Pharmacology, Toxicology and Environmental Health Commons^™

An Objective Assessment Of The Variability In Number Of Drops Per Bottle Of Glaucoma Medication, Daniel B. Moore, Judy Beck, Richard J. Kryscio

Ophthalmology and Visual Science Faculty Publications

Background: The purpose of this study is to evaluate the number of eyedrops available per bottle of a variety of commonly prescribed glaucoma medications.

Methods: Six bottles of each glaucoma medication were tested: three each in the vertical and horizontal orientations. Bottles were housed in a customized force gauge apparatus designed to mimic ballpoint fingertip contact with a bottle. At a standard rate, all drops were expressed from each bottle and counted with an automated drop counter. Simultaneously, bottle volume was measured and drop size and number were also estimated. The main outcome measures were: total number of drops, volume …

Immunotherapy Against Drugs Of Abuse, Gianna Raimondi (Class Of 2017)

Writing Across the Curriculum

Current treatments for drug addiction involve classical pharmacological therapy, involving the use of competitive or noncompetitive agonists (full, partial, or inverse) and antagonists. Drugs of abuse enter the brain after crossing the blood-brain barrier rapidly and binding to the proper receptor(s). They are able to do so because they are small and lipid soluble, and produce reinforcing effects by increasing levels of dopamine in brain areas associated with reward. This occurs in specific systems associated with addiction. In the mesolimbic system, neuron cell bodies originate in the ventral tegmental area (VTA) and project to the nucleus accumbens (NAc), amygdala, hippocampus, …

Development Of A Course-Based Undergraduate Research Experience To Introduce Drug-Receptor Concepts, Hollie I. Swanson, Ok-Kyong Park-Sarge, Thushani Rodrigo-Peiris, Lin Xiang, Vincent M. Cassone

Pharmacology and Nutritional Sciences Faculty Publications

Course-based research experiences (CUREs) are currently of high interest due to their potential for engaging undergraduate students in authentic research and maintaining their interest in science, technology, engineering, and mathematics (STEM) majors. As part of a campuswide initiative called STEMCats, which is a living learning program offered to freshman STEM majors at the University of Kentucky funded by a grant from Howard Hughes Medical Institute, we have developed a CURE for freshmen interested in pursuing health care careers. Our course, entitled “Drug–Drug Interactions in Breast Cancer,” utilized a semester-long, in-class authentic research project and instructor-led discussions to engage students in …

Optimizing Pharmacological Lifespan Extension: Testing Chemical Compounds For Additive Effects On Longevity, Elizabeth Chao

Dissertations, Masters Theses, Capstones, and Culminating Projects

No abstract available

Drug Eluding Stents For Malignant Airway Obstruction: A Critical Review Of The Literature, Wolfgang Hohenforst-Schmidt, Paul Zarogoulidis, Georgia Pitsiou, Bernd Linsmeier, Drosos Tsavlis, Ioannis Kioumis, Eleni Papadaki, Lutz Freitag, Theodora Tsiouda, J. Francis Turner, Robert Browning, Michael Simoff, Nikolaos Sachpekidis, Kosmas Tsakiridis, Bojan Zaric, Lonny Yarmus, Sofia Baka, Grigoris Stratakos, Harald Rittger

Internal Medicine Faculty Publications

Lung cancer being the most prevalent malignancy in men and the 3rd most frequent in women is still associated with dismal prognosis due to advanced disease at the time of diagnosis. Novel targeted therapies are already on the market and several others are under investigation. However non-specific cytotoxic agents still remain the cornerstone of treatment for many patients. Central airways stenosis or obstruction may often complicate and decrease quality of life and survival of these patients. Interventional pulmonology modalities (mainly debulking and stent placement) can alleviate symptoms related to airways stenosis and improve the quality of life of patients. Mitomycin …

Differentially Functionalized Silver Nanoparticles Alter K Metabolism In Human Red Blood Cells, Praveen Kumar Alla

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Silver nano particles (AgNPs) are the most frequently used nanomaterials (NMs) in industrial and biomedical applications, and extensive knowledge about their properties is fast accumulating. In addition, functionalization of nanoparticles significantly impacts their properties and potential applications. In spite the urge to produce, investigate and apply them, the toxicity of nanoparticles and their interaction with blood components, such as erythrocytes, has been insufficiently investigated. Here, we report on the effect of AgNPs in cellular function, and particularly on ion transport in human red blood cells (HRBCs). Two methods of synthesis were used for the functionalization of AgNPs, Creighton, and Lee-Meisel. …

Interaction Of Na+/K+ Atpase With Bcl-2 Proteins: Isolated Enzyme Vs Epithelial Cell Extracts, Chandra Kumar Maharjan

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The nearly complete inhibition of Na+/K+ ATPase (NKA) in fetal human lens (FHL) epithelial cells by chelerythrine (CHE), a Bcl-2 homology (BH)3-mimetic quaternary benzophenanthridine alkaloid was proposed to be the consequence of CHE binding at a BH1-like hydrophobic groove at the cytosolic aspect of NKA. This conclusion was based on in silico analysis showing at least two motifs in the N-terminal domain of NKA’s a1 subunit- i) aa 59-71 (ARAAEILARDGPN) and ii) aa 42-48 (DELHRKY) homologous to the BH1 and BH3 motifs of Bcl-2 (B-cell lymphoma) respectively, leading to a novel hypothesis that NKA could interact with these proteins by …

The Influence Of Abiotic Factors On The Uptake And Elimination Of 3-Trifluoromethyl-4-Nitrophenol By Larval Sea Lamprey (Petromyzon Marinus), Benjamin Livingston Hlina

Theses and Dissertations (Comprehensive)

The backbone of sea lamprey (Petromyzon marinus) control in the Great Lakes is the use of the piscicide, 3-trifluoromethyl-4-nitrophenol (TFM), which is applied to streams containing larval sea lampreys. However, TFM effectiveness can be influenced by abiotic factors such as pH and temperature, which fluctuate daily and seasonally. The objectives of this thesis were to evaluate the influence of pH, temperature, and season on the toxicity, uptake, and elimination of TFM by larval sea lamprey. Radio-labeled TFM (¹⁴C-TFM) was used to determine how TFM uptake rates varied at different water pHs or temperatures during exposure to …

Behavior Of Gold Nanoparticles In Physiological Environment And The Role Of Agglomeration And Fractal Dimension, Rose Cooper

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The Present study was designed to examine the role of agglomeration, density and the resulting fractal dimension of nanomaterials in cell culture media. Studies were completed on the kinetics and the process of agglomeration, as well as how to calculate fractal dimensions. The correlation of such complex agglomeration patterns of nanomaterials in culture media, their translocation into cells, and toxic effects were observed. Our results showed that smaller primary particles agglomerated at an accelerated rate when compared to the larger primary particles. They also demonstrated increased cellular uptake, but exhibited lower fractal dimensions. The larger primary particle agglomerates displayed obvious …

The Role Of Nkcc2a On The Nervous System Activity, Kavya Annu

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The NKCC2A is a splice variant of the Na+K+2Cl- co-transporter 2 (Slc12a1), which is abundantly expressed in macula densa and in the apical membrane of the tubular cells in the kidney. Most of our knowledge regarding NKCC2 function is limited to the kidney, the organ where NKCC2 is abundantly expressed. However, recent studies have demonstrated that NKCC2 is also expressed in extra-renal tissues. This study was designed to determine if NKCC2A, a splice variant of NKCC2 has an impact on behavior and nervous system activity of mice. To these ends, we used mice (wild type, WT), lacking a single or …

Role Of Angiotensin Ii Type 1a Receptors On Renal And Urinary Angiotensin Converting Enzyme 2 (Ace2) And Neprilysin (Nep) In The Two-Kidney One-Clip (2k1c) Model Of Renovascular Hypertension, Laale F. Alawi

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Activation of the renin angiotensin system (RAS) and increased formation of angiotensin (Ang) II contribute to the progression of chronic kidney disease (CKD). Ang II, the major biologically active peptide of RAS, acts mainly as a vasoconstrictor through binding to the Ang II type 1 receptor (AT1R), which leads to increased blood pressure, fluid retention, and aldosterone secretion. The actions of Ang II are antagonized by its conversion to the vasodilator Ang (1-7), partly generated by the action of angiotensin converting enzyme 2 (ACE2) and/or neprilysin (NEP). The metalloprotease ADAM17 has a crucial role in the shedding of renal ACE2 …

Expression And Pharmacological Modulation Of Pain-Depressed Behavior In Rats, Michael D. Leitl

Theses and Dissertations

Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This goal of this dissertation was to conduct preclinical research experiments designed to address a set of three inter-related aims that examine the expression, mechanisms and treatment of pain-related depression of Intracranial Self-Stimulation (ICSS) in rats. First, studies evaluated the hypothesis that acute acid-induced depression of ICSS was mediated by a kappa opioid receptor mediated decrease in mesolimbic dopamine release in the nucleus accumbens. Results support a role for depressed mesolimbic dopamine release in pain-related depression of ICSS; however, …

Role Of Bumetanide On Insulin Secretion, Mohammed Mashari Almutairi

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Insulin secretion depends on the electrical properties of the ß-cells in pancreatic islets. The consensus mechanism of insulin secretion involves glucose-stimulated metabolic increase in the ATP/ADP ratio. This increase closes ATP-sensitive K+ (KATP) channels resulting in ß-cell plasma membrane depolarization, which in turn activates voltage-dependent Ca2+ channels further resulting in Ca2+ influx and release of insulin stored in granules. In addition to this well-known consensus mechanism, insulin secretion also depends on electrogenic efflux of Cl- ions. The Na+K 2Cl- cotransporters (NKCCs) maintain the intracellular concentration of Cl- ([Cl-]i) at values higher than those predicted at thermodynamic equilibrium. This distribution of …

Characterization Of Small Conductance Calcium-Activated Potassium Channels In A Human Lens Epithelium Cell Line (B3), Wedad Ali Saqar

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Small conductance calcium-activated potassium (SK) channels belong to the family of K+ channels. They play a significant role in cell volume regulation and in lens homeostasis, and thus are associated with cataract formation. This study was designed to demonstrate the presence of the four different isoforms of SK channels (SK1, SK2, SK3, and SK4) in human lens epithelial (HLE)-B3 cell line using Western blot (WB), immunofluorescence (IF), and reverse transcriptase coupled to the polymerase chain reaction (RT-PCR). Cataract formation involves SK-mediated K+ loss and gain of Na+ ions by lens cells. Further, it has been shown in previous studies that …

Recovery From Acute Toluene Intoxication Is Facilitated By The Nmda Receptor Co-Agonist D-Serine, But Not The Gabaa Receptor Antagonist Picrotoxin, Susan R. Samuel-Herter

Theses and Dissertations (Comprehensive)

Toluene is a volatile solvent found in many household products and when intentionally inhaled results in intoxication. In rats, acute inhalation of toluene results in sedation and neurological impairments, with marked increases in ambulation and vertical behaviour during the recovery period. Previous in vitro research has shown that toluene may exert its effects by inhibiting NMDA receptors, and / or by activating GABA_A receptors. To test whether modulation of these receptors are also implicated in the changes in motor behaviour and neurological impairments resulting from toluene vapour inhalation, rats were injected with the NMDA receptor co-agonist D-serine (1000 mg/kg …

Sensitization Of Human Cancer Cells To Gemcitabine By The Chk1 Inhibitor Mk-8776: Cell Cycle Perturbation And Impact Of Administration Schedule In Vitro And In Vivo, Ryan Montano, Ruth Thompson, Injae Chung, Huagang Hou, Nadeem Khan, Alan Eastman

Dartmouth Scholarship

Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence.

Chronic Swim Stress Attenuates Endocrine Response And Improves Cardiac Function In Mice Lacking The Angiotensin Ii Type 1a Receptor, Najat Khalifa Almahroug

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Stress is a stimulus that causes an often abrupt but always large change in autonomic activity and hormone secretion. Angiotensin II (AngII) is one of the main neurohormonal mediators that are stimulated by stress. AngII mediates most of its relevant biological effects via AngII type1 receptor (AT1R) activation. Stress increases tissue and circulating levels of Ang II which contributes to stimulation of adrenal AT1R, mediating stressinduced hormone release. Ang II through the activation of AT1R not only elevates blood pressure but also has a patho-physiological relevance in cardiac remodeling. The goal of this study was to assess the influence of …

Characterisation Of Pharmaceutical Grade Horse Chestnut Waste, Joanna Przyborska

Theses

Horse chestnut residue was made available by a local pharmaceutical company. The residue was subjected to compositional analysis and studied to determine potential for residual biological activity, including prebiotic, antimicrobial, anti-hyaluronidase and anti-elastase effects.

The residue had 52 % total solids, including 2.97% ash, 6.93% protein, 1.89% crude fat. Oleic acid (74.7%) was the main fatty acid components in the crude lipid component. The major ash components were potassium, phosphorus, calcium and magnesium.

Prebiotic potential of aqueous extract (HCE) from horse chestnut residue was confirmed. A new formula for calculation of prebiotic index (PI) was developed. PI for probiotics (Lactobacillus …

Enhanced Angiotensin Ii-Induced Cardiac And Aortic Remodeling In Ace2 Knockout Mice, Mahmoud Alghamri

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Activation of the renin angiotensin system (RAS) is a well-known driving force, governing the aggravation and progression of CVD and associated target organ damage. Angiotensin (Ang) converting enzyme 2 (ACE2), a new member within the RAS family, was first cloned from the ventricle of patient with heart failure. ACE2 was shown to be upregulated under pathological conditions. We hypothesize that loss of ACE2 negatively affects cardiac function and exacerbates hypertrophic cardiomyopathy and aortic remodeling in response to Ang II. Eight weeks old ACE2 knock out (KO) and wild type (WT) mice were infused with Ang II s.c. (1000 ng/kg/min for …

Modelling Β2ar Regulation, Sharat J. Vayttaden

Dissertations and Theses (Open Access)

The β2 adrenergic receptor (β2AR) regulates smooth muscle relaxation in the vasculature and airways. Long- and Short-acting β-agonists (LABAs/SABAs) are widely used in treatment of chronic obstructive pulmonary disorder (COPD) and asthma. Despite their widespread clinical use we do not understand well the dominant β2AR regulatory pathways that are stimulated during therapy and bring about tachyphylaxis, which is the loss of drug effects. Thus, an understanding of how the β2AR responds to various β-agonists is crucial to their rational use. Towards that end we have developed deterministic models that explore the mechanism of drug- induced β2AR regulation. These mathematical models …

National Center For Pharmaceutical Crops, Wei Yuan, Shiyou Li, Zushang Su, Ping Wang

NCPC Presentations

The mission of the National Center for Pharmaceutical Crops is to develop crops for the production of pharmaceutical and other bioactive compounds. The NCPC, located in the Arthur Temple College of Forestry and Agriculture, is the only one of its kind in the U.S. and it seeks to improve human health, revitalize rural economies and enhance U.S. security in strategic pharmaceuticals. This poster provides a background to the department, its functions and activities and notable achievements.

Response Of Monovalent Cation Transporters To Pro-Apoptotic Protein Kinase C Modulators In Human Lens Epithelial Cells, Michael Anthony Lepera

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Protein kinase inhibition by staurosporine causes apoptotic volume decrease involving potassium (K) channels in immortalized human B3 lens epithelial cells (LECs). Here, the effect of two pro-apoptotic protein kinase C (PKC) inhibitors [12-O-tetradecanoyl-phorbol-13-acetate (TPA) and chelerythrine (CET)] were studied on membrane K transport in a fetal human LEC line (FHL124) by western blotting, immunofluorescence, ion flux, ATP, apoptosis, and biotinylation assays. Long term TPA exposure (0-6 h) inhibited 75% of Na-K-2Cl cotransport (NKCC). In contrast, short term (0-20 min) exposure to 50 μM CET reduced Na/K pump and NKCC by >90% and >70%, respectively, without retrieval from the membrane into …

Differentiation Of Megakaryocytes/Platelets And Neurons From Human Endometrial Stromal Progenitor Cells, Jinju Wang

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Human endometrium is a high dynamic tissue that contains stem/progenitor cells. These endometrial stromal progenitor cells (hESCs) have been differentiated into a number of mesodermal lineages. There is limited information on differentiating hESCs into neurons, and no information on differentiating hESCs into megakaryocytes (MKs) and platelets (PLTs). The aim of this work was to investigate the possibility of differentiating hESCs into two distinct lineages: MKs, with subsequent PLT formation, and neurons.

We isolated hESCs from human endometrial tissue and cultured the cells for 4-6 passages. Before each differentiation experiment, the purity of hESCs was confirmed by flow cytometry analysis which …

Response Of Neuroinflammatory And Neurodegenerative Markers Following Sub-Lethal Sarin Exposure And Subsequent Treatment Via An In-Vivo Caspase Inhibitor, Douglas F. Chmura

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Organophosphorus nerve agents are amongst the most deadly chemical compounds ever synthesized. Sarin is an organophosphate (OP) ester that irreversibly forms a phosphoester bond at the active site of acetylcholinesterase and thereby induces a rapid and lethal cholinergic crisis. It remains an active threat to vulnerable civilian populations due to its ease of synthesis and known use by rogue nations and terrorist groups. Death is the most extreme consequence of sarin toxicity. Current treatments fail to provide protection against progressive cognitive impairments years after mild exposure. Q-VD-OPh is an in-vivo caspase inhibitor with potent anti-apoptotic and anti-inflammatory properties. In this …

Layer-By-Layer Self -Assembly For Enzyme And Dna Encapsulation And Delivery, Amish Patel

Doctoral Dissertations

Thin wall microcapsules were formed via Layer-by-Layer Self-Assembly of alternate adsorption of oppositely charged polyelectrolyte on microcores. After the core dissolution, empty polymeric shells with 20–25 nm thick walls were obtained. These microcapsules were loaded with Myoglobin, Hemoglobin and Glucose Oxidase by opening capsule pores at low pH and closing them at higher pH. The native structure of the enzyme was not affected due to different treatments. Biocompatible nanoshells were also prepared for encasing DNA. Using the same Layer-by-Layer Self-Assembly approach nanoparticle were constructed containing DNA as one of the layers. The nanoparticles of different architecture were used to deliver …

Modulation Of The Pharmacokinetics And Pharmacodynamics Of Proteins By Polyethylene Glycol Conjugation, Reza Mehvar

Pharmacy Faculty Articles and Research

With the rapid advances in the field of biotechnology during the last decade, many peptides and proteins have been produced and evaluated for therapy of various diseases, including cancer. However, rapid clearance and the possibility of immunogenicity after the in vivo administration of these biotechnology-driven products have impeded their marketing. To circumvent these problems, synthetic and natural polymers such as polyethylene glycol (PEG) and dextrans, respectively, have been covalently attached to proteins, and some of these protein-polymer conjugates have shown promising therapeutic results. The conjugation of proteins with polymers usually causes a reduction in the recognition of the protein by …

Signaling Mechanisms For Muscarinic Receptor-Mediated Coronary Vasoconstriction In Isolated Rat Hearts, Yi Zhang

Electronic Theses and Dissertations

The signaling mechanisms for muscarinic receptor-mediated vasoconstriction in coronary resistance arteries were studied in KCl-arrested isolated rat hearts perfused at a constant flow rate. The cholinergic agonists acetylcholine and bethanechol were given by bolus injection or constant infusion. The coronary vascular resistance was monitored by measuring the changes in perfusion pressure. The selective muscarinic agonist bethanechol caused a similar vasoconstrictor response as ACh, but with less potency and efficacy. Bolus injection of bethanechol evoked a phasic vasoconstriction in a dose-dependent manner, while infusion of bethanechol evoked a tonic vasoconstriction without producing tachyphylaxis. Coronary vascular responses to bethanechol were further examined …

Modeling Chemical Absorption Through Membranes, Jeffrey M. Hemmes

Theses and Dissertations

Understanding the processes involved in dermal penetration of chemicals and drugs is important to both toxicologists and pharmacologists. Researchers developing new drugs are interested in enhancing the penetration of chemicals through the skin, while environmental professionals are interested in limiting such penetration. For both types of applications, predictive biologically-based mathematical models can be very useful in understanding the processes involved, particularly when such models are based on physiological and biochemical parameters which can be measured experimentally. In this thesis we study two existing physiologically-based pharmacokinetic (PBPK) models that predict concentrations of neat and aqueous dibromomethane (DBM) absorbed into and through …

Comparison Of Beta-Adrenoceptor Coupled Camp Production In Cultured Human Mononuclear Leukocytes And Myometrial Cells, Yu-Li Liu

Electronic Theses and Dissertations

$\beta\sb2$-Adrenoceptor ($\beta\sb2$-AR) agonists, such as terbutaline, are used as tocolytic agents in the treatment of preterm labor. $\beta$-Adrenoceptor stimulation relaxes myometrium through specific receptors coupled through Gs to adenylyl cyclase (AC) that catalyzes the conversion of ATP to cAMP. The purpose of this study was to compare $\beta$-adrenoceptors and cAMP production in cultured human leukocytes and myometrial cells, and to determine the importance of $\beta$-adrenoceptors and cAMP production in isoproterenol-induced myometrial relaxation. $\sp{125}$I-iodopindolol was used to assess $\beta$-adrenoceptor affinity and number cAMP levels were analyzed before and after stimulation by isoproterenol, AlF$\sb4\sp-$, forskolin, and PGE$\sb1$. Isometric recording was used to …

Persistent Oral Dyskinesias Induced By Long-Term Haloperidol Treatment Is Dissociated From Changes In Neostriatal B(Max) And Mrna Content For Dopamine D(2) Receptors, Nuoyu Huang

Electronic Theses and Dissertations

Due to the presumed associations of dopamine (DA) receptor supersensitivity phenomena in both long-term neuroleptic-treated tardive dyskinetic rats and neonatal 6-hydroxydopamine (n6-OHDA)-lesioned rats, we studied the influence of haloperidol on n6-OHDA-lesioned rats. At 3 days after birth rats received 6-OHDA-HBr (200 $\mu$g, bilateral intracerebroventricularly; desipramine pretreatment, 20 mg/kg, 1h) or vehicle. Two months later haloperidol (1.5/kg/day $\times$ 2 days/week for 4 weeks, then 1.5 mg/kg/day, every day for 10 months) was added to the drinking water. Spontaneous oral activity of intact and n6-OHDA-lesioned rats receiving haloperidol was reached and maintained at significantly higher levels after 15 weeks of haloperidol treatment. …