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Table S1: Sensitivity, Specificity, PPV, NPV, and F1 Score of NLP Vs. ICD for Identification of Symptoms for (A) Biome Developm
Table S1: Sensitivity, specificity, PPV, NPV, and F1 score of NLP vs. ICD for identification of symptoms for (A) BioMe development cohort; (B) BioMe validation cohort; (C) MIMIC-III; (D) 1 year of notes from patients in BioMe calculated using manual chart review. A) Fatigue Nausea and/or vomiting Anxiety Depression NLP (95% ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P CI) 0.99 (0.93- 0.59 (0.43- <0.00 0.25 (0.12- <0.00 <0.00 0.54 (0.33- Sensitivity 0.99 (0.9 – 1) 0.98 (0.88 -1) 0.3 (0.15-0.5) 0.85 (0.65-96) 0.02 1) 0.73) 1 0.42) 1 1 0.73) 0.57 (0.29- 0.9 (0.68- Specificity 0.89 (0.4-1) 0.75 (0.19-1) 0.68 0.97 (0.77-1) 0.03 0.98 (0.83-1) 0.22 0.81 (0.53-0.9) 0.96 (0.79-1) 0.06 0.82) 0.99) 0.99 (0.92- 0.86 (0.71- 0.94 (0.79- 0.79 (0.59- PPV 0.96 (0.82-1) 0.3 0.95 (0.66-1) 0.02 0.95 (0.66-1) 0.16 0.93 (0.68-1) 0.12 1) 0.95) 0.99) 0.92) 0.13 (0.03- <0.00 0.49 (0.33- <0.00 0.66 (0.48- NPV 0.89 (0.4-1) 0.007 0.94 (0.63-1) 0.34 (0.2-0.51) 0.97 (0.81-1) 0.86 (0.6-0.95) 0.04 0.35) 1 0.65) 1 0.81) <0.00 <0.00 <0.00 F1 Score 0.99 0.83 0.88 0.57 0.95 0.63 0.82 0.79 0.002 1 1 1 Itching Cramp Pain NLP (95% ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P CI) 0.98 (0.86- 0.24 (0.09- <0.00 0.09 (0.01- <0.00 0.52 (0.37- <0.00 Sensitivity 0.98 (0.85-1) 0.99 (0.93-1) 1) 0.45) 1 0.29) 1 0.66) 1 0.89 (0.72- 0.5 (0.37- Specificity 0.96 (0.8-1) 0.98 (0.86-1) 0.68 0.98 (0.88-1) 0.18 0.5 (0-1) 1 0.98) 0.66) 0.88 (0.69- PPV 0.96 (0.8-1) 0.8 (0.54-1) 0.32 0.8 (0.16-1) 0.22 0.99 (0.93-1) 0.98 (0.87-1) NA* 0.97) 0.98 (0.85- 0.57 (0.41- <0.00 0.58 (0.43- <0.00 NPV 0.98 (0.86-1) 0.5 (0-1) 0.02 (0-0.08) NA* 1) 0.72) 1 0.72) 1 <0.00 <0.00 <0.00 F1 Score 0.97 0.56 0.91 0.28 0.99 0.68 1 1 1 *Denotes 95% confidence intervals and P values that could not be calculated due to insufficient cells in 2x2 tables. -
Nitrate Prodrugs Able to Release Nitric Oxide in a Controlled and Selective
Europäisches Patentamt *EP001336602A1* (19) European Patent Office Office européen des brevets (11) EP 1 336 602 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07C 205/00, A61K 31/00 20.08.2003 Bulletin 2003/34 (21) Application number: 02425075.5 (22) Date of filing: 13.02.2002 (84) Designated Contracting States: (71) Applicant: Scaramuzzino, Giovanni AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 20052 Monza (Milano) (IT) MC NL PT SE TR Designated Extension States: (72) Inventor: Scaramuzzino, Giovanni AL LT LV MK RO SI 20052 Monza (Milano) (IT) (54) Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases (57) New pharmaceutical compounds of general effects and for this reason they are useful for the prep- formula (I): F-(X)q where q is an integer from 1 to 5, pref- aration of medicines for prevention and treatment of in- erably 1; -F is chosen among drugs described in the text, flammatory, ischemic, degenerative and proliferative -X is chosen among 4 groups -M, -T, -V and -Y as de- diseases of musculoskeletal, tegumental, respiratory, scribed in the text. gastrointestinal, genito-urinary and central nervous sys- The compounds of general formula (I) are nitrate tems. prodrugs which can release nitric oxide in vivo in a con- trolled and selective way and without hypotensive side EP 1 336 602 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 336 602 A1 Description [0001] The present invention relates to new nitrate prodrugs which can release nitric oxide in vivo in a controlled and selective way and without the side effects typical of nitrate vasodilators drugs. -
The Role of Organic Small Molecules in Pain Management
molecules Review The Role of Organic Small Molecules in Pain Management Sebastián A. Cuesta and Lorena Meneses * Laboratorio de Química Computacional, Facultad de Ciencias Exactas y Naturales, Escuela de Ciencias Químicas, Pontificia Universidad Católica del Ecuador, Av. 12 de Octubre 1076 Apartado, Quito 17-01-2184, Ecuador; [email protected] * Correspondence: [email protected]; Tel.: +593-2-2991700 (ext. 1854) Abstract: In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented. Keywords: anti-inflammatory drugs; QSAR; pain management; cyclooxygenase; multitarget drug; Citation: Cuesta, S.A.; Meneses, L. cannabinoid; neuropathic pain The Role of Organic Small Molecules in Pain Management. -
Crowdsourcing Analysis of Off-Label Intervention Usage in Amyotrophic Lateral Sclersosis
CROWDSOURCING ANALYSIS OF OFF-LABEL INTERVENTION USAGE IN AMYOTROPHIC LATERAL SCLERSOSIS A Thesis Presented to The Academic Faculty by Benjamin I. Mertens In Partial Fulfillment of the Requirements for the Degree B.S. in Biomedical Engineering with the Research Option in the Wallace H. Coulter School of Biomedical Engineering Georgia Institute of Technology Spring 2017 1 ACKNOWLEDGEMENTS I would like to thank my research advisor, Dr. Cassie Mitchell, first and foremost, for helping me through this long process of research, analysis, writing this thesis and the corresponding article to be submitted for peer-reviewed journal publication. There is no way I could have done this, or written it as eloquently without her. Next, I would like to acknowledge Grant Coan, Gloria Bowen, and Nathan Neuhart for all helping me on the road to writing this paper. Lastly, I would like to thank Dr. Lena Ting for her consultation as the faculty reader. 2 TABLE OF CONTENTS Page ACKNOWLEDGEMENTS 2 LIST OF TABLES 4 LIST OF FIGURES 5 LIST OF ABBREVIATIONS 6 SUMMARY 7 CHAPTERS 1 Philosophy 9 2 Crowdsourced Off-label Medications to Extend ALS Disease Duration 12 Introduction 12 Methodology 15 Results 18 Discussion 25 Tables 33 Figures 38 APPENDIX A: All Table 2 Appearance in Patients and Visits 44 APPENDIX B: All Table 3 Appearance in Patients and Visits 114 REFERENCES 129 3 LIST OF TABLES Page Table 1: Database Overview 33 Table 2: Ontology of Individual Medications 34 Table 3: Ontology of Intervention Groups 36 4 LIST OF FIGURES Page Figure 1: Relational circle -
Research Article RP-HPLC Method for Determination of Several Nsaids and Their Combination Drugs
Hindawi Publishing Corporation Chromatography Research International Volume 2013, Article ID 242868, 13 pages http://dx.doi.org/10.1155/2013/242868 Research Article RP-HPLC Method for Determination of Several NSAIDs and Their Combination Drugs Prinesh N. Patel, Gananadhamu Samanthula, Vishalkumar Shrigod, Sudipkumar C. Modh, and Jainishkumar R. Chaudhari Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Andhra Pradesh 500037, India Correspondence should be addressed to Gananadhamu Samanthula; [email protected] Received 29 June 2013; Accepted 13 October 2013 Academic Editor: Andrew Shalliker Copyright © 2013 Prinesh N. Patel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. An RP-HPLC method for simultaneous determination of 9 NSAIDs (paracetamol, salicylic acid, ibuprofen, naproxen, aceclofenac, diclofenac, ketorolac, etoricoxib, and aspirin) and their commonly prescribed combination drugs (thiocolchicoside, moxifloxacin, clopidogrel, chlorpheniramine maleate, dextromethorphan, and domperidone) was established. The separation was performed on ∘ Kromasil C18 (250 × 4.6 mm, 5 m) at 35 C using 15 mM phosphate buffer pH 3.25 and acetonitrile with gradient elution ata flow rate of 1.1 mL/min. The detection was performed by a diode array detector (DAD) at 230 nm with total run time of 30min. 2 Calibration curves were linear with correlation coefficients of determinationr ( ) > 0.999. Limit of detection (LOD) and Limit of quantification (LOQ) ranged from 0.04 to 0.97 g/mL and from 0.64 to 3.24 g/mL, respectively. -
Targeting the Deubiquitinase STAMBP Inhibits NALP7 Inflammasome
ARTICLE Received 19 Jul 2016 | Accepted 8 Mar 2017 | Published 11 May 2017 DOI: 10.1038/ncomms15203 OPEN Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity Joseph S. Bednash1, Nathaniel Weathington1, James Londino1, Mauricio Rojas1, Dexter L. Gulick1, Robert Fort1, SeungHye Han1, Alison C. McKelvey1, Bill B. Chen1 & Rama K. Mallampalli1,2,3 Inflammasomes regulate innate immune responses by facilitating maturation of inflammatory cytokines, interleukin (IL)-1b and IL-18. NACHT, LRR and PYD domains-containing protein 7 (NALP7) is one inflammasome constituent, but little is known about its cellular handling. Here we show a mechanism for NALP7 protein stabilization and activation of the inflammasome by Toll-like receptor (TLR) agonism with bacterial lipopolysaccharide (LPS) and the synthetic acylated lipopeptide Pam3CSK4. NALP7 is constitutively ubiquitinated and recruited to the endolysosome for degradation. With TLR ligation, the deubiquitinase enzyme, STAM-binding protein (STAMBP) impedes NALP7 trafficking to lysosomes to increase NALP7 abundance. STAMBP deubiquitinates NALP7 and STAMBP knockdown abrogates LPS or Pam3CSK4-induced increases in NALP7 protein. A small-molecule inhibitor of STAMBP deubiquitinase activity, BC-1471, decreases NALP7 protein levels and suppresses IL-1b release after TLR agonism. These findings describe a unique pathway of inflammasome regulation with the identification of STAMBP as a potential therapeutic target to reduce pro-inflammatory stress. 1 Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore, NW 628, Pittsburgh, Pennsylvania 15213, USA. 2 Departments of Cell Biology and Physiology and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. 3 Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, USA. -
Métrologie De La Douleur Animale Sur Modèles Expérimentaux : Développement Et Validation De Biomarqueurs Neuroprotéomiques
Université de Montréal Métrologie de la douleur animale sur modèles expérimentaux : développement et validation de biomarqueurs neuroprotéomiques. par Colombe Otis Département de biomédecine vétérinaire Faculté de médecine vétérinaire Thèse présentée à la Faculté de médecine vétérinaire en vue de l’obtention du grade de philosophiæ doctor (Ph. D.) en sciences vétérinaires option pharmacologie Août, 2017 © Colombe Otis, 2017 Résumé La douleur est un phénomène complexe et dynamique comprenant un processus primaire et sensoriel, la nociception, auquel se rajoutent des réactions de défense et d'alarme psychophysiologiques. Ceci conduit au développement d'une véritable mémoire de la douleur, individuelle et modulée (plasticité neuronale) par des expériences précédentes de douleur, incluant entre autres, des phénomènes de sensibilisation nociceptive. Pour bien comprendre les mécanismes de sensibilisation centrale, les modèles animaux mimant les pathologies humaines sont d’une importance primordi ale. Or, pour ce faire, nous avons proposé une série d'approches expérimentales translationnelles par le développement de modèles expérimentaux de douleur bovine, canine et murine afin de caractériser les atteintes du protéome spinal en fonction du niveau de douleur perçu par l'animal et d’identifier le (les) marqueur (s) potentiellement modulé (s) par la sensibilisation nociceptive. À l’aide de la neuroprotéomique, nous avons identifié sur un modèle bovin de douleur viscérale, la protéine transthyrétine (TTR) comme étant sous-exprimée dans le protéome spinal en présence de douleur et ce, vérifié également dans le modèle canin de douleur chronique liée à l’arthrose chirurgicale. Ces résultats suggèrent la possibilité d’entrevoir la TTR comme un biomarqueur potentiel de la douleur chronique. Notre découverte de la relation entre les niveaux spinaux de TTR par neuroprotéomique et l’ hypersensibilité à la douleur dans les modèles bovin et canin soutiennent l’implication de composantes inflammatoires nociceptives et immunitaires. -
Calcium Channel Blocker As a Drug Candidate for the Treatment of Generalised Epilepsies
UNIVERSITAT DE BARCELONA Faculty of Pharmacy and Food Sciences Calcium channel blocker as a drug candidate for the treatment of generalised epilepsies Final degree project Author: Janire Sanz Sevilla Bachelor's degree in Pharmacy Primary field: Organic Chemistry, Pharmacology and Therapeutics Secondary field: Physiology, Pathophysiology and Molecular Biology March 2019 This work is licensed under a Creative Commons license ABBREVIATIONS AED antiepileptic drug AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANNA-1 antineuronal nuclear antibody 1 BBB blood-brain barrier Bn benzyl BnBr benzyl bromide BnNCO benzyl isocyanate Boc tert-butoxycarbonyl Bu4NBr tetrabutylammonium bromide Ca+2 calcium ion CACNA1 calcium channel voltage-dependent gene cAMP cyclic adenosine monophosphate CCB calcium channel blocker cGMP cyclic guanosine monophosphate CH3CN acetonitrile Cl- chlorine ion Cmax maximum concentration CMV cytomegalovirus CTScan computed axial tomography DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF dimethylformamide DMPK drug metabolism and pharmacokinetics DNET dysembryoplastic neuroepithelial tumours EEG electroencephalogram EPSP excitatory post-synaptic potential FDA food and drug administration Fe iron FLIPR fluorescence imaging plate reader fMRI functional magnetic resonance imaging GABA γ-amino-α-hydroxybutyric acid GAD65 glutamic acid decarboxylase 65 GAERS generalised absence epilepsy rat of Strasbourg GluR5 kainate receptor GTC generalised tonic-clonic H+ hydrogen ion H2 hydrogen H2O dihydrogen dioxide (water) -
01012100 Pure-Bred Horses 0 0 0 0 0 01012900 Lives Horses, Except
AR BR UY Mercosu PY applied NCM Description applied applied applied r Final Comments tariff tariff tariff tariff Offer 01012100 Pure-bred horses 0 0 0 0 0 01012900 Lives horses, except pure-bred breeding 2 2 2 2 0 01013000 Asses, pure-bred breeding 4 4 4 4 4 01019000 Asses, except pure-bred breeding 4 4 4 4 4 01022110 Purebred breeding cattle, pregnant or lactating 0 0 0 0 0 01022190 Other pure-bred cattle, for breeding 0 0 0 0 0 Other bovine animals for breeding,pregnant or 01022911 lactating 2 2 2 2 0 01022919 Other bovine animals for breeding 2 2 2 2 4 01022990 Other live catlle 2 2 2 2 0 01023110 Pure-bred breeding buffalo, pregnant or lactating 0 0 0 0 0 01023190 Other pure-bred breeding buffalo 0 0 0 0 0 Other buffalo for breeding, ex. pure-bred or 01023911 pregnant 2 2 2 2 0 Other buffalo for breeding, except pure-bred 01023919 breeding 2 2 2 2 4 01023990 Other buffalos 2 2 2 2 0 01029000 Other live animals of bovine species 0 0 0 0 0 01031000 Pure-bred breedig swines 0 0 0 0 0 01039100 Other live swine, weighing less than 50 kg 2 2 2 2 0 01039200 Other live swine, weighing 50 kg or more 2 2 2 2 0 01041011 Pure-bred breeding, pregnant or lactating, sheep 0 0 0 0 0 01041019 Other pure-bred breeding sheep 0 0 0 0 0 01041090 Others live sheep 2 2 2 2 0 01042010 Pure-bred breeding goats 0 0 0 0 0 01042090 Other live goats 2 2 2 2 0 Fowls spec.gallus domestic.w<=185g pure-bred 01051110 breeding 0 0 0 0 0 Oth.live fowls spec.gall.domest.weig.not more than 01051190 185g 2 2 2 2 0 01051200 Live turkeys, weighing not more than 185g 2 2 -
About Pain Pharmacology: What Pain Physicians Should Know Kyung-Hoon Kim1, Hyo-Jung Seo1, Salahadin Abdi2, and Billy Huh2
Korean J Pain 2020;33(2):108-120 https://doi.org/10.3344/kjp.2020.33.2.108 pISSN 2005-9159 eISSN 2093-0569 Review Article All about pain pharmacology: what pain physicians should know Kyung-Hoon Kim1, Hyo-Jung Seo1, Salahadin Abdi2, and Billy Huh2 1Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Yangsan, Korea 2Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Received February 8, 2020 Revised March 12, 2020 From the perspective of the definition of pain, pain can be divided into emotional Accepted March 13, 2020 and sensory components, which originate from potential and actual tissue dam- age, respectively. The pharmacologic treatment of the emotional pain component Correspondence includes antianxiety drugs, antidepressants, and antipsychotics. The anti-anxiety Kyung-Hoon Kim drugs have anti-anxious, sedative, and somnolent effects. The antipsychotics are Department of Anesthesia and Pain effective in patients with positive symptoms of psychosis. On the other hand, the Medicine, Pusan National University sensory pain component can be divided into nociceptive and neuropathic pain. Yangsan Hospital, 20 Geumo-ro, Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are usually applied for Mulgeum-eup, Yangsan 50612, Korea Tel: +82-55-360-1422 somatic and visceral nociceptive pain, respectively; anticonvulsants and antide- Fax: +82-55-360-2149 pressants are administered for the treatment of neuropathic pain with positive and E-mail: [email protected] negative symptoms, respectively. The NSAIDs, which inhibit the cyclo-oxygenase pathway, exhibit anti-inflammatory, antipyretic, and analgesic effects; however, they have a therapeutic ceiling. -
Gabapentin Abuse Gabapentin (Neurontin®) Is Indicated for the Treatment of Epilepsy and Neuro- Pathic Pain, Including Post-Herpetic Neuralgia
November 2018 Poison Center Hotline: 1-800-222-1222 The Maryland Poison Center’s Monthly Update: News, Advances, Information Gabapentin Abuse Gabapentin (Neurontin®) is indicated for the treatment of epilepsy and neuro- pathic pain, including post-herpetic neuralgia. Gabapentin is often prescribed off -label for a variety of conditions including insomnia, anxiety, bipolar disorder, migraines, drug and alcohol addiction, and others. Off-label use exceeds use for FDA approved indications. Termed a gabapentinoid, it is an analog of γ- aminobutyric acid (GABA) that increases GABA but does not bind to GABA re- ceptors. It has a selective inhibitory effect on voltage-gated calcium channels containing the α2δ1 subunit. Its exact mechanism for epilepsy and pain is un- clear. Gabapentin is not a controlled substance as it was believed that gabapentin had no abuse potential when approved by the FDA in 1993. Overall, if used at thera- Did you know? peutic doses by patients without a substance abuse/misuse history, the risk of misuse is probably lower than that of other drugs such as benzodiazepines. There are reports of abuse of However, reports are increasing of gabapentin misuse and abuse. Motivations pregabalin (Lyrica ®), another for misuse include recreational use, mood and/or anxiety control, potentiating gabapentinoid used for the effects of drug abuse treatment, pain management, reducing cravings for neuropathic pain, post-herpetic other drugs, managing withdrawal from other drugs, substituting for other pain and fibromyalgia. drugs, and gabapentin addiction (Addiction 2016;11:1160-74). The risk of misuse Approved by the FDA in 2004, increases in people with a history of recreational drug abuse who take gabapen- pregabalin is Schedule V. -
85 Mv Respectively. When the Membranewas Depolarized, Th
J. Physiol. (1985), 360, pp. 161-185 161 With 14 text-figurem Printed in Great Britain COMPARISON OF THE ACTION OF BACLOFEN WITH y-AMINOBUTYRIC ACID ON RAT HIPPOCAMPAL PYRAMIDAL CELLS IN VITRO BY N. R. NEWBERRY* AND R. A. NICOLLt From the Departments of Pharmacology and Physiology, University of California, San Francisco, CA 94143, U.S.A. (Received 13 June 1984) SUMMARY 1. Intracellular recordings from CAI pyramidal cells in the hippocampal slice preparation were used to compare the action of baclofen, a y-aminobutyric acid (GABA) analogue, with GABA. 2. Ionophoretic application of GABA or baclofen into stratum (s.) pyramidale evoked hyperpolarizations associated with reductions in the input resistance of the cell. Baclofen responses were easier to elicit in the dendrites than in the cell body layer. 3. Blockade of synaptic transmission, with tetrodotoxin or cadmium, did not reduce baclofen responses, indicating a direct post-synaptic action. 4. (+ )-Bicuculline (10 ,UM) and bicuculline methiodide (100 /SM) had little effect on baclofen responses but strongly antagonized somatic GABA responses of equal amplitude. The bicuculline resistance of the baclofen response was not absolute, as higher concentrations of these compounds did reduce it. Pentobarbitone (100 /M) enhanced somatic GABA responses without affecting baclofen responses. (-)-Baclofen was approximately 200 times more potent than (+ )-baclofen. 5. The reversal potentials for the somatic GABA and baclofen responses were -70 mV and -85 mV respectively. When the membrane was depolarized, the baclofen response was reduced. This apparent voltage sensitivity was not seen with somatic GABA responses. 6. Altering the chloride gradient across the cell membrane altered the reversal potential of the somatic GABA response but not that ofthe baclofen response.