2019 |
Dinis-Oliveira, R J Metabolism and metabolomics of opiates: A long way of forensic implications to unravel Journal Article Journal of Forensic and Legal Medicine, 61 , pp. 128-140, 2019, (cited By 0). @article{Dinis-Oliveira2019128, title = {Metabolism and metabolomics of opiates: A long way of forensic implications to unravel}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85058810618&doi=10.1016%2fj.jflm.2018.12.005&partnerID=40&md5=dca05f90b5ec44a7c90eb6085e636c2b}, doi = {10.1016/j.jflm.2018.12.005}, year = {2019}, date = {2019-01-01}, journal = {Journal of Forensic and Legal Medicine}, volume = {61}, pages = {128-140}, abstract = {Opium poppy has important medical, socioeconomic, forensic and political implications. More than 80 benzylisoquinoline alkaloids have been described, many of them with relevant therapeutic properties such as morphine, codeine, papaverine and noscapine. Heroin, a semi-synthetic drug produced from morphine is a worldwide serious cause of morbidity and mortality. Heroin dependence is complex phenomenon with environmental and genetic influence, and several biomarkers of exposure have been proposed. This work aims to review the metabolism and metabolomics of opiates with particular interest on their relevance as potential clinical and forensic antemortem and postmortem biomarkers. It is known that the heroin is mainly a prodrug that is rapidly deacetylated in blood to its active metabolite, 6-acetylmorphine, which is then subsequently slowly deacetylated to morphine. Therefore, 6-acetylmorphine has been used as the main target metabolite to prove heroin abuse in clinical, but mostly in forensic routine. Nevertheless, its applicability is limited due to the reduced detection window. Therefore, morphine (and its metabolites morphine-3-glucuronide and morphine-6-glucuronide), codeine, codeine-6-glucuronide, 6-acetylcodeine, noscapine (and its metabolites meconine, desmethylmeconine, and cotarnine), papaverine (and its metabolites 6-desmethylpapaverine, hydroxypapaverine, dihydroxypapaverine, 6-desmethylpapaverine-glucuronide) and thebaine (and acetylthebaol and the non-acetylated analog thebaol) have been additionally recommended to obtain the most reliable results possible. More recently, the identification by metabolomics analysis of several endogenous compounds offered an alternative approach of significant importance to uncover toxic effects. Profound alterations in the neurotransmitters levels and energy and amino acid metabolism have been reported with l-tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetate being suggested as potential non-specific biomarkers of long-term heroin addiction. These endogenous metabolic profiles and exogenous components that together comprise the exposome will certainly help to uncover metabolic disturbances and patterns that may be associate to addiction with relevant clinical and forensic implications. © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Opium poppy has important medical, socioeconomic, forensic and political implications. More than 80 benzylisoquinoline alkaloids have been described, many of them with relevant therapeutic properties such as morphine, codeine, papaverine and noscapine. Heroin, a semi-synthetic drug produced from morphine is a worldwide serious cause of morbidity and mortality. Heroin dependence is complex phenomenon with environmental and genetic influence, and several biomarkers of exposure have been proposed. This work aims to review the metabolism and metabolomics of opiates with particular interest on their relevance as potential clinical and forensic antemortem and postmortem biomarkers. It is known that the heroin is mainly a prodrug that is rapidly deacetylated in blood to its active metabolite, 6-acetylmorphine, which is then subsequently slowly deacetylated to morphine. Therefore, 6-acetylmorphine has been used as the main target metabolite to prove heroin abuse in clinical, but mostly in forensic routine. Nevertheless, its applicability is limited due to the reduced detection window. Therefore, morphine (and its metabolites morphine-3-glucuronide and morphine-6-glucuronide), codeine, codeine-6-glucuronide, 6-acetylcodeine, noscapine (and its metabolites meconine, desmethylmeconine, and cotarnine), papaverine (and its metabolites 6-desmethylpapaverine, hydroxypapaverine, dihydroxypapaverine, 6-desmethylpapaverine-glucuronide) and thebaine (and acetylthebaol and the non-acetylated analog thebaol) have been additionally recommended to obtain the most reliable results possible. More recently, the identification by metabolomics analysis of several endogenous compounds offered an alternative approach of significant importance to uncover toxic effects. Profound alterations in the neurotransmitters levels and energy and amino acid metabolism have been reported with l-tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetate being suggested as potential non-specific biomarkers of long-term heroin addiction. These endogenous metabolic profiles and exogenous components that together comprise the exposome will certainly help to uncover metabolic disturbances and patterns that may be associate to addiction with relevant clinical and forensic implications. © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine |
Valente-Aguiar, M S; Dinis-Oliveira, R J Massive gas embolism in a child Journal Article Forensic Science, Medicine, and Pathology, 2019, (cited By 0; Article in Press). @article{Valente-Aguiar2019, title = {Massive gas embolism in a child}, author = {M S Valente-Aguiar and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85059897942&doi=10.1007%2fs12024-018-0072-x&partnerID=40&md5=7e492cf186b3773fcdbb822cf4135e10}, doi = {10.1007/s12024-018-0072-x}, year = {2019}, date = {2019-01-01}, journal = {Forensic Science, Medicine, and Pathology}, abstract = {A 16-month-old girl who was hospitalized with pneumonia and treated with antibiotics died after the nurse erroneously connected her intravenous left forearm catheter to the oxygen supply. Autopsy revealed an impressive gas embolism in the left subclavian and brachiocephalic veins, reduced crepitus and enlarged lung volume, and congestion of the meningeal vessels with some areas showing small air bubbles. Dilation of the right atrium and the right ventricle with efflux under pressure of large amounts of air bubbles were observed. The coronary arteries and veins were filled with air bubbles intercalated with segments containing blood. After exclusion of putrefactive artifacts as the source of such a large amount of gas in the body death was considered to be due to a massive air embolism. While embolisms are well recognized in adults, these cases are only infrequently encountered in forensic practice in younger decedents. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.}, note = {cited By 0; Article in Press}, keywords = {}, pubstate = {published}, tppubtype = {article} } A 16-month-old girl who was hospitalized with pneumonia and treated with antibiotics died after the nurse erroneously connected her intravenous left forearm catheter to the oxygen supply. Autopsy revealed an impressive gas embolism in the left subclavian and brachiocephalic veins, reduced crepitus and enlarged lung volume, and congestion of the meningeal vessels with some areas showing small air bubbles. Dilation of the right atrium and the right ventricle with efflux under pressure of large amounts of air bubbles were observed. The coronary arteries and veins were filled with air bubbles intercalated with segments containing blood. After exclusion of putrefactive artifacts as the source of such a large amount of gas in the body death was considered to be due to a massive air embolism. While embolisms are well recognized in adults, these cases are only infrequently encountered in forensic practice in younger decedents. © 2019, Springer Science+Business Media, LLC, part of Springer Nature. |
2018 |
Leal, S; Rocha, L; Silva, A; Faria, J; Dinis-Oliveira, R J; Sá, S I Evaluation of progressive hepatic histopathology in long-term tamoxifen therapy Journal Article Pathology Research and Practice, 214 (12), pp. 2115-2120, 2018, (cited By 1). @article{Leal20182115, title = {Evaluation of progressive hepatic histopathology in long-term tamoxifen therapy}, author = {S Leal and L Rocha and A Silva and J Faria and R J Dinis-Oliveira and S I Sá}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85054444491&doi=10.1016%2fj.prp.2018.09.030&partnerID=40&md5=54c7203c282aee7d93e0058e757c75e7}, doi = {10.1016/j.prp.2018.09.030}, year = {2018}, date = {2018-01-01}, journal = {Pathology Research and Practice}, volume = {214}, number = {12}, pages = {2115-2120}, abstract = {Tamoxifen (TAM) therapy is the better treatment for breast cancer and the drug use the prophylaxis of this disease in young premenopausal women. Yet, the effects associated with this therapy are unknown. To better understand the extension of this problem, we developed an animal model to mimic this therapy, aiming to evaluate its potential biochemical and histopathological changes in the liver. Young cycling female rats were treated with TAM for one, two and three months and toxicological biomarkers and liver histomorphometry were evaluated. Starting at two months, TAM-treatment prevented the normal age-dependent increase in body weight, without inducing changes in food intake. Serum levels of cholesterol and of the metabolic enzymes creatine kinase and aspartate aminotransferase were reduced in all TAM treatment periods. Serum levels of the metabolic enzymes alkaline phosphatase and lactate dehydrogenase were increased after the first month but returned to control levels upon 3 months of drug exposition. Moderate microvesicular steatosis, classified only at the first month of TAM treatment, was reduced afterwards. Our model showed an adaptive response of liver upon 3 months of treatment, suggesting that at the stated conditions, TAM will not promote hepatotoxicity. In this way, the present model may be useful in the study of possible key endocrine effects of TAM use and the search for better clinical outcomes. © 2018 Elsevier GmbH}, note = {cited By 1}, keywords = {}, pubstate = {published}, tppubtype = {article} } Tamoxifen (TAM) therapy is the better treatment for breast cancer and the drug use the prophylaxis of this disease in young premenopausal women. Yet, the effects associated with this therapy are unknown. To better understand the extension of this problem, we developed an animal model to mimic this therapy, aiming to evaluate its potential biochemical and histopathological changes in the liver. Young cycling female rats were treated with TAM for one, two and three months and toxicological biomarkers and liver histomorphometry were evaluated. Starting at two months, TAM-treatment prevented the normal age-dependent increase in body weight, without inducing changes in food intake. Serum levels of cholesterol and of the metabolic enzymes creatine kinase and aspartate aminotransferase were reduced in all TAM treatment periods. Serum levels of the metabolic enzymes alkaline phosphatase and lactate dehydrogenase were increased after the first month but returned to control levels upon 3 months of drug exposition. Moderate microvesicular steatosis, classified only at the first month of TAM treatment, was reduced afterwards. Our model showed an adaptive response of liver upon 3 months of treatment, suggesting that at the stated conditions, TAM will not promote hepatotoxicity. In this way, the present model may be useful in the study of possible key endocrine effects of TAM use and the search for better clinical outcomes. © 2018 Elsevier GmbH |
Mesquita, I; Ferreira, C; Barbosa, A M; Ferreira, C M; Moreira, D; Carvalho, A; Cunha, C; Rodrigues, F; Dinis-Oliveira, R J; Estaquier, J; Castro, A G; Torrado, E; Silvestre, R The impact of IL-10 dynamic modulation on host immune response against visceral leishmaniasis Journal Article Cytokine, 112 , pp. 16-20, 2018, (cited By 1). @article{Mesquita201816, title = {The impact of IL-10 dynamic modulation on host immune response against visceral leishmaniasis}, author = {I Mesquita and C Ferreira and A M Barbosa and C M Ferreira and D Moreira and A Carvalho and C Cunha and F Rodrigues and R J Dinis-Oliveira and J Estaquier and A G Castro and E Torrado and R Silvestre}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85049860664&doi=10.1016%2fj.cyto.2018.07.001&partnerID=40&md5=768554919fb627c8dec91c721701e818}, doi = {10.1016/j.cyto.2018.07.001}, year = {2018}, date = {2018-01-01}, journal = {Cytokine}, volume = {112}, pages = {16-20}, abstract = {Leishmaniasis is a vector-borne disease caused by protozoan parasites from the genus Leishmania. The most severe form of disease is visceral leishmaniasis (VL), which is fatal if left untreated. It has been demonstrated that interleukin (IL)-10, is associated with disease progression and susceptibility. In this work, we took advantage of a transgenic mouse model that expresses high levels of IL-10 upon zinc sulfate administration (pMT-10). We addressed the role of IL-10 during the initial stages of L. donovani infection by analyzing the parasite burden in the spleen and liver of the infected pMT-10 and WT mice as well as the histopathological alterations upon IL-10 induction. Furthermore, the profile of cytokines expressed by T cells was assessed. Our results demonstrate that an increase in IL-10 production has an impact early but not later after infection. This specific temporal role for IL-10-mediated susceptibility to VL is of interest. © 2018 Elsevier Ltd}, note = {cited By 1}, keywords = {}, pubstate = {published}, tppubtype = {article} } Leishmaniasis is a vector-borne disease caused by protozoan parasites from the genus Leishmania. The most severe form of disease is visceral leishmaniasis (VL), which is fatal if left untreated. It has been demonstrated that interleukin (IL)-10, is associated with disease progression and susceptibility. In this work, we took advantage of a transgenic mouse model that expresses high levels of IL-10 upon zinc sulfate administration (pMT-10). We addressed the role of IL-10 during the initial stages of L. donovani infection by analyzing the parasite burden in the spleen and liver of the infected pMT-10 and WT mice as well as the histopathological alterations upon IL-10 induction. Furthermore, the profile of cytokines expressed by T cells was assessed. Our results demonstrate that an increase in IL-10 production has an impact early but not later after infection. This specific temporal role for IL-10-mediated susceptibility to VL is of interest. © 2018 Elsevier Ltd |
Magalhães, N; Carvalho, F; Dinis-Oliveira, R J Human and experimental toxicology of diquat poisoning: Toxicokinetics, mechanisms of toxicity, clinical features, and treatment Journal Article Human and Experimental Toxicology, 37 (11), pp. 1131-1160, 2018, (cited By 0). @article{Magalhães20181131, title = {Human and experimental toxicology of diquat poisoning: Toxicokinetics, mechanisms of toxicity, clinical features, and treatment}, author = {N Magalhães and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85044614469&doi=10.1177%2f0960327118765330&partnerID=40&md5=192a10ba921c8080e6aa67f5a3026f08}, doi = {10.1177/0960327118765330}, year = {2018}, date = {2018-01-01}, journal = {Human and Experimental Toxicology}, volume = {37}, number = {11}, pages = {1131-1160}, abstract = {Diquat (1,1′-ethylene-2,2′-bipyridinium ion; DQ) is a nonselective quick-acting herbicide, which is used as contact and preharvest desiccant to control terrestrial and aquatic vegetation. Several cases of human poisoning were reported worldwide mainly due to intentional ingestion of the liquid formulations. Its toxic potential results from its ability to produce reactive oxygen and nitrogen species through redox cycling processes that can lead to oxidative stress and potentially cell death. Kidney is the main target organ due to DQ toxicokinetics and redox cycling. There is no antidote against DQ intoxications, and the efficacy of treatments currently applied is still unsatisfactory. The aim of this work was to review the most relevant human and experimental findings related to DQ, characterizing its chemistry, activity as herbicide, mechanisms of toxicity, consequences of poisoning, and potential therapeutic approaches taking into account previous experience in developing antidotes for paraquat, a more toxic bipyridinium herbicide. © The Author(s) 2018.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Diquat (1,1′-ethylene-2,2′-bipyridinium ion; DQ) is a nonselective quick-acting herbicide, which is used as contact and preharvest desiccant to control terrestrial and aquatic vegetation. Several cases of human poisoning were reported worldwide mainly due to intentional ingestion of the liquid formulations. Its toxic potential results from its ability to produce reactive oxygen and nitrogen species through redox cycling processes that can lead to oxidative stress and potentially cell death. Kidney is the main target organ due to DQ toxicokinetics and redox cycling. There is no antidote against DQ intoxications, and the efficacy of treatments currently applied is still unsatisfactory. The aim of this work was to review the most relevant human and experimental findings related to DQ, characterizing its chemistry, activity as herbicide, mechanisms of toxicity, consequences of poisoning, and potential therapeutic approaches taking into account previous experience in developing antidotes for paraquat, a more toxic bipyridinium herbicide. © The Author(s) 2018. |
Oliveira, N G; Dinis-Oliveira, R J Drugs of abuse from a different toxicological perspective: an updated review of cocaine genotoxicity Journal Article Archives of Toxicology, 92 (10), pp. 2987-3006, 2018, (cited By 0). @article{Oliveira20182987, title = {Drugs of abuse from a different toxicological perspective: an updated review of cocaine genotoxicity}, author = {N G Oliveira and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85051776075&doi=10.1007%2fs00204-018-2281-1&partnerID=40&md5=77ba2c2839a204948684a5412278af78}, doi = {10.1007/s00204-018-2281-1}, year = {2018}, date = {2018-01-01}, journal = {Archives of Toxicology}, volume = {92}, number = {10}, pages = {2987-3006}, abstract = {Cocaine is one of the most widely consumed psychoactive substances and has been recognized as a major public health concern for many years. While several aspects of the toxicology of cocaine have been thoroughly described in the literature, namely its effects on different target organs, other toxicological features should not be disregarded. In this perspective, the in vitro and in vivo genotoxic effects of cocaine, along with the genotoxicity data from human exposure, especially in the context of “crack” smoking, were reviewed. Some concerns regarding (1) the chronic abuse and forms of cocaine, (2) the role of metabolism and (3) the mode of action of cocaine were discussed. The major limitations of the experimental and human studies available were also addressed and some research gaps in this field identified. Overall, although the genotoxicity of cocaine is still a matter of discussion, this psychoactive substance exhibits a genotoxic potential that should be further considered. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Cocaine is one of the most widely consumed psychoactive substances and has been recognized as a major public health concern for many years. While several aspects of the toxicology of cocaine have been thoroughly described in the literature, namely its effects on different target organs, other toxicological features should not be disregarded. In this perspective, the in vitro and in vivo genotoxic effects of cocaine, along with the genotoxicity data from human exposure, especially in the context of “crack” smoking, were reviewed. Some concerns regarding (1) the chronic abuse and forms of cocaine, (2) the role of metabolism and (3) the mode of action of cocaine were discussed. The major limitations of the experimental and human studies available were also addressed and some research gaps in this field identified. Overall, although the genotoxicity of cocaine is still a matter of discussion, this psychoactive substance exhibits a genotoxic potential that should be further considered. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature. |
Gaifem, J; Gonçalves, L G; Dinis-Oliveira, R J; Cunha, C; Carvalho, A; Torrado, E; Rodrigues, F; Saraiva, M; Castro, A G; Silvestre, R L-threonine supplementation during colitis onset delays disease recovery Journal Article Frontiers in Physiology, 9 (SEP), 2018, (cited By 0). @article{Gaifem2018, title = {L-threonine supplementation during colitis onset delays disease recovery}, author = {J Gaifem and L G Gonçalves and R J Dinis-Oliveira and C Cunha and A Carvalho and E Torrado and F Rodrigues and M Saraiva and A G Castro and R Silvestre}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85053078274&doi=10.3389%2ffphys.2018.01247&partnerID=40&md5=83b35bc77411baeeb7cc5d5cf2cf143f}, doi = {10.3389/fphys.2018.01247}, year = {2018}, date = {2018-01-01}, journal = {Frontiers in Physiology}, volume = {9}, number = {SEP}, abstract = {Dietary nutrients have emerged as potential therapeutic adjuncts for inflammatory bowel disease (IBD) given their impact on intestinal homeostasis through the modulation of immune response, gut microbiota composition and epithelial barrier stability. Several nutrients have already been associated with a protective phenotype. Yet, there is a lack of knowledge toward the most promising ones as well as the most adequate phase of action. To unveil the most prominent therapy candidates we characterized the colon metabolic profile during colitis development. We have observed a twofold decrease in threonine levels in mice subjected to DSS-induced colitis. We then assessed the effect of threonine supplementation in the beginning of the inflammatory process (DSS + Thr) or when inflammation is already established (DSS + Thr D8). Colitis progression was similar between the treated groups and control colitic mice, yet threonine had a surprisingly detrimental effect when administered in the beginning of the disease, with mice displaying a delayed recovery when compared to control mice and mice supplemented with threonine after day 8. Although no major changes were found in their metabolic profile, DSS + Thr mice displayed altered expression in mucin-encoding genes, as well as in goblet cell counts, unveiling an impaired ability to produce mucus. Moreover, IL-22 secretion was decreased in DSS + Thr mice when compared to DSS + Thr D8 mice. Overall, these results suggest that supplementation with threonine during colitis induction impact goblet cell number and delays the recovery period. This reinforces the importance of a deeper understanding regarding threonine supplementation in IBD. © 2018 Gaifem, Gonçalves, Dinis-Oliveira, Cunha, Carvalho, Torrado, Rodrigues, Saraiva, Castro and Silvestre.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Dietary nutrients have emerged as potential therapeutic adjuncts for inflammatory bowel disease (IBD) given their impact on intestinal homeostasis through the modulation of immune response, gut microbiota composition and epithelial barrier stability. Several nutrients have already been associated with a protective phenotype. Yet, there is a lack of knowledge toward the most promising ones as well as the most adequate phase of action. To unveil the most prominent therapy candidates we characterized the colon metabolic profile during colitis development. We have observed a twofold decrease in threonine levels in mice subjected to DSS-induced colitis. We then assessed the effect of threonine supplementation in the beginning of the inflammatory process (DSS + Thr) or when inflammation is already established (DSS + Thr D8). Colitis progression was similar between the treated groups and control colitic mice, yet threonine had a surprisingly detrimental effect when administered in the beginning of the disease, with mice displaying a delayed recovery when compared to control mice and mice supplemented with threonine after day 8. Although no major changes were found in their metabolic profile, DSS + Thr mice displayed altered expression in mucin-encoding genes, as well as in goblet cell counts, unveiling an impaired ability to produce mucus. Moreover, IL-22 secretion was decreased in DSS + Thr mice when compared to DSS + Thr D8 mice. Overall, these results suggest that supplementation with threonine during colitis induction impact goblet cell number and delays the recovery period. This reinforces the importance of a deeper understanding regarding threonine supplementation in IBD. © 2018 Gaifem, Gonçalves, Dinis-Oliveira, Cunha, Carvalho, Torrado, Rodrigues, Saraiva, Castro and Silvestre. |
Martins, M J; Bravo, Roque R; Enea, M; Carmo, H; Carvalho, F; Bastos, M L; Dinis-Oliveira, R J; da Silva, Dias D Ethanol addictively enhances the in vitro cardiotoxicity of cocaine through oxidative damage, energetic deregulation, and apoptosis Journal Article Archives of Toxicology, 92 (7), pp. 2311-2325, 2018, (cited By 1). @article{Martins20182311, title = {Ethanol addictively enhances the in vitro cardiotoxicity of cocaine through oxidative damage, energetic deregulation, and apoptosis}, author = {M J Martins and R Roque Bravo and M Enea and H Carmo and F Carvalho and M L Bastos and R J Dinis-Oliveira and D Dias da Silva}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85047818632&doi=10.1007%2fs00204-018-2227-7&partnerID=40&md5=3a89dd812658943ee6dd53e61615b61d}, doi = {10.1007/s00204-018-2227-7}, year = {2018}, date = {2018-01-01}, journal = {Archives of Toxicology}, volume = {92}, number = {7}, pages = {2311-2325}, abstract = {Cocaine (COC) is frequently consumed in polydrug abuse settings, and ethanol (EtOH) is the most prominent co-abused substance. Clinical data and experimental evidence suggest that the co-administration of COC with EtOH can be more cardiotoxic than EtOH or COC alone, but information on the molecular pathways involved is scarce. Since these data are crucial to potentiate the identification of therapeutic targets to treat intoxications, we sought to (i) elucidate the type of interaction that occurs between both substances, and (ii) assess the mechanisms implicated in the cardiotoxic effects elicited by COC combined with EtOH. For this purpose, H9c2 cardiomyocytes were exposed to COC (104 µM–6.5 mM) and EtOH (977 µM–4 M), individually or combined at a molar ratio based on blood concentrations of intoxicated abusers (COC 1: EtOH 9; 206 µM–110 mM). After 24 h, cell metabolic viability was recorded by the MTT assay and mixture toxicity expectations were calculated using the independent action (IA) and concentration addition (CA) models. EtOH (EC50 305.26 mM) proved to act additively with COC (EC50 2.60 mM) to significantly increase the drug in vitro cardiotoxicity, even when both substances were combined at individually non-cytotoxic concentrations. Experimental mixture testing (EC50 19.18 ± 3.36 mM) demonstrated that the cardiotoxicity was fairly similar to that predicted by IA (EC50 22.95 mM) and CA (EC50 21.75 mM), supporting additivity. Concentration-dependent increases of intracellular ROS/RNS and GSSG, depletion of GSH and ATP, along with mitochondrial hyperpolarization and activation of intrinsic, extrinsic, and common apoptosis pathways were observed both for single and combined exposures. In general, the mixture exhibited a toxicological profile that mechanistically did not deviate from the single drugs, suggesting that interventions such as antioxidant administration might aid in the clinical treatment of this type of polydrug intoxication. In a clinical perspective, the observed additive mixture effect may reflect the increased hazards at which users of this combination are exposed to in recreational settings. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.}, note = {cited By 1}, keywords = {}, pubstate = {published}, tppubtype = {article} } Cocaine (COC) is frequently consumed in polydrug abuse settings, and ethanol (EtOH) is the most prominent co-abused substance. Clinical data and experimental evidence suggest that the co-administration of COC with EtOH can be more cardiotoxic than EtOH or COC alone, but information on the molecular pathways involved is scarce. Since these data are crucial to potentiate the identification of therapeutic targets to treat intoxications, we sought to (i) elucidate the type of interaction that occurs between both substances, and (ii) assess the mechanisms implicated in the cardiotoxic effects elicited by COC combined with EtOH. For this purpose, H9c2 cardiomyocytes were exposed to COC (104 µM–6.5 mM) and EtOH (977 µM–4 M), individually or combined at a molar ratio based on blood concentrations of intoxicated abusers (COC 1: EtOH 9; 206 µM–110 mM). After 24 h, cell metabolic viability was recorded by the MTT assay and mixture toxicity expectations were calculated using the independent action (IA) and concentration addition (CA) models. EtOH (EC50 305.26 mM) proved to act additively with COC (EC50 2.60 mM) to significantly increase the drug in vitro cardiotoxicity, even when both substances were combined at individually non-cytotoxic concentrations. Experimental mixture testing (EC50 19.18 ± 3.36 mM) demonstrated that the cardiotoxicity was fairly similar to that predicted by IA (EC50 22.95 mM) and CA (EC50 21.75 mM), supporting additivity. Concentration-dependent increases of intracellular ROS/RNS and GSSG, depletion of GSH and ATP, along with mitochondrial hyperpolarization and activation of intrinsic, extrinsic, and common apoptosis pathways were observed both for single and combined exposures. In general, the mixture exhibited a toxicological profile that mechanistically did not deviate from the single drugs, suggesting that interventions such as antioxidant administration might aid in the clinical treatment of this type of polydrug intoxication. In a clinical perspective, the observed additive mixture effect may reflect the increased hazards at which users of this combination are exposed to in recreational settings. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature. |
Guimarães, R; Rodrigues, P; Santos, A; Dinis-Oliveira, R J Acta Medica Portuguesa, 31 (6), pp. 299-302, 2018, (cited By 0). @article{Guimarães2018299, title = {Reuse of clinical records for scientific research: Legal issues related to the authorization of the holders and anonymisation [Reutilização de registos clínicos para investigação científica: Questões jurídicas relacionadas com a autorização dos titulares e a anonimização]}, author = {R Guimarães and P Rodrigues and A Santos and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85049523864&doi=10.20344%2famp.10147&partnerID=40&md5=955799e9f2aa14fdf64ae55a1cc6222a}, doi = {10.20344/amp.10147}, year = {2018}, date = {2018-01-01}, journal = {Acta Medica Portuguesa}, volume = {31}, number = {6}, pages = {299-302}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Ventura, L; Carvalho, F; Dinis-Oliveira, R J Opioids in the frame of new psychoactive substances network: A complex pharmacological and toxicological issue Journal Article Current Molecular Pharmacology, 11 (2), pp. 97-108, 2018, (cited By 4). @article{Ventura201897, title = {Opioids in the frame of new psychoactive substances network: A complex pharmacological and toxicological issue}, author = {L Ventura and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045343437&doi=10.2174%2f1874467210666170704110146&partnerID=40&md5=9a8be1afc429620f0b06f0ff9aae7deb}, doi = {10.2174/1874467210666170704110146}, year = {2018}, date = {2018-01-01}, journal = {Current Molecular Pharmacology}, volume = {11}, number = {2}, pages = {97-108}, abstract = {Background: New psychoactive substances (NPS), often referred to as “legal highs” or “de-signer drugs”, are derivatives and analogues of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse. Objective: This systematic review aims to gather the state of the art regarding chemical, molecular pharmacology and toxicological information of opioid class of NPS. Methods: Chemical, pharmacological, toxicological and clinical effects of opioid class of NPS were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Results: Within this class, fentanyl analogues are among the most frequently abused and pose several clinical concerns and therefore will be thoroughly discussed. Other opioid sub-categories of NPS frequently misused include AH-7921, MT-45, U-47700, U-50488, desomorphine, mitragynine, tramadol, tapentadol, salvinorin A and its analogue herkinorin. Conclusion: Due to inefficient monitoring techniques, as well as limited knowledge regarding the acute and long-term effects of opioids NPS, further clinical and forensic toxicological studies are required. © 2018 Bentham Science Publishers.}, note = {cited By 4}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: New psychoactive substances (NPS), often referred to as “legal highs” or “de-signer drugs”, are derivatives and analogues of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse. Objective: This systematic review aims to gather the state of the art regarding chemical, molecular pharmacology and toxicological information of opioid class of NPS. Methods: Chemical, pharmacological, toxicological and clinical effects of opioid class of NPS were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Results: Within this class, fentanyl analogues are among the most frequently abused and pose several clinical concerns and therefore will be thoroughly discussed. Other opioid sub-categories of NPS frequently misused include AH-7921, MT-45, U-47700, U-50488, desomorphine, mitragynine, tramadol, tapentadol, salvinorin A and its analogue herkinorin. Conclusion: Due to inefficient monitoring techniques, as well as limited knowledge regarding the acute and long-term effects of opioids NPS, further clinical and forensic toxicological studies are required. © 2018 Bentham Science Publishers. |
Faria, J; Barbosa, J; Moreira, R; Queirós, O; Carvalho, F; Dinis-Oliveira, R J Comparative pharmacology and toxicology of tramadol and tapentadol Journal Article European Journal of Pain (United Kingdom), 22 (5), pp. 827-844, 2018, (cited By 0). @article{Faria2018827, title = {Comparative pharmacology and toxicology of tramadol and tapentadol}, author = {J Faria and J Barbosa and R Moreira and O Queirós and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042087108&doi=10.1002%2fejp.1196&partnerID=40&md5=d30fb184f5af5c9b89138e71c92e067d}, doi = {10.1002/ejp.1196}, year = {2018}, date = {2018-01-01}, journal = {European Journal of Pain (United Kingdom)}, volume = {22}, number = {5}, pages = {827-844}, abstract = {Moderate-to-severe pain represents a heavy burden in patients’ quality of life, and ultimately in the society and in healthcare costs. The aim of this review was to summarize data on tramadol and tapentadol adverse effects, toxicity, potential advantages and limitations according to the context of clinical use. We compared data on the pharmacological and toxicological profiles of tramadol and tapentadol, after an extensive literature search in the US National Library of Medicine (PubMed). Tramadol is a prodrug that acts through noradrenaline and serotonin reuptake inhibition, with a weak opioid component added by its metabolite O-desmethyltramadol. Tapentadol does not require metabolic activation and acts mainly through noradrenaline reuptake inhibition and has a strong opioid activity. Such features confer tapentadol potential advantages, namely lower serotonergic, dependence and abuse potential, more linear pharmacokinetics, greater gastrointestinal tolerability and applicability in the treatment of chronic and neuropathic pain. Although more studies are needed to provide clear guidance on the opioid of choice, tapentadol shows some advantages, as it does not require CYP450 system activation and has minimal serotonergic effects. In addition, it leads to less side effects and lower abuse liability. However, in vivo and in vitro studies have shown that tramadol and tapentadol cause similar toxicological damage. In this context, it is important to underline that the choice of opioid should be individually balanced and a tailored decision, based on previous experience and on the patient's profile, type of pain and context of treatment. Significance: This review underlines the need for a careful prescription of tramadol and tapentadol. Although both are widely prescribed synthetic opioid analgesics, their toxic effects and potential dependence are not completely understood yet. In particular, concerning tapentadol, further research is needed to better assess its toxic effects. © 2018 European Pain Federation - EFIC®}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Moderate-to-severe pain represents a heavy burden in patients’ quality of life, and ultimately in the society and in healthcare costs. The aim of this review was to summarize data on tramadol and tapentadol adverse effects, toxicity, potential advantages and limitations according to the context of clinical use. We compared data on the pharmacological and toxicological profiles of tramadol and tapentadol, after an extensive literature search in the US National Library of Medicine (PubMed). Tramadol is a prodrug that acts through noradrenaline and serotonin reuptake inhibition, with a weak opioid component added by its metabolite O-desmethyltramadol. Tapentadol does not require metabolic activation and acts mainly through noradrenaline reuptake inhibition and has a strong opioid activity. Such features confer tapentadol potential advantages, namely lower serotonergic, dependence and abuse potential, more linear pharmacokinetics, greater gastrointestinal tolerability and applicability in the treatment of chronic and neuropathic pain. Although more studies are needed to provide clear guidance on the opioid of choice, tapentadol shows some advantages, as it does not require CYP450 system activation and has minimal serotonergic effects. In addition, it leads to less side effects and lower abuse liability. However, in vivo and in vitro studies have shown that tramadol and tapentadol cause similar toxicological damage. In this context, it is important to underline that the choice of opioid should be individually balanced and a tailored decision, based on previous experience and on the patient's profile, type of pain and context of treatment. Significance: This review underlines the need for a careful prescription of tramadol and tapentadol. Although both are widely prescribed synthetic opioid analgesics, their toxic effects and potential dependence are not completely understood yet. In particular, concerning tapentadol, further research is needed to better assess its toxic effects. © 2018 European Pain Federation - EFIC® |
Nóbrega, L; Dinis-Oliveira, R J The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP): pharmacokinetic and pharmacodynamic clinical and forensic aspects Journal Article Drug Metabolism Reviews, 50 (2), pp. 125-139, 2018, (cited By 3). @article{Nóbrega2018125, title = {The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP): pharmacokinetic and pharmacodynamic clinical and forensic aspects}, author = {L Nóbrega and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85046075069&doi=10.1080%2f03602532.2018.1448867&partnerID=40&md5=30703888122c2a3468b4933810ad2daa}, doi = {10.1080/03602532.2018.1448867}, year = {2018}, date = {2018-01-01}, journal = {Drug Metabolism Reviews}, volume = {50}, number = {2}, pages = {125-139}, abstract = {New psychoactive substances (NPS), often referred as ‘legal highs’ or ‘designer drugs’, are derivatives and analogs of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse. This work aims to review the state-of-the-art regarding chemical, molecular pharmacology, and in vitro and in vivo data on toxicokinetics of the potent synthetic cathinone α-pyrrolidinovalerophenone (α-PVP or flakka or zombie drug). Chemical, pharmacological, toxicological, and clinical effects of α-PVP were searched in PubMed (U.S. National Library of Medicine) and governmental websites without limitation of the period. α-PVP is a wide spread and easy to get special type of synthetic cathinone with seemingly powerful cocaine-like stimulant effects, high brain penetration, high liability for abuse and with increased risk of adverse effects such as tachycardia, agitation, hypertension, hallucinations, delirium, mydriasis, self-injury, aggressive behavior, and suicidal ideations. α-PVP undergoes extensive metabolism via different pathways and the α-PVP itself or its metabolites β-hydroxy-α-PVP and α-PVP lactam represent the main targets for toxicological analysis in urine. There is a limited knowledge regarding the short- and long-term effects of α-PVP and metabolites, and pharmacogenetic influence, hence further clinical and forensic toxicological studies are required. Moreover, since α-PVP cannot be detected with classic routine analysis procedures, statements on the frequency of their consumption cannot be made. © 2018 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 3}, keywords = {}, pubstate = {published}, tppubtype = {article} } New psychoactive substances (NPS), often referred as ‘legal highs’ or ‘designer drugs’, are derivatives and analogs of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse. This work aims to review the state-of-the-art regarding chemical, molecular pharmacology, and in vitro and in vivo data on toxicokinetics of the potent synthetic cathinone α-pyrrolidinovalerophenone (α-PVP or flakka or zombie drug). Chemical, pharmacological, toxicological, and clinical effects of α-PVP were searched in PubMed (U.S. National Library of Medicine) and governmental websites without limitation of the period. α-PVP is a wide spread and easy to get special type of synthetic cathinone with seemingly powerful cocaine-like stimulant effects, high brain penetration, high liability for abuse and with increased risk of adverse effects such as tachycardia, agitation, hypertension, hallucinations, delirium, mydriasis, self-injury, aggressive behavior, and suicidal ideations. α-PVP undergoes extensive metabolism via different pathways and the α-PVP itself or its metabolites β-hydroxy-α-PVP and α-PVP lactam represent the main targets for toxicological analysis in urine. There is a limited knowledge regarding the short- and long-term effects of α-PVP and metabolites, and pharmacogenetic influence, hence further clinical and forensic toxicological studies are required. Moreover, since α-PVP cannot be detected with classic routine analysis procedures, statements on the frequency of their consumption cannot be made. © 2018 Informa UK Limited, trading as Taylor & Francis Group. |
Magalhães, T P; Cravo, S; da Silva, Dias D; Dinis-Oliveira, R J; Afonso, C; de Bastos, Lourdes M; Carmo, H Quantification of methadone and main metabolites in Nails Journal Article Journal of Analytical Toxicology, 42 (3), pp. 192-206, 2018, (cited By 0). @article{Magalhães2018192, title = {Quantification of methadone and main metabolites in Nails}, author = {T P Magalhães and S Cravo and D Dias da Silva and R J Dinis-Oliveira and C Afonso and M de Lourdes Bastos and H Carmo}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045926344&doi=10.1093%2fjat%2fbkx099&partnerID=40&md5=5a0ce16cfb7738e2448816853cf46819}, doi = {10.1093/jat/bkx099}, year = {2018}, date = {2018-01-01}, journal = {Journal of Analytical Toxicology}, volume = {42}, number = {3}, pages = {192-206}, abstract = {The quantification of drugs of abuse in keratinized matrices is becoming of special relevance for monitoring consumption and for post-mortem investigations. We aimed to implement an analytical method for the simultaneous detection of morphine (MORF), 6-monoacetylmorphine (6-MAM), methadone (MET), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl- 3,3-diphenylpyrrolidine (EMDP) in nails. After decontamination, the nail samples (30 mg) were submitted to an alkaline digestion followed by a two-step liquid-liquid and SPE extraction using mixed-mode cation exchange cartridges. The analytes were eluted with 5% NH4OH/methanol. After derivatization with N-methyl-N-(trimethylsilyl) trifluoroacetamide, the analytes were quantified by gas chromatography-mass spectrometry. The method was optimized and fully validated only for MET, EDDP and EMDP, since for MOR and 6-MAM it was not possible to obtain adequate recovery rates after extraction, although detection of MOR was still possible. The method was selective, accurate and precise. Regression analysis demonstrated linearity over a concentration range of 20.8-333.3 ng/mg for MET and 10.4-166.7 ng/mg for EDDP and EMDP. Limits of detection and quantification values ranged from 3.3 to 6.0 ng/mg and 10.4 to 20.8 ng/mg, respectively, and recovery rates ranged from 82% to 98%. The applicability of the method was demonstrated by analyzing nail and urine samples obtained from heroin consumers under substitution therapy with MET. © The Author(s) 2017. Published by Oxford University Press. All rights reserved.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } The quantification of drugs of abuse in keratinized matrices is becoming of special relevance for monitoring consumption and for post-mortem investigations. We aimed to implement an analytical method for the simultaneous detection of morphine (MORF), 6-monoacetylmorphine (6-MAM), methadone (MET), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl- 3,3-diphenylpyrrolidine (EMDP) in nails. After decontamination, the nail samples (30 mg) were submitted to an alkaline digestion followed by a two-step liquid-liquid and SPE extraction using mixed-mode cation exchange cartridges. The analytes were eluted with 5% NH4OH/methanol. After derivatization with N-methyl-N-(trimethylsilyl) trifluoroacetamide, the analytes were quantified by gas chromatography-mass spectrometry. The method was optimized and fully validated only for MET, EDDP and EMDP, since for MOR and 6-MAM it was not possible to obtain adequate recovery rates after extraction, although detection of MOR was still possible. The method was selective, accurate and precise. Regression analysis demonstrated linearity over a concentration range of 20.8-333.3 ng/mg for MET and 10.4-166.7 ng/mg for EDDP and EMDP. Limits of detection and quantification values ranged from 3.3 to 6.0 ng/mg and 10.4 to 20.8 ng/mg, respectively, and recovery rates ranged from 82% to 98%. The applicability of the method was demonstrated by analyzing nail and urine samples obtained from heroin consumers under substitution therapy with MET. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. |
Dinis-Oliveira, R J Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects Journal Article BioMed Research International, 2018 , 2018, (cited By 0). @article{Dinis-Oliveira2018, title = {Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85048201148&doi=10.1155%2f2018%2f6852857&partnerID=40&md5=8001c776a2b6d74398db4a67851073b8}, doi = {10.1155/2018/6852857}, year = {2018}, date = {2018-01-01}, journal = {BioMed Research International}, volume = {2018}, abstract = {Propofol is an intravenous short-acting anesthetic widely used to induce and maintain general anesthesia and to provide procedural sedation. The potential for propofol dependency and abuse has been recognized, and several cases of accidental overdose and suicide have emerged, mostly among the health professionals. Different studies have demonstrated an unpredictable interindividual variability of propofol pharmacokinetics and pharmacodynamics with forensic and clinical adverse relevant outcomes (e.g., pronounced respiratory and cardiac depression), namely, due to polymorphisms in the UDP-glucuronosyltransferase and cytochrome P450 isoforms and drugs administered concurrently. In this work the pharmacokinetics of propofol and fospropofol with particular focus on metabolic pathways is fully reviewed. It is concluded that knowing the metabolism of propofol may lead to the development of new clues to help further toxicological and clinical interpretations and to reduce serious adverse reactions such as respiratory failure, metabolic acidosis, rhabdomyolysis, cardiac bradyarrhythmias, hypotension and myocardial failure, anaphylaxis, hypertriglyceridemia, renal failure, hepatomegaly, hepatic steatosis, acute pancreatitis, abuse, and death. Particularly, further studies aiming to characterize polymorphic enzymes involved in the metabolic pathway, the development of additional routine forensic toxicological analysis, and the relatively new field of "omics" technology, namely, metabolomics, can offer more in explaining the unpredictable interindividual variability. © 2018 Ricardo Jorge Dinis-Oliveira.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Propofol is an intravenous short-acting anesthetic widely used to induce and maintain general anesthesia and to provide procedural sedation. The potential for propofol dependency and abuse has been recognized, and several cases of accidental overdose and suicide have emerged, mostly among the health professionals. Different studies have demonstrated an unpredictable interindividual variability of propofol pharmacokinetics and pharmacodynamics with forensic and clinical adverse relevant outcomes (e.g., pronounced respiratory and cardiac depression), namely, due to polymorphisms in the UDP-glucuronosyltransferase and cytochrome P450 isoforms and drugs administered concurrently. In this work the pharmacokinetics of propofol and fospropofol with particular focus on metabolic pathways is fully reviewed. It is concluded that knowing the metabolism of propofol may lead to the development of new clues to help further toxicological and clinical interpretations and to reduce serious adverse reactions such as respiratory failure, metabolic acidosis, rhabdomyolysis, cardiac bradyarrhythmias, hypotension and myocardial failure, anaphylaxis, hypertriglyceridemia, renal failure, hepatomegaly, hepatic steatosis, acute pancreatitis, abuse, and death. Particularly, further studies aiming to characterize polymorphic enzymes involved in the metabolic pathway, the development of additional routine forensic toxicological analysis, and the relatively new field of "omics" technology, namely, metabolomics, can offer more in explaining the unpredictable interindividual variability. © 2018 Ricardo Jorge Dinis-Oliveira. |
2017 |
Dinis-Oliveira, R J Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance Journal Article 49 (1), pp. 84-91, 2017, (cited By 0). @article{Dinis-Oliveira201784, title = {Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85013339853&doi=10.1080%2f03602532.2016.1278228&partnerID=40&md5=ad936295282108d91be6cda1d3a7b08f}, doi = {10.1080/03602532.2016.1278228}, year = {2017}, date = {2017-01-01}, volume = {49}, number = {1}, pages = {84-91}, abstract = {Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the “magic mushrooms” and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis. © 2017 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the “magic mushrooms” and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis. © 2017 Informa UK Limited, trading as Taylor & Francis Group. |
Dinis-Oliveira, R J Metabolomics of Methylphenidate and Ethylphenidate: Implications in Pharmacological and Toxicological Effects Journal Article 42 (1), pp. 11-16, 2017, (cited By 0). @article{Dinis-Oliveira201711, title = {Metabolomics of Methylphenidate and Ethylphenidate: Implications in Pharmacological and Toxicological Effects}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979210469&doi=10.1007%2fs13318-016-0362-1&partnerID=40&md5=8542768b42eae9b162ec6c8091d6ab98}, doi = {10.1007/s13318-016-0362-1}, year = {2017}, date = {2017-01-01}, volume = {42}, number = {1}, pages = {11-16}, abstract = {Methylphenidate (MPH) is primarily indicated for attention-deficit hyperactivity disorder and narcolepsy therapy. A marked individual variability in the dose–response has been observed, and therefore dosage must be titrated for optimal therapeutic effect with minimal toxicity. This variability has been claimed to be predominantly pharmacokinetic. Moreover, due to its similar pharmacodynamics to amphetamine, MPH has been abused and fatalities have been reported. This review aims to discuss metabolomics of MPH, namely by presenting all major and minor metabolites. Ritalinic acid is the main metabolite. In addition, minor pathways involving aromatic hydroxylation, microsomal oxidation and conjugation have also been reported to form the p-hydroxy-, oxo- and conjugated metabolites, respectively. MPH may undergo transesterification with ethanol producing ethylphenidate, which is also pharmacologically active. It is expected that knowing the metabolomics of MPH may provide further insights regarding individual contribution for MPH pharmacodynamics and toxicological effects, namely if ethanol is co-consumed. © 2016, Springer International Publishing Switzerland.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Methylphenidate (MPH) is primarily indicated for attention-deficit hyperactivity disorder and narcolepsy therapy. A marked individual variability in the dose–response has been observed, and therefore dosage must be titrated for optimal therapeutic effect with minimal toxicity. This variability has been claimed to be predominantly pharmacokinetic. Moreover, due to its similar pharmacodynamics to amphetamine, MPH has been abused and fatalities have been reported. This review aims to discuss metabolomics of MPH, namely by presenting all major and minor metabolites. Ritalinic acid is the main metabolite. In addition, minor pathways involving aromatic hydroxylation, microsomal oxidation and conjugation have also been reported to form the p-hydroxy-, oxo- and conjugated metabolites, respectively. MPH may undergo transesterification with ethanol producing ethylphenidate, which is also pharmacologically active. It is expected that knowing the metabolomics of MPH may provide further insights regarding individual contribution for MPH pharmacodynamics and toxicological effects, namely if ethanol is co-consumed. © 2016, Springer International Publishing Switzerland. |
Dinis-Oliveira, R J Metabolic profile of flunitrazepam: Clinical and forensic toxicological aspects Journal Article 11 (1), pp. 14-20, 2017, (cited By 1). @article{Dinis-Oliveira201714, title = {Metabolic profile of flunitrazepam: Clinical and forensic toxicological aspects}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85034627153&doi=10.2174%2f1872312811666170407164216&partnerID=40&md5=15754674bdb842dd419e166f9eae3009}, doi = {10.2174/1872312811666170407164216}, year = {2017}, date = {2017-01-01}, volume = {11}, number = {1}, pages = {14-20}, abstract = {Background: Flunitrazepam (FNZ) is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault led to important clinical and forensic concerns. Objective: In this work the metabolism of FNZ, and pharmacological-and toxicological-related effects, were fully reviewed. Methods: FNZ and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Results: Major metabolic pathways include N-demethylation, 3-hydroxylation, nitro-reduction, and further N-acetylation of the amino group, yielding N-desmethylflunitrazepam, 3-hydroxy-flunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam, respectively. A combination of these reactions may lead to the formation of 7-amino-N-desmethylflunitrazepam, 7-acetamido-N-desmethylflunitrazepam, 3-hydroxy-7-aminoflunitrazepam, 3-hydroxy-7-acetamidoflunitrazepam, 3-hydroxy-N-desmethylflunitrazepam and glucuronide conjugates. Genotypic variations in enzymes, interactions with other drugs or stability of FNZ during storage can result in large interindividual variability in the toxicological results. Conclusion: It is aimed that knowing the metabolism of FNZ may lead to the development of new analytical strategies for early detection, since this drug is typically present in very low concentrations in blood and urine when used to facilitate sexual assault. © 2017 Bentham Science Publishers.}, note = {cited By 1}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Flunitrazepam (FNZ) is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault led to important clinical and forensic concerns. Objective: In this work the metabolism of FNZ, and pharmacological-and toxicological-related effects, were fully reviewed. Methods: FNZ and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Results: Major metabolic pathways include N-demethylation, 3-hydroxylation, nitro-reduction, and further N-acetylation of the amino group, yielding N-desmethylflunitrazepam, 3-hydroxy-flunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam, respectively. A combination of these reactions may lead to the formation of 7-amino-N-desmethylflunitrazepam, 7-acetamido-N-desmethylflunitrazepam, 3-hydroxy-7-aminoflunitrazepam, 3-hydroxy-7-acetamidoflunitrazepam, 3-hydroxy-N-desmethylflunitrazepam and glucuronide conjugates. Genotypic variations in enzymes, interactions with other drugs or stability of FNZ during storage can result in large interindividual variability in the toxicological results. Conclusion: It is aimed that knowing the metabolism of FNZ may lead to the development of new analytical strategies for early detection, since this drug is typically present in very low concentrations in blood and urine when used to facilitate sexual assault. © 2017 Bentham Science Publishers. |
Guimarães, R; Dinis-Oliveira, R J; Pereira, A; Rodrigues, P; Santos, A 30 (3), pp. 159-162, 2017, (cited By 0). @article{Guimarães2017159, title = {Reutilization of clinical data for research: The footprint scientific model of the hospital center of São João [Reutilização de informação clínica para investigação: O modelo da pegada científica do centro hospitalar de São João]}, author = {R Guimarães and R J Dinis-Oliveira and A Pereira and P Rodrigues and A Santos}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85016711271&doi=10.20344%2famp.8592&partnerID=40&md5=58bbd725062994032e221c40a7400e87}, doi = {10.20344/amp.8592}, year = {2017}, date = {2017-01-01}, volume = {30}, number = {3}, pages = {159-162}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Alves, E A; Agonia, A S; Cravo, S M; Afonso, C M; Netto, A D P; de Bastos, Lourdes M; Carvalho, F; Dinis-Oliveira, R J GC-MS method for the analysis of thirteen opioids, cocaine and cocaethylene in whole blood based on a modified quechers extraction Journal Article 13 (3), pp. 215-223, 2017, (cited By 1). @article{Alves2017215, title = {GC-MS method for the analysis of thirteen opioids, cocaine and cocaethylene in whole blood based on a modified quechers extraction}, author = {E A Alves and A S Agonia and S M Cravo and C M Afonso and A D P Netto and M de Lourdes Bastos and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019686660&doi=10.2174%2f1573412912666160502163846&partnerID=40&md5=bb2e4c0fae2eb5e3c6b5a4d2ff8ca48e}, doi = {10.2174/1573412912666160502163846}, year = {2017}, date = {2017-01-01}, volume = {13}, number = {3}, pages = {215-223}, abstract = {Background: QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) is a methodology previously developed to extract pesticides from vegetables and fruits and has been fully applied for different analytical approaches. Objective: In the present study, a rapid and less laborious modified QuEChERS extraction method for the quantification of 13 opioids [codeine, morphine, heroin, 6-acetylmorphine (6-AM), desomorphine, ethylmorphine, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP), papaverine, tramadol, O-desmetyltramadol (M1) and, tapentadol], cocaine and cocaethylene in whole blood was developed and validated by Gas Chromatography-Mass Spectrometry. Method: The modification of QuEChERS method consisted in the pretreatment of the whole blood samples using ultrasonication, the use of ethyl acetate as extraction solvent and a previous step of sample alcalinization. The use of dispersive separation steps such as Dispersive Solid-Phase Extraction (dSPE) or sorbents such as Primary Secondary Amine (PSA) was suppressed to minimize the errors and, to improve the velocity of the analysis. Results: The method proved to be selective and the regression analysis for the analytes was linear in the range of 31.2-2000 ng/mL with correlation coefficients > 0.98. The coefficients of variation did not exceed 15%. The lowest limit of detection and quantification for all the analytes were below the therapeutic range of the drugs. The recoveries of the analytes ranged from 52.4 to 95.0%. Conclusion: The developed method can provide a rapid, effective and “greener” process for the analysis of a wide range of opioids drugs in whole blood samples and can be applied to clinical and forensic antemortem and postmortem cases. © 2017 Bentham Science Publishers.}, note = {cited By 1}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) is a methodology previously developed to extract pesticides from vegetables and fruits and has been fully applied for different analytical approaches. Objective: In the present study, a rapid and less laborious modified QuEChERS extraction method for the quantification of 13 opioids [codeine, morphine, heroin, 6-acetylmorphine (6-AM), desomorphine, ethylmorphine, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP), papaverine, tramadol, O-desmetyltramadol (M1) and, tapentadol], cocaine and cocaethylene in whole blood was developed and validated by Gas Chromatography-Mass Spectrometry. Method: The modification of QuEChERS method consisted in the pretreatment of the whole blood samples using ultrasonication, the use of ethyl acetate as extraction solvent and a previous step of sample alcalinization. The use of dispersive separation steps such as Dispersive Solid-Phase Extraction (dSPE) or sorbents such as Primary Secondary Amine (PSA) was suppressed to minimize the errors and, to improve the velocity of the analysis. Results: The method proved to be selective and the regression analysis for the analytes was linear in the range of 31.2-2000 ng/mL with correlation coefficients > 0.98. The coefficients of variation did not exceed 15%. The lowest limit of detection and quantification for all the analytes were below the therapeutic range of the drugs. The recoveries of the analytes ranged from 52.4 to 95.0%. Conclusion: The developed method can provide a rapid, effective and “greener” process for the analysis of a wide range of opioids drugs in whole blood samples and can be applied to clinical and forensic antemortem and postmortem cases. © 2017 Bentham Science Publishers. |
Alves, E A; Brandão, P; Neves, J F; Cravo, S M; Soares, J X; Grund, J -P C; Duarte, J A; Afonso, C M M; Netto, Pereira A D; Carvalho, F; Dinis-Oliveira, R J Repeated subcutaneous administrations of krokodil causes skin necrosis and internal organs toxicity in Wistar rats: putative human implications Journal Article 32 (3), 2017, (cited By 2). @article{Alves2017b, title = {Repeated subcutaneous administrations of krokodil causes skin necrosis and internal organs toxicity in Wistar rats: putative human implications}, author = {E A Alves and P Brandão and J F Neves and S M Cravo and J X Soares and J -P C Grund and J A Duarte and C M M Afonso and A D Pereira Netto and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85021330125&doi=10.1002%2fhup.2572&partnerID=40&md5=dbb914a7a07f091db1ecc6874151737e}, doi = {10.1002/hup.2572}, year = {2017}, date = {2017-01-01}, volume = {32}, number = {3}, abstract = {Objective: “Krokodil” is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model. Methods: Animals were divided into seven groups and exposed subcutaneously to NaCl 0.9% (control), krokodil mixture free of psychotropic substances (blank krokodil), pharmaceutical grade desomorphine 1 mg/kg, and four different concentrations of krokodil (containing 0.125, 0.25, 0.5, and 1 mg/kg of desomorphine) synthesized accordingly to a “domestic” protocol followed by people who inject krokodil (PWIK). Daily injections for five consecutive days were performed, and animals were sacrificed 24 hr after the last administration. Biochemical and histological analysis were carried out. Results: It was shown that the continuous use of krokodil may cause injury at the injection area, with formation of necrotic zones. The biochemical results evidenced alterations on cardiac and renal biomarkers of toxicity, namely, creatine kinase, creatine kinase-MB, and uric acid. Significant alteration in levels of reduced and oxidized glutathione on kidney and heart suggested that oxidative stress may be involved in krokodil-mediated toxicity. Cardiac congestion was the most relevant finding of continuous krokodil administration. Conclusions: These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil. Copyright © 2017 John Wiley & Sons, Ltd.}, note = {cited By 2}, keywords = {}, pubstate = {published}, tppubtype = {article} } Objective: “Krokodil” is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model. Methods: Animals were divided into seven groups and exposed subcutaneously to NaCl 0.9% (control), krokodil mixture free of psychotropic substances (blank krokodil), pharmaceutical grade desomorphine 1 mg/kg, and four different concentrations of krokodil (containing 0.125, 0.25, 0.5, and 1 mg/kg of desomorphine) synthesized accordingly to a “domestic” protocol followed by people who inject krokodil (PWIK). Daily injections for five consecutive days were performed, and animals were sacrificed 24 hr after the last administration. Biochemical and histological analysis were carried out. Results: It was shown that the continuous use of krokodil may cause injury at the injection area, with formation of necrotic zones. The biochemical results evidenced alterations on cardiac and renal biomarkers of toxicity, namely, creatine kinase, creatine kinase-MB, and uric acid. Significant alteration in levels of reduced and oxidized glutathione on kidney and heart suggested that oxidative stress may be involved in krokodil-mediated toxicity. Cardiac congestion was the most relevant finding of continuous krokodil administration. Conclusions: These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil. Copyright © 2017 John Wiley & Sons, Ltd. |
Faria, J; Barbosa, J; Leal, S; Afonso, L P; Lobo, J; Moreira, R; Queirós, O; Carvalho, F; Dinis-Oliveira, R J Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats Journal Article 385 , pp. 38-47, 2017, (cited By 1). @article{Faria201738, title = {Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats}, author = {J Faria and J Barbosa and S Leal and L P Afonso and J Lobo and R Moreira and O Queirós and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019229989&doi=10.1016%2fj.tox.2017.05.003&partnerID=40&md5=7f4ad161a79c4b6d8f8cf0fc38f1e0b8}, doi = {10.1016/j.tox.2017.05.003}, year = {2017}, date = {2017-01-01}, volume = {385}, pages = {38-47}, abstract = {Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50 mg/kg – typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24 h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. © 2017 Elsevier B.V.}, note = {cited By 1}, keywords = {}, pubstate = {published}, tppubtype = {article} } Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50 mg/kg – typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24 h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. © 2017 Elsevier B.V. |
Barbosa, J; Faria, J; Leal, S; Afonso, L P; Lobo, J; Queirós, O; Moreira, R; Carvalho, F; Dinis-Oliveira, R J 389 , pp. 118-129, 2017, (cited By 0). @article{Barbosa2017118, title = {Acute administration of tramadol and tapentadol at effective analgesic and maximum tolerated doses causes hepato- and nephrotoxic effects in Wistar rats}, author = {J Barbosa and J Faria and S Leal and L P Afonso and J Lobo and O Queirós and R Moreira and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85021952522&doi=10.1016%2fj.tox.2017.07.001&partnerID=40&md5=488bba0a24e4e98b8587a34e517c208a}, doi = {10.1016/j.tox.2017.07.001}, year = {2017}, date = {2017-01-01}, volume = {389}, pages = {118-129}, abstract = {Tramadol and tapentadol are two atypical synthetic opioid analgesics, with monoamine reuptake inhibition properties. Mainly aimed at the treatment of moderate to severe pain, these drugs are extensively prescribed for multiple clinical applications. Along with the increase in their use, there has been an increment in their abuse, and consequently in the reported number of adverse reactions and intoxications. However, little is known about their mechanisms of toxicity. In this study, we have analyzed the in vivo toxicological effects in liver and kidney resulting from an acute exposure of a rodent animal model to both opioids. Male Wistar rats were intraperitoneally administered with 10, 25 and 50 mg/kg tramadol and tapentadol, corresponding to a low, effective analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively, for 24 h. Toxicological effects were assessed in terms of oxidative stress, biochemical and metabolic parameters and histopathology, using serum and urine samples, liver and kidney homogenates and tissue specimens. The acute exposure to tapentadol caused a dose-dependent increase in protein oxidation in liver and kidney. Additionally, exposure to both opioids led to hepatic commitment, as shown by increased serum lipid levels, decreased urea concentration, increased alanine aminotransferase and decreased butyrylcholinesterase activities. It also led to renal impairment, as reflected by proteinuria and decreased glomerular filtration rate. Histopathological findings included sinusoidal dilatation, microsteatosis, vacuolization, cell infiltrates and cell degeneration, indicating metabolic changes, inflammation and cell damage. In conclusion, a single effective analgesic dose or the maximum recommended daily dose of both opioids leads to hepatotoxicity and nephrotoxicity, with tapentadol inducing comparatively more toxicity. Whether these effects reflect risks during the therapeutic use or human overdoses requires focused attention by the medical community. © 2017 Elsevier B.V.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Tramadol and tapentadol are two atypical synthetic opioid analgesics, with monoamine reuptake inhibition properties. Mainly aimed at the treatment of moderate to severe pain, these drugs are extensively prescribed for multiple clinical applications. Along with the increase in their use, there has been an increment in their abuse, and consequently in the reported number of adverse reactions and intoxications. However, little is known about their mechanisms of toxicity. In this study, we have analyzed the in vivo toxicological effects in liver and kidney resulting from an acute exposure of a rodent animal model to both opioids. Male Wistar rats were intraperitoneally administered with 10, 25 and 50 mg/kg tramadol and tapentadol, corresponding to a low, effective analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively, for 24 h. Toxicological effects were assessed in terms of oxidative stress, biochemical and metabolic parameters and histopathology, using serum and urine samples, liver and kidney homogenates and tissue specimens. The acute exposure to tapentadol caused a dose-dependent increase in protein oxidation in liver and kidney. Additionally, exposure to both opioids led to hepatic commitment, as shown by increased serum lipid levels, decreased urea concentration, increased alanine aminotransferase and decreased butyrylcholinesterase activities. It also led to renal impairment, as reflected by proteinuria and decreased glomerular filtration rate. Histopathological findings included sinusoidal dilatation, microsteatosis, vacuolization, cell infiltrates and cell degeneration, indicating metabolic changes, inflammation and cell damage. In conclusion, a single effective analgesic dose or the maximum recommended daily dose of both opioids leads to hepatotoxicity and nephrotoxicity, with tapentadol inducing comparatively more toxicity. Whether these effects reflect risks during the therapeutic use or human overdoses requires focused attention by the medical community. © 2017 Elsevier B.V. |
Soares, J X; Alves, E A; Silva, A M N; Figueiredo, De N G; Neves, J F; Cravo, S M; Rangel, M; Netto, A D P; Carvalho, F; Dinis-Oliveira, R J; Afonso, C M Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans Journal Article 30 (8), pp. 1609-1621, 2017, (cited By 0). @article{Soares20171609, title = {Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans}, author = {J X Soares and E A Alves and A M N Silva and N G De Figueiredo and J F Neves and S M Cravo and M Rangel and A D P Netto and F Carvalho and R J Dinis-Oliveira and C M Afonso}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85027872301&doi=10.1021%2facs.chemrestox.7b00126&partnerID=40&md5=1193addf11bfbec1afbb9935d9c6b29b}, doi = {10.1021/acs.chemrestox.7b00126}, year = {2017}, date = {2017-01-01}, volume = {30}, number = {8}, pages = {1609-1621}, abstract = {"Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to a photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT-Orbitrap-MS). Besides desomorphine, codeine, and morphine, profiting from the high resolution mass spectrometry (HRMS) data, an endeavor to study the morphinans content in krokodil was set for the first time. Considering codeine as the only morphinan precursor and the possible chemical transformations that can occur during krokodil synthesis, the morphinan chemical space was designed, and 95 compounds were defined. By making use of the morphinan chemical space in krokodil, the exact masses featured by HRMS, and the morphinan mass fragmentations patterns, a targeted identification approach was designed and implemented.The proposed 95 morphinans were searched using the full scan chromatogram of krokodil, and findings were validated by mass fragmentation of the correspondent precursor ions (MS2 spectra). Following this effort, a total of 54 morphinans were detected, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil. © 2017 American Chemical Society.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } "Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to a photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT-Orbitrap-MS). Besides desomorphine, codeine, and morphine, profiting from the high resolution mass spectrometry (HRMS) data, an endeavor to study the morphinans content in krokodil was set for the first time. Considering codeine as the only morphinan precursor and the possible chemical transformations that can occur during krokodil synthesis, the morphinan chemical space was designed, and 95 compounds were defined. By making use of the morphinan chemical space in krokodil, the exact masses featured by HRMS, and the morphinan mass fragmentations patterns, a targeted identification approach was designed and implemented.The proposed 95 morphinans were searched using the full scan chromatogram of krokodil, and findings were validated by mass fragmentation of the correspondent precursor ions (MS2 spectra). Following this effort, a total of 54 morphinans were detected, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil. © 2017 American Chemical Society. |
Dinis-Oliveira, R J Metabolic profile of oxazepam and related benzodiazepines: clinical and forensic aspects Journal Article 49 (4), pp. 451-463, 2017, (cited By 0). @article{Dinis-Oliveira2017451, title = {Metabolic profile of oxazepam and related benzodiazepines: clinical and forensic aspects}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85034624303&doi=10.1080%2f03602532.2017.1377223&partnerID=40&md5=2adb1f100948f95b9f5ce506b2fe0c3d}, doi = {10.1080/03602532.2017.1377223}, year = {2017}, date = {2017-01-01}, volume = {49}, number = {4}, pages = {451-463}, abstract = {Anxiolytic drugs, namely benzodiazepines, are the most commonly used psychoactive substances since anxiety disorders are prevalent mental disorders particularly in the Western world. Oxazepam is a short-acting benzodiazepine and one of the most frequently prescribed anxiolytic drugs. It is also the active metabolite of a wide range of other benzodiazepines, such as diazepam, ketazolam, temazepam, chlordiazepoxide, demoxazepam, halazepam, medazepam, prazepam, pinazepam, and chlorazepate. Therefore, relevant clinical and forensic outocomes may arise, namely those related to interference in driving performance. It is clinically available as a racemic formulation, with S-enantiomer being more active than R-enantiomer. In humans, it is mainly polimorphically metabolized by glucuronide conjugation at the 3-carbon hydroxyl group, yielding stable diastereomeric glucuronides (R- and S-oxazepam glucuronide). Relevant metabolic and stereoselective interspecies differences have been reported. In this work, the pharmacokinetics of oxazepam with particular focus on metabolic pathways is fully reviewed. Moreover, the metabolic profile of other prescribed benzodiazepines that produce oxazepam as a metabolite is also discussed. It is aimed that knowing the metabolism of oxazepam and related benzodiazepines may lead to the development of new analytical strategies for its early detection and help in further toxicological and clinical interpretations. © 2017 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Anxiolytic drugs, namely benzodiazepines, are the most commonly used psychoactive substances since anxiety disorders are prevalent mental disorders particularly in the Western world. Oxazepam is a short-acting benzodiazepine and one of the most frequently prescribed anxiolytic drugs. It is also the active metabolite of a wide range of other benzodiazepines, such as diazepam, ketazolam, temazepam, chlordiazepoxide, demoxazepam, halazepam, medazepam, prazepam, pinazepam, and chlorazepate. Therefore, relevant clinical and forensic outocomes may arise, namely those related to interference in driving performance. It is clinically available as a racemic formulation, with S-enantiomer being more active than R-enantiomer. In humans, it is mainly polimorphically metabolized by glucuronide conjugation at the 3-carbon hydroxyl group, yielding stable diastereomeric glucuronides (R- and S-oxazepam glucuronide). Relevant metabolic and stereoselective interspecies differences have been reported. In this work, the pharmacokinetics of oxazepam with particular focus on metabolic pathways is fully reviewed. Moreover, the metabolic profile of other prescribed benzodiazepines that produce oxazepam as a metabolite is also discussed. It is aimed that knowing the metabolism of oxazepam and related benzodiazepines may lead to the development of new analytical strategies for its early detection and help in further toxicological and clinical interpretations. © 2017 Informa UK Limited, trading as Taylor & Francis Group. |
Dinis-Oliveira, R J Metabolic profile of oxazepam and related benzodiazepines: clinical and forensic aspects Journal Article Drug Metabolism Reviews, 49 (4), pp. 451-463, 2017, (cited By 5). @article{Dinis-Oliveira2017451b, title = {Metabolic profile of oxazepam and related benzodiazepines: clinical and forensic aspects}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85034624303&doi=10.1080%2f03602532.2017.1377223&partnerID=40&md5=2adb1f100948f95b9f5ce506b2fe0c3d}, doi = {10.1080/03602532.2017.1377223}, year = {2017}, date = {2017-01-01}, journal = {Drug Metabolism Reviews}, volume = {49}, number = {4}, pages = {451-463}, abstract = {Anxiolytic drugs, namely benzodiazepines, are the most commonly used psychoactive substances since anxiety disorders are prevalent mental disorders particularly in the Western world. Oxazepam is a short-acting benzodiazepine and one of the most frequently prescribed anxiolytic drugs. It is also the active metabolite of a wide range of other benzodiazepines, such as diazepam, ketazolam, temazepam, chlordiazepoxide, demoxazepam, halazepam, medazepam, prazepam, pinazepam, and chlorazepate. Therefore, relevant clinical and forensic outocomes may arise, namely those related to interference in driving performance. It is clinically available as a racemic formulation, with S-enantiomer being more active than R-enantiomer. In humans, it is mainly polimorphically metabolized by glucuronide conjugation at the 3-carbon hydroxyl group, yielding stable diastereomeric glucuronides (R- and S-oxazepam glucuronide). Relevant metabolic and stereoselective interspecies differences have been reported. In this work, the pharmacokinetics of oxazepam with particular focus on metabolic pathways is fully reviewed. Moreover, the metabolic profile of other prescribed benzodiazepines that produce oxazepam as a metabolite is also discussed. It is aimed that knowing the metabolism of oxazepam and related benzodiazepines may lead to the development of new analytical strategies for its early detection and help in further toxicological and clinical interpretations. © 2017 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 5}, keywords = {}, pubstate = {published}, tppubtype = {article} } Anxiolytic drugs, namely benzodiazepines, are the most commonly used psychoactive substances since anxiety disorders are prevalent mental disorders particularly in the Western world. Oxazepam is a short-acting benzodiazepine and one of the most frequently prescribed anxiolytic drugs. It is also the active metabolite of a wide range of other benzodiazepines, such as diazepam, ketazolam, temazepam, chlordiazepoxide, demoxazepam, halazepam, medazepam, prazepam, pinazepam, and chlorazepate. Therefore, relevant clinical and forensic outocomes may arise, namely those related to interference in driving performance. It is clinically available as a racemic formulation, with S-enantiomer being more active than R-enantiomer. In humans, it is mainly polimorphically metabolized by glucuronide conjugation at the 3-carbon hydroxyl group, yielding stable diastereomeric glucuronides (R- and S-oxazepam glucuronide). Relevant metabolic and stereoselective interspecies differences have been reported. In this work, the pharmacokinetics of oxazepam with particular focus on metabolic pathways is fully reviewed. Moreover, the metabolic profile of other prescribed benzodiazepines that produce oxazepam as a metabolite is also discussed. It is aimed that knowing the metabolism of oxazepam and related benzodiazepines may lead to the development of new analytical strategies for its early detection and help in further toxicological and clinical interpretations. © 2017 Informa UK Limited, trading as Taylor & Francis Group. |
Soares, J X; Alves, E A; Silva, A M N; Figueiredo, De N G; Neves, J F; Cravo, S M; Rangel, M; Netto, A D P; Carvalho, F; Dinis-Oliveira, R J; Afonso, C M Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans Journal Article Chemical Research in Toxicology, 30 (8), pp. 1609-1621, 2017, (cited By 3). @article{Soares20171609b, title = {Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans}, author = {J X Soares and E A Alves and A M N Silva and N G De Figueiredo and J F Neves and S M Cravo and M Rangel and A D P Netto and F Carvalho and R J Dinis-Oliveira and C M Afonso}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85027872301&doi=10.1021%2facs.chemrestox.7b00126&partnerID=40&md5=1193addf11bfbec1afbb9935d9c6b29b}, doi = {10.1021/acs.chemrestox.7b00126}, year = {2017}, date = {2017-01-01}, journal = {Chemical Research in Toxicology}, volume = {30}, number = {8}, pages = {1609-1621}, abstract = {"Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to a photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT-Orbitrap-MS). Besides desomorphine, codeine, and morphine, profiting from the high resolution mass spectrometry (HRMS) data, an endeavor to study the morphinans content in krokodil was set for the first time. Considering codeine as the only morphinan precursor and the possible chemical transformations that can occur during krokodil synthesis, the morphinan chemical space was designed, and 95 compounds were defined. By making use of the morphinan chemical space in krokodil, the exact masses featured by HRMS, and the morphinan mass fragmentations patterns, a targeted identification approach was designed and implemented.The proposed 95 morphinans were searched using the full scan chromatogram of krokodil, and findings were validated by mass fragmentation of the correspondent precursor ions (MS2 spectra). Following this effort, a total of 54 morphinans were detected, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil. © 2017 American Chemical Society.}, note = {cited By 3}, keywords = {}, pubstate = {published}, tppubtype = {article} } "Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to a photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT-Orbitrap-MS). Besides desomorphine, codeine, and morphine, profiting from the high resolution mass spectrometry (HRMS) data, an endeavor to study the morphinans content in krokodil was set for the first time. Considering codeine as the only morphinan precursor and the possible chemical transformations that can occur during krokodil synthesis, the morphinan chemical space was designed, and 95 compounds were defined. By making use of the morphinan chemical space in krokodil, the exact masses featured by HRMS, and the morphinan mass fragmentations patterns, a targeted identification approach was designed and implemented.The proposed 95 morphinans were searched using the full scan chromatogram of krokodil, and findings were validated by mass fragmentation of the correspondent precursor ions (MS2 spectra). Following this effort, a total of 54 morphinans were detected, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil. © 2017 American Chemical Society. |
Barbosa, J; Faria, J; Leal, S; Afonso, L P; Lobo, J; Queirós, O; Moreira, R; Carvalho, F; Dinis-Oliveira, R J Toxicology, 389 , pp. 118-129, 2017, (cited By 2). @article{Barbosa2017118b, title = {Acute administration of tramadol and tapentadol at effective analgesic and maximum tolerated doses causes hepato- and nephrotoxic effects in Wistar rats}, author = {J Barbosa and J Faria and S Leal and L P Afonso and J Lobo and O Queirós and R Moreira and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85021952522&doi=10.1016%2fj.tox.2017.07.001&partnerID=40&md5=488bba0a24e4e98b8587a34e517c208a}, doi = {10.1016/j.tox.2017.07.001}, year = {2017}, date = {2017-01-01}, journal = {Toxicology}, volume = {389}, pages = {118-129}, abstract = {Tramadol and tapentadol are two atypical synthetic opioid analgesics, with monoamine reuptake inhibition properties. Mainly aimed at the treatment of moderate to severe pain, these drugs are extensively prescribed for multiple clinical applications. Along with the increase in their use, there has been an increment in their abuse, and consequently in the reported number of adverse reactions and intoxications. However, little is known about their mechanisms of toxicity. In this study, we have analyzed the in vivo toxicological effects in liver and kidney resulting from an acute exposure of a rodent animal model to both opioids. Male Wistar rats were intraperitoneally administered with 10, 25 and 50 mg/kg tramadol and tapentadol, corresponding to a low, effective analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively, for 24 h. Toxicological effects were assessed in terms of oxidative stress, biochemical and metabolic parameters and histopathology, using serum and urine samples, liver and kidney homogenates and tissue specimens. The acute exposure to tapentadol caused a dose-dependent increase in protein oxidation in liver and kidney. Additionally, exposure to both opioids led to hepatic commitment, as shown by increased serum lipid levels, decreased urea concentration, increased alanine aminotransferase and decreased butyrylcholinesterase activities. It also led to renal impairment, as reflected by proteinuria and decreased glomerular filtration rate. Histopathological findings included sinusoidal dilatation, microsteatosis, vacuolization, cell infiltrates and cell degeneration, indicating metabolic changes, inflammation and cell damage. In conclusion, a single effective analgesic dose or the maximum recommended daily dose of both opioids leads to hepatotoxicity and nephrotoxicity, with tapentadol inducing comparatively more toxicity. Whether these effects reflect risks during the therapeutic use or human overdoses requires focused attention by the medical community. © 2017 Elsevier B.V.}, note = {cited By 2}, keywords = {}, pubstate = {published}, tppubtype = {article} } Tramadol and tapentadol are two atypical synthetic opioid analgesics, with monoamine reuptake inhibition properties. Mainly aimed at the treatment of moderate to severe pain, these drugs are extensively prescribed for multiple clinical applications. Along with the increase in their use, there has been an increment in their abuse, and consequently in the reported number of adverse reactions and intoxications. However, little is known about their mechanisms of toxicity. In this study, we have analyzed the in vivo toxicological effects in liver and kidney resulting from an acute exposure of a rodent animal model to both opioids. Male Wistar rats were intraperitoneally administered with 10, 25 and 50 mg/kg tramadol and tapentadol, corresponding to a low, effective analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively, for 24 h. Toxicological effects were assessed in terms of oxidative stress, biochemical and metabolic parameters and histopathology, using serum and urine samples, liver and kidney homogenates and tissue specimens. The acute exposure to tapentadol caused a dose-dependent increase in protein oxidation in liver and kidney. Additionally, exposure to both opioids led to hepatic commitment, as shown by increased serum lipid levels, decreased urea concentration, increased alanine aminotransferase and decreased butyrylcholinesterase activities. It also led to renal impairment, as reflected by proteinuria and decreased glomerular filtration rate. Histopathological findings included sinusoidal dilatation, microsteatosis, vacuolization, cell infiltrates and cell degeneration, indicating metabolic changes, inflammation and cell damage. In conclusion, a single effective analgesic dose or the maximum recommended daily dose of both opioids leads to hepatotoxicity and nephrotoxicity, with tapentadol inducing comparatively more toxicity. Whether these effects reflect risks during the therapeutic use or human overdoses requires focused attention by the medical community. © 2017 Elsevier B.V. |
Faria, J; Barbosa, J; Leal, S; Afonso, L P; Lobo, J; Moreira, R; Queirós, O; Carvalho, F; Dinis-Oliveira, R J Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats Journal Article Toxicology, 385 , pp. 38-47, 2017, (cited By 4). @article{Faria201738b, title = {Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats}, author = {J Faria and J Barbosa and S Leal and L P Afonso and J Lobo and R Moreira and O Queirós and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019229989&doi=10.1016%2fj.tox.2017.05.003&partnerID=40&md5=7f4ad161a79c4b6d8f8cf0fc38f1e0b8}, doi = {10.1016/j.tox.2017.05.003}, year = {2017}, date = {2017-01-01}, journal = {Toxicology}, volume = {385}, pages = {38-47}, abstract = {Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50 mg/kg – typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24 h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. © 2017 Elsevier B.V.}, note = {cited By 4}, keywords = {}, pubstate = {published}, tppubtype = {article} } Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50 mg/kg – typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24 h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. © 2017 Elsevier B.V. |
Alves, E A; Agonia, A S; Cravo, S M; Afonso, C M; Netto, A D P; de Bastos, Lourdes M; Carvalho, F; Dinis-Oliveira, R J GC-MS method for the analysis of thirteen opioids, cocaine and cocaethylene in whole blood based on a modified quechers extraction Journal Article Current Pharmaceutical Analysis, 13 (3), pp. 215-223, 2017, (cited By 5). @article{Alves2017215b, title = {GC-MS method for the analysis of thirteen opioids, cocaine and cocaethylene in whole blood based on a modified quechers extraction}, author = {E A Alves and A S Agonia and S M Cravo and C M Afonso and A D P Netto and M de Lourdes Bastos and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019686660&doi=10.2174%2f1573412912666160502163846&partnerID=40&md5=bb2e4c0fae2eb5e3c6b5a4d2ff8ca48e}, doi = {10.2174/1573412912666160502163846}, year = {2017}, date = {2017-01-01}, journal = {Current Pharmaceutical Analysis}, volume = {13}, number = {3}, pages = {215-223}, abstract = {Background: QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) is a methodology previously developed to extract pesticides from vegetables and fruits and has been fully applied for different analytical approaches. Objective: In the present study, a rapid and less laborious modified QuEChERS extraction method for the quantification of 13 opioids [codeine, morphine, heroin, 6-acetylmorphine (6-AM), desomorphine, ethylmorphine, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP), papaverine, tramadol, O-desmetyltramadol (M1) and, tapentadol], cocaine and cocaethylene in whole blood was developed and validated by Gas Chromatography-Mass Spectrometry. Method: The modification of QuEChERS method consisted in the pretreatment of the whole blood samples using ultrasonication, the use of ethyl acetate as extraction solvent and a previous step of sample alcalinization. The use of dispersive separation steps such as Dispersive Solid-Phase Extraction (dSPE) or sorbents such as Primary Secondary Amine (PSA) was suppressed to minimize the errors and, to improve the velocity of the analysis. Results: The method proved to be selective and the regression analysis for the analytes was linear in the range of 31.2-2000 ng/mL with correlation coefficients > 0.98. The coefficients of variation did not exceed 15%. The lowest limit of detection and quantification for all the analytes were below the therapeutic range of the drugs. The recoveries of the analytes ranged from 52.4 to 95.0%. Conclusion: The developed method can provide a rapid, effective and “greener” process for the analysis of a wide range of opioids drugs in whole blood samples and can be applied to clinical and forensic antemortem and postmortem cases. © 2017 Bentham Science Publishers.}, note = {cited By 5}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) is a methodology previously developed to extract pesticides from vegetables and fruits and has been fully applied for different analytical approaches. Objective: In the present study, a rapid and less laborious modified QuEChERS extraction method for the quantification of 13 opioids [codeine, morphine, heroin, 6-acetylmorphine (6-AM), desomorphine, ethylmorphine, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP), papaverine, tramadol, O-desmetyltramadol (M1) and, tapentadol], cocaine and cocaethylene in whole blood was developed and validated by Gas Chromatography-Mass Spectrometry. Method: The modification of QuEChERS method consisted in the pretreatment of the whole blood samples using ultrasonication, the use of ethyl acetate as extraction solvent and a previous step of sample alcalinization. The use of dispersive separation steps such as Dispersive Solid-Phase Extraction (dSPE) or sorbents such as Primary Secondary Amine (PSA) was suppressed to minimize the errors and, to improve the velocity of the analysis. Results: The method proved to be selective and the regression analysis for the analytes was linear in the range of 31.2-2000 ng/mL with correlation coefficients > 0.98. The coefficients of variation did not exceed 15%. The lowest limit of detection and quantification for all the analytes were below the therapeutic range of the drugs. The recoveries of the analytes ranged from 52.4 to 95.0%. Conclusion: The developed method can provide a rapid, effective and “greener” process for the analysis of a wide range of opioids drugs in whole blood samples and can be applied to clinical and forensic antemortem and postmortem cases. © 2017 Bentham Science Publishers. |
Alves, E A; Brandão, P; Neves, J F; Cravo, S M; Soares, J X; Grund, J -P C; Duarte, J A; Afonso, C M M; Netto, Pereira A D; Carvalho, F; Dinis-Oliveira, R J Repeated subcutaneous administrations of krokodil causes skin necrosis and internal organs toxicity in Wistar rats: putative human implications Journal Article Human Psychopharmacology, 32 (3), 2017, (cited By 3). @article{Alves2017d, title = {Repeated subcutaneous administrations of krokodil causes skin necrosis and internal organs toxicity in Wistar rats: putative human implications}, author = {E A Alves and P Brandão and J F Neves and S M Cravo and J X Soares and J -P C Grund and J A Duarte and C M M Afonso and A D Pereira Netto and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85021330125&doi=10.1002%2fhup.2572&partnerID=40&md5=dbb914a7a07f091db1ecc6874151737e}, doi = {10.1002/hup.2572}, year = {2017}, date = {2017-01-01}, journal = {Human Psychopharmacology}, volume = {32}, number = {3}, abstract = {Objective: “Krokodil” is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model. Methods: Animals were divided into seven groups and exposed subcutaneously to NaCl 0.9% (control), krokodil mixture free of psychotropic substances (blank krokodil), pharmaceutical grade desomorphine 1 mg/kg, and four different concentrations of krokodil (containing 0.125, 0.25, 0.5, and 1 mg/kg of desomorphine) synthesized accordingly to a “domestic” protocol followed by people who inject krokodil (PWIK). Daily injections for five consecutive days were performed, and animals were sacrificed 24 hr after the last administration. Biochemical and histological analysis were carried out. Results: It was shown that the continuous use of krokodil may cause injury at the injection area, with formation of necrotic zones. The biochemical results evidenced alterations on cardiac and renal biomarkers of toxicity, namely, creatine kinase, creatine kinase-MB, and uric acid. Significant alteration in levels of reduced and oxidized glutathione on kidney and heart suggested that oxidative stress may be involved in krokodil-mediated toxicity. Cardiac congestion was the most relevant finding of continuous krokodil administration. Conclusions: These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil. Copyright © 2017 John Wiley & Sons, Ltd.}, note = {cited By 3}, keywords = {}, pubstate = {published}, tppubtype = {article} } Objective: “Krokodil” is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model. Methods: Animals were divided into seven groups and exposed subcutaneously to NaCl 0.9% (control), krokodil mixture free of psychotropic substances (blank krokodil), pharmaceutical grade desomorphine 1 mg/kg, and four different concentrations of krokodil (containing 0.125, 0.25, 0.5, and 1 mg/kg of desomorphine) synthesized accordingly to a “domestic” protocol followed by people who inject krokodil (PWIK). Daily injections for five consecutive days were performed, and animals were sacrificed 24 hr after the last administration. Biochemical and histological analysis were carried out. Results: It was shown that the continuous use of krokodil may cause injury at the injection area, with formation of necrotic zones. The biochemical results evidenced alterations on cardiac and renal biomarkers of toxicity, namely, creatine kinase, creatine kinase-MB, and uric acid. Significant alteration in levels of reduced and oxidized glutathione on kidney and heart suggested that oxidative stress may be involved in krokodil-mediated toxicity. Cardiac congestion was the most relevant finding of continuous krokodil administration. Conclusions: These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil. Copyright © 2017 John Wiley & Sons, Ltd. |
Dinis-Oliveira, R J Metabolic profile of flunitrazepam: Clinical and forensic toxicological aspects Journal Article Drug Metabolism Letters, 11 (1), pp. 14-20, 2017, (cited By 4). @article{Dinis-Oliveira201714b, title = {Metabolic profile of flunitrazepam: Clinical and forensic toxicological aspects}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85034627153&doi=10.2174%2f1872312811666170407164216&partnerID=40&md5=15754674bdb842dd419e166f9eae3009}, doi = {10.2174/1872312811666170407164216}, year = {2017}, date = {2017-01-01}, journal = {Drug Metabolism Letters}, volume = {11}, number = {1}, pages = {14-20}, abstract = {Background: Flunitrazepam (FNZ) is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault led to important clinical and forensic concerns. Objective: In this work the metabolism of FNZ, and pharmacological-and toxicological-related effects, were fully reviewed. Methods: FNZ and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Results: Major metabolic pathways include N-demethylation, 3-hydroxylation, nitro-reduction, and further N-acetylation of the amino group, yielding N-desmethylflunitrazepam, 3-hydroxy-flunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam, respectively. A combination of these reactions may lead to the formation of 7-amino-N-desmethylflunitrazepam, 7-acetamido-N-desmethylflunitrazepam, 3-hydroxy-7-aminoflunitrazepam, 3-hydroxy-7-acetamidoflunitrazepam, 3-hydroxy-N-desmethylflunitrazepam and glucuronide conjugates. Genotypic variations in enzymes, interactions with other drugs or stability of FNZ during storage can result in large interindividual variability in the toxicological results. Conclusion: It is aimed that knowing the metabolism of FNZ may lead to the development of new analytical strategies for early detection, since this drug is typically present in very low concentrations in blood and urine when used to facilitate sexual assault. © 2017 Bentham Science Publishers.}, note = {cited By 4}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Flunitrazepam (FNZ) is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault led to important clinical and forensic concerns. Objective: In this work the metabolism of FNZ, and pharmacological-and toxicological-related effects, were fully reviewed. Methods: FNZ and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Results: Major metabolic pathways include N-demethylation, 3-hydroxylation, nitro-reduction, and further N-acetylation of the amino group, yielding N-desmethylflunitrazepam, 3-hydroxy-flunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam, respectively. A combination of these reactions may lead to the formation of 7-amino-N-desmethylflunitrazepam, 7-acetamido-N-desmethylflunitrazepam, 3-hydroxy-7-aminoflunitrazepam, 3-hydroxy-7-acetamidoflunitrazepam, 3-hydroxy-N-desmethylflunitrazepam and glucuronide conjugates. Genotypic variations in enzymes, interactions with other drugs or stability of FNZ during storage can result in large interindividual variability in the toxicological results. Conclusion: It is aimed that knowing the metabolism of FNZ may lead to the development of new analytical strategies for early detection, since this drug is typically present in very low concentrations in blood and urine when used to facilitate sexual assault. © 2017 Bentham Science Publishers. |
Guimarães, R; Dinis-Oliveira, R J; Pereira, A; Rodrigues, P; Santos, A Acta Medica Portuguesa, 30 (3), pp. 159-162, 2017, (cited By 2). @article{Guimarães2017159b, title = {Reutilization of clinical data for research: The footprint scientific model of the hospital center of São João [Reutilização de informação clínica para investigação: O modelo da pegada científica do centro hospitalar de São João]}, author = {R Guimarães and R J Dinis-Oliveira and A Pereira and P Rodrigues and A Santos}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85016711271&doi=10.20344%2famp.8592&partnerID=40&md5=58bbd725062994032e221c40a7400e87}, doi = {10.20344/amp.8592}, year = {2017}, date = {2017-01-01}, journal = {Acta Medica Portuguesa}, volume = {30}, number = {3}, pages = {159-162}, note = {cited By 2}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Dinis-Oliveira, R J Metabolomics of Methylphenidate and Ethylphenidate: Implications in Pharmacological and Toxicological Effects Journal Article European Journal of Drug Metabolism and Pharmacokinetics, 42 (1), pp. 11-16, 2017, (cited By 3). @article{Dinis-Oliveira201711b, title = {Metabolomics of Methylphenidate and Ethylphenidate: Implications in Pharmacological and Toxicological Effects}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979210469&doi=10.1007%2fs13318-016-0362-1&partnerID=40&md5=8542768b42eae9b162ec6c8091d6ab98}, doi = {10.1007/s13318-016-0362-1}, year = {2017}, date = {2017-01-01}, journal = {European Journal of Drug Metabolism and Pharmacokinetics}, volume = {42}, number = {1}, pages = {11-16}, abstract = {Methylphenidate (MPH) is primarily indicated for attention-deficit hyperactivity disorder and narcolepsy therapy. A marked individual variability in the dose–response has been observed, and therefore dosage must be titrated for optimal therapeutic effect with minimal toxicity. This variability has been claimed to be predominantly pharmacokinetic. Moreover, due to its similar pharmacodynamics to amphetamine, MPH has been abused and fatalities have been reported. This review aims to discuss metabolomics of MPH, namely by presenting all major and minor metabolites. Ritalinic acid is the main metabolite. In addition, minor pathways involving aromatic hydroxylation, microsomal oxidation and conjugation have also been reported to form the p-hydroxy-, oxo- and conjugated metabolites, respectively. MPH may undergo transesterification with ethanol producing ethylphenidate, which is also pharmacologically active. It is expected that knowing the metabolomics of MPH may provide further insights regarding individual contribution for MPH pharmacodynamics and toxicological effects, namely if ethanol is co-consumed. © 2016, Springer International Publishing Switzerland.}, note = {cited By 3}, keywords = {}, pubstate = {published}, tppubtype = {article} } Methylphenidate (MPH) is primarily indicated for attention-deficit hyperactivity disorder and narcolepsy therapy. A marked individual variability in the dose–response has been observed, and therefore dosage must be titrated for optimal therapeutic effect with minimal toxicity. This variability has been claimed to be predominantly pharmacokinetic. Moreover, due to its similar pharmacodynamics to amphetamine, MPH has been abused and fatalities have been reported. This review aims to discuss metabolomics of MPH, namely by presenting all major and minor metabolites. Ritalinic acid is the main metabolite. In addition, minor pathways involving aromatic hydroxylation, microsomal oxidation and conjugation have also been reported to form the p-hydroxy-, oxo- and conjugated metabolites, respectively. MPH may undergo transesterification with ethanol producing ethylphenidate, which is also pharmacologically active. It is expected that knowing the metabolomics of MPH may provide further insights regarding individual contribution for MPH pharmacodynamics and toxicological effects, namely if ethanol is co-consumed. © 2016, Springer International Publishing Switzerland. |
Dinis-Oliveira, R J Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance Journal Article Drug Metabolism Reviews, 49 (1), pp. 84-91, 2017, (cited By 5). @article{Dinis-Oliveira201784b, title = {Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85013339853&doi=10.1080%2f03602532.2016.1278228&partnerID=40&md5=ad936295282108d91be6cda1d3a7b08f}, doi = {10.1080/03602532.2016.1278228}, year = {2017}, date = {2017-01-01}, journal = {Drug Metabolism Reviews}, volume = {49}, number = {1}, pages = {84-91}, abstract = {Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the “magic mushrooms” and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis. © 2017 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 5}, keywords = {}, pubstate = {published}, tppubtype = {article} } Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the “magic mushrooms” and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis. © 2017 Informa UK Limited, trading as Taylor & Francis Group. |
Alves, E A; Brandao, P; Magalhaes, T; Carvalho, F; Dinis-Oliveira, R J Fatal Intoxications in the North of Portugal: 12 Years of Retrospective Analysis Journal Article Current drug safety, 12 (1), pp. 39-45, 2017, (cited By 1). @article{Alves201739, title = {Fatal Intoxications in the North of Portugal: 12 Years of Retrospective Analysis}, author = {E A Alves and P Brandao and T Magalhaes and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045926287&doi=10.2174%2f1574886311666160724212407&partnerID=40&md5=33286a2d5d5c9aa4f703929a5246a6fb}, doi = {10.2174/1574886311666160724212407}, year = {2017}, date = {2017-01-01}, journal = {Current drug safety}, volume = {12}, number = {1}, pages = {39-45}, abstract = {BACKGROUND: Fatal intoxications are a topic of great relevance in today's society. They typically occur by accidental or voluntary ingestion, but its characterization by a forensic perspective was not fully explored. OBJECTIVE: This study retrospectively reviews fatal intoxication cases autopsied at the northern forensic medicine services of Portugal, between 2001 and 2013. METHOD: For this purpose, we analyzed postmortem forensic medical reports with positive qualitative analysis for xenobiotics. RESULTS: A total of 27,778 autopsy reports were analyzed, of which 1,269 cases fulfilled the selection criteria, representing 4.6% of total number of individuals autopsied during the period under analysis. Men were involved in most of the cases (73.8%) and most individuals were adults with ages between 36 and 65 years old (57.0%). The highest incidences were medicines (22.9%) and alcohol (15.8%), followed by their association. Cases of fatal intoxications involving opioids come on fifth place (5.8%) namely due to accidental overdoses. Moreover, intoxications appeared as the leading cause of death in reports concerning accidental etiology, with drugs and alcohol associations having a great expression. CONCLUSION: Due to morbidity and relevant number of fatal cases, risk prevention measures, such as public health policies should be implemented to reduce the number of intoxications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.}, note = {cited By 1}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Fatal intoxications are a topic of great relevance in today's society. They typically occur by accidental or voluntary ingestion, but its characterization by a forensic perspective was not fully explored. OBJECTIVE: This study retrospectively reviews fatal intoxication cases autopsied at the northern forensic medicine services of Portugal, between 2001 and 2013. METHOD: For this purpose, we analyzed postmortem forensic medical reports with positive qualitative analysis for xenobiotics. RESULTS: A total of 27,778 autopsy reports were analyzed, of which 1,269 cases fulfilled the selection criteria, representing 4.6% of total number of individuals autopsied during the period under analysis. Men were involved in most of the cases (73.8%) and most individuals were adults with ages between 36 and 65 years old (57.0%). The highest incidences were medicines (22.9%) and alcohol (15.8%), followed by their association. Cases of fatal intoxications involving opioids come on fifth place (5.8%) namely due to accidental overdoses. Moreover, intoxications appeared as the leading cause of death in reports concerning accidental etiology, with drugs and alcohol associations having a great expression. CONCLUSION: Due to morbidity and relevant number of fatal cases, risk prevention measures, such as public health policies should be implemented to reduce the number of intoxications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org. |
2016 |
Dinis-Oliveira, R J; Magalhães, T The Inherent Drawbacks of the Pressure to Publish in Health Sciences: Good or Bad Science Journal Article 4 , 2016, (cited By 4). @article{Dinis-Oliveira2016, title = {The Inherent Drawbacks of the Pressure to Publish in Health Sciences: Good or Bad Science}, author = {R J Dinis-Oliveira and T Magalhães}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84964603323&doi=10.12688%2ff1000research.6809.2&partnerID=40&md5=128aed89a4d66d9391f6d56eb2e6815f}, doi = {10.12688/f1000research.6809.2}, year = {2016}, date = {2016-01-01}, volume = {4}, abstract = {In recent years, there has been a significant increase in the number of scientific publications- it is the era of "hunting the article". This commentary discusses the drawbacks of the pressure to publish that certainly contribute to the 'dark side' of science. In fact, health science career progression greatly relies on the number of scientific publications a researcher has, and in many cases these may be more valorized than the health services provided. Of course, scientific publications help to develop the skills of health care professionals, but as Einstein highlighted " not everything that counts can be counted, and not everything that can be counted counts". © 2016 Dinis-Oliveira RJ and Magalhães T.}, note = {cited By 4}, keywords = {}, pubstate = {published}, tppubtype = {article} } In recent years, there has been a significant increase in the number of scientific publications- it is the era of "hunting the article". This commentary discusses the drawbacks of the pressure to publish that certainly contribute to the 'dark side' of science. In fact, health science career progression greatly relies on the number of scientific publications a researcher has, and in many cases these may be more valorized than the health services provided. Of course, scientific publications help to develop the skills of health care professionals, but as Einstein highlighted " not everything that counts can be counted, and not everything that can be counted counts". © 2016 Dinis-Oliveira RJ and Magalhães T. |
Dinis-Oliveira, R J; Magalhães, T Teaching and learning based on peer review: A realistic approach in forensic sciences [version 1; referees: 2 approve Journal Article 5 , 2016, (cited By 1). @article{Dinis-Oliveira2016b, title = {Teaching and learning based on peer review: A realistic approach in forensic sciences [version 1; referees: 2 approve}, author = {R J Dinis-Oliveira and T Magalhães}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85010976387&doi=10.12688%2fF1000RESEARCH.8726.1&partnerID=40&md5=42b6de103067c3c9e161467db1552af3}, doi = {10.12688/F1000RESEARCH.8726.1}, year = {2016}, date = {2016-01-01}, volume = {5}, abstract = {Teaching and learning methods need a continuous upgrade in higher education. However it is also true that some of the modern methodologies do not reduce or prevent school failure. Perhaps the real limitation is the inability to identify the true reasons that may explain it or ignore/undervalue the problem. In our opinion, one of the current constraints of the teaching/learning process is the excess of and inadequate bibliography recommended by the teacher, which results in continuous student difficulties and waste of time in searching and selecting useful information. The need to change the paradigm of the teaching/learning process comes also from employers. They claim forensic experts armed with useful knowledge to face professional life. It is therefore mandatory to identify the new needs and opportunities regarding pedagogical methodologies. This article reflects on the recent importance of peer review in teaching/learning forensic sciences based on the last 10 years of pedagogical experience inseparably from the scientific activity. © 2016 Dinis-Oliveira RJ and Magalhães T.}, note = {cited By 1}, keywords = {}, pubstate = {published}, tppubtype = {article} } Teaching and learning methods need a continuous upgrade in higher education. However it is also true that some of the modern methodologies do not reduce or prevent school failure. Perhaps the real limitation is the inability to identify the true reasons that may explain it or ignore/undervalue the problem. In our opinion, one of the current constraints of the teaching/learning process is the excess of and inadequate bibliography recommended by the teacher, which results in continuous student difficulties and waste of time in searching and selecting useful information. The need to change the paradigm of the teaching/learning process comes also from employers. They claim forensic experts armed with useful knowledge to face professional life. It is therefore mandatory to identify the new needs and opportunities regarding pedagogical methodologies. This article reflects on the recent importance of peer review in teaching/learning forensic sciences based on the last 10 years of pedagogical experience inseparably from the scientific activity. © 2016 Dinis-Oliveira RJ and Magalhães T. |
Dinis-Oliveira, R J; Carvalho, F; Costa, I; Silvestre, R; Magalhães, T Response to the comment on "promising blood-derived biomarkers for estimation of the postmortem interval" Journal Article 5 (2), pp. 716-718, 2016, (cited By 0). @article{Dinis-Oliveira2016716, title = {Response to the comment on "promising blood-derived biomarkers for estimation of the postmortem interval"}, author = {R J Dinis-Oliveira and F Carvalho and I Costa and R Silvestre and T Magalhães}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84959535961&doi=10.1039%2fc5tx00461f&partnerID=40&md5=2f241344341dfe4f4afb906358e9d7f4}, doi = {10.1039/c5tx00461f}, year = {2016}, date = {2016-01-01}, volume = {5}, number = {2}, pages = {716-718}, abstract = {Following Meurs and Szykuła's comment on our published article titled "Promising blood-derived biomarkers for estimation of the postmortem interval", we recognize the importance of the issues raised, but we would like to emphasize that these contain some misinterpretations and that most of the points were already discussed in depth in our manuscript particularly in the conclusion section. We also aim to highlight further data regarding the difficulties of postmortem interval estimation. © 2016 The Royal Society of Chemistry.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Following Meurs and Szykuła's comment on our published article titled "Promising blood-derived biomarkers for estimation of the postmortem interval", we recognize the importance of the issues raised, but we would like to emphasize that these contain some misinterpretations and that most of the points were already discussed in depth in our manuscript particularly in the conclusion section. We also aim to highlight further data regarding the difficulties of postmortem interval estimation. © 2016 The Royal Society of Chemistry. |
Dinis-Oliveira, R J Metabolomics of δ9-tetrahydrocannabinol: Implications in toxicity Journal Article 48 (1), pp. 80-87, 2016, (cited By 7). @article{Dinis-Oliveira201680, title = {Metabolomics of δ9-tetrahydrocannabinol: Implications in toxicity}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84961050997&doi=10.3109%2f03602532.2015.1137307&partnerID=40&md5=d96c2b52d31000bf83946ded03b64dad}, doi = {10.3109/03602532.2015.1137307}, year = {2016}, date = {2016-01-01}, volume = {48}, number = {1}, pages = {80-87}, abstract = {Cannabis sativa is the most commonly used recreational drug, δ9-tetrahydrocannabinol (δ9-THC) being the main addictive compound. Biotransformation of cannabinoids is an important field of xenobiochemistry and toxicology and the study of the metabolism can lead to the discovery of new compounds, unknown metabolites with unique structures and new therapeutic effects. The pharmacokinetics of δ9-THC is dependent on multiple factors such as physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol. This review aims to discuss metabolomics of δ9-THC, namely by presenting all known metabolites of δ9-THC described both in vitro and in vivo, and their roles in the δ9-THC-mediated toxic effects. Since medicinal use is increasing, metabolomics of δ9-THC will also be discussed in order to uncover potential active metabolites that can be made available for this purpose. © 2016 Taylor & Francis.}, note = {cited By 7}, keywords = {}, pubstate = {published}, tppubtype = {article} } Cannabis sativa is the most commonly used recreational drug, δ9-tetrahydrocannabinol (δ9-THC) being the main addictive compound. Biotransformation of cannabinoids is an important field of xenobiochemistry and toxicology and the study of the metabolism can lead to the discovery of new compounds, unknown metabolites with unique structures and new therapeutic effects. The pharmacokinetics of δ9-THC is dependent on multiple factors such as physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol. This review aims to discuss metabolomics of δ9-THC, namely by presenting all known metabolites of δ9-THC described both in vitro and in vivo, and their roles in the δ9-THC-mediated toxic effects. Since medicinal use is increasing, metabolomics of δ9-THC will also be discussed in order to uncover potential active metabolites that can be made available for this purpose. © 2016 Taylor & Francis. |
Dinis-Oliveira, R J Erratum: Heterogeneous and homogeneous immunoassays for drug analysis (Bioanalysis (2014) 6:21 (2877-2896)) Journal Article 8 (3), pp. 253, 2016, (cited By 0). @article{Dinis-Oliveira2016253, title = {Erratum: Heterogeneous and homogeneous immunoassays for drug analysis (Bioanalysis (2014) 6:21 (2877-2896))}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84959048980&doi=10.4155%2fbio.16.1&partnerID=40&md5=a04d1037dcb3b177717cadef17338ca9}, doi = {10.4155/bio.16.1}, year = {2016}, date = {2016-01-01}, volume = {8}, number = {3}, pages = {253}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Neves, J F; Alves, E A; Soares, J X; Cravo, S M; Silva, A M S; Netto, Pereira A D; Carvalho, F; Dinis-Oliveira, R J; Afonso, C M Data analysis of "krokodil" samples obtained by street-like synthesis Journal Article 6 , pp. 83-88, 2016, (cited By 3). @article{Neves201683, title = {Data analysis of "krokodil" samples obtained by street-like synthesis}, author = {J F Neves and E A Alves and J X Soares and S M Cravo and A M S Silva and A D Pereira Netto and F Carvalho and R J Dinis-Oliveira and C M Afonso}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84949035703&doi=10.1016%2fj.dib.2015.11.046&partnerID=40&md5=8b162bca51486b05d81ea4bb70f5d871}, doi = {10.1016/j.dib.2015.11.046}, year = {2016}, date = {2016-01-01}, volume = {6}, pages = {83-88}, abstract = {The data described in this work is related to be the subject of an article in the Forensic Science International, titled: "The harmful chemistry behind "krokodil": street-like synthesis and product analysis" (http://dx.doi.org/10.1016/j.forsciint.2015.07.042) [1]. The data presented here provides additional description of the chemical profile of "krokodil". Physicochemical and organoleptic characteristics, TLC profile, UV/Vis, 1H NMR and FTIR spectrum are presented. These data validate the proposed synthetic procedure and pathway and give further information about the contaminants present in "krokodil". © 2015 The Authors.}, note = {cited By 3}, keywords = {}, pubstate = {published}, tppubtype = {article} } The data described in this work is related to be the subject of an article in the Forensic Science International, titled: "The harmful chemistry behind "krokodil": street-like synthesis and product analysis" (http://dx.doi.org/10.1016/j.forsciint.2015.07.042) [1]. The data presented here provides additional description of the chemical profile of "krokodil". Physicochemical and organoleptic characteristics, TLC profile, UV/Vis, 1H NMR and FTIR spectrum are presented. These data validate the proposed synthetic procedure and pathway and give further information about the contaminants present in "krokodil". © 2015 The Authors. |
Dinis-Oliveira, R J Oxidative and non-oxidative metabolomics of ethanol Journal Article 17 (4), pp. 327-335, 2016, (cited By 12). @article{Dinis-Oliveira2016327, title = {Oxidative and non-oxidative metabolomics of ethanol}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84961754980&doi=10.2174%2f1389200217666160125113806&partnerID=40&md5=8d39ff57a62185e7378477c52b6d5eca}, doi = {10.2174/1389200217666160125113806}, year = {2016}, date = {2016-01-01}, volume = {17}, number = {4}, pages = {327-335}, abstract = {Background: It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile. Objective: This work performs a complete review of the metabolism of ethanol focusing on both major and minor metabolites. Method: An exhaustive literature search was carried out using textual and structural queries for ethanol and related known metabolizing enzymes and metabolites. Results: The main pathway of metabolism is catalyzed by cytosolic alcohol dehydrogenase, which exhibits multiple isoenzymes and genetic polymorphisms with clinical and forensic implications. Another two oxidative routes, the highly inducible CYP2E1 system and peroxisomal catalase may acquire relevance under specific circumstances. In addition to oxidative metabolism, ethanol also originates minor metabolites such as ethyl glucuronide, ethyl sulfate, ethyl phosphate, ethyl nitrite, phosphatidylethanol and fatty acid ethyl esters. These metabolites represent alternative biomarkers since they can be detected several hours or days after ethanol exposure. Conclusion: It is expected that knowing the metabolomics of ethanol may provide additional insights to better understand the toxicological effects and the variability of dose response. © 2016 Bentham Science Publishers.}, note = {cited By 12}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile. Objective: This work performs a complete review of the metabolism of ethanol focusing on both major and minor metabolites. Method: An exhaustive literature search was carried out using textual and structural queries for ethanol and related known metabolizing enzymes and metabolites. Results: The main pathway of metabolism is catalyzed by cytosolic alcohol dehydrogenase, which exhibits multiple isoenzymes and genetic polymorphisms with clinical and forensic implications. Another two oxidative routes, the highly inducible CYP2E1 system and peroxisomal catalase may acquire relevance under specific circumstances. In addition to oxidative metabolism, ethanol also originates minor metabolites such as ethyl glucuronide, ethyl sulfate, ethyl phosphate, ethyl nitrite, phosphatidylethanol and fatty acid ethyl esters. These metabolites represent alternative biomarkers since they can be detected several hours or days after ethanol exposure. Conclusion: It is expected that knowing the metabolomics of ethanol may provide additional insights to better understand the toxicological effects and the variability of dose response. © 2016 Bentham Science Publishers. |
Faria, J; Barbosa, J; Queirós, O; Moreira, R; Carvalho, F; Dinis-Oliveira, R J Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells Journal Article 359-360 , pp. 1-10, 2016, (cited By 7). @article{Faria20161, title = {Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells}, author = {J Faria and J Barbosa and O Queirós and R Moreira and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84975527349&doi=10.1016%2fj.tox.2016.06.010&partnerID=40&md5=a639db333f94f63111b694c3edfe2285}, doi = {10.1016/j.tox.2016.06.010}, year = {2016}, date = {2016-01-01}, volume = {359-360}, pages = {1-10}, abstract = {Opioid therapy and abuse are increasing, justifying the need to study their toxicity and underlying mechanisms. Given opioid pharmacodynamics at the central nervous system, the analysis of toxic effects in neuronal models gains particular relevance. The aim of this study was to compare the toxicological effects of acute exposure to tramadol and tapentadol in the undifferentiated human SH-SY5Y neuroblastoma cell line. Upon exposure to tramadol and tapentadol concentrations up to 600 μM, cell toxicity was assessed through evaluation of oxidative stress, mitochondrial and metabolic alterations, as well as cell viability and death mechanisms through necrosis or apoptosis, and related signalling. Tapentadol was observed to trigger much more prominent toxic effects than tramadol, ultimately leading to energy deficit and cell death. Cell death was shown to predominantly occur through necrosis, with no alterations in membrane potential or in cytochrome c release. Both drugs were shown to stimulate glucose uptake and to cause ATP depletion, due to changes in the expression of energy metabolism enzymes. The toxicity mechanisms in such a neuronal model are relevant to understand adverse reactions to these opioids and to contribute to dose adjustment in order to avoid neurological damage. © 2016 Elsevier Ireland Ltd}, note = {cited By 7}, keywords = {}, pubstate = {published}, tppubtype = {article} } Opioid therapy and abuse are increasing, justifying the need to study their toxicity and underlying mechanisms. Given opioid pharmacodynamics at the central nervous system, the analysis of toxic effects in neuronal models gains particular relevance. The aim of this study was to compare the toxicological effects of acute exposure to tramadol and tapentadol in the undifferentiated human SH-SY5Y neuroblastoma cell line. Upon exposure to tramadol and tapentadol concentrations up to 600 μM, cell toxicity was assessed through evaluation of oxidative stress, mitochondrial and metabolic alterations, as well as cell viability and death mechanisms through necrosis or apoptosis, and related signalling. Tapentadol was observed to trigger much more prominent toxic effects than tramadol, ultimately leading to energy deficit and cell death. Cell death was shown to predominantly occur through necrosis, with no alterations in membrane potential or in cytochrome c release. Both drugs were shown to stimulate glucose uptake and to cause ATP depletion, due to changes in the expression of energy metabolism enzymes. The toxicity mechanisms in such a neuronal model are relevant to understand adverse reactions to these opioids and to contribute to dose adjustment in order to avoid neurological damage. © 2016 Elsevier Ireland Ltd |
Dinis-Oliveira, R J; Soares, M; Rocha-Pereira, C; Carvalho, F Human and experimental toxicology of orellanine Journal Article 35 (9), pp. 1016-1029, 2016, (cited By 0). @article{Dinis-Oliveira20161016, title = {Human and experimental toxicology of orellanine}, author = {R J Dinis-Oliveira and M Soares and C Rocha-Pereira and F Carvalho}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979650178&doi=10.1177%2f0960327115613845&partnerID=40&md5=8712c297e0eeb2164cd9b282a0912af4}, doi = {10.1177/0960327115613845}, year = {2016}, date = {2016-01-01}, volume = {35}, number = {9}, pages = {1016-1029}, abstract = {Orellanine is a nephrotoxic toxin produced by some mushroom species of the Cortinarius genus, typically found in Europe and North America. The nephrotoxicity of Cortinarius orellanus is well known and was first recognized in the 1950s when this mushroom was identified as the cause of a mass poisoning in Poland. Typically, onset of symptoms is delayed for 1-2 weeks after ingestion. Some patients suffer mild gastrointestinal discomfort in the latency period before developing signs of renal impairment due to severe interstitial nephritis, acute focal tubular damage, and interstitial fibrosis. There is no specific antidote to orellanine poisoning. The mainstay of treatment is the prevention of secondary complications of kidney failure, adequate dialysis and, in the case of incomplete recovery, management of chronic renal insufficiency. In this work, we aim to review about Cortinarius species, including epidemiological studies, chemical structure, toxicokinetics, toxic doses, mechanisms of toxicity, diagnosis, prognosis, and treatment options. © SAGE Publications.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Orellanine is a nephrotoxic toxin produced by some mushroom species of the Cortinarius genus, typically found in Europe and North America. The nephrotoxicity of Cortinarius orellanus is well known and was first recognized in the 1950s when this mushroom was identified as the cause of a mass poisoning in Poland. Typically, onset of symptoms is delayed for 1-2 weeks after ingestion. Some patients suffer mild gastrointestinal discomfort in the latency period before developing signs of renal impairment due to severe interstitial nephritis, acute focal tubular damage, and interstitial fibrosis. There is no specific antidote to orellanine poisoning. The mainstay of treatment is the prevention of secondary complications of kidney failure, adequate dialysis and, in the case of incomplete recovery, management of chronic renal insufficiency. In this work, we aim to review about Cortinarius species, including epidemiological studies, chemical structure, toxicokinetics, toxic doses, mechanisms of toxicity, diagnosis, prognosis, and treatment options. © SAGE Publications. |
Dinis-Oliveira, R J Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response Journal Article 48 (4), pp. 568-576, 2016, (cited By 6). @article{Dinis-Oliveira2016568, title = {Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84991110349&doi=10.1080%2f03602532.2016.1192642&partnerID=40&md5=9391afb3820c2b1dd3a67d6f3a6bba4d}, doi = {10.1080/03602532.2016.1192642}, year = {2016}, date = {2016-01-01}, volume = {48}, number = {4}, pages = {568-576}, abstract = {Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile. This review aims to discuss metabolomics of methadone, namely by presenting all major and minor metabolites and pharmacokinetic drug interactions. The main mechanism for methadone metabolism is hepatic through the cytochrome P450, specifically isoenzymes 2B6, 3A4 and 2D6. Firstly, methadone is N-demethylated and cyclize to form its major 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) metabolites. Several alternate minor pathways have been described namely various methadol metabolites, which proved to be active. It is expected that knowing the metabolomics of methadone may provide further insights, attempting a personalized therapy aiming to attain effective blood concentrations. The historical record is therefore especially important when investigating clinical and forensic cases related to methadone administration, since interindividual responses are known to vary considerably. © 2016 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 6}, keywords = {}, pubstate = {published}, tppubtype = {article} } Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile. This review aims to discuss metabolomics of methadone, namely by presenting all major and minor metabolites and pharmacokinetic drug interactions. The main mechanism for methadone metabolism is hepatic through the cytochrome P450, specifically isoenzymes 2B6, 3A4 and 2D6. Firstly, methadone is N-demethylated and cyclize to form its major 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) metabolites. Several alternate minor pathways have been described namely various methadol metabolites, which proved to be active. It is expected that knowing the metabolomics of methadone may provide further insights, attempting a personalized therapy aiming to attain effective blood concentrations. The historical record is therefore especially important when investigating clinical and forensic cases related to methadone administration, since interindividual responses are known to vary considerably. © 2016 Informa UK Limited, trading as Taylor & Francis Group. |
Barbosa, J; Faria, J; Queirós, O; Moreira, R; Carvalho, F; Dinis-Oliveira, R J Comparative metabolism of tramadol and tapentadol: a toxicological perspective Journal Article 48 (4), pp. 577-592, 2016, (cited By 7). @article{Barbosa2016577, title = {Comparative metabolism of tramadol and tapentadol: a toxicological perspective}, author = {J Barbosa and J Faria and O Queirós and R Moreira and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84991085677&doi=10.1080%2f03602532.2016.1229788&partnerID=40&md5=5435636519828c63a71e3947bf61f554}, doi = {10.1080/03602532.2016.1229788}, year = {2016}, date = {2016-01-01}, volume = {48}, number = {4}, pages = {577-592}, abstract = {Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol, and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy. © 2016 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 7}, keywords = {}, pubstate = {published}, tppubtype = {article} } Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol, and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy. © 2016 Informa UK Limited, trading as Taylor & Francis Group. |
Alves, E A; Brandão, P; Magalhães, T; Carvalho, F; Dinis-Oliveira, R J Fatal intoxications in the north of portugal: 12 years of retrospective analysis Journal Article 11 (3), pp. 1-7, 2016, (cited By 0). @article{Alves20161, title = {Fatal intoxications in the north of portugal: 12 years of retrospective analysis}, author = {E A Alves and P Brandão and T Magalhães and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85011009004&doi=10.2174%2f1574886311666160724212407&partnerID=40&md5=b3ae583789ec2d486d85da4bc2dbd491}, doi = {10.2174/1574886311666160724212407}, year = {2016}, date = {2016-01-01}, volume = {11}, number = {3}, pages = {1-7}, abstract = {Fatal intoxications are a topic of great relevance in today’s society. This study retrospectively reviews fatal intoxication cases autopsied at the northern forensic medicine services of Portugal, between 2001 and 2013. For this purpose, we analyzed postmortem forensic medical reports with positive results for the presence of xenobiotics. A total of 27,778 autopsy reports were analyzed, of which 1,269 cases fulfilled the selection criteria, representing 4.6% of total number of individuals autopsied during the period under analysis. Men were involved in most of the cases (73.8%) and most individuals were adults with ages between 36 and 65 years old (57.0%). The highest incidences were medicines (22.9%) and alcohol (15.8%), followed by the association of these two xenobiotics. Cases of fatal intoxications involving opioids come on fifth place (5.8%) namely due to accidental overdoses. Moreover, intoxications appeared as the leading cause of death in reports concerning accidental ethiology, with drugs and alcohol associations having a great expression. Due to morbidity and relevant number of fatal cases, risk prevention measures, such as public health policies should be implemented to reduce the number of intoxications. © 2016 Bentham Science Publishers.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Fatal intoxications are a topic of great relevance in today’s society. This study retrospectively reviews fatal intoxication cases autopsied at the northern forensic medicine services of Portugal, between 2001 and 2013. For this purpose, we analyzed postmortem forensic medical reports with positive results for the presence of xenobiotics. A total of 27,778 autopsy reports were analyzed, of which 1,269 cases fulfilled the selection criteria, representing 4.6% of total number of individuals autopsied during the period under analysis. Men were involved in most of the cases (73.8%) and most individuals were adults with ages between 36 and 65 years old (57.0%). The highest incidences were medicines (22.9%) and alcohol (15.8%), followed by the association of these two xenobiotics. Cases of fatal intoxications involving opioids come on fifth place (5.8%) namely due to accidental overdoses. Moreover, intoxications appeared as the leading cause of death in reports concerning accidental ethiology, with drugs and alcohol associations having a great expression. Due to morbidity and relevant number of fatal cases, risk prevention measures, such as public health policies should be implemented to reduce the number of intoxications. © 2016 Bentham Science Publishers. |
Alves, E A; Brandão, P; Magalhães, T; Carvalho, F; Dinis-Oliveira, R J Fatal intoxications in the north of portugal: 12 years of retrospective analysis Journal Article Current Drug Safety, 11 (3), pp. 1-7, 2016, (cited By 0). @article{Alves20161b, title = {Fatal intoxications in the north of portugal: 12 years of retrospective analysis}, author = {E A Alves and P Brandão and T Magalhães and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85011009004&doi=10.2174%2f1574886311666160724212407&partnerID=40&md5=b3ae583789ec2d486d85da4bc2dbd491}, doi = {10.2174/1574886311666160724212407}, year = {2016}, date = {2016-01-01}, journal = {Current Drug Safety}, volume = {11}, number = {3}, pages = {1-7}, abstract = {Fatal intoxications are a topic of great relevance in today’s society. This study retrospectively reviews fatal intoxication cases autopsied at the northern forensic medicine services of Portugal, between 2001 and 2013. For this purpose, we analyzed postmortem forensic medical reports with positive results for the presence of xenobiotics. A total of 27,778 autopsy reports were analyzed, of which 1,269 cases fulfilled the selection criteria, representing 4.6% of total number of individuals autopsied during the period under analysis. Men were involved in most of the cases (73.8%) and most individuals were adults with ages between 36 and 65 years old (57.0%). The highest incidences were medicines (22.9%) and alcohol (15.8%), followed by the association of these two xenobiotics. Cases of fatal intoxications involving opioids come on fifth place (5.8%) namely due to accidental overdoses. Moreover, intoxications appeared as the leading cause of death in reports concerning accidental ethiology, with drugs and alcohol associations having a great expression. Due to morbidity and relevant number of fatal cases, risk prevention measures, such as public health policies should be implemented to reduce the number of intoxications. © 2016 Bentham Science Publishers.}, note = {cited By 0}, keywords = {}, pubstate = {published}, tppubtype = {article} } Fatal intoxications are a topic of great relevance in today’s society. This study retrospectively reviews fatal intoxication cases autopsied at the northern forensic medicine services of Portugal, between 2001 and 2013. For this purpose, we analyzed postmortem forensic medical reports with positive results for the presence of xenobiotics. A total of 27,778 autopsy reports were analyzed, of which 1,269 cases fulfilled the selection criteria, representing 4.6% of total number of individuals autopsied during the period under analysis. Men were involved in most of the cases (73.8%) and most individuals were adults with ages between 36 and 65 years old (57.0%). The highest incidences were medicines (22.9%) and alcohol (15.8%), followed by the association of these two xenobiotics. Cases of fatal intoxications involving opioids come on fifth place (5.8%) namely due to accidental overdoses. Moreover, intoxications appeared as the leading cause of death in reports concerning accidental ethiology, with drugs and alcohol associations having a great expression. Due to morbidity and relevant number of fatal cases, risk prevention measures, such as public health policies should be implemented to reduce the number of intoxications. © 2016 Bentham Science Publishers. |
Dinis-Oliveira, R J Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response Journal Article Drug Metabolism Reviews, 48 (4), pp. 568-576, 2016, (cited By 15). @article{Dinis-Oliveira2016568b, title = {Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response}, author = {R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84991110349&doi=10.1080%2f03602532.2016.1192642&partnerID=40&md5=9391afb3820c2b1dd3a67d6f3a6bba4d}, doi = {10.1080/03602532.2016.1192642}, year = {2016}, date = {2016-01-01}, journal = {Drug Metabolism Reviews}, volume = {48}, number = {4}, pages = {568-576}, abstract = {Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile. This review aims to discuss metabolomics of methadone, namely by presenting all major and minor metabolites and pharmacokinetic drug interactions. The main mechanism for methadone metabolism is hepatic through the cytochrome P450, specifically isoenzymes 2B6, 3A4 and 2D6. Firstly, methadone is N-demethylated and cyclize to form its major 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) metabolites. Several alternate minor pathways have been described namely various methadol metabolites, which proved to be active. It is expected that knowing the metabolomics of methadone may provide further insights, attempting a personalized therapy aiming to attain effective blood concentrations. The historical record is therefore especially important when investigating clinical and forensic cases related to methadone administration, since interindividual responses are known to vary considerably. © 2016 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 15}, keywords = {}, pubstate = {published}, tppubtype = {article} } Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile. This review aims to discuss metabolomics of methadone, namely by presenting all major and minor metabolites and pharmacokinetic drug interactions. The main mechanism for methadone metabolism is hepatic through the cytochrome P450, specifically isoenzymes 2B6, 3A4 and 2D6. Firstly, methadone is N-demethylated and cyclize to form its major 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) metabolites. Several alternate minor pathways have been described namely various methadol metabolites, which proved to be active. It is expected that knowing the metabolomics of methadone may provide further insights, attempting a personalized therapy aiming to attain effective blood concentrations. The historical record is therefore especially important when investigating clinical and forensic cases related to methadone administration, since interindividual responses are known to vary considerably. © 2016 Informa UK Limited, trading as Taylor & Francis Group. |
Barbosa, J; Faria, J; Queirós, O; Moreira, R; Carvalho, F; Dinis-Oliveira, R J Comparative metabolism of tramadol and tapentadol: a toxicological perspective Journal Article Drug Metabolism Reviews, 48 (4), pp. 577-592, 2016, (cited By 14). @article{Barbosa2016577b, title = {Comparative metabolism of tramadol and tapentadol: a toxicological perspective}, author = {J Barbosa and J Faria and O Queirós and R Moreira and F Carvalho and R J Dinis-Oliveira}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84991085677&doi=10.1080%2f03602532.2016.1229788&partnerID=40&md5=5435636519828c63a71e3947bf61f554}, doi = {10.1080/03602532.2016.1229788}, year = {2016}, date = {2016-01-01}, journal = {Drug Metabolism Reviews}, volume = {48}, number = {4}, pages = {577-592}, abstract = {Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol, and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy. © 2016 Informa UK Limited, trading as Taylor & Francis Group.}, note = {cited By 14}, keywords = {}, pubstate = {published}, tppubtype = {article} } Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol, and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy. © 2016 Informa UK Limited, trading as Taylor & Francis Group. |
Ricardo Dinis-Oliveira
PhD, European PhD, Post-Doc, DSc
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