High quantities: Evaluating the association between cannabis use and propofol anesthesia during endoscopy.

BACKGROUND: Endoscopy under propofol sedation has become a routine procedure. Given the number of Canadians undergoing an endoscopy annually, as well as the pervasive use of cannabis by many patients, understanding the effect of cannabis use on the propofol dose at endoscopy is highly relevant. We aimed to evaluate the association between cannabis exposure and the propofol dose needed to achieve adequate sedation at endoscopy. METHODS: A case-control study of individuals undergoing endoscopy was conducted at a single outpatient endoscopy clinic in London, Ontario between 2014 and 2017. Cases included all individuals with any self-reported cannabis exposure, while controls included all individuals without any self-reported history of cannabis use. Dose of propofol administered by a single anesthetist was collected on each subject as well as additional demographic and procedure-related covariates. RESULTS: Three hundred and eighteen participants were included (cases, n = 151; controls, n = 167). Cannabis exposure was associated with an increase in propofol dose (cases 0.33 mg/kg/minute ±0.24; controls, 0.18 mg/kg/minute ±0.11; p<0.0001). Cannabis exposure remained an independent predictor of propofol dose on multivariate linear regression accounting for other important covariates (p<0.0001). Daily cannabis users required a higher propofol dose than weekly or monthly users. Three procedural sedation-related complications occurred in the cannabis-exposed group, while none occurred in the unexposed group. CONCLUSION: Our data suggest that cannabis use is significantly associated with the quantity of propofol needed for sedation at endoscopy. Further study is needed to better understand the molecular basis for this possible drug-drug interaction.

Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer.

PURPOSE: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. METHODS: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. RESULTS: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. CONCLUSIONS: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

CYP2D6 genotype and endoxifen plasma concentration do not predict hot flash severity during tamoxifen therapy.

PURPOSE: Tamoxifen is frequently prescribed to prevent breast cancer recurrence. Tamoxifen is a prodrug and requires bioactivation by CYP2D6. Tamoxifen use is often limited by adverse effects including severe hot flashes. There is paucity of prospectively collected data in terms of CYP2D6 genotype and measured tamoxifen, 4-hydroxytamoxifen and endoxifen concentrations in relation to hot flash severity during tamoxifen therapy. METHODS: We conducted a longitudinal prospective study of breast cancer patients on tamoxifen (n = 410). At each visit, blood samples were collected, and patients completed a standardized hot flash survey (n = 1144) that reflected hot flash severity during the 7 days prior to the visit. Plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using liquid chromatography-tandem mass spectrometry and genotyping was carried out for CYP2D6. A linear mixed-effects regression analysis assessed the association of covariates in relation to the hot flash severity score (HFSS). RESULTS: Median age at first assessment was 50 years with 61.9% of patients considered peri-menopausal. Most patients (92.2%) experienced hot flash symptoms with 51.0% having low HFSS (0-4) and 7.32% experiencing HFSS > 25. Age was significantly associated with hot flash severity, with patients aged 45-59 more likely to have higher HFSS. Neither duration of tamoxifen therapy nor observed tamoxifen, endoxifen and 4-hydroxy tamoxifen plasma concentration predicted hot flash severity. Genetic variation in CYP2D6 or CYP3A4 was not predictive of hot flash severity. CONCLUSIONS: Hot flash severity during tamoxifen therapy can not be accounted for by CYP2D6 genotype or observed plasma concentration of tamoxifen, 4-hydroxytamoxifen, or endoxifen.

Interpatient Variation in Rivaroxaban and Apixaban Plasma Concentrations in Routine Care.

BACKGROUND: Direct-acting oral anticoagulants (DOACs) are widely prescribed for stroke prevention in patients with atrial fibrillation (AF). An important advantage of DOACs is that routine monitoring of an anticoagulation response is not necessary. Nevertheless, because of their mechanism of action, a DOAC anticoagulation effect can be inferred based on the observed plasma concentration. However, there is a paucity of data relating to observed interpatient variation in DOAC plasma concentrations in the postmarket clinical setting. METHODS: We determined rivaroxaban and apixaban plasma concentrations in patients with AF during routine clinic visits. RESULTS: Among 243 patients (rivaroxaban, n = 94; apixaban, n = 149) enrolled in this study, a 60- and 50-fold interpatient variation in plasma concentration was observed for rivaroxaban and apixaban, respectively. Approximately 12% of patients receiving rivaroxaban and 13% of patients receiving apixaban exceeded the 95th percentile for predicted maximum plasma concentration observed in clinical trials. CONCLUSIONS: In this routine-care setting, rivaroxaban and apixaban plasma concentrations tended to be more variable than those observed in clinical trials. Identification of additional clinical and molecular determinants that more fully predict patients at risk for excessively high or low DOAC concentrations may enable a more precise DOAC dosing regimen for the individual patient.