Canagliflozin,a sodium glucose co-transporter 2 inhibitor,reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial

Objective

Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin.

Materials/Methods

Patients (N = 37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods. Patients received Treatments (A) placebo/placebo, (B) canagliflozin 300 mg/placebo, (C) canagliflozin 300 mg/canagliflozin 300 mg, or (D) canagliflozin 300 mg/canagliflozin 150 mg on Day 2/Day 3 in one of four treatment sequences (similar urinary glucose excretion [UGE] expected for Treatments B–D). A mixed-meal tolerance test (MMTT) was given 20 minutes post-dose on Day 3 of each period.

Results

A single dose of canagliflozin 300 mg reduced both fasting and postprandial PG compared with placebo, with generally similar effects on fasting PG and UGE observed for Treatments B–D. An additional dose of canagliflozin 300 mg (Treatment C), but not 150 mg (Treatment D), prior to the MMTT on Day 3 provided greater postprandial PG reduction versus placebo (difference in incremental glucose AUC_0–2h, − 7.5% for B vs A; − 18.5% for C vs A; − 12.0% [P = 0.012] for C vs B), leading to modestly greater reductions in total glucose AUC_0–2h with Treatment C versus Treatment B or D. Canagliflozin was generally well tolerated.

Conclusions

These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.     

Mental health conditions and the risk of chronic opioid therapy among patients with rheumatoid arthritis: a retrospective veterans affairs cohort study

Clinical Rheumatology - Patients with rheumatoid arthritis (RA) often receive opioid analgesics for pain management. We examined the association between mental health conditions and the risk of...     

User-Identified Gel Characteristics: A Qualitative Exploration of Perceived Product Efficacy of Topical Vaginal Microbicides

Research has demonstrated that certain vaginal gel products—microbicides containing antiretroviral drugs—may reduce HIV infection risk among women. But for vaginal gels to avert HIV and other sexually transmitted infections (STIs), at-risk women must be willing to use them as directed. These products must therefore be “acceptable” to women and an important component of acceptability is users’ perception that the product will work to prevent infection. We sought to understand how women’s perceptions of vaginal gel properties may shape their understanding of product efficacy for HIV and STI prevention. Sixteen women completed two in-depth qualitative interviews (k = 32) to identify the range and types of sensory perceptions they experienced when using two vaginal gels. We identified emergent themes and linkages between users’ sensory perceptions and their beliefs about product efficacy. Users’ predictions about product efficacy for preventing infection corresponded to measurable physical properties, including gel volume, location in the vagina, coating behavior, sensation of the gel in the vagina, leakage, and gel changes during coital acts. Although the women described similar sensory experiences (e.g., gel leaked from the vagina), they interpreted these experiences to have varying implications for product efficacy (e.g., leakage was predicted to increase or decrease efficacy). To improve microbicide acceptability, gel developers should investigate and deliberately incorporate properties that influence users’ perceptions of efficacy. When a microbicide is approved for use, providers should educate users to anticipate and understand their sensory experiences; improving users’ experience can maximize adherence and product effectiveness.     

Protective immunity to H7N9 influenza viruses elicited by synthetic DNA vaccine

Despite an intensive vaccine program influenza infections remain a major health problem, due to the viruses’ ability to change its envelope glycoprotein hemagglutinin (HA), through shift and drift, permitting influenza to escape protection induced by current vaccines or natural immunity. Recently a new variant, H7N9, has emerged in China causing global concern. First, there have been more than 130 laboratory-confirmed human infections resulting in an alarmingly high death rate (32.3%). Second, genetic changes found in H7N9 appear to be associated with enabling avian influenza viruses to spread more effectively in mammals, thus transmitting infections on a larger scale. Currently, no vaccines or drugs are effectively able to target H7N9. Here, we report the rapid development of a synthetic consensus DNA vaccine (pH7HA) to elicit potent protective immunity against the H7N9 viruses. We show that pH7HA induces broad antibody responses that bind to divergent HAs from multiple new members of the H7N9 family. These antibody responses result in high-titer HAI against H7N9. Simultaneously, this vaccine induces potent polyfunctional effector CD4 and CD8T cell memory responses. Animals vaccinated with pH7HA are completely protected from H7N9 virus infection and any morbidity associated with lethal challenge. This study establishes that this synthetic consensus DNA vaccine represents a new tool for targeting emerging infection, and more importantly, its design, testing and development into seed stock for vaccine production in a few days in the pandemic setting has significant implications for the rapid deployment of vaccines protecting against emerging infectious diseases.     

Tyrosine enhances behavioral and mesocorticolimbic dopaminergic responses to aversive conditioning

Tyrosine is a precursor in the biosynthesis of catecholamines and, when administered systemically, has been shown to enhance the in vivo rate of tyrosine hydroxylation in the medial prefrontal cortex. Additionally, exogenous tyrosine has been demonstrated to enhance the pharmacologically-induced increase in dopamine metabolism seen following administration of haloperidol or the anxiogenic B-carboline, FG-7142. In this report, we examine the effect of a physiologically relevant dose of tyrosine (25 mg/kg) on biochemical and behavioral consequences of aversive conditioning. Rats were conditioned to fear a tone by pairing it with footshock, so that when challenged with the tone alone, rats responded with immobility, defecation, and elevated dopamine metabolism in the medial prefrontal cortex and nucleus accumbens. When tyrosine was administered on the test day (tones alone), the rats displayed an even greater elevation of dopamine metabolism in the nucleus accumbens and prolonged immobility to the tone, compared to the saline/conditioned controls. Tyrosine did not alter mobility or dopamine utilization in the nucleus accumbens in nonconditioned controls. However, dopamine metabolism in the medial prefrontal cortex of nonconditioned rats treated with tyrosine was increased to levels similar to those in the conditioned groups. This may be accounted for by handling and by exposure to an unfamiliar environment necessary for nonconditioned controls. We conclude that exogenous tyrosine is able to 1) elevate stress-induced dopamine metabolism in the nucleus accumbens, 2) alter dopamine utilization in the medial prefrontal cortex of handled, nonconditioned controls, and 3) enhance fear-induced immobilization. These data suggest a role for dietary tyrosine in biochemical and behavioral responses to aversive stimuli. © 1996 Wiley-Liss, Inc.