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.
- Clinical Pharmacology and Receptor Theory | Cardio Vascular Pharmacology | Pharmacokinetic and Pharmacodynamic | Drug Screening and Discovery | Topical Medicine and Infectious Diseases | Advances in Pharmacological Research | Biochemical Pharmacology
Location: Wien 1
Session Introduction
Shirley Taniguchi
University of São Paulo, Brazil
Title: Pharmacological advice for clinical practice
Biography:
Shirley earned her M.S. in Pharmacology at the University of São Paulo in 1993. From 1994-1996, she worked as a researcher for the Japanese Ministry of Education in the Department of Pharmacology at the University of Kitasato in Tokyo. She has been an instructor in Pharmacology since 1997 and a researcher at the Medical School at the University of São Paulo (Faculdade de Medicina /Universidade de São Paulo). Shirley has been teaching undergraduate Pharmacology classes within Healthcare courses under the theme ‘Education to Prevent the Misuse of Drugs’.
Abstract:
Statement of the Problem: Treating drugs symptomatically, reversing drug side effects without considering the receptors involved, and combining drugs without following specific criteria, may result in inefficient attempts to resolve clinical events.
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Methodology & Theoretical Orientation: This was a retrospective survey of patients hospitalized in a large general hospital located in the city of São Paulo (Brazil) and individual patients treated at several hospitals in the region.
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blockers such as phenytoin without accompanying cardiac function may
Conclusion & Significance: An individualized medical prescription should contain drugs selected based on their mechanism of action, half life, albumin binding rate, and predicted side effects. This would help reduce risks and increase the chances of therapeutic success.
Emelie Land
The University of Sydney, Australia
Title: The effects of inhaled rapamycin solid lipid particle size on transport across lung epithelial cells
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.
Femina Dawer
Grant Govt. Medical College and Sir J.J Hospital, India
Title: A prospective cross-sectional study to evaluate the economic burden of patients diagnosed with depression in a tertiary care hospital
Biography:
Femina Dawer a postgraduate resident in department of pharmacology, Grant Govt Medical College and Sir J.J Group of Hospitals, Mumbai, India is dedicated towards clinical research both in experimental and clinical aspects. Considering different modalities while doing a research helps in giving a wisdom to explore impact of various factors in treating a patient. With the intent of helping the population this study was conducted to explore the financial aspect and calculate the burden of the disease comparing it with international available data. Thus, helping the patients by spreading a word.
Abstract:
Abstract
Statement of the Problem: Depression is a common psychiatric disorder having important medical, social and psychological consequences. It is a disorder associated with enormous burden in terms of reduced quality of life as well as direct and indirect costs. It is a well -known fact that the majority of the economic burden of depression results from non- depression expenditures. Hence, the study was undertaken to evaluate economic burden of depression. The purpose of this study is to evaluate the cost off depression in terms of direct and indirect costs.
Methodology & Theoretical Orientation: 150 patients diagnosed with depression attending psychiatry OPD at Sir J.J. Group of Hospitals, Mumbai, fulfilling the inclusion criteria were explained about the study. Written informed consent were taken. Direct and Indirect costs were recorded in Structured Case Record Forms by interviewing the patients. Cost driving factors were identified.
Findings: Total annual direct cost was 6,378.16 INR while annual Indirect Cost was INR 16,860. Annual cost of Depression was 1NR 23,238.16/331.97 USD per patient. Total cost was 16.30% of per capita GDP 2018 among Depression patients in India. The annual economic burden of depression in India is 1.2% of GNP of India.
Conclusion & Significance: The indirect cost was almost thrice the direct costs. Hospitalisation cost and loss of working days due to depression was contributed the most to the direct costs and indirect costs respectively. Economic burden of Depression is found out to be 16.30% of per capita GDP in year 2018-2019.
Recommendation: Multi-centric studies to evaluate pharmaco-economic burden across the country and analyse the burden of the disease. Thus, shifting the approach to prevention rather treatment reducing the economic burden of the illness.
Sherri A Smith,
Relay Therapeutics, USA
Title: Pharmacokinetic and pharmacodynamic considerations for drugs binding to alpha-1-acid glycoprotein
Biography:
Sherri Smith is experienced in drug metabolism and pharmacokinetics (DMPK) of small molecules from discovery through clinical development in the pharmaceutical industry. Recent publication efforts have focused on explaining discrepancies in plasma protein binding values due to interference of plasticizers commonly used in blood collection bags, to highlight species, ontogeny, and disease state differences in expression of α-1-acid glycoprotein (AAG) and to provide examples where human PK of drugs have been impacted by preferential binding to AAG. The overall aim is to bring attention to the relevance of accurate measurement of fraction unbound for the prediction human PK and pharmacodynamics
Abstract:
Abstract
According to the free drug hypothesis only the unbound drug is available to act at physiological sites of action. Albumin, the most abundant plasma protein (~50 mg/mL), and alpha-1-acid glycoprotein (AAG, ~1 mg/mL) are both involved with drug binding and distribution. While albumin levels are similar across species, marked species, age, and disease state differences in AAG expression, homology and drug binding affinity have been reported. Drug binding to plasma proteins can help aid and improve the translation of pharmacokinetic/pharmacodynamic (PK/PD), safety margin predictions, and relationships from preclinical species to human as well as adults to neonates (Smith and Waters, 2019). The impact of AAG binding on PK has been reported for multiple drug/candidate molecules including pinometostat (Smith et al., 2016), vismodegib (Gianetti et al., 2011), imatinib (Widmer et al., 2006), and UCN-01(Fuse et al., 1998). Obtaining accurate fraction unbound (fu) values, especially for highly bound drugs, is critical to PK and safety predictions (Di et al., 2017). The role of plasticizers used in blood collection bags has recently been reported to contribute to inaccurate overestimation of fu for drugs that preferentially bind to AAG (Butler et al., 2015, Ingram et al., 2019). Experimental considerations as well as recommendations for understanding the potential impact of AAG on PK through drug discovery and early development will be reviewed.
Jun Li
The First Affiliated Hospital of Xinjiang Medical University, China
Title: Screening of kinase inhibitor library revealing lead compounds for treatment of cystic echinococcosis
Biography:
Biography
Jun Li is a professor of Xinjiang Medical University and a senior research fellow of State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China. He received her B. Sc from Xinjiang Medical University. In 2004, she obtained her PhD at the University of Queensland working on developing diagnosis tool for detecting cystic echinococcosis. She then spent 3 years working on PanBio for developing diagnosis kit for infectious diseases. From 2008-2013, she worked on molecular biology of Echinococcus as a senior research officer in Molecular Parasitology Laboratory, Infectious Diseases Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. She has published more than 30 papers/articles in the international journals in her research career.
Abstract:
Abstract
Aims: The metacestode stage of two Echinococcus species, E. granulosus sensu lato and E. multilocularis cause cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. These diseases remarkably impact on the health of population. Although surgical removal of cyst is the cure treatment, about 90% of patients with echinococcal infection are treated by albendazole. However, as the drug is not parasiticidal, the patients with AE or CE have to take the drug for a long time, even for the whole life. The treatment of these diseases urgently need an effective drug.
Material and Methods: In the study, by using in vitro cultivation of E. granulosus protoscoleces and micro-cysts, we primarily screened 378 kinase inhibitors at 5 μM, which revealed 51 compounds showing killing efficacy. Further using 1 μM, 7 compounds were keeping killing efficacy in vitro. Dose-response assays revealed that 2 of the compounds, S2243 and S2895, had LC50 value below 2.5 μM. We then incubated cysts of E. granulosus collected from infected mice with S2895 and S2243 at 20 μg/L, which resulted in 60% of the cysts dead in 24 h. For in vivo efficacy trial, BALB/c mice were transferred with 50 micro-cysts and after 3 month postinfection, each of the mice was orally given these two drugs a dose of 15 mg/kg of body weight for one month. An increase in cyst mortality rate was observed compared to that of those collected from control mice.
Conclusions: Our study identifies that the two kinase inhibitors showed parasiticidal in both in vitro and in vivo, indicating these two inhibitor may be the lead-compounds for drug development against echinococcosis.
Biography:
Biography
Hesham R. El-Seedi working in the area of isolation, structure elucidation and synthesis of biologically active natural products from medicinal plants, marine and bee products. Recently, we started also a project on nanoparticles synthesis. Prof. Hesham is a former fellow of the Japanese Society of Promotion of Science (JSPS), Faculty of Science and Technology, Keio University, Japan, under direction of Prof. Shosuke Yamamura and Prof. S. Nishiyama. Throughout his carrier, he worked in pioneer internationally recognized laboratories including Geneva University, Switzerland, in collaboration with Prof. Kurt Hostettmann, Kunglia Tekniska Högskola (KTH), Stockholm, Sweden (since 2007), Faculty of Pharmacy, Uppsala Biomedical Center, Uppsala University,
Abstract:
Abstract
Statement of the Problem: According to the World Health Organization, two billion people will be aged 60 years or older by 2050. Aging is a major risk factor for a number of neurodegenerative disorders. These age-related disorders currently represent one of the most important and challenging health problems have impact on the economic and social. Therefore, much attention has been directed towards the design and development of neuroprotective agents derived from natural sources.
The honeybees (Apis mellifera L.) have several products, including honey, propolis, royal jelly, bee venom, and bee pollen. Bee products meet the criteria of being natural products that have long-recognized medicinal properties. Historically, bee products nutritional and medicinal values have been considered for thousands of years by Ancient Egyptian, Persians, Romans and Chinese in supplementary nutrition and alternative diets. Bee products are often sold as nutritional supplements and/or health products, and with potential anticancer, antimicrobial activities, antioxidant, anti-nociceptive, and anti-inflammatory. Bee products polyphenols have neuroprotective actions via quench biological reactive oxygen species that cause neurotoxicity and aging as well as the pathological deposition of misfolded proteins, such as amyloid beta.