RESUMO
Clopidogrel acyl-ß-d-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8 in human liver microsomes (HLMs). However, time-dependent inactivation (TDI) of CYP2C8 could not be detected in an earlier study in human recombinant CYP2C8 (Supersomes). Here, we investigate whether different enzyme sources exhibit differences in detection of CYP2C8 TDI under identical experimental conditions. Inactivation of CYP2C8 by amiodarone (100 µM), clopidogrel acyl-ß-d-glucuronide (100 µM), gemfibrozil 1-O-ß-glucuronide (100 µM), and phenelzine (100 µM) was investigated in HLMs and three recombinant human CYP2C8 preparations (Supersomes, Bactosomes, and EasyCYP Bactosomes) using amodiaquine N-deethylation as the marker reaction. Furthermore, the inactivation kinetics of CYP2C8 by clopidogrel glucuronide (5-250 µM) was determined in Supersomes and Bactosomes. Amiodarone caused weak TDI in all enzyme preparations tested, while the extent of inactivation by clopidogrel glucuronide, gemfibrozil glucuronide, and phenelzine varied markedly between preparations, and even different Supersome lots. Both glucuronides caused strong inactivation of CYP2C8 in HLMs, Bactosomes and in one Supersome lot (>50% inhibition), but significant inactivation could not be reliably detected in other Supersome lots or EasyCYP Bactosomes. In Bactosomes, the concentration producing half of kinact (KI) and maximal inactivation rate (kinact) of clopidogrel glucuronide (14 µM and 0.054 minute-1) were similar to those determined previously in HLMs. Phenelzine caused strong inactivation of CYP2C8 in one Supersome lot (91% inhibition) but not in HLMs or other recombinant CYP2C8 preparations. In conclusion, different enzyme sources and different lots of the same recombinant enzyme preparation are not equally sensitive to detect inactivation of CYP2C8, suggesting that recombinant CYPs should be avoided when identifying mechanism-based inhibitors.
Assuntos
Citocromo P-450 CYP2C8/metabolismo , Amiodarona/metabolismo , Clopidogrel/metabolismo , Genfibrozila/metabolismo , Glucuronídeos/metabolismo , Humanos , Cinética , Microssomos Hepáticos/metabolismo , Fenelzina/metabolismo , Sensibilidade e EspecificidadeRESUMO
AIM: The aim of the present case report was to describe a novel pharmacokinetic drugdrug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel. METHODS: The patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl-ß-D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry. RESULTS: The patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h−1, which was only 62% of the cohort geometric mean (385 l h−1; range 176726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100 µM clopidogrel acyl-ß-D-glucuronide inhibited the depletion rate of 0.5 µM paclitaxel by 51% and the formation rate of 6-hydroxypaclitaxel by 77%. CONCLUSION: This is the first report of a clopidogrelpaclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Inibidores do Citocromo P-450 CYP2C8/sangue , Síndromes Neurotóxicas/etiologia , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/efeitos adversos , Ticlopidina/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/metabolismo , Clopidogrel , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Neurotóxicas/sangue , Neoplasias Ovarianas/sangue , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Paclitaxel/uso terapêutico , Ticlopidina/administração & dosagem , Ticlopidina/sangue , Ticlopidina/uso terapêuticoRESUMO
AIM: The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers. METHODS: In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h. RESULTS: The area under the plasma concentration-time curve from 0 h to infinity (AUC0-∞) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0-∞ ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril. CONCLUSIONS: The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.
Assuntos
Hidrolases de Éster Carboxílico/genética , Enalapril/farmacocinética , Polimorfismo de Nucleotídeo Único/genética , Tetra-Hidroisoquinolinas/farmacocinética , Adulto , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/urina , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Enalapril/sangue , Enalapril/farmacologia , Enalapril/urina , Enalaprilato/sangue , Enalaprilato/urina , Feminino , Genótipo , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Quinapril , Tetra-Hidroisoquinolinas/sangue , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/urina , Adulto JovemRESUMO
BACKGROUND: Although buprenorphine therapy has proved to be successful in opioid maintenance treatments, the drug is also widely abused in many countries by intravenous injection or sniffing ("snorting"). In Finland, buprenorphine is the most important abused opioid causing fatal poisonings. PURPOSE: To evaluate the drug and alcohol findings as well as the cause and manner of death in all buprenorphine-related post-mortem cases for the age group 14-44 years in Finland from 2000 to 2008. METHOD: This was a retrospective analysis of data on opioid-associated deaths in the Finnish comprehensive postmortem toxicology database based on medico-legal autopsies, case background information and laboratory analyses. RESULTS: Buprenorphine was found in 29% of all 1,363 opioid-positive cases, and buprenorphine poisoning was the cause of death in 182 cases out of 391 buprenorphine-positive cases (47%). In these fatal poisonings, the blood buprenorphine/norbuprenorphine concentration ratio was significantly higher than in cases with other causes of death. The manner of death in buprenorphine poisonings that were almost exclusively accidental differed significantly from other buprenorphine-related cases, which also involved diseases and suicides. Death was immediate in 10% of fatal buprenorphine poisonings, was delayed, during sleep, in 52%, and followed an unknown course of events in 38%. In immediate poisonings, the median blood buprenorphine concentration (3.0 µg/l) was significantly higher than that in delayed poisonings (1.2 µg/l). In most buprenorphine poisonings (92%), no opioids other than buprenorphine were involved, but benzodiazepines and alcohol were found in 82 and 58% of cases, respectively. The median concentrations of opioids and benzodiazepines in buprenorphine poisonings were in the therapeutic range. Only one fatal poisoning was found in which neither alcohol nor drugs other than buprenorphine were found. CONCLUSION: A fatal buprenorphine poisoning is typically accidental, and the average victim is a 27-year-old male addict. Circumstantial and environmental factors seem to be crucial in determining the outcome of the poisoning.
Assuntos
Analgésicos Opioides/intoxicação , Benzodiazepinas/sangue , Buprenorfina/intoxicação , Depressores do Sistema Nervoso Central/sangue , Etanol/sangue , Adolescente , Adulto , Analgésicos Opioides/sangue , Buprenorfina/sangue , Causas de Morte , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Adulto JovemRESUMO
Venlafaxine (VEN) is an antidepressant found to possess a higher fatal toxicity index (FTI, i.e., deaths in proportion to consumption) than other newer antidepressants and selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to elucidate using post-mortem cases whether the apparent high toxicity of VEN is associated with adverse drug interactions, pharmacogenetic factors and/or the manner of death. Within a 2-year period, a comprehensive post-mortem database and death certificates were searched for cases with laboratory findings of VEN, findings of other drugs, associated background information and the cause and manner of death. In 123 cases, the concentrations of VEN and its two metabolites, O-desmethylvenlafaxine (O-VEN) and N-desmethylvenlafaxine (N-VEN), and the CYP2D6 genotype were determined in post-mortem blood. The median concentrations of VEN, O-VEN and N-VEN were 560, 420 and 49 µg/l, respectively. A prominent feature of the VEN-positive cases was the high abundance of interacting drugs (46%), being more common with higher VEN concentrations. Compared to other common antidepressants, VEN-positive cases showed the highest suicide frequency, but also the proportion of suicidal VEN poisonings of all suicides was substantially higher than that of mirtazapine or SSRIs. Relative CYP2D6 activity did not predispose to high VEN concentrations, and the frequency of the extreme phenotypes followed the general population. In conclusion, the high suicide potential of VEN in combination with the high prevalence of drugs causing adverse interactions could be the reason for the observed high FTI.
Assuntos
Antidepressivos de Segunda Geração/intoxicação , Cicloexanóis/intoxicação , Inibidores Seletivos de Recaptação de Serotonina/intoxicação , Cicloexanóis/farmacocinética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Bases de Dados Factuais , Succinato de Desvenlafaxina , Interações Medicamentosas , Feminino , Patologia Legal , Cromatografia Gasosa-Espectrometria de Massas , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Cloridrato de VenlafaxinaRESUMO
INTRODUCTION: To obtain reliable information on nicotine and drug use through a population-based study, the prevalence of nicotine use in deceased young adults was studied in the Finnish postmortem toxicology database for a 3-year period. The nicotine user and non-nicotine user groups were compared by alcohol, drug, and drug-of-abuse findings and by the manner of death. METHODS: Nicotine users were identified based on detection of nicotine, cotinine, and/or trans-3'-hydroxycotinine in urine from a population-based sample of deceased young adults aged 15-34 years at the time of death (n = 1,623, â¼60% of all fatalities). Background information from case referrals was used to distinguish the abuse of medicines from their therapeutic use. The manner of death was taken from death certificates. RESULTS: Nicotine use was more common in young adults (75%) than among all cases in the database (55%). There were twice as many ethanol-positive cases in nicotine users (60%) than in non-nicotine users (30%). Nicotine use was common (70%-79%) among individuals on antipsychotics, antidepressants, anxiolytics, and/or hypnotics and sedatives. The proportion of nicotine users was also high among the drugs-of-abuse positive cases (85%). There were fewer deaths that were classified as natural in the nicotine users group. CONCLUSIONS: Among deceased young adults, nicotine use was two to three times as common as has been estimated for the corresponding living population (20%-30%). Nicotine use was also strongly associated with substance abuse and mental illnesses requiring pharmacotherapy. This group of young adults usually cannot be reached by traditional health surveys.
Assuntos
Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Tabagismo/epidemiologia , Adolescente , Adulto , Autopsia , Causas de Morte , Cotinina/urina , Etanol/urina , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Nicotina/urina , Psicotrópicos/urina , Transtornos Relacionados ao Uso de Substâncias/urina , Tabagismo/urina , Urina/química , Adulto JovemRESUMO
We developed an in vitro high-throughput cocktail assay with nine major drug-metabolizing CYP enzymes, optimized for screening of time-dependent inhibition. The method was applied to determine the selectivity of the time-dependent CYP2C8 inhibitors gemfibrozil 1-O-ß-glucuronide and clopidogrel acyl-ß-D-glucuronide. In vitro incubations with CYP selective probe substrates and pooled human liver microsomes were conducted in 96-well plates with automated liquid handler techniques and metabolite concentrations were measured with quantitative UHPLC-MS/MS analysis. After determination of inter-substrate interactions and Km values for each reaction, probe substrates were divided into cocktails I (tacrine/CYP1A2, bupropion/CYP2B6, amodiaquine/CYP2C8, tolbutamide/CYP2C9 and midazolam/CYP3A4/5) and II (coumarin/CYP2A6, S-mephenytoin/CYP2C19, dextromethorphan/CYP2D6 and astemizole/CYP2J2). Time-dependent inhibitors (furafylline/CYP1A2, selegiline/CYP2A6, clopidogrel/CYP2B6, gemfibrozil 1-O-ß-glucuronide/CYP2C8, tienilic acid/CYP2C9, ticlopidine/CYP2C19, paroxetine/CYP2D6 and ritonavir/CYP3A) and direct inhibitor (terfenadine/CYP2J2) showed similar inhibition with single substrate and cocktail methods. Established time-dependent inhibitors caused IC50 fold shifts ranging from 2.2 to 30 with the cocktail method. Under time-dependent inhibition conditions, gemfibrozil 1-O-ß-glucuronide was a strong (>90% inhibition) and selective (<< 20% inhibition of other CYPs) inhibitor of CYP2C8 at concentrations ranging from 60 to 300 µM, while the selectivity of clopidogrel acyl-ß-D-glucuronide was limited at concentrations above its IC80 for CYP2C8. The time-dependent IC50 values of these glucuronides for CYP2C8 were 8.1 and 38 µM, respectively. In conclusion, a reliable cocktail method including the nine most important drug-metabolizing CYP enzymes was developed, optimized and validated for detecting time-dependent inhibition. Moreover, gemfibrozil 1-O-ß-glucuronide was established as a selective inhibitor of CYP2C8 for use as a diagnostic inhibitor in in vitro studies.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Espectrometria de Massas em Tandem , Citocromo P-450 CYP2C8 , Inibidores do Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450 , Interações Medicamentosas , Humanos , Microssomos HepáticosRESUMO
PURPOSE: The aim of the study was to establish the prevalence and nature of potential adverse drug combinations of warfarin in a large post-mortem toxicology database. The concomitant use of warfarin and non-steroidal anti-inflammatory drugs (NSAIDs) was of interest as these drugs have been associated with internal bleeding both in clinical and post-mortem study settings. Another purpose was to obtain facts related to the questioned safety of warfarin-paracetamol and warfarin-tramadol combinations. METHODS: The post-mortem database was searched for a 1-year period. All warfarin-positive cases and cases containing interacting drugs, as defined by the SFINX interaction database (Swedish, Finnish, Interaction X-referencing), were included. For controls, all cases containing paracetamol or tramadol were also included, and for each warfarin-positive case, an age-, sex- and alcohol-matched control case was sourced. The contribution of anticoagulant use to the deaths was evaluated from the death certificates based on medico-legal autopsies. RESULTS: In 33% of the 328 warfarin-positive cases, at least one interacting drug was present, and paracetamol was the most abundant, accounting for 49% (n = 53). When paracetamol and warfarin were detected simultaneously, the number of fatal bleeds was 4.6 and 2.7 times higher compared to paracetamol or warfarin use alone respectively. The presence of an NSAID in combination with warfarin was rare, as only six cases were identified. A majority (66%) of the post-mortem blood samples had a warfarin concentration below 0.5 mg/l, and for the rest of the cases, the mean concentration was 0.70 mg/l. CONCLUSIONS: This study supports the clinical evidence suggesting that warfarin-paracetamol interactions may create significant life-threatening conditions. It also accentuates the significant role post-mortem database research can have in improving drug safety.
Assuntos
Acetaminofen/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos , Analgésicos não Narcóticos/efeitos adversos , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Varfarina/efeitos adversos , Acetaminofen/administração & dosagem , Idoso , Analgésicos não Narcóticos/administração & dosagem , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anticoagulantes/administração & dosagem , Autopsia , Causas de Morte , Bases de Dados Factuais , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tramadol/administração & dosagem , Tramadol/efeitos adversos , Varfarina/administração & dosagemRESUMO
In vitro, esomeprazole is a time-dependent inhibitor of CYP2C19. Additionally, racemic omeprazole induces CYP1A2 and omeprazole and its metabolites inhibit CYP3A4 in vitro. In this 5-phase study, 10 healthy volunteers ingested 20 mg pantoprazole, 0.5 mg midazolam, and 50 mg caffeine as respective index substrates for CYP2C19, 3A4, and 1A2 before and 1, 25, 49 (pantoprazole only), and 73 hours after an 8-day pretreatment with 80 mg esomeprazole twice daily. The area under the plasma concentration-time curve (AUC) of R-pantoprazole increased 4.92-fold (90% confidence interval (CI) 3.55-6.82), 2.31-fold (90% CI 1.85-2.88), and 1.33-fold (90% CI 1.06-1.68) at the 1-hour, 25-hour, and 73-hour phases, respectively, consistent with a substantial and persistent inhibition of CYP2C19. The AUC of midazolam increased up to 1.44-fold (90% CI 1.22-1.72) and the paraxanthine/caffeine metabolic ratio up to 1.19-fold (90% CI 1.04-1.36), when the index substrates were taken 1 hour after esomeprazole. Based on the recovery of R-pantoprazole oral clearance, the turnover half-life of CYP2C19 was estimated to average 53 hours. Pharmacokinetic simulation based on the observed concentrations of esomeprazole and its metabolites as well as their published CYP2C19 inhibitory constants was well in line with the observed changes in R-pantoprazole pharmacokinetics during the course of the study. Extrapolations assuming linear pharmacokinetics of esomeprazole suggested weak to moderate inhibition at 20 and 40 mg twice daily dosing. In conclusion, high-dose esomeprazole can cause strong inhibition of CYP2C19, but only weakly inhibits CYP3A4 and leads to minor induction of CYP1A2. The enzymatic activity of CYP2C19 recovers gradually in ~ 3-4 days after discontinuation of esomeprazole treatment.
Assuntos
Citocromo P-450 CYP1A2/metabolismo , Inibidores do Citocromo P-450 CYP2C19/farmacologia , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/metabolismo , Esomeprazol/farmacologia , Administração Oral , Cafeína/farmacocinética , Estudos Cross-Over , Indutores do Citocromo P-450 CYP1A2/farmacologia , Citocromo P-450 CYP2C19/genética , Inibidores do Citocromo P-450 CYP2C19/administração & dosagem , Inibidores do Citocromo P-450 CYP2C19/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Esomeprazol/administração & dosagem , Esomeprazol/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Midazolam/farmacocinética , Modelos Biológicos , Pantoprazol/farmacocinética , Variantes FarmacogenômicosRESUMO
To investigate how variability in multiple pharmacokinetic genes associates with telmisartan exposure, we determined telmisartan single-dose (40 mg) pharmacokinetics and sequenced 379 genes in 188 healthy volunteers. Intronic UGT1A variants showed the strongest associations with the area under the plasma concentration-time curve from zero hours to infinity (AUC0-∞ ) and peak plasma concentration (Cmax ) of telmisartan. These variants were strongly linked with the increased function UGT1A3*2 allele, suggesting that it is the causative allele underlying these associations. In addition, telmisartan plasma concentrations were lower in men than in women. The UGT1A3*2 was associated with a 64% and 63% reduced AUC0-∞ of telmisartan in UGT1A3*2 heterozygous and homozygous men, respectively (P = 1.21 × 10-16 and 5.21 × 10-8 ). In women, UGT1A3*2 heterozygosity and homozygosity were associated with 57% (P = 1.54 × 10-11 ) and 72% (P = 3.31 × 10-15 ) reduced AUC0-∞ , respectively. Furthermore, a candidate gene analysis suggested an association of UGT1A3*3 and the SLCO1B3 c.767G>C missense variant with telmisartan pharmacokinetics. A genotype score, which reflects the effects of sex and genetic variants on telmisartan AUC0-∞ , associated with the effect of telmisartan on diastolic blood pressure. These data indicate that sex and UGT1A3 are major determinants and suggest a role for OATP1B3 in telmisartan pharmacokinetics.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Glucuronosiltransferase/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Telmisartan/farmacocinética , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/sangue , Feminino , Glucuronosiltransferase/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Mutação de Sentido Incorreto , Farmacogenética , Fatores Sexuais , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Telmisartan/administração & dosagem , Telmisartan/sangue , Adulto JovemRESUMO
The prevalence of important adverse drug combinations was studied among the 37,367 cases included in the Finnish post-mortem toxicology database during 2000-2006. The new SFINX interaction database (Swedish, Finnish, INteraction X-referencing) was utilised to identify adverse drug combinations. Consequently, the 24 drugs chosen for the study generated 96 two-compound combinations possessing potentially severe interactions. The total number of hits for the combinations found in the post-mortem database was 267, which accounts for approximately 0.71% of all cases. The potential role of adverse drug interaction (ADI) in these cases was evaluated from the background information and death certificate. The possible ADI cases comprised 23% of all hits and 0.17% of all cases analysed. In cases with a pharmacodynamic mechanism, the most prominent combinations were medicines causing serotonin syndrome or a beta(1)-blocker with verapamil or diltiazem. In cases with a pharmacokinetic mechanism, half of the cases involved digoxin in combination with verapamil. In one third of the possible ADI cases, a forensic pathologist had noted the studied compounds as an underlying or contributing cause of death, although the agents' specific role in ADIs was rarely recognised.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Interações Medicamentosas , Causas de Morte , Bases de Dados Factuais , Feminino , Finlândia , Toxicologia Forense , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Therapeutic drug concentrations measured in plasma are of limited value as reference intervals for interpretation in post-mortem (PM) toxicology. In this study, drug concentration distributions were studied in PM femoral venous blood from 57 903 Finnish autopsy cases representing all causes of death during an 11-year period. Cause-of-death information was obtained from death certificates issued by forensic pathologists. Median, mean, and upper percentile (90th, 95th, 97.5th) concentrations were calculated for 129 drugs. To illustrate how PM median concentrations relate to established therapeutic ranges in plasma, a PM blood/plasma relationship was calculated for each drug. Males represented 75% of the subjects and showed a lower median age (55 yrs) than females (59 yrs). In 43% of these cases, blood alcohol concentration was higher than 0.2, and the median was 1.8. Sixty-one (47%) of the 129 drugs showed a PM blood/plasma relationship of 1. For 22 drugs (17%), the relationship was <1, and for 46 drugs (35%), the relationship was >1. No marked correlation was found between the PM blood/plasma relationship and the volume of distribution (Vd ). For 36 drugs, more than 10% of cases were fatal poisonings attributed to this drug as the main finding. These drug concentration distributions based on a large database provide a helpful reference not only to forensic toxicologists and pathologists but also to clinical pharmacologists in charge of interpreting drug concentrations in PM cases.
Assuntos
Preparações Farmacêuticas/sangue , Mudanças Depois da Morte , Adulto , Idoso , Causas de Morte , Feminino , Toxicologia Forense , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Meconium drug testing is a non-invasive method to detect prenatal drug exposure, which can cause severe problems for the infant, indicating the need for follow-up measures to ensure the welfare of the child. Meconium samples for drug testing were collected from 143 infants as part of routine clinical work among addicted mothers. The drug testing findings were combined with medical records including clinical background and follow-up data. The substances screened for included medicinal opioids, 6-monoacetylmorphine (a metabolite of heroin), amphetamines and tetrahydrocannabinolic acid. At least one of the 13 target drugs was detected in 57 (40%) meconium samples. In 21 cases, the findings were unexpected on the basis of clinical data or denied by the mother. Medicinal opioids, especially the opioid substitution treatment drugs buprenorphine and methadone, comprised the majority of the findings of both admitted and unexpected drug misuse. Meconium drug testing methods should target not just traditional illicit drugs but also prescription drugs with misuse potential.
Assuntos
Mecônio/química , Síndrome de Abstinência Neonatal/diagnóstico , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Detecção do Abuso de Substâncias/métodos , Feminino , Seguimentos , Humanos , Recém-Nascido , Mecônio/metabolismo , Síndrome de Abstinência Neonatal/epidemiologia , Síndrome de Abstinência Neonatal/metabolismo , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Detecção do Abuso de Substâncias/normasRESUMO
There is a rising trend of fatal poisonings due to medicinal opioids in several countries. The present study evaluates the drug and alcohol findings as well as the cause and manner of death in opioid-related post-mortem cases in Finland from 2000 to 2008. During this period, fatal poisonings by prescription opioids (buprenorphine, codeine, dextropropoxyphene, fentanyl, methadone, oxycodone, tramadol) increased as a share of all drug poisonings from 9.5% to 32.4%, being 22.3% over the whole period. A detailed study including the most prevalent opioids was carried out for the age group of 14-44 years, which is the most susceptible age for drug abuse in Finland. Poisonings by the weak opioids, codeine and tramadol, were found to be associated with large, often suicidal overdoses resulting in high drug concentrations in blood. Methadone poisonings were associated with accidental overdoses with the drug concentration in blood remaining within a therapeutic range. The manner of death was accidental in 43%, 55% and 94% of cases in codeine, tramadol and methadone poisonings, respectively. The median concentration of codeine and the median codeine/morphine concentration ratio were higher in codeine poisonings (1.4 and 22.5 mg/l, respectively) than in other causes of death (0.09 and 5.9 mg/l, respectively). The median concentrations of tramadol and O-desmethyltramadol were higher in tramadol poisonings (5.3 and 0.8 mg/l, respectively) than in other causes of death (0.6 and 0.2 mg/l, respectively). In methadone poisonings, the median concentration of methadone (0.35 mg/l) was not different from that in other causes of death (0.30 mg/l). Sedative drugs and/or alcohol were very frequently found in fatal poisonings involving these prescription opioids.