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Hypercholesterolemia is a risk factor for cardiovascular disease. Conventional treatment methods include lifestyle changes and pharmaceutical interventions, but recently Health Canada approved a health claim for whole ground flaxseed as an alternative treatment for hypercholesterolemia. The literature suggests flaxseed lignans are responsible for the cholesterol-reducing effects of flaxseed. In this study, 96.1% secoisolariciresinol diglucoside (SDG) and a 50% SDG enriched polymer (SDG polymer) were investigated as treatments for hypercholesterolemia in rats. Wistar female rats were fed a 1% high-cholesterol diet for a one-week acclimatization prior to a 23-day intervention with enriched SDG or SDG polymer. A reduction in body weight normalized liver weight was observed in rats treated with enriched SDG when compared to the controls. Both enriched SDG (96.1%) and SDG polymer reduced serum triacylglycerol (19% and 15%, respectively) and increased high-density lipoprotein cholesterol (15% and 24%, respectively). Histopathologic analyses revealed lipid-lowering effects of either enriched SDG or SDG polymer along with lower steatosis scores and nonalcoholic fatty liver disease activity. Furthermore, the lack of statistical significance between SDG and SDG polymer treatment groups suggests that SDG polymer may be a potential alternative to enriched SDG for hypercholesterolemia with similar efficacy but lower cost.

Background: Aerobic exercise is recommended for reducing blood pressure; however, recent studies indicate that stretching may also be effective. The authors compared 8 weeks of stretching versus walking exercise in men and women with high–normal blood pressure or stage 1 hypertension (ie, 130/85–159/99 mm Hg). Methods: Forty men and women (61.6 y) were randomized to a stretching or brisk walking exercise program (30 min/d, 5 d/wk for 8 wk). Blood pressure was assessed during sitting and supine positions and for 24 hours using a portable monitor before and after the training programs. Results: The stretching program elicited greater reductions than the walking program (P P Conclusions: An 8-week stretching program was superior to brisk walking for reducing blood pressure in individuals with high–normal blood pressure or stage 1 hypertension.

Key points Children with chronic debilitating illness and pain are increasingly using cannabis for medical purposes, particularly when conventional treatment options have limited benefit or substantial adverse effects. Caregivers are becoming aware of evidence that suggests medical cannabis provides

Experiential education is a critical component of any pharmacy undergraduate curriculum. Establishing new, high-quality practice sites can be challenging. We designed a new advanced pharmacy practice experiential rotation suitable for implementation in most community pharmacy settings. The aim of this article is to describe the design of this rotation entitled the Targeted Pharmacy Intervention in Inflammatory Bowel Disease (TPI-IBD) and to determine its impact on student knowledge and confidence using a before-after survey design. The TPI-IBD utilizes a student-delivered intervention as a platform for experiential learning in community pharmacy practice. The TPI was focused on patients with IBD, and implementation was guided by a co-preceptor from the university in collaboration with onsite-preceptors at each pharmacy. The TPI-IBD rotation was delivered from 6 community pharmacies during 5 weeks in 2018. Students conducted standardized monitoring on patients with IBD and met weekly with the university preceptor for case presentations and therapeutic discussions. Electronic charts were maintained by students who were responsible for ensuring detailed documentation on each patient. Knowledge, confidence, and overall satisfaction were assessed by a survey given to students before and after the rotation. Students were highly satisfied with the learning experience and improvements in knowledge and confidence were clearly demonstrated. The TPI strategy was an effective way to expand rotation options in community pharmacy sites with minimal burden on local preceptors.

Objective: To determine the pharmacokinetics (PK) and safety of various oral doses of a Cannabis herbal extract (CHE) containing a 1:20 ratio of Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) in 13 healthy Beagle-cross dogs.Methods: Single-dose PK was assessed after oral administration of CHE at low, medium, or high doses [2, 5, or 10 mg CBD and 0.1, 0.25, or 0.5 mg THC per kg of body weight (bw), respectively; n = 6 per group]. Dogs were monitored for adverse events for up to 48 h post-dose. Evaluations of neurological signs, clinical laboratory abnormalities, and other adverse events were performed in two separate study phases: a multiple-dose phase with 12 dogs receiving five medium doses (5 mg CBD/kg bw) at 12 h intervals, and a single low-dose (2 mg CBD/kg bw), randomized, blinded, negative controlled study with 13 dogs.Results: Cannabinoids CBD, THC, CBC, and metabolites 6-OH-CBD, 7-OH-CBD, 11-OH-THC, and THC-COOH were quantified in plasma. CBD and THC were rapidly absorbed (mean Tmax of 1.9–2.3 h) and initially depleted rapidly (mean CBD T1/2β of 2.3–2.6 h). A prolonged elimination phase (mean CBD T1/2λ of 13.3–24.4 h) was observed. CBD and THC concentrations increased in a dose-dependent (non-linear) manner, with disproportionally greater cannabinoid exposure relative to the dose increase. Neurological signs (hyperesthesia or proprioceptive deficits) were noted in five of six dogs in the high-dose group, but only occasionally or rarely in the medium- and low-dose groups, respectively. Presence and severity of clinical signs correlated with plasma cannabinoid concentrations. Dogs appeared to develop a tolerance to cannabinoid effects after multiple CHE doses, with fewer neurological signs noted after the final (fifth) vs. first dose. No clinically meaningful changes in blood count or chemistry values occurred after multiple CHE doses.Clinical Significance: Dogs tolerated the 1:20 THC:CBD formulation well at low and medium doses, but clinically meaningful neurological signs were observed at high doses. Because of non-proportional increases in plasma cannabinoid concentrations with increasing doses, as well as potential differences in CHE product composition and bioavailability, the possibility of adverse events and dose regimen consistency should be discussed with dog owners.

Objective To determine the pharmacokinetics and effects on thermal thresholds (TT) of two fentanyl constant rate infusions in awake cats. Study design A blinded, randomized crossover study. Animals A group of six healthy female cats, aged 3 ± 1 years, weighing 4.1 ± 0.7 kg. Methods Skin temperature (TSKIN) and TT were evaluated using a wireless TT device. TSKIN, TT, sedation score (SS) and blood samples were collected before an intravenous loading dose (LD; over 5 seconds) and at specific time points during (360 minutes) and after infusion. Each cat was administered two treatments: fentanyl (LD 3 μg kg−1, infusion 3 μg kg−1 hour−1; treatment F3) or fentanyl (LD 5 μg kg−1, infusion 5 μg kg−1 hour−1; treatment F5). SS between treatments was analyzed using a Kruskal–Wallis test. Statistical analysis of TT and TSKIN was performed using analysis of variance with appropriate post hoc test (p Results TSKIN did not vary over time for each treatment. SS did not differ between treatments. TTs were significantly higher than baseline at 15 minutes after LD for F3 and F5. TT was significantly increased at 30, 90, 120, 180 and 300 minutes in treatment F5 but not in F3. Plasma fentanyl concentrations decreased rapidly in both treatments over the first 30 minutes after infusion. The terminal half-life was 3.31 (2.93–4.41) hours for F3 and 3.67 (3.39–4.32) hours for F5 (median, range). Systemic clearance for treatments F3 and F5 was 1.95 (1.46–2.44) and 2.25 (1.98–2.47) L hour−1 kg−1 (median, range), respectively. Plasma concentrations Conclusions and clinical relevance A fentanyl infusion rate of 5 μg kg−1 hour−1 increased TT during the infusion period. Effects on TT were lost rapidly with cessation of the infusion.

Objectives Endoscopy remains the gold standard to diagnose and evaluate inflammatory bowel disease (IBD) activity. Current biomarkers or their combinations cannot adequately predict IBD risk, diagnosis, progression or relapse, and response to therapy. Pyruvate kinase M2 (PKM2) is emerging as a significant mediator of the inflammatory process. We aimed to assess levels of serum PKM2 in healthy and newly diagnosed IBD patients and its relationship with IBD indices and microbiota changes. Design and methods IBD serum samples from newly diagnosed patients were collected and analyzed using a PKM2-ELISA and correlated with disease activity scores , IBD disease type, and intestinal microbiota . Furthermore, we tested the genetic and protein expression of PKM2 in an in vitro intestinal cell model of inflammation. Results Serum PKM2 levels were 6-fold higher in IBD patients compared to healthy controls, with no sensitivity to disease phenotype (Crohn's Disease or Ulcerative Colitis) or localization of inflammation. Serum PKM2 had considerably less interindividual variability than established IBD fecal biomarkers. A positive Pearson correlation (r = 0.6121) existed between serum PKM2 and Bacteroidetes fecal levels in Crohn's disease (CD), while a negative (r = − 0.6128) correlation was observed with Actinobacteria fecal levels. Furthermore, LPS (500 ng/mL) significantly increased PKM2 expression in vitro , which was significantly suppressed by an anti-inflammatory flaxseed bioactive agent. Conclusion Our data suggests PKM2 as a putative biomarker for IBD and the dysbiosis of microflora in CD. Investigations involving larger number of clinical patients are necessary to validate its use as a serum biomarker of IBD.

Systemic cytotoxic chemotherapy remains the mainstay of metastatic breast cancer; however, prognosis and overall survival is unfavorable due to inadequate treatment response and/or unacceptable toxicity. Natural compounds and their active metabolites receive increasing attention as possible adjuvant therapy with cancer chemotherapeutics to improve treatment response, survival rates, and quality of life of breast cancer patients. This study investigated the combination of flaxseed lignans (Secoisolariciresinol and Enterolactone) with classic chemotherapeutic agents (Docetaxel, Doxorubicin, and Carboplatin) with different mechanisms of action to determine whether flaxseed lignans could enhance the cytotoxic effect of such drugs in the metastatic breast cancer cell lines, SKBR3 and MDA-MB-231. The experimental data suggests that flaxseed lignans significantly enhanced the ability of chemotherapeutic agents to cause cytotoxicity in SKBR3 and MDA-MB-231 breast cancer cells. A three compound combination study found that enterolactone and metformin together in combination with relatively low concentrations of chemotherapeutic drugs were able to significantly decrease cancer cell viability, compared to low concentrations of the individual chemotherapeutic drug alone. Our in vitro evaluation suggests a future direction in improving chemotherapeutic efficacy in breast cancer by adjuvant therapy with the flaxseed lignans.

BackgroundDespite the lack of evidence on the use of cannabis for the treatment of attention-deficit/hyperactivity disorder (ADHD), the growing perception that cannabis is safe has led more patients and caregivers to self-medicate. Some psychiatrists now authorize medicinal cannabis for patients with ADHD with features of oppositional defiant disorder (ODD) to curtail the unregulated (ie, self-medicated) use of recreational cannabis or to offer a therapeutic option to those who continue to experience symptoms after exhausting all other treatment options.ObjectiveThis protocol aims to explore the perceived effectiveness and pharmacokinetics of cannabis in youth and young adults, who are currently taking it as part of their treatment plan for ADHD with features of ODD, under the supervision of a psychiatrist.MethodsPatients between the ages of 12 and 25 years with a diagnosis of ADHD and features of ODD, who are currently taking cannabis herbal extract (at a Δ9-tetrahydrocannabinol [THC]:cannabidiol [CBD] ratio of 1:20) as a treatment adjunct to stimulant pharmacotherapy will be recruited. A sample size of 10-20 individuals is estimated. The study interview will consist of (1) validated symptom rating scales (Swanson, Nolan, and Pelham-IV Questionnaire [SNAP-IV], 90-item; Patient Health Questionnaire, 9-item [PHQ-9]; and Screen for Child Anxiety Related Emotional Disorders [SCARED] tool to measure symptoms of ADHD and ODD, depression, and anxiety, respectively); (2) a semistructured interview to probe the experiences of using cannabis; and (3) a cannabis side effects survey. A cannabis product sample as well as 2 blood samples (a trough level and 2-hour postdose level) will be collected to measure plasma concentrations of cannabinoids and relevant metabolites (THC, CBD, 11-hydroxy-THC, 7-hydroxy-CBD, cannabichromene, and 11-nor-9-carboxy-THB) using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Self-report rating scales (SNAP-IV, SCARED, and PHQ-9) will be scored in accordance with standard protocols and compared to retrospective scores obtained from the participant’s chart. Demographic variables (age, weight, and race), symptom scores, and blood levels (peaks and troughs) of THC, CBD, cannabichromene (CBC), and metabolites will be summarized using descriptive statistics. Relationships between plasma concentrations and symptom scores will be determined using analysis of variance, and multiple regression analysis will be performed to determine associations between plasma concentrations and demographic variables (age, weight, and ethnicity). The qualitative data will be audio-recorded and transcribed and organized into themes.ResultsThe protocol was approved by the Biomedical Research Ethics Board at the University of Saskatchewan (protocol #1726), and recruitment began in May 2021.ConclusionsThis proof-of-concept study will explore the potential treatment effectiveness of medical cannabis in participants with ADHD and ODD through a mixed methods approach to inform future research in this area.International Registered Report Identifier (IRRID)DERR1-10.2196/31281

OBJECTIVE To investigate the pharmacokinetics of metformin hydrochloride in healthy dogs after IV and oral bolus administrations and determine the oral dose of metformin that yields serum concentrations equivalent to those thought to be effective in humans. ANIMALS 7 healthy adult mixed-breed dogs. PROCEDURES Each dog was given a single dose of metformin IV (mean ± SD dose, 24.77 ± 0.60 mg/kg) or PO (mean dose, 19.14 ± 2.78 mg/kg) with a 1-week washout period between treatments. For each treatment, blood samples were collected before and at intervals up to 72 hours after metformin administration. Seventy-two hours after the crossover study, each dog was administered metformin (mean dose, 13.57 ± 0.55 mg/kg), PO, twice daily for 7 days. Blood samples were taken before treatment initiation on day 0 and immediately before the morning drug administration on days 2, 4, 6, and 7. Serum metformin concentrations were determined by means of a validated flow injection analysis–tandem mass spectrometry method. RESULTS After IV or oral administration to the 7 dogs, there was high interindividual variability in mean serum metformin concentrations over time. Mean ± SD half-life of metformin following IV administration was 20.4 ± 4.1 hours. The mean time to maximum serum concentration was 2.5 ± 0.4 hours. Mean systemic clearance and volume of distribution were 24.1 ± 7.8 mL/min/kg and 44.8 ± 23.5 L/kg, respectively. The mean oral bioavailability was 31%. CONCLUSIONS AND CLINICAL RELEVANCE The study data indicated that the general disposition pattern and bioavailability of metformin in dogs are similar to those reported for cats and humans.

Evidence from the literature suggests that dietary flaxseed lignans have the ability to modulate inflammation, which is recognized as the underlying basis of multiple chronic human diseases in older adults. Our objective was to determine the effects of oral lignan supplementation on biochemical and functional indicators of inflammation as well as safety and tolerability in older healthy adults. We designed a randomized, double-blind, placebo-controlled clinical trial in older healthy adults (60-80 years) to assess flaxseed lignan-enriched complex (∼38% secoisolariciresinol diglucoside [SDG]; 600 mg SDG dose) oral supplementation effects on biochemical and functional indicators of inflammation and safety and tolerability in older healthy adults after 6 months of once-daily oral administration. The clinical trial confirmed that plasma concentration of total flaxseed lignans (free and conjugated forms) secoisolariciresinol (SECO), enterodiol (ED), and enterolactone (ENL) were significantly associated with daily oral supplementation of flaxseed lignan-enriched complex (p0.05). A significant decrease in systolic blood pressure (SBP; from a mean of 155 ± 13 mm Hg at baseline to 140 ± 11 mm Hg at 24 weeks) was observed in lignan-supplemented participants stratified into an SBP ≥140 mm Hg subcategory (p = 0.04). No differences were found between treatment or placebo groups in terms of cognition, pain, activity, physical measurements (calf, waist, and upper arm circumstances), and grip strength. With respect to blood inflammatory markers, lipid profiles, and biochemical parameters, no significant differences were found between treatment and placebo groups at the end of the 6-month supplementation. No adverse effects were reported during supplementation. These data further support the safety and tolerability of long-term flaxseed lignan-enriched complex supplementation in older adults and identify an ability to favorably modulate SBP, an important risk factor in cardiovascular disease.

Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

We performed a scoping review on sought-after complementary therapies for patients with inflammatory bowel disease (IBD), specifically diet, physical activity and exercise (PA/E), and psychotherapy. We aim to update patients with IBD on therapies for self-care and provide physicians with guidance on how to direct their patients for the management of IBD. A search of MEDLINE, EMBASE, and PUBMED was completed in Sept 2016. Studies on diet, PA/E, or psychotherapy in patients with IBD were included. Medical Subject Heading terms and Boolean operators were used. The search was limited to full-text English articles describing an adult population. This review included 67 studies: Diet (n = 19); PA/E (n = 19); and psychotherapy (n = 29). We have made the following recommendations: (1) Diet: Consumption of diets rich in vegetables, fruit and soluble fiber may be beneficial in IBD. A trial of a low FODMAP diet can be considered in those patients with functional gastrointestinal symptoms. Restrictive diets are lacking in evidence and should be avoided; (2) PA/E: Regular low-moderate intensity activity, including cardiovascular and resistance exercise, has been shown to improve quality of life (QOL) and may improve inflammation; and (3) psychotherapy: Therapies such as cognitive-behavioural interventions, mindfulness, hypnosis, and stress management have been shown to improve QOL, but evidence is limited on their impact on anxiety, depression, and disease activity. Overall, these complementary therapies are promising and should be used to treat patients with IBD from a more holistic perspective.

Background: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life. Methods: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects. Discussion: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. Trial registration http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827

Objective—To evaluate the pharmacokinetics and thermal and mechanical antinociceptive effects of a fentanyl constant rate infusion (CRI) in conscious cats. Animals—8 healthy adult cats. Procedures—At a ≥ 14-day interval, 7 cats received a loading dose (LD) of fentanyl (5 μg/kg, IV [administered at 0 hours]) followed by fentanyl infusion (5 μg/kg/h, IV) for 2 hours or similar administrations of equivalent volumes of 0.9% saline (NaCl) solution. One cat received only the fentanyl treatment. For both treatments, sedation and adverse events were evaluated and mechanical threshold (MT) and thermal threshold (TT) testing was performed prior to (baseline) and at predetermined times up to 26 hours after LD administration; plasma fentanyl concentrations were determined at similar times when the cats received fentanyl. Results—Fentanyl induced mild sedation during the infusion. The only adverse effect associated with fentanyl LD administration was profuse salivation (1 cat). Saline solution administration did not significantly change MT or TT over time. For the duration of the CRI, MT and TT differed significantly between treatments, except for TT 1 hour after LD administration. For the fentanyl treatment, MT and TT were significantly higher than baseline at 0.25 to 0.75 hours and at 0.25 to 1 hour, respectively. During the fentanyl CRI, mean ± SD plasma fentanyl concentration decreased from 4.41 ± 1.86 ng/mL to 2.99 ± 1.28 ng/mL and was correlated with antinociception; plasma concentrations < 1.33 ± 0.30 ng/mL were not associated with antinociception. Conclusions and Clinical Relevance—Fentanyl CRI (5 μg/kg/h) induced mechanical and thermal antinociception in cats.

The natural health product, BeneFlax, is a standardized flaxseed [Linum usitatissimum L. (Linaceae)] lignan enriched product with evidence of product quality and known quantity of the bioactive component, lignan. The acceptance of this natural health product for its various health benefits requires greater evidence of its safety in the general population.We determined whether flaxseed lignan causes clinical hypoglycemia or hypotension in healthy older adults as an important aspect of safety.Participants aged 49-87 years were randomized in a double-blind trial to receive flaxseed lignan (543 mg/day in BeneFlax) or placebo while completing a 6-month walking program. The 94 participants who completed the study were stratified by age (65 years versus ≥65 years) and treatment category to determine whether older adults were more susceptible to adverse effects.After 6 months of treatment, average plasma glucose level (5.4 ± 0.6 mmol/L), systolic blood pressure (127 ± 14 mm Hg), and diastolic blood pressure (80 ± 9 mm Hg) were within normal clinical range. Controlling for sex and body mass index covariates resulted in no observed differences between plasma glucose or blood pressure measurements between treatment or age groups (p 0.05). No incidents of hypoglycemia or hypotension were observed during BeneFlax treatment, suggesting that 543 mg falls at or below the no observable adverse effect level (NOAEL).These data suggest the flaxseed lignan product BeneFlax does not pose a risk of hypoglycemia or hypotension in healthy adults aged 49-87 years.

Sphingosine-1-phosphate (S1P) is an important sphingolipid metabolite regulating key physiological and pathophysiological processes such as cell growth and survival and tumor angiogenesis. Significant research evidence links elevated cellular S1P concentration to cancer cell proliferation, migration and angiogenesis. Physiological levels of S1P are tightly regulated and maintained at the low nanomolar level. In cancer, S1P may exist well beyond the low nanomolar level. Recently, we reported that S1P selectively induces cell apoptosis of the breast cancer MCF7 cell line at concentrations higher than 1 µM and co-administration of 1 µM S1P significantly increased the cytotoxicity of chemotherapy drug docetaxel. In this study, we show that S1P caused minor increases in cell proliferation or apoptosis, in a concentration-dependent manner, yet co-administration of 10 µM S1P exhibited a significant synergistic effect with chemotherapy drugs docetaxel, doxorubicin and cyclophosphamide. S1P increased the cytotoxic potential of each drug by 2-fold, 3-fold, and 10-fold, respectively, against the breast cancer metastatic cell line MDA-MB-361. This synergism may suggest improved anticancer drug therapy by co-administration of exogenous S1P.

Objective To determine blood remifentanil concentration in isoflurane-anesthetized horses during and after a 1 h remifentanil and dexmedetomidine infusion. Study design Prospective study. Animals Six adult mixed breed horses with (mean ± SD) bodyweight of 507 ± 61 kg and 14 ± 4 years of age. Methods Following sedation with xylazine IV, anesthesia was induced with ketamine IV mixed with diazepam IV. Anesthesia was maintained with isoflurane in oxygen. After 52 ± 7 min for instrumentation, dexmedetomidine (0.25 μg kg − 1 followed by 1.0 μg − 1 kg − 1 h − 1 ) and remifentanil infusions (6 μg kg − 1 h − 1 ) were administered for a minimum of 60 min and horses recovered from anesthesia. Drug infusions were administered into the left jugular vein. Blood was sampled (4 mL) from the right jugular vein at predefined intervals before and during administration of remifentanil infusion. Following catheter flush, blood was sampled from the left jugular vein after the infusion was terminated while the horse was recovering from anesthesia. Blood was placed into tubes containing sodium heparin with citric acid, flash frozen in liquid nitrogen, and stored at − 80 °C until analysis. Blood remifentanil concentration was measured using high performance liquid chromatography and tandem mass spectrometry. Results Mean peak remifentanil concentration was 7.14 ηg mL − 1 at 50 min after start of infusion. Mean volume of distribution was 268 ± 40 mL kg − 1 and mean half-life was 12.8 min. Blood concentration decreased to 1 ηg mL − 1 27 min after termination of infusion. Limit of quantification was 0.2 ηg mL − 1 .

Vitamin–mineral supplementation may offer older adults health and cognition-related benefits but overuse may contribute to polypharmacy. We examined the prevalence of supplement usage in long-term care facility (LTC) residents (≥65 years of age). As cognition may be affected by nutrition, we also examined use in those with diagnosis of dementia and those with no dementia diagnosis. The prevalence of supplement usage and overall “pill count” from pharmaceutical use was assessed in 189 LTC residents and a subsample of 56 older adults with dementia diagnosis, respectively. Participants were residing in an LTC facility of a mid-size metropolitan area during 2009. The average use of supplements was 1.0 per day for all residents, with 35% taking vitamin D supplements, 20% multivitamins, and 26% calcium. Supplement use was similar (p ≥ 0.05) for those with dementia diagnosis (53%, average 2.0 per day) and for those without such diagnosis (45%, average 2.2 per day). Usage ranged between 1–6 supplements per day. In both of these groups, ∼73% of users were taking vitamin D. The number of prescribed medications ranged from 4 to 24 (average 10.2) in a subsample of residents whose supplement intake was 0 to 6 (average 2). These findings suggest an overall low rate of supplement use, with no significant differences (p ≥ 0.05) in use between residents with and without dementia diagnosis. However, some residents were at risk for supplement overuse.

The purpose of our study was to assess the influence of lactation stage–dependent differences in milk-to-serum (M/S) ratio for an actively transported drug (cefepime) on the calculation of 2 exposure indices, EIDoseand EIConc. Age-dependent differences in cefepime pharmacokinetics at postnatal days 4 and 10 as well as cefepime M/S values at lactation days 4 and 10 in rats were determined. Significantly higher elimination rate constant and systemic clearance and lower half-life were found in day 10 compared to day 4 pups with no differences in oral bioavailability. The EIConcwas quantitatively higher than EIDoseat both lactation stages. The ~7-fold decrease in cefepime M/S values at lactation day 10 resulted in ~7-fold reduction in the EIDoseand ~13-fold reduction in EIConc. Our study confirms the need to evaluate M/S at different lactation stages for actively transported drugs to avoid over- or underestimation of neonatal exposure risk.

Richardson ground squirrels (Spermophilus richardsonii) are prominent pests on the prairies of North America. Rodenticides have been used for their control for several decades, but this pest continues to thrive. In this study we considered the possibility that this apparent lack of success in controlling this pest may be associated with systemic adaptation of Richardson ground squirrels to toxins. Accordingly, we examined the hepatic cytochrome P450 (CYP) enzyme system (phase I biotransformation) in Richardson ground squirrels selected from fields where rodenticides were used (exposed) and from fields where no toxins were distributed (naive). We found that the content and activity of individual components of the CYP system including CYP, cytochrome b5, and NADPH–CYP reductase in liver microsomes were higher in exposed Richardson ground squirrels than in naive Richardson ground squirrels. In vitro CYP-mediated activities for generic substrates representing major groups of reactions were found to be highly variable among individuals. However, systemic activity was comparable among the naive and exposed Richardson ground squirrels. These findings indicate that Richardson ground squirrels may readily develop resistance to toxins by enhancing the functional capacity of enzymes responsible for detoxification. Therefore, it is important to carefully monitor the efficiency of toxicological methods of Richardson ground squirrels control and to revise management strategies accordingly.

Sudden death syndrome (SDS) in fast growing broiler chickens has been recognized as a patho-physiological entity for four decades, but its pathogenesis still remains unknown. More recent investigations provided evidence that link SDS to cardiac arrhythmia, but the mechanism triggering arrhythmogenesis and factors responsible for fatal outcome are poorly understood. In order to understand the chain of events leading to SDS in broilers, the present study focused on putative mechanisms that trigger arrhythmia and mechanisms that predispose the myocardium to fatal arrhythmia. Susceptibility of broilers to cardiac arrhythmia under stress conditions was evaluated using a simulated stress test with epinephrine. Detailed histopathological evaluation of the broiler heart was undertaken to identify structural features that may predispose the myocardium to fatal arrhythmia. The simulated stress challenge revealed that many broilers are highly susceptible to stress induced cardiac arrhythmia. In some broilers the stress challenge induced severe ventricular arrhythmia, and the life threatening nature of this arrhythmia was evidenced by the fact that several birds showing the most severe arrhythmic responses, died suddenly within several days after the stress challenge. Examination of hearts of broilers that died of SDS revealed microscopic lesions in the cardiomyocytes, and widespread changes in the sub-endocardial and mural His-Purkinje system (HPS). Immune staining for Caspase-3 confirmed that numerous Purkinje cells in the left ventricular myocardium from broiler chickens that died of SDS were undergoing apoptosis. The observed lesions suggest that the electrical stability of the myocardium was compromised. Taken together, our findings indicate that stress is a most likely trigger of cardiac arrhythmia in broilers, whereas the pathological changes seen in the myocardium and in the HPS in fast growing broilers provide a very conducive milieu for sustained ventricular arrhythmia. In cases where the electrical stability of the myocardium is compromised, even an episodic arrhythmic event may readily degenerate to catastrophic ventricular fibrillation and sudden death. We conclude that the combination of stress and changes in the cardiomyocytes and HPS are the key requisite features in the pathogenesis of SDS.

High-resolution computed tomography (CT) imaging of a live animal within a lead-lined synchrotron light hutch presents several unique challenges. In order to confirm that the animal is under a stable plane of anaesthesia, several physiological parameters (e.g.heart rate, arterial oxygen saturation, core body temperature and respiratory rate) must be remotely monitored from outside the imaging hutch. In addition, to properly scan the thoracic region using CT, the animal needs to be held in a vertical position perpendicular to the fixed angle of the X-ray beam and free to rotate 180°–360°. A new X-ray transparent mouse restraint designed and fabricated using computer-aided design software and three-dimensional rapid prototype printing has been successfully tested at the Biomedical Imaging and Therapy bending-magnet (BMIT-BM) beamline at the Canadian Light Source.

Background: Increased oxidative stress and inflammation are associated with aging, and contribute to an increased risk of chronic disease in older adults. Flaxseed lignans demonstrate antioxidant and anti-inflammatory activity, but their ability to reduce oxidative stress and inflammation markers in older adult populations has received limited investigation. Objective: This is a chronic intervention trial of community-dwelling healthy older adults to examine the effects of a flaxseed lignan (secoisolariciresinol diglucoside; SDG) enriched supplement (BeneFlax) compared to a placebo. The primary aim was to demonstrate the safety of BeneFlax and confirm its anti-inflammatory efficacy on markers of oxidative stress and inflammation, and subsequent functional outcomes, including those associated with its anti-inflammatory efficacy. A secondary aim was to determine flaxseed lignan metabolite concentrations in blood. Methods: A double-blind randomized clinical trial was conducted. Subjects were healthy community-dwelling adults aged 60-80 years. Testing was performed at baseline, 8, 16, and 24 weeks. The 24-week intervention consisted of 600 milligrams (mg) of SDG daily or an equivalent amount (volume) of placebo. All participants received 1000 international units of vitamin D to ensure adequate vitamin D status. Measurements consisted of blood pressure, hematology, and tolerability for safety assessments; blood oxidative stress and inflammatory biomarkers for efficacy; and cognition, muscle strength, and pain as functional outcomes. Secondary endpoints of plasma levels of lignan metabolites were analyzed by mass spectrometry. Other tests, such as bone turnover markers and fecal levels of flax cyclolinopeptides, will be performed at a later date. Results: Thirty-two participants were recruited (19 intervention and 13 control) and all completed the trial. Numerous Health Canada-imposed exclusion criteria limited recruitment success. Analyses are ongoing, but the baseline data available for a number of parameters indicate no differences between treatment groups. Safety measures (vital signs) did not change from baseline and were not significantly different between treatment and placebo groups at 24 weeks. Conclusions: Preliminary results indicate that no safety concerns are associated with administering 600 mg SDG for 24 weeks to adults between the ages of 60 and 80 years. Trial Registration: Clinicaltrials.gov NCT01846117; https://clinicaltrials.gov/ct2/show/NCT01846117 (Archived by WebCite at http://www.webcitation.org/6nlDZNjmA) [JMIR Res Protoc 2017;6(2):e14]

Tulathromycin is approved for the treatment of respiratory disease in cattle and swine. It is intended for long-acting, single-dose injection therapy (Draxxin), making it particularly desirable for use in bison due to the difficulty in handling and ease of creating stress in these animals. The pharmacokinetic properties of tulathromycin in bison were investigated. Ten wood bison received a single 2.5 mg/kg subcutaneous injection of Draxxin. Serum concentrations were measured by liquid chromatography-mass spectrometry (LC-MS) detection. Tulathromycin demonstrated early maximal serum concentrations, extensive distribution, and slow elimination characteristics. The mean maximum serum concentration (Cmax) was 195 ng/mL at 1.04 h (tmax) postinjection. The mean area under the serum concentration-time curve, extrapolated to infinity (AUC0-inf ), was 9341 ng · h/mL. The mean apparent volume of distribution (Vd /F) and clearance (Cls/F) was 111 L/kg and 0.4 L/h/kg, respectively, and the mean half-life (t1/2) was 214 h (8.9 days). Compared to values for cattle, Cmax and AUC0-inf were lower in bison, while the Vd /F was larger and the t1/2 longer. Tissue distribution and clinical efficacy studies in bison are needed to confirm the purported extensive distribution of tulathromycin into lung tissue and to determine whether a 2.5 mg/kg subcutaneous dosage is adequate for bison.

The popularity in natural product use we witness today arose from a growing public skepticism about taking “pharmaceutical chemicals” to treat illness. Such skepticism was supplanted by a public perception that “medications” from natural sources are safer to use and have similar efficacies as their pharmaceutical equivalents. The diverse assortment of natural products on the shelves of pharmacies, health food stores, and grocery stores attest to this enhanced public demand, but has compelled regulatory agencies to question the adequacy of the safety and efficacy data associated with the use of these products (Natural Health Products Directorate 2007). In the current regulatory environment, full realization of the wellness and therapeutic value of these natural products can only come about with more rigorous assessments of their safety and efficacy.

Elk velvet antler (EVA) has a traditional use for promotion of general health. However, evidence of EVA effects at different lifestages is generally lacking. This paper investigated the effects of long-term maternal dietary EVA supplementation on physical, reflexological and neurological development of rat offspring. Female Wistar rats were fed standard chow or chow containing 10% EVA for 90 days prior to mating and throughout pregnancy and lactation. In each dietary group, 56 male and 56 female pups were assessed for physical, neuromotor, and reflexologic development postnatally. Among the examined physical developmental parameters, incisor eruption occurred one day earlier in pups nursing dams receiving EVA. Among neuromotor developmental parameters, duration of supported and unsupported standing was longer for pups nursing EVA supplemented dams. Acquisition of neurological reflex parameters (righting reflex, negative geotaxis, cliff avoidance acoustic startle) occurred earlier in pups nursing dams receiving EVA. Longterm maternal EVA supplementation prior to and during pregnancy and lactation accelerated certain physical, reflexologic, and neuromotor developmental milestones and caused no discernible adverse effects on developing offspring. The potential benefits of maternal EVA supplementation on postnatal development warrants further investigation to determine whether EVA can be endorsed for the promotion of maternal and child health.

Significant drug-nutrient interactions are possible when drugs and nutrients share the same absorption and disposition mechanisms. During postnatal development, the outcomes of drug-nutrient interactions may change with postnatal age since these processes undergo ontogenesis through the postnatal period. Our study investigated the dependence of a significant drug-nutrient interaction (cefepime-carnitine) on the timing and duration of drug exposure relative to postnatal age. Rat pups were administered cefepime (5 mg/kg) twice daily subcutaneously according to different dosing schedules (postnatal day 1-4, 1-8, 8-11, 8-20, or 1-20). Cefepime significantly reduced serum and heart L-carnitine levels in postnatal day 1-4, 1-8 and 8-11 groups and caused severe degenerative changes in ventricular myocardium in these groups. Cefepime also altered the ontogeny of several key L-carnitine homeostasis pathways. The qualitative and quantitative changes in levels of hepatic γ-butyrobetaine hydroxylase mRNA and activity, hepatic trimethyllysine hydroxlase mRNA, intestinal organic cation/carnitine transporter (Octn) mRNA, and renal Octn2 mRNA depended on when during postnatal development the cefepime exposure occurred and duration of exposure. Despite lower levels of heart L-carnitine in earlier postnatal groups, levels of carnitine palmitoyltransferase mRNA and activity, heart Octn2 mRNA and ATP levels in all treatment groups remained unchanged with cefepime exposure. However, changes in other high energy phosphate substrates were noted and reductions in the phosphocreatine/ATP ratio were found in rat pups with normal serum L-carnitine levels. In summary, our data suggest a significant drug-nutrient transport interaction in developing neonates, the nature of which depends on the timing and duration of exposure relative to postnatal age.

We report a positive newborn screen for 3-hydroxyisovalerylcarnitine (C(5)OH) with an absence of 3-methylcrotonyl-coenzyme A carboxylase deficiency in the neonate. Subsequent blood tests demonstrated persistently elevated C(5)OH. Serial testing of the mother identified markedly elevated C(5)OH in both maternal blood and breast milk. High C(5)OH milk concentrations provide a significant source of C(5)OH to the nursing neonate and possibly explains its persistent elevation in the neonate, a commonly observed finding in maternal 3-MCC deficiency.

Our incomplete understanding of the developmental maturation of drug elimination mechanisms poses a serious challenge to paediatric dosage regimen design and toxicological risk assessment. The dynamic and variable nature of maturation also limits our ability to acquire pharmacokinetic data in all relevant paediatric populations. However, recent attempts to use the available human ontogeny data to build predictive models of paediatric drug elimination hold promise to assist dosage regimen design and risk assessment. This review identifies population pharmacokinetic, allometric scaling and physiologically based clearance scaling models as principal approaches to estimate paediatric systemic clearance in the absence of comprehensive age-group-specific data.

Objectives To identify the prevalence of Borzoi chorioretinopathy in western Canada, characterize lesions with fluorescein angiography, determine if lesions were progressive, clarify the association of progressive retinal atrophy and investigate the etiology. Materials and methods Serial ophthalmic examination, fundus photography, electroretinography, and fluorescein angiography were used to evaluate Borzoi dogs with lesions of Borzoi chorioretinopathy. Pedigree analysis and test breeding of two affected dogs were completed to determine the heritability of Borzoi chorioretinopathy. Results One hundred three Borzoi dogs were examined between 1998 and 2003. Focal, peripheral, tapetal, hyper-reflective and pigmented areas consistent with focal retinal degeneration and RPE pigmentation were identified in 12 dogs between 7 months and 7 years of age. Seven males and five female dogs were affected. Ophthalmoscopy and fundus photography over 5 years revealed individual lesions that did not progress or coalesce in 12 affected dogs. Electroretinography of affected and normal Borzoi dogs confirmed that retinal function was similar in normal and affected dogs up to 7 years of age. Fluorescein angiography was performed in three affected dogs and confirmed intact blood–ocular barriers, focal retinal pigment epithelium hypertrophy, and focal absence of choroiocapillaris corresponding to chronic, focal lesions. Pedigree analysis precluded simple dominant, X-linked dominant, or X-linked recessive inheritance. One male dog from the test-bred litter developed bilateral lesions at 14 months of age. Simple recessive, polygenetic, and acquired etiologies of these lesions cannot be ruled out at this time. Conclusions Borzoi chorioretinopathy is an acquired condition that initially manifests as focal retinal edema and loss of choriocapillaris and tapetum. With time the retina degenerates becoming hyper-reflective and with RPE hyper-pigmentation and clumping within the borders of the tapetal lesions. Choriocapillaris remains hypofluorescent on fluorescein angiography. Progressive retinal atrophy was excluded as an etiology of multifocal chorioretinopathy in Borzois dogs. This condition is not inherited by simple autosomal dominant or sex-linked modes of inheritance.