students in the College of Pharmacy have enthusiastically participated in national and ..... Research based projects pose very challenging technical issues,.
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
Editors’ Note
ISSUE IX, FALL 2014
Table of Contents SCIENCE NEWS FACULTY SPOTLIGHT RESEARCHER OF THE ISSUE ALUMNI CORNER
“Scientists are not people who give the right answers; they are the ones who ask the right questions.” -Claude Levi-Strauss
MINI REVIEWS BOOK REVIEW
Mercer University has always demonstrated that hard work TECH CORNER and dedication in research can lead to great success. Graduate students in the College of Pharmacy have enthusiastically FDA UPDATES participated in national and regional conferences which won them a MARK YOUR CALENDAR chance to host GRASP 2015. Students in the Department of Pharmaceutical Sciences have received numerous honors in the form DEPARTMENT NEWS of fellowships and travelships for their excellent ideas and progress in research. This year, 20 students will be en route to great careers CHILLIN’ WITH FACULTY following their proposals and/or defenses. Contributing to the scientific community on a larger scale has earned students various publications that highlight their expertise in their respective fields of research. This ninth issue of Pharmabeat will showcase these numerous achievements along with multiple noteworthy individuals who have created great created great careers for themselves. Dr. Valerie Quarmby, Staff Scientist and Director in the Department of Bioanalytical Sciences at Genentech will be featured as the ‘Researcher of the Issue’. This 2013- 2014 issue gives us a chance to peep into the cliques of the faculty where we can learn some interesting facts about our professors with the spotlight on Dr. Tan and her experiences as a graduate student. We would like to thank all our contributors for their participation in this issue and to Dr. Murnane & the freshly picked graduate students, Welcome to Mercer! Sincerely, Sucheta D’Sa, Kim Braz Gomes & Mahima Manian 1
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
A Novel Promising Approach for Skin Cancer Treatment
A Hopeful Drug Therapy for Brain Cancer Treatment
A study in a genetically engineered mouse model was conducted at University of California, Los Angeles to investigate the effect of Ultraviolet (UV) exposure on skin cancer (melanoma) metastasis. They found that besides traveling in the bloodstream, melanoma cells can move along the outside of blood vessels in a process termed extravascular migratory metastasis (EVMM) to accumulate and form new tumors in other parts of the body. The mice with melanoma that were exposed to UV light had greater amount of EVMM and lung metastases than those not exposed to it. Based on this novel finding, researchers can now look for a drug target that interferes with this EVMM process to treat skin cancer.
Professors at the Karolinska Institute in Sweden have recently discovered a substance called Vacquinol-1 that removes the glioblastoma cells, the most aggressive type of brain tumor. Research conducted on a mouse model illustrated that mice transplanted human glioblastoma cells that ingested Vacquinol-1 for 5 days were still alive after 80 days while those that did not recieve Vacquinol-1 had the average survival of about 30 days. This substance attacked glioblastoma cells in an entirely new way and may also work for other cancer diseases. The research is now in basic preclinical development before the phase 1 trial.
Surprising New Way to Kill Cancer Cells Dr. Marcus Peter at Northwestern University, Feinberg School of Medicine has recently discovered a promising new way to kill cancer cells by eliminating either the FAS receptor (CD95) or its binding component (CD95 ligand). This discovery was opposite to the previous finding that CD95 was a tumor suppressor. In fact, when CD95 receptor or its ligand were removed from the tumor cells in animal models, the cells increased their size, produced harmful reactive oxygen species, damaged their DNA and finally died. CD95 and CD95 ligand are essential for survival of cancer cells which distinguishes them from normal cells. Reference: www.sciencenews.org Page 2
MICRONEEDLES- A Promising Approach to Vaccination The combination of vaccines and microneedles is most likely a major step forward in vaccination. Microneedles protect drugs from environmental factors as well as achieve controlled release of drugs to the desired site and time. These days the microneedle influenza vaccine is readily available in the pharmaceutical market. Instead of being in liquid form, the vaccine is developed and formulated into tiny particles before they are coated on microneedles. The effectiveness of this method is observed in a study of Sang-Moo Kang at Georgia State University “This method can induce higher levels of IgG2a antibodies as well as rapid recall immune responses following lethal challenge infection”. “Our previous study showed that microneedle vaccination induced higher levels of antibody-secreting cells in spleen and bone marrow”.
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
Dr. Chalet Tan received her B.S degree in Pharmacy from Shanghai Medical University (now known as Fudan University), China. Coming to the US and pursuing a career in research was her childhood dream. However, it wasn’t a smooth journey. After she graduated with a B.S degree, government restrictions made it compulsory for her to fulfill a 5-year work commitment. She started her career as a Patent Agent and worked on projects with large pharmaceutical companies like Du Pont and Bristol Myers Squibb. Two years into her job, the Chinese government changed the rules and she was able to come to the US to pursue her PhD. She finished her PhD at University of Georgia in the field of Classical Pharmacokinetics and successfully defended her dissertation titled “Intracellular Transport and Pharmacokinetics of Nucleoside and Nucleotide Analogs”. As a graduate student, she felt limited by the applied nature of pharmacokinetics research and decided to pursue basic research after PhD. Aspiring to become an independent investigator, she decided to undergo post-doctoral training and took up a position in the field of cancer biology at National Institute of Health (NIH) with the famous Thomas Waldmann. It was during her stint at NIH that she developed a passion for and learned the ropes of cancer research. Later, she worked as a research track instructor in a Molecular NeuroOncology lab at Winship Cancer Institute in Emory University. There, her work on hypoxia-inducing factor pathway really expanded her knowledge in the field of cancer biology. She says, “I realized that as a pharmacokineticist and a cancer biologist, I can really design and study drug delivery in cancer”. When asked about her decision to work in academia, she replied, “Academia was always my calling; I feel I need to grow and expand”. A self-described non-conformist, she says, “in industry we have to go to work at eight and leave at five, I don’t like that schedule”. Dr. Tan’s research focus lies in Micellar Nanocarrier based drug delivery in cancer. She fondly recollected her first grant, “even though it was a small grant, it really got us started, helped me recruit my first graduate student and laid foundation for my preliminary work”. A year later she received half a million dollar NIH grant, she adds “I was so happy and I became really ambitious. We decided that we should synthesize our own polymer”.
Dr. Tan is currently guiding three graduate students and working with one post-doctoral fellow in her lab. When asked about the advice she wants to give students, she says “do not try to take any shortcuts, it might be convenient to get quick rewards but in the long run, working hard always pays off. Always keep making deposits of skill and knowledge”. Dr. Tan also stressed on the inter-connected nature of science. Her graduate student experience in working with nucleoside analogs became very useful when she moved into cancer research and found many anti-cancer agents to be nucleoside analogs. She concluded saying, “Just work hard, do not argue whether it will be useful or not, because it will be”. 3
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
Researcher of the Issue
Dr. Valerie Quarmby
Dr. Quarmby is a Staff Scientist and Director in the Department of BioAnalytical Sciences at Genentech. At Genentech, Dr. Quarmby has developed bioanalytical methods & strategies to enable IND, BLA and related filings for: Nutropin, Xolair, Raptiva, Rituxan, Avastin, Lucentis, Perjeta and Kadcyla. She currently chairs the internal group that establishes bioanalytical strategies for all protein therapeutics in the gRED drug development pipeline. She is also the current Chair of the AAPS Therapeutic Protein Immunogenicity Focus Group and a member of the USP Expert Panel on Immunogenicity Assays. Dr. Quarmby holds a Ph.D. in Hormone Physiology from the Imperial Cancer Research Fund and the University of London, England. She was an NIH Visiting Postdoctoral Fellow, and then joined the Laboratories for Reproductive Biology and the Department of Pediatric Endocrinology at the University of North Carolina in Chapel Hill. Prior to joining Genentech, she worked in the field of clinical diagnostics at Bio-Rad Laboratories and at Endocrine Sciences/Esoterix.
1. What is the most rewarding aspect of your job? The most rewarding aspect of my job is developing medicines that translate to the clinic for treatment/management of life threatening diseases. The mission of Genentech is to develop medicines that address unmet medical needs of patients. I find it especially satisfying to have successfully contributed in developing safe and effective medicines to improve the quality of life of cancer patients. 2. What are the current challenges faced by the industry with respect to protein therapeutics? A significant challenge to developing protein therapeutics is the escalating cost of development of these products, which have very long cycle times. It can take 10 years and more than a billion dollars to take an idea from the research lab through the preclinical phase, clinical trials and to final registration. Therefore, substantial financial resources are needed to successfully develop a drug.
How can a fresh graduate launch him/herself into a career in the bio/pharma industry? What are the challenges and opportunities? Students who are about to graduate should be open to a broad range of opportunities. Careers and industries change rapidly, especially the sciences. It is not reasonable for a student to sit down and chalk out their career plan for the next 5-10 years as their personal circumstances may change, the industry may change, the discipline that they were trained in may change and their interests may change with time. The important thing is to follow something that you are passionate about and interested in and to not be too constrained when thinking about your career path.
3. As a scientist, please share with us the attributes that helped you keep up to the ever-changing field of pharmaceutical biotechnology. One fascinating aspect of biotech is that it is everchanging, which means that you are always on a learning curve, constantly building on experience and continuing to gather new information about your field. So, the willingness to continue to learn and be open to adopting new approaches and ideas is critical. Since drug development is a highly complex environment, the more you understand about your subject area and the areas of your collaborators, the more you can contribute.
5. What skill-sets according to you would help graduate students succeed in the industry? Many people here at Genentech have backgrounds in life sciences, chemistry, engineering, biophysics or biostatistics. Apart from having sound technical skills, having good soft skills is very important. We always look for candidates who are proactive, passionate about their work and who are willing to learn and contribute in a cross-functional project team setting.
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4.
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
ALUMNI CORNER 2. Please describe your experience postgraduation with regards to internships, jobs etc.? I did not have to struggle a lot to secure an internship; a sincere preparation was good enough to clear multiple rounds of interviews. However, it took me a while to get a job as the market was in a very bad shape at that time. Getting an interview opportunity was nearly impossible. I used several strategies to network and find a 3. Describe your journey from being a job, of which LinkedIn and conference graduate student at Mercer to your contacts were the most resourceful. current position. 4. What advice would you give It was a long journey of 5 years at graduate students who are still Mercer which included 6 months of th studying/looking for job internship at MedImmune in my 4 opportunities? year. I received my initial I would highly recommend going scientific training from Dr. for an internship soon after Zhang and then was trained course work or before delving into for industrial research through my the core of your research project internship. After my graduation, I (e.g. end of 2nd year). Many qualities accepted an offer as a scientist at KBI R.K Maroju useful to becoming a good scientist Biopharma Inc., in Durham, NC. I can be acquired, such as right have now moved to CMC thought process, strategies or Management in biologics at Teva approaches for accomplishing a Biopharmaceuticals, Rockville MD. given task, diplomacy & 5. Tell us about some of the most professionalism. memorable and challenging 6. Describe some of the challenges you face in everyday situations at situations you faced at Mercer. your workplace and the way you deal with them? The initial groundwork for my PhD I basically do two types of projects - platform and research based. research represents my most Platform projects require executing approved protocols. It is very memorable as well as challenging important that we execute every protocol or a test method strictly time at Mercer. Some other according to approved documents without any assumptions. For memorable moments include our example, even if we find that a lyophilization cycle set up to AAPS student chapter activities manufacture a batch of $100K worth is running out of control in where I introduced several changes middle of the cycle, we should not adjust the cycle parameters to to promote interest and elevate save the batch. Instead, we need to make sure that we have set up chapter status, such as rotating the cycle according to the procedure described in its protocol. journal club responsibilities, raising Research based projects pose very challenging technical issues, memberships through community which sometimes may result in losing a project. Technical issues programs and building relations during analytical method developments are the most common with the COS. which often require experience rather than knowledge.
1. Please give an overview of your academic background prior to Mercer? How did you decide to join Mercer? I received my Bachelors in Pharmacy from University College of Pharmaceutical Sciences at Kakatiya University, India. Based on the advice from my senior, Dr. Chandrasekhar Kolli, who was a post-doc in Dr. Banga's lab, I applied to Mercer to pursue graduate studies, and got the opportunity to work in Dr. Hailing Zhang's lab.
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
Organophosphate Poisoning and its Detection Organophosphorus (OP) compounds are generally used as warfare agents, insecticides, pesticides and as anti-wear agents.1 OP compounds can be amides, ester and thiols of various phosphoric, phosphonic and phosphinic acids2. OP compounds are widely used as pest control agents in agriculture with the most common OP pesticides being malathion and parathion. Tricresyl phosphate serves as an antiwear agent and can be found in jet engine lubricants. Soman and sarin are two OP nerve agents which comprise a class of chemicals that are listed in the Organization for the Prohibition of Chemical Weapons’ Schedule 1 list of agents. These are highly toxic substances and exposure can be occupational, intentional or accidental.3 Mechanism of action of organophosphorus compounds: OP compounds covalently bind to serine esterase enzymes like acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and carboxylesterase inhibiting them irreversibly. AChE rapidly inactivates the neurotransmitter acetylcholine by hydrolysis. During this hydrolysis, an acetyl group is transferred to the active serine site of the enzyme. This reaction only takes microseconds and serves to regenerate the enzyme and yields the acetate. OP compounds react in a similar pattern with these enzymes as shown in the figure.4 The only difference is that, they phosphorylate or phosphonylate the
Figure 1. OP compound reactions
the serine hydroxyl group of the enzyme. The phosphylated serine residue takes hours or sometimes days to regenerate and therefore the enzyme is irreversibly inactivated. In case of OP poisoning, the acetylcholine accumulates within the nerve synapses due to the inhibition of AChE and results in overstimulation of cholinergic receptors. Characteristic symptoms of OP poisoning are hyper-salivation, an increase in the secretions from nasal, bronchial and gastrointestinal routes, constriction of pupils and bronchioles, tremors, convulsions and even death. Death occurs due to respiratory system failure that is characterized by paralysis of diaphragm and intercostal muscles. Diagnosis of Organophosphate poisoning: According to the fate of pesticides in the body, different analytical methods have been developed to diagnose exposure to organophosphates. A commonly used method for the diagnosis of OP poisoning is to determine the activity of AChE and BuChE in plasma and whole blood. Ellman’s assay and its modifications, is a cheap, rapid, convenient, specific and sensitive Page 6
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
method to determine the activity of AChE and BuChE. However, this method has some disadvantages. First, this assay does not provide identification of the specific agent that is bound to AChE and BuChE. Second, it cannot detect poisoning if less than 20% of AChE or BuChE is bound. Third, the results do not correlate on an individual specimen basis due to large variations in AChE and BuChE concentrations in individual people. The second most specific method currently used is the identification and quantitation of unbound OP compounds in plasma using gas chromatography-mass spectroscopy (GC-MS) or liquid chromatography-mass spectroscopy (LC-MS). The disadvantage of this method is that OP compounds have short half-lives that make their detection difficult after several hours of exposure. The third method of diagnosis is to measure the metabolized products of OP compounds, which are phosphonic acids, in urine and plasma using GC-MS or LC-MS. The main disadvantage of this method is that these metabolites have a high rate of elimination and therefore cannot be detected retrospectively. The fourth method is to perform the fluoride reactivation of AChE and BuChE. Once the AChE and BuChE are reactivated, the OP compounds react with fluorides quantitatively to give phosphorofluoridate and phosphonofluoridate. These products are then identified and quantified by GC-MS or LC-MS. This method is good for retrospective analysis but not for verification of specific OP compounds. Additionally, it yields highly reactive OP compounds that can be dangerous if proper safety measures are not taken. This method does not work for rapidly aging OP -inhibited AChE and BuChE. The most recent method of detection is the determination of phosphyl adducts of AChE and BuChE using LC-MS after protein digestion. This is the most specific and sensitive method developed and has overcome the disadvantages of previous methods. It can be used in retrospective analysis and determination of aged phosphyl adducts and verifies the specific agent of poisoning.2 Treatment of OP poisoning: Treatment of OP poisoning generally includes the combination of atropine and pralidoxime. Pralidoxime assists in the regeneration of AChE and BuChE. Atropine is a muscarinic antagonist that inhibits the action of acetylcholine and reverses all the cholinergic symptoms of poisoning. The main aim of using atropine is to recover cardiac and respiratory functions.4 References: 1. Aryal UK, Lin C, Kim J, Heibeck TH, Wang J, Qian W, Lin Y. Identification of phosphorylated butyrylcholinesterase in human plasma using immunoaffinity purification and mass spectrometry; Analytica Chimica Acta, 2012, 723; 68– 75. 2. Worek F, Koller M, Thiermann H, Szinicz L. Diagnostic aspects of organophosphate poisoning; Toxicology, 2005, 214; 182–189 3. http://emedicine.medscape.com/article/167726-overview#a0199 4. Black RM, Read RW. Biological markers of exposure to organophosphorus nerve agents; Arch Toxicology, 2013, 87; 421–437
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
Fabrication and Characterization of Biodegradable Polymer Microneedles
1. Introduction Biodegradable polymer microneedles offer a great deal of advantages over hypodermic needle injections. Microneedle delivery is a minimally invasive, painless method of drug delivery that can be easily self-administered by patients [1, 3]. Microneedles can penetrate the outer barrier of skin i.e. stratum corneum and deliver drug into epidermis and superficial dermis. The polymer in the microneedles imparts versatile controlled-release properties to the delivery system. Furthermore, polymers such as polylactic acid (PLA), polyglycolic acid (PGA) and their co-polymer (PLGA) are inexpensive, biocompatible and mechanically strong materials, facilitating rapid scale-up and mass production [1]. Biodegradable polymers are safe and can be easily disposed by burning, dissolving in a solvent or by mechanical destruction. Polymer microneedles can be used to deliver a wide variety of drugs at desired depths by choosing the appropriate needle length to pierce the skin. However, a disadvantage of using microneedles is that they can only load a limited dose. Usually, this is amounts to be less than 1 mg of the maximum dose, since additional drug loading reduces the needle mechanical strength [1]. 2. Fabrication of Biodegradable Polymer Microneedles In general, there are 3 steps to fabricate polymer microneedles, namely; preparing the master structure, making the inverse mold, and fabricating replicates of microneedles. One master structure can make several molds and one mold can then yield multiple microneedles [1,2].
Figure 1. Biodegradable polymer microneedle fabrication process. 2.1 Fabrication of master structure The master structure can be developed in the beveled-tip, chisel-tip or tapered-cone shape. The beveled-tip master structure is made from SU-8 epoxy using ultraviolet (UV) lithography. Chisel-tip microneedles are made by the combination of wet etching and reactive ion etching. The tapered-cone is made by a novel lens-based technique [1]. 2.2 Fabrication of PDMS mold In order to prevent the master structure from sticking to PDMS (PolyDimethylsiloxane) mold, the master structure is deposited with a silanizing agent in vacuum vessel or sputter-coated with 100 nm gold. PDMS is the mold material of choice since it has several desirable properties including viscoelasticity, biocompatibility, high chemical inertness, optical transparency, adhesion to metals, low surface energy, non-hygroscopic, good thermal stability, mechanically Page 8
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durable properties. PDMS mixture contains two parts liquid component kits comprised of base/curing agent. After that, the mixture is heat cured under vacuum. The master structures are coated with aforementioned PDMS and centrifuged or placed under vacuum to eliminate the entrapped air. The PDMS mold is then formed in the convection oven. The hardened PDMS is peeled off by hand and cleaned by sonicating in warm water [1]. 2.3 Fabrication of PLGA microneedles The molds are covered with pellets of biocompatible polymer (PLGA) and placed in a vacuum oven in order to remove entrapped bubbles and help pull the polymer melt into the mold. The PLGA-filled mold is placed in a -200C freezer for 5 min to facilitate demolding. The molds and polymerized microneedle arrays are then separated by hand. The final polymer needles are stored in a desiccated container in the refrigerator for future use [1]. 3. Characterization of Biodegradable Polymer Microneedles 3.1 Scanning electron microscopy (SEM) Images of microneedles are obtained using a SEM to explore the microneedle geometry such as needle density, shank height, the width and tip feature, needle-needle spacing, needle base radius and base shape [4]. 3.2 Energy dispersive x-ray spectroscopy Energy dispersive x-ray spectroscopy is performed to determine the chemical composition of the microneedle [1]. 3.3 Compressive force failure testing Compression testing of microneedles against hard surfaces such as polytetrafluoroethylene has been used to examine the mechanical properties of microneedle arrays. Mechanical failure of microneedles can be due to axial loading and transverse loading [1,2]. 3.4 Other assessments Skin samples treated with microneedles are examined using field emission scanning electron microscope and by imaging the microneedle insertion. Dye binding studies are conducted to test the visualization of microchannels. Confocal microscopy studies are used to visualize the distribution of calcein in the skin penetrated with microneedles. The skin barrier perturbation is assessed by TEWL measurements [4]. 4. CONCLUSION Based on their ease of use and numerous advantages, microneedles made from biodegradable polymers are a novel, promising approach in the development of topical and transdermal dosage forms. References: [1]. J.-H. Park, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J. Control. Release (2005) 104:51Y6. [2]. Park J, Allen MG, Prausnitz MR. Polymer Microneedles for Controlled-Release Drug Delivery. Pharmaceutical Research. (2006); 23(5), 1008-1019. [3]. Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater (2008); 20: 933–938. [4]. Kolli CS, Banga AK. Characterization of solid maltose microneedles and their use for transdermal delivery. Pharm Res. 2008; 25(1):104-13
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
Textbook of Cosmetic Dermatology The flexibility of the skin has been studied in recent years for its ability to be maintained aesthetically in terms of cosmetics and cosmeceuticals, and to be a route for drug administration, as is seen in transdermal technology. As an asset to the transdermal specialists, student researcher, and lay person with general interest in the better care and structure of the skin, the book Textbook of Cosmetic Dermatology by world-renowned and highly accomplished dermatologist Dr. Howard Maibach (Professor of Dermatology at the University of California School of Medicine in San Francisco, California) and Dr. Robert Baran (Dermatologist at the Nail Disease Center in Cannes, France) is an invaluable resource to all levels of active learners. Currently in its fourth edition, Textbook of Cosmetic Dermatology is a combination primary, secondary, and tertiary source, comprised of reference compilations, reviews, and original research that delve into the advances in dermatology that have occurred in recent years. Topics include a wide range from cosmetic enhancement, to dermatology breakthroughs, and even gender-based skin care. The book is divided into eight sections, with the first section providing an overview on the structure of the skin, and the various influences that aging and environmental factors have on the skin. The second and third sections go deeper into pharmacology and transdermal technology, discussing topics such as percutaneous absorption, efficacy of antioxidants and retinoids, and occlusion properties of topicals. Sections four, five and six discuss cosmetology treatments for aesthetic improvement of the skin and the different types of skin based on ethnicity, gender, and disease states (examples of hirsutism, keloids, and acne are mentioned, just to name a few). Lastly, sections seven and eight discuss dermatology treatment both of invasive and non-invasive procedures (microneedles are cited under section seven and discussed at length) that are tailored to the different skin conditions that were covered in sections four through six. With graphical and pictorial representations of results and findings, this book is not only mentally enriching, but is also a visually stimulating read for those who are unaware of what the field of dermatology encompasses.
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
Terahertz Scanning Reflectometer
Topical and transdermal formulations contain various ingredients. In addition to the active ingredient, permeation enhancers or retardants are an essential part of topical/transdermal formulation. The permeation of the analyte through the substrate may vary in its concentration distribution across the varying thickness of the substrate. The determination of the penetration or the depth profile of the analyte within the substrate is a significant factor for optimizing the dermatological formulations. Terahertz Scanning Reflectometer is a noninvasive quantification technique for measurement of permeation kinetics and analyte in the skin. This technique applies a broadband terahertz spectrometry through which the spectroscopic differences between the blank skin and the analyte treated skin can be identified. The molecular events within the substrate can be probed by using a wide range (20THz or more) broadband terahertz spectrometry. These events are vital in quantifying the transdermal drug delivery formulations. This technique can be applied to any substrate and analyte combination. With a frequency ranging from around 100GHz to 30THz, the tomographic details of both the tissue surface and interior as well as the interaction of the actives with Figure 1. TeraView instrument the tissue can be identified. The method involves using a terahertz beam focused at a perpendicular angle on the substrate via an offaxis parabolic reflector on the specimen. The reflected beam from the substrate directed towards the detector towards a detection system via a beam splitter. The cell that holds the specimen has a platform controlled by a 1-D motion controller. The beam that falls on the specimen is focused by the offaxis reflector on the surface of the substrate. By using the motion control, the focal point of the beam is aligned to engage inside the substrate by which the reflectance across the thickness of the substrate can be measured. By locking the motion control in a fixed position with the focused beam on the surface of the substrate, the sample formulation can be applied on the substrate. The sample is allowed to permeate across the thickness of the substrate while the reflectance is measured at the same time. The reflectance from this measurement is directly proportional to the rate of permeation of the ingredient across the substrate. TeraR scan is a commercially available non-invasive, non-destructive and label-free equipment to measure the permeation kinetics or the concentration profile across a substrate with varying thickness. The T rays from this equipment can penetrate deep enough so that both the change in concentration with time and change in concentration with thickness can be measured across the depth or sub-surface locations of the substrate. References: 1. Rahman A, Frenchek S, Kilfoyle B, Patterkine L, Michiniak-Kohn B. Diffusion Kinetics & Permeation Concentration of Human SC Characterization by Terahertz Scanning Reflectometry. Drug Development and Delivery (2012) Volume 12;No.4 2. http://arphotonics.net/Reflctometer_2012_brochure_short.pdf from Applied Research and Photonics Inc.
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
FDA UPDATES Product
Hetlioz (TASIMELTEON)
Imbruvica (IBRUTINIB)
Aprolix
Indication
Sedative – Sleep/Wake Disorders
Cancer Agent (Leukemia)
Hemophilia-B
(COAGULATION FACTOR IX)
Cyramza (RAMUCIRUMAB)
Gastric Cancer
Mechanism of Action Agonist of melatonin receptors MT1 and MT2 (greater affinity for the MT2 receptor than the MT1 receptor). Agonism of MT1 is thought to preferentially induce sleepiness, while MT2 receptor activation preferentially influences regulation of circadian rhythms. Potent irreversible inhibitor of Bruton’s tyrosine kinase (BTK), an integral component of the B-cell receptor (BCR) and cytokine receptor pathways. BTK inhibition results in decreased malignant B-cell proliferation and survival. Replaces the missing coagulation factor IX, required for homeostasis. Contains Fc region of human IgG 1, which binds to neonatal Fc receptor (FcRn). FcRn is a part of a natural occurring pathway that delays lysosomal degradation. Vascular Endothelial Growth Factor-2 (VEGF-2) antagonist, inhibits proliferation, migration of human endothelial cells. Page 12
Manufacturer/ Type
Date
Vanda Pharmaceuticals Inc. (NME)
Jan. 2014
Pharmacyclics Inc. (NME)
Feb. 2014
Biogen Idec
Mar. 2014
Eli Lilly
Apr. 2014
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
Product
Entyvio (VEDOLIZUMAB)
Reyataz (ATAZANAVIR SULFATE)
Ryanodex (DANTROLENE SODIUM)
Indication
Ulcerative Colitis & Crohn’s Disease
HIV-1 protease inhibitor for paediatric patients
Treatment of malignant hyperthermia
Mechanism of Action Blocks the interaction of a4 β7 integrin with Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), & inhibits migration of memory Tlymphocytes across the endothelium into inflamed GI tissue.
When HIV infects a CD4 cell line, in a person's body, it copies its own genetic code into the cell's DNA. The CD4 cell is then "programmed to make new HIV genetic material and proteins. The proteases must be cut up by the HIV proteases to make functional new HIV particles. Protease inhibitors block the protease enzyme and prevent the cell from producing new viruses. In isolated nerve-muscle preparation, dantrolene has been shown to produce relaxation by affecting the contractile response of the muscle at a site beyond the myoneural junction. In skeletal muscle, dantrolene dissociates the excitation-contraction coupling, probably by interfering with the release of Ca ++ from the sarcoplasmic reticulum.
ISSUE IX, FALL 2014
Manufacturer/ Type
Millennium Pharmaceuticals
Date
May. 2014
Bristol MyersSquibb
Jun. 2014
Eagle Pharmaceuticals
Jul. 2014
Reference: www.fda.gov
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
What
When
Where
ACCP (American College of Clinical Pharmacology)
September 14-16, 2014
Atlanta, USA
Georgia Bio Innovation Summit
October 16, 2014
Atlanta, USA
International Conference and Exhibition on Biowaivers and Biosimilars
October 27-29, 2014
Hyderabad, India
AAPS (American Association of Pharmaceutical Scientists)
Nov. 2-6, 2014
San Diego, USA
ASCPT (American Society of Clinical Pharmacology & Therapeutics)
March 3-7, 2015
New Orleans, USA
American Association for Cancer Research
April 18-22, 2015
Philadelphia, USA
PEGS (The Essential Protein Engineering Summit)
May 4-8, 2015
Boston, USA
National Biotechnology Conference
June 8-10, 2015
San Francisco, USA
GRASP (Graduate Research Association of Students in Pharmacy)- Hosted by MERCER
June 12-14, 2015
Atlanta, USA
Annual Meeting and Exposition of the Controlled Release Society
July 26-29, 2015
Edinburgh, Scotland
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MERCER UNIVERSITY, DEPARTMENT OF PHARMACEUTICAL SCIENCES
ISSUE IX, FALL 2014
DEPARTMENT NEWS Compiled by: Padmanabhan Eangoor PhD Proposals:
‘’Indocyanine Green Loaded Theranostic Liposome Nanocarriers for Near Infrared Triggered Photodynamic Therapy’’ by Colby Shemesh
“Analgesic Patches: Formulation, Stability and Disposal” by Ranadheer Ravula
“Intranasal Delivery of Multivalent Pneumococcal Vaccine using Modified Polycaprolactone Microparticles” by Yamini Gorantla
“Enhanced Tumor Delivery and Modified Metabolism of Gemcitabine via PEG-DSPE/TPGS Mixed Micelles.” by Yingzhe Wang
“Development of an Oral Microparticulate HPV Vaccine.” by Trinh Vo
“Development of a Microparticulate Vaccine for Prostate Cancer.” by Ashwin Parenky
“Development and Evaluation of Vaccine Microparticles for Treatment of Breast Cancer” by Nihal Mulla
PhD Defenses:
“Enhancement of Topical and Transdermal Microdermabrasion” by Yingcong Zhou.
“Characterization of the effects of 4-phenyl-3-butenoic acid on tumorigenic cell signaling and growth” by Timothy Burns.
“Formulation Design and Development of Theranostic Nanoparticles for Tumor Targeted Drug Delivery” by Prasanna Kolluru.
“Delivery of cosmeceuticals and herbals into skin” by Mehtab Abla
“Transdermal Delivery and Disposal of Ropinirole Hydrochloride” by Neha D.Singh
“Development of Microencapsulated Formulations for Prostate Cancer” by Archana Akalkotkar.
“Development and Evaluation of Nasally Delivered PsaA Microspheres for Pneumococcal Vaccine” by Simon Paulos
‘’Characterization of the Effects of Chaetoglobosin K and 4-Phenyl-3-Butenoic Acid in Tumorigenic Cells” by Amna Ali
Investigation of Multi-Functional Theranostic Liposomes and Bi-Modal Combination Therapy of Cancer” by Delaram Moshkelani
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Delivery
Using
Nanoparticles
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
‘’Characterization of Reactive Oxygen Species as Signal Transducers in β2-Adrenergic Receptor Signaling and Evaluation of their Role in Receptor-β-Arrestin Interactions’’ by Monalisa Singh
“Transdermal and Transbuccal Delivery of Small Molecules” by Gaurav Bhatia
“Delivery of Small Molecules through Intact and Compromised Skin” by Meera Gujjar
“Formulation Development and Characterization of Polycaprolactone/Pluronic F108 ® Nanoparticles for Targeted Breast Cancer Therapy’’ by Thripthy Chandran
“Polymeric Nanocarriers for Sub-cellular Drug Delivery- A Case Study of the Inhibitor of Differentiation-4(ID4) Protein in Prostate Cancer” by Maxwell Korang-Yeboah
Jobs and Internships:
Archana Akalkotkar- Post doctoral Fellow, Kansas University
Gaurav Bhatia- Postdoctoral fellow, SRI International
Maxwell Korang-Yeboah- Postdoctoral fellow, US FDA.
Mehtab Abla- Lecturer at London College of Fashion, UK
Colby Shemesh- Intern, Novartis
Neha Singh- Research Scientist, Cirrus Pharmaceuticals
Yincong Zhou- Research Scientist, Novel laboratories Inc.
Meera Gujjar- Senior Scientist, GSK Stiefel
Travelships: AAPS- National Biotechnology Conference- San Diego, CA, 2014 Rikhav: FDD (Formulation Design & Development) Section Ashwin & Trinh: PPB (Physical Pharmacy & Biopharmaceutics) Section Nihal: Amgen Graduate Research Association of Students in Pharmacy- Queens, NY, 2014 Trinh Vo & Vineet Goti Awards: International Conference on Microneedles- College Park,MD, 2014 Arun Sivaraman & Dr. Banga- Poster Award Graduate Research Association of Students in Pharmacy- Queens, NY, 2014 Trinh Vo & Dr. D’Souza- 2nd place award for podium presentation The American Foundation for Pharmaceutical Education (APFE) Fellowship:
Trinh Vo Page 16
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
Publications:
Matesic DF, Ali A, Tatyana SS, Burns TJ (2013). A Cell-Cell Communication Marker for Identifying Targeted Tumor Therapies. Current Bioactive compounds,9(3):255-262.
Chaturvedula A, Fossler MJ, Hendrix CW (2013). Estimation of tenofovir's population pharmacokinetic parameters without reliable dosing histories and application to tracing dosing history using simulation strategies. J Clin Pharmacol, 54(2):150-160
Chaturvedula A, Sale ME, Lee H (2013). Genetic algorithm guided population pharmacokinetic model development for simvastatin, concurrently or non-concurrently co-administered with amlodipine. J Clin Pharmacol, 54(2): 141-149
Saluja S, Kasha PC, Paturi J, Anderson C, Morris R, Banga AK. (2013). A novel electronic skin patch for delivery and pharmacokinetic evaluation of donepezil following transdermal iontophoresis. Int J Pharm, 453(2):395-9
Abney CW, Knaack JL, Ali AA, Johnson RC (2013). Novel dual-mode immunomagnetic method for studying reactivation of nerve agent-inhibited butyrylcholinesterase. Chem Res Toxicol, 26(5):775-82
Burns RN., Singh M., Senotorov IS., & Moniri NH.(2014). Mechanisms of homologous and heterologous phosphorylation of FFA receptor 4 (GPR120): GRK6 and PKC mediate phosphorylation of Thr(347), Ser(350), and Ser(357) in the C-terminal tail. Biochem Pharmacol, 87(4):650-9.
Shemesh CS, Hardy CW, Yu DS, Fernandez B & Zhang H.(2014). Indocyanine Green Loaded Liposome Nanocarriers For Photodynamic Therapy Using Human Triple Negative Breast Cancer Cells. Photodiagnosis Photodyn Ther
Parenky A, Myler H, Amaravadi L, Bechtold-Peters K, Rosenberg A, Kirshner S, Quarmby V. (2014) New FDA Draft Guidance on Immunogenicity. AAPS J, 1–5.
Wang Y, Fan W, Dai X, Katragadda U, McKinley D, Teng Q, Tan C. (2014). Enhanced Tumor Delivery of Gemcitabine via PEG-DSPE/TPGS Mixed Micelles. Mol Pharm, 11(4): 1140–1150
Gujjar M, Banga AK. (2014) Vehicle influence on permeation through intact and compromised skin. Int J Pharm. Sep 10;472(1-2):362–8.
Ubale RV, Gala RP, Zughaier SM, D’Souza MJ. (2014) Induction of Death Receptor CD95 and Costimulatory Molecules CD80 and CD86 by Meningococcal Capsular Polysaccharide-Loaded Vaccine Nanoparticles. AAPS J. 2014 Jul 1;
Nguyen H., Banga AK, (2014) Determination of Vismodegib by Gradient Reverse-Phase HighPerformance Liquid Chromatography. Int J Pharm Analysis.
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
First we eat, then we teach DR. STROM *Baingan Bhartha*
DR. MATESIC *Palak Paneer*
DR. TAN *KING Crab*
DR. BANGA *Dry Meat & Beer*
DR. MONIRI *Ghormeh Sabzi*
DR. BURNS *Bacon*
Favourite FOOD DR. MOMARY *Nachos*
DR. MURNANE *Brazilian Steak*
DR. KNAACK *Veg Korma, Strawberry Shortcake*
DR. BOWEN *Spaghetti + Marinara + Turkey*
DR. D’SOUZA *Panang Curry*
DR. PALANIAPPAN *Fish Fry*
DR. HAYSLETT *Bacon Pizza*
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DR. CHATURVEDULA *Vada Pav*
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
SPOT ‘EM HERE! 1.
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Across 1. Dr. Palaniappan enjoys the view of both USA & Canada from one of the largest water falls in the world. 4. Dr. Hayslett likes the sand ‘n’ surf of this Floridian beach in Santa Rosa. 5. Dr. Murnane’s favorite island in South Carolina has one of the most beautiful lighthouses & shares its name with one of the most common hotel chains in the world. 7. Dr. Banga’s favorite place to be is at _ _ _ _ where he can enjoy good food and spend time with his family. 9. Dr. Chaturvedula’s vacation spot is home to the Taj Mahal & great cuisines filled with sugar & spice 10 + 11. Dr. Bowen loves to read a good book on quantum mechanics at Mailbu _ _ _ _ _ or the Rocky _ _ _ _ _ _ _ _ _. 12. Dr. Strom’s favorite vacation spot is the city of Asheville also known as the “Land of the Sky” located in this beautiful state. 13. Dr. Matesic enjoys camping and hiking to the top of this breathtaking mountain range which extends through the Carolina’s. Down 1. Dr. Knaack loves to travel to this state through which the Rio Grande flows & is one of the “Four Corners” in the US 2. Dr. Burns & Dr. Momary enjoy vacationing in this northern state whose capital is Augusta and is home to Acadia National Park. 3. Dr. Tan likes to holiday in the city of Vancouver in the cold north, in this country that neighbors the US. 6. Dr. Moniri likes to take his 3 children to meet Mickey & Minnie mouse in this magical land. 8. Dr. D’Souza loves the food from Top Spice which belongs to this Asian country, whose capital is Bangkok. Answer Key on Page 21
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
“WORDS TO LIVE BY” Grady Strom “Before you tell your life what you intend to do with it, listen for what it intends to do with you. Before you tell your life what truths and values you have decided to live up to, let your life tell you what truths you embody, what values you represent.” -Parker Palmer Ajay Banga “Between stimulus and response time is a space. In that space lies our freedom and power to choose our response. In those choices lie our growth and happiness.” Steven Covey J. Phillip Bowen “The best way to have a good idea is to have a lot of ideas.” -Linus Pauling Ayyappa Chaturvedula “Awake, Arise, Stop not till you reach your goal.” -Swami Vivekanand Reneé Hayslett “Happiness is not getting what you want, it’s wanting what you’ve got.” Jennifer Knaack ‘’Two roads diverge in a wood, and I took the one less traveled by, and that has made all the difference.’’ -Robert Frost
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
Diane Matesic “The real and lasting victories are those of peace, and not war.” -Ralph Waldo Emerson Kathryn Momary “Patience is a virtue, but persistence to the point of success is a blessing.” -Peter Diamandis Nader Moniri “I’ve missed more than 9000 shots in my career. I’ve lost almost 300 games. 26 times I have been trusted to take the game winning shot and missed. I’ve failed over and over and over again in my life, and that is why I succeed.” -Michael Jordan Kevin Murnane There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don't know. But there are also unknown unknowns. There are things we don't know we don't know.”-Donald Rumsfield Ravi Palaniappan Thathwamasi (Sanskrit Tat Tavam Asi) “You are that”. Chalet Tan “Chance favours the prepared mind.” -Louis Pasteur
Across: 1. NIAGARA FALLS, 4. PENSACOLA, 5. HILTONHEAD, 7. HOME, 9. INDIA, 10. BEACH, 11. MOUNTAINS, 12. NORTH CAROLINA, 13. BLUERIDGE Down: 1. NEWMEXICO, 2. MAINE, 3. CANADA, 6. DISNEY, 8. THAILAND
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
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ISSUE IX, FALL 2014
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
MUSCA
MUSCA received $1000 funding from AAPS as part of the Pharmacokinetics, Pharmacodynamics, and Drug Metabolism (PPDM) Education Initiative! MUSCA organized a webinar in May exclusively for Mercer students titled ‘Role of Dissolution Testing in Drug Product Development’ by Ms. Vivian Gray. She is the owner of V.A. Gray Consulting, Inc and member of IVRDT focus group at AAPS. 23
MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
www.facebook.com/pages/PhD-Jokes
“Life as a PhD Student” The secret to writing your thesis…
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MERCER UNIVERSITY, PHARMACEUTICAL SCIENCES GRADUATE PROGRAM E-NEWSLETTER
ISSUE IX, FALL 2014
Pharmabeat Team- Issue IX 2014
(Left to Right) Top Row: Padmanabhan, Vineet, Hiep, Arun Bottom Row: Amruta, Jessica, Xinyi Not in Picture: Ashwin
www.facebook.com/pages/PhD-Jokes
Disclaimer This is to state that the newsletter contains information from various sources and references that have been provided for the respective news and contents. The editors/ authors are not liable for any copyright issues as the information collected from various sources was combined and rephrased in the author’s own words. Copyright permissions are taken from respective sources. The fact remains same as mentioned in the references. The information is portrayed in the interest of Mercer University’s graduate students/alumni/staff and related readers, and is a non-profit publication. The newsletter does not intend to plagiarize information stated anywhere else. If any concerns, please contact the editors for further information.
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