Pharmacology Commons^™

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.

Repeated Asenapine Treatment Produces A Sensitization Effect In Two Preclinical Tests Of Antipsychotic Activity, Rongyin Qin, Yingzhu Chen, Ming Li

Department of Psychology: Faculty Publications

Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)- induced hyperlocomotion paradigms – two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, …

Comparison Of Theophylline And 8-Cyclopentyltheophylline On The Heart Rates Of Neonatal Rats, Stephanie Arnold

Undergraduate Honors Theses

Neonatal apnea is a serious condition that affects the health of infants, especially those born prematurely. To stimulate breathing, methylxanthine drugs, such as theophylline and caffeine, are administered to reverse this condition in humans and avoid the use of breathing-assistance equipment. These drugs cause stimulation of the central nervous system and the heart, however, both detrimental side effects in preterm infants. Antagonism of adenosine receptors is the proposed mechanism of methylxanthine action. Synthetic chemists have produced xanthine analogs with increased affinity for adenosine receptors that could lead to respiratory stimulation while reducing cardiostimulant effects. For this study, theophylline and 8-cyclopentyltheophylline …

Investigating Apoptosis Pathway In Chronic Lymphocytic Leukemia: Stromal Influence And Therapeutic Activation, Viralkumar M. Patel

Dissertations & Theses (Open Access)

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy. High levels of Bcl-2 and IAP family proteins are responsible for apoptotic-resistance and accumulation of mature CLL lymphocytes in bone-marrow, lymph nodes and peripheral blood. Besides pro-survival proteins, supporting stromal cells as well as soluble factors in the microenvironment of bone-marrow and lymph nodes provide survival advantage to CLL leukemic cells.

Though the stromal – leukemia cell interactions has been studied extensively, in-depth-knowledge on the regulation of apoptotic pathway proteins in the context of microenvironment is still limited. To address this, the first part of our study focused on comprehensive analysis of …

Importance Of Clinical Toxicology Teaching And Its Impact In Improving, Nadeem Ullah Khan, Jabeen Fayyaz, Uzma R. Khan, Asher Feroze

Department of Emergency Medicine

Objective: To assess the impact of a one-day clinical toxicology workshop in improving knowledge.
Methods: A one-day clinical toxicology workshop was conducted as a pre-conference workshop of the Annual Emergency Medicine Conference at the Aga Khan University Hospital, Karachi, in April 2012. The course was composed of poisoning-related common clinical scenarios. The pre-test and post-test understanding was used to assess the impact of the course in improving knowledge. The participants also evaluated the workshop as a whole thorough written evaluation forms. SPSS 19 was ued for statistical analysis of the data.
Result: There were 22 participants in the course. The …

Prolactin And Fmri Response To Skf38393 In The Baboon, Brad D. Miller, Lauren A. Marks, Jonathan M. Koller, Blake J. Newman, G Larry Bretthorst, Kevin J. Black

Kevin J. Black, MD

Background: This study’s goal was to provide dose-response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently validate a novel pharmacological MRI (phMRI) method. Dependent variables were functional MRI (fMRI) data from brain regions selected a priori, and systemic prolactin release. Necessary first steps included estimating the magnitude and time course of prolactin response to anesthesia alone and to various doses of agonist. These first steps (“time course studies”) were performed with three agonists, and the results were used to select …

High Dose, Variable Length, N-Acetylcysteine (Hinac) Therapy For Late-Presenting Acetaminophen Poisoning, Jessica K. Eygnor Do, Suprina Dorai Md, Philip W. Moore Do, J Ward Donovan Md, Keith K. Burkhart Md

Department of Emergency Medicine

No abstract provided.

Seizure Protection By Intrapulmonary Delivery Of Midazolam In Mice, Ashish Dhir, Dorota Zolkowska, Michael A. Rogawski

Michael A. Rogawski

The lung provides a portal of entry that could be used to rapidly deliver anticonvulsant substances to the brain to treat seizures. In the present study, we demonstrate that midazolam, a water-soluble anticonvulsant benzodiazepine, confers potent seizure protection when administered via the intrapulmonary route. High dose (100 mg/kg) intraperitoneal midazolam induced loss-of-righting reflex in mice. Lower doses of midazolam (100–1000 μg/kg) when administered intraperitoneally did not induce loss-of-righting reflex but protected animals against pentylenetetrazol (PTZ)-induced seizures. Intrapulmonary administration of midazolam via a tracheal cannula protected against intraperitoneal PTZ seizures at lower doses. The minimal intraperitoneal and intravenous doses of midazolam …

Long-Lasting Attenuation Of Amygdala-Kindled Seizures After Convection-Enhanced Delivery Of Botulinum Neurotoxins A And B Into The Amygdala In Rats, Maciej Gasior, Rebecca Tang, Michael A. Rogawski

Michael A. Rogawski

Botulinum neurotoxins (BoNTs) are well recognized to cause potent, selective and long-lasting neuroparalytic actions by blocking cholinergic neurotransmission to muscles and glands. There is evidence that BoNT isoforms can also inhibit neurotransmission in the brain. Here we examined whether locally delivered BoNT/A and BoNT/B can attenuate kindling measures in amygdala-kindled rats. Male rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully-kindled animals received a single infusion of vehicle or BoNT/A or BoNT/B at doses of 1, 3.2, or 10 ng over a 20-min period by convection enhanced delivery (CED). Electrographic (EEG) and behavioral …

Planarians Require An Intact Brain To Behaviorally React To Cocaine, But Not To React To Nicotine, Oné R. Pagán, Sean Deats, Debra Baker, Erica Montgomery, Galia Wilk, Matthew Tenaglia, Joshua Semon

Biology Faculty Publications

Planarians possess a rudimentary brain with many features in common with vertebrate brains. They also display a remarkable capacity for tissue regeneration including the complete regeneration of the nervous system. Using the induction of planarian seizure-like movements (pSLMs) as a behavioral endpoint, we demonstrate that an intact nervous system is necessary for this organism to react to cocaine exposure, but not necessary to react to nicotine administration. Decapitated planarians (Girardia tigrina) display pSLMs indistinguishable from intact worms when exposed to nicotine, but cocaine-induced pSLMs are reduced by about 95% upon decapitation. Decapitated worms recover their normal sensitivity to cocaine within …

Physiologically-Based Pharmacokinetic Modeling For Predicting Caffeine/Theophylline-Ciprofloxacin Interactions, David M. Ng, Ali Navid

STAR Program Research Presentations

Dynamics of interactions between the drugs caffeine, theophylline, and ciprofloxacin are predicted using physiologically-based pharmacokinetic (PBPK) modeling. Pharmacokinetic means the model determines where the drugs are distributed in the body over time. Physiologically-based means the anatomy and physiology of the human body are reflected in the structure and functioning of the model. Multiple drugs can interact to increase or decrease their beneficial and/or undesired effects. This is important because some common substances, such as caffeine in coffee, soft drinks, and energy drinks, are actually drugs that affect the body. Ciprofloxacin is an inhibitor of caffeine and theophylline metabolism; such inhibition …

Selected Neuropharmacology Of Resurgence, Adam D. Pyszczynski

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

The reemergence of problem behavior (i.e., relapse) is a key concern in most behavioral interventions. Resurgence refers to the reappearance of a previously rewarded behavior when reward for an alternative behavior is also discontinued. It is especially relevant to the reappearance of problem behavior because many behavioral interventions discontinue reward for aberrant behavior while simultaneously rewarding an appropriate response.

Understanding the underlying neuropharmacology of behavioral phenomena such as resurgence is important because it helps elucidate the neural processes at the root of such behavior, and also has implications for pharmacotherapies. Existing information about the neuropharmacology of resurgence is scarce, but …

Issues Related To Development Of New Antiseizure Treatments, Karen S. Wilcox, Tracy Dixon-Salazar, Graeme J. Sills, Elinor Ben-Menachem, H. Steve White, Roger J. Porter, Marc A. Dichter, Solomon L. Moshe, Jeffrey L. Noebels, Michael D. Privitera, Michael A. Rogawski

Michael A. Rogawski

This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. We also briefly address …

Molecular Mechanisms Underlying The Early Life Programming Of The Liver, Gurjeev Sohi

Electronic Thesis and Dissertation Repository

Clinical studies have demonstrated that intrauterine growth restriction (IUGR) offspring, faced with a nutritional mismatch postpartum, have an increased risk of developing the metabolic syndrome. The maternal protein restriction (MPR) rat model has been extensively studied to investigate the adverse effects of a nutritional mismatch in postnatal life of IUGR offspring. Previous studies have demonstrated that MPR leads to impaired function of the liver, an important metabolic organ. However the underlying mechanisms which predispose these offspring to the metabolic syndrome remain elusive. In the following studies, low protein diet during pregnancy and lactation led to IUGR offspring with decreased liver …

N-Acetylcysteine As A Chemoprotectant Against Ifosfamide Nephrotoxicity; From Mechanism To Prevention, Lauren Hanly

Electronic Thesis and Dissertation Repository

The chemotherapy drug ifosfamide is used in the treatment of several childhood cancers. While effective, its use in children results in a 30% incidence of nephrotoxicity, and 5% incidence of Fanconi syndrome. This late effect is caused by oxidative damage, generated by chloroacetaldehyde, a toxic metabolite of ifosfamide cytochrome P450-mediated bioactivation in the kidney tubules. N-acetylcysteine has been identified as a promising strategy to mitigate nephrotoxicity through its antioxidant and glutathione stimulating properties. Furthermore, with current use in children for acetaminophen poisoning, its clinical utility is evident. Both cell and animal models have demonstrated n-acetylcysteine’s effectiveness in mitigating ifosfamide kidney …

Mechanism Of Ascorbate Protection Against Sepsis-Induced Capillary Blood Flow Impairment, Dan Secor

Electronic Thesis and Dissertation Repository

Sepsis is a systemic inflammatory response to an infection. The overwhelming inflammation has many deleterious effects, including cessation of capillary blood flow. This cessation may lead to organ failure and subsequent death, but the cause of cessation during sepsis is not fully understood. Ascorbate (reduced vitamin C) has been shown to restore capillary blood flow by an unknown mechanism. I hypothesized that activation of both platelets and the coagulation pathway in sepsis contributes to the cessation of capillary blood flow and that ascorbate protects against cessation by reducing platelet activation.

Using intravital microscopy in the mouse hindlimb skeletal muscle in …

Design, Synthesis And Development Of Transporter Targeting Agents For Image-Guided Therapy And Drug Delivery, Ning Tsao

Dissertations & Theses (Open Access)

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with ^99mTc and ⁶⁸Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both ^99mTc-N4amG and ^99mTc-GP were stable up to 6 hours, whereas ⁶⁸Ga-GP was stable up to 2 hours. Cell culture studies …

Liposomal Fasudil, A Rho-Kinase Inhibitor, For Prolonged Pulmonary Preferential Vasodilation In Pulmonary Arterial Hypertension, Vivek Gupta, Nilesh Gupta, Imam H. Shaik, Reza Mehvar, Ivan F. Mcmurty, Masahiko Osa, Eva Nozik-Grayck, Fakhrul Ahsan

Pharmacy Faculty Articles and Research

Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were …

The Effects Of Selected Drugs On The Memory Recall Of Sleep Deprived Mice, Jenn Pauldurai

Senior Research Projects

Humans often make use of the neurotransmission altering effects of drugs such as caffeine, ephedrine, and ethanol. These drugs induce changes in memory and learning ability, specifically when used for sleep deprivation. English white mice (Mus musculus) have been shown to exhibit similar cognitive changes when administered drugs while sleep deprived. A sample of 20 mice was divided into three experimental groups (each group receiving a different drug) and one control group. Maze-testing demonstrated that mice performance decreased with sleep deprivation (Treatment-1) but all groups returned to baseline performance when injected (IP) with selected drugs (Treatment-2), regardless of …

Modulation Of Synaptic Transmission By Adenosine In Layer 2/3 Of The Rat Visual Cortex In Vitro, Nicholas M. Bannon

Master's Theses

No abstract provided.

Overcoming Tumor Drug Resistance By Activating Amp-Activated Protein Kinase And Destabilizing Oncoproteins, Min Shen

Wayne State University Dissertations

Although considerable progress has been achieved in the field of cancer therapeutics, primary or acquired drug resistance remains a fundamental cause of therapeutic failure in cancer therapy. Among different mechanisms characterized that are responsible for tumor drug resistance, there is increasing evidence suggesting that dysregulation of gene expression, especially oncogene or tumor suppressor gene expression, at either gene transcription or protein synthesis level, can contribute to the drug-resistant phenotype. AMP-activated protein kinase (AMPK) is a well-known major cellular energy sensor, which negatively regulates metabolic pathways such as protein synthesis, fatty acid oxidation and glucose consumption. Activation of AMPK may suppress …

The Effects Of Acute Nicotine Administration On Memory Formation And Neural Activity In The Hippocampus, Perirhinal Cortex, And Medial Septum: Implications For Neurodegenerative Disorders, Matthew Wishnoff

Behavioral Neuroscience Honors Papers

Within the general public, nicotine is commonly thought of as a harmful molecule due to its role in tobacco addiction. However, nicotinic stimulation of the cholinergic system has also been shown to enhance cognitive functioning. This enhancement is thought to be caused by an increase in the release of the neurotransmitter, acetylcholine (ACh), which is responsible for mediating a variety of cognitive processes, such as REM sleep and memory formation. Recent research by Melichercik and colleagues shows that systemic nicotine administration enhances memory acquisition for both object location and object recognition memory in rats, as assessed by a modified version …

Psychologists And Medications In The Era Of Interprofessional Care: Collaboration Is Less Problematic And Costly Than Prescribing, William N. Robiner, Tim R. Tumlin, Tanya Tompkins

Faculty Publications

Increasing emphasis on interprofessionalism and teamwork in healthcare renders psychologists’ collaborations critical and invites reexamination of psychologists’ roles related to medications. The Collaboration Level outlined by the APA’s Ad Hoc Task Force is more achievable and in synch with health reform than prescription privileges (RxP). RxP remains controversial due to training and safety concerns, lacking support from health professionals, psychologists, and consumers. Differences in educational preparation of psychologists relative to prescribing professionals are discussed. Enactment of only three of 170 RxP initiatives reveals RxP to be a costly, ineffectual agenda. Alternatives (e.g., integrated care, collaboration, telehealth) increase access without risks …

The Effect Of Alpha-Cyclodextrin On Acute Blood Lipid And Glycemic Responses To A Fat Containg Meal, Evan Neil Fletcher

Wayne State University Theses

Obesity and hyperlipidemia have become major concerns in the United States over the past 30 years. Alpha-Cyclodextrin (á-CD), a naturally occurring soluble dietary fiber, has been shown to reduce dietary fat absorption and improve blood lipid levels in an animal model (mouse and rat) and in human studies. In the current double blind study, 34 healthy male and female participants were recruited to test if á-CD had any acute effect on blood lipid and glycemic responses to a fat containing meal. The participants received the á-CD on one occasion and a placebo the other to determine if there was any …

Does The Use Of Varenicline For Smoking-Cessation Therapy Create Or Increase Depression In Patients Without Existing Depressive Illness?, Brett R. Brown

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not the use of varenicline for smoking-cessation therapy creates or increases depression in patients without existing depressive illness.

STUDY DESIGN: Review of two randomized controlled trials published in 2011 and one observational cohort study published in 2009, all English language.
DATA SOURCES: Two randomized, double-blind, controlled clinical trials comparing varenicline to placebo in smoking cessation, and one observational cohort study comparing varenicline use within subjects. All articles were found using PubMed and EBSCO.

OUTCOMES MEASURED: Changes in depression was evaluated using the MontgomeryÅsberg Depression Rating Scale …

Androgen Receptor-Target Genes In African American Prostate Cancer Disparities, Bi-Dar Wang, Qi Yang, Kristin Ceniccola, Fernando Bianco, Ramez Andrawis, Thomas W. Jarrett, Harold A. Frazier, Steven R. Patierno, Norman H. Lee

Pharmacology and Physiology Faculty Publications

The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter …

The Analgesic And Anticonvulsant Effects Of Piperine In Mice, I A. Bukhari, M S. Alhumayyd, A L. Mahesar, A H. Gilani

Department of Biological & Biomedical Sciences

Piperine, is the major active principal of black pepper. In traditional medicine, black pepper has been used as an analgesic, anti-inflammatory agent and in the treatment of epilepsy. This study was conducted to evaluate the in vivo analgesic and anticonvulsant effects of piperine in mice. The analgesic and anticonvulsant effects of piperine were studied in mice using acetic acid-induced writhing, tail flick assay, pentylenetetrazole (PTZ)- and picrotoxin (PIC)-induced seizures models. The intraperitoneal (i.p.) administration of piperine (30, 50 and 70 mg/kg) significantly inhibited (P<0.01) the acetic acid-induced writhing in mice, similar to the effect of indomethacin (20 mg/kg i.p.). In the tail flick assay, piperine (30 and 50 mg/kg, i.p.) and morphine (5 mg/kg, i.p.) caused a significant increase (P<0.01) in the reaction time of mice. Pre-treatment of animals with naloxone (5 mg/kg i.p.), reversed the analgesic effects of both piperine and morphine in the tail flick assay. Piperine (30, 50 and 70 mg/kg, i.p.) and standard drugs, valproic acid (200 mg/kg, i.p.), carbamazepine (30 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) significantly (P<0.01) delayed the onset of PTZ-and PIC-induced seizures in mice. These findings indicate that piperine exhibits analgesic and anticonvulsant effects possibly mediated via opioid and GABA-ergic pathways respectively. Moreover, piperine being the main constituent of black pepper, may be contributing factor in the medicinal uses of black pepper in pain and epilepsy

Methylphenidate And Atomoxetine Treatment During Adolescence In The Spontaneously Hypertensive Rat: Mechanisms Underlying High Cocaine Abuse Liability In Attention Deficit/Hyperactivity Disorder, Sucharita S. Somkuwar

Theses and Dissertations--Pharmacy

Effects of pharmacotherapies for Attention Deficit/Hyperactivity Disorder (ADHD) on cocaine abuse liability in ADHD are not understood. Spontaneously Hypertensive Rats (SHR), an ADHD model, exhibited greater cocaine self-administration than control Wistar-Kyoto and Wistar rats. Methylphenidate, but not atomoxetine during adolescence enhanced cocaine self-administration in adult SHRs compared to controls. The mesocortical dopaminergic system, including medial prefrontal (mPFC) and orbitofrontal (OFC) cortices, is important for ADHD and cocaine addiction. Dopamine and norepinephrine transporter (DAT and NET) are molecular targets for methylphenidate, atomoxetine and cocaine action.

In the current studies, SHR, Wistar-Kyoto and Wistar were administered methylphenidate (1.5 mg/kg/day, p.o.), atomoxetine (0.3 …

Fine Tuning A Well-Oiled Machine: Influence Of Nk1.1 And Nkg2d On Nkt Cell Development And Function, Sunil K. Joshi, Mark L. Lang

Bioelectrics Publications

Natural killer T cells (NKT) represent a group of CD1d-restricted T-lineage cells that provide a functional interface between innate and adaptive immune responses in infectious disease, cancer, allergy and autoimmunity. There have been remarkable advances in understanding the molecular events that underpin NKT development in the thymus and in the complex array of functions in the periphery. Most functional studies have focused on activation of T cell antigen receptors expressed by NKT cells and their responses to CD1d presentation of glycolipid and related antigens. Receiving less attention has been several molecules that are hallmarks of Natural Killer (NK) cells, but …

The Inflammatory Response Initiated By The Spleen To Ischemic Stroke, Hilary Seifert

USF Tampa Graduate Theses and Dissertations

The peripheral immune system plays a role in delayed neural injury after stroke. This response originates from the spleen as splenectomy prior to middle cerebral artery occlusion (MCAO) in rats significantly reduces infarct volume in the brain. This research is based on the hypothesis that inhibiting the splenic response will reduce neurodegeneration after stroke. Studies in animals have implicated lymphocytes as the immune cell type that is detrimental following MCAO. Interferon gamma (IFNγ) has been identified as a pro-inflammatory cytokine that is also detrimental following stroke. IFNγ is important because it activates microglia and macrophages in a pro-inflammatory nature that …