Day 2 :
Keynote Forum
Jahanshah Amin1
University of South Florida, USA
Keynote: A ketoxime analogue of ketamine with distinct molecular actions on GABAA and NMDA receptors demonstrates superior antidepressant activity
Time : 10:00-10:30
Biography:
Biography
J Amin laboratory has a primary interest in GABAA and NMDA receptor-channels. We have studied the structure/function relationship of subtypes of GABAA receptors to enhance our understanding of the molecular mechanism of action of sedative/hypnotic drugs. By co-expression of wild-type with anesthetic-sensitive subunits of GABAA receptors, we have determined the minimal number of subunits required for orthosteric- versus allosteric-dependent activation of GABAA receptor channels. The laboratory is also focused on drug discovery with particular interest in ketamine. In the last several years, we have synthesized a number of ketamine analogues and characterized their molecular actions on the NMDA and GABAA receptors. One oxime analogues of ketamine has shown great promise in terms of molecular signature on NMDA and GABAA receptors and in an animal model test for antidepressants.
Abstract:
Abstract
Dissociative anesthetic ketamine can rapidly alleviate symptoms of psychiatric depression with prolonged duration of action. Despite the promise, untoward psycho-mimetic manifestations of ketamine have curbed its clinical application. In a search for a ketamine substitute with higher antidepressant activity and lower side effects, we synthesized several novel ketamine analogs and tested them in vitro and in vivo. A ketoxime analog, termed oximeamine, shows the following pharmacological properties compared to ketamine: First, oximeamine potentiates the activity of GABAA receptors, specifically that of cerebellar a6b2d subtype, with higher potency. Second, oximeamine blocks NMDA receptors with similar potency and efficacy yet associates with (on-rate) and dissociates from (off-rate) the NMDA receptors at a significantly faster rate. The relatively faster on- and off-rate of oximeamine appears most prominent at the NMDA NR1/NR2B receptor subtype. Third, neither oximeamine nor ketamine display any significant action on AMPA receptor subtypes. Finally, in forced swim test, oximeamine demonstrates a significantly greater antidepressant activity than ketamine. In conclusion, the differential yet lower intensity block of the NMDA receptor subtypes and the higher activity on the GABAA receptors, together with the more robust antidepressant activity herald the superiority of oximeamine over ketamine with higher antidepressant efficacy and lower side effects.
Keynote Forum
Emelie Land,
The University of Sydney, Australia
Keynote: The effects of inhaled rapamycin solid lipid particle size on transport across lung epithelial cells
Time : 11:40- 12:00
Biography:
Emelie Landh completed her Bachelor in Medical Sciences, majoring in Pharmacology at the University of Sydney in 2013. She went on to complete a Graduate Diploma in pharmacology with the Respiratory Technology Group at the Woolcock Institute of Medical research at the University of Sydney in 2014. She is currently at the end of the second year of her PhD under the supervision of Dr. Hui Xin Ong with the Respiratory Technology Group. Her PhD project involves developing an inhaled combination treatment using Solid-Lipid Nanoparticles for treating Lymphangioleiomyomatosis (LAM).
Abstract:
Background: Lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by the uncontrolled growth of smooth like muscle cells (LAM cells) in the lungs that can spread to other body parts via the lymphatic system Current treatment for LAM is oral Rapamycin, which is limited by its low bioavailability (~15%) and side effects [1, 2]. It’s been shown that particles of approximately <1000nm with a negative surface charge are able to enter the lymphatic system [3].
Aim: The current study aimed to determine the optimum size of Rapamycin solid lipid nanoparticles (SLN) that will facilitate drug entry into the lymphatic system through the inhaled route in order to increase lung bioavailability, reduce systemic side effects and potentially have increased efficacy.
Methods: Three different sized (1-3) of Rapamycin-SLN: 200, 500 and 800nm, were produced by dissolving Rapamycin and glyceryl behenate in methanol and dichloromethane. The organic solvents were evaporated prior to mixing with hot Tween80 (1.5 %w/v) solution. The solution was either homogenized (1700rpm) or passed through a membrane with specified pore sizes mini-extruder before being freeze-dried overnight. Size and charge were determined using a Zetasizer. Transepithelial drug transport of the formulations was evaluated in-vitro using a Calu-3 air-liquid interface bronchial epithelial cell model.
Results: All Rapamycin-SLNs formulations had negative surface charge (table 1) and average particle sizes: 237 ± 1.8nm, 583 ± 1.3nm and 790 ± 2.3nm, respectively. The formulations showed varying encapsulation efficiencies ranging from 65.8 to 97.32%. The transport studies showed that 83 ± 4.2% and 68 ± 2.5 % of SLN200 and SLN500 formulations were transported, respectively, across the epithelium after 4hrs compared to 22 ± 2.15% of the SLN800 formulation.
Conclusion & Discussion: The current study showed that Rapamycin-SLN with negative surface charge and size of approximately 200nm is able to cross the lung epithelium faster than larger particles. Future studies will be expanded to evaluate the entry of these SLN particles into the lymphatic vessels in order to target the extra pulmonary LAM cells.