Comparison of direct oral anticoagulants and warfarin in chronic limb-threatening ischemia.

OBJECTIVE: The role of direct oral anticoagulants (DOACs) in chronic limb-threatening ischemia after revascularization is unknown. Current evidence-based guidelines do not provide clear guidance on the role of anticoagulation or the selection of anticoagulant. Current practice is highly varied and based on provider and patient preference. The purpose of this study was to measure the impact of different anticoagulants on the incidence of major adverse limb events (MALEs) after revascularization for chronic limb-threatening ischemia, major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for major bleeding events. METHODS: This was a single-center, observational, retrospective cohort study. Subjects were eligible if they were 18 years or older; underwent endovascular or open revascularization for chronic limb-threatening ischemia, rest pain, or tissue loss; and were subsequently prescribed apixaban, rivaroxaban, or warfarin. The primary end point was the incidence of MALEs, including above-ankle amputation or major index-limb reintervention, within 1 year of index event. Secondary end points included the rate of all-cause mortality, MACEs, and incidence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding. RESULTS: From January 1, 2017, to September 20, 2022, 141 patients met the inclusion and exclusion criteria and were reviewed. The median age was 67 years, with 92 patients prescribed apixaban or rivaroxaban and 49 patients prescribed warfarin. Of these, 42 patients were prescribed triple antithrombotic therapy, 88 dual antithrombotic therapy, and 13 anticoagulant monotherapy. The primary outcome of 1-year MALEs occurred in 36.7% of the warfarin group and 33.7% of the DOAC group (relative risk [RR], 1.09; 95% CI, 0.53-2.25; P = .72). Secondary outcomes of 1-year MACEs (10.2% vs 4.3%; RR, 2.35; 95% CI, 0.60-9.18; P = .18) and 1-year all-cause mortality (26.5% vs 16.3%; RR, 1.63; 95% CI, 0.70-3.78; P = .15) did not differ between the groups. The secondary safety outcome of 1-year ISTH major bleeding occurred in 16.3% of the warfarin group and 4.3% of the DOAC group (RR, 3.76; 95% CI, 1.07-13.19; P = .015). CONCLUSIONS: In patients with chronic limb-threatening ischemia who were revascularized and prescribed anticoagulation with apixaban, rivaroxaban, or warfarin on discharge, no difference in MALEs, MACEs, or all-cause mortality was found. However, 1-year admissions for ISTH major bleeding were significantly higher among patients prescribed warfarin. A randomized trial may confirm these findings.

Predictors of Occlusion after Carotid Stenting.

BACKGROUND: Carotid artery stent (CAS) occlusion is a rare complication not well studied. We used a national dataset to assess real world CAS experience to determine the rate of stent occlusion. The purpose of this study was to 1) Identify risk factors associated with CAS occlusion on long-term follow-up (LTFU) and 2) Determine the adjusted odds of death/transient ischemic attack (TIA)/stroke (cerebrovascular accident (CVA)) in patients with occlusion. METHODS: The national Vascular Quality Initiative CAS dataset (2016-2021) comprised the sample. The primary endpoint was occlusion on LTFU (9-21 months postoperatively as defined by the Vascular Quality Initiative LTFU dataset) with secondary endpoint examining a composite of death/TIA/CVA. Descriptive analyses used chi-square and Wilcoxon tests for categorical and continuous variables respectively. Adjustment variables were selected a priori based on clinical expertise and univariate analyses. Multivariable logistic regression was used to model the odds of occlusion and the odds of death/TIA/CVA. Generalized estimating equations accounted for center level variation. RESULTS: During the study period, 109 occlusions occurred in 12,143 cases (0.9%). On univariate analyses, symptomatic indication, prior stroke, prior neck radiation, lesion calcification (>50%), stenosis (>80%), distal embolic protection device (compared to flow reversal), balloon size, >1 stent and current smoking at time of LTFU were predictive for occlusion. Age ≥ 65, coronary artery disease (CAD), elective status, preoperative statin, preoperative and discharge P2Y12 inhibitor, use of any protection device intraoperatively and protamine were protective. On multivariable analyses, age ≥ 65, CAD, elective status and P2Y12 inhibitor on discharge were protective for occlusion, while patients with prior radiation and those taking P2Y12 inhibitor on LTFU were at increased odds. The adjusted odds of death/TIA/CVA in patients with occlusion on LTFU were 6.05; 95% confidence interval: 3.61-10.11, P < 0.0001. CONCLUSIONS: This study provides an in-depth analysis of predictors for CAS occlusion on LTFU. On univariate analyses, variables related to disease severity (urgency, degree of stenosis, nature of lesion) and intraoperative details (balloon diameter, >1 stent) were predictive for occlusion. These variables were not statistically significant after risk adjustment. On multivariable analyses, prior neck radiation was strongly predictive of occlusion. Elective status, patient age ≥ 65, CAD, and P2Y12 inhibitor upon discharge (but not on LTFU) were protective for occlusion. Additionally, patients who developed occlusion had high odds for death/TIA/CVA. These findings provide important data to guide clinical decision-making for carotid disease management, particularly identifying high-risk features for CAS occlusion. Closer postoperative follow-up and aggressive risk factor modification in these patients may be merited.

Mechanism of Increased LDL (Low-Density Lipoprotein) and Decreased Triglycerides With SGLT2 (Sodium-Glucose Cotransporter 2) Inhibition.

Objective- SGLT2 (sodium-glucose cotransporter 2) inhibition in humans leads to increased levels of LDL (low-density lipoprotein) cholesterol and decreased levels of plasma triglyceride. Recent studies, however, have shown this therapy to lower cardiovascular mortality. In this study, we aimed to determine how SGLT2 inhibition alters circulating lipoproteins. Approach and Results- We used a mouse model expressing human CETP (cholesteryl ester transfer protein) and human ApoB100 (apolipoprotein B100) to determine how SGLT2 inhibition alters plasma lipoprotein metabolism. The mice were fed a high-fat diet and then were made partially insulin deficient using streptozotocin. SGLT2 was inhibited using a specific antisense oligonucleotide or canagliflozin, a clinically available oral SGLT2 inhibitor. Inhibition of SGLT2 increased circulating levels of LDL cholesterol and reduced plasma triglyceride levels. SGLT2 inhibition was associated with increased LpL (lipoprotein lipase) activity in the postheparin plasma, decreased postprandial lipemia, and faster clearance of radiolabeled VLDL (very-LDL) from circulation. Additionally, SGLT2 inhibition delayed turnover of labeled LDL from circulation. Conclusions- Our studies in diabetic CETP-ApoB100 transgenic mice recapitulate many of the changes in circulating lipids found with SGLT2 inhibition therapy in humans and suggest that the increased LDL cholesterol found with this therapy is because of reduced clearance of LDL from the circulation and greater lipolysis of triglyceride-rich lipoproteins. Most prominent effects of SGLT2 inhibition in the current mouse model were seen with antisense oligonucleotides-mediated knockdown of SGLT2.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants.

OBJECTIVE: Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor approved for the management of type-2 diabetes mellitus, and an oral contraceptive (OC), warfarin, and digoxin were evaluated in three phase 1 studies in healthy participants. METHODS: All studies were open-label; study 1 included a fixed-sequence design, and studies 2 and 3 used a crossover design. Regimens were: study 1: OC (levonorgestrel (150 µg) + ethinyl estradiol (30 µg))/day (day 1), canagliflozin 200 mg/day (days 4 - 8), and canagliflozin with OC (day 9); study 2: canagliflozin 300 mg/day (days 1 - 12) with warfarin 30 mg/day (day 6) in period 1, and only warfarin 30 mg/day (day 1) in period 2, or vice versa; study 3: digoxin alone (0.5 mg/day (day 1) + 0.25 mg/day (days 2 - 7)) in period 1, and with canagliflozin 300 mg/day (days 1 - 7) in period 2, or vice versa. Pharmacokinetics (PK) were assessed at prespecified intervals; OC: days 1 and 9, canagliflozin: days 8 - 9 (study 1); warfarin: days 6 (period 1) and 1 (period 2) (study 2); and digoxin: days 5 - 7 (periods 1 and 2) (study 3). Warfarin's pharmacodynamics (PD; International Normalized Ratio (INR)) was assessed on days 6 (period 1) and 1 (period 2). RESULTS: Canagliflozin increased the plasma exposure of OC (maximum plasma concentration (Cmax): 22%, area under the curve (AUC): 6%) and digoxin (Cmax: 36%, AUC: 20%); but did not alter warfarin'€™s PK and PD. No clinically relevant safety findings (including hypoglycemia) were noted. CONCLUSION: Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were well-tolerated.

Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

OBJECTIVE: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. METHODS: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4-12); study 2: canagliflozin 300 mg (days 1-17), probenecid 500 mg twice daily (days 15-17); and study 3: canagliflozin 300 mg (days 1-8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2-8 (study 3). RESULTS: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. CONCLUSION: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.

Intersection of Race, Rurality, and Income in Defining Access to Minimally Invasive Lung Surgery.

BACKGROUND: Race is a potent influencer of health care access. Geography and income may exert equal or greater influence on patient outcomes. We sought to define the intersection of race, rurality, and income and their influence on access to minimally invasive lung surgery in Medicare beneficiaries. METHODS: Centers for Medicare and Medicaid Services data were used to evaluate patients with lung cancer who underwent right upper lobectomy, by open, robotic-assisted thoracic surgery (RATS), or video-assisted thoracic surgery (VATS) between 2018 and 2020. International Classification of Diseases, 10th Edition, was used to define diagnoses and procedures. We excluded sublobar, segmental, wedge, bronchoplasty, or reoperative patients with nonmalignant or metastatic disease or a history of neoadjuvant chemotherapy. Risk adjustment was performed using inverse probability of treatment weighting (IPTW) propensity scores with generalized linear models and Cox proportional hazards models. RESULTS: The cohort comprised 13,404 patients, 4291 open (32.1%), 4317 RATS (32.2%), and 4796 VATS (35.8%). Black/urban patients had significantly higher RATS and VATS rates (P < .001), longer long-term survival (P = .007), fewer open resections (P < .001), and lower overall mortality (P = .007). Low-income Black/urban patients had higher RATS (P = .002), VATS (P < .001), longer long-term survival (P = .005), fewer open resections (P < .001), and lower overall mortality compared with rural White patients (P = .005). CONCLUSIONS: Rural White populations living close to the federal poverty line may suffer a burden of disparity traditionally observed among poor Black people. This suggests a need for health policies that extend services to impoverished, rural areas to mitigate social determinants of health.

Mortality index is more accurate than volume in predicting outcome and failure to rescue in Medicare beneficiaries undergoing robotic right upper lobectomy.

Background: Surgical volume is known to influence failure to rescue (FTR), defined as death following a complication. Robotic lung surgery continues to expand and there is variability in outcomes among hospitals. We sought to estimate the contribution of hospital-based factors on outcomes and FTR following robotic right upper lobectomy (RRUL). Methods: Using the Centers for Medicare and Medicaid Services inpatient claims database, we evaluated all patients age ≥65 years with a diagnosis of lung cancer who underwent RRUL between January 2018 and December 2020. We excluded patients who had undergone segmentectomy, sublobar, wedge, or bronchoplastic resection; had metastatic or nonmalignant disease; or had a history of neoadjuvant chemotherapy. Primary outcomes included FTR rate, length of stay (LOS), readmissions, conversion to open surgery, complications, and costs. We analyzed hospitals by tertiles of volume and Medicare Mortality Index (MMI). Defined as the institutional number of deaths per number of survivors, MMI is a marker of overall hospital performance and quality. Propensity score models were adjusted for confounding using goodness of fit. Results: Data for 4317 patients who underwent robotic right upper lobectomy were analyzed. Hospitals were categorized by volume of cases (low, <9; medium, 9-20; high, >20) and MMI (low, <0.04; medium, 0.04-0.13; high, >0.13). After propensity score balancing, patients from tertiles of lowest volume and highest MMI had higher costs ($34,222 vs $30,316; P = .006), as well as higher mortality (odds ratio, 7.46; 95% confidence interval, 2.67-28.2; P < .001). Compared to high-volume centers, low-volume centers had higher rates of conversion to open surgery, respiratory failure, hemorrhagic anemia, and death; longer LOS; and greater cost (P < .001 for all). The C-statistic for volume as a predictor of overall mortality was 0.6, and the FTR was 0.8. Hospitals in the highest tertile of MMI had the highest rates of conversion to open surgery (P = .01), pneumothorax (P = .02), and respiratory failure (P < .001). They also had the highest mortality and rate of readmission, longest LOS, and greatest costs (P < .001 for all) and the shortest survival (P < .001). The C-statistic for MMI as a predictor of overall mortality was 0.8, and FTR was 0.9. Conclusions: The MMI incorporates hospital-based factors in the adjudication of outcomes and is a more sensitive predictor of FTR rates than volume alone. Combining MMI and volume may provide a metric that can guide quality improvement and cost-effectiveness measures in hospitals seeking to implement robotic lung surgery programs.

The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake.

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.

Usability of telepresence in a level 1 trauma center.

OBJECTIVES: Limited resources and the diminishing physician workforce in trauma require unique and innovative solutions. Our hypothesis is that telepresence by a remote physician is an appropriate application in an urban trauma setting. The purpose of this study is to assess user satisfaction and usability of a mobile telemedicine robot in trauma care. MATERIALS AND METHODS: A usability study of trauma patient assessments utilizing the Remote Presence-7 (RP-7) robot (InTouch Health, Santa Barbara, CA) with real-time, two-way communication between remote and local physicians was conducted at a Level 1 trauma center. Usability and acceptability was measured using survey questionnaires, open-ended feedback, and general observations. Comparisons were made between remote and local physician responses. RESULTS: One hundred fourteen patient encounters utilizing telepresence were performed. Remote and local physicians expressed a high level of satisfaction with the mobility (92% and 79%, respectively), communication (97% and 90%, respectively), and visual abilities (91% and 97%, respectively) of the RP-7 robot for remote consultation purposes. On average, 89% of remote and local physician participants rated their overall telemedicine experience as "excellent" or "above average." CONCLUSIONS: This study suggests that telepresence of a remote trauma surgeon may be a useful and functional adjunct in the trauma setting. Further development of these technologies could mitigate current and future concerns about gaps in rural and urban trauma care and critical care staffing shortages and during mass casualty or disaster scenarios.

Phase 0 study of the inhibition of cholesteryl ester transfer protein activity by JNJ-28545595 in plasma from normolipidemic and dyslipidemic humans.

OBJECTIVE: To assess and validate the application of a non-radioactive assay for cholesteryl ester transfer protein (CETP) activity in clinical samples. DESIGN AND METHODS: In this Phase 0 study, CETP activity was measured following addition of the CETP inhibitor JNJ-28545595 to plasma samples from normolipidemic and three subgroups of dyslipidemic subjects with differing lipid profiles. RESULTS: CETP activity was elevated in plasma samples from dyslipidemic subjects compared to normolipidemic subjects. Increased triglyceride levels correlated with decreased CETP inhibition. The assay was found to have good analytical precision and high throughput potential as required for clinical trial sample analysis. CONCLUSIONS: The results demonstrate that pharmacological inhibition of CETP is affected by the dyslipidemic nature of plasma samples. In addition, since the optimal degree of CETP inhibition for maximal cardiovascular benefit in patients is not known, this assay may be used to help define optimal dosing of CETP inhibitors.

Whole-body biodistribution and radiation dosimetry of the human cannabinoid type-1 receptor ligand 18F-MK-9470 in healthy subjects.

UNLABELLED: The cannabinoid type-1 (CB1) receptor is one of the most abundant G-coupled protein receptors in the human body and is responsible for signal transduction of both endogenous and exogenous cannabinoids. The endocannabinoid system is strongly implicated in regulation of homeostasis and several neuropsychiatric disorders, obesity, and associated comorbidities, such as dyslipidemia and metabolic syndrome. We have used whole-body PET/CT to characterize the biodistribution and dosimetry of a novel high-affinity, subtype-selective radioligand, (18)F-MK-9470, in healthy male and female subjects. METHODS: Eight nonobese subjects (5 men, 3 women; age, 22-54 y) underwent serial whole-body PET/CT for 6 h after a bolus injection of 251 +/- 25 MBq (18)F-MK-9470 (N-[2-(3-cyano-phenyl)-3-(4-(2-(18)F-fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylproponamide). Source organs were delineated 3-dimensionally using the combined morphologic and functional data. Residence times were derived from time-activity profiles using both the trapezoid rule and curve fitting. Individual organ doses and effective doses were determined using the OLINDA software package, with different approaches for gastrointestinal and urinary excretion modeling. RESULTS: (18)F-MK-9470 is taken up slowly in the brain, reaching a plateau at approximately 90-120 min after bolus injection and is excreted predominantly through the hepatobiliary system. The gallbladder, upper large intestine, small intestine, and liver are the organs with the highest absorbed dose (average: 159, 98, 87, and 86 microGy/MBq, respectively). The mean effective dose (ED) was 22.8 +/- 4.3 microSv/MBq, indicating relatively low intersubject variability and a mean value in the range of many commercially available (18)F-labeled radiopharmaceuticals. Brain uptake was relatively high compared with that of existing central nervous system ligands for other receptors, between 3.2% and 4.9% of the injected dose. CONCLUSION: The estimated radiation burden of (18)F-MK-9470 for PET CB1 receptor imaging shows relatively low variability between subjects and has an acceptable ED, which allows multiple serial cerebral scans of good image quality, while remaining within the risk category class II-b defined by the World Health Organization and the International Commission for Radiation Protection for a standard injected activity (185-370 MBq).

Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers.

Taranabant is a novel cannabinoid CB-1 receptor (CB1R) inverse agonist in clinical development for the treatment of obesity. This double-blind, randomized, placebo-controlled, single oral dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of taranabant (0.5-600 mg) in 24 healthy male volunteers. Single-dose AUC(0-infinity) and C(max) values for taranabant increased approximately linearly with dose up to 200 mg, with slightly less than dose-proportional increases in AUC(0-infinity) and C(max) values for doses >200 mg. Plasma taranabant had a biphasic disposition, with a median t(max) of 1 to 2.5 hours and a terminal elimination t((1/2)) of 38 to 69 hours. Coadministration of taranabant with a high-fat meal led to a 14% increase in C(max) and a 74% increase in AUC(0-infinity). Clinical adverse experiences associated with single doses of taranabant were generally mild and transient. Of the 198 clinical adverse experiences reported, the most common drug-related ones were nausea (36), headache (22), drowsiness (14), abdominal discomfort/abdominal pain/stomachache (14), hiccups (9), dizziness (8), decreased appetite (7), increased bowel movement (7), mood change (6), tiredness (4), vomiting (4), and sweating increased (4). Taranabant has pharmacokinetic characteristics suitable for a once-daily dosing regimen.

Multiple-dose pharmacokinetics, pharmacodynamics, and safety of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, in healthy male volunteers.

Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median t(max) of 1.0 to 2.0 hours and a t(1/2) of approximately 74 to 104 hours. Moderate accumulation was observed in C(max) (1.18- to 1.40-fold) and AUC(0-24 h) (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC(0-24 h) and C(max) of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.

Factors during training which predict future use of minimally invasive thoracic surgery.

BACKGROUND: While minimally invasive thoracic surgery (MIS) has increased nationwide over the years, most patients undergoing lung and esophageal resections still undergo an open approach. We performed a national survey to analyze factors associated with a propensity to perform MIS after completing a cardiothoracic training program. MATERIALS AND METHODS: Cardiothoracic surgery trainees in 2 or 3-year programs from 2010 to 2016 were sent an online survey regarding the numbers and types of cases performed during training and current practice patterns as attending surgeons. Comfort level with MIS was also assessed. Responses were recorded and analyzed using SPSS. RESULTS: One hundred thirty-six trainees responded, with a mean of 121 lobectomies (30-250) and 40 esophagectomies (8-110) performed during training. Mean minimally invasive lobectomy and esophagectomy rates during training were 53% and 30% respectively. A greater ratio of MIS procedures performed during training correlated with a higher rate performed as an attending (lobectomies, p = 0.04; esophagectomies, p = 0.01) and a greater comfort level with performing these procedures (lobectomies, p = 0.01 and esophagectomies, p < 0.01). CONCLUSIONS: Based on these results, performing a greater ratio of minimally invasive lobectomies and esophagectomies during fellowship training increases the likelihood of performing them as an attending.

Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers.

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (i.v.) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.

Knee Injuries in American Football: An Epidemiological Review.

Football has the highest injury rate amongst popular American sports. Of those injuries that end seasons or careers, the knee is the most common culprit. This is of particular concern because knee injuries are most common in football. This article reviews 4 of the most common knee injuries in American football, with emphasis on epidemiology, risk factors, and treatment outcomes. The injuries reviewed are tears of the anterior cruciate ligament, medial collateral ligament, medial patellofemoral ligament, and posterior cruciate ligament.

Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, and assessment of dose proportionality in healthy participants.

Canagliflozin, an orally active inhibitor of sodium glucose co-transporter 2, is approved for the treatment of type-2 diabetes mellitus. The effect of food on the pharmacokinetics of 300 mg canagliflozin, and dose proportionality of 50, 100, and 300 mg canagliflozin, were evaluated, in two studies, in healthy participants. Study 1 used a randomized, 2-way crossover design: canagliflozin 300 mg/day was administered under fasted (Period-1) and fed (Period-2) conditions or vice versa. Study 2 was a 3-way crossover: participants were randomized to receive three single-doses of canagliflozin (50, 100, and 300 mg), one in each period. In both studies, treatment periods were separated by washout intervals of 10-14 days, and pharmacokinetics assessed up to 72 hours postdose of each treatment period. No clinically relevant food effects on canagliflozin exposure parameters were observed: 90% confidence intervals (CIs) for the fed/fasted geometric mean ratios of AUC∞ (ratio: 100.51; 90% CI: 89.47-112.93) and Cmax (ratio: 108.09; 90% CI: 103.45-112.95) were entirely within bioequivalence limits (80-125%). Plasma canagliflozin exposures were dose-proportional as the 90% CI of the slope of the regression line for dose-normalized AUC∞ and Cmax fell entirely within the prespecified limits of -0.124 to 0.124. No clinically significant safety issues were noted, and canagliflozin was generally well-tolerated.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on C-peptide kinetics.

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves indices of ß-cell function estimated based on circulating C-peptide and glucose concentrations (e.g., Homeostasis Model Assessment [HOMA2-%B], meal tolerance test-based indices). However, use of these ß-cell function indices assumes C-peptide kinetics are not altered by canagliflozin. This 2-period crossover study assessed the effect of a single canagliflozin 300-mg dose on C-peptide kinetics in 10 healthy participants. Two hours after receiving canagliflozin or placebo, participants received intravenous somatostatin infusion to suppress endogenous C-peptide secretion and 1 hour later received a bolus injection of synthetic human C-peptide 150 µg. Serum C-peptide was measured over 3 hours and urinary glucose and C-peptide excretion were measured. C-peptide kinetic parameters, including total clearance (CLtotal ) and renal clearance (CLrenal ), were calculated. Serum C-peptide profiles were similar following canagliflozin or placebo treatment. C-peptide CLtotal was slightly lower with canagliflozin versus placebo (mean (SD) of 190 (37) vs. 197 (30) mL/min; canagliflozin/placebo ratio [90% CI] = 96.1% [93.0%; 99.3%]). Other kinetic parameters, including CLrenal , were generally similar between treatments. Results indicate canagliflozin 300 mg does not meaningfully alter C-peptide clearance or other kinetic parameters; therefore, C-peptide-based measurements of insulin secretion are appropriate for assessing ß-cell function in canagliflozin-treated participants.

Absolute oral bioavailability and pharmacokinetics of canagliflozin: A microdose study in healthy participants.

Absolute oral bioavailability of canagliflozin was assessed by simultaneous oral administration with intravenous [(14) C]-canagliflozin microdose infusion in nine healthy men. Pharmacokinetics of canagliflozin, [(14) C]-canagliflozin, and total radioactivity, and safety and tolerability were assessed at prespecified timepoints. On day 1, single-dose oral canagliflozin (300 mg) followed 105 minutes later by intravenous [(14) C]-canagliflozin (10 µg, 200 nCi) was administered. After oral administration, the mean (SD) Cmax of canagliflozin was 2504 (482) ng/mL at 1.5 hours, AUC∞ 17,375 (3555) ng.h/mL, and t1/2 11.6 (0.70) hours. After intravenous administration, the mean (SD) Cmax of unchanged [(14) C]-canagliflozin was 17,605 (6901) ng/mL, AUC∞ 27,100 (10,778) ng.h/mL, Vdss 83.5 (29.2) L, Vdz 119 (41.6) L, and CL 12.2 (3.79) L/h. Unchanged [(14) C]-canagliflozin and metabolites accounted for about 57% and 43% of the plasma total [(14) C] radioactivity AUC∞ , respectively. For total [(14) C] radioactivity, the mean (SD) Cmax was 15,981 (2721) ng-eq/mL, and AUC∞ 53,755 (15,587) ng-eq.h/mL. Renal (34.5% in urine) and biliary (34.1% in feces) excretions were the major elimination pathways for total [(14) C] radioactivity. The absolute oral bioavailability of canagliflozin was 65% (90% confidence interval: 55.41; 76.07). Overall, oral canagliflozin 300 mg coadministered with intravenous [(14) C]-canagliflozin (10 µg) was generally well-tolerated in healthy men, with no treatment-emergent adverse events.