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Relevant toxicokinetic and dynamic differences in ecstasy-induced toxic effects
Abstracts / Toxicology Letters 211S (2012) S43–S216
some hypnotic and haemodynamic depressant effects and/or may amplify the propofol effects during anaesthesia. References Simons, P.J., et al., 1991. Species differences in blood profiles, metabolism and excretion of 14 C-propofol after intravenous dosing to rat, dog and rabbit. Xenobiotica 21 (10), 1243–1256. Silva, A., et al., 2011. Performance of anesthetic depth indexes in rabbits under propofol anesthesia: prediction probabilities and concentration–effect relations. Anesthesiology.
doi:10.1016/j.toxlet.2012.03.224
P06-06 Evaluation of quetiapine therapy in patients with generalized anxiety disorder Daniela Ionescu 1 , Cristina Dehelean 1 , Simona Funar-Timofei 2 , Elena Galca 3 , Raluca Dumache 1 , Codruta Soica 1 University of Medicine and Pharmacy, Romania, 2 Romanian Academy, Romania, 3 Psychiatry Hospital, Romania
S57
ticides 5%, poisonous mushrooms 4%, ethanol 3%, toxic gases from fires (2%) and carbon monoxyde (1%), Datura stramonium, colchicines and lead, very rare. Severe rhabdomyolysis was caused by 2,4-dichlorophenoxyacetic acid, opiates alone or combined with benzodiazepine (two cases), multiple drug intake (benzodiazepines and atypical antipsychotics) and illicit psychoactive substance use. Total of 12% patients developed acute renal failure (ARF), mostly due to toxicity characteristics, except in combined drugs (moderate) and two (severe rhabdomyolysis) heroin-overdose predominantly rhabdomyolytic. ARF, latest with fatal outcomes. Death was noted in 60% ARF patients and in 13% all rhabdomyolytic patients. Conclusion of the study: Rhabdomyolysis is common in acute poisonings, mostly caused by psychotropic agents. Aggressive therapy is necessary. doi:10.1016/j.toxlet.2012.03.226
P06-08 Relevant toxicokinetic and dynamic differences in ecstasy-induced toxic effects
1
Purpose: Generalized anxiety disorder (GAD) represents a chronic mental disorder associated with significant morbidity and disability. Traditional therapies are associated with poor levels of remission, and often result some side effects. Methods: Our study was made along the 12 week (June 2011–September 2011) with a flexible dose to assess the efficacy and tolerability of quetiapine as an adjunctive treatment to traditional medication. 60 outpatients with GAD who had not achieved remission following at least 8 weeks of an adequate dose of traditional therapy were enrolled. The primary endpoint was the mean change from pre-treatment to week 12 in the Hamilton Anxiety Rating Scale (HAM-A) total scores. Secondary endpoints included: the proportion of patients achieving remission (HAM-A total score of ≤10 at week 12), Clinical Global Impressions-Severity of Illness, Clinical Global ImpressionsGlobal Improvement and Penn State Worry Questionnaire. Results and conclusion: Adjunctive quetiapine (mean dose 368 mg/day) significantly reduced the HAM-A total scores from pre-treatment (28.7 ± 5.4) to week 12 (9.2 ± 8.6). doi:10.1016/j.toxlet.2012.03.225
P06-07 Rhabdomyolysis in acute poisonings: 229 hospitalized patients Snezana Jankovic, Jasna Jovic-Stosic, Silva Dobric, Slavica Vucinic Military Medical Academy, Serbia Purpose: The purpose of this study is to determine the incidence, etiology and clinical course of rhabdomyolysis in the patients with acute poisoning. Methods: We evaluated the hospital charts of 972 patients treated from January 1 to December 31, 2009. According to PSS score, all poisoned patients with rhabdomyolysis were classified into groups: with mild-creatine kinase (CK) 250–1500 U/L, moderate (CK 1500–10,000 U/L) and severe rhabdomyolysis (CK > 10,000 U/L). Results: Out of 811 poisoned patients, rhabdomyolysis occurred in 229 (27%) patients (122 male; age mean, 40 years). Mild, moderate and severe rhabdomyolysis had 145 (63%), 77 (34%) and 7 (3%) patients, respectively. Most common were drugs (60%), rather psychotropic drugs (52% cases – benzodiazepines 28%, antipsychotics 8%, carbamazepine 5%, antidepressants 4%), then opiates 10%, corrosives 7%, pes-
Laura Hondebrink, Saskia Rietjens, Jan Meulenbelt University Medical Center Utrecht, Netherlands Purpose: Despite >2000 published articles on ecstasy (MDMA) it remains unclear which mechanisms are most relevant for acute intoxications and treatment. Triage and treatment of intoxicated patients is complicated by variability in clinical effects and could improve through insight in interindividual differences in MDMA toxicokinetics and dynamics. Approach: A comprehensive search in PubMed was performed of all published articles regarding MDMA. Findings: Several enzymes are involved in MDMA metabolism and although CYP2D6 is the main phase I enzyme, CYP3A4 also seems important. Low CYP2D6 activity polymorphisms reduce MDMA metabolism and increase MDMA levels. Polymorphic-induced low activities of phase II enzymes likely enhance MDMA-induced toxicity via accumulation of highly reactive MDMA metabolites and subsequent oxidative stress which increases even further by autooxidation of accumulated neurotransmitters. Co-ingestion of other xenobiotics may cause inhibition or induction of enzymes involved in MDMA metabolism and consequently may influence MDMA toxicity. Neurotransmitter transporters and receptors involved in toxicodynamic brain effects are also polymorphic expressed, contributing to variable MDMA-induced clinical effects. Furthermore, co-exposure to serotonergic drugs increases the risk for the serotonin syndrome, a serious clinical complication. Implications: Specific combinations of polymorphisms increase susceptibility for MDMA-induced toxicity. The relevance of polymorphisms in pharmacokinetics and dynamics should be investigated by genotyping individuals with a clinically severe MDMA intoxication. Research should focus on translating knowledge on mechanisms of action into implementation for clinical toxicology. For example, treatment of ecstasy-intoxicated patients can be optimized when the individual vulnerability due to polymorphisms, tolerance and concomitant drug use is known. doi:10.1016/j.toxlet.2012.03.227
P06-09 Methylphenidate exposure: What is the risk? Saskia Rietjens, Laura Hondebrink, Jan Meulenbelt, Irma de Vries University Medical Center Utrecht, Netherlands
some hypnotic and haemodynamic depressant effects and/or may amplify the propofol effects during anaesthesia. References Simons, P.J., et al., 1991. Species differences in blood profiles, metabolism and excretion of 14 C-propofol after intravenous dosing to rat, dog and rabbit. Xenobiotica 21 (10), 1243–1256. Silva, A., et al., 2011. Performance of anesthetic depth indexes in rabbits under propofol anesthesia: prediction probabilities and concentration–effect relations. Anesthesiology.
doi:10.1016/j.toxlet.2012.03.224
P06-06 Evaluation of quetiapine therapy in patients with generalized anxiety disorder Daniela Ionescu 1 , Cristina Dehelean 1 , Simona Funar-Timofei 2 , Elena Galca 3 , Raluca Dumache 1 , Codruta Soica 1 University of Medicine and Pharmacy, Romania, 2 Romanian Academy, Romania, 3 Psychiatry Hospital, Romania
S57
ticides 5%, poisonous mushrooms 4%, ethanol 3%, toxic gases from fires (2%) and carbon monoxyde (1%), Datura stramonium, colchicines and lead, very rare. Severe rhabdomyolysis was caused by 2,4-dichlorophenoxyacetic acid, opiates alone or combined with benzodiazepine (two cases), multiple drug intake (benzodiazepines and atypical antipsychotics) and illicit psychoactive substance use. Total of 12% patients developed acute renal failure (ARF), mostly due to toxicity characteristics, except in combined drugs (moderate) and two (severe rhabdomyolysis) heroin-overdose predominantly rhabdomyolytic. ARF, latest with fatal outcomes. Death was noted in 60% ARF patients and in 13% all rhabdomyolytic patients. Conclusion of the study: Rhabdomyolysis is common in acute poisonings, mostly caused by psychotropic agents. Aggressive therapy is necessary. doi:10.1016/j.toxlet.2012.03.226
P06-08 Relevant toxicokinetic and dynamic differences in ecstasy-induced toxic effects
1
Purpose: Generalized anxiety disorder (GAD) represents a chronic mental disorder associated with significant morbidity and disability. Traditional therapies are associated with poor levels of remission, and often result some side effects. Methods: Our study was made along the 12 week (June 2011–September 2011) with a flexible dose to assess the efficacy and tolerability of quetiapine as an adjunctive treatment to traditional medication. 60 outpatients with GAD who had not achieved remission following at least 8 weeks of an adequate dose of traditional therapy were enrolled. The primary endpoint was the mean change from pre-treatment to week 12 in the Hamilton Anxiety Rating Scale (HAM-A) total scores. Secondary endpoints included: the proportion of patients achieving remission (HAM-A total score of ≤10 at week 12), Clinical Global Impressions-Severity of Illness, Clinical Global ImpressionsGlobal Improvement and Penn State Worry Questionnaire. Results and conclusion: Adjunctive quetiapine (mean dose 368 mg/day) significantly reduced the HAM-A total scores from pre-treatment (28.7 ± 5.4) to week 12 (9.2 ± 8.6). doi:10.1016/j.toxlet.2012.03.225
P06-07 Rhabdomyolysis in acute poisonings: 229 hospitalized patients Snezana Jankovic, Jasna Jovic-Stosic, Silva Dobric, Slavica Vucinic Military Medical Academy, Serbia Purpose: The purpose of this study is to determine the incidence, etiology and clinical course of rhabdomyolysis in the patients with acute poisoning. Methods: We evaluated the hospital charts of 972 patients treated from January 1 to December 31, 2009. According to PSS score, all poisoned patients with rhabdomyolysis were classified into groups: with mild-creatine kinase (CK) 250–1500 U/L, moderate (CK 1500–10,000 U/L) and severe rhabdomyolysis (CK > 10,000 U/L). Results: Out of 811 poisoned patients, rhabdomyolysis occurred in 229 (27%) patients (122 male; age mean, 40 years). Mild, moderate and severe rhabdomyolysis had 145 (63%), 77 (34%) and 7 (3%) patients, respectively. Most common were drugs (60%), rather psychotropic drugs (52% cases – benzodiazepines 28%, antipsychotics 8%, carbamazepine 5%, antidepressants 4%), then opiates 10%, corrosives 7%, pes-
Laura Hondebrink, Saskia Rietjens, Jan Meulenbelt University Medical Center Utrecht, Netherlands Purpose: Despite >2000 published articles on ecstasy (MDMA) it remains unclear which mechanisms are most relevant for acute intoxications and treatment. Triage and treatment of intoxicated patients is complicated by variability in clinical effects and could improve through insight in interindividual differences in MDMA toxicokinetics and dynamics. Approach: A comprehensive search in PubMed was performed of all published articles regarding MDMA. Findings: Several enzymes are involved in MDMA metabolism and although CYP2D6 is the main phase I enzyme, CYP3A4 also seems important. Low CYP2D6 activity polymorphisms reduce MDMA metabolism and increase MDMA levels. Polymorphic-induced low activities of phase II enzymes likely enhance MDMA-induced toxicity via accumulation of highly reactive MDMA metabolites and subsequent oxidative stress which increases even further by autooxidation of accumulated neurotransmitters. Co-ingestion of other xenobiotics may cause inhibition or induction of enzymes involved in MDMA metabolism and consequently may influence MDMA toxicity. Neurotransmitter transporters and receptors involved in toxicodynamic brain effects are also polymorphic expressed, contributing to variable MDMA-induced clinical effects. Furthermore, co-exposure to serotonergic drugs increases the risk for the serotonin syndrome, a serious clinical complication. Implications: Specific combinations of polymorphisms increase susceptibility for MDMA-induced toxicity. The relevance of polymorphisms in pharmacokinetics and dynamics should be investigated by genotyping individuals with a clinically severe MDMA intoxication. Research should focus on translating knowledge on mechanisms of action into implementation for clinical toxicology. For example, treatment of ecstasy-intoxicated patients can be optimized when the individual vulnerability due to polymorphisms, tolerance and concomitant drug use is known. doi:10.1016/j.toxlet.2012.03.227
P06-09 Methylphenidate exposure: What is the risk? Saskia Rietjens, Laura Hondebrink, Jan Meulenbelt, Irma de Vries University Medical Center Utrecht, Netherlands