| 1. |
- Beck, Olof, et al.
(author)
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Volumetric dried blood spots for determination of phosphatidylethanol: Validation of a liquid chromatography tandem masspectrometry method and clinical application
- 2024
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In: DRUG TESTING AND ANALYSIS. - 1942-7603 .- 1942-7611.
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Journal article (peer-reviewed)abstract
- Phosphatidylethanol (PEth) measurement in whole blood samples is established as a specific alcohol biomarker with clinical and forensic applications. Establishment of dried blood spots (DBSs) as a specimen for PEth determination offers several advantages and was the focus of this work. A liquid chromatography tandem mass spectrometry method using a 96-well format for sample preparation was developed and validated. PEth was extracted from DBSs by using isopropanol containing PEth-d5 as internal standard. The blood sampling used a commercial volumetric DBS device having a phosholipase D inhibitor incorporated to stop continuous PEth formation. The method quantified PEth in the range of 0.05-10 mu mol/L, with a bias and imprecision of less than 15%. In a clinical study (n = 25) using fingerprick blood, the volumetric device offered more precise quantifications (CV 4.6%) compared with the Whatman 903 Protein Saver card device (CV 16.6%). In another clinical study (n = 48), the use of dried venous and capillary blood, and liquid venous blood was compared under real-life conditions with samples sent by postal service. The capillary and venous DBS samples gave identical results while the liquid blood gave slightly higher values. Calculation of elimination half-life (PEth 16:0/18:1) in 31 cases based on two consecutive samples with 2-9 days in between gave results (mean 6.2 days) that agree with literature but several cases with values over 10 days. In conclusion, this study demonstrates that volumetric DBS is a valid specimen for determination of PEth blood concentrations, offering several advantages. Phosphatidylethanol, a specific alcohol biomarker, measured in dried blood spots was the focus of this work. A liquid chromatography tandem mass spectrometry method was developed, validated, and applied. The blood sampling used a volumetric DBS device. The volumetric device gave accurate and precise quantifications and the dried capillary blood gave the same results as that of venous blood. image
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| 2. |
- De Bejczy, Andrea, 1975, et al.
(author)
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A randomized, double-blind, placebo-controlled, multicentre trial on the efficacy of varenicline and bupropion in combination and alone for treatment of alcohol use disorder: Protocol for the COMB study
- 2024
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In: PLOS ONE. - 1932-6203. ; 19:1
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Journal article (peer-reviewed)abstract
- BackgroundAlcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a pressing need for a well-tolerated and effective treatment option for AUD. Dopamine is hypothesized to be involved in the development of alcohol dependence. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies.MethodsConsenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5-2 mg; bupropion SR 150-300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022.DiscussionThe COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction.
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| 3. |
- De Bejczy, Andrea, 1975, et al.
(author)
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AUD in perspective
- 2024
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In: International Review of Neurobiology. - : Academic Press Inc.. - 0074-7742 .- 2162-5514.
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Book chapter (other academic/artistic)abstract
- Alcohol is a major cause of pre-mature death and individual suffering worldwide, and the importance of diagnosing and treating AUD cannot be overstated. Given the global burden and the high attributable factor of alcohol in a vast number of diseases, the need for additional interventions and the development of new medicines is considered a priority by the World Health Organization (WHO). As of today, AUD is severely under-treated with a treatment gap nearing 90%, strikingly higher than that for other psychiatric disorders. Patients often seek treatment late in the progress of the disease and even among those who seek treatment only a minority receive medication, mirroring the still-prevailing stigma of the disease, and a lack of access to effective treatments, as well as a reluctance to total abstinence. To increase adherence, treatment goals should focus not only on maintaining abstinence, but also on harm reduction and psychosocial functioning. A personalised approach to AUD treatment, with a holistic view, and tailored therapy has the potential to improve AUD treatment outcomes by targeting the heterogeneity in genetics and pathophysiology, as well as reason for, and reaction to drinking. Also, the psychiatric co-morbidity rates are high in AUD and dual diagnosis can worsen symptoms and influence treatment response and should be considered in the treatment strategies.
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| 4. |
- De Bejczy, Andrea, 1975
(author)
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Phosphatidylethanol (B-PEth) and other direct and indirect biomarkers of alcohol consumption
- 2024
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In: International Review of Neurobiology. - : Academic Press Inc.. - 0074-7742 .- 2162-5514.
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Book chapter (other academic/artistic)abstract
- When identifying, preventing and treating alcohol use disorder, a correct estimation of alcohol intake is essential. An objective marker is preferred as self-reported alcohol intake suffers from bias, and the use of alcohol biomarkers is increasing globally. An easy-to-use blood biomarker to correctly assess alcohol consumption is an invaluable asset in alcohol treatment strategies, as well as in alcohol research studies. The specific, cumulative, biomarker phosphatidylethanol, mirroring the past two weeks of consumption, has shown superiority over traditional biomarkers and is an attractive choice of proxy for alcohol intake.
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| 5. |
- Guiraud, J., et al.
(author)
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Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration
- 2023
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In: Alcohol and Alcoholism. - : Oxford University Press (OUP). - 0735-0414 .- 1464-3502. ; 58:2, s. 125-133
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Journal article (peer-reviewed)abstract
- Aims: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. Methods: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. Results: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. Conclusions: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.
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| 6. |
- Guiraud, J., et al.
(author)
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Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial
- 2022
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In: Journal of Psychopharmacology. - : SAGE Publications. - 0269-8811 .- 1461-7285. ; 36:10
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Journal article (peer-reviewed)abstract
- Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3-3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6-68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites (n = 3-66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD.
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| 7. |
- Guiraud, J., et al.
(author)
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Treating alcohol dependence with an abuse and misuse deterrent formulation of sodium oxybate: Results of a randomised, double-blind, placebo-controlled study
- 2021
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In: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X. ; 52, s. 18-30
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Journal article (peer-reviewed)abstract
- Sodium oxybate (SMO) has been approved in Italy and Austria for the maintenance of abstinence in alcohol dependent (AD) patients. Although SMO is well tolerated in AD patients, cases of abuse and misuse have been reported outside the therapeutic setting. Here we report on a phase IIb double-blind, randomized, placebo-controlled trial for the maintenance of abstinence in AD patients with a new abuse and misuse deterrent formulation of SMO. A total of 509 AD patients were randomized to 12 weeks of placebo or one of four SMO doses (0.75, 1.25, 1.75 or 2.25 g t.i.d.) followed by a one-week medication-free period. The primary endpoint was the percentage of days abstinent (PDA) at end of treatment. An unexpectedly high placebo response (mean 73%, median 92%) was observed. This probably compromised the demonstration of efficacy in the PDA, but several secondary endpoints showed statistically significant improvements. A post-hoc subgroup analysis based on baseline severity showed no improvements in the mild group, but statistically significant improvements in the severe group: PDA: mean difference +15%, Cohen's d = 0.42; abstinence: risk difference +18%, risk ratio = 2.22. No safety concerns were reported. Although the primary endpoint was not significant in the overall population, several secondary endpoints were significant in the intent-to-treat population and post-hoc results showed that treatment with SMO was associated with a significant improvement in severe AD patients which is consistent with previous findings. New trials are warranted that take baseline severity into consideration. (C) 2021 The Authors. Published by Elsevier B.V.
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| 8. |
- Hildebrand Karlén, Malin, 1984, et al.
(author)
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What does current science tell us about the accuracy, reliability, and completeness of intoxicated witnesses? A case example of the murder of a prime minister
- 2022
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In: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 13
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Journal article (peer-reviewed)abstract
- Generally, the testimony of intoxicated witnesses has been considered relatively unreliable, but recent research has nuanced the knowledge base regarding these vulnerable witnesses. PurposeTo demonstrate the application of recent research findings regarding intoxicated witnesses to the statements made by a key witness to the murder of Olof Palme, Sweden's prime minister, in 1986. An additional purpose was to illustrate the use of a nuanced calculation of blood alcohol concentration (BAC) for researchers. MethodsThe Palme murder has been debated since the crime was committed and no one has yet been sentenced. One of the witnesses was intoxicated and to estimate a range for his BAC at the time, a comprehensive BAC calculation was conducted in this study to illustrate important factors to consider in these types of cases. ResultsThrough the demonstration of the use of a nuanced BAC formula and by applying recent research results from studies on intoxicated witnesses, it was estimated that the possible BAC of the witness in the Palme-case at the time of the witnessed crime ranged between BAC = 0 to BAC = 0.13, depending on the type of alcoholic beverage consumed and whether the witness was a social or heavy drinker. This puts the witness either well within the span of maintained completeness as well as maintained accuracy rate (if considering: lowest dose and heavy drinker), or slightly exceeding this span into the BAC-range of reduced completeness but maintained accuracy rate (if considering: highest dose and social drinker). He was questioned immediately, and thereafter repeatedly, and he reported similar information throughout the interviews, which is in line with previous results on information maintenance over repeated interviews among intoxicated witnesses. ConclusionThe current case example shows how recent research on intoxicated witnesses can be applied in praxis, illustrating important factors for legal practitioners to consider when interpreting information from intoxicated witnesses. It also provides legal practitioners and researchers with an example of a structured approach to more nuanced BAC-calculations.
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| 9. |
- Scherrer, B., et al.
(author)
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Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy
- 2021
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In: Alcoholism-Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 45:9, s. 1722-1734
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Journal article (peer-reviewed)abstract
- Background There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. Methods We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis. Results Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months). Conclusions Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.
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