Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice

Exendin-4 is now considered as a promising drug for the treatment of cerebral ischemia. To determine the neuroprotective effects of intranasal exendin-4, C57BL/6J mice were intranasally administered with exendin-4 daily for 7 days before middle cerebral artery occlusion (MCAO) surgery. Intranasally administered exendin-4 produced higher brain concentrations and lower plasma concentrations when compared to identical doses administered interperitoneally. Neurological deficits and volume of infarcted lesions were analyzed 24 h after ischemia. Intranasal administration of exendin-4 exhibited significant neuroprotection in C57BL/6 mice subjected to MCAO by reducing neurological deficit scores and infarct volume. The neuroprotective effects of exendin-4 were blocked by the knockdown of GLP-1R with shRNA. However, exendin-4 has no impact on glucose and insulin levels which indicated that the neuroprotective effect was mediated by the activation of GLP-1R in the brain. Exendin-4 intranasal administration restored the balance between pro- and anti-apoptotic proteins and decreased the expression of Caspase-3. The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway. These findings provided evidence that exendin-4 intranasal administration exerted a neuroprotective effect mediated by an anti-apoptotic mechanism in MCAO mice and protected neurons against ischemic injury through the GLP-1R pathway in the brain. Intranasal delivery of exendin-4 might be a promising strategy for the treatment of ischemic stroke.     

Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement

This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity.     

Efficacy and safety of topical difluprednate in persistent diabetic macular edema

To evaluate the efficacy and safety of treatment of diabetic macular edema (persistent type) with difluprednate ophthalmic emulsion 0.05 % (off label use). 20 patients with persistent diabetic macular edema were enrolled. In all subjects, more than 4 months had passed since prior treatment. All patients were treated with difluprednate ophthalmic emulsion 0.05 % three times daily for 3 months. At the end of 3 months the visual acuity had increased by two lines to a mean value of 0.61 ± 0.18 on logMAR from a baseline value of 0.885 ± 0.20 and the central retinal thickness had decreased from 423 ± 72.04 microns to 345 ± 68.7 microns. Hence, there was a total of 18.4 % decrease in retinal thickness on difluprednate. Major side effects included raised intraocular pressure in 20 %. Difluprednate is a potent and strong steroid which causes a rapid decrease in persistent diabetic macular edema. However, the potential side effect of raised intraocular pressure limits its use as an adjuvant therapy in non-steroid responders.     

Building Tobacco Cessation Capacity in Homeless Shelters: A Pilot Study

Tobacco use is common among homeless adults, yet few homeless shelters offer tobacco dependence treatment. Using a pre-intervention and post-intervention study design, we pilot tested the feasibility of a capacity building intervention that consisted of a 3.5-h training for shelter staff to provide cessation counseling. Staff (n = 12) and homeless clients (n = 46) completed questionnaires at pre-intervention, post-intervention (6 weeks), and at 12-weeks follow-up. Staff completed a questionnaire on tobacco-related knowledge, attitudes toward and practices around treating tobacco dependence, and self-efficacy in providing cessation counseling (score range 1–5). Clients completed a questionnaire on tobacco-related knowledge, attitudes toward tobacco dependence, and receipt of tobacco-related services from the program (score range 1–5). We used repeated measures linear regression analysis to examine change in scores over time. From pre-intervention to post-intervention, staff knowledge (β coefficient 0.4, 95 % CI 0.1–0.8) and efficacy (β coefficient 0.4, 95 % CI 0.2–0.7) in treating tobacco dependence increased. Client receipt of tobacco-related program services increased significantly from post-intervention to follow-up (β coefficient 0.3, 95 % CI 0.1–0.5). A brief capacity building intervention has the potential to increase tobacco-related interventions among clients in homeless shelters.     

Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing

Continuous processing in pharmaceutical manufacturing is a relatively new approach that has generated significant attention. While it has been used for decades in other industries, showing significant advantages, the pharmaceutical industry has been slow in its adoption of continuous processing, primarily due to regulatory uncertainty. This paper aims to help address these concerns by introducing methods for batch definition, raw material traceability, and sensor frequency determination. All of the methods are based on established engineering and mathematical principles, especially the residence time distribution (RTD). This paper introduces a risk-based approach to address content uniformity challenges of continuous manufacturing. All of the detailed methods are discussed using a direct compaction manufacturing line as the main example, but the techniques can easily be applied to other continuous manufacturing methods such as wet and dry granulation, hot melt extrusion, capsule filling, etc.     

The challenges of outcome research

Cognitive pharmacy trials seek to identify interventions that benefit patients. The potential benefits of an intervention are primarily evaluated by outcome measures. The question then is: What is the optimal outcome measure? Unfortunately, the question remains unsolved. Several factors must be taken into consideration when conducting outcome research—particularly within cognitive pharmacy trials. The interventions are often complex and non-specific, and seek to improve symptom control, optimise the use of medications and reduce medication-related risks. “Hard” endpoints, such as mortality and hospital admissions, may not be the optimal outcome measures, since cognitive pharmacy interventions are unlikely to result in changes in these measures. Instead, adverse drug events or “soft” endpoints, such as quality of life, drug-related problems and patient satisfaction may be appropriate choices of outcome measures. Finally, it is not only outcome measures that may pose a challenge when conducting outcome research; other essential components include study design, type of intervention, the patient population, etc.