Rapid Cycle Deliberate Practice in Virtual Reality: Teaching Transvenous Pacemaker Insertion to Emergency Medicine Residents.

Introduction Transvenous pacemaker insertion is a critical life-saving procedure that is infrequently performed. Traditional mannequin-based training paradigms are resource intensive and sometimes inadequate due to time constraints. Rapid Cycle Deliberate Practice (RCDP) is an effective teaching modality for highly scripted procedures. We propose using a simulation-based technique of RCDP in virtual reality (VR) to teach this procedure. Methods Sixteen emergency medicine residents were recruited. A pre-survey was administered at the start of the session, followed by a baseline task trainer checklist-based assessment. This checklist was created based on expert consensus. Participants then underwent the RCDP VR intervention with a subsequent repeat checklist-based assessment as well as a post-survey.  Results Post-test scores were found to be significantly higher than pre-test scores after residents completed VR deliberate practice simulation (19.5±3.5 vs 24.1±2.0; p<0.001). Subanalysis did not reveal any significant difference based on post-graduate year, previous performance of procedure on a live patient, or previous VR experience. The experience increased participant feelings of preparedness and comfort in performing the procedure (2-disagree vs 4-agree) based on a 5-point Likert scale.  Conclusions Virtual reality using RCDP to teach transvenous pacemaker insertion demonstrated an improvement in task trainer performance. Further investigation into whether this translates into better patient outcomes or can be generalized to other procedures needs to be considered.

Cumulative Incidence of Methicillin-Resistant Staphylococcus aureus Colonization in Resident Physicians Over Time.

Background Methicillin-resistant Staphylococcus aureus (MRSA) can colonize up to 14.5% of healthcare workers (HCWs). The colonization rate of HCWs or the hospital setting that contributes most to MRSA colonization is less clear. In this study, we studied new resident physicians (PGY-1), as a model for HCWs, to measure their colonization rate and hypothesized that the incidence of colonization would increase during their first year. Methodology We prospectively enrolled PGY-1 residents of multiple specialties at three academic medical centers. After obtaining informed consent, PGY-1 residents were tested for MRSA in June 2019 before starting any clinical rotations and then retested every three to four months thereafter. The coronavirus disease 2019 pandemic forced us to end the study early. If MRSA-positive, residents were treated with 2% mupirocin and retested for a cure. For comparison, upper-level residents (PGY-2-5) were also enrolled to obtain a baseline prevalence of colonization. Results We enrolled 80 PGY-1 and 81 PGY-2-5 residents in the study. The baseline prevalence of MRSA colonization was 4.94% (4/81) in PGY-2-5 residents and 2.50% (2/80) for new PGY-1 residents; however, this was not statistically significant (p = 0.68). The cumulative yearly incidence of developing MRSA colonization in PGY-1 residents was 4.51%. MRSA colonization was successfully treated in 75% of cases. Conclusions PGY-1 residents had a lower MRSA colonization rate compared to PGY-2-5 residents, although this was not statistically significant. PGY-1 residents had a small incidence of developing MRSA colonization while working in the hospital. Further research is needed to determine if this is clinically relevant to HCWs or their patients.

Understanding Minimally Invasive Gynaecologic Surgery Fellowship Training in Canada: A National Survey of Recent Graduates.

OBJECTIVE: To characterize fellowship training experiences in the 11 Canadian minimally invasive gynaecologic surgery (MIGS) programs and compare the surgical exposure of fellows in these programs to that of the American Association of Gynecologic Laparoscopists (AAGL) accredited fellowship in MIGS (FMIGS). METHODS: In this cross-sectional study, 2017 and 2018 MIGS fellowship graduates across Canada were given a web-based survey via SurveyMonkey software to evaluate 5 key components of postgraduate fellowship curricula: 1) surgical exposure; 2) teaching and evaluation methods; 3) research experience; 4) clinical responsibilities; and 5) pursuit of other academic endeavours. Interest in creating a national standardized curriculum and seeking accreditation for MIGS fellowships were also examined. RESULTS: The survey attained a 91% (20/22) response rate of the target population. All Canadian MIGS programs met the minimum standards for at least 62% (8/13) of the surgical competencies listed by the AAGL, with office hysteroscopy being the procedure with the largest discordance. Half of respondents (10/20) attended a program with an established curriculum, and 75% (15/20) believed there would be a benefit to standardizing training nationwide. Seventy percent (14/20) had published at least one manuscript during their fellowship and 60% (12/20) pursued postgraduate degrees. The majority (55%; 11/20) felt certain that MIGS should become a credentialed fellowship in Canada. CONCLUSION: Canada has made meaningful progress in MIGS training over the past decade with 11 well-established fellowship programs. Although this survey identifies a general interest in standardized training and accreditation for Canadian MIGS programs, more research is needed on how best to accomplish this.

Assessment of Emergency Medicine Residents' Clinical Reasoning: Validation of a Script Concordance Test.

INTRODUCTION: A primary aim of residency training is to develop competence in clinical reasoning. However, there are few instruments that can accurately, reliably, and efficiently assess residents' clinical decision-making ability. This study aimed to externally validate the script concordance test in emergency medicine (SCT-EM), an assessment tool designed for this purpose. METHODS: Using established methodology for the SCT-EM, we compared EM residents' performance on the SCT-EM to an expert panel of emergency physicians at three urban academic centers. We performed adjusted pairwise t-tests to compare differences between all residents and attending physicians, as well as among resident postgraduate year (PGY) levels. We tested correlation between SCT-EM and Accreditation Council for Graduate Medical Education Milestone scores using Pearson's correlation coefficients. Inter-item covariances for SCT items were calculated using Cronbach's alpha statistic. RESULTS: The SCT-EM was administered to 68 residents and 13 attendings. There was a significant difference in mean scores among all groups (mean + standard deviation: PGY-1 59 + 7; PGY-2 62 + 6; PGY-3 60 + 8; PGY-4 61 + 8; 73 + 8 for attendings, p < 0.01). Post hoc pairwise comparisons demonstrated that significant difference in mean scores only occurred between each PGY level and the attendings (p < 0.01 for PGY-1 to PGY-4 vs attending group). Performance on the SCT-EM and EM Milestones was not significantly correlated (r = 0.12, p = 0.35). Internal reliability of the exam was determined using Cronbach's alpha, which was 0.67 for all examinees, and 0.89 in the expert-only group. CONCLUSION: The SCT-EM has limited utility in reliably assessing clinical reasoning among EM residents. Although the SCT-EM was able to differentiate clinical reasoning ability between residents and expert faculty, it did not between PGY levels, or correlate with Milestones scores. Furthermore, several limitations threaten the validity of the SCT-EM, suggesting further study is needed in more diverse settings.

An Inexpensive Adult Lumbar Puncture Task-Trainer with Simulated Cerebrospinal Fluid.

Background: Simulation is beneficial in achieving competence and success in the performance of procedures. Unfortunately, costs associated with purchasing simulation equipment is a significant barrier to implement this training. The objective was to create a model for lumbar puncture that allowed performance of the procedure using anatomic landmarks, ability to obtain cerebrospinal fluid, and measure opening pressure. Methods: A model was built using several readily available and low-cost items and was iterated based on feedback. The task trainer was used as part of multiple educational sessions and simulations with different groups of learners, including residents and medical students. Results: A reusable task trainer was built to simulate the performance of a lumbar puncture that met our objective of using anatomic landmarks with the ability to collect simulated cerebrospinal fluid and measure opening pressure. The model had a low fixed cost for the initial investment (less than $75) and minimal variable costs. Conclusions: An innovative and easy to make low-cost model is presented as an option to use for lumbar puncture training at institutions with limited resources. This do-it-yourself model is unique in providing learners the opportunity to obtain cerebrospinal fluid and measure opening pressure. The model is easy to transport and can be implemented as part of educational sessions and simulation scenarios.

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a ß-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants.

Relebactam is a novel class A and C ß-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals. Following single- or multiple-dose intravenous administration over 30 min, plasma relebactam concentrations declined biexponentially, with a terminal half-life (t1/2) ranging from 1.35 to 1.85 h independently of the dose. Exposures increased in a dose-proportional manner across the dose range. No clinically significant differences in pharmacokinetics between men and women, or between adult and elderly participants, were observed. Urine pharmacokinetics demonstrated that urinary excretion is the major route of relebactam elimination. No drug-drug interaction between relebactam and imipenem-cilastatin was observed, and the observed t1/2 values for relebactam, imipenem, and cilastatin were comparable, thus supporting coadministration. Relebactam administered alone or in combination with imipenem-cilastatin was well tolerated across the dose ranges studied. No serious adverse events or deaths were reported. The pharmacokinetic profile and favorable safety results supported q6h dosing of relebactam with imipenem-cilastatin in clinical treatment trials.

Amenamevir: Studies of Potential CYP2C8- and CYP2B6-Mediated Pharmacokinetic Interactions With Montelukast and Bupropion in Healthy Volunteers.

Amenamevir (formerly ASP2151) induces cytochrome P450 (CYP)2B6 and CYP3A4 and inhibits CYP2C8.  We conducted 2 studies, 1 using montelukast as a probe to assess CYP2C8 and the other bupropion to assess CYP2B6.  The montelukast study examined the effect of amenamevir on the pharmacokinetics of montelukast in 24 healthy men: each subject received montelukast 10 mg alone, followed by montelukast 10 mg with amenamevir 400 mg, or vice versa after a washout period.  In the bupropion study, 24 subjects received a single dose of 150 mg bupropion on days 1, 15, 22, and 29, and repeated once-daily doses of 400 mg amenamevir on days 6-15.  Amenamevir increased peak concentration and area under the concentration-time curve of montelukast by about 22% (ratio 121.7%, 90%CI [114.8, 129.1]; 121% [116.2, 128.4], respectively) with a similar increase in hydroxymontelukast (ratio 121.4%, 90%CI [106.4, 138.5]; 125.6 % [111.3, 141.7]).  Amenamevir reduced peak concentration and area under the concentration-time curve of bupropion by 16% (84.29%, 90%CI [78.00, 91.10]; 84.07%, 90%CI [78.85, 89.63]), with recovery after 1 week; the pharmacokinetics of the primary metabolite hydroxybupropion was unaffected.  Thus, amenamevir increased plasma concentrations of montelukast and decreased those of bupropion, but it did not do so enough to require dose adjustment of coadministered substrates of either CYP2C8 or CYP2B6.

A Randomized, Placebo-Controlled, Double-Blind Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeated Doses of Mirogabalin in Healthy Asian Volunteers.

Mirogabalin is a novel, preferentially selective α2 δ-1 ligand under investigation to treat neuropathic pain. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of various doses of mirogabalin in healthy subjects of different ethnicities. This randomized, placebo-controlled, double-blind, sequential, ascending-dose study evaluated single (10-40 mg) and repeated (10, 15 mg twice a day) doses of mirogabalin in Japanese subjects, and a single dose of mirogabalin in Korean, Chinese, and white subjects. Mirogabalin was rapidly absorbed, with a median time to maximum plasma concentration of 1 hour, and rapidly eliminated, with a mean elimination half-life of 2 to 3 hours. Single-dose mirogabalin pharmacokinetic parameters were comparable between Asian and white subjects. Exposure increased proportionally as mirogabalin dose increased in Japanese subjects. Mean mirogabalin steady-state clearance and volume of distribution values were comparable across dose levels. No accumulation of mirogabalin was observed on repeated dosing in Japanese subjects. Mirogabalin had an acceptable safety and tolerability profile in Asian and white subjects at doses up to 15 mg twice a day for 7 days. The most common treatment-emergent adverse events (somnolence, headache, and dizziness) were consistent with the known mechanism of action and safety profile of mirogabalin.

Inter-rater Agreement of End-of-shift Evaluations Based on a Single Encounter.

INTRODUCTION: End-of-shift evaluation (ESE) forms, also known as daily encounter cards, represent a subset of encounter-based assessment forms. Encounter cards have become prevalent for formative evaluation, with some suggesting a potential for summative evaluation. Our objective was to evaluate the inter-rater agreement of ESE forms using a single scripted encounter at a conference of emergency medicine (EM) educators. METHODS: Following institutional review board exemption, we created a scripted video simulating an encounter between an intern and a patient with an ankle injury. That video was shown during a lecture at the Council of EM Residency Director's Academic Assembly with attendees asked to evaluate the "resident" using one of eight possible ESE forms randomly distributed. Descriptive statistics were used to analyze the results with Fleiss' kappa to evaluate inter-rater agreement. RESULTS: Most of the 324 respondents were leadership in residency programs (66%), with a range of 29-47 responses per evaluation form. Few individuals (5%) felt they were experts in assessing residents based on EM milestones. Fleiss' kappa ranged from 0.157 - 0.308 and did not perform much better in two post-hoc subgroup analyses. CONCLUSION: The kappa ranges found show only slight to fair inter-rater agreement and raise concerns about the use of ESE forms in assessment of EM residents. Despite limitations present in this study, these results and a lack of other studies on inter-rater agreement of encounter cards should prompt further studies of such methods of assessment. Additionally, EM educators should focus research on methods to improve inter-rater agreement of ESE forms or other evaluating other methods of assessment of EM residents.

Safety, Tolerability and Pharmacokinetics of FAAH Inhibitor V158866: A Double-Blind, Randomised, Placebo-Controlled Phase I Study in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: The inhibition of fatty acid amide hydrolase 1 (FAAH) has been proposed as a novel mechanism for treating pain syndromes by increasing the levels of endogenous cannabinoids (ECs). This study describes the safety, tolerability, pharmacokinetics and pharmacodynamics of V158866, a reversible FAAH inhibitor, after first administration to man. METHODS: 51 healthy male subjects were recruited into this double-blind, randomised, placebo-controlled, adaptive dose, phase I single (Part A) and repeated ascending dose (Part B) study. The primary outcome was the safety and tolerability of V158866. Secondary outcomes were (1) pharmacokinetics of V158866 and (2) pharmacodynamics of V158866, as assessed by changes in plasma EC concentrations. RESULTS: Single oral doses of 5-300 mg and repeated oral doses of 50-500 mg were evaluated. V158866 was well tolerated, with no apparent treatment-related effects on laboratory variables. V158866 was rapidly absorbed with a mean terminal elimination half-life of 9.6-18.3 h (Day 7; Part B). V158866 reached steady state within 2-3 days of administration, with an accumulation ratio, based on AUC0-24h, of approximately 2 on Day 7. V158866 showed a linear relationship between dose and AUC across the entire dose range. V158866 caused reversible, dose-related increases in plasma ECs. At hemi-equilibrium, there was a sigmoidal maximum effect relationship between plasma V158866 concentrations and changes in plasma ECs. CONCLUSIONS: V158866 is well tolerated, with linear pharmacokinetics suitable for once-daily administration, and reversible effects on plasma ECs. Maximum increases in plasma ECs occur with V158866 doses of 300-500 mg/day.

A novel peptide-based pan-influenza A vaccine: a double blind, randomised clinical trial of immunogenicity and safety.

BACKGROUND: FP-01.1 is a novel synthetic influenza A vaccine consisting of six fluorocarbon-modified 35-mer peptides that encapsulate multiple CD4+ and CD8+ T-cell epitopes and is designed to induce an immune response across a broad population. METHODS: FP-01.1 was evaluated for safety and immunogenicity in a randomised, double-blind, placebo-controlled, dose-escalation, phase I clinical study in healthy adult volunteers (n=49). IFNγ ELISpot assays and multicolour flow cytometry were used to characterise the immune response. RESULTS: FP-01.1 was safe and well tolerated at all doses tested with a similar adverse event profile in actively vaccinated subjects compared with controls. Maximum immunogenicity was in the 150 µg/peptide dose group where a robust response (243 spots/million PBMC) was demonstrated in 75% subjects compared with 0% in placebo controls. All six peptides were immunogenic. FP-01.1 induced dual CD4+ and CD8+ T cell responses and vaccine-specific T cells cross-recognise divergent influenza strains. CONCLUSIONS: This first-in-human study showed that FP-01.1 has an acceptable safety and tolerability profile and generated robust anti-viral T cell responses in a high proportion of subjects tested. The results support the further clinical testing of FP-01.1 prior to clinical, proof-of-concept, live viral challenge studies.

Entrustable professional activities: making sense of the emergency medicine milestones.

BACKGROUND: The Next Accreditation System (NAS) is being implemented by the Accreditation Council for Graduate Medical Education with seven specialties, including Emergency Medicine (EM), which began in July 2013. The NAS represents a more structured method of accreditation, with dependence on outcomes and less emphasis on educational process. A key component of the NAS is the individual resident semiannual reporting of the Milestone proficiency levels for all sub-competencies, which are more specific areas of domain for the general competencies. All specialties are struggling to some extent with developing assessment mechanisms for the Milestones. At the heart of this struggle is the conceptualization of the Milestones themselves-descriptors of the individual. In practice, faculty assess clinical care provided to the patient by the resident. This creates difficulty for faculty to assign a resident to a specific sub-competency proficiency level when their focus has been on assessment of clinical care. OBJECTIVES: The objectives of this article include the discussion of whether Entrustable Professional Activities (EPAs) could be defined and linked to milestones in a way that, once implemented, could inform Clinical Competency Committees of the Milestone proficiency reporting. DISCUSSION: EPAs are units of professional work, or clinical care that may help translate aspects of clinical care into Milestone proficiencies. This article explores EPAs in depth, and discusses how EPAs may be used within EM as one method of assigning proficiency levels to residents. CONCLUSIONS: EPAs may be a useful tool to inform Milestone proficiency placement of residents. Because EPAs are based on clinical descriptions rather than individual physician descriptions, there may be less faculty development needed for Milestone sub-competency assessment.

Are Simulation Stethoscopes a Useful Adjunct for Emergency Residents' Training on High-fidelity Mannequins?

INTRODUCTION: Emergency medicine residents use simulation training for many reasons, such as gaining experience with critically ill patients and becoming familiar with disease processes. Residents frequently criticize simulation training using current high-fidelity mannequins due to the poor quality of physical exam findings present, such as auscultatory findings, as it may lead them down an alternate diagnostic or therapeutic pathway. Recently wireless remote programmed stethoscopes (simulation stethoscopes) have been developed that allow wireless transmission of any sound to a stethoscope receiver, which improves the fidelity of a physical examination and the simulation case. METHODS: Following institutional review committee approval, 14 PGY1-3 emergency medicine residents were assessed during 2 simulation-based cases using pre-defined scoring anchors on multiple actions, such as communication skills and treatment decisions (Appendix 1). Each case involved a patient presenting with dyspnea requiring management based off physical examination findings. One case was a patient with exacerbation of heart failure, while the other was a patient with a tension pneumothorax. Each resident was randomized into a case associated with the simulation stethoscope. Following the cases residents were asked to fill out an evaluation questionnaire. RESULTS: Residents perceived the most realistic physical exam findings on those associated with the case using the simulation stethoscope (13/14, 93%). Residents also preferred the simulation stethoscope as an adjunct to the case (13/14, 93%), and they rated the simulation stethoscope case to have significantly more realistic auscultatory findings (4.4/5 vs. 3.0/5 difference of means 1.4, p=0.0007). Average scores of residents were significantly better in the simulation stethoscope-associated case (2.5/3 vs. 2.3/3 difference of means 0.2, p=0.04). There was no considerable difference in the total time taken per case. CONCLUSION: A simulation stethoscope may be a useful adjunct to current emergency medicine simulation-based training. Residents both preferred the use of the simulation stethoscope and perceived physical exam findings to be more realistic, leading to improved fidelity. Potential sources of bias include the small population, narrow scoring range, and the lack of blinding. Further research, focusing on use for resident assessment and clinical significance with a larger population and blinding of graders, is needed.

Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study.

AIMS: To assess the steady-state pharmacokinetic and QT(c) effects of domperidone and ketoconazole, given alone and together. METHODS: A randomized, placebo-controlled, double-blind, crossover study was carried out. Healthy subjects (14 men, 10 women; age 18-39 years; mean weight 73.5kg, range 53.8-98.8kg; 23 Europid, 1 Afro-Caribbean) received orally, for 7 days each, placebo, domperidone 10mg, four doses daily, at 4h intervals, ketoconazole 200mg 12-hourly and domperidone and ketoconazole together. The washout period was 15 days. Pharmacokinetics and serial 12-lead ECGs were assessed on day 7, and serial ECGs on day -1 and at follow-up. Two subjects withdrew before the third treatment period, so data were available for 22-24 subjects. RESULTS Ketoconazole tripled domperidone concentrations at steady-state. Domperidone, ketoconazole and their combination significantly increased QT(c) F in men. Overall adjusted mean differences from placebo were 4.20 (95% CI 0.77, 7.63), 9.24 (95% CI 5.85, 12.63) and 15.90 (95% CI 12.47, 19.33) ms, respectively. In women, QT(c) F was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QT(c) was positively correlated with plasma drug concentrations, in both men and women. ΔQT(c) F increased by about 2ms per 10ngml(-1) rise in domperidone concentration, and per 1µgml(-1) rise in ketoconazole concentration. CONCLUSIONS: Ketoconazole tripled the plasma concentrations of domperidone. Domperidone and ketoconazole increased QT(c) F in men, whether given together or separately. The effect of domperidone alone was below the level of clinical importance. The negative result in women is unexplained.

Incidence of Staphylococcus aureus nasal colonization and soft tissue infection among high school football players.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections have been documented with increasing frequency in both team and individual sports in recent years. It also seems that the level of MRSA skin and soft tissue infections in the general population has increased. METHODS: One hundred ninety athletes from 6 local high school football teams were recruited for this prospective observational study to document nasal colonization and the potential role this plays in skin and soft tissue infections in football players and, in particular, MRSA infections. Athletes had nasal swabs done before their season started, and they filled out questionnaires regarding potential risk factors for skin and soft tissue infections. Those enrolled in the study were then observed over the course of the season for skin and soft tissue infections. Those infected had data about their infections collected. RESULTS: One hundred ninety of 386 available student athletes enrolled in the study. Forty-four of the subjects had nasal colonization with methicillin-susceptible S. aureus, and none were colonized with MRSA. There were 10 skin and soft tissue infections (8 bacterial and 2 fungal) documented over the course of the season. All were treated as outpatients with oral or topical antibiotics, and none were considered serious. Survey data from the preseason questionnaire showed 21% with skin infection, 11% with methicillin-susceptible S. aureus, and none with MRSA infection during the past year. Three reported a remote history of MRSA infection. CONCLUSIONS: We documented an overall skin infection rate of 5.3% among high school football players over a single season. Our results suggest that skin and soft tissue infection may not be widespread among high school athletes in northeast Ohio.

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.

Comparison of the effects of single and repeated oral doses of lansoprazole and rabeprazole on ambulatory 24-hour intragastric pH in healthy volunteers.

BACKGROUND: As the comparative pharmacokinetics and pharmacodynamics of lansoprazole and rabeprazole have not previously been studied, we set out in this study to compare the pharmacokinetics and pharmacodynamics of single and repeated daily doses of lansoprazole 15 mg and 30 mg with those of rabeprazole 10 mg and 20 mg. METHODS: This was an open-label, randomised, crossover, two-centre study in 72 healthy volunteers. Each subject received each of the four treatments for 5 days, with 2-week washout periods. Continuous 24-hour intragastric pH and pharmacokinetics were studied on days 1 and 5. RESULTS: Mean 24-hour pH and percentage time for pH > 4 were not significantly different between lansoprazole 30 mg and rabeprazole 20 mg. Mean 24-hour pH and percentage time for pH > 4 were significantly greater after lansoprazole 30 mg and rabeprazole 20 mg than after lansoprazole 15 mg and rabeprazole 10 mg, respectively. Lansoprazole resulted in greater acid suppression during hours 0-5 on days 1 and 5, whereas rabeprazole had greater suppression during hours 11-24 on day 5. Time to maximum plasma concentration was significantly shorter for lansoprazole on both days. CONCLUSION: Lansoprazole had a consistently faster onset of action, whereas rabeprazole had a greater effect during the evening hours after 5 days of administration.

Measuring SSRI occupancy of SERT using the novel tracer [123I]ADAM: a SPECT validation study.

PURPOSE: Serotonergic brain regions play a crucial role in the modulation of emotion, and serotonergic dysfunction may contribute to several neurological disorders. [123I]ADAM is a novel SPECT tracer which binds with high affinity to serotonin transporters (SERT). The objective of this study was to compare different methods for the quantification of tracer binding and to develop a simplified single-scan protocol for this tracer, as well as to investigate its potential for characterisation of the transporter occupancy versus plasma concentration curve of a selective serotonin re-uptake inhibitor (SSRI). METHODS: Dynamic SPECT scans were performed on 16 healthy volunteers after administration of approximately 150 MBq [123I]ADAM. Data were acquired from the time of injection until approximately 5.5 h after injection in 30- or 45-min sessions. Each subject was scanned twice: with and without pre-treatment with the SSRI citalopram in various dosage regimens. The plasma concentration of citalopram (C(p)) was determined from venous samples. Images were reconstructed by filtered back-projection with scatter and attenuation correction. Tracer binding was quantified for midbrain, striatum and thalamus using cerebellum as a reference region. Quantification was done by kinetic modelling, graphical analysis and multi-linear regression, as well as by the ratio method, with binding potential (BP2) as the outcome measure. The SERT occupancy by citalopram was determined relative to the baseline scan for each subject, and the occupancy versus C(p) curve was fitted with the E(max) model. RESULTS: The highest binding of [123I]ADAM was in midbrain (mean baseline BP2+/-SD=1.31+/-0.29), with lower binding in thalamus (0.79+/-0.16) and striatum (0.66+/-0.13). There was good agreement between BP2 values obtained by different quantification methods. Using the ratio method, the best agreement with kinetic modelling was obtained with data from the time interval [200,260] min after injection. The fitting of the midbrain occupancy curve yielded a maximum occupancy of 84% and a plasma concentration required to reach 50% of the maximum of 2.5 ng/ml, with a goodness-of-fit variability of 13% (SD). CONCLUSION: Binding of [123I]ADAM to SERT in midbrain can be quantified with a single scan starting 200 min after injection. However, the variability of estimated occupancy values may be too high for critical assessment of occupancy of SERT by SSRI.

Are published normal ranges of serum testosterone too high? Results of a cross-sectional survey of serum testosterone and luteinizing hormone in healthy men.

OBJECTIVE: To derive normal ranges of serum testosterone and luteinizing hormone (LH) concentrations in healthy men, and thus evaluate whether testosterone replacement therapy is prescribed inappropriately. SUBJECTS AND METHOD: The study comprised 266 healthy male volunteers (aged 18-75 years) who were defined as healthy by strict eligibility criteria. Subjects had a body mass index (BMI) of 18.6-32.2 kg/m2, smoked 0-10 cigarettes/day, and had an alcohol intake 0-40 units/week (one unit = 8 g ethanol). We measured serum testosterone and LH concentrations in the morning (08.00-09.00 hours) and evening (20.00-21.00 hours). RESULTS: Morning normal ranges of testosterone for men aged < or = 40 years were 10.07-38.76 nmol/L (2.90-11.18 microg/L), and for men age > or = 40 years, 7.41-24.13 (2.14-6.96); the respective evening normal ranges were 6.69-31.51 (1.93-9.09) and 6.46-21.93 (1.86-6.33). Both morning and evening serum testosterone declined significantly with increasing age and BMI. LH was significantly higher in the morning than in the evening, but did not vary between the age groups or with BMI. The calculated normal ranges of LH were 0.9-7.0 IU/L (morning) and 0.7-6.8 IU/L (evening). CONCLUSIONS: The lower limit of normal for serum testosterone was 3-4 nmol/L (0.86-1.15 microg/L) lower than that of published ranges. The results have important implications for the diagnosis of hypogonadism and use of testosterone replacement therapy.