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The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as an inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT)-based solid dispersions using continuous melt extrusion (HME) processing. Twin-screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterization showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, in-line NIR studies revealed a possible intermolecular H-bonding formation between the drug and the carrier resulting in the increase of TLT dissolution rates. The capsules containing TLT-extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben ® product.

Objectives: Few studies of oral glucose-lowering drugs exist in newly diagnosed type 2 diabetes (T2D) patients with marked hyperglycemia, and insulin is often proposed as initial treatment. We evaluated the oral initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in this population., Methods: We performed a pre-specified subgroup analysis of a randomized study in which newly diagnosed T2D patients with glycated hemoglobin A1c (HbA1c) 8.5%-12.0% received linagliptin/metformin or linagliptin monotherapy. Subgroups of baseline HbA1c, age, body-mass index (BMI), renal function, race, and ethnicity were evaluated, with efficacy measured by HbA1c change from baseline after 24 weeks., Results: HbA1c reductions from baseline (mean 9.7%) at week 24 in the overall population were an adjusted mean -2.81% ± 0.12% with linagliptin/metformin (n = 132) and -2.02% ± 0.13% with linagliptin (n = 113); treatment difference -0.79% (95% CI -1.13 to -0.46, P < 0.0001). In patients with baseline HbA1c ≥9.5%, HbA1c reduction was -3.37% with linagliptin/metformin (n = 76) and -2.53% with linagliptin (n = 61); difference -0.84% (95% CI -1.32 to -0.35). In those with baseline HbA1c <9.5%, HbA1c reduction was -2.08% with linagliptin/metformin (n = 56) and -1.39% with linagliptin (n = 52); difference -0.69% (95% CI -1.23 to -0.15). Changes in HbA1c and treatment differences between the linagliptin/metformin and linagliptin groups were of similar magnitudes to the overall population across patient subgroups based on age, BMI, renal function, and race. Drug-related adverse events occurred in 8.8% and 5.7% of linagliptin/metformin and linagliptin patients, respectively; no severe hypoglycemia occurred., Conclusion: Linagliptin/metformin combination in newly diagnosed T2D patients with marked hyperglycemia was well tolerated and elicited substantial improvements in glycemic control regardless of baseline HbA1c, age, BMI, renal function, or race. Thus, newly diagnosed, markedly hyperglycemic patients may be effectively treated by combinations of oral agents., Clinical Trial Registration: www.clinicaltrials.gov identifier is NCT01512979.

Objective: Current type 2 diabetes (T2D) treatment guidelines include weight maintenance or loss, avoidance of hypoglycemia, and targets for blood pressure and circulating lipids, in addition to glycemic control. Increasingly, clinical trials and meta-analyses employ composite endpoints to capture the net clinical benefit of a given T2D intervention. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represent a new class of injected antihyperglycemic agents that may be well suited to reaching many of these targets among patients failing on metformin monotherapy., Research Designs and Methods: Using MEDLINE, Embase and Google Scholar, studies were sought that employed composite endpoints and that reported outcomes with exenatide and/or liraglutide. Bibliographies of relevant review articles were consulted to search for additional reports., Results: Many trials have used the combination of HbA1c <7%, no weight gain and no hypoglycemic episodes as the composite endpoint in evaluating T2D therapies; however, at least 15 other distinct composite endpoints have been reported. Findings were relatively consistent across studies, regardless of how the composite endpoint was defined. Specifically, the GLP-1 RAs appear to be superior to other agents in their efficacy in providing T2D patients failing on metformin with a net clinical benefit, which can include avoidance of hyperglycemia and maintenance or improvement in body weight., Conclusions: Use of composite endpoints represents an important advance in T2D. While no single such endpoint has achieved dominance in the field, widely used composite endpoints capture efficacy in glycemic control as well as safety and effects on markers of cardiovascular risk.

The purpose of this study was to establish intra-rater, intra-session, and inter-rater, reliability of sagittal plane hip, knee, and ankle angles with and without reflective markers using the GAITRite walkway and single video camera between student physical therapists and an experienced physical therapist. This study included thirty-two healthy participants age 20-59, stratified by age and gender. Participants performed three successful walks with and without markers applied to anatomical landmarks. GAITRite software was used to digitize sagittal hip, knee, and ankle angles at two phases of gait: (1) initial contact; and (2) mid-stance. Intra-rater reliability was more consistent for the experienced physical therapist, regardless of joint or phase of gait. Intra-session reliability was variable, the experienced physical therapist showed moderate to high reliability (intra-class correlation coefficient (ICC) = 0.50-0.89) and the student physical therapist showed very poor to high reliability (ICC = 0.07-0.85). Inter-rater reliability was highest during mid-stance at the knee with markers (ICC = 0.86) and lowest during mid-stance at the hip without markers (ICC = 0.25). Reliability of a single camera system, especially at the knee joint shows promise. Depending on the specific type of reliability, error can be attributed to the testers (e.g. lack of digitization practice and marker placement), participants (e.g. loose fitting clothing) and camera systems (e.g. frame rate and resolution). However, until the camera technology can be upgraded to a higher frame rate and resolution, and the software can be linked to the GAITRite walkway, the clinical utility for pre/post measures is limited.

Objective: To evaluate the efficacy and safety of the available glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exenatide and liraglutide (marketed as Byetta * and Victoza † , respectively) in first- or second-line pharmacotherapy for type 2 diabetes (T2D), described here as 'early use'., Research Design and Methods: MEDLINE, EMBASE and Google Scholar databases were queried for clinical trial reports using the terms incretin, GLP-1, exenatide and liraglutide. Relevant articles were those that employed these agents in treatment-naïve patients with T2D and in patients who had failed on metformin monotherapy. Additional targeted searches were conducted on diabetes treatment guidelines and on the range of physiological responses to GLP-1 RAs. Most evidence is level I and II., Results: Effective therapy for T2D should be implemented early in the course of this progressive disease. The recently revised 2013 Canadian Diabetes Association (CDA) guidelines now identify the GLP-1 RAs among various injected and oral agents recommended for the management of T2D. The rationale for early use of GLP-1 RAs in T2D management is manifold: these agents offer effective management of hyperglycemia in early-stage T2D, minimal risk of hypoglycemia, weight loss, improvement in multiple non-glycemic cardiovascular risk factors, and potential enhancement of patient adherence to antihyperglycemic treatment. Available data from clinical trials support second-line use of GLP-1 RAs among patients who fail on metformin, as well as first-line use of these agents in a subset of T2D patients., Conclusions: The ability to achieve glycemic targets using GLP-1 RAs while simultaneously avoiding hypoglycemia and weight gain could provide substantial reassurance to physicians and patients who might otherwise resist the transition to injected therapies. Exenatide and liraglutide represent appropriate second-line choices for pharmacological treatment of T2D, as indicated in the 2013 CDA guidelines.

Unlabelled: Manual muscle testing (MMT), the trapezius muscle is an important part of the examination in patients with upper extremity dysfunction or pain., Purpose: The purpose of this study was to assess the reliability and validity of a new MMT that assesses the entire trapezius muscle instead of the usual method of separating it into three different parts. The new trapezius MMT is similar to the serratus anterior muscle test; however, the testing is performed in the frontal versus sagittal plane., Methods: A convenience sample of 11 subjects was recruited with no known shoulder pathology. Surface electromyography electrodes were placed on the upper, middle, and lower trapezius fibers according to a previously validated method and MMTs for the three different trapezius muscle test positions were normalized against the new trapezius test position., Results: The new trapezius MMT showed very high maximal voluntary isometric contraction (MVIC; 160.80%) for the upper trapezius muscle, high for the middle trapezius muscle (59.23%), and high for the lower trapezius muscle (47.54%) when normalized against the MVICs for each individual trapezius muscle tests., Conclusions: A new MMT that assesses the whole trapezius in its role as an upward scapular rotator was found to be reliable and valid.

Objective: Glycaemic control in patients with type 2 diabetes (T2DM) is often not achieved or not sustained using monotherapy such as metformin, necessitating the addition of other antihyperglycaemic agents. Linagliptin, a dipeptidyl peptidase-4 inhibitor, is licensed for 5 mg once-daily dosing. As metformin is administered twice daily, a fixed-dose combination of these compounds would require twice-daily administration of linagliptin. This study evaluated whether 2.5 mg twice-daily dosing of linagliptin has comparable efficacy and safety to 5 mg once-daily dosing when given in addition to metformin twice daily in patients with inadequate glycaemic control., Methods: A total of 491 T2DM patients with glycated haemoglobin (HbA1c) 7.0-10.0% were randomised (5:5:1) to double-blind treatment with linagliptin 2.5 mg twice daily, 5 mg once daily or placebo, respectively, in addition to continuing metformin twice daily (≥1500 mg/day or maximally tolerated dose). The primary endpoint was change from baseline in HbA1c after 12 weeks. ClinicalTrials.gov, NCT01012037., Results: Mean baseline HbA1c for all patients was 7.97%. After 12 weeks, linagliptin 2.5 mg twice daily and 5 mg once daily both significantly reduced HbA1c (placebo-adjusted changes from baseline -0.74% (95% CI -0.97, -0.52) and -0.80% (95% CI -1.02, -0.58), respectively, both p<0.0001). The treatment difference (twice daily-once daily) between the linagliptin regimens was 0.06 (95% CI -0.07, 0.19), the upper bound of which was less than the predefined noninferiority margin (0.35%). The overall incidence of adverse events with linagliptin 2.5 mg twice daily, 5 mg once daily and placebo was 43.0%, 34.8%, and 38.6% respectively. Hypoglycaemia was rare (3.1% with linagliptin 2.5 mg twice daily, 0.9% with 5 mg once daily, 2.3% with placebo) with no severe episodes. Study limitations include duration, patient population (mainly white) and absence of postprandial glucose data., Conclusions: Linagliptin 2.5 mg twice daily had non-inferior HbA1c-lowering effects after 12 weeks compared to 5 mg once daily, with comparable safety and tolerability, in T2DM patients inadequately controlled with metformin.

Background: Contrary to longstanding recommendations on type 2 diabetes (T2D) management, the de facto standard of care in Canada includes lag times of many years prior to introducing effective glycemic control. Even patients transitioned to insulin may continue to experience poor glycemic control, with attendant diabetic complications, suggesting poor adherence or inadequate dose titration., Objective: To identify barriers to timely and effective use of insulin in T2D., Methods: PubMed searches were conducted to find research articles on insulin initiation, adherence and intensification. Also, because recent data on the consequences of intensive glycemic control may be taken as justification for relaxing glycemic targets, a secondary search on this literature was conducted, including the UKPDS and ACCORD trials, plus post hoc and meta-analyses of these data. No formal evaluation of level of evidence was conducted while researching this narrative literature review., Findings: Timely, effective glycemic control remains an important clinical goal but is complicated by patient, physician and treatment factors. Patient barriers to accepting insulin initiation include fear of hypoglycemia, injections and weight gain, and reluctance to accommodate the inflexible timing of scheduled insulin doses. Adherence issues, including dose omission, are common and are associated with some of the same factors. Fear of hypoglycemia also underlies many physicians' reluctance to prescribe insulin. Caregivers' failure to provide training or answer questions about insulin's risks and benefits was also associated with low patient adherence. Poor communication may also be at fault when patients on insulin fail to titrate or intensify their treatment adequately. Conversely, glycemic control can be significantly improved by facilitating ongoing communication between patients and caregivers., Discussion: Although innovations in injectable therapy for T2D may help address the current pattern of poor glycemic control, improved communication between patients and caregivers is also a powerful approach and can be implemented with existing therapies.

Background: The majority of patients with type 2 diabetes mellitus (T2DM) are overweight or obese. Obesity is a significant risk factor for increased morbidity and mortality in people with T2DM, and increased weight has been shown to worsen glycemic control and increase the risk of diabetes progression., Methods: A search was conducted of the National Library of Medicine (PubMed) for articles published from 1990 to 2009 about the treatments of T2DM, relationship between T2DM and weight gain, obesity-related comorbidities of T2DM, and T2DM therapies associated with increased weight. Reference lists of retrieved articles were reviewed for additional publications., Findings: Results from large, prospective clinical trials have shown that weight reduction significantly improves glycemic control and blood pressure in T2DM patients and lowers the risk of progression of T2DM as well as CV disease and cancer. Treatment-related weight gain is a side effect of many oral antidiabetes agents and insulin. The thiazolidinediones (TZD), sulfonylureas, and glinides are associated with weight gain. Despite the weight gain, TZDs also redistribute fat from the central to peripheral compartments, which may lead to a beneficial effect on insulin resistance. Among insulin products, the basal insulin analog detemir is typically associated with a smaller weight increase than human insulin and insulin analog preparations, including glargine, biphasic, and prandial insulin regimens. Alpha-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors are weight neutral, whereas glucagon-like peptide1-R agonists and metformin are associated with weight loss., Discussion: An effective approach to management of the obese patient with diabetes is to communicate the significant benefits of a 1 kg reduction in body weight or prevention of weight gain on glycemic control and reduced morbidity and mortality., Limitation: This article is based on an extensive literature review rather than the prospective studies needed to define further the effect of weight gain on the management of T2DM., Conclusion: Weight management should be an integral part of a T2DM treatment strategy that includes selecting oral antidiabetes medications and insulin products that are weight beneficial.

The purpose of this study was to determine and compare the bioadhesive profiles of hydroxypropylcellulose (HPC) polymer matrices as a function of delta9-tetrahydrocannabinol (THC) content. In addition, the effect of processing temperature on the stability of THC and its extent of degradation to cannabinol (CBN) was investigated. A hot-melt cast molding method was used to prepare HPC polymer matrix systems incorporated with THC at 0, 4, 8, and 16 percent. Bioadhesive measurements including peak adhesive force, area under the curve, and elongation at adhesive failure were recorded utilizing the TA.XT2i Texture Analyzer. Data obtained from these tests at various contact time intervals suggested that the incorporation of THC led to an increase in the bioadhesive strength of the HPC polymer matrices. To determine the stability of THC and the resulting CBN content in the matrices, three different processing temperatures were utilized (120, 160, and 200 degrees C). Post-production High Performance Liquid Chromotography (HPLC) analysis revealed that the processed systems contained at least 94% of THC and the relative percent formation of CBN was 0.5% at 120 degrees C and 0.4% at 160 degrees C compared to 1.6% at 200 degrees C. These findings indicate that the cannabinoid may be a plausible candidate for incorporation into systems utilizing hot-melt extrusion techniques for the development of an effective mucoadhesive transmucosal matrix system for delivery of THC.