Jean-Paul Bernard

• Smith, Robert Løvsletten; Molden, Espen & Bernard, Jean-Paul Anthony (2023). Effect of CYP2D6 and CYP2C19 genotypes on atomoxetine serum levels: A study based on therapeutic drug monitoring data. British Journal of Clinical Pharmacology. ISSN 0306-5251. 89(7), p. 2246–2253. doi: 10.1111/bcp.15706. Full text in Research Archive Show summary

  Aims Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced‐function CYP2C19 genotype on atomoxetine concentrations in real‐world settings. Methods Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced‐function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfunctional or reduced variant alleles comprised CYP2D6*3 ‐ *6 , *9 ‐ *10 and *41 . For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose‐adjusted serum atomoxetine concentration was the exposure measure. Results Using a patient cohort ( n  = 315), it was found that CYP2D6 IM and PM patients had 1.9‐fold (95% confidence interval: 1.4–2.7) and 9.6‐fold (5.9–16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5‐fold (1.1–2.2) higher atomoxetine exposure than noncarriers regardless of CYP2D6 genotype. Conclusion CYP2D6 genotype has a great impact on atomoxetine exposure, where our real‐world data suggest atomoxetine dose requirements to be around half and 1/10 in CYP2D6 IM and PM vs . NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre‐emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects.

• Kringen, Marianne K.; Chalabianloo, Fatemeh; Bernard, Jean-Paul Anthony; Bramness, Jørgen Gustav; Molden, Espen & Høiseth, Gudrun (2017). Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady-State Serum Concentration of Methadone in Opioid Maintenance Treatment. Therapeutic Drug Monitoring. ISSN 0163-4356. 39(5), p. 550–555. doi: 10.1097/FTD.0000000000000437. Full text in Research Archive
• Bjånes, Tormod Karlsen; Hjertø, Espen Mjåset; Lønne, Lars; Aronsen, Lena; Berg, Jon Andsnes & Bergan, Stein [Show all 16 contributors for this article] (2016). Pharmacology portal: an open database for clinical pharmacologic laboratory services. Clinical Therapeutics. ISSN 0149-2918. 38(1), p. 222–226. doi: 10.1016/j.clinthera.2015.10.015. Full text in Research Archive
• Hjelmeland, Knut Johan; Gustavsen, Ingebjørg G.; Bernard, Jean-Paul Anthony & Mørland, Jørg (2015). Can a simple clinical test detect impairment of zopiclone and alcohol? - A randomized controlled trial. Forensic Science International. ISSN 0379-0738. 248, p. 129–133. doi: 10.1016/j.forsciint.2014.12.028. Full text in Research Archive
• Bernard, Jean-Paul Anthony; Khiabani, Hassan; Hilberg, Thor; Karinen, Ritva Anneli; Slørdal, Lars & Waal, Helge [Show all 7 contributors for this article] (2015). Characteristics of methadone-related fatalities in Norway. Journal of Forensic and Legal Medicine. ISSN 1752-928X. 36, p. 114–120. doi: 10.1016/j.jflm.2015.09.011. Full text in Research Archive
• Bernard, Jean-Paul Anthony (2014). Farmakologiske prinsipper ved legemiddelassistert rehabilitering. Norsk Farmaceutisk Tidsskrift (NFT). ISSN 0029-1935. 122(10), p. 43–46. Full text in Research Archive
• Bernard, Jean-Paul Anthony; Havnes, Ingrid Amalia; Slørdal, Lars; Waal, Helge; Mørland, Jørg & Khiabani, Hassan (2013). Methadone-related deaths in Norway. Forensic Science International. ISSN 0379-0738. 224(1-3), p. 111–116. doi: 10.1016/j.forsciint.2012.11.010. Full text in Research Archive
• Gustavsen, Ingebjørg G.; Hjelmeland, Knut Johan; Bernard, Jean-Paul Anthony & Mørland, Jørg (2012). Individual psychomotor impairment in relation to zopiclone and ethanol concentrations in blood - a randomized controlled double-blinded trial. Addiction. ISSN 0965-2140. 107(5), p. 925–932. doi: 10.1111/j.1360-0443.2011.03693.x. Full text in Research Archive
• Vindenes, Vigdis; Yttredal, Borghild; Øiestad, Elisabeth Leere; Waal, Helge; Bernard, Jean-Paul Anthony & Mørland, Jørg [Show all 7 contributors for this article] (2011). Oral Fluid is a Viable Alternative for Monitoring Drug Abuse: Detection of Drugs in Oral Fluid by Liquid Chromatography-Tandem Mass Spectrometry and Comparison to the Results from Urine Samples from Patients Treated with Methadone or Buprenorphine. Journal of Analytical Toxicology. ISSN 0146-4760. 35(1), p. 32–39. Full text in Research Archive
• Gustavsen, Ingebjørg G.; Hjelmeland, Knut Johan; Bernard, Jean-Paul Anthony & Mørland, Jørg (2011). Psychomotor performance after intake of Zopiclone compared with intake of Ethanol a randomized, controlled, double-blinded trial. Journal of Clinical Psychopharmacology. ISSN 0271-0749. 31(4), p. 481–488. doi: 10.1097/JCP.0b013e3182214be6. Full text in Research Archive
• Gjerde, Hallvard; Øiestad, Elisabeth Leere; Øiestad, Åse Marit Leere; Langødegård, Marit; Gustavsen, Ingebjørg & Hjelmeland, Knut Johan [Show all 8 contributors for this article] (2010). Comparison of zopiclone concentrations in oral fluid sampled with intercept(®) oral specimen collection device and statsure saliva sampler™ and concentrations in blood. Journal of Analytical Toxicology. ISSN 0146-4760. 34(9), p. 590–593. Full text in Research Archive
• Bernard, Jean-Paul; Mørland, Jørg; Krogh, Mette & Khiabani, Hassan (2009). Methadone and impairment in apprehended drivers. Addiction. ISSN 0965-2140. 104(3), p. 457–464. doi: 10.1111/j.1360-0443.2008.02470.x. Full text in Research Archive
• Vindenes, Vigdis; Karinen, Ritva Anneli; Hasvold, Inger; Bernard, Jean-Paul; Mørland, Jørg & Christophersen, Asbjørg S. (2008). Bromadiolone poisoning: LC-MS method and pharmacokinetic data. Journal of Forensic Sciences. ISSN 0022-1198. 53(4), p. 993–996. doi: 10.1111/j.1556-4029.2008.00737.x. Full text in Research Archive
• Høiseth, Gudrun; Bernard, Jean-Paul; Stephanson, Nicolai; Normann, Per Trygve; Christophersen, Asbjørg S. & Mørland, Jørg [Show all 7 contributors for this article] (2008). Comparison between the urinary alcohol markers EtG, EtS, and GTOL/5-HIAA in a controlled drinking experiment. Alcohol and Alcoholism. ISSN 0735-0414. 43(2), p. 187–191. doi: 10.1093/alcalc/agm175. Full text in Research Archive
• Høiseth, Gudrun; Bernard, Jean-Paul; Karinen, Ritva Anneli; Johnsen, Lene; Helander, Anders & Christophersen, Asbjørg S. [Show all 7 contributors for this article] (2007). A pharmacokinetic study of ethyl glucuronide in blood and urine: Applications to forensic toxicology. Forensic Science International. ISSN 0379-0738. 172(2-3), p. 119–124. doi: 10.1016/j.forsciint.2007.01.005. Full text in Research Archive
• Bernard, Jean-Paul; Stokke, Mimi Opdal; Karinen, Ritva Anneli; Mørland, Jørg & Khiabani, Hassan (2007). Relationship between methadone and EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) in urine samples from Norwegian prisons. European Journal of Clinical Pharmacology. ISSN 0031-6970. 63(8), p. 777–782. doi: 10.1007/s00228-007-0314-4. Full text in Research Archive Show summary

  Background: Methadone is a widely used maintenance treatment in rehabilitation of opioid addiction the world over. Methadone is metabolised in the body to a number of inactive metabolites, but primarily to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). The Division of Forensic Toxicology and Drug Abuse (DFTDA), at the Norwegian Institute of Public Health, carries out drug analysis in urine samples from all prisons in Norway. Testing for methadone and EDDP in urine is also carried out, on request. Results are stored in a secure database at the DFTDA. Objectives: The aims of the present study were to 1. Observe variation of methadone and EDDP concentrations in urine with urinary pH, in a large material of prison inmate urine samples, and 2. Analyse methadone positive/EDDP negative results, and investigate whether such results could occur naturally and without sample tampering. Methods: All urine results positive for methadone over the period 2004-2005 were collected from our result database. The relationship between methadone and EDDP excretion in urine, and urinary pH, was observed for these cases. Cases that were positive for methadone but negative for EDDP were picked out and studied individually. Results: 1539 urine samples positive for methadone were found in our database for the period 2004-2005. Our results showed a strong correlation between the concentration of methadone in urine and urinary pH, with higher concentrations of methadone present at lower pH levels. Cases that were positive for methadone but negative for EDDP were rare, and amounted to only 5 (0.3% of the case material). These cases are presented in further detail. Conclusion: Methadone excretion in urine is dependent on urinary pH. Methadone positive/EDDP negative results may suggest sample tampering in some, but not all, cases.

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• Frost, Joachim; Bernard, Jean-Paul Anthony; Dietrichs, Erik Sveberg; Kjeldstadli, Kari Grandaunet; Riedel, Bettina & Skråstad, Ragnhild Bergene [Show all 8 contributors for this article] (2019). Nye anbefalinger ved serumkonsentrasjonsmålinger av sentralstimulerende legemidler. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 139(13). doi: 10.4045/tidsskr.19.0385. Full text in Research Archive
• Havnes, Ingrid Amalia; Bernard, Jean-Paul Anthony; Waal, Helge; Clausen, Thomas & Mørland, Jørg (2010). Methadone treatment and methadone-related deaths in Norway. Full text in Research Archive
• Bernard, Jean-Paul; Mørland, Jørg & Khiabani, Hassan Zare (2007). Metadonbehandling og hjerteartymi. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 127(13), p. 1810–1810. Full text in Research Archive
• Bernard, Jean-Paul; Stokke, Mimi Opdal; Mørland, Jørg & Khiabani, Hassan Zare (2007). Methadone related deaths in Norway 2004 - 2006. Full text in Research Archive Show summary

  Objective: Methadone, a potent opioid receptor agonist, is the most commonly used drug in the treatment of opioid dependence in Norway. Methadone’s side-effects and toxicity are well documented, and the potential for a rise in the incidence of methadone related deaths due to greater methadone availability is worrying. This study aims to follow the occurrence and pattern of methadone related deaths over a three year period. We will also examine cases where methadone was present at toxicological analysis post-mortem and assess what role methadone toxicity played in the cause of death. Methods: Toxicological results where methadone was positive were collected from a database of forensic autopsies at the Division of Forensic Toxicology and Drug Abuse (DFTDA). Cases were divided into those where methadone was the only drug present and those where other drugs were present in addition to methadone. All cases were assessed individually. Results: A total of 176 methadone related deaths were identified from our database of approximately 5400 cases for the period 2004 through 2006. Of these, 143 were male and 33 female. Methadone was the only finding at toxicological analysis in just 6 (3.4%) of these cases. Methadone concentrations in blood varied from 0.06 mg/l to 4.64 mg/l, with a median concentration of 0.43 mg/l. A variety of other substances were also detected in blood, the 3 most common being tetrahydrocannabinol (THC, the primary psychoactive constituent of cannabis), and metabolic products of the benzodiazepines diazepam (N-desmethyldiazepam) and clonazepam (7-aminoclonazepam), respectively. Morphine was detected in 35 cases. The mean number of additional substances detected in these cases was 4. Conclusion: Methadone related deaths in Norway have risen over the past years. Methadone was most often detected in combination with other substances. These results may suggest that patients using methadone have a significant use of other substances, both illegal and prescription medicines. Alternatively, results may indicate that the majority of those involved in methadone related deaths are not enrolled in rehabilitation programs, and that the source of methadone in these cases is diversion. The study is still ongoing, and further analysis of the results is necessary. We are in the process of coupling our material to the National cause of death register and regional registers of patients enrolled in rehabilitation programs (LAR).

• Bernard, Jean-Paul; Mørland, Jørg & Khiabani, Hassan Zare (2007). Methadone and impairment in apprehended drivers. Full text in Research Archive Show summary

  Objective: Methadone is a potent opioid receptor agonist used in the treatment of opioid dependence. Approximately 4000 patients enrolled in rehabilitation programs for heroin addiction, in Norway, received methadone by the end of 2006. In addition, illegal misuse of methadone, although of unknown magnitude, is a well-known problem. According to Norwegian guidelines, patients who are in rehabilitation programs are permitted to drive a motor vehicle provided, firstly, that they have been stabilized on a fixed dose of methadone for a period of at least 6 months, secondly, that the treating doctor finds them fit, and thirdly, that no other drugs are used. The purpose of this study was to investigate apprehended drivers who had; 1. methadone as the only drug in their blood at the time of apprehension, 2. methadone in the presence of other psychoactive drugs in their blood at the time of apprehension. Lastly, it was also desirable to study the relationship between blood methadone concentration and impairment as measured by clinical test of impairment (CTI). Methods: The division of Forensic Toxicology and Drug Abuse (DFTDA) at the Norwegian Institute of Public Heath analyses blood samples from all drivers suspected of driving under the influence of drugs. Cases with positive results for methadone in blood were collected over the period 2000 to 2006. Results: 670 cases of drugged driving with methadone were identified from a total of approximately 55000 for the period 2000 to 2006. The majority of drivers were men (> 80 %), aged between 30 and 40 years. No significant difference in methadone concentration was found for sex. Methadone was the only psychoactive drug detected in blood in only 12 cases. A significant difference in blood methadone concentration was found between cases where only methadone was detected (median 0.46 mg/L (range 0.19 – 0.65)), and cases where methadone was detected in combination with other psychoactive drugs (median 0.28 mg/L (range 0.06 – 1.24)). A CTI had been carried out in 609 of the cases. Interestingly, a concentration-impairment relationship was not seen for these cases. Approximately 90 % of cases had at least one benzodiazepine present in blood (most commonly flunitrazepam), while the most frequently observed other substances were amphetamine (in 228 cases), delta 9 tetrahydrocannabinol (THC, in 192 cases) and morphine (in 165 cases), in descending order. Conclusion: Cases of driving impairment involving methadone alone were very rare (only 12 over a 7 year period), while methadone in combination with other drugs was more common; in descending order of frequency, benzodiazepines (flunitrazepam, diazepam, clonazepam etc.), amphetamine, THC and morphine. No relationship between methadone concentration and impairment as judged by CTI was seen for either methadone-only cases, although these were very few, or cases involving methadone and other psychoactive drugs.

• Høiseth, Gudrun; Bernard, Jean-Paul; Stephansson, Nicolai; Normann, Per Trygve; Christophersen, Asbjørg S. & Mørland, Jørg [Show all 7 contributors for this article] (2007). Comparison of GTOL/5HIAA vs EtG and EtS as relapse markers. Full text in Research Archive
• Bernard, Jean-Paul; Stokke, Mimi Opdal & Khiabani, Hassan (2006). Generelle farmakodynamiske prinsipper. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 126(16), p. 2107–2109. Full text in Research Archive Show summary

  Sammendrag: Farmakodynamikk handler om hvordan ligander (legemidler, rusmidler, giftstoffer og hormoner) virker på sine målorganer i kroppen og utløser effekter (enten ønsket eller uønsket). Interaksjon mellom legemidler og mottakerproteiner er spesifikk og selektiv i organismen. Mottakerproteinene tilhører stort sett til en av fire grupper; enzymer, transportproteiner, ionekanaler og reseptorer.

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