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  • 151.
    Jakobsen Falk, Ingrid
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Khan, Muhammad Suleman
    COMSATS Institute of Information Technology, Abbottabad, Pakistan.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nahi, Hareth
    Karolinska University Hospital and Karolinska Institutet, Huddinge, Sweden.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Association of CYP2B6 Genotype with Survival and Progression Free Survival in Cyclophosphamide Treated Multiple Myeloma2012Inngår i: Journal of Cancer Therapy, ISSN 2151-1934, E-ISSN 2151-1942, Vol. 3, nr 1, s. 20-27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Cyclophosphamide is a conventional pro-drug used in Multiple Myeloma (MM) and other malignancies. The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST en-zymes are involved in detoxification. Polymorphisms of these enzymes may affect enzyme expression and function as well as treatment outcome. The aim of this study was to investigate the impact of the CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 SNP Ile105Val, and GSTM1 and GSTT1 null variants, on the outcome for cyclophosphamide treated MM patients, in order to find markers of value for individualised therapy. Methods: We used allele specific PCR and Pyrosequencing to investigate the impact of CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 Ile105Val, and GSTM1 and GSTT1 variants, on the outcome for 26 cyclophosphamide treated multiple myeloma patients. Results and Major Conclusion:

    The CYP2B6 785G carriers had significantly shorter progression free survival (p = 0.048*) and overall survival (p = 0.037*) with 785G/G patients having the worst outcome compared to patients carrying the wild type. A shorter progression free survival was also indicated in patients carrying both CYP2B6 516T & 785G (p = 0.068). These results indicate a predictive role of CYP2B6 SNPs, particularly A785G, in cyclophosphamide treatment.

  • 152.
    Johansson, Inger
    et al.
    Fakulteten för samhälls- och livsvetenskaper, Avdelningen för omvårdnad, Karlstads universitet.
    Hamrin, Elisabeth
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bedömning av akut förvirringstillstånd med hjälp av NEECHAM Confusion Scale2009Inngår i: Vård i Norden, ISSN 0107-4083, E-ISSN 1890-4238, Vol. 29, nr 2, s. 42-43Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To assess and identify early sign as well as to follow up the progress or regress of acute confusion are important in nursing care. For this purpose different instruments have been developed and tested psychometrically. One of these instruments is the NEECHAM Confusion Scale. The aim of this article is to describe the development and content of the NEECHAM Confusion Scale and its application in a Swedish sample. This scale is a screening instrument for rapid and non-intrusive assessment and contains nine items organized in three domains; cognitive functions; behavioral measures; physiological control and stability. Possible total score ranging from 0 (minimal responsiveness) to 30 (normal function). A score equal to or less than 24 indicated the presence of confusion. The scale has been psychometrically tested among elderly patients with hip fractures in Sweden. The internal consistency (Cronbach´s alpha coefficient) was satisfactory at two test occasions .73 versus .82 and the construct validity with a three-factor solution accounted for 69% and 73% of the variance. Four months after discharge the predictive value showed a correlation between level of confusion, quality of life, and functional capacity. The study and the literature confirmed that the NEECHAM-scale can be helpful both for patients with delirium and those responsible of the care.

  • 153.
    Johansson, Marie-Louise
    et al.
    Sahlgrens University Hospital.
    Brunlof, Gertrud
    Sahlgrens University Hospital.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Wallerstedt, Susanna M
    Sahlgrens University Hospital.
    Effects of a One Page ADR Information Letter on the Reporting Rate and the Information Value of ADR Reports2009Inngår i: in PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, vol 18, 2009, Vol. 18, s. S251-S252Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 154.
    Johansson, Marie-Louise
    et al.
    Sahlgrenska University Hospital.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Wallerstedt, Susanna M
    Sahlgrenska University Hospital.
    Impact of information letters on the reporting rate of adverse drug reactions and the quality of the reports: a randomized controlled study2011Inngår i: BMC clinical pharmacology, ISSN 1472-6904, Vol. 11, nr 14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Spontaneous reporting of adverse drug reactions (ADRs) is an important method for pharmacovigilance, but under-reporting and poor quality of reports are major limitations. The aim of this study was to evaluate if repeated one-page ADR information letters affect (i) the reporting rate of ADRs and (ii) the quality of the ADR reports.

    METHODS: All 151 primary healthcare units in the Region Västra Götaland, Sweden, were randomly allocated (1:1) to an intervention (n = 77) or a control group (n = 74). The intervention consisted of one-page ADR information letters administered at three occasions during 2008 to all physicians and nurses in the intervention units. The number of ADR reports received from the 151 units was registered, as was the quality of the reports, which was defined as high if the ADR was to be reported according to Swedish regulations, that is, if the ADR was (i) serious, (ii) unexpected, and/or (iii) related to the use of new drugs and not labelled as common in the Summary of Product Characteristics. A questionnaire was administered to evaluate if the ADR information letter had reached the intended recipient.

    RESULTS: Before the intervention, no significant differences in reporting rate or number of high quality reports could be detected between the randomization groups. In 2008, 79 reports were sent from 37 intervention units and 52 reports from 30 control units (mean number of reports per unit ± standard deviation: 1.0 ± 2.5 vs. 0.7 ± 1.2, P = 0.34). The number of high quality reports was higher in intervention units than in control units (37 vs. 15 reports, 0.5 ± 0.9 vs. 0.2 ± 0.6, P = 0.048). According to the returned questionnaires (n = 1,292, response rate 57%), more persons in the intervention than in the control group had received (29% vs. 19%, P < 0.0001) and read (31% vs. 26%, P < 0.0001) an ADR information letter.

    CONCLUSIONS: This study suggests that repeated ADR information letters to physicians and nurses do not increase the ADR reporting rate, but may increase the number of high quality reports.

  • 155.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Holmgren, A
    National Board for Forensic Medicine.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Concentrations of free-morphine in peripheral blood after recent use of heroin in overdose deaths and in apprehended drivers2012Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 215, nr 1-3, s. 18-24Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The concentration of free-morphine was determined in peripheral (femoral) blood from heroin-related deaths and compared with the concentration in venous blood from impaired drivers. The presence of 6-MAM in blood or urine served as a biomarker for recent use of heroin. Males dominated over females (p andlt; 0.001) in both the autopsy cases (88%) and the drivers (91%), although their mean age was about the same 33-35 y (p andgt; 0.05). Concentrations of free-morphine in blood were not associated with age of heroin users in Sweden (p andgt; 0.05). The median concentration of free-morphine was higher in autopsy cases (0.24 mg/L, N = 766) compared with apprehended drivers with 6-MAM in blood (0.15 mg/L, N = 124, p andlt; 0.05), and appreciably higher than in drivers with 6-MAM in urine but not in blood (0.03 mg/L, N = 1823, p andlt; 0.001). The free-morphine concentration was above 0.20 mg/L in 65% of autopsy cases, 36% of drivers with 6-MAM in blood but only 1.4% of drivers with 6-MAM in urine. Poly-drug deaths had about the same concentrations of free-morphine in blood (0.24 mg/L, N = 703) as heroin-only deaths (0.25 mg/L, N = 63). The concentration of morphine in drug overdose deaths (median 0.25 mg/L, N = 669) was about the same as in traumatic deaths among heroin users (0.23 mg/L, N = 97). However, the concentration of morphine was lower when the deceased had consumed alcohol (0.18 mg/L, N = 104) compared with taking a benzodiazepine (0.32 mg/L, N = 94). The concentration distributions of free-morphine in blood in heroin-related deaths overlapped with the concentrations in impaired drivers, which makes the interpretation of toxicology results difficult without knowledge about tolerance to opiates in any individual case.

  • 156.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Holmgren, A.
    Department of Forensic Genetics and Forensic Toxicology National Board of Forensic Medicine, Linköping.
    Kugelberg, Fredrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Concentrations of cocaine and its major metabolite benzoylecgonine in blood samples from apprehended drivers in Sweden2008Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 177, nr 2-3, s. 133-139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cocaine and its major metabolite benzoylecgonine (BZE) were determined in blood samples from people arrested in Sweden for driving under the influence of drugs (DUID) over a 5-year period (2000-2004). Venous blood or urine if available, was subjected to a broad toxicological screening analysis for cannabis, cocaine metabolite, amphetamines, opiates and the major benzodiazepines. Verification and quantitative analysis of cocaine and BZE in blood was done by gas chromatography-mass spectrometry (GC-MS) at limits of quantitation (LOQ) of 0.02 mg/L for both substances. Over the study period 26,567 blood samples were analyzed and cocaine and/or BZE were verified in 795 cases (3%). The motorists using cocaine were predominantly men (>96%) with an average age of 28.3 ± 7.1 years (±standard deviation, S.D.). The concentration of cocaine was below LOQ in 574 cases although BZE was determined at mean, median and highest concentrations of 0.19 mg/L, 0.12 mg/L and 1.3 mg/L, respectively. In 221 cases, cocaine and BZE were together in the blood samples at mean and (median) concentrations of 0.076 mg/L (0.05 mg/L) and 0.859 mg/L (0.70 mg/L), respectively. The concentrations of BZE were always higher than the parent drug, mean BZE/cocaine ratio 14.2 (median 10.9) range 1-55. Cocaine and BZE were the only psychoactive substances reported in N = 61 cases at mean (median) and highest concentrations of 0.095 (0.07) and 0.5 mg/L for cocaine and 1.01 (0.70) and 3.1 mg/L for BZE. Typical signs of drug influence noted by the arresting police officers included bloodshot and glossy eyes, agitation, difficulty in sitting still and incoherent speech. © 2007 Elsevier Ireland Ltd. All rights reserved.

  • 157.
    Jones, A Wayne
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Holmgren, A
    Nationall Board of Forensic Medicine.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Driving under the influence of cannabis: a 10-year study of age and gender differences in the concentrations of tetrahydrocannabinol in blood2008Inngår i: Addiction, ISSN 0965-2140, E-ISSN 1360-0443, Vol. 103, nr 3, s. 452-461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Delta(9)-Tetrahydrocannabinol (THC) is the major psychoactive constituent of cannabis and its various preparations Increasing use of cannabis for recreational purposes has created a problem for road-traffic safety. This paper compares age, gender and the concentrations of THC in blood of individuals apprehended for driving under the influence of drugs (DUID) in Sweden, where a zero-tolerance law operates. Measurements Specimens of blood or urine were subjected to a broad screening analysis by enzyme immunoassay methods. THC positives were verified by analysis of blood by gas chromatography-mass spectrometry (GC-MS) with a deuterium-labelled internal standard (d(3)-THC). All toxicology results were entered into a database (TOXBASE) along with the age and gender of apprehended drivers. Findings Over a 10-year period (1995-2004), between 18% and 30% of all DUID suspects had measurable amounts of THC in their blood (greater than 0.3 ng/ml) either alone or together with other drugs. The mean age [+/- standard deviation (SD)] of cannabis users was 33 +/- 9.4 years (range 15-66 years), with a strong predominance of men (94%, P less than 0.001). The frequency distribution of THC concentrations (n = 8794) was skewed markedly to the right with mean, median and highest values of 2.1 ng/ml, 1.0 ng/ml and 67 ng/ml, respectively. The THC concentration was less than 1.0 ng/ml in 43% of cases and below 2.0 ng/ml in 61% of cases. The age of offenders was not correlated with the concentration of THC in blood (r = -0.027, P greater than 0.05). THC concentrations in blood were higher when this was the only psychoactive substance present (n = 1276); mean 3.6 ng/ml, median 2.0 ng/ml compared with multi-drug users; mean 1.8 ng/ml, median 1.0 ng/ml (P less than 0.001). In cases with THC as the only drug present the concentration was less than 1.0 ng/ml in 26% and below 2.0 ng/ml in 41% of cases. The high prevalence of men, the average age and the concentrations of THC in blood were similar in users of illicit drugs (non-traffic cases). Conclusions The concentration of THC in blood at the time of driving is probably a great deal higher than at the time of sampling (30-90 minutes later) The notion of enacting science-based concentration limits of THC in blood (e.g. 3-5 ng/ml), as discussed in some quarters, would result in many individuals evading prosecution. Zero-tolerance or limit of quantitation laws are a much more pragmatic way to enforce DUID legislation

  • 158.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Holmgren, A.
    Department of Forensic Genetics and Forensic Toxicology National Board of Forensic Medicine, Linköping.
    Kugelberg, Fredrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Driving under the influence of central stimulant amines: Age and gender differences in concentrations of amphetamine, methamphetamine, and ecstasy in blood2008Inngår i: Journal of Studies on Alcohol and Drugs, ISSN 1937-1888, Vol. 69, nr 2, s. 202-208Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: A zero-tolerance law for driving under the influence of drugs (DUID) was introduced in Sweden in 1999. This change in legislation has led to a 12-fold increase in the number of blood samples sent by the police for toxicological analysis. Here we report the age and gender of offenders, along with the concentrations of amphetamine, methamphetamine, and ecstasy (3,4-methylenedioxymeth-amphetamine) in blood samples analyzed since the institution of the new legislation. Method: A forensic toxicology database (TOXBASE) was used to identify cases of DUID in which central stimulant amines were verified in blood during a 5-year period (2000-2004). Results: Amphetamine was present in 15,898 of 26,556 cases of DUID (60%) either alone or together with other licit or illicit drugs. In 6,094 cases, amphetamine was the only psychoactive substance in blood at mean (median) and highest concentrations of 1.01 mg/L (0.80 mg/L) and 11.9 mg/L, respectively. The users of amphetamine were mainly men (85% vs 15% women, p < .001), and men tended to be a few years older than the women, the mean (SD) age for men was 37 (9.2) years and for women it was 35 (8.1) years (p < .001). In 644 cases, amphetamine and methamphetamine were present in blood samples at mean (median) concentrations of 0.85 mg/L (0.60 mg/L) and 0.34 mg/L (0.20 mg/L), respectively (p < .001). The mean (median) and highest concentrations of ecstasy in 493 DUID offenders were 0.23 mg/L (0.10 mg/L) and 3.5 mg/L, respectively. The mean age of ecstasy users was 26 (7.2) years, which was about 10 years younger than those using amphetamine (p < .001). Conclusions: The high prevalence of amphetamines in blood of apprehended drivers in Sweden verifies widespread use of these stimulants as recreational drugs. The findings from this study suggest that a zero-tolerance DUID law has not deterred offenders, which suggests that more attention should be given to the underlying substance-abuse problem instead of conventional penalties such as monetary fines and/or imprisonment.

  • 159.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Holmgren, Anita
    Nationall Board of Forensic Medicine.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Blood Methadone Concentrations in Living and Deceased Persons: Variations Over Time, Subject Demographics, and Relevance of Coingested Drugs2012Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 36, nr 1, s. 12-18Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    n/a

  • 160.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Holmgren, Anita
    National Board of Forensic Medicine.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Heroin poisoning deaths with 6-acetylmorphine in blood: demographics of the victims, previous drug-related offences, polydrug use, and free morphine concentrations in femoral blood2012Inngår i: FORENSIC TOXICOLOGY, ISSN 1860-8965, Vol. 30, nr 1, s. 19-24Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This article discusses cases of drug-poisoning death in which 6-acetylmorphine (6-AM) was identified in blood as evidence for recent use of heroin. We report the demographics of the victims, previous drug-related offences, polydrug use, and the concentrations of free morphine in peripheral blood. After solid-phase extraction, morphine, codeine, and 6-AM were determined in blood samples by isotope-dilution gas chromatography-mass spectrometry (GC-MS) using limits of quantitation of 0.005 mg/l for each opiate. The victims of heroin poisoning were mainly men (88%), with a mean age of 35.4 +/- A 8.4 years (+/- SD) and no significant gender difference in age (men 35 +/- A 8.4 years; women 35 +/- A 8.6 years). The median concentration of free morphine in blood (n = 671) was 0.25 mg/l (66% andgt; 0.20 mg/l) and women had a higher concentration (0.30 mg/l) than men (0.24 mg/l) (P andlt; 0.05). No significant difference (P andgt; 0.05) was found for the concentration of free morphine in blood when heroin was the only drug taken (median 0.26 mg/l, n = 53) compared with multidrug deaths (median 0.24 mg/l, n = 618) (P andgt; 0.05). The coingested drugs most commonly identified in heroin-related deaths were ethanol (44%), diazepam (27%), cannabis (20%), and flunitrazepam (19%). We found that 61% of victims had previous drug-related offences ranging from 1 to 48 times. The close agreement between the concentrations of free morphine in blood when heroin was the only drug taken and multidrug deaths suggests that differences in tolerance to opiates is more important in causing death than adverse drug-drug interactions.

  • 161.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Holmgren, Anita
    National Board for Forensic Medicine.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Quantitative analysis of amphetamine in femoral blood from drug-poisoning deaths compared with venous blood from impaired drivers2011Inngår i: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 3, nr 19, s. 2195-2204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Amphetamine is a major drug of abuse worldwide. Here we compare the concentrations of this stimulant amine in femoral blood in drug fatalities with venous blood from impaired drivers. Method: Amphetamine was determined in blood by isotope-dilution GC-MS after liquid-liquid extraction. Results: Amphetamine was the only drug identified in 36 fatalities at mean (median) and highest concentrations of 2.0 mg/l (1.5 mg/l) and 14.0 mg/l. In multiple-drug deaths (n = 383), the concentrations were 0.94 mg/l (0.4 mg/l) and 13.3 mg/l. In impaired drivers with amphetamine as the only drug (n = 6138), the concentrations were 1.0 mg/l (0.8 mg/l) and 11.9 mg/l, compared with 0.78 mg/l (0.6 mg/l) and 22.3 mg/l in multidrug users (n = 8250). Conclusion: Fatal amphetamine poisonings cannot be identified on the basis of the concentration in blood alone, owing to the development of tolerance and the toxicity of co-ingested substances.

  • 162.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Holmgren, Anita
    National Board for Forensic Medicine, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Toxicological analysis of blood and urine samples from female victims of alleged sexual assault2012Inngår i: Clinical Toxicology, ISSN 1556-3650, E-ISSN 1556-9519, Vol. 50, nr 7, s. 555-561Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. The toxicological analysis of blood and urine samples from victims of alleged sexual assault represents a crucial part of the forensic evidence when this crime is investigated. Material and methods. We searched a national forensic toxicology database (TOXBASE) to find cases registered as sexual assault, rape, including date-rape that the police had requested the analysis of ethanol and other drugs. Between 2008 and 2010, N = 1460 such cases met this criteria. After immunological screening of urine or blood samples, all positive results were verified by more specific analytical methods, such as gas chromatography-mass spectrometry (GC-MS) for illicit drugs. A large number of prescription drugs and their metabolites were determined by capillary GC with nitrogen-phosphorous (N-P) detector. GC with flame ionization detector (FID) was used to analyze ethanol and gamma-hydroxybutyrate (GHB) in blood at limits of quantitation (LOQ) of 0.1 g/L and 8 mg/L, respectively. Results. The average age (+/- standard deviation) of all victims was 24 +/- 10.3 years and 72% were between 15 and 29 years. Ethanol and other drugs were not detected in 31% of cases (N +/- 459). Blood-ethanol was positive in N = 658 cases at mean, median and highest concentrations of 1.23 g/L, 1.22 g/L and 4.3 g/L, respectively. Ethanol plus drugs were present in N = 188 cases (13%) and one or more other drugs alone in N = 210 cases (14%). Cannabis (marijuana) and amphetamines were the major illicit drugs, whereas diazepam, alprazolam, zopiclone as well as newer antidepressants were the major prescription drugs identified. Conclusions. The mean age of victims of sexual assault in Sweden, the proportion of drug positive to drug negative cases, the predominance of ethanol positive cases as well as the types of other drugs showed a remarkably good agreement in two studies spanning a period of 8 years.

  • 163.
    Jones, A Wayne
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Holmgren, Anita
    National Board for Forensic Medicine.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Driving under the influence of gamma-hydroxybutyrate (GHB)2008Inngår i: FORENSIC SCIENCE MEDICINE AND PATHOLOGY, ISSN 1547-769X, Vol. 4, nr 4, s. 205-211Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We used an in-house forensic toxicology database (TOXBASE) to evaluate the occurrences of gamma-hydroxybutyrate (GHB) in blood samples from people arrested in Sweden for driving under the influence of drugs (DUID) between 1998 and 2007. Age, gender, and concentrations of GHB in blood were compared and contrasted when GHB was the only drug present and when it occurred along with other drugs. GHB was determined in blood by gas chromatography (GC) after conversion to gamma-butyrolactone (GBL) and analysis of the latter with a flame ionization detector. The cut-off concentration of GHB in blood for reporting a positive result was 8 mg/l, which served as limit of quantitation. The mean and median GHB concentrations were 89 mg/l and 82 mg/l, respectively (2 1/2 and 97 1/2 percentiles 12 and 220 mg/l) in 548 arrested drivers. These individuals were predominantly men (95%) with an average age of 26 +/- 5.5 years (range 15-50 years) and women (5%) were several years older with an average age of 32 +/- 8.0 years (range 19-47). There were 102 individuals (29%) who were arrested more than once with GHB in blood (average similar to 3 times per person) and one as many as 10 times. GHB was the only psychoactive substance detected in 215 cases (39%) at mean and median blood-concentrations of 91 mg/l and 83 mg/l, respectively. These concentrations were not significantly different from poly-drug users. A weak but statistically significant correlation existed between the concentration of GHB in blood and the persons age (N = 548, r = 0.135, P less than 0.01). The signs of drug influence noted by arresting police officers included sedation, agitation, unsteady gait, slurred speech, irrational behavior, jerky body movements, dilated Pupils, and spitting. The blood concentrations reported here are probably appreciably less than at time of driving (30-90 min earlier) owing to the short elimination half-life of GHB (t1/2 = 30-40 min).

  • 164.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Holmgren, Anita
    Department of Forensic Genetics and Forensic Toxicology National Board of Forensic Medicine, Linköping.
    Kugelberg, Fredrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Driving under the influence of opiates: Concentration relationships between morphine, codeine, 6-acetyl morphine, and ethyl morphine in blood2008Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 32, nr 4, s. 265-272Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Morphine and codeine are frequently identified in blood samples from impaired drivers. But whether these opiates reflect the use of prescription analgesics or abuse of the illicit drug heroin (diacetyl morphine) is not always obvious. Opiates, either alone or together with other drugs, were determined in 2573 blood specimens from impaired drivers by sensitive and specific methods of analysis. The specific metabolite of heroin 6-acetyl morphine (6-AM) was quantifiable in only 52 cases (2%) at mean, median, and highest concentrations of 0.015, 0.010, and 0.10 mg/L, respectively. The mean, median, and highest concentrations of morphine were 0.046, 0.03, and 1.13 mg/L, respectively (N = 2029). The corresponding concentrations of codeine (N = 1391) were 0.047, 0.01, and 2.40 mg/L. Ethyl morphine was identified in 63 cases at a mean concentration of 0.055 mg/L (median 0.03 mg/L). When 6-AM was present in urine (N = 324), the mean morphine/codeine ratio in blood was 7.5 (median 6.7), and this important ratio was less than unity in only two cases. This study finds compelling evidence that ∼90% of apprehended drivers in Sweden with morphine and codeine in their blood had used heroin.

  • 165.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Relationship between blood and urine alcohol concentrations in apprehended drivers who claimed consumption of alcohol after driving with and without supporting evidence2010Inngår i: FORENSIC SCIENCE INTERNATIONAL, ISSN 0379-0738, Vol. 194, nr 1-3, s. 97-102Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    For various reasons, many people suspected of driving under the influence of alcohol (DUIA) are not apprehended sitting behind the wheel, but some time after the driving. This gives them the opportunity to claim they drank alcohol after the time of driving or after they were involved in a road-traffic crash. Alleged post-offence drinking is not easy for the prosecution to disprove, which often means that the DUIA charge is dropped or the person is acquitted if the case goes to trial. The routine practice of sampling and measuring the concentration of alcohol in blood (BAC) and urine (UAC) and calculating urine/blood ratios (UAC/BAC) and the changes in UAC between two successive voids furnishes useful information to support or challenge alleged drinking after driving. We present here a retrospective case series of DUIA offenders (N = 40) in half of which there was supporting evidence of an after-drink (eye witness or police reports) and in the other half no such evidence existed apart from the suspects admission. When there was supporting evidence of an after-drink, the UAC/BAC ratio for the first void was close to or less than unity (mean 1.04, median 1.08, range 0.54-1.21) and the UAC increased by 0.21 g/L (range 0.02-0.57) between the two voids. Without any supporting evidence of post-offence drinking the mean UAC/BAC ratio was 1.46 (range 1.35-1.93) for the first void, verifying that absorption and distribution of alcohol in all body fluids and tissues was complete. In these cases, the UAC between successive voids decreased by 0.25 g/L on average (range 0.10-0.49), indicating the post-absorptive phase of the BAC curve. Long experience from investigating claims of post-offence drinking leads us to conclude that in the vast majority of cases this lacks any substance and is simply a last resort by DUIA offenders to evade justice. Unless supporting evidence exists (eye witness, police reports, etc.) of post-offence drinking the courts are encouraged to ignore this defence argument.

  • 166.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Holmgren, A
    National Board for Forensic Medicine.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Drug poisoning deaths in Sweden show a predominance of ethanol in mono-intoxications, adverse drug-alcohol interactions and poly-drug use2011Inngår i: FORENSIC SCIENCE INTERNATIONAL, ISSN 0379-0738, Vol. 206, nr 1-3, s. 43-51Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Over a 10-year period (1998-2007) all deaths in Sweden classified by forensic pathologists as fatal drug poisonings (N = 6894) were retrieved from a toxicology database (TOXBASE) belonging to the National Board of Forensic Medicine. The deaths were further classified as suicides N = 2288 (33%), undetermined N = 2260 (33%) and accidental N = 2346 (34%). The average age (+/- SD) of all victims was 49.1 +/- 15.9 years and men 47.4 +/- 15.6 years were 5-year younger than women 52.2 +/- 15.8 years (p andlt; 0.01). Most of the deceased (78%) were poly-drug users although a single drug (mono-intoxications) was found in 22% of all poisoning deaths (p andlt; 0.001). The number of drugs in blood samples varied from 1 to 12 with a median of 3-4 per case. Mono-intoxication deaths were mostly ethanol-related (N = 976) and the mean and median blood-alcohol concentration (BAC) was 3.06 g/L and 3.10 g/L, respectively. The BAC decreased as the number of additional drugs in blood increased from 2.15 g/L with one drug to 1.25 g/L with 6 or more drugs. The mean (median) concentrations of non-alcohol drugs in mono-intoxication deaths were morphine (N = 93) 0.5 mg/L (0.2 mg/L), amphetamine (N = 39) 2.0 mg/L (1.2 mg/L), dextropropoxyphene (N = 33) 3.9 mg/L (2.9 mg/L), dihydro-propiomazine (N = 32) 1.6 mg/L (1.0 mg/L) and 7-amino-flunitrazepam (N = 28), 0.4 mg/L (0.3 mg/ L). Elevated blood morphine in these poisoning deaths mostly reflected abuse of heroin as verified by finding 6-monoacetyl morphine (6-MAM) in the blood samples. When investigating drug poisoning deaths a comprehensive toxicological analysis is essential although the results do not reveal the extent of prior exposure to drugs or the development of pharmacological tolerance. The concentrations of drugs determined in post-mortem blood are one element in the case. The autopsy report, the police investigation, the findings at the scene and eye-witness statements should all be carefully considered when the cause and manner of death are determined.

  • 167.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Holmgren, Anita
    National Board for Forensic Medicine.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Five-year update on the occurrence of alcohol and other drugs in blood samples from drivers killed in road-traffic crashes in Sweden2009Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 186, nr 01-Mar, s. 56-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    According to statistics provided by the Swedish National Road Administration (Vagverket). a total of 1403 drivers were killed in road-traffic crashes in Sweden between 2003 and 2007. Forensic autopsies were performed in similar to 97% of all deaths and specimens of blood and urine were sent for toxicological analysis. In 60% of cases (N = 835) the toxicology results were negative and 83% of these victims were men. The blood-alcohol concentration (BAC) was above the legal limit for driving (greater than0.2 g/L) in 22% of cases (N = 315) at mean, median and highest concentrations of 1.7 g/L, 1.7 g/L and 4.9 g/L, respectively. The proportions of male to female drivers with BAC greater than 0.2 g/L were 93% vs 7% compared with 83% vs 17% for those with drugs other than alcohol in blood. Drivers with a punishable BAC were over-represented in single vehicle crashes compared with multiple vehicle crashes (67% vs 33%). The opposite held for drivers who had taken a prescription drug (39% vs 61%) and also for drug-negative cases (31% vs 69%). Drugs other than alcohol were identified in 253 cases (18%); illicit drugs only in 39 cases (2.8%), both licit and illicit in 28 cases (2.0%) and in 186 cases (13.3%) one or more therapeutic drugs were present. Amphetamine was the most common illicit drug identified at mean, median and highest concentrations of 1.5 mg/L, 1.1 mg/L and 5.0 mg/L, respectively (N = 39). Blood specimens contained a wide spectrum of pharmaceutical products (mean 2.4 drugs/person), comprising sedative-hypno tics (N = 93), opiates/opioids (N = 69) as well non-scheduled substances, such as paracetamol (N = 78) and antidepressants (N = 93). The concentrations of these substances in blood were mostly in the therapeutic range. Despite an appreciable increase (12-fold) in number of arrests made by the police for drug-impaired driving after a zero-tolerance law was introduced (July 1999), alcohol still remains the psychoactive substance most frequently identified in the blood of drivers killed in road-traffic crashes. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

  • 168.
    Jones, A Wayne
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Kugelberg, Fredrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Holmgren, Anita
    Department of Forensic Genetics and Forensic Toxicology National Board of Forensic Medicine, Linköping.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Occurrence of ethanol and other drugs in blood and urine specimens from female victims of alleged sexual assault2008Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 181, nr 1-3, s. 40-46Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Results of toxicological analysis of blood and urine specimens from 1806 female victims of alleged non-consensual sexual activity are reported. After making contact with the police authorities, the victims were examined by a physician for injuries and biological specimens were taken for forensic toxicology and other purposes (e.g. DNA). Urine if available or otherwise on an aliquot of blood after protein precipitation was screened for the presence of drugs by enzyme immunoassay methods (EMIT/CEDIA). All positive results from screening were verified by more specific methods, involving isotope dilution gas chromatography-mass spectrometry (GC-MS) for illicit drugs. A large number of prescription drugs were analyzed in blood by capillary column gas chromatography with a nitrogen-phosphorous (N-P) detector. Ethanol was determined in blood and urine by headspace gas chromatography and concentrations less than 0.1 g/L were reported as negative. The number of reported cases of alleged sexual assault was highest during the warmer summer months and the mean age of victims was 24 years (median 20 years), with ∼60% being between 15 and 25 years. In 559 cases (31%) ethanol and drugs were negative. In 772 cases (43% of total) ethanol was the only drug identified in blood or urine. In 215 cases (12%) ethanol occurred together with at least one other drug. The mean, median and highest concentrations of ethanol in blood (N = 806) were 1.24 g/L, 1.19 g/L and 3.7 g/L, respectively. The age of victims and their blood-alcohol concentration (BAC) were positively correlated (r = 0.365, p < 0.001). Because BAC decreases at a rate of 0.10-0.25 g/(L h), owing to metabolism the concentration in blood at time of sampling is often appreciably less than when the crime was committed several hours earlier. Licit or illicit drugs were identified in blood or urine in N = 262 cases (15%). Amphetamine and tetrahydrocannabinol were the most common illicit drugs at mean (median) concentrations in blood of 0.22 mg/L (0.1 mg/L) and 0.0012 mg/L (0.0006 mg/L), respectively. Among prescription drugs, sedative-hypnotics such as diazepam and zopiclone were common findings along with SSRI antidepressants and various opiate analgesics. Interpreting the analytical results in terms of voluntary vs. surreptitious administration of drugs and the degree of incapacitation in the victim as well as ability to give informed consent for sexual activity is fraught with difficulties. © 2008 Elsevier Ireland Ltd. All rights reserved.

  • 169.
    Jonsson, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Spigset, Olav
    Division of Clinical Pharmacology and Department of Laboratory Medicine and Women’s Health, Trondheim, Norway.
    Tjäderborn, Micaela
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Druid, Henrik
    Department of Forensic Medicine, Karolinska Institute.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Fatal drug poisonings in a Swedish general population.2009Inngår i: BMC clinical pharmacology, ISSN 1472-6904, Vol. 9, nr 7, s. 1-5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ABSTRACT: BACKGROUND: Pharmaceutical drug poisonings have previously been reported using single sources of information, either hospital data or forensic data, which might not reveal the true incidence. We therefore aimed to estimate the incidence of suspected fatal drug poisonings, defined as poisonings by pharmaceutical agents, by using all relevant case records from various sources in a Swedish population. METHODS: Every seventh randomly selected deceased in three counties in southeastern Sweden during a one-year period was identified in the Cause of Death Register. Relevant case records (death certificates, files from hospitals and/or primary care centres and medico-legal files) were reviewed for all study subjects. RESULTS: Of 1574 deceased study subjects, 12 cases were classified as pharmaceutical drug poisonings according to the death certificates and 10 according to the medico-legal files. When reviewing all available data sources, 9 subjects (0.57%; 95% confidence interval: 0.20-0.94%) were classified as drug poisonings, corresponding to an incidence of 6.5 (95% confidence interval: 2.3-10.7) per 100 000 person-years in the general population. The drug groups most often implicated were benzodiazepines (33%), antihistamines (33%) and analgesics (22%). CONCLUSIONS: Fatal drug poisonings is a relatively common cause of death in Sweden. By using multiple sources of information when investigating the proportion of fatal poisonings in a population, more accurate estimates may be obtained.

  • 170.
    Jornil, J
    et al.
    Aarhus University, Denmark .
    Nielsen, T S.
    Aarhus University, Denmark .
    Rosendal, I
    Aarhus University, Denmark .
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Zackrisson, Anna Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Boel, L W T.
    Aarhus University, Denmark .
    Brock, B
    Aarhus University, Denmark .
    A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine2013Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 226, nr 1-3, s. E26-E31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We present a fatal drug poisoning case involving venlafaxine (VEN). The deceased took his medication regularly (including 150 mg VEN twice daily), and nothing in the case or autopsy findings pointed towards suicide. The toxicological assessment concluded that the cause of death was most likely due to a poisoning with a combination of VEN, oxycodone and ethanol, and the manner of death was considered to be an accident. The blood concentration of VEN was high (4.5 mg/kg), and the ratio of the VEN metabolite O-desmethylvenlafaxine (ODV) to VEN was exceptionally low (0.006). Mechanistic pharmacokinetic simulations suggested that the low metabolite ratio was the result of combined poor metabolizer (PM) status of cytochrome P450 (CYP) 2C19 and CYP2D6. This hypothesis was confirmed by genetic analysis. Simulations revealed that it was likely that the combined missing CYP2D6 and CYP2C19 activity would cause higher concentrations of VEN, but the simulations also suggested that there could be additional reasons to explain the high VEN concentration found in this case. Thus, it seems likely that the potentially toxic VEN concentration was caused by reduced metabolic capacity. The simulations combined with genotyping were considered very useful in this fatal drug poisoning case.

  • 171.
    Josefsson, M
    et al.
    National Board Forensic Medicine.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Letter: Amlodipine and grapefruit juice2002Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 53, nr 4, s. 405-405Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 172.
    Josefsson, Martin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Studies on the enantioselective disposition of amlodipine: A challenge in bioanalysis1996Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    To study the disposition of the enantiomers of the calcium channel blocker amlodipine in human plasma, an enantioselective high performance liquid chromatographic (HPLC) assay was developed. Several HPLC techniques such as chiral ion-pair forming, chiral derivatisation and direct separation on chiral columns were evaluated. A robust assay withhigh sensitivity for amlodipine's enantiomers, suitable for large scale analysis of plasma samples, was established by combining enantiomeric separation on Chiral-AGP i.e., an alfa1 acid glycoprotein material, with achiral HPLC using electrochemical detection, in a coupledcolumn system. The enantiomeric separation on the AGP material was evaluated andoptimised by performing chemometric i.e., multivariate analysis.

    Enantioselective pharmacokinetics, in healthy human subjects, after a single oral dose of amlodipine (Norvasc®) was shown. The pharmacologically active (S)-enantiomer was found in higher plasma concentrations than the (R)-enantiomer in all subjects, but the individual SIR ratios ranged from about 50:50 to 70:30. Comparable inter-individual differences in amlodipine concentration SIR ratio was found in patients during long-term treatment with Norvasc®. However, the changes over time, in the individual subjects, were low and were not significantly influenced if the dose was increased. A difference in systemic blood clearance of the two enantiomers is the most likely cause of the observed difference in pharmacokinetic behavior. At present, however, it cannot be discerned whether this is caused by differences in protein-binding or in intrinsic clearance of the unbound drug.

    Administration together with grapefruit juice was found to increase the amlodipine plasma concentrations in healthy volunteers without markedly change the plasma concentration SIR ratio. A nonstereoselective inhibition of the first-pass metabolism is proposed. Even though the effects seen were small the clinical significance of this food/drug interaction cannot be totally neglected since there are considerable differences seen between individuals.

  • 173.
    Jönsson, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Brudin, Lars
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk fysiologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hedenmalm, Karin
    Uppsala University, Sweden.
    Eriksson, Anders
    Umeå, University, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Antipsychotics associated with pulmonary embolism in a Swedish medicolegal autopsy series2008Inngår i: International Clinical Psychopharmacology, ISSN 0268-1315, E-ISSN 1473-5857, Vol. 23, nr 5, s. 263-268Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To determine the association between fatal pulmonary embolism and use of antipsychotic drugs in a Swedish medicolegal autopsy series. Persons aged 18-65 years and subjected to a medicolegal autopsy in 1992-2005 were selected. On the basis of external cause of death, determined by the forensic pathologist, unnatural deaths (including fatal intoxications) were excluded and participants in whom pulmonary embolism was the cause of death were identified. Use of antipsychotics was based on the results of the postmortem analyses and categorized as use of high-potency first-generation antipsychotics, low-potency first-generation antipsychotics, second-generation antipsychotics or no use of antipsychotics. Logistic regression analyses were performed. Use of antipsychotics was verified in 538 of the 14,439 included participants. Pulmonary embolism was recorded as the cause of death in 279 participants and 33 of these used antipsychotics. Use of low-potency first-generation antipsychotics and second-generation antipsychotics was significantly associated with fatal pulmonary embolism (adjusted odds ratio: 2.39, 95% confidence interval: 1.46-3.92 and 6.91, 95% confidence interval: 3.95-12.10, respectively). Out of 26 participants classified as high-potency first-generation antipsychotic drug users, none had pulmonary embolism as the cause of death. Pulmonary embolism was overrepresented among medicolegal autopsy cases identified as users of low-potency first-generation and second-generation antipsychotics.

  • 174.
    Jönsson, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Brudin, Lars
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk fysiologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hedenmalm, Karin
    Dpt of Clinical Pharmacology, Uppsala universitet. Clinical Trial Unit, Medical Products Agency, Uppsala.
    Eriksson, Anders
    Section of Forensic Medicine, Umeå universitet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Antispychotics Associated with Pulmonary Emboi in a Swedish Medico-Legal Autopsy Series2007Konferansepaper (Fagfellevurdert)
  • 175.
    Jönsson, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Holmgren, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Fatal intoxications in a Swedish forensic autopsy material during 1992-20022004Inngår i: Forensic Science International, ISSN 0379-0738, Vol. 143, nr 1, s. 53-59Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Compilations of substances detected in fatal intoxications are important in order to observe changes in intoxication patterns, to monitor effects of preventive work and to discover new trends in drug usage. The aim of the present study was to describe the current pattern of substances detected in fatal intoxications in Sweden. Fatal intoxications investigated at the Department of Forensic Chemistry, Linköping, Sweden, during 1992–2002, were analysed. All suicides, uncertain cases and accidents where the cause of death were fatal intoxications (ICD-9: E950, E980 and E859) were included and substances detected in more than 50 fatal intoxications (in femoral blood) were listed. For each substance, a cut off value was set, above which concentrations were considered toxic. Fatal intoxications were detected by forensic-chemical analyses in 12% (6998/60,314) of the forensic autopsies during the study period. Among the suicides, an average of 3.8 substances were detected per case, the corresponding figure for uncertain cases and accidents were 3.5 and 4.1 substances, respectively. Ethanol was by far the most frequently detected substance, detected in 43% (3039) of the fatal intoxications, of which 32% (960) had toxic concentrations, followed by propoxyphene, detected in 27% (1863) of the fatal intoxications of which 74% (1370) had toxic concentrations. The number of cases where ethanol and propoxyphene were detected decreased during the study period. Moreover, other CNS-active drugs such as antidepressants, analgesics and anxiolytics were also frequently detected. The drugs with high proportions of cases with toxic concentrations detected were propoxyphene, amitriptyline, zolpidem, carisoprodol, alprazolam, thioridazine, methadone and ketobemidone. Selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) were detected in 12% (833) and 10% (665), respectively. A significantly (P<0.001) higher proportion of cases where TCA were detected had toxic concentrations when compared with cases where SSRI were detected (64% versus 31%).

  • 176.
    Jönsson, Anna
    et al.
    Nordiska högskolan för folkhälsovetenskap, Göteborg.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Många läkemedelsorsakade dödsfall kan förhindras2010Inngår i: Läkartidningen, ISSN 0023-7205, Vol. 107, nr 11, s. 745-Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Flera studier visar att läkemedelsbiverkningar som leder till döden är relativt vanliga. Dock saknas kunskap om hur stor andel som är möjlig att förebygga. Syftet med denna studie var att beskriva andelen undvikbara letala läkemedelsbiverkningar och förgiftningar i en svensk population.

    I en tidigare studie identifierades läkemedelsbiverkningar och förgiftningar bland 1 574 slumpmässigt utvalda personen som avlidit i den sydöstra sjukvårdsregionen under 2001. Detta gjordes genom att granska dödsbevis, sjukhus- och vårdcentralsjournaler och resultat av genomförda rättsmedicins­ka obduktioner. Man fann då 49 fall (3 procent) av läkemedelsbiverkningar och 9 fall (0,6 procent) av förgiftningar hos 57 personer.

    I den aktuella studien värderades om de identifierade letala läkemedelsbiverkningarna och förgiftningarna hade kunnat förhindras. Detta gjordes stegvis av kliniska experter (klinisk farmakologi, rättsmedicin, farmaci) med hjälp av fördefinierade väletablerade kriterier för prevention.

    Av de 49 läkemedelsbiverkningarna var 14 procent (sju fall) säkert eller möjligt undvikbara. Fyra av dessa berodde på att läkemedlet var kontraindicerat för dessa patienter. Alla nio förgiftningsdödsfall bedömdes vara möjliga att förebygga. Hos en person bidrog både en läkemedelsbiverkan och en förgiftning till dödsfallet, därför bedömdes totalt 15 personer (26 procent) ha en förebyggbar läkemedelsbiverkan eller förgiftning.

    Detta innebär att cirka 1 procent av alla dödsfall i Sverige beror på misstänkta läkemedelsbiverkningar eller förgiftningar som skulle kunna förebyggas. Att arbeta mer aktivt för att reducera antalet biverkningar som går att förebygga bedöms angeläget. Det är dock fortfarande oklart vilka interventioner som har bäst möjlighet att förhindra biverkningar.

  • 177.
    Jönsson, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Jacobsson, Ingela
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Andersson, Karolina
    Nordic School of Public Health, Göteborg.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Sundström, Anders
    Centre of Pharmacoepidemiology, KI, Stockholm. , Dpt of Drug Safety, Medical Products Agency, Uppsala .
    Factors Predisposing an Abstract To Be Accepted for Oral Presentation2008Inngår i: Pharmacoepidemiology and drug safety, Wiley-Blackwell , 2008, s. 190-191Konferansepaper (Fagfellevurdert)
  • 178.
    Jönsson, Anna K.
    et al.
    Nordic School of Public Health, Gothenburg, Sweden.
    Hakkarainen, Katja M.
    Nordic School of Public Health, Gothenburg, Sweden.
    Spigset, Olav
    Department of Laboratory medicine, Children´s and Women´s Health, Norwegian University of Science and Technology, Trondheim, Norway. Division of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.
    Druid, Henrik
    Division of Forensic Medicine, Department of Oncology-pathology, Karolinska institute Stockholm, Sweden.
    Hiselius, Anne
    Jönköping County Council, Jönköping, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Preventable drug related mortality in a Swedish population2010Inngår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 19, nr 2, s. 211-215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Several studies indicate that the medical burden of fatal adverse drug reactions (FADRs) is significant, but the preventability of FADRs in the general population is largely unknown. The aim of this study was to determine the proportion of preventable FADRs and preventable fatal drug poisonings (FDPs) in a Swedish population. METHODS: Previously, a population-based sample of 1574 deceased subjects was scrutinised for FADRs and FDPs using relevant case records, including death certificates, medical charts and medico-legal files. Forty-nine cases (3%) of FADRs and nine cases (0.6%) of FDPs were identified in 57 subjects. In this study, the preventability of all these identified FADRs and FDPs was evaluated by clinical experts in a stepwise manner, applying a set of predefined and well established preventability criteria. Only cases for which consensus was achieved were included in the study. RESULTS: Of 49 FADRs, 14% (seven fatalities) was considered definitely or possibly preventable and four of these were due to the presence of a contraindication for the drug. All nine FDPs were considered possibly preventable. As one subject had a combination of an FADR and an FDP, a total of 15 persons (26%) were considered having a definitely or possibly preventable FADR or FDP, corresponding to 0.95% of all deceased subjects in Sweden. CONCLUSIONS: The results of this study indicate that approximately one fourth of FADRs and FDPs could be prevented. Therefore, an increased awareness of the possibility to reduce the risk of fatal events due to pharmaceutical drugs is warranted.

  • 179.
    Jönsson, Anna K.
    et al.
    Nordic School of Public Health, Gothenburg, Sweden.
    Horváth-Puhó, Erzsebet
    Aarhus Danmark.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Pedersen, Lars
    Aarhus Danmark.
    Sörensen, Henrik T
    Aarhus Danmark.
    Antipsychotics and risk for venous thromboembolism: A population based case-control study2009Inngår i: Clinical Epidemiology, ISSN 1179-1349, Vol. 1, s. 19-26Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During the last decade, the risk of venous thromboembolism (VTE) has been reported in users of antipsychotic drugs. However, the reports have been inconclusive. This study aimed to determine the relative risk of VTE in antipsychotic drug users. Using data from medical databases in North Jutland and Aarhus Counties, Denmark, and the Danish Civil Registration System, we identified 5,999 cases with a first-time diagnosis of VTE and, based on risk set sampling, 59,990 sex- and age-matched population controls during 1997–2005. Users of antipsychotic drugs were identified from population-based prescription databases and categorized based on filled prescriptions prior to admission date for VTE or index date for controls as current (at least one prescription within 90 days), recent (at least one prescription within 91–180 days), former (at least one prescription within 181–365 days) or nonusers (no recorded prescription within 365 days). Compared with nonusers, current users of any antipsychotic drugs had an increased risk of VTE (adjusted relative risk [ARR]: 1.99, 95% confidence interval [CI]: 1.69–2.34). Former users of any antipsychotic drugs had a nonsignificant elevated risk of VTE compared with nonusers (ARR: 1.54, 95% CI: 0.99–2.40, p-value: 0.056). In conclusion, users of antipsychotic drugs have an increased risk of VTE, compared with nonusers, which might be due to the treatment itself, to lifestyle factors, to the underlying disease, or to residual confounding.

  • 180.
    Jönsson, Anna K.
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Spigset, Olav
    Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Venous Thromboembolism in Recipients of Antipsychotics: Incidence, Mechanisms and Management2012Inngår i: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 26, nr 8, s. 649-662Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Since chlorpromazine was introduced to the market in the early 1950s, theuse of antipsychotic drugs has been associated with venous thromboembolism(VTE) in a number of reports. During the last decade the evidence hasbeen strengthened with large epidemiological studies. Whether all antipsychoticsincrease the risk for VTE or the risk is confined to certain drugs is stillunclear. The aim of this article is to present an updated critical reviewfocusing on the incidence, mechanisms and management of VTE in users ofantipsychotics. After searching the databases PubMed and Scopus for relevantarticles we identified 12 observational studies, all of which were publishedafter the year 2000. In most of these studies an elevated risk of VTE wasobserved for antipsychotic drugs, with the highest risk for clozapine, olanzapineand low-potency first-generation antipsychotics. The risk seems to becorrelated with dose. The elderly, who mainly use lower doses, do not showan increased risk of VTE to the same extent as younger subjects.The underlying biological mechanisms explaining the association betweenantipsychotic medication and VTE are to a large extent unknown. Severalhypotheses have been proposed, such as body weight gain, sedation, enhancedplatelet aggregation, increased levels of antiphospholipid antibodies,hyperprolactinaemia and hyperhomocysteinaemia. The risk of VTE in schizophreniaand other psychotic disorders may also be related to the underlyingdisease rather than the medication.Very limited evidence exists to guide how cases of VTE in subjects usingantipsychotics should be handled. An attempt to compile an algorithm wherethe patients’ individual risk of VTE is assessed and preventive clinical measuresare suggested has been published recently. Strong consideration shouldbe given to discontinuation of the offending antipsychotic drug in patientsexperiencing a VTE, and another antipsychotic drug with a presumably lowerrisk should be chosen if antipsychotic drug treatment is still indicated. It isessential that physicians and patients are aware that VTE may be an adversedrug reaction to the antipsychotic treatment so the condition is identifiedearly and treated appropriately.

  • 181.
    Jönsson, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Sörensen, Henrik
    Dpt of Clinical Epidemiology, Aalborg University Hospital, Denmark.
    Horváth-Puhó, Erzébet
    Dpt of Human Genetics and Teratology, National Center for Epidemiology, Budapest, Hungary.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Association between Venous Thromboembolism and Antipsychotics: A Population Based Case-Control Study2007Inngår i: Pharmacoepidemiology and Drug Safety, Wiley , 2007, s. 256-256Konferansepaper (Fagfellevurdert)
  • 182.
    Karimi, Ghazaleh
    et al.
    Uppsala Monitoring Centre, Sweden .
    Star, Kristina
    Uppsala Monitoring Centre, Sweden .
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Noren, Niklas G.
    Uppsala Monitoring Centre, Sweden .
    Letter: Time-to-onset in spontaneous reports: the possibility to detect the unexpected2013Inngår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 22, nr 5, s. 556-557Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 183.
    Karlsson, John
    et al.
    Sektionen för klinisk farmakologi, Sahlgrenska universitetssjukhuset, Göteborg.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Star, Kristina
    WHO Collaborating Centre for International Drug Monitoring, Uppsala.
    Wallerstedt, Susanna M
    Sektionen för klinisk farmakologi, Sahlgrenska universitetssjukhuset, Göteborg.
    Plötslig död och behandling med andra generationens antispykotika: Data från WHO:s Biverkningsdatabas (Vigibase)2008Konferansepaper (Fagfellevurdert)
  • 184.
    Karlsson, John
    et al.
    Dpt of Clinical Pharmacology, Sahlgrenska university Hospital, Göteborg.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Star, Kristina
    WHO Collaborating Centre for International Drug Monitoring, Uppsala.
    Wallerstedt, Susanna M
    Dpt of Clinical Pharmacology, Sahlgrenska university Hospital, Göteborg.
    Sudden Death and Treatmet with New Generation Antipsychotics: Data from the WHO Database of Adverse Drug Reactions (Vigibase)2008Inngår i: Pharmacoepidemiology and drug safety, Wiley-Blackwell , 2008Konferansepaper (Fagfellevurdert)
  • 185.
    Karlsson, John
    et al.
    Sahlgrens University Hospital.
    Wallerstedt, Susanna M
    Sahlgrens University Hospital.
    Star, Kristina
    Uppsala Monitoring Centre.
    Bate, Andrew
    Uppsala Monitoring Centre.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Letter: Sudden Cardiac Death in Users of Second-Generation Antipsychotics2009Inngår i: Journal of Clinical Psychiatry, ISSN 0160-6689, E-ISSN 1555-2101, Vol. 70, nr 12, s. 1725-1726Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 186.
    Karlsson, Louise
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    P-glycoprotein and chiral antidepressant drugs: Pharmacokinetic, pharmacogenetic and toxicological aspects2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The blood-brain barrier (BBB) is formed by the capillary endothelial cells, joined together by tight junctions, with transporter proteins. BBB acts to regulate the brain concentrations of substances including many drugs. Transport across the cells is necessary for a drug to ensure that the drug reaches the site of action and transport proteins such as P-glycoprotein (P-gp; ABCB1) can limit the entrance into various tissues, including the brain.

    Molecules that are not superimposable on their mirror images and thus exist in two enantiomeric forms (enantiomers) are said to be chiral. A racemic compound is one composed of a 50:50 mixture of two enantiomers, S- and R-enantiomers. Two examples of frequently prescribed racemic drugs are the chiral antidepressants venlafaxine (VEN) and citalopram (CIT). The enantiomers of VEN possess different pharmacodynamic profiles where the R-enantiomer is a potent inhibitor of both serotonin and noradrenaline reuptake (SNRI), while the S-enantiomer is more selective in inhibiting serotonin reuptake (SSRI). The SSRI effect of CIT resides in the S-enantiomer, whereas the R-enantiomer is considered to be therapeutically inactive, or even that it counteracts the effects. The S-enantiomer of CIT is now available as a separate SSRI (escitalopram, EsCIT). VEN and CIT are also among the most commonly found drugs in forensic autopsy cases.

    Few previous studies have examined a possible enantioselective activity of P-gp. Thus, the general aim of this thesis was to study the enantiomeric distribution of chiral antidepressant drugs, focusing on the role of P-gp in the BBB. For this purpose, a mouse model disrupted of the genes coding for P-gp (abcb1ab (-/-) mice) was used. Brain and serum concentrations of the enantiomers of VEN and CIT, and their major metabolites, were compared to the corresponding wild-type mice (abcb1ab (+/+) mice). The open-field locomotor and rearing activities were examined after chronic VEN administration. In addition to the animal studies, genetic and toxicological aspects of P-gp were studied in a forensic autopsy material, where intoxication cases were compared with cases that were not related to intoxications.

    The brain to serum concentration ratios for VEN, CIT and EsCIT differed between knockout mice and wild-type mice, with 2-3 fold higher brain concentrations in mice with no expression of P-gp. Hence, all studied drugs, and their major metabolites, were substrates for P-gp. There was no evidence for a stereoselective P-gp mediated transport. The P-gp substrate properties were reflected in the open-field behavior test where the knockout mice displayed increased center activity compared with wild-type mice following chronic VEN exposure. The genotype distribution of ABCB1 SNPs C1236T, G2677T and C3435T in VEN positive cases was significantly (or borderline) different between the intoxication cases and the non-intoxication cases. This difference in genotype distribution was not observed for the CIT positive cases.

    To conclude, the present work has led to an increased knowledge about how the enantiomers of VEN and CIT are affected by the BBB transporter P-gp. Using an animal model, VEN and CIT have proved to be actively transported out of the brain by P-gp and no difference was observed for the enantiomers with regard to P-gp transport. Further, the ABCB1 genotype distribution was different in intoxication cases compared with non-intoxication cases. Taken together, these findings offer the possibility that the expression of P-gp in humans may be a contributing factor for limited treatment response and increased risk of side-effects following antidepressant drug treatment.

    Delarbeid
    1. Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein
    Åpne denne publikasjonen i ny fane eller vindu >>Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein
    Vise andre…
    2010 (engelsk)Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, nr 9, s. 632-640Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    According to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10 mg/kg bw) was intraperitoneally injected to knockout (-/-) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9 h following drug administration for analysis by LC/MS/MS. One to six hours post-dose, the brain concentrations of venlafaxine, O-desmethylvenlafaxine and N-desmethylvenlafaxine were 2-3, 2-6 and 3-12 times higher in abcb1ab (-/-) mice compared to abcb1ab (+/+) mice, respectively. No major differences in the serum and brain disposition of the S- and R-enantiomers of venlafaxine and its metabolites were found between the groups. We conclude that P-gp decreases the penetration of the S- and R-enantiomers of venlafaxine and its major metabolites into the brain. No evidence of a stereoselective P-gp mediated transport of these substances was observed.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-58805 (URN)10.1016/j.euroneuro.2010.04.004 (DOI)20466523 (PubMedID)
    Merknad
    Original Publication: Louise Karlsson, Ulrich Schmitt, Martin Josefsson, Björn Carlsson, Johan Ahlner, Finn Bengtsson, Fredrik C Kugelberg and Christoph Hiemke, Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein, 2010, European Neuropsychopharmacology, (20), 9, 632-640. http://dx.doi.org/10.1016/j.euroneuro.2010.04.004 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Tilgjengelig fra: 2010-08-27 Laget: 2010-08-27 Sist oppdatert: 2017-12-12
    2. Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model
    Åpne denne publikasjonen i ny fane eller vindu >>Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model
    Vise andre…
    2011 (engelsk)Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, nr 2, s. 367-377Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Our results show that P-gp at the blood-brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.

    sted, utgiver, år, opplag, sider
    Springer, 2011
    Emneord
    abcb1ab . Blood–brain barrier . Knockout mice . P-glycoprotein . Pharmacodynamic . Pharmacokinetic .Venlafaxine
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-68038 (URN)10.1007/s00213-010-2148-5 (DOI)000289985700016 ()21191569 (PubMedID)
    Merknad
    The original publication is available at www.springerlink.com: Louise Karlsson, Christoph Hiemke, Björn Carlsson, Martin Josefsson, Johan Ahlner, Finn Bengtsson, Ulrich Schmitt and Fredrik C Kugelberg, Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model., 2011, Psychopharmacology, (215), 2, 367-377. http://dx.doi.org/10.1007/s00213-010-2148-5 Copyright: Springer Science Business Media http://www.springerlink.com/Tilgjengelig fra: 2011-05-06 Laget: 2011-05-06 Sist oppdatert: 2017-12-11
    3. Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment
    Åpne denne publikasjonen i ny fane eller vindu >>Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment
    Vise andre…
    2013 (engelsk)Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 11, s. 1636-1644Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the Senantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp.

    Methods: P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. Results: In brain, 3-fold higher concentrations of S- and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls.

    Conclusions: The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

    sted, utgiver, år, opplag, sider
    Elsevier, 2013
    Emneord
    Citalopram, enantiomers, escitalopram, mice knockout, P-glycoprotein
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-76122 (URN)10.1016/j.euroneuro.2013.01.003 (DOI)000328014700033 ()
    Tilgjengelig fra: 2012-03-28 Laget: 2012-03-28 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    4. ABCB1 gene polymorphisms in forensic autopsy cases positive for citalopram and venlafaxine
    Åpne denne publikasjonen i ny fane eller vindu >>ABCB1 gene polymorphisms in forensic autopsy cases positive for citalopram and venlafaxine
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter expressed on e.g. the endothelial cells of the blood-brain barrier which regulates the efflux of many drugs. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates. It has previously been shown that the antidepressant drugs citalopram and venlafaxine are actively transported out of the brain by P-gp using a mouse model. In the present study we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases positive for these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The present study included 228 forensic autopsy cases positive for venlafaxine and citalopram with different causes of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined by Pyrosequencing. The SNPs C1236T, G2677T and C3435T in venlafaxine positive cases were significantly different between the intoxication cases and non-intoxications. The latter novel finding should, however, be confirmed in future studies with larger number of cases.

    Emneord
    ABCB1, citalopram, forensic material, genotype, postmortem, venlafaxine
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-76125 (URN)
    Tilgjengelig fra: 2012-03-28 Laget: 2012-03-28 Sist oppdatert: 2013-09-03bibliografisk kontrollert
  • 187.
    Karlsson, Louise
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Hiemke, Christoph
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Schmitt, Ulrich
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
    Kugelberg, Fredrik C.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment2013Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 11, s. 1636-1644Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the Senantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp.

    Methods: P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. Results: In brain, 3-fold higher concentrations of S- and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls.

    Conclusions: The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

  • 188.
    Karlsson, Louise
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Zackrisson, Anna Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jakobsen Falk, I
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram2013Inngår i: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 127, nr 3, s. 579-586Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter at the blood–brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases.

  • 189.
    Karlsson, Louise
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Zackrisson, Anna Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kugelberg, Fredrik C.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    ABCB1 gene polymorphisms in forensic autopsy cases positive for citalopram and venlafaxineManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter expressed on e.g. the endothelial cells of the blood-brain barrier which regulates the efflux of many drugs. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates. It has previously been shown that the antidepressant drugs citalopram and venlafaxine are actively transported out of the brain by P-gp using a mouse model. In the present study we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases positive for these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The present study included 228 forensic autopsy cases positive for venlafaxine and citalopram with different causes of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined by Pyrosequencing. The SNPs C1236T, G2677T and C3435T in venlafaxine positive cases were significantly different between the intoxication cases and non-intoxications. The latter novel finding should, however, be confirmed in future studies with larger number of cases.

  • 190.
    Karlsson, Louise
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hiemke, Christoph
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Josefsson, Martin
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Schmitt, Ulrich
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
    Kugelberg, Fredrik C
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model2011Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, nr 2, s. 367-377Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our results show that P-gp at the blood-brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.

  • 191.
    Karlsson, Louise
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kingbäck, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Josefsson, M
    Rättsmedicinalverket, Rättskemi.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Rättskemi. Linköpings universitet, Hälsouniversitetet.
    Schmidt, U
    Tyskland.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hiemke, Ch
    Tyskland.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Penetration of the enantiomers of venlafaxine and its metabolites into the brain in mice lacking P-glycoprotein (mdr1ab)2008Konferansepaper (Annet vitenskapelig)
  • 192.
    Karlsson, Louise
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Schmitt, Ulrich
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Kugelberg, Fredrik C
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hiemke, Christoph
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
    Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein2010Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, nr 9, s. 632-640Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    According to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10 mg/kg bw) was intraperitoneally injected to knockout (-/-) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9 h following drug administration for analysis by LC/MS/MS. One to six hours post-dose, the brain concentrations of venlafaxine, O-desmethylvenlafaxine and N-desmethylvenlafaxine were 2-3, 2-6 and 3-12 times higher in abcb1ab (-/-) mice compared to abcb1ab (+/+) mice, respectively. No major differences in the serum and brain disposition of the S- and R-enantiomers of venlafaxine and its metabolites were found between the groups. We conclude that P-gp decreases the penetration of the S- and R-enantiomers of venlafaxine and its major metabolites into the brain. No evidence of a stereoselective P-gp mediated transport of these substances was observed.

  • 193.
    Kechagias, Stergios
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Lofti, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Läkemedelsorsakad leverskada av kosttillskottet Fortodol: Manipulerat preparat försenade diagnos2010Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, nr 4, s. 186-188Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Summary:

    Pharmaceutical preparations are serious contributors to liver disease. The diagnostic approach of drug-induced liver injury is difficult and requires a high degree of suspicion and the exclusion of alternative causes of liver damage. Adulteration of food supplements is a potential cause of serious hepatotoxicity. A case of severe jaundice after consumption of Fortodol, which according to the manufacturer contained the active substances turmeric and phenylalanine, is reported. Several months later more patients experiencing hepatotoxicity from Fortodol was reported and it was discovered that the toxicity was related to adulteration by nimesulide.

  • 194.
    Kechagias, Stergios
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet.
    Jönsson, K. Å.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Norlander, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jones, A. Wayne
    Linköpings universitet, Institutionen för medicin och hälsa, Rättskemi. Linköpings universitet, Hälsouniversitetet.
    Low-dose aspirin decreases blood alcohol concentrations by delaying gastric emptying1997Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 53, nr 04-Mar, s. 241-246Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To determine if treatment with low-dose aspirin (ASA) influences the bioavailability of orally administered alcohol and to assess whether this is caused by altered gastric emptying as measured by the paracetamol absorption test.

    Methods: In a single-center controlled crossover trial, ten healthy male medical students, aged 20–27 years, participated in two experiments in random order. Both times they took paracetamol (1.5 g together with a standardized breakfast) and drank ethanol (0.3 g/kg) 1 h after eating breakfast. On one drinking occasion, no previous medication was given. The other alcohol session was performed after the subjects had taken 75 mg ASA once daily for 7 days. On both occasions, venous blood samples were obtained at exactly timed intervals for a period of 3.5 h.

    Results: The blood-ethanol profiles showed large interindividual variations for both experiments. After treatment with ASA, the maximum blood-ethanol concentration was distinctly lower in seven subjects, almost unchanged in two subjects and increased in one subject. Overall, a statistically significant decrease in the peak blood-ethanol concentration was observed. The time required to reach peak blood-ethanol levels was somewhat longer after treatment with ASA. Although the areas under the concentration–time profiles were smaller after ASA treatment, these differences were not statistically significant. The concentrations of paracetamol in plasma were lower when ethanol was ingested after treatment with ASA and the areas under the concentration–time curves (0–170 min) were smaller.

    Conclusions: Intake of low-dose ASA (75 mg daily) tends to delay the absorption of a moderate dose of ethanol, which results in lower peak blood-ethanol concentrations and smaller areas under the concentration–time curves. The underlying mechanism seems to be delayed gastric emptying as indicated by the paracetamol absorption test.

  • 195.
    Khodabakhshi, G
    et al.
    Uppsala University.
    Star, K
    WHO Collaborating Centre.
    Noren, G N
    WHO Collaborating Centre.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Variations Across Drug Classes in Reported Time-to-Onset of Suspected Adverse Drug Reactions in DRUG SAFETY, vol 33, issue 10, pp 926-9262010Inngår i: DRUG SAFETY, Adis International , 2010, Vol. 33, nr 10, s. 926-926Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 196.
    Kingbäck, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Genetic influence on enantiomeric drug disposition: Focus on venlafaxine and citalopram2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    A molecule that is not identical to its mirror image is said to be chiral. A racemic mixture, or a racemate, is one that has equal amounts of S- and R-enantiomers of a chiral molecule. Two examples of frequently prescribed racemic drugs are the antidepressants venlafaxine (VEN) and citalopram (CIT). The R-enantiomer of VEN is a potent inhibitor of serotonin and noradrenaline reuptake, while the S-enantiomer is more selective in inhibiting serotonin reuptake. CIT is a selective serotonin reuptake inhibitor and the S-enantiomer is responsible for this effect. The R-enantiomer of CIT is therapeutically inactive, but displays other effects or side-effects. Due to the potential of different pharmacological and toxicological activities of the VEN and CIT enantiomers, it is of great interest to investigate the individual enantiomers of these drugs, concerning both pharmacokinetics and pharmacodynamics. For this purpose, it is necessary to develop stereoselective bioanalytical methods. A major clinical problem in the use of many drugs is the inter-individual variability in drug metabolism and response. Genetic variations contribute to this variability, including e.g. polymorphisms in the cytochrome P450 (CYP) enzymes. Approximately 7% of all Caucasians lack the polymorphic isoenzyme CYP2D6 and these individuals are classified as poor metabolisers. Both VEN and CIT are partly metabolised by CYP2D6. However, it is not completely known how CYP2D6 deficiency may influence the in vivo pharmacokinetics of these drugs, especially regarding the enantiomeric disposition. The overall aim of this thesis was to study the relationship between pharmacokinetics and pharmacogenetics for VEN and CIT, with emphasis on enantiomeric drug disposition in different biomatrices. In Paper I, a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for enantioselective determination of VEN and its three major metabolites was developed and applied in plasma from patients and whole blood samples from forensic autopsy cases. In Papers II and III, the genetic influence on enantiomeric drug disposition in serum and brain following administration of racemic CIT and VEN to Sprague-Dawley and Dark Agouti rats was studied. The female Sprague-Dawley and Dark Agouti rats are considered the animal counterparts of the human extensive and poor metaboliser CYP2D6 phenotypes, respectively. Significant quantitative strain-related differences in the pharmacokinetics of CIT and VEN, and their metabolites, were observed. The results indicate that the CYP2D enzymes display a significant impact on the stereoselective metabolism of these drugs. The findings also highlight the importance of comparing different rat strains when conducting experimental pharmacokinetic studies. In Paper IV, the relation between CYP2D6 genotype and the disposition of the enantiomers of VEN and its metabolites in femoral blood from forensic autopsy cases was studied. A substantial variation in the relationship between the S- and R-enantiomers of VEN, and metabolites, was found. In individuals lacking two functional CYP2D6 alleles, a low enantiomeric S/R VEN ratio was strongly related to a high S/R ratio for the main metabolite O-desmethylvenlafaxine. Hence, by using enantioselective analysis of VEN and O-desmethylvenlafaxine, it is possible to predict if a person is a poor metaboliser genotype/phenotype for CYP2D6.

    Delarbeid
    1. Stereoselective determination of venlafaxine and its three demethylated metabolites in human plasma and whole blood by liquid chromatography with electrospray tandem mass spectrometric detection and solid phase extraction
    Åpne denne publikasjonen i ny fane eller vindu >>Stereoselective determination of venlafaxine and its three demethylated metabolites in human plasma and whole blood by liquid chromatography with electrospray tandem mass spectrometric detection and solid phase extraction
    Vise andre…
    2010 (engelsk)Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 53, nr 3, s. 583-590Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A stereoselective method is described for simultaneous determination of the S- and R-enantiomers of venlafaxine and its three demethylated metabolites in human plasma and whole blood samples. This validated method involved LC/MS/MS with positive electrospray ionization and solid phase extraction. Chromatographic separation was performed on a 250 mm x 2.1mm Chirobiotic V column with a total run time of 35 min. In plasma, calibration curves were in the range of 1-1000 nM for the S- and R-enantiomers of venlafaxine and O-desmethylvenlafaxine, and 0.5-500 nM for N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. In whole blood the corresponding concentrations were 10-4000 and 5-2000 nM, respectively. The intra-day precision was <6.3% and the inter-day precision was <9.9% for plasma and <15% and <19% for whole blood. LLOQ ranged between 0.25 and 0.5 nM. No ion suppression/enhancement or other matrix effects were observed. The method was successfully applied for determination of venlafaxine and its metabolites in plasma from patients and whole blood samples from forensic autopsy cases.

    Emneord
    Venlafaxine; Enantiomers; LC–ESI-MS/MS; Metabolites; Human
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-58798 (URN)10.1016/j.jpba.2010.03.043 (DOI)20435422 (PubMedID)
    Tilgjengelig fra: 2010-08-27 Laget: 2010-08-27 Sist oppdatert: 2017-12-12
    2. Cytochrome P450-Dependent Disposition of the Enantiomers of Citalopram and Its Metabolites: In Vivo Studies in Sprague-Dawley and Dark Agouti Rats
    Åpne denne publikasjonen i ny fane eller vindu >>Cytochrome P450-Dependent Disposition of the Enantiomers of Citalopram and Its Metabolites: In Vivo Studies in Sprague-Dawley and Dark Agouti Rats
    Vise andre…
    2011 (engelsk)Inngår i: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 23, nr 2, s. 172-177Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The female Sprague-Dawley (SD) and Dark Agouti (DA) rats are considered the animal counterparts of the human extensive and poor metabolizer cytochrome P450 (CYP) 2D6 phenotypes, respectively. The aim of this work was to study possible rat strain differences in the steady-state pharmacokinetics of the (+)-(S)- and (-)-(R)-enantiomers of citalopram and its demethylated metabolites. A chronic drug treatment regimen (15 mg/kg daily) was implemented for 13 days in separate groups of SD (n 5 9) and DA (n 5 9) rats by using osmotic pumps. The concentrations of citalopram and two major metabolites in serum and two brain regions were analyzed by an enantioselective high-performance liquid chromatography assay. Higher serum and brain levels of citalopram and demethylcitalopram, but lower levels of didemethylcitalopram, were observed in DA rats when compared with SD rats. The enantiomeric (S/R) concentrations ratios of citalopram were lower in the DA rats when compared with the SD rats (0.53 +/- 0.05 vs. 0.80 +/- 0.03, P andlt; 0.001), indicating a possibly decreased capacity in the metabolism of the (-)-(R)-enantiomer in the DA rats. This study shows that CYP2D deficiency results in steady-state pharmacokinetic differences of the enantiomers of citalopram and its metabolites.

    sted, utgiver, år, opplag, sider
    John Wiley and Sons, Ltd, 2011
    Emneord
    citalopram, CYP2D6, Dark Agouti, enantiomer, pharmacokinetics, Sprague-Dawley
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-65566 (URN)10.1002/chir.20901 (DOI)000285976800013 ()
    Tilgjengelig fra: 2011-02-11 Laget: 2011-02-11 Sist oppdatert: 2017-12-11
    3. Pharmacokinetic Differences in the Disposition of the Enantiomers of Venlafaxine and Its Metabolites in Sprague-Dawley and Dark Agouti Rats
    Åpne denne publikasjonen i ny fane eller vindu >>Pharmacokinetic Differences in the Disposition of the Enantiomers of Venlafaxine and Its Metabolites in Sprague-Dawley and Dark Agouti Rats
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Venlafaxine is a frequently prescribed racemic antidepressant drug worldwide, consisting of two enantiomers that exhibit similar but not identical biological activity profiles. Venlafaxine is extensively metabolised by the cytochrome P450 (CYP) system. CYP2D6 is involved in the formation of O-desmethylvenlafaxine (Odm-venlafaxine) and CYP3A4 in the formation of Ndesmethylvenlafaxine (Ndm-venlafaxine). The female Dark Agouti and Sprague-Dawley rats are considered the animal counterparts of the human CYP2D6 poor and extensive metaboliser phenotypes, respectively. Since CYP2D6 seems to play a major role in the metabolism of venlafaxine, the aim of this work was to study possible differences in the pharmacokinetics of the enantiomers of venlafaxine and its metabolites in these two different rat strains. Following single administration of racemic venlafaxine (15 mg/kg) serum and brain samples were collected and the concentrations of the enantiomers of venlafaxine and its three major metabolites were determined using an enantioselective LC/MS/MS method. Higher serum and brain concentrations of venlafaxine were observed in Dark Agouti rats as compared to Sprague-Dawley rats (p=0.0002). In relation to the Odm-venlafaxine concentration, the Ndmvenlafaxine concentrations were much higher in Dark Agouti rats than in Sprague-Dawley rats (p<0.0001). The enantiomeric (S/R) venlafaxine ratios were almost two times higher in Dark Agouti rats than in Sprague-Dawley rats, which was observed in both serum and brain (p<0.0001). The present results give hints for possible differences in the pharmacokinetics of venlafaxine in human extensive and poor metaboliser CYP2D6 phenotype subjects.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-72239 (URN)
    Tilgjengelig fra: 2011-11-23 Laget: 2011-11-23 Sist oppdatert: 2011-11-23bibliografisk kontrollert
    4. Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood
    Åpne denne publikasjonen i ny fane eller vindu >>Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood
    Vise andre…
    2012 (engelsk)Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 214, nr 1-3, s. 124-134Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.

    sted, utgiver, år, opplag, sider
    Elsevier, 2012
    Emneord
    CYP2D6; Enantiomers; Forensic toxicology; Postmortem toxicology; Venlafaxine
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-72238 (URN)10.1016/j.forsciint.2011.07.034 (DOI)000298634900032 ()21840145 (PubMedID)
    Merknad

    Funding agencies|Forensic Science Center of Linkoping University||National Board of Forensic Medicine in Sweden||Swedish Research Council| 2009-4740 |

    Tilgjengelig fra: 2011-11-23 Laget: 2011-11-23 Sist oppdatert: 2017-12-08bibliografisk kontrollert
  • 197.
    Kingbäck, Maria
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Cytochrome P450-Dependent Disposition of the Enantiomers of Citalopram and Its Metabolites: In Vivo Studies in Sprague-Dawley and Dark Agouti Rats2011Inngår i: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 23, nr 2, s. 172-177Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The female Sprague-Dawley (SD) and Dark Agouti (DA) rats are considered the animal counterparts of the human extensive and poor metabolizer cytochrome P450 (CYP) 2D6 phenotypes, respectively. The aim of this work was to study possible rat strain differences in the steady-state pharmacokinetics of the (+)-(S)- and (-)-(R)-enantiomers of citalopram and its demethylated metabolites. A chronic drug treatment regimen (15 mg/kg daily) was implemented for 13 days in separate groups of SD (n 5 9) and DA (n 5 9) rats by using osmotic pumps. The concentrations of citalopram and two major metabolites in serum and two brain regions were analyzed by an enantioselective high-performance liquid chromatography assay. Higher serum and brain levels of citalopram and demethylcitalopram, but lower levels of didemethylcitalopram, were observed in DA rats when compared with SD rats. The enantiomeric (S/R) concentrations ratios of citalopram were lower in the DA rats when compared with the SD rats (0.53 +/- 0.05 vs. 0.80 +/- 0.03, P andlt; 0.001), indicating a possibly decreased capacity in the metabolism of the (-)-(R)-enantiomer in the DA rats. This study shows that CYP2D deficiency results in steady-state pharmacokinetic differences of the enantiomers of citalopram and its metabolites.

  • 198.
    Kingbäck, Maria
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Josefsson, M
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Rättskemi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Stereoselective analysis of venlafaxine and its three major metabolites by liquid chromatography with electrospray tandem mass spectrometry2008Konferansepaper (Annet vitenskapelig)
  • 199.
    Kingbäck, Maria
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Karlsson, Louise
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Kugelberg, Fredrik C
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Stereoselective determination of venlafaxine and its three demethylated metabolites in human plasma and whole blood by liquid chromatography with electrospray tandem mass spectrometric detection and solid phase extraction2010Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 53, nr 3, s. 583-590Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A stereoselective method is described for simultaneous determination of the S- and R-enantiomers of venlafaxine and its three demethylated metabolites in human plasma and whole blood samples. This validated method involved LC/MS/MS with positive electrospray ionization and solid phase extraction. Chromatographic separation was performed on a 250 mm x 2.1mm Chirobiotic V column with a total run time of 35 min. In plasma, calibration curves were in the range of 1-1000 nM for the S- and R-enantiomers of venlafaxine and O-desmethylvenlafaxine, and 0.5-500 nM for N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. In whole blood the corresponding concentrations were 10-4000 and 5-2000 nM, respectively. The intra-day precision was <6.3% and the inter-day precision was <9.9% for plasma and <15% and <19% for whole blood. LLOQ ranged between 0.25 and 0.5 nM. No ion suppression/enhancement or other matrix effects were observed. The method was successfully applied for determination of venlafaxine and its metabolites in plasma from patients and whole blood samples from forensic autopsy cases.

  • 200.
    Kingbäck, Maria
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Louise
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Josefsson, Martin
    Department of Forensic Genetics and Forensic Toxicology,National Board of Forensic Medicine.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacokinetic Differences in the Disposition of the Enantiomers of Venlafaxine and Its Metabolites in Sprague-Dawley and Dark Agouti RatsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Venlafaxine is a frequently prescribed racemic antidepressant drug worldwide, consisting of two enantiomers that exhibit similar but not identical biological activity profiles. Venlafaxine is extensively metabolised by the cytochrome P450 (CYP) system. CYP2D6 is involved in the formation of O-desmethylvenlafaxine (Odm-venlafaxine) and CYP3A4 in the formation of Ndesmethylvenlafaxine (Ndm-venlafaxine). The female Dark Agouti and Sprague-Dawley rats are considered the animal counterparts of the human CYP2D6 poor and extensive metaboliser phenotypes, respectively. Since CYP2D6 seems to play a major role in the metabolism of venlafaxine, the aim of this work was to study possible differences in the pharmacokinetics of the enantiomers of venlafaxine and its metabolites in these two different rat strains. Following single administration of racemic venlafaxine (15 mg/kg) serum and brain samples were collected and the concentrations of the enantiomers of venlafaxine and its three major metabolites were determined using an enantioselective LC/MS/MS method. Higher serum and brain concentrations of venlafaxine were observed in Dark Agouti rats as compared to Sprague-Dawley rats (p=0.0002). In relation to the Odm-venlafaxine concentration, the Ndmvenlafaxine concentrations were much higher in Dark Agouti rats than in Sprague-Dawley rats (p<0.0001). The enantiomeric (S/R) venlafaxine ratios were almost two times higher in Dark Agouti rats than in Sprague-Dawley rats, which was observed in both serum and brain (p<0.0001). The present results give hints for possible differences in the pharmacokinetics of venlafaxine in human extensive and poor metaboliser CYP2D6 phenotype subjects.

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