Medical Pharmacology Commons^™

Mitochondrial And Neuroprotective Effects Of Phenelzine Related To Scavenging Of Neurotoxic Lipid Peroxidation Products, John Cebak

Theses and Dissertations--Neuroscience

Lipid peroxidation is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either the initiation or propagation of lipid peroxidation (LP). However, targeting free radicals after TBI is difficult as they rapidly react with other cellular macromolecules, and thus has a limited post-injury time window in which they may be intercepted by a radical scavenging agent. In contrast, our laboratory has begun testing an antioxidant approach that scavenges the final stages of LP i.e. formation of carbonyl-containing breakdown products. By scavenging breakdown products such as the …

Functional Conservation Of An Ancestral Pellino Protein In Helminth Species, Christopher Cluxton, Brian Caffrey, Gemma Kinsella, Paul Moynagh, Mario Fares, Padraic Fallon

Articles

The immune system of H. sapiens has innate signaling pathways that arose in ancestral species. This is exemplified by the discovery of the Toll-like receptor (TLR) pathway using free-living model organisms such as Drosophila melanogaster. The TLR pathway is ubiquitous and controls sensitivity to pathogen-associated molecular patterns (PAMPs) in eukaryotes. There is, however, a marked absence of this pathway from the plathyhelminthes, with the exception of the Pellino protein family, which is present in a number of species from this phylum. Helminth Pellino proteins are conserved having high similarity, both at the sequence and predicted structural protein level, with that …

Feasibility Of Integrating Tripterygium Wilfordii Into Modern Cancer Therapy For Increased Efficacy And Minimal Toxicity, Ngoc T. Vo

UROP Posters

Cancer is the second leading cause of death in the U.S. and millions of novel cancer cases are being diagnosed each year. While chemotherapy and ionizing radiation are effective treatments against these malignant tumors, the adverse effects that accompany such treatments are devastating. In order to find alternative treatment methods with less side effects, we turn to Eastern herbal medicine. Recent scientific research has found that Tripterygium wilfordii, an herbal medicine traditionally used to treat inflammation in China, contains compounds (triptolide and celastrol) that prevent the growth of solid tumors, induce apoptosis, and prevent metastasis of developed tumors. Investigations …

Drug Interactions With Glutaredoxin Orthologues, Kahlilah R. Napper, Thomas C. Leeper, Ram Khattri, Daniel Morris, Caroline Davis

Williams Honors College, Honors Research Projects

Glutaredoxin, an enzymatic protein, is an important component of cell viability and function. It catalyzes reactions involved in DNA synthesis and innate immunity [1,4]. Glutaredoxin is also essential in antibiotic resistance in pathogenic bacterial species. Pseudomonas aeruginosa in particular is responsible for infecting the lung tissue of its human hosts, resulting in the development of pneumonia and cystic fibrosis [3]. Because glutaredoxin is pertinent in cell proliferation of eukaryotic and bacterial cells alike, medicinal fragments that take advantage of the subtle differences in protein structure of the orthologous proteins can be synthesized and enhanced to bind bacterial glutaredoxins, without inhibiting …

Predicting Aqueous Solubility Of Pharmaceutical Agents By Solid Dispersion Prepared By Solvent Evaporation Method, Karthik Reddy Patlolla

University of the Pacific Theses and Dissertations

Solubility of active pharmaceutical agents is a crucial process that determines drug absorption and ultimately its bioavailability. Many of the new therapeutically beneficial compounds discovered are lipophilic requiring various solubility enhancement strategies to improve their solubility. Among these strategies, solubility enhancement using solid dispersions is a leading method. To obtain a desirable increase in the solubility of a poorly-soluble compound, a good understanding of the molecular descriptors influencing the enhancement of solubility is essential. Therefore, the major research objective was to determine the descriptors which significantly influence the solubility enhancement by solid dispersions. After enhancing the solubility of selected poorly-soluble …

Dual Pi3k/Mtor Inhibition With Bez235 Augments The Therapeutic Efficacy Of Doxorubicin In Cancer Without Influencing Cardiac Function, David E. Durrant

Theses and Dissertations

Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. …

Efficacy Of Female Rat Models In Translational Cardiovascular Aging Research, Kevin M. Rice, J. C. Fannin, C. Gillette, Eric Blough

Pharmaceutical Science and Research

Cardiovascular disease is the leading cause of death in women in the United States. Aging is a primary risk factor for the development of cardiovascular disease as well as cardiovascular-related morbidity and mortality. Aging is a universal process that all humans undergo; however, research in aging is limited by cost and time constraints. Therefore, most research in aging has been done in primates and rodents; however it is unknown how well the effects of aging in rat models translate into humans. To compound the complication of aging gender has also been indicated as a risk factor for various cardiovascular diseases. …

Cd151-Α3Β1 Integrin Complexes Suppress Ovarian Tumor Growth By Repressing Slug-Mediated Emt And Canonical Wnt Signaling, Lauren A. Baldwin, John T. Hoff, Jason Lefringhouse, Michael Zhang, Changhe Jia, Zeyi Liu, Sonia Erfani, Hongyan Jin, Mei Xu, Qing-Bai She, John R. Van Nagell Jr., Chi Wang, Li Chen, Rina Plattner, David M. Kaetzel, Jia Luo, Michael Lu, Dava West, Chunming Liu, Fred R. Ueland, Ronny Drapkin, Binhua P. Zhou, Xiuwei H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by …

Long-Acting Antituberculous Therapeutic Nanoparticles Target Macrophage Endosomes., Benson J. Edagwa, Dongwei Guo, Pavan Puligujja, Han Chen, Joellyn Mcmillan, Xinming Liu, Howard Gendelman, Prabagaran Narayanasamy

Journal Articles: Pharmacology & Experimental Neuroscience

Eradication of Mycobacterium tuberculosis (MTB) infection requires daily administration of combinations of rifampin (RIF), isoniazid [isonicotinylhydrazine (INH)], pyrazinamide, and ethambutol, among other drug therapies. To facilitate and optimize MTB therapeutic selections, a mononuclear phagocyte (MP; monocyte, macrophage, and dendritic cell)-targeted drug delivery strategy was developed. Long-acting nanoformulations of RIF and an INH derivative, pentenyl-INH (INHP), were prepared, and their physicochemical properties were evaluated. This included the evaluation of MP particle uptake and retention, cell viability, and antimicrobial efficacy. Drug levels reached 6 μg/10(6) cells in human monocyte-derived macrophages (MDMs) for nanoparticle treatments compared with 0.1 μg/10(6) cells for native drugs. …

Pupillometry: A Non-Invasive Technique For Pain Assessment In Paediatric Patients., Mark A. Connelly, Jacob T. Brown, Gregory L. Kearns, Rawni A. Anderson, Shawn D. St Peter, Kathleen A. Neville

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Pupillometry has been used to assess pain intensity and response to analgesic medications in adults. The aim of this observational study was to explore proof of concept for the use of this technique in paediatric patients. Changes in pupil parameters before and after opioid exposure also were evaluated.

DESIGN AND SETTING: This was a single-centre, prospective study conducted at an academic paediatric medical centre.

PATIENTS: Children 9-17 years of age undergoing elective surgical correction of pectus excavatum were enrolled into a protocol approved by the human ethical committee (institutional review board).

INTERVENTIONS: Pupil size and reactivity were measured using …

Analysis For Co-Occurring Sequence Features Identifies Link Between Common Synonymous Variant And An Early-Terminated Npc1 Isoform, Mercedeh Movassagh, Prakriti Mudvari, Maria Kokkinaki, Nathan J. Edwards, Nady Golestaneh, Anelia Horvath

Pharmacology and Physiology Faculty Publications

Direct assessment of allelic phase for DNA and RNA features of diploid genomes has been challenging for Sanger sequencing, due to its allele-conflating base-calling signal. Massively parallel sequencing technologies are based on the generation of a continuous copy of a single strand sequence segments, thus preserving the allelic relation between the features of the original molecules. We have performed a transcriptome-wide search for co-occurrence of variant nucleotides and exon-intron boundaries positioned within the length of a single sequencing read. Analysis of 75 human transcriptomes from retinal pigment epithelia (RPE), glioblastoma, low-grade brain tumor, breast cancer and colon cancer, have identified …

3,4,5-Trichloroaniline Nephrotoxicity In Vitro: Potential Role Of Free Radicals And Renal Biotransformation, Christopher Racine, Dakota Ward, Dianne K. Anestis, Travis Ferguson, Deborah Preston, Gary O. Rankin

Pharmaceutical Science and Research

Chloroanilines are widely used in the manufacture of drugs, pesticides and industrial intermediates. Among the trichloroanilines, 3,4,5-trichloroaniline (TCA) is the most potent nephrotoxicant in vivo. The purpose of this study was to examine the nephrotoxic potential of TCA in vitro and to determine if renal biotransformation and/or free radicals contributed to TCA cytotoxicity using isolated renal cortical cells (IRCC) from male Fischer 344 rats as the animal model. IRCC (~4 million cells/mL; 3 mL) were incubated with TCA (0, 0.1, 0.25, 0.5 or 1.0 mM) for 60–120 min. In some experiments, IRCC were pretreated with an antioxidant or a …

Dual Destructive And Protective Roles Of Adaptive Immunity In Neurodegenerative Disorders., Kristi M. Anderson, Katherine E. Olson, Katherine A. Estes, Ken Flanagan, Howard E. Gendelman, R. Lee Mosley

Journal Articles: Pharmacology & Experimental Neuroscience

Inappropriate T cell responses in the central nervous system (CNS) affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include, but are not limited to, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. On the one hand immune responses can exacerbate neurotoxic responses; while on the other hand, they can lead to neuroprotective outcomes. The temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent attention. Spatially, immune responses that affect neurodegeneration may occur within or outside the CNS. Migration of …

A Pilot Study On The Use Of Lecture Tools To Enhance The Teaching Of Pharmacokinetics And Pharmacodynamics, Hollie I. Swanson, Michael T. Piascik

Pharmacology and Nutritional Sciences Faculty Publications

Pharmacokinetics and pharmacodynamics are essential topics contained within the medical curriculum and are highly amenable to active-learning approaches. In this pilot study, we incorporated Lecture Tools, a cloud-based audience response system, into a lecture-based graduate course. Lecture Tools was used by both the instructors and the students during peer presentations. Advantages noted by the instructors include the versatility of the questions that can be presented and the ease with which student assessment can be conducted. Student surveys revealed that, overall, the use of Lecture Tools enhanced student attentiveness and engagement and facilitated student participation in questions and answers. Some disadvantages …

Visualization Of Oxytocin Release That Mediates Paired Pulse Facilitation In Hypothalamic Pathways To Brainstem Autonomic Neurons, Ramon A. Pinol, Heather Jameson, Anastas Popratiloff, Norman H. Lee, David Mendelowitz

Pharmacology and Physiology Faculty Publications

Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN) contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work …

Management Of Severe Hyponatremia: Infusion Of Hypertonic Saline And Desmopressin Or Infusion Of Vasopressin Inhibitors?, Antonios H. Tzamaloukas Md, Joseph I. Shapiro Md, Dominic S. Raj Md, Glen H. Murata Md, Robert H. Glew Phd, Deepak Malhotra Md, Phd

Pharmaceutical Science and Research

Rapid correction of severe hyponatremia carries the risk of osmotic demyelination. Two recently introduced methods of correction of hyponatremia have diametrically opposite effects on aquaresis. Inhibitors of vasopressin V2 receptor (vaptans) lead to the production of dilute urine, whereas infusion of desmopressin causes urinary concentration. Identification of the category of hyponatremia that will benefit from one or the other treatment is critical. In general, vaptans are effective in hyponatremias presenting with concentrated urine and, with the exception of hypovolemic hyponatremia, can be used as their primary treatment. Desmopressin is effective in hyponatremias presenting with dilute urine or developing urinary dilution …

Calmodulin Enhances Ribbon Replenishment And Shapes Filtering Of Synaptic Transmission By Cone Photoreceptors., Matthew J. Van Hook, Caitlyn M. Parmelee, Minghui Chen, Karlene M. Cork, Carina Curto, Wallace B. Thoreson

Journal Articles: Pharmacology & Experimental Neuroscience

At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca(2+)) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the …

Impact Of Preadmission Beta-Blocker Use On Cardiac Abnormalities And In-Hospital Mortality In Patients With Aneurysmal Subarachnoid Hemorrhage, Toshimasa Okabe, Md, Anushya Jeyabalan, Md, Benjamin E. Leiby, Phd, Fred Rincon, Md, Walter K. Kraft, Md

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Introduction:

Various cardiac abnormalities, including dysrhythmias, left ventricular (LV) dysfunction, and myocardial injury, are commonly seen after subarachnoid hemorrhage (SAH). In patients taking a beta-blocker (BB) chronically, the medication is generally discontinued after hospitalization due to the concern of compromising cerebral perfusion. We hypothesized that sudden BB discontinuation might inadvertently lead to an increased incidence of composite cardiac abnormalities and higher in-hospital mortality in patients presenting with nontraumatic SAH.

Ethanol Pharmacokinetics In Neonates And Infants, Elizabeth Marek, Pharmd., Walter K. Kraft, Md

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Introduction:

Ethanol has been used for years in neonatal and infant liquid medications, yet the pharmacokinetics, pharmacodynamics, and safety of ethanol in this vulnerable population have not been well characterized. The purpose of this review is to raise awareness of ethanol use as an excipient in neonatal and infant medications and to provide insight, based on the available evidence, into clearance rates of ethanol in babies. We also discuss ethanol pharmacokinetics in adults, theoretical pharmaco-kinetic changes in neonates and infants as it may apply to ethanol disposition, and case reports involving ethanol exposure in neonates and infants.

Materials and methods: …

Sex-Specific Alterations In Nos Regulation Of Vascular Function In Aorta And Mesenteric Arteries From Spontaneously Hypertensive Rats Compared To Wistar Kyoto Rats, Analia S. Loria, Krystal N. Brinson, Brandon M. Fox, Jennifer C. Sullivan

Pharmacology and Nutritional Sciences Faculty Publications

The present study tested the hypothesis that spontaneously hypertensive rats (SHR) have impaired nitric oxide synthase (NOS)-mediated regulation of vascular function versus Wistar-Kyoto rats (WKY). Aorta and small mesenteric arteries were studied from male and female SHR (M SHR and F SHR) and WKY (M WKY and F WKY). Phenylephrine (PE)-induced vasoconstriction was greater in aorta of M SHR versus all others (P < 0.05); there were neither sex nor strain differences in PE contraction in mesenteric arteries. The NOS inhibitor l-Nitro-Arginine Methyl Ester (l-NAME) increased PE-induced vasoconstriction in all rats, although the increase was the least in male SHR (P < 0.05), revealing a blunted vasoconstrictor buffering capacity of NOS. l-NAME increased sensitivity to PE-induced constriction only in mesenteric arteries of SHR, although, the maximal percent increase in contraction was comparable among groups. ACh-induced relaxation was also less in aorta from M SHR versus all others (P < 0.05). ACh relaxation was comparable among groups in mesenteric arteries, although SHR exhibited a greater NOS component to ACh-induced relaxation than WKY. To gain mechanistic insight into sex and strain differences in vascular function, NOS activity and NOS3 protein expression were measured. Aortic NOS activity was comparable between groups and M SHR had greater NOS3 expression than M WKY. In contrast, although vascular function was largely maintained in mesenteric arteries of SHR, NOS activity was less in SHR versus WKY. In conclusion, M SHR exhibit a decrease in NOS regulation of vascular function compared to F SHR and WKY, although this is not mediated by decreases in NOS activity and/or expression.