The prevalence of low muscle mass associated with obesity in the USA.

BACKGROUND: Sarcopenia is defined as age-related low muscle mass and function, and can also describe the loss of muscle mass in certain medical conditions, such as sarcopenic obesity. Sarcopenic obesity describes loss of muscle and function in obese individuals; however, as sarcopenia is an age-related condition and obesity can occur in any age group, a more accurate term is obesity with low lean muscle mass (OLLMM). Given limited data on OLLMM (particularly in those aged < 65 years), the purpose of this study was to estimate the prevalence of OLLMM in adults aged ≥ 20 years in the USA. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and 1999-2006 were used. OLLMM was defined as an appendicular lean mass, adjusted for body mass index (BMI), cut-off point < 0.789 for males and < 0.512 for females, measured by dual-energy X-ray absorptiometry (DXA). DXA was only measured in individuals 20-59 years old in NHANES 2017-2018; we therefore utilized logistic regression models to predict OLLMM from NHANES 1999-2006 for those aged ≥ 60 years. The prevalence of OLLMM was estimated overall, and by sex, age, race/ethnicity, and clinical subgroup (high BMI, prediabetes, type 2 diabetes mellitus [T2DM], non-alcoholic fatty liver disease [NAFLD] with fibrosis, or post-bariatric surgery). Prevalence estimates were extrapolated to the USA population using NHANES sampling weights. RESULTS: We estimated that, during 2017-2018, 28.7 million or 15.9% of the USA population had OLLMM. The prevalence of OLLMM was greater in older individuals (8.1%, aged 20-59 years vs 28.3%, aged ≥ 60 years), highest (66.6%) in Mexican-American females aged ≥ 60 years, and lowest (2.6%) in non-Hispanic Black males aged 20-59 years. There was a higher prevalence of OLLMM in adults with prediabetes (19.7%), T2DM (34.5%), NAFLD with fibrosis (25.4%), or post-bariatric surgery (21.8%), compared with those without each condition. CONCLUSIONS: Overall, the burden of OLLMM in the USA is substantial, affecting almost 30 million adults. The prevalence of OLLMM increased with age, and among those with prediabetes, T2DM, NAFLD with fibrosis, or post-bariatric surgery. A unified definition of OLLMM will aid diagnosis and treatment strategies.

Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. OBJECTIVES: This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. METHODS: This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. RESULTS: Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period. CONCLUSIONS: In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.).

Efficacy and safety of alirocumab in statin-intolerant patients over 3 years: open-label treatment period of the ODYSSEY ALTERNATIVE trial.

BACKGROUND: The 24-week randomized, double-blind ODYSSEY ALTERNATIVE trial (NCT01709513) demonstrated significant low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 inhibitor alirocumab vs ezetimibe in statin-intolerant patients, with significantly fewer skeletal muscle events (SMEs; 32.5%) vs atorvastatin (46.0%; hazard ratio: 0.61, 95% confidence interval: 0.38 to 0.99, P = .042). OBJECTIVE: ALTERNATIVE participants could enter an open-label treatment period (OLTP) for assessment of long-term safety. METHODS: Two hundred and eighty one patients entered the OLTP; 93.7%, 84.0%, and 92.9% of patients who received atorvastatin, ezetimibe, and alirocumab, respectively, during double-blind treatment, including 216 patients (76.9%) who completed double-blind treatment, as well as patients who either prematurely discontinued treatment due to SME (n = 51 [18.1%]) or other reasons (n = 14 [5.0%]) but completed week 24 assessments. All patients in the OLTP received alirocumab (75 or 150 mg every 2 weeks based on investigator decision) for ∼3 years or until commercial availability, whichever came first. RESULTS: SMEs were reported by 38.4% of patients in the OLTP. Safety results from the OLTP were similar to those of the alirocumab group in the double-blind period, except for a lower rate of discontinuations due to SMEs observed with alirocumab in the OLTP (3.2% vs 15.9% in the double-blind period). At OLTP week 8, mean LDL-C reduction from baseline (=week 0 of double-blind period) was 52.0%, with reductions sustained through to the end-of-treatment visits (55.4% and 53.7% reduction at weeks 100 and 148, respectively). CONCLUSIONS: In this population of statin-intolerant patients, alirocumab was well tolerated and produced durable LDL-C reductions over 3 years.

Efficacy and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function or Apolipoprotein B Loss-of-Function Mutations.

Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns.

Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations.

BACKGROUND: Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). OBJECTIVE: The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. METHODS: Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. RESULTS: At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. CONCLUSIONS: Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. CLINICAL TRIAL REGISTRATION: NCT01604824; clinicaltrials.gov.

Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial.

OBJECTIVE: To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies (NCT01730053). METHODS: Patients receiving baseline rosuvastatin regimens (10 or 20 mg) were randomized to: add-on alirocumab 75 mg every-2-weeks (Q2W) (1-mL subcutaneous injection via pre-filled pen); add-on ezetimibe 10 mg/day; or double-dose rosuvastatin. Patients had cardiovascular disease (CVD) and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL-C ≥100 mg/dL (2.6 mmol/L). In the alirocumab group, dose was blindly increased at Week 12 to 150 mg Q2W (also 1-mL volume) in patients not achieving their LDL-C target. Primary endpoint was percent change in calculated LDL-C from baseline to 24 weeks (intent-to-treat). RESULTS: 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDL-C reductions were observed with add-on alirocumab (-50.6%) versus ezetimibe (-14.4%; p < 0.0001) and double-dose rosuvastatin (-16.3%; p < 0.0001). In the baseline rosuvastatin 20 mg group, LDL-C reduction with add-on alirocumab was -36.3% compared with -11.0% with ezetimibe and -15.9% with double-dose rosuvastatin (p = 0.0136 and 0.0453, respectively; pre-specified threshold for significance p < 0.0125). Overall, ∼80% alirocumab patients were maintained on 75 mg Q2W. Of alirocumab-treated patients, 84.9% and 66.7% in the baseline rosuvastatin 10 and 20 mg groups, respectively, achieved risk-based LDL-C targets. Treatment-emergent adverse events occurred in 56.3% of alirocumab patients versus 53.5% ezetimibe and 67.3% double-dose rosuvastatin (pooled data). CONCLUSIONS: The addition of alirocumab to rosuvastatin provided incremental LDL-C lowering versus adding ezetimibe or doubling the rosuvastatin dose.

Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial.

CONTEXT: Despite current standard of care, many patients at high risk of cardiovascular disease (CVD) still have elevated low-density lipoprotein cholesterol (LDL-C) levels. Alirocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9. OBJECTIVE: The objective of the study was to compare the LDL-C-lowering efficacy of adding alirocumab vs other common lipid-lowering strategies. DESIGN, PATIENTS, AND INTERVENTIONS: Patients (n = 355) with very high CVD risk and LDL-C levels of 70 mg/dL or greater or high CVD risk and LDL-C of 100 mg/dL or greater on baseline atorvastatin 20 or 40 mg were randomized to one of the following: 1) add-on alirocumab 75 mg every 2 weeks (Q2W) sc; 2) add-on ezetimibe 10 mg/d; 3) double atorvastatin dose; or 4) for atorvastatin 40 mg regimen only, switch to rosuvastatin 40 mg. For patients not achieving protocol-defined LDL-C goals, the alirocumab dose was increased (blinded) at week 12 to 150 mg Q2W. MAIN OUTCOME MEASURE: The primary end point was percentage change in calculated LDL-C from baseline to 24 weeks (intent to treat). RESULTS: Among atorvastatin 20 and 40 mg regimens, respectively, add-on alirocumab reduced LDL-C levels by 44.1% and 54.0% (P < .001 vs all comparators); add-on ezetimibe, 20.5% and 22.6%; doubling of atorvastatin dose, 5.0% and 4.8%; and switching atorvastatin 40 mg to rosuvastatin 40 mg, 21.4%. Most alirocumab-treated patients (87.2% and 84.6%) achieved their LDL-C goals. Most alirocumab-treated patients (86%) maintained their 75-mg Q2W regimen. Treatment-emergent adverse events occurred in 65.4% of alirocumab patients vs 64.4% ezetimibe and 63.8% double atorvastatin/switch to rosuvastatin (data were pooled). CONCLUSIONS: Adding alirocumab to atorvastatin provided significantly greater LDL-C reductions vs adding ezetimibe, doubling atorvastatin dose, or switching to rosuvastatin and enabled greater LDL-C goal achievement.

Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies.

The phase 3 ODYSSEY OPTIONS studies (OPTIONS I, NCT01730040; OPTIONS II, NCT01730053) are multicenter, multinational, randomized, double-blind, active-comparator, 24-week studies evaluating the efficacy and safety of alirocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, as add-on therapy in ∼ 650 high-cardiovascular (CV)-risk patients whose low-density lipoprotein cholesterol (LDL-C) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV-risk category, high and very high CV risk, respectively, with atorvastatin (20-40 mg/d) or rosuvastatin (10-20 mg/d). Patients are randomized to receive alirocumab 75 mg via a single, subcutaneous, 1-mL injection by prefilled pen every 2 weeks (Q2W) as add-on therapy to atorvastatin (20-40 mg) or rosuvastatin (10-20 mg); or to receive ezetimibe 10 mg/d as add-on therapy to statin; or to receive statin up-titration; or to switch from atorvastatin to rosuvastatin (OPTIONS I only). At week 12, based on week 8 LDL-C levels, the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL-C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk, respectively. The primary efficacy endpoint in both studies is difference in percent change in calculated LDL-C from baseline to week 24 in the alirocumab vs control arms. The studies may provide guidance to inform clinical decision-making when patients with CV risk require additional lipid-lowering therapy to further reduce LDL-C levels. The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL-C reduction required to achieve the desired LDL-C level.

Simulation training for surgical residents in pediatric trauma scenarios.

INTRODUCTION: Pediatric trauma requires several medical professionals working together as a highly functioning team. Since critical pediatric medical events are rare, routine practice can be one method of ensuring that all members communicate and provide quality care. The goal of this study was to evaluate whether high-fidelity simulation training improved surgery residents' knowledge and self-efficacy in relation to pediatric trauma scenarios. METHODS: Participants attended training that included initial assessments of knowledge and self-efficacy, lecture, and practice with three trauma scenarios. After the training, residents completed pretest measures again. RESULTS: Findings indicated that resident knowledge and self-efficacy significantly increased afterthe simulation training. CONCLUSION: The current study suggests that for the adequate care of pediatric patients during trauma/emergency situations, high-fidelity simulation training may be beneficial. This may be particularly true for emergencies that are less frequent and not well practiced by clinicians and students.

Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice.

OBJECTIVE AND DESIGN: Angiotensin-converting enzyme 2 (ACE2) is expressed in gastrointestinal tissue. Previous studies of GL1001, a potent and selective ACE2 inhibitor, have revealed anti-inflammatory activity in the mouse digestive tract. We hypothesized that GL1001 might also produce beneficial effects in a mouse DSS model of inflammatory bowel disease. MATERIALS: Female mice were used for study. TREATMENT: Animals were treated for 5 days with 5% DSS in the drinking water to induce colitis. For the following 9 days, animals were treated twice daily with GL1001 (30, 100, 300 mg/kg, s.c.), sulfasalazine (150 mg/kg, p.o.), or vehicle. METHODS: Throughout the experiment, body weight, rectal prolapse, stool consistency, and fecal occult blood were monitored. At termination, colon length, histopathology, and myeloperoxidase activity were assessed. RESULTS: High-dose GL1001 ameliorated DSS-induced disease activity, including rectal prolapse and intestinal bleeding. The most robust effect of GL1001 was observed 48-96 h post DSS treatment and was comparable in magnitude to that of sulfasalazine. Colon pathology and myeloperoxidase activity were also markedly attenuated by high-dose GL1001 treatment, with the most profound effects observed in the distal segment. CONCLUSIONS: The findings support the previously observed anti-inflammatory effects of ACE2 inhibition in gastrointestinal tissue and suggest that GL1001 may have therapeutic utility for inflammatory bowel disease.

Comparison of use of the the Airtraq with direct laryngoscopy by paramedics in the simulated airway.

INTRODUCTION: Paramedics often encounter patients with difficult airways requiring emergent airway management. OBJECTIVE: The purpose of this study was to compare intubation utilizing the Airtraq with direct laryngoscopy (DL) in the manikin model. We evaluated the number of attempts, the time to successful intubation, and the Airtraq's learning curve. METHODS: This was a randomized, crossover study involving paramedics. Each participant was given a standardized lecture and a demonstration of the Airtraq device. After a 5-minute practice session on a Laerdal Airway Management Trainer with the Airtraq and DL, participants managed the following four scenarios on a Laerdal SimMan manikin: 1) normal airway; 2) tongue edema; 3) cervical spine immobilization; and 4) repeated normal airway. Results were analyzed using the Wilcoxon signed rank test. RESULTS: Thirty paramedics participated in this study. For scenario 1, there were no significant differences in either the number of attempts or the time to ventilation between the devices. For scenario 2, the mean time to ventilation was significantly faster, and fewer intubation attempts were observed with the Airtraq when compared with DL. For scenario 3, there were no significant differences in number of attempts and time to ventilation. Scenario 4 demonstrated significantly less time to ventilation and fewer intubation attempts with the Airtraq. A significant decrease in time to ventilation was observed with the Airtraq when comparing scenarios 1 and 4. CONCLUSIONS: The Airtraq was shown to be equal to or faster than DL. The Airtraq has a rapid learning curve demonstrated by a significantly decreased time to ventilation between scenarios 1 and 4.

Short-term tolerability of a nonazapirone selective serotonin 1A agonist in adults with generalized anxiety disorder: a 28-day, open-label study.

BACKGROUND: The serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor likely plays a critical role in anxiety pathophysiology. OBJECTIVE: In this proof-of-concept investigation, we tested the short-term tolerability of PRX-00023, a nonazapirone 5-HT1A selective partial agonist, in outpatients with generalized anxiety disorder (GAD). METHODS: Patients with a diagnosis of GAD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Hamilton Anxiety (HAM-A) Rating Scale scores > or =20 were recruited. A 1-week, single-blind placebo run-in was followed by a 28-day,open-label treatment with PRX-00023 QD in a forced-titration protocol: 40 mg (days 1-4), 80 mg (days 5-14), and 120 mg (days 15-28). The primary outcome measures were tolerability and rate of completion of the study. Tolerability was recorded using a table of adverse events (AEs), and measured using laboratory tests, vital signs, and electrocardiogram (ECG) readings. Secondary outcomes included the baseline-to-end point change in HAM-A total score, percentage meeting remission (HAM-A< or =7), and response criteria (> or =50% reduction in HAM-A total score). RESULTS: Twenty-three patients (56.5% female, 65.2% white; mean age, 37.4 years) were enrolled in the study. A total of 21 patients (91.3%) received study medication and 18 (78.3%) completed the study. Two patients withdrew for personal reasons, 1 was discontinued for noncompliance, and 1 was lost to follow-up. One patient was discontinued from the study due to a history of premature ventricular contractions deemed unrelated to the study drug. AEs were reported in 15 patients, with the most common being back pain (3 patients), influenza-like symptoms (without fever) (2), diarrhea (2), dyspepsia (2), and nausea (2). No serious AEs, withdrawal symptoms, ataxia/ dizziness, or sexual dysfunction were reported; there were no clinically significant laboratory, vital sign, or ECG abnormalities. Mean HAM-A total scores were significantly lower at study end point compared with enrollment (13.9 vs 22.9; P < 0.001), with 32% of patients achieving remission and 52% meeting response criteria. CONCLUSION: In this preliminary, short-term study, PRX-00023 appeared to be generally well tolerated in this sample of patients with GAD.

The fifth vital sign--what does it mean?

Acute pain is reported as a presenting symptom in over 80% of physician visits. Chronic pain affects an estimated 76.2 million Americans--more than diabetes, heart disease, and cancer combined. It has been estimated to be undertreated in up to 80% of patients in some settings. Pain costs the American public more than $100 billion each year in health care, compensation, and litigation. That's why pain was officially declared "The Fifth Vital Sign." Henceforth the evaluation of pain became a requirement of proper patient care as important and basic as the assessment and management of temperature, blood pressure, respiratory rate, and heart rate. The numeric pain scale certainly has a place in care and in pain management; however, it is important to assess the patient's communication and self-management style and to recognize that patients, like pain, are on a continuum with varied styles of communication and adaptation. It is easy to get lost in the process, even when the process is initiated with the best of intentions. In the quest for individualized medicine, it might be best to keep pain assessment in the individualization arena.

Effects of PRX-00023, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial.

PRX-00023, a serotonin 1A receptor agonist, was designed to provide high potency and selectivity for its target. To assess the possible therapeutic utility in anxiety, a randomized, double-blind, placebo-controlled trial was conducted in 311 subjects who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for generalized anxiety disorder. All subjects underwent a 1-week placebo run-in and were randomized to receive once-daily capsules containing either PRX-00023 (80 mg/d) or placebo for an additional 8 weeks. The primary outcome measure was the Hamilton Anxiety Scale (HAM-A). The Montgomery-Asberg Depression Rating Scale was used as a secondary endpoint to measure depressive symptoms. Statistical testing was performed with analysis of covariance, between baseline and week 8, with baseline values as a covariate. The anxiolytic effect of PRX-00023, compared with placebo, showed trends across all anxiolytic measures but failed to reach significance on the primary endpoint (HAM-A total score). Among the components of the HAM-A total score, the anxious mood item was significantly different from placebo in the PRX-00023-treated group (-1.015 vs -0.748; P = 0.02). The scores of the Montgomery-Asberg Depression Rating Scale were significantly improved compared with placebo at week 8 (-4.5 vs -1.6; P = 0.0094 in the last observation carried forward analysis). PRX-00023 was well tolerated; of note, there were no drug-related serious adverse events, and more patients discontinued due to adverse events in the placebo group (2.9%) than in the PRX-00023 group (1.4%). The most common adverse event was headache, observed in 15.7% and 10.9% of PRX-00023- and placebo-treated patients, respectively. Furthermore, there was no evidence of impaired sexual function, as measured by the Massachusetts General Hospital Sexual Function Scale. Collectively, these results support further clinical investigation of higher doses of PRX-00023 in anxiety and depression.

Tolerability, pharmacokinetics, and neuroendocrine effects of PRX-00023, a novel 5-HT1A agonist, in healthy subjects.

PRX-00023 is a novel, nonazapirone 5-HT1A agonist in clinical development for treatment of affective disorders. The objectives of the initial clinical phase I studies (a single ascending dose study and multiple dose-ascending and high-dose titration studies) were to measure the pharmacokinetics, pharmacodynamic (neuroendocrine) effects, and tolerability of PRX-00023 in healthy subjects. The studies evaluated 10-mg to 150-mg doses of PRX-00023 in up to 112 healthy male and female subjects aged 18 to 54 years. Single and multiple oral doses of PRX-00023 were found to be safe and well tolerated in healthy subjects. PRX-00023 was absorbed relatively rapidly, with a tmax of 0.5 to 2 hours, and eliminated with a half-life of approximately 12 hours. PRX-00023 treatment transiently increased blood prolactin levels 2 to 3 hours after administration, consistent with its mechanism as a 5-HT1A agonist.

A review and assessment of potential sources of ethnic differences in drug responsiveness.

The International Conference on Harmonization (ICH) E5 guidelines were developed to provide a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with the underlying objective to facilitate global drug development and registration. It is well recognized that all drugs exhibit significant inter-subject variability in pharmacokinetics and pharmacologic response and that such differences vary considerably among individual drugs and depend on a variety of factors. One such potential factor involves ethnicity. The objective of the present work was to perform an extensive review of the world literature on ethnic differences in drug disposition and responsiveness to determine their general significance in relation to drug development and registration. A few examples of suspected ethnic differences in pharmacokinetics or pharmacodynamics were identified. The available literature, however, was found to be heterologous, including a variety of study designs and research methodologies, and most of the publications were on drugs that were approved a long time ago.

Pharmacokinetics and pharmacodynamics of glyburide/metformin tablets (Glucovance) versus equivalent doses of glyburide and metformin in patients with type 2 diabetes.

OBJECTIVE: To compare the effects of two different formulations of glibenclamide (glyburide) combined with metformin on postprandial glucose excursions, and to assess their pharmacokinetics. The formulations were a combination glibenclamide/metformin tablet (Glucovance; controlled-particle-size glibenclamide and metformin) versus glibenclamide (Micronase) and metformin (Glucophage) coadministered separately. DESIGN: A randomised, double-blind, two-way crossover study in which patients with type 2 diabetes received either glibenclamide/metformin 2.5/500mg tablets or glibenclamide 2.5mg with metformin 500mg twice daily for 14 days. After a 2-week washout, patients were crossed over to the other treatment for 14 days. Patients consumed standardised meals on the days when pharmacokinetic and pharmacodynamic evaluations were performed. PARTICIPANTS: Forty patients with type 2 diabetes were enrolled; 37 were randomised (18 men, 19 women) and 35 completed the study. Mean age was 58 years; mean body mass index was 31 kg/m(2). The baseline glycated haemoglobin (HbA(1c)) was 9.3% for both treatment groups. MAIN OUTCOME MEASURE: Two-hour postprandial glucose excursion (PPGE) was used to assess postprandial glucose dynamics. RESULTS: Treatment with glibenclamide/metformin resulted in a significantly smaller mean PPGE than was attained by treatment with glibenclamide plus metformin, according to measurements taken after the day 14 afternoon standardised meal (89.5 vs 117.4 mg/dl, p = 0.011). The mean glibenclamide peak concentration (C(max)) was significantly greater (approximately 16%) after glibenclamide/metformin treatment on both days 1 and 14. Glibenclamide/metformin treatment was associated with a 2-fold greater area under the concentration-time curve to 3 hours for glibenclamide (AUC(3)) [p < 0.001], although the AUC over the administration interval was equivalent for both formulations. CONCLUSION: In patients with type 2 diabetes, glibenclamide/metformin resulted in lower PPGE, suggesting that the higher glibenclamide AUC(3) observed with this formulation may contribute to better postprandial glycaemic control than is attained by glibenclamide plus metformin separately.