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Carbon Monoxide Down-Regulates Α4β1 Integrin
Chigaev et al. BMC Immunology 2014, 15:52 http://www.biomedcentral.com/1471-2172/15/52 RESEARCH ARTICLE Open Access Carbon monoxide down-regulates α4β1 integrin-specific ligand binding and cell adhesion: a possible mechanism for cell mobilization Alexandre Chigaev1,2,3*, Yelena Smagley1,2,3 and Larry A Sklar1,2,3 Abstract Background: Carbon monoxide (CO), a byproduct of heme degradation, is attracting growing attention from the scientific community. At physiological concentrations, CO plays a role as a signal messenger that regulates a number of physiological processes. CO releasing molecules are under evaluation in preclinical models for the management of inflammation, sepsis, ischemia/reperfusion injury, and organ transplantation. Because of our discovery that nitric oxide signaling actively down-regulates integrin affinity and cell adhesion, and the similarity between nitric oxide and CO-dependent signaling, we studied the effects of CO on integrin signaling and cell adhesion. Results: We used a cell permeable CO releasing molecule (CORM-2) to elevate intracellular CO, and a fluorescent Very Late Antigen-4 (VLA-4, α4β1-integrin)-specific ligand to evaluate the integrin state in real-time on live cells. We show that the binding of the ligand can be rapidly down-modulated in resting cells and after inside-out activation through several Gαi-coupled receptors. Moreover, cell treatment with hemin, a natural source of CO, resulted in comparable VLA-4 ligand dissociation. Inhibition of VLA-4 ligand binding by CO had a dramatic effect on cell-cell interaction in a VLA-4/VCAM-1-dependent cell adhesion system. Conclusions: We conclude that the CO signaling pathway can rapidly down-modulate binding of the VLA-4 -specific ligand. -
Eslicarbazepine Acetate Longer Procedure No
European Medicines Agency London, 19 February 2009 Doc. Ref.: EMEA/135697/2009 CHMP ASSESSMENT REPORT FOR authorised Exalief International Nonproprietary Name: eslicarbazepine acetate longer Procedure No. EMEA/H/C/000987 no Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. product Medicinal 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 16 E-mail: [email protected] http://www.emea.europa.eu TABLE OF CONTENTS 1. BACKGROUND INFORMATION ON THE PROCEDURE........................................... 3 1.1. Submission of the dossier ...................................................................................................... 3 1.2. Steps taken for the assessment of the product..................................................................... 3 2. SCIENTIFIC DISCUSSION................................................................................................. 4 2.1. Introduction............................................................................................................................ 4 2.2. Quality aspects ....................................................................................................................... 5 2.3. Non-clinical aspects................................................................................................................ 8 2.4. Clinical aspects.................................................................................................................... -
Long-Term Administration of Tolvaptan to Patients with Decompensated
Int. J. Med. Sci. 2020, Vol. 17 874 Ivyspring International Publisher International Journal of Medical Sciences 2020; 17(7): 874-880. doi: 10.7150/ijms.41454 Research Paper Long-term administration of Tolvaptan to patients with decompensated cirrhosis Kengo Kanayama1, Tetsuhiro Chiba1, Kazufumi Kobayashi1, Keisuke Koroki1, Susumu Maruta1, Hiroaki Kanzaki1, Yuko Kusakabe1, Tomoko Saito1, Soichiro Kiyono1, Masato Nakamura1, Sadahisa Ogasawara1, Eiichiro Suzuki1, Yoshihiko Ooka1, Shingo Nakamoto1, Shin Yasui1, Tatsuo Kanda2, Hitoshi Maruyama3, Jun Kato1, Naoya Kato1 1. Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. 2. Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan. 3. Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Corresponding author: Tetsuhiro Chiba, M.D., Ph.D. Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Telephone: +81-43-2262083, Fax: +81-43-2262088, E-mail: [email protected]. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2019.10.24; Accepted: 2020.02.20; Published: 2020.03.15 Abstract Aim: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. -
Mechanisms of Action of Antiepileptic Drugs
Review Mechanisms of action of antiepileptic drugs Epilepsy affects up to 1% of the general population and causes substantial disability. The management of seizures in patients with epilepsy relies heavily on antiepileptic drugs (AEDs). Phenobarbital, phenytoin, carbamazepine and valproic acid have been the primary medications used to treat epilepsy for several decades. Since 1993 several AEDs have been approved by the US FDA for use in epilepsy. The choice of the AED is based primarily on the seizure type, spectrum of clinical activity, side effect profile and patient characteristics such as age, comorbidities and concurrent medical treatments. Those AEDs with broad- spectrum activity are often found to exert an action at more than one molecular target. This article will review the proposed mechanisms of action of marketed AEDs in the US and discuss the future of AEDs in development. 1 KEYWORDS: AEDs anticonvulsant drugs antiepileptic drugs epilepsy Aaron M Cook mechanism of action seizures & Meriem K Bensalem-Owen† The therapeutic armamentarium for the treat- patients with refractory seizures. The aim of this 1UK HealthCare, 800 Rose St. H-109, ment of seizures has broadened significantly article is to discuss the past, present and future of Lexington, KY 40536-0293, USA †Author for correspondence: over the past decade [1]. Many of the newer AED pharmacology and mechanisms of action. College of Medicine, Department of anti epileptic drugs (AEDs) have clinical advan- Neurology, University of Kentucky, 800 Rose Street, Room L-455, tages over older, so-called ‘first-generation’ First-generation AEDs Lexington, KY 40536, USA AEDs in that they are more predictable in their Broadly, the mechanisms of action of AEDs can Tel.: +1 859 323 0229 Fax: +1 859 323 5943 dose–response profile and typically are associ- be categorized by their effects on the neuronal [email protected] ated with less drug–drug interactions. -
Chapter 25 Mechanisms of Action of Antiepileptic Drugs
Chapter 25 Mechanisms of action of antiepileptic drugs GRAEME J. SILLS Department of Molecular and Clinical Pharmacology, University of Liverpool _________________________________________________________________________ Introduction The serendipitous discovery of the anticonvulsant properties of phenobarbital in 1912 marked the foundation of the modern pharmacotherapy of epilepsy. The subsequent 70 years saw the introduction of phenytoin, ethosuximide, carbamazepine, sodium valproate and a range of benzodiazepines. Collectively, these compounds have come to be regarded as the ‘established’ antiepileptic drugs (AEDs). A concerted period of development of drugs for epilepsy throughout the 1980s and 1990s has resulted (to date) in 16 new agents being licensed as add-on treatment for difficult-to-control adult and/or paediatric epilepsy, with some becoming available as monotherapy for newly diagnosed patients. Together, these have become known as the ‘modern’ AEDs. Throughout this period of unprecedented drug development, there have also been considerable advances in our understanding of how antiepileptic agents exert their effects at the cellular level. AEDs are neither preventive nor curative and are employed solely as a means of controlling symptoms (i.e. suppression of seizures). Recurrent seizure activity is the manifestation of an intermittent and excessive hyperexcitability of the nervous system and, while the pharmacological minutiae of currently marketed AEDs remain to be completely unravelled, these agents essentially redress the balance between neuronal excitation and inhibition. Three major classes of mechanism are recognised: modulation of voltage-gated ion channels; enhancement of gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission; and attenuation of glutamate-mediated excitatory neurotransmission. The principal pharmacological targets of currently available AEDs are highlighted in Table 1 and discussed further below. -
Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva
REVIEW ARTICLE Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva Philip N. Patsalos, FRCPath, PhD*† and Dave J. Berry, FRCPath, PhD† INTRODUCTION Abstract: Blood (serum/plasma) antiepileptic drug (AED) therapeu- Measuring antiepileptic drugs (AEDs) in serum or tic drug monitoring (TDM) has proven to be an invaluable surrogate plasma as an aid to personalizing drug therapy is now a well- marker for individualizing and optimizing the drug management of established practice in the treatment of epilepsy, and guidelines patients with epilepsy. Since 1989, there has been an exponential are published that indicate the particular features of epilepsy and increase in AEDs with 23 currently licensed for clinical use, and the properties of AEDs that make the practice so beneficial.1 recently, there has been renewed and extensive interest in the use of The goal of AED therapeutic drug monitoring (TDM) is to saliva as an alternative matrix for AED TDM. The advantages of saliva ’ fl optimize a patient s clinical outcome by supporting the man- include the fact that for many AEDs it re ects the free (pharmacolog- agement of their medication regimen with the assistance of ically active) concentration in serum; it is readily sampled, can be measured drug concentrations/levels. The reason why TDM sampled repetitively, and sampling is noninvasive; does not require the has emerged as an important adjunct to treatment with the expertise of a phlebotomist; and is preferred by many patients, AEDs arises from the fact that for an individual patient -
Anticonvulsants
Clinical Pharmacy Program Guidelines for Anticonvulsants Program Prior Authorization - Anticonvulsants Medication Aptiom (eslicarbazepine), Briviact (brivaracetam), Fycompa (perampanel), Vimpat (lacosamide), Gabitril (tiagabine), Banzel (rufinamide), Onfi (clobazam), Epidiolex (cannabidiol), Sympazan (clobazam), Sabril, (vigabatrin), Diacomit (stiripentol), Xcopri (cenobamate), Fintepla (fenfluramine) Markets in Scope Arizona, California, Colorado, Hawaii, Nevada, New Jersey, New York, New York EPP, Pennsylvania- CHIP, Rhode Island, South Carolina Issue Date 6/2016 Pharmacy and 10/2020 Therapeutics Approval Date Effective Date 12/2020 1. Background: Aptiom (eslicarbazepine acetate), Briviact (brivaracetam), Vimpat (lacosamide) and Xcopri are indicated in the treatment of partial-onset seizures. Banzel (rufinamide), Onfi (clobazam), and Sympazan (clobazam) are indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS). There is some clinical evidence to support the use of clobazam for refractory partial onset seizures. Diacomit (stiripentol) is indicated for seizures associated with Dravet syndrome in patients taking clobazam. Epidiolex (cannabadiol) is indicated for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome or tuberous sclerosis complex. Fintepla (fenfluramine) is indicated for the treatment of seizures associated with Dravet syndrome. Fycompa (perampanel) is indicated for the treatment of partial-onset seizures with or without secondarily generalized seizures and as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures. Gabitril (tiagabine) is indicated ad adjunctive therapy in the treatment of partial-onset seizures. Confidential and Proprietary, © 2020 UnitedHealthcare Services Inc. Sabril (vigabatrin) is indicated as adjunctive therapy for refractory complex partial seizures in patients who have inadequately responded to several alternative treatments and for infantile spasms for whom the potential benefits outweigh the risk of vision loss. -
Emerging Concepts on the Anti-Inflammatory Actions of Carbon Monoxide-Releasing Molecules (CO-Rms)
Emerging concepts on the anti-inflammatory actions of carbon monoxide-releasing molecules (CO-RMs). Roberto Motterlini, Benjamin Haas, Roberta Foresti To cite this version: Roberto Motterlini, Benjamin Haas, Roberta Foresti. Emerging concepts on the anti-inflammatory actions of carbon monoxide-releasing molecules (CO-RMs).. Medical Gas Research, BioMed Central, 2012, 2 (1), pp.28. 10.1186/2045-9912-2-28. inserm-00769904 HAL Id: inserm-00769904 https://www.hal.inserm.fr/inserm-00769904 Submitted on 3 Jan 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Motterlini et al. Medical Gas Research 2012, 2:28 http://www.medicalgasresearch.com/content/2/1/28 MEDICAL GAS RESEARCH REVIEW Open Access Emerging concepts on the anti-inflammatory actions of carbon monoxide-releasing molecules (CO-RMs) Roberto Motterlini*, Benjamin Haas and Roberta Foresti* Abstract Carbon monoxide-releasing molecules (CO-RMs) are a class of organometallo compounds capable of delivering controlled quantities of CO gas to cells and tissues thus exerting a broad spectrum of pharmacological effects. CO-RMs containing transition metal carbonyls were initially implemented to mimic the function of heme oxygenase-1 (HMOX1), a stress inducible defensive protein that degrades heme to CO and biliverdin leading to anti-oxidant and anti-inflammatory actions. -
From99mtc@Citrateand9smtc-Pertechnetateion Netate in Saline Solution and Subsequently Treated with a Sephadex G25 Column
jnin/CONCISE COMMUNICATION BINDING OF 9OmTcION TO HEMOGLOBIN MrinaI Kanti Dewanjee New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts The mechanism and preferential site of bind removed, and the red cells were washed free of ing of 99―'Tcion to hemoglobin had been deter plasma with isotonic saline solution. The cells were mined by the separation of 9@Tc-hemoglobin then incubated with a small volume of oomTc@pertech@ from99mTc@citrateand9smTc-pertechnetateion netate in saline solution and subsequently treated with a Sephadex G25 column. This purified with the content of a kit containing mainly stannous fraction was analyzed by the HC1/acetone mix citrate and glucose. The method of labeling (6) is ture to determine the OsmTc activity distribution described below. with heme and globin. Most of the ssmTc activity Twenty milligrams of SnCl2 were dissolved in 20 is associated with globin fraction. The preferred ml of ACD solution (Abbott). The solution was fit chain for O9mTc ion binding was determined by tered with 0.22-micron Millipore filter paper. A 1-mi the splitting of otmTc.hemoglobin with para aliquot transferred to a serum vial was freeze-dried chloromercuribenzoate solution followed by sep and preserved under nitrogen atmosphere to prevent aration with a diethylaminoethyl cellulose col hydrolysis and oxidation of Sn(II) citrate. The kit umn equilibrated with phosphate buffer. The was reconstituted with I ml of isotonic saline solu @ tsmTc ion, like Cr' ion, tends to bind preferen tion, and the content was transferred to a washed red tially with the beta chain of hemoglobin. -
Subject: Samsca (Tolvaptan) Original Effective Date: 07/27/15
Subject: Samsca (tolvaptan) Original Effective Date: 07/27/15 Policy Number: MCP-252 Revision Date(s): Review Date(s): 12/15/2016; 6/22/2017 DISCLAIMER This Medical Policy is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this Molina Clinical Policy (MCP) document and provide the directive for all Medicare members. SUMMARY OF EVIDENCE/POSITION This policy addresses the coverage of Samsca (tolvaptan) for the treatment of clinically significant hypervolemic and euvolemic hyponatremia when appropriate criteria are met. -
Experience with Rufinamide in a Pediatric Population: a Single
Original Articles Experience With Rufinamide in a Pediatric Population: A Single Center’s Experience Martina Vendrame, MD, PhD*1, Tobias Loddenkemper, MD*†1, Vasu D. Gooty, MD*†, Masanori Takeoka, MD*†, Alexander Rotenberg, MD, PhD*†, Ann M. Bergin, MD*†, Yaman Z. Eksioglu, MD*†, Annapurna Poduri, MD*†, Frank H. Duffy, MD*†, Mark Libenson, MD*†, Blaise F. Bourgeois, MD*†, and Sanjeev V. Kothare, MD*† Rufinamide is a new antiepileptic drug recently ap- with rapid and almost complete oral absorption, low plasma proved as adjunctive treatment for generalized seizures protein-binding, high renal excretion, and low propensity to in Lennox-Gastaut syndrome. We undertook a retro- drug-drug interactions [1,2]. Although these properties spective analysis of 77 patients with refractory epilepsy make rufinamide a potentially useful drug in the treatment and receiving rufinamide to evaluate the drug’s effi- of intractable epilepsy in children, rufinamide is currently cacy, tolerability, safety, and dosing schedules. It ap- only approved for the adjunctive treatment of generalized peared efficacious in diverse epilepsy syndromes, with seizures in Lennox-Gastaut syndrome. the highest responder rate in focal cryptogenic epilep- In this study, we retrospectively analyzed the use of rufi- sies (81.1% of patients with >50% response rate), and namide in children with diverse epilepsy syndromes in a ter- in diverse seizure types, with the highest responder tiary pediatric epilepsy center. We describe the safety, rate in tonic/atonic and partial seizures (48.6% and tolerability, efficacy, and dosing of rufinamide, to identify 46.7% of patients with >50% response rate, respec- the advantages or difficulties of its use across a diverse tively). -
Center for Drug Evaluation and Research
CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-006 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology Review By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology OND IO NDA: 20-427 and 22-006 Submission date: December 28, 2007 (Complete response) Drug: vigabatrin Sponsor: Ovation Pharmaceuticals Indication: 20-427: refractory complex partial seizures in adults 22-006: infantile spasms Reviewing Division: Division of Neurology Products Introductory Comments: The regulatory history of these two NDAs is summarized in the supervisory pharm/tox review. The pharm/tox review of NDA 20-427 found the nonclinical information adequate to support approval. The pharm/tox reviewer for NDA 22-006 did not find the nonclinical information adequate to support approval primarily based on evidence that juvenile animals were sensitive to neurotoxic effects of vigabatrin. The pharm/tox supervisor recognized this concern but did not object to the approval of NDA 22-006 based on the clinical benefit of vigabatrin in infantile spasms which is a serious indication with no other approved therapy. The supervisor recommended that additional studies on the retinal damage and neurotoxicity induced by vigabatrin be conducted as postmarketing requirements. This includes the following studies: 1. A toxicology study in the juvenile rat examining the potential of vigabatrin exposure during development to produce neuronal damage. 2. A juvenile animal toxicology study of vigabatrin in a non-rodent species. 3. A study examining the effect of taurine on vigabatrin-induced retinal damage in rodent. Conclusions: I have discussed these NDAs with the division pharm/tox supervisor and agree that they may be approved from a pharm/tox perspective.