Self-Reported Level of Sports Compared With Objective Data in Athletes With Femoroacetabular Impingement Syndrome.

BACKGROUND: Femoroacetabular impingement syndrome (FAIS) is common among ice hockey and soccer players. To evaluate the prevalence of return to sports after hip arthroscopy or level of sports before surgery, self-reported questionnaires such as the Hip Sports Activity Scale (HSAS) are frequently used. There is a risk of self-reporting bias when using these tools. PURPOSE: To evaluate how self-reported levels of sports using HSAS correspond to objective data. STUDY DESIGN: Cohort study, Level of evidence: 3. METHOD: Ice hockey and soccer players undergoing hip arthroscopy for FAIS between 2011 and 2019 and included in the local hip arthroscopy registry in Gothenburg, Sweden, aged ≥18 years at the time of surgery, with a self-reported HSAS level of 7 or 8 before onset of symptoms, were included. Objective data on level of sports were collected through sports-specific sources (https://football.instatscout.com, https://hockey.instatscout.com, https://www.eliteprospects.com, and Swedish Football Association). Objective data were collected for the corresponding season when the athletes reported their symptom onset. Agreement between subjective and objective data was described using descriptive statistics, and comparison between subgroups was made. RESULTS: A total of 483 athletes met the inclusion criteria: 80 ice hockey and 403 soccer players. The majority were men (90%). The mean age was 26.5 years (SD, 8.3 years). When comparing HSAS level with objective data, 112 athletes (23%) had a correct self-reported HSAS level. Of 251 athletes with a self-reported HSAS level of 8, 76 (30%) had a matching objective HSAS level, and 36 of 232 (16%) athletes with a self-reported HSAS level of 7 had a matching objective HSAS level. Of the erroneous subjective ratings, 98% were higher than the objective data. Athletes reporting a correct HSAS level were younger (24.6 vs 26.4 years; P = .04) and had a shorter symptom duration (18 vs 24 months; P < .001). Ice hockey players scored themselves correctly more often than soccer players (P < .001). CONCLUSION: Only 23% of athletes undergoing hip arthroscopy for FAIS self-reported an HSAS level before onset of symptoms that was accurate according to the objectively recorded data. The majority self-reported an HSAS level above their correct level of sports. Ice hockey players, younger age, and shorter symptom duration were associated with correct self-assessment.

Taking control of one's everyday life - a qualitative study of experiences described by participants in an occupational intervention.

BACKGROUND: Sick leave due to stress-related ill-health is increasing and is often caused by occupational imbalance. These types of issues tend to affect both the ability to work and cope with everyday life, as well as the overall experience of health, negatively. There is still little knowledge on how to prepare people and workplaces for the return-to-work process after participation in a work rehabilitation program due to stress and occupational ill-health. Therefore, this study aimed to describe what is needed to achieve a balanced everyday life that includes paid work as experienced by individuals who had participated in a ReDO® intervention due to occupational imbalance and ill-health. METHODS: The concluding notes from 54 informants' medical records were used for qualitative content analysis. The informants had participated in an occupational therapy group intervention to promote occupational health and regain full work capacity. RESULTS: The analysis resulted in one major theme and four categories describing how the informants perceive that they must take control of their everyday life as a whole. By doing so, they need to work with structurization and prioritization, social interaction, boundary setting, and occupational meaningfulness. CONCLUSION: The study indicates a highly relational process, where it is impossible to divide life into private and work, and presupposes balance in everyday life in multiple dimensions. Its contribution includes the formulation of perceived needs in the transition between intervention and return to work and could, through further research, be used to generate a more effective and sustainable return- and rehabilitation models.

Good functional outcomes after endoscopic treatment for greater trochanteric pain syndrome.

PURPOSE: Greater trochanteric pain syndrome (GTPS) is a term covering different conditions generating lateral hip pain. Recalcitrant cases may require surgery but there are only a few studies evaluating endoscopic treatment. This study aimed to evaluate the outcome of endoscopically treated GTPS at minimum two years postoperatively using patient-reported outcome measures (PROMs), and to assess the complication rate associated with endoscopic surgery. METHODS: A total of 33 patients, mean age 43.2 years, 88% women, with a mean symptom duration of 3.5 years, were included in the study. A total of 36 operated hips were included. Pre- and at minimum two years postoperatively the patients completed questionnaires consisting of the International Hip Outcome Tool (iHOT-12) and the Hip Sports Activity scale (HSAS), the Visual analogue scale for overall hip function (VAS-OHF), the Copenhagen Hip and Groin Outcome Score (HAGOS), the EuroQoL-5 Dimension Questionnaire (EQ-5D) and the EQ-VAS. Complications were assessed using the Clavien-Dindo classification. RESULTS: Median follow-up time was 24.5 months postoperatively. Statistically significant improvements were seen for the following PROMs (p < 0.05); iHOT-12 (36.3 vs 54.0), HAGOS different subscores (40.8 vs 59.0, 46.5 vs 62.6, 29.9 vs 53.1, 33.5 vs 51.4, 20.7 vs 41.4, 23.4 vs 43.3), EQ-VAS (55.9 vs 63.3) and EQ-5D (0.392 vs 0.648). VAS-OHF and HSAS did not reach significance. There was a 71% satisfaction rate with the surgery. Three Clavien-Dindo grade 1 and one grade 2 complications were registered postoperatively, with 41% of patients achieving PASS for iHOT-12 at two years follow-up. CONCLUSION: Endoscopic surgery for greater trochanteric pain syndrome improved patient-reported outcomes and the procedure was associated with low risk of complications. LEVEL OF EVIDENCE: Level IV.

Arthroscopic iliopsoas tenotomy after total hip arthroplasty: safe method for the right patient.

PURPOSE: To evaluate the outcome of arthroscopic treatment for iliopsoas impingement after total hip arthroplasty (THA) 2 years after surgery using patient reported outcomes (PROM). METHODS: In this study 12 patients (13 hips) were included from a local hip arthroscopy registry. Patients completed web-based PROMs preoperatively and at a minimum of 2 years postoperatively. The PROMs included the International Hip Outcome Tool short version (iHOT-12), the Copenhagen Hip and Groin Outcome Score (HAGOS), the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hip Sports Activity Scale (HSAS) for physical activity level, the Visual Analog Scale (VAS) for overall hip function and a single question regarding overall satisfaction with the surgery. RESULTS: The mean age was 64.4 years (±15.1SD), mean body mass index (BMI) was 26.6 (±4.3SD), mean follow-up time was 49.8 months (±25SD). Comparing PROMs preoperatively with 2-year follow up showed an improvement for many of the PROMs used. The PROMs scores were iHOT-12 (24.9 vs 34.5, p = 0.13), HAGOS subscales (symptoms 38.2 vs 54.5, p = 0.05; pain 36 vs 53, p = 0.04; sport 14.1 vs 35.1, p = 0.03; daily activity 31 vs 47.5, p = 0.04; physical activity 21.8 vs 24, p = 0.76; quality of life 24 vs 35, p = 0.03), EQ-VAS (57.9 vs 58, p = 0.08), EQ-5D (0.34 vs 0.13, p = 0.07) and VAS for overall hip function (43.1 vs 46.2, p = 0.14). In total, 10 out of the 12 patients (83%) were satisfied with the intervention. CONCLUSION: Patients undergoing surgery for iliopsoas impingement after previous THA showed improved self-reported hip function where most patients were satisfied with treatment.

Rapid determination of acyclovir, its main metabolite 9-carboxymethoxymethylguanine, ganciclovir, and penciclovir in human serum using LC-MS/MS.

A novel MS-based analytical method for simultaneous analysis of the antiviral drugs acyclovir, its metabolite 9-carboxymethoxymethylguanine, ganciclovir, and penciclovir in human serum is described. These antiviral drugs are active against herpes virus infections. Acyclovir and penciclovir are regarded as safe and effective medicines with mild side effects such as headache and gastrointestinal discomfort, and ganciclovir is regarded as more toxic and is known to cause, for example, bone marrow suppression. Acyclovir's main metabolite 9-carboxymethoxymethylguanine is a presumptive neurotoxin and should be monitored in patients with impaired renal function or in cases with neurotoxic symptoms. A sample was prepared using protein precipitation with 1% formic acid in methanol containing isotopically labeled internal standard. Chromatographic separation on a biphenyl column and mass spectrometric detection were performed in multiple reaction monitoring (MRM) mode on a Xevo TQ-S micro with ESI in positive ion mode, within 3 min. Inter-day assay accuracies for the quality controls varied between 95 and 104% and intra-day assay between 93 and 105%. Inter-day and intra-day assay imprecision for the quality controls ranged between 1.4 and 4.2% and 1.7 and 6.5% respectively. The lower limit of quantification for all four substances was 0.156 µmol/L. It is an accurate and reproducible method for therapeutic drug monitoring.

Simultaneous Measurement of 11 Antibiotics for Use in the Intensive Care Unit by Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Recent studies indicate that a high proportion of patients in the intensive care unit fail to attain adequate antibiotic levels. Thus, there is a need to monitor the antibiotic concentration to ensure effective treatment. In this article, the authors aimed to develop an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of antimicrobials to assess individualized therapeutic drug monitoring. METHODS: A UHPLC-MS/MS method with 11 antibiotics (ciprofloxacin, moxifloxacin, benzylpenicillin, levofloxacin, linezolid, rifampicin, meropenem, cloxacillin, cefotaxime, clindamycin, and piperacillin) was developed. Chromatographic separation was performed using a Kinetex Biphenyl reversed-phase column, with gradient elution using 0.1% formic acid and methanol with 0.1% formic acid. Sample preparation was performed using methanol protein precipitation. The total run time was 5 minutes. RESULTS: For all analytes, the interassay inaccuracies for calibrators were ≤5%. The interday inaccuracies for the quality controls (QCs) were ≤5% for all analytes. The interassay precision for calibration standards ranged between 1.42% and 6.11%. The interassay imprecision for QCs of all antibiotics and concentrations ranged between 3.60% and 16.1%. Interassay inaccuracy and imprecision for the QCs and calibration standards were ≤15% for all drugs, except benzylpenicillin. CONCLUSIONS: A rapid UHPLC-MS/MS method was developed for the simultaneous quantification of 11 different antibiotics. Minimal sample preparation was required to ensure a rapid turnaround time. The method was applied to clinical samples collected from 4 intensive care units.

Exploring risk factors for developing occupational ill health - departing from an occupational perspective.

BACKGROUND: Sick leave due to stress-related mental ill health increases in society. In occupational therapy, occupational balance is considered important for experiencing health and well-being. Thus, knowledge regarding occupational balance and occupational value constitute essential parts of occupational therapists' work with people suffering from occupational ill health. OBJECTIVE: The aim of this study is to analyse the relationships between sociodemographic factors, occupational value, occupational balance and perceived health in people suffering from occupational ill health. METHODS: In a quantitative cross-sectional study data from a total of 218 individuals were included, 192 women, 22 men and 4 individuals who did not specify their gender. Data were collected by means of surveys prior to an occupational therapy intervention. The instruments used included OVal-pd, OBQ, EQ5D and a sociodemographic questionnaire. Data were analysed using regression and decision tree analysis. RESULTS: The results show that individuals who experience an imbalance in their everyday life and who have few or no experiences of daily occupations imprinted by socio-symbolic occupational value experienced lower perceived health. CONCLUSIONS: Low level of experiences of balance in daily life and occupational value seems to be the main risk factors for the development of occupational ill health, rather than sociodemographic factors.

Delayed and cancelled orthopaedic surgery; are there solutions to reduce the complex set of problems? A systematic literature review.

BACKGROUND: Unexpected cancellations of, and delays to, orthopaedic surgery have adverse effects, with a negative impact on hospital performance and undesirable patient outcomes. As cancellations and delays are common, finding measures to prevent them is a matter of urgency. METHODS: The present systematic review conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines and the Cochrane Handbook. Peer-reviewed studies reporting on cancellations or delays in patients requiring emergency orthopaedic or planned orthopaedic surgery that compared care action/intervention with no action or traditional care were included. The Grading of Recommendations Assessment, Development and Evaluation used to assess the quality of evidence of the results from the included studies. The objective of the present study was systematically to search and review the literature for qualitative evidence of factors that might reduce cancellations of and delays to orthopaedic surgical procedures. RESULTS: The electronic search yielded 1209 studies and eight articles were included in the performed quality assessment. The heterogeneity of the studies and the lack of calculations and statistics in the studies resulted in no meta-analysis. The result of the quality assessment indicated that the evidence ranked from low to very low across the different outcomes. The main limiting factor, which was the reason for a decrease in quality in some outcomes, was the study designs, which were non-randomised control or retrospective approach. The interventions in the included studies could help to support a reduction in the risk of cancelled and delayed orthopaedic procedures. CONCLUSION: This systematic literature review has revealed important evidence to help reduce the risk of cancelled and delayed orthopaedic procedures associated with a variety of care action exposures. They include a fast-track pathway, pre-operative guidelines and telephone contact with patients prior to surgery, as well as careful consideration of additional pre-operative tests.

Prior hip arthroscopy does not affect 1-year patient-reported outcomes following total hip arthroplasty: a register-based matched case-control study of 675 patients.

Background and purpose - Femoroacetabular impingement syndrome (FAIS) is a common cause of hip pain and may contribute to the development of osteoarthritis. We investigated whether a prior hip arthroscopy affects the patient-reported outcomes (PROMs) of a later total hip arthroplasty (THA).Patients and methods - Patients undergoing hip arthroscopy between 2011 and 2018 were identified from a hip arthroscopy register and linked to the Swedish Hip Arthroplasty Register (SHAR). A propensity-score matched control group without a prior hip arthroscopy, based on demographic data and preoperative score from the EuroQoL visual analogue scale (EQ VAS) and hip pain score, was identified from SHAR. The group with a hip arthroscopy (treated group) consisted of 135 patients and the matched control group comprised 540 patients. The included PROMs were EQ-5D and EQ VAS of the EuroQoL group, and a questionnaire regarding hip pain and another addressing satisfaction. Rate of reoperation was collected from the SHAR. The follow-up period was 1 year.Results - The mean interval from arthroscopy to THA was 27 months (SD 19). The EQ-5D was 0.81 and 0.82, and EQ VAS was 78 and 79 in the treated group and the matched control group respectively. There were no differences in hip pain, and reported satisfaction was similar with 87% in the treated group and 86% in the matched control group.Interpretation - These results offer reassurance that a prior hip arthroscopy for FAIS does not appear to affect the short-term patient-reported outcomes of a future THA and indicate that patients undergoing an intervention are not at risk of inferior results due to their prior hip arthroscopy.

Generalised joint hypermobility increases ACL injury risk and is associated with inferior outcome after ACL reconstruction: a systematic review.

OBJECTIVES: To investigate the association between generalised joint hypermobility (GJH) and ACL injury risk. Secondary aims involved evaluating associations between GJH and postoperative outcome (including graft-failure risk, knee laxity and patient-reported outcome). Furthermore, we aimed to compare the performance of different grafts in patients with GJH. METHODS: Databases MEDLINE/PubMed, EMBASE and the Cochrane Library were searched, including 2760 studies. Two reviewers independently screened studies for eligibility. A modified version of the MINORS score was applied for quality appraisal. Studies assessing GJH while reporting the risk of ACL injury and/or postoperative outcome were included. RESULTS: Twenty studies were included, using several different methods to determine GJH. There was consistent evidence showing that GJH is a risk factor for unilateral ACL injury in males, while in females, the results were conflicting. There was limited evidence associating GJH with increased knee laxity 5 years postoperatively. There was consistent evidence of inferior postoperative patient-reported outcome in patients with GJH. Moreover, there was limited yet consistent evidence indicating that patellar-tendon autografts are superior to hamstring-tendon autografts in patients with GJH in terms of knee laxity and patient-reported outcome. There was insufficient evidence to draw conclusions regarding the outcomes of bilateral ACL injury and graft failure. CONCLUSIONS: In men, GJH was associated with an increased risk of unilateral ACL injury. Moreover, GJH was associated with greater postoperative knee laxity and inferior patient-reported outcome. Based on the available evidence, a patellar-tendon autograft appears to be superior to a hamstring-tendon autograft in patients with GJH. However, the included studies were heterogeneous and there is a need for consensus in the assessment of GJH within sports medicine.

Graft Diameter and Graft Type as Predictors of Anterior Cruciate Ligament Revision: A Cohort Study Including 18,425 Patients from the Swedish and Norwegian National Knee Ligament Registries.

BACKGROUND: It is important to investigate and compare graft diameters as well as graft types to identify risk factors for revision after an anterior cruciate ligament (ACL) reconstruction. We performed the current study in order to analyze the early ACL revision rate among patients treated with hamstring tendon (HT) autografts or patellar tendon (PT) autografts of different diameters. Our hypothesis was that an increase in both HT and PT autograft diameters would reduce the risk of early ACL revision. METHODS: This retrospective study was based on prospectively collected data from the national knee ligament registries of Norway and Sweden and included patients who underwent primary ACL reconstruction during the period of 2004 through 2014. The primary end point was the 2-year incidence of ACL revision. The impact of graft type and diameter on the incidence of revision surgery was reported as relative risks (RRs) with 95% confidence intervals (CIs), estimated by using generalized linear models with a binomial distribution and log-link function. RESULTS: Of 58,692 patients identified, a total of 18,425 patients were included in this study. The 2-year rate of ACL revision was 2.10% (PT autografts, 2.63%; HT autografts, 2.08%; RR = 0.93 [95% CI = 0.60 to 1.45]). There was an increased risk of ACL revision among patients treated with HT autografts with a diameter of <8 mm compared with larger HT autografts (RR = 1.25 [95% CI = 1.01 to 1.57]). Patients treated with HT autografts with a diameter of ≥9.0 mm or ≥10.0 mm had a reduced risk of early ACL revision compared with patients treated with PT autografts. CONCLUSIONS: Patients treated with larger-diameter HT autografts had a lower risk of early ACL revision compared with those treated with HT autografts of <8 mm. Patients treated with HT autografts of ≥9 or ≥10 mm had a reduced risk of early ACL revision compared with patients treated with PT autografts. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Quality Assessment of Prospective Cohort Studies Evaluating Arthroscopic Treatment for Femoroacetabular Impingement Syndrome: A Systematic Review.

BACKGROUND: Femoroacetabular impingement (FAI) syndrome is a cause of pain and reduced range of motion in the hip joint. Given the limited number of randomized controlled trials, prospective cohort studies constitute the dominant part of the available prospective evidence evaluating relevant clinical outcomes after arthroscopic hip surgery for FAI. PURPOSE: To assess the methodological quality of prospective cohort studies evaluating arthroscopic surgery for FAI and to determine whether there has been an improvement in methodological quality over time. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic literature search was performed in PubMed, Embase (OvidSP), and the Cochrane Library. Included studies were clinical prospective cohort studies of primary arthroscopic surgery for cam and/or pincer morphology FAI. Methodological quality was assessed with the Methodological Index for Non-randomized Studies (MINORS). The mean MINORS score for studies published during the first 5 years of the period was compared with those published during the last 5 years to evaluate methodological improvement over time. The methodological quality of randomized controlled trials was also assessed with the Coleman Methodology Score. RESULTS: The search yielded 53 studies. There were 34 noncomparative studies, 15 nonrandomized comparative studies, and 4 randomized controlled trials. The included studies were published between 2008 and 2017. The mean ± SD MINORS score for noncomparative and comparative studies was 10.4 ± 1.4 of 16 possible and 18.7 ± 2.0 of 24 possible, respectively. The mean Coleman Methodology Score for randomized controlled trials was 79.0 ± 7.0 of 100 possible. CONCLUSION: The methodological quality of prospective cohort studies evaluating arthroscopic surgery for FAI is moderate for comparative and noncomparative studies. Common areas for improvement include unbiased assessment of study endpoints and prospective sample-size calculations. Despite an increase in the number of published studies, an improvement in methodological quality over time was not observed.

Mephedrone, methylone and 3,4-methylenedioxypyrovalerone (MDPV) induce conditioned place preference in mice.

During the last decade, there has been a worldwide increase in popularity and abuse of synthetic cathinones. Common ingredients of the so-called bath salts include mephedrone, methylone and 3,4-methylenedioxypyrovalerone (MDPV). Relatively little information about the pharmacology and addiction potential of these drugs is available. We used the conditioned place preference (CPP) paradigm to explore the reinforcing effects of three different synthetic cathinones. The primary aim of this study was to investigate whether mephedrone, methylone and MDPV induce CPP in mice. The secondary aims were to investigate a possible dose-response CPP and whether the synthetic cathinones induce higher CPP than amphetamine at equal dose. C57BL/6 mice were conditioned to mephedrone, methylone, MDPV and amphetamine at doses of 0.5, 2, 5, 10 or 20 mg/kg (i.p.). During the conditioning, the mice received two training sessions per day for 4 days. All four tested drugs showed a significant place preference compared with controls. Mice conditioned with MDPV (5 and 10 mg/kg) displayed a greater preference score compared to mice conditioned with amphetamine (5 and 10 mg/kg). Our findings show that mephedrone, methylone and MDPV produce CPP equal or higher than amphetamine strongly suggesting addictive properties. Given the public health concern of abuse, future pharmacological studies are necessary to fully understand the effects of these drugs.

ABCB1 gene polymorphisms are associated with suicide in forensic autopsies.

BACKGROUND: Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics. OBJECTIVE: The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T in deaths by suicide. PATIENTS AND METHODS: A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases. RESULTS: There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases. CONCLUSION: Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.

The SWedish Eating Assessment for Autism spectrum disorders (SWEAA)-Validation of a self-report questionnaire targeting eating disturbances within the autism spectrum.

The aim was to design and validate a questionnaire pertaining to eating problems in individuals with normal intelligence, within the autism spectrum. The questionnaire was based on literature search and clinical experience. The validation focused on psychometric properties of reliability and validity using a clinical group of individuals with autism spectrum disorders (ASD) (n=57) and a matched, healthy comparison group (n=31). The instrument showed high levels of reliability, convergent and discriminant validity and scaling properties. Logistic regression analyses discerned the single item Simultaneous capacity and the subscale Social situation at mealtime as the best predictors of ASD. In conclusion, the questionnaire is valid and reliable to detect disturbed eating behaviours in individuals with ASD and normal intelligence.

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment.

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 S-enantiomer, 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. P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10mg/kg) or escitalopram (5mg/kg) Serum and brain samples were collected 1-6h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. 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. 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.

Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood.

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.

Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model.

RATIONALE: P-glycoprotein (P-gp) plays an important role in the efflux of drugs from the brain back into the bloodstream and can influence the pharmacokinetics and pharmacodynamics of drug molecules. To our knowledge, no studies have reported pharmacodynamic effects of any antidepressant drug in the P-gp knockout mice model. OBJECTIVE: The aim of this study was to investigate the enantiomeric venlafaxine and metabolite concentrations in serum and brain of abcb1ab⁻/⁻ mice compared to wild-type mice upon chronic dosing, and to assess the effect of venlafaxine treatment on open-field behavior. METHODS: P-gp knockout and wild-type mice received two daily intraperitoneal injections of venlafaxine (10 mg/kg) over ten consecutive days. Locomotor and rearing activities were assessed on days 7 and 9. After 10 days, drug and metabolite concentrations in brain and serum were determined using an enantioselective LC/MS/MS method. RESULTS: The brain concentrations of venlafaxine and its three demethylated metabolites were two to four times higher in abcb1ab⁻/⁻ mice compared to abcb1ab+/+ mice. The behavioral results indicated an impact on exploration-related behaviors in the open-field as center activity was increased, and rears were decreased by venlafaxine treatment. CONCLUSION: 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.

Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein.

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.

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.

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.