of Murcia, Murcia, Spain.

The dietary use of phytochemicals may contribute to improving lamb meat preservation under different packing atmospheres. The objective was to test the preservative potential of a dietary rosemary extract (RE) containing carnosic acid and carnosol (at 1:1 w:w) in chilled lamb patties packed in air, vacuum and 70/30 O /CO modified atmosphere. Three experimental diets, (C) control, (RE) C plus 600 mg RE/kg feed and (E) C plus 600 mg vitamin E/kg, were given to fattening lambs. Unlike the C- and E-diets, the RE-diet had a double antimicrobial and antioxidant effect on the lamb patties packed in all the environments studied. The RE-diet inhibited total viable and lactic acid bacteria and Enterobacteriaceae, but not Brochothrix thermosphacta and Pseudomonas spp. and also improved oxidative stability (measured as CIE Lab color and thiobarbituric reagent substances), appearance and odor. The E-diet had a better antioxidant effect than the RE-diet but had no antimicrobial effects. Escherichia coli and Salmonella spp. were not detected. The dietary use of RE was most suitable for preserving vacuum-packed meat, which is more exposed to spoilage by anaerobic bacteria, while the use of dietary vitamin E allowed better control of oxidation in the meat packed in a bacteriostatic and oxidizing environment.
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http://dx.doi.org/10.1111/asj.12768DOI Listing
September 2017

Impact of Brassica and Lucerne Finishing Feeds and Intramuscular Fat on Lamb Eating Quality and Flavor. A Cross-Cultural Study Using Chinese and Non-Chinese Australian Consumers.

J Agric Food Chem 2016 Sep 6;64(36):6856-68. Epub 2016 Sep 6.

Faculty of Veterinary and Agricultural Science, The University of Melbourne , Royal Parade, Parkville, VIC 3010, Australia.

Use of forage brassicas (Brassica napus) and lucerne (alfalfa; Medicago sativa) as ruminant feeds has been linked to unacceptable flavors in sheepmeat. Lambs from low and high intramuscular fat sires were allocated to one of four finishing feeds-perennial ryegrass (Lolium perenne), lucerne, and two brassica forages-for a 6 week period. Grilled loins (Longissimus thoracis et lumborum) were subjected to chemical and sensory analysis by a trained panel and also evaluated by non-Chinese and Chinese background Australian consumers. Consumer liking was similar for both groups, and liking was highest for the brassica- and lucerne-finished lamb, especially from high intramuscular fat sires. No evidence of a distinctive lucerne- or brassica-induced flavor taint was measured by the trained panel or gas chromatography-mass spectrometry-olfactometry. The diets influenced the composition of lipids and branched-chain fatty acids in the subcutaneous fat, and the concentration of total branched-chain fatty acids was positively correlated with flavor and overall liking. Significantly higher levels of key aroma volatiles were measured in the higher fat samples.
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http://dx.doi.org/10.1021/acs.jafc.6b02018DOI Listing
September 2016

Relationship between antioxidant status and oxidative stability in lamb meat reinforced with dietary rosemary diterpenes.

Food Chem 2016 Jan 20;190:1056-1063. Epub 2015 Jun 20.

Department of Food Science and Technology and Nutrition, Faculty of Veterinary Science, University of Murcia, Espinardo 30071, Murcia, Spain. Electronic address:

The relationship between the antioxidant status of fresh meat and oxidative stability of chilled-packed meat obtained from lambs fed on a diet supplemented with two different doses of a rosemary extract containing carnosic acid and carnosol was studied. The incorporation of rosemary extract in the lamb diet led to the deposition of functional levels of the diterpenic metabolite C19H22O3 in meat, which improved its stability against oxidation. The antioxidant status could be assessed through both the radical scavenging capacity (DPPH and TEAC) and the ferric reducing antioxidant power (FRAP). In general, antioxidant status values correlated better (P < 0.05) with the changes in CIELAB colour, malondialdehyde and sensory scoring than with the changes in hexanal and protein carboxylation measured in the lamb cuts kept under protective atmosphere for up to 14 days. The FRAP and DPPH assays were more suitable than the TEAC assay for predicting meat oxidation and any resulting discolouration and rancidity.
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http://dx.doi.org/10.1016/j.foodchem.2015.06.060DOI Listing
January 2016

Antioxidant and antimicrobial effects of dietary supplementation with rosemary diterpenes (carnosic acid and carnosol) vs vitamin E on lamb meat packed under protective atmosphere.

Meat Sci 2015 Dec 12;110:62-9. Epub 2015 Jul 12.

Department of Food Science and Technology and Nutrition, Faculty of Veterinary Science, University of Murcia, Espinardo, 30071 Murcia, Spain. Electronic address:

The antioxidant and antimicrobial effects on lamb meat of the dietary use of rosemary diterpenes and vitamin E were compared. Thirty fattening lambs were assigned to three diets: (C) control; (R) C plus 600 mg kg(-1) carnosic acid and carnosol at 1:1 w:w; or (E) C plus 600 mg kg(-1) α-tocopherol. The deposition of the dietary supplements in the muscle was determined. Microbial quality (total viable counts, Lactic Acid Bacteria, Enterobacteriaceae, Escherichia coli and Salmonella spp), oxidative stability (CIELab color, malondialdehyde and total carbonyls) and sensory attributes (appearance and odor) were determined in loin stored at 2°C under 70% O2/30% CO2 atmosphere. Microbial quality was ensured by packaging and chilling. The E-diet was more effective (P ≤ 0.05) than the R-diet in preventing meat oxidation, although the latter had antimicrobial effects on meat. The shelf life of lamb (assessed as the loss of freshness) could be increased by 5 (R-diet) or 10 (E-diet) days.
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http://dx.doi.org/10.1016/j.meatsci.2015.07.011DOI Listing
December 2015

Single-Dose, Randomized, Open-Label, Two-Way, Crossover Bioequivalence Study of Two Formulations of Pregabalin 300 mg Hard Capsules in Healthy Volunteers Under Fasting Conditions.

Drugs R D 2015 Jun;15(2):195-201

Medical Department, Tecnimede, Sociedade Técnico-Medicinal, S.A., Zona Industrial da Abrunheira, Rua da Tapada Grande, No. 2 Abrunheira, 2710-089, Sintra, Portugal,

Aims: This bioequivalence study was conducted to assess the bioequivalence of two formulations, test and reference, of pregabalin 300 mg hard capsules, under fasting conditions.

Methods: This was a single-center, randomized, single-dose, open-label, laboratory-blinded, two-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected prior to and up to 36 h after dosing. Pregabalin plasma concentrations were determined, using a validated method, by reversed phase high performance liquid chromatography coupled to a tandem mass spectrometry detector (LC-MS-MS). Pharmacokinetic metrics used for bioequivalence assessment were the AUC(0-t) (area under the plasma concentration-time curve from time zero to time of last observed non-zero plasma concentration) and the C max (maximum observed plasma concentration). These parameters were determined from the pregabalin plasma concentration data using noncompartmental analysis.

Results: Forty healthy subjects, age ranging from 18 to 43 years old, were enrolled and randomized, of whom 39 completed the study. The ratio of geometric least square means for C max was 99.29 % (90 % confidence interval [CI] 93.29-105.67). The ratio of geometric least square means for AUC(0-t) was 101.54 % (90 % CI 100.13-102.98). The 90 % CIs were within the predefined range (80.00-125.00).

Conclusions: Bioequivalence between test and reference formulations, under fasting conditions, was concluded both in terms of rate and extent of absorption.
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http://dx.doi.org/10.1007/s40268-015-0094-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488182PMC
June 2015

8th GCC: consolidated feedback to US FDA on the 2013 draft FDA guidance on bioanalytical method validation.

Bioanalysis 2014 ;6(22):2957-63

Covance Laboratories, Chantilly, VA, USA.

The 8th GCC Closed Forum for Bioanalysis was held in Baltimore, MD, USA on 5 December 2013, immediately following the 2013 AAPS Workshop (Crystal City V): Quantitative Bioanalytical Methods Validation and Implementation--The 2013 Revised FDA Guidance. This GCC meeting was organized to discuss the contents of the draft revised FDA Guidance on bioanalytical method validation that was published in September 2013 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants, from seven countries, representing 46 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the draft FDA Guidance, and to build unified comments to be provided to the FDA.
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http://dx.doi.org/10.4155/bio.14.287DOI Listing
July 2015

Improving the sensory and oxidative stability of cooked and chill-stored lamb using dietary rosemary diterpenes.

J Food Sci 2014 Sep 20;79(9):S1805-10. Epub 2014 Aug 20.

Dept. of Food Science and Technology and Nutrition, Faculty of Veterinary Science, Univ. of Murcia, Espinardo, 30071, Murcia, Spain.

Two dietary rosemary extracts (DREs) containing diterpenes (carnosic acid and carnosol at 1:1 and 2:1 w:w) were tested in fattening lambs to stabilize the sensory quality of cooked and chill-stored patties. A total of 63 lambs were fed freely for 80 ± 5 d with a basal diet supplemented or not with DRE. Minced leg meat from each lamb was used to make patty batches. The patties were cooked at 72 ºC for 2 min, aerobically packed, kept at 2 ºC for up to 4 d and then reheated. Sensory traits (color, odor, flavor, and texture), CIELab color, and lipid oxidation (assessed as TBARS) were determined. In a first experiment, the lamb diet was supplemented with 600 mg of 1:1-DRE or 2:1-DRE kg(-1) feed. The 1:1-DRE diet delayed discoloration, flavor deterioration, and rancidity, while the 2:1-DRE diet was ineffective in this respect. In a second experiment, 4 supplementation levels of 1:1-DRE (0, 200, 400, and 600 mg kg(-1) feed) were compared. Flavor deterioration was delayed when the lamb diet was supplemented with at least 400 mg 1:1-DRE kg(-1) feed. The effects of the diet on the odor, flavor, and color were corroborated by differences in TBARS and CIELab. The results obtained suggest that rosemary diterpenes and/or their active secondary compounds deposited in muscle can act as endogenous antioxidants in cooked lamb. The carnosol intake seems crucial in the antioxidant actions achieved through DRE. The use of rosemary antioxidants in animal feeding would allow meat-based dishes to be preserved longer without adding preservatives.
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http://dx.doi.org/10.1111/1750-3841.12585DOI Listing
September 2014

Shelf life of meat from lambs given essential oil-free rosemary extract containing carnosic acid plus carnosol at 200 or 400 mg kg⁻¹.

Meat Sci 2014 Apr 1;96(4):1452-9. Epub 2013 Dec 1.

Department of Food Science and Technology and Nutrition, Faculty of Veterinary Science, University of Murcia, Espinardo, 30071 Murcia, Spain. Electronic address:

The use of dietary rosemary extract (DRE) at low doses is proposed as a nutritional strategy to improve meat preservation. Lamb diet was supplemented with 0, 200 or 400mg DRE (containing carnosic acid and carnosol at 1:1 w:w) per kg feed during the fattening stage. Meat quality was evaluated in lamb fillets packed under protective atmosphere and kept in retail conditions for up to 14 days. The effects of diet and storage time were determined on different physical-chemical (L*a*b* color, pH, TBARS, protein oxidation and volatiles from lipid oxidation), microbial (total viable and psychrophilic bacteria, Enterobacteriaceae, molds and yeasts) and sensory (appearance and odor) characteristics of the meat. The antioxidant and antimicrobial effects of DRE on meat were demonstrated. DRE delayed lean and fat discoloration, lipid oxidation, odor deterioration and microbial spoilage, extending the shelf life time of fillets from around 9 to 13 days. Both DRE doses provided similar shelf life extension.
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http://dx.doi.org/10.1016/j.meatsci.2013.11.021DOI Listing
April 2014

Bioequivalence studies of two different film-coated tablet formulations of valacyclovir of two different strengths in healthy volunteers.

Arzneimittelforschung 2010 ;60(5):273-81

Medical Department, Grupo Tecnimede, Sintra, Portugal.

These studies were conducted in order to assess the bioequivalence of two film-coated formulations containing 250 mg and 1000 mg of valacyclovir (INN: valaciclovir; CAS 124832-26-4), which is the L-valyl ester and a pro-drug of the antiviral drug acyclovir (INN: aciclovir). In the study with valacyclovir 250 mg, 36 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 10 days. In the study with valacyclovir 1000 mg, 46 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 7 days. Plasma samples were collected up to 36 h postdose for both studies. Valacyclovir levels were determined by liquid chromatography with tandem mass detection (ie, the LC/MS/MS method) (lower limit of quantification: 0.50 ng/ mL for valacyclovir and 9.93 ng/mL for acyclovir for the 250 mg study and 1.00 ng/mL for valacyclovir and 20.00 ng/ mL for acyclovir for the 1000 mg study). Pharmacokinetic parameters used for bioequivalence assessment were the area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(0-t)) and from time zero to infinity (AUC(0-inf) and maximum observed concentration (C(max)). These parameters were determined from the valacyclovir concentration data using non-compartmental analysis. In the tained by analysis of variance (ANOVA) for valacyclovir were 107.54-124.26% for C(max), 95.45-103.46% for AUC(0-Inf) and 95.53-103.63% for AUC(0-t) whereas for acyclovir the 90% confidence intervals obtained were 103.19-117.02% for C(max), 99.61-106.92% for AUC(0-Inf) and 99.58-106.94% for AUC(0-t). In the study with valacyclovir 1000 mg formulations, the 90% confidence intervals obtained for valacyclovir were 93.20-107.35% for C(max), 90.87-96.27% for AUC(0-inf) and 90.87-96.27% for AUC(0-t) whereas for acyclovir the 90% CIs obtained were 95.98-104.94% for C(max), 97.13-103.94% for AUC(0-inf) and 97.14-104.09% for AUC(0-t). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined range (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.
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http://dx.doi.org/10.1055/s-0031-1296285DOI Listing
July 2010

Mycophenolate mofetil 500-mg tablet under fasting conditions: single-dose, randomized-sequence, open-label, four-way replicate crossover, bioequivalence study in healthy subjects.

Clin Ther 2010 Mar;32(3):556-74

Medical Department, Grupo Tecnimede, Sociedade Tecnico-Medicinal S.A., Sintra, Portugal.

Background: Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an immunosuppressive agent indicated for the prophylaxis of organ rejection in allogeneic kidney, heart, or liver transplant recipients. The European regulatory authorities require bioequivalence studies for the marketing of generic products.

Objective: The aim of this study was to assess the bioequivalence of a generic (test) and branded (reference) formulation of MMF 500 mg and MPA.

Methods: This single-center, single-dose, randomized, open-label, 4-way crossover study was conducted at Anapharm's Clinical Research Facility, Québec, Québec, Canada. Healthy volunteers aged 18 to 55 years were eligible. Subjects were assigned to receive, in randomized order, a single dose of the test and reference formulations of MMF 500 mg under fasting conditions. Because the study design was 4-way replicate, there were 2 test periods and 2 reference periods. The 4 study periods were each separated by a 14-day washout period. Blood samples were collected over a period of 12 hours after administration for the determination of MMF pharmacokinetic properties, and over 48 (+/-0.5) hours, for MPA properties. Concentrations of the analytes were determined by reverse LC and detected using LC-MS/MS. Pharmacokinetic parameters were calculated from MMF and MPA concentration data using noncompartmental analysis. C(max) and AUC(0-t) were the primary evaluation criteria, while AUC(0-infinity) was a secondary parameter. The drugs were to be considered bioequivalent if the 90% CIs for the test/reference ratios of natural logarithm-transformed values of these parameters (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored using physical examination, including vital sign measurements, laboratory analysis, and adverse-events (AE) monitoring (including patient interview).

Results: A total of 103 subjects were enrolled (64 men, 39 women; 101 white, 2 black; mean [SD] age, 38 [10] years; weight, 68.2 [9.1] kg). The 90% CIs were as follows: MMF, C(max), 85.94% to 106.63%; AUC(0-t), 91.94% to 102.20%; and AUC(0-infinity), 93.15% to 105.48%; MPA, C(max), 92.03% to 105.82%; AUC(0-t), 97.42% to 100.59%; and AUC(0-infinity), 96.96% to 100.90%. These values met with the regulatory definition of bioequivalence. A total of 148 AEs were reported (68 in subjects who received the test treatment and 80 in subjects who received the reference treatment). The most commonly reported AEs were procedural pain (13/102 [12.7%] and 10/101 [9.9%] with the test and reference formulations, respectively), procedural site reaction (12 [11.8%] and 4 [4.0%]), and somnolence (7 [6.9%] and 14 [13.9%]).

Conclusions: The generic and branded formulations of MMF 500 mg met the European regulatory criteria for assuming bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated in these healthy volunteers.
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http://dx.doi.org/10.1016/j.clinthera.2010.03.008DOI Listing
March 2010

Bioequivalence study of two letrozole tablet formulations. Single dose, randomized, open-label, two-way crossover bioequivalence study of letrozole 2.5 mg tablets in healthy volunteers under fasting conditions.

Arzneimittelforschung 2008 ;58(8):419-22

Medical Department, Grupo Tecnimede, Prior Velho, Portugal.

The study was conducted in order to compare the bioavailability of two tablet formulations containing letrozole 2.5 mg (CAS 112809-51-5). Twenty healthy subjects were enrolled in a single-centre, bioequivalence, randomised, single-dose, open-label, two-way crossover study, performed under fasting conditions with a minimum washout period of 21 days. Plasma samples were collected up to 240 h post-dosing. Letrozole levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC/MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(0-t)) and from time zero to infinitive (AUC(0-inf)) and maximum observed concentration (Cmax), were determined from the letrozole concentration data using non-compartmental analysis. The 90% confidence intervals obtained by analysis of variance were 90% geometric confidence Intervals of the ratio (A/B) of least-squares means from the analysis of variance (ANOVA) of the In-transformed AUC(0-t), and Cmax was within 80% to 125%. Bloequivalence between formulations was concluded both in terms of rate and extent of absorption.
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http://dx.doi.org/10.1055/s-0031-1296530DOI Listing
October 2008

Bioequivalence study of two different film-coated tablet formulations of losartan-hydrochlorothiazide in healthy volunteers.

Arzneimittelforschung 2008 ;58(8):369-75

Medical Department, Grupo Tecnimede, Prior Velho, Portugal.

The study was conducted in order to assess the bioequivalence of two film-coated formulations containing 100 mg of losartan (CAS 124750-99-8) and 12.5 mg of hydrochlorothiazide (CAS 58-93-5). Seventy-three healthy subjects were enrolled in a randomised, single-dose, open-label, two-way crossover study, with a minimum washout period of 7 days. A total of 21 blood samples were collected up to 36 h post-dosing. Losartan, losartan carboxy acid and hydrochlorothiazide levels were determined by liquid chromatography with tandem mass detection (lower limit of quantification: 1.01 ng/mL for hydrochlorothiazide, 2.02 ng/mL for losartan and 2.51 ng/mL for losartan carboxy acid). Pharmacokinetic parameters used for bioequivalence assessment (AUC(0-t) and Cmax as primary and AUC(0-inf) as secondary pharmacokinetic parameters) were determined from the losartan and hydrochlorothiazide concentration data using non-compartmental analysis. Data from losartan carboxy acid was reported and presented as supportive data. The 90% confidence intervals (obtained by ANOVA) for losartan were 97.05-118.48% for Cmax 100.76-106.10% for AUC(0-t) and 100.80-106.10% for AUC(0-inf) whereas for hydrochlorothiazide the 90% confidence intervals obtained were 103.94-115.33% for Cmax, 101.97-109.61% for AUC(0-t) and 101.77-109.02% for AUC(0-inf), and for losartan carboxy acid the intervals obtained were 98.31-107.82% for Cmax, 97.89-104.30% for AUC(0-t) and 98.06-104.30% for AUC(0-inf). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined ranges (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.
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http://dx.doi.org/10.1055/s-0031-1296523DOI Listing
October 2008

Evaluation of RNA isolation procedures from human blood and its application for gene expression studies (Sod-1, Sod-2).

Anal Biochem 2005 Dec 3;347(1):156-8. Epub 2005 Aug 3.

Pharmacology Research Unit, Institut Municipal d'Investigació Médica, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.ab.2005.07.007DOI Listing
December 2005

MDMA (ecstasy) pharmacokinetics in a CYP2D6 poor metaboliser and in nine CYP2D6 extensive metabolisers.

Eur J Clin Pharmacol 2005 Aug 23;61(7):551-4. Epub 2005 Jul 23.

Pharmacology Unit, Institut Municipal d'Investigació Mèdica (IMIM), Doctor Aiguader 80, 08003 Barcelona, Spain.

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http://dx.doi.org/10.1007/s00228-005-0965-yDOI Listing
August 2005

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

Clin Pharmacokinet 2005 ;44(6):649-60

Pharmacology Research Unit, Barcelona, Spain.

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.
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http://dx.doi.org/10.2165/00003088-200544060-00006DOI Listing
August 2005

The rewarding properties of MDMA are preserved in mice lacking mu-opioid receptors.

Eur J Neurosci 2004 Aug;20(3):853-8

Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, c/Dr Aiguader 80, 08003 Barcelona, Spain.

The involvement of mu-opioid receptors in the rewarding properties of MDMA was explored in mu-opioid receptor knockout mice using the conditioning place preference paradigm. The associated release of dopamine in the nucleus accumbens was investigated by in vivo microdialysis. A significant rewarding effect of MDMA (10 mg/kg, i.p.) was observed in both wild-type and mu-opioid receptor knockout mice. MDMA (10 mg/kg, i.p.) also induced similar increases in dopamine and decreases in 3,4-dihydroxyphenylacetic acid and homovanillic acid in the nucleus accumbens dialysates of both wild-type and mu-opioid receptor knockout mice. No significant differences in basal levels of dopamine, 3,4-dihydroxyphenylacetic or homovanillic acids between wild-type and mu-opioid receptor knockout mice were observed. In summary, the present results suggest that, in contrast to what has been reported for other drugs of abuse such as opioids, ethanol, nicotine and Delta(9)-tetrahydrocannabinol, mu-opioid receptors do not play a major role in the rewarding properties of MDMA. These differences could be due to distinct mechanisms controlling dopamine release in the nucleus accumbens and suggest that the effects of MDMA on dopaminergic neurons are independent of micro -opioid receptors.
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http://dx.doi.org/10.1111/j.1460-9568.2004.03532.xDOI Listing
August 2004

Paroxetine inhibits acute effects of 3,4-methylenedioxymethamphetamine on the immune system in humans.

J Pharmacol Exp Ther 2004 Apr 13;309(1):285-92. Epub 2004 Jan 13.

Istituto Superiore di Sanità, Rome, Italy.

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.
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http://dx.doi.org/10.1124/jpet.103.061374DOI Listing
April 2004

Usefulness of sweat testing for the detection of MDMA after a single-dose administration.

J Anal Toxicol 2003 Jul-Aug;27(5):294-303

Istituto Superiore di Sanità, Roma, Italy.

Nine healthy male subjects and recreational users of 3,4-methylenedioxymethamphetamine (MDMA) participated in a study aimed to assess the usefulness of sweat testing for the detection of MDMA after a single 100-mg dose. Sweat was collected for up to 24 h with the PharmChek sweat patches from which drugs were eluted and then analyzed by immunoassay and gas chromatography-mass spectrometry using deuterated internal standards. The usefulness of a rapid onsite test, the Drugwipe immunochemical strip test, was also assessed. In the sweat patches, MDMA was detected as early as 1.5 h after consumption and peaked at 24 h. Intersubject variability was large; peak MDMA concentrations for the same dose varied in magnitude 30-fold. MDMA concentrations ranged between 3.2 and 1326.1 ng/patch. Only traces of the minor metabolite 3,4-methylenedioxyamphetamine were detected. In all subjects, the onsite test with the Drugwipe was positive at 1.5 h (peak time of MDMA plasma concentration). However, few false-negative results (18%) appeared in the first 6 h after administration. Both sweat patch testing and the onsite sweat strip test may find useful application for noninvasive monitoring of MDMA abuse in sweat.
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http://dx.doi.org/10.1093/jat/27.5.294DOI Listing
July 2004

Quantitative determination of paroxetine and its 4-hydroxy-3-methoxy metabolite in plasma by high-performance liquid chromatography/electrospray ion trap mass spectrometry: application to pharmacokinetic studies.

Rapid Commun Mass Spectrom 2003 ;17(13):1455-61

Institut Municipal d'Investigació Mèdica (IMIM), Barcelona, Spain.

A high-performance liquid chromatography (HPLC) method with tandem mass spectrometric detection is described for the determination of paroxetine, an antidepressant drug, and its metabolite (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine (HM paroxetine) in human plasma. Plasma samples were hydrolysed with hydrochloric acid and then analytes were extracted with ethyl acetate at alkaline pH. Extracts were analysed by HPLC coupled to an atmospheric pressure ionisation-electrospray (ESI) interface and an ion trap mass spectrometer. Chromatography was performed on a reversed-phase column using acetonitrile/0.02% formic acid (66:34, v/v) as a mobile phase. The mass spectrometer was operated in the multiple reaction monitoring mode. The method was validated over concentration ranges of 0.75-100 microg/L and 5-100 microg/L for paroxetine and HM paroxetine, respectively. Mean recoveries of 77% for paroxetine and 76% for HM paroxetine were found, with precision always better than 15%. The limits of detection and quantification were 0.20 and 0.70 microg/L for paroxetine, and 0.70 and 2.20 microg/L for its metabolite. The method was applied to the analysis of plasma samples obtained from nine healthy male volunteers administered with a single oral dose of 20 mg paroxetine. After the 20-mg dose, the mean peak plasma concentration was 8.60 microg/L for paroxetine and 92.40 microg/L for HM paroxetine showing a tenfold ratio between the metabolite and the parent drug along the entire time-concentration curve.
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http://dx.doi.org/10.1002/rcm.1067DOI Listing
September 2003

Hydroxytyrosol disposition in humans.

Clin Chem 2003 Jun;49(6 Pt 1):945-52

Unitat de Farmacologia de l'Institut Municipal d'Investigació Mèdica (URAF-IMIM), Doctor Aiguader No. 80, 08003 Barcelona, Spain.

Background: Animal and in vitro studies suggest that phenolic compounds in virgin olive oil are effective antioxidants. In animal and in vitro studies, hydroxytyrosol and its metabolites have been shown to be strong antioxidants. One of the prerequisites to assess their in vivo physiologic significance is to determine their presence in human plasma.

Methods: We developed an analytical method for both hydroxytyrosol and 3-O-methyl-hydroxytyrosol in plasma. The administered dose of phenolic compounds was estimated from methanolic extracts of virgin olive oil after subjecting them to different hydrolytic treatments. Plasma and urine samples were collected from 0 to 12 h before and after 25 mL of virgin olive oil intake, a dose close to that used as daily intake in Mediterranean countries. Samples were analyzed by capillary gas chromatography-mass spectrometry before and after being subjected to acidic and enzymatic hydrolytic treatments.

Results: Calibration curves were linear (r >0.99). Analytical recoveries were 42-60%. Limits of quantification were <1.5 mg/L. Plasma hydroxytyrosol and 3-O-methyl-hydroxytyrosol increased as a response to virgin olive oil administration, reaching maximum concentrations at 32 and 53 min, respectively (P <0.001 for quadratic trend). The estimated hydroxytyrosol elimination half-life was 2.43 h. Free forms of these phenolic compounds were not detected in plasma samples.

Conclusions: The proposed analytical method permits quantification of hydroxytyrosol and 3-O-methyl-hydroxytyrosol in plasma after real-life doses of virgin olive oil. From our results, approximately 98% of hydroxytyrosol appears to be present in plasma and urine in conjugated forms, mainly glucuronoconjugates, suggesting extensive first-pass intestinal/hepatic metabolism of the ingested hydroxytyrosol.
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http://dx.doi.org/10.1373/49.6.945DOI Listing
June 2003

Determination of N,N-dimethyltryptamine and beta-carboline alkaloids in human plasma following oral administration of Ayahuasca.

J Chromatogr B Analyt Technol Biomed Life Sci 2002 Nov;779(2):271-81

Area d'Investigació Farmacològica, Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Departament de Farmacologia i Terapèutica, Universitat Autònoma de Barcelona, St. Antoni Maria Claret, 167, Barcelona 08025, Spain.

Ayahuasca is a South American psychotropic beverage prepared from plants native to the Amazon River Basin. It combines the hallucinogenic agent and 5-HT(2A/2C) agonist N,N-dimethyltryptamine (DMT) with beta-carboline alkaloids showing monoamine oxidase-inhibiting properties. In the present paper, an analytical methodology for the plasma quantification of the four main alkaloids present in ayahuasca plus two major metabolites is described. DMT was extracted by liquid-liquid extraction with n-pentane and quantified by gas chromatography with nitrogen-phosphorus detection. Recovery was 74%, and precision and accuracy were better than 9.9%. The limit of quantification (LOQ) was 1.6 ng/ml. Harmine, harmaline, and tetrahydroharmine (THH), the three main beta-carbolines present in ayahuasca, and harmol and harmalol (O-demethylation metabolites of harmine and harmaline, respectively) were measured in plasma by means of high-performance liquid chromatography (HPLC) with fluorescence detection. Sample preparation was accomplished by solid-phase extraction, which facilitated the automation of the process. All five beta-carbolines were measured using a single detector by switching wavelengths. Separation of harmol and harmalol required only slight changes in the chromatographic conditions. Method validation demonstrated good recoveries, above 87%, and accuracy and precision better than 13.4%. The LOQ was 0.5 ng/ml for harmine, 0.3 ng/ml for harmaline, 1.0 ng/ml for THH, and 0.3 ng/ml for harmol and harmalol. Good linearity was observed in the concentration ranges evaluated for DMT (2.5-50 ng/ml) and the beta-carbolines (0.3-100 ng/ml). The gas chromatography and HPLC methods described allowed adequate characterization of the pharmacokinetics of the four main alkaloids present in ayahuasca, and also of two major beta-carboline metabolites not previously described in the literature.
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http://dx.doi.org/10.1016/s1570-0232(02)00397-5DOI Listing
November 2002

Determination of MDMA and its metabolites in blood and urine by gas chromatography-mass spectrometry and analysis of enantiomers by capillary electrophoresis.

J Anal Toxicol 2002 Apr;26(3):157-65

Pharmacology Research Unit, Institut Municipal d'Investigació Mèdica (IMIM), Barcelona, Spain.

A gas chromatography-mass spectrometry (GC-MS) method was used for the simultaneous quantitation of 3,4-methylenedioxymethamphetamine (MDMA) and the 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) metabolites in plasma and urine samples after the administration of 100 mg MDMA to healthy volunteers. Samples were hydrolyzed prior to a solid-phase extraction with Bond Elut Certify columns. Analytes were eluted with ethyl acetate (2% ammonium hydroxide) and analyzed as their trifluoroacyl derivatives. Linear calibration curves were obtained at plasma and urine concentration ranges of 25-400 ng/mL and 250-2000 ng/mL for MDMA and HMMA, and of 2.5-40 ng/mL and 100-1000 ng/mL for MDA and HMA. Following the same urine preparation procedure but without the derivatization step, a capillary electrophoresis (CE) method for enantiomerical resolution of compounds was developed using (2-hydroxy)propyl-beta-cyclodextrin at two different concentrations (10 and 50mM in 50mM H3PO4, pH 2.5) as chiral selector. Calibration curves for the CE method were prepared with the corresponding racemic mixture and were linear between 125 and 2000 ng/mL, 50 and 1000 ng/mL, and 125 and 1500 ng/mL for each enantiomer of MDMA, MDA, and HMMA, respectively. Stereoselective disposition of MDMA and MDA was confirmed. HMMA disposition seems to be in apparent contradiction with MDMA findings as the enantiomer ratio is close to 1 and constant over the time.
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http://dx.doi.org/10.1093/jat/26.3.157DOI Listing
April 2002

3,4-Methylenedioxymethamphetamine (ecstasy) and alcohol interactions in humans: psychomotor performance, subjective effects, and pharmacokinetics.

J Pharmacol Exp Ther 2002 Jan;300(1):236-44

Unit of Pharmacology, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Barcelona, Spain.

3,4-Methylenedioxymethamphetamine (MDMA) is frequently consumed in association with alcohol. The effect of this combination in humans has not been previously investigated. Nine male healthy volunteers received single oral doses of 100 mg of MDMA plus 0.8 g/kg ethanol, 100 mg of MDMA, 0.8 g/kg of ethanol, and placebo in a double blind, double dummy, randomized crossover trial. Measurements included psychomotor performance, subjective effects, and pharmacokinetics. Plasma concentrations of MDMA showed a 13% increase after the use of alcohol, whereas plasma concentrations of alcohol showed a 9 to 15% decrease after MDMA administration. The MDMA-alcohol combination induced longer lasting euphoria and well being than MDMA or alcohol alone. MDMA reversed the subjective sedation induced by alcohol but did not reduce drunkenness feelings. MDMA did not reverse the actions of alcohol on psychomotor abilities. Combined use of MDMA and alcohol causes dissociation between subjective and objective sedation. Subjects may feel euphoric and less sedated and might have the feeling of doing better, but actual performance ability continues to be impaired by the effect of alcohol. Confirmation of these findings in further studies will be highly relevant in terms of road safety.
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http://dx.doi.org/10.1124/jpet.300.1.236DOI Listing
January 2002