DOCSLIB.ORG

Pharmacological Targeting of Long QT Mutant Sodium Channels

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pharmacological Targeting of Long QT Mutant Sodium Channels Pharmacological targeting of long QT mutant sodium channels. D W Wang, … , A L George Jr, P B Bennett J Clin Invest. 1997;99(7):1714-1720. https://doi.org/10.1172/JCI119335. Research Article The congenital long QT syndrome (LQTS) is an inherited disorder characterized by a delay in cardiac cellular repolarization leading to cardiac arrhythmias and sudden death often in young people. One form of the disease (LQT3) involves mutations in the voltage-gated cardiac sodium channel. The potential for targeted suppression of the LQT defect was explored by heterologous expression of mutant channels in cultured human cells. Kinetic and steady state analysis revealed an enhanced apparent affinity for the predominantly charged, primary amine compound, mexiletine. The affinity of the mutant channels in the inactivated state was similar to the wild type (WT) channels (IC50 approximately 15-20 microM), but the late-opening channels were inhibited at significantly lower concentrations (IC50 = 2-3 microM) causing a preferential suppression of the late openings. The targeting of the defective behavior of the mutant channels has important implications for therapeutic intervention in this disease. The results provide insights for the selective suppression of the mutant phenotype by very low concentrations of drug and indicate that mexiletine equally suppresses the defect in all three known LQT3 mutants. Find the latest version: https://jci.me/119335/pdf Pharmacological Targeting of Long QT Mutant Sodium Channels D.W. Wang, K. Yazawa, N. Makita, A.L. George, Jr., and P.B. Bennett Department of Pharmacology and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602 Abstract cently been described (7–9). The mutations cause the normally transiently opening sodium channels to continue to reopen at The congenital long QT syndrome (LQTS) is an inherited depolarized membrane potentials giving rise to a sustained in- disorder characterized by a delay in cardiac cellular repo- ward current which prolongs the cardiac action potential. larization leading to cardiac arrhythmias and sudden death An important goal for rational treatment of this disorder is often in young people. One form of the disease (LQT3) in- to define the molecular basis and conditions for suppression of volves mutations in the voltage-gated cardiac sodium chan- this defect (10). One strategy is to target and selectively sup- nel. The potential for targeted suppression of the LQT defect press the phenotype produced by the mutation. A recent study was explored by heterologous expression of mutant chan- suggests that this may be possible. An et al. (11) demonstrated nels in cultured human cells. Kinetic and steady state analy- suppression of late-opening sodium channels by high concen- sis revealed an enhanced apparent affinity for the predomi- trations of lidocaine in the ⌬KPQ mutant channels. However, nantly charged, primary amine compound, mexiletine. The lidocaine may not be the optimal drug for this purpose because affinity of the mutant channels in the inactivated state was its mechanism of action is to block inactivated rather than ف similar to the wild type (WT) channels (IC50 15–20 ␮M), open sodium channels (12, 13) and it must be given intrave- but the late-opening channels were inhibited at significantly nously to patients. Dumaine et al. (8) have recently reported lower concentrations (IC50 ϭ 2–3 ␮M) causing a preferen- that there are multiple distinct mechanisms for the three LQT3 tial suppression of the late openings. The targeting of the mutant channels and that high concentrations of mexiletine defective behavior of the mutant channels has important could inhibit these mutant channels when expressed in Xeno- implications for therapeutic intervention in this disease. The pus laevis oocytes. However, the range of therapeutic plasma results provide insights for the selective suppression of the concentrations of mexiletine for treatment of arrhythmias is mutant phenotype by very low concentrations of drug and much lower than they tested (4–11 ␮M), and X. laevis oocytes indicate that mexiletine equally suppresses the defect in all can be problematic for studies of drug effects possibly due to three known LQT3 mutants. (J. Clin. Invest. 1997. 99:1714– their large lipophilic yolk. Thus, it is unknown whether thera- 1720.) Key words: SCN5A • human heart • hH1 • LQT3 • peutic levels of an antiarrhythmic agent can affect these chan- Naϩ channel • antiarrhythmic agent • mexiletine nels, how the inhibition compares to wild type (WT) channels, or whether such a drug will affect each of the mutant channels Introduction differently. Mexiletine is an orally available antiarrhythmic agent which The congenital long QT syndrome (LQTS)1 is a myocardial like lidocaine inhibits sodium channels (4, 12–27). The charged disease caused by mutations at distinct genetic loci (1, 2). One form interacts with the open state and the uncharged form form of the disease (LQT3) is caused by mutations in the hu- interacts with the inactivated state of the channel (14–17). The man voltage-gated cardiac sodium channel gene (SCN5A) (3–6). primary mechanism of inhibition of WT Naϩ channels by mex- Three different mutations in SCN5A were identified in subsets iletine involves the uncharged drug interacting with the in- of long QT syndrome patients (5, 6). These include an in- activated state of the channel (25, 26, 28). The open state is frame deletion of three amino acids (lys 1,505, proline 1,506, normally too brief to permit significant interactions with mex- and glutamine 1,507, ⌬KPQ), and two point mutations: iletine (13, 22, 29–32). Nevertheless, the pKa of mexiletine is N1325S (asparagine 1,325 converted to serine) and R1644H 9.3, therefore, 99% of the drug is charged at physiological pH. (arginine 1,644 converted to histidine). The functional defects Thus, under normal conditions, only 1% of mexiletine is in the caused by these sodium channel mutations on gating have re- form that blocks inactivated channels. We reasoned that the major charged species of mexiletine may opportunistically sup- press the abnormal repetitive reopenings of sodium channels in LQT3. To test this hypothesis, LQT3 sodium channel mutations Address correspondence to Paul B. Bennett, Ph.D., Department of were engineered in the recombinant human heart sodium Pharmacology, 558 MRB II, Vanderbilt University School of Medi- channel (hH1) by site-directed mutagenesis (9). WT and mu- cine, Nashville, TN 37232-6602. Phone: 615-936-1683; FAX: 615-322- tant channels were expressed heterologously in human embry- 4707; E-mail: [email protected] Received for publication 3 September 1996 and accepted in revised onic kidney cells. Channel behavior and inhibition by mexile- form 21 January 1997. tine were investigated by whole-cell patch clamp methods. Voltage clamp protocols were used to favor occupancy of dis- 1. Abbreviations used in this paper: LQT, long QT; WT, wild type. tinct conformational states of the antiarrhythmic drug receptor (i.e., primarily rested or primarily inactivated). Remarkably, J. Clin. Invest. the results show that LQT3 mutant channels are much more © The American Society for Clinical Investigation, Inc. sensitive to inhibition by mexiletine than are WT sodium chan- 0021-9738/97/04/1714/07 $2.00 nels. The defective late openings are selectively suppressed Volume 99, Number 7, April 1997, 1714–1720 more than the peak sodium current and these late openings 1714 Wang et al. can be suppressed by concentrations at the lower end of the where Imax is the unblocked current in the absence of mexiletine (M) therapeutic range. Furthermore, the defect is suppressed in and I is the magnitude of the current in the presence of a given con- each of the three mutant channels to approximately the same centration ([M]) of the drug. Alternatively, Eq. 2 can be fitted to con- extent indicating that mexiletine may be useful for treatment centration-block data to estimate the apparent KD (IC50). Assuming a of this disorder regardless of the specific sodium channel muta- first-order binding interaction between the drug and the channel, the time constant for block development should depend on the mexile- tion. tine concentration ([M]) according to the following relationship where k and l represent the association and dissociation rate con- stants, respectively: Methods τ ([] )Ϫ1 Block = M k+1 . (4) Voltage clamp methods. The methods used have been described pre- viously (9, 27, 32, 33). Sodium currents were recorded using the whole-cell patch clamp technique (34). Electrodes resistances ranged from 0.8–2 M⍀. Voltage clamp command pulses were generated us- ing pCLAMP software (v6.03; Axon Instruments, Inc., Foster City, CA). Currents were filtered at 5 kHz (Ϫ3 dB, 4-pole Bessel filter). An Axopatch 200 patch clamp amplifier was used with series resis- tance compensation (Axon Instruments, Inc.). The holding potential for all pulse protocols was Ϫ120 mV. Experiments were done at room temperature (20–22ЊC). The bath solution contained: 145 mM NaCl; 4 mM KCl; 1.8 nM CaCl2; 1.0 mM MgCl2; 10 mM Hepes; and 10 mM glucose, pH 7.35. The pipette solution contained (intracellular solu- tion): 10 mM NaF; 110 nM CsF; 20 nM CsCl; 10 nM EGTA ; and 10 nM Hepes, pH 7.35. Data are presented as meanϮSEM. Site-directed mutagenesis of human heart sodium channel (3) was performed as described (7, 9). Mutant and WT cDNAs were sub- cloned into pRc/CMV (Invitrogen Corp., San Diego, CA) for expres- sion in mammalian cells (9, 27, 33). Multiple independent recombinants were sequenced thoroughly in the mutated region and and tested to confirm expression and identical behavior. At least three indepen- dent clones were tested for expression studies. The calcium phosphate method was used to express mutant and WT human heart sodium channel in a transformed human kidney cell line (HEK 293t, also called tsA-201) stably expressing the SV40 T-antigen.
Load more

Recommended publications
  • Skeletal Muscle Relaxants Review 12/17/2008
    Skeletal Muscle Relaxants Review 12/17/2008 Copyright © 2007 - 2008 by Provider Synergies, L.L.C. All rights reserved. Printed in the United States of America. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage and retrieval system without the express written consent of Provider Synergies, L.L.C. All requests for permission should be mailed to: Attention: Copyright Administrator Intellectual Property Department Provider Synergies, L.L.C. 5181 Natorp Blvd., Suite 205 Mason, Ohio 45040 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to
    [Show full text]
  • Pain Management in Patients with Substance-Use Disorders
    Pain Management in Patients with Substance-Use Disorders By Valerie Prince, Pharm.D., FAPhA, BCPS Reviewed by Beth A. Sproule, Pharm.D.; Jeffrey T. Sherer, Pharm.D., MPH, BCPS; and Patricia H. Powell, Pharm.D., BCPS Learning Objectives regarding drug interactions with illicit substances or prescribed pain medications. Finally, there are issues 1. Construct a therapeutic plan to overcome barri- ers to effective pain management in a patient with related to the comorbidities of the patient with addic- addiction. tion (e.g., psychiatric disorders or physical concerns 2. Distinguish high-risk patients from low-risk patients related to the addiction) that should influence product regarding use of opioids to manage pain. selection. 3. Design a treatment plan for the management of acute pain in a patient with addiction. Epidemiology 4. Design a pharmacotherapy plan for a patient with Pain is the second most common cause of work- coexisting addiction and chronic noncancer pain. place absenteeism. The prevalence of chronic pain may 5. Design a pain management plan that encompasses be much higher among patients with substance use dis- recommended nonpharmacologic components for orders than among the general population. In the 2006 a patient with a history of substance abuse. National Survey on Drug Use and Health, past-year alco- hol addiction or abuse occurred in 10.3% of men and 5.1% of women. In the same survey, 12.3% of men and Introduction 6.3% of women were reported as having a substance-use Pain, which is one of the most common reasons disorder (abuse or addiction) during the past year.
    [Show full text]
  • 2021 Formulary List of Covered Prescription Drugs
    2021 Formulary List of covered prescription drugs This drug list applies to all Individual HMO products and the following Small Group HMO products: Sharp Platinum 90 Performance HMO, Sharp Platinum 90 Performance HMO AI-AN, Sharp Platinum 90 Premier HMO, Sharp Platinum 90 Premier HMO AI-AN, Sharp Gold 80 Performance HMO, Sharp Gold 80 Performance HMO AI-AN, Sharp Gold 80 Premier HMO, Sharp Gold 80 Premier HMO AI-AN, Sharp Silver 70 Performance HMO, Sharp Silver 70 Performance HMO AI-AN, Sharp Silver 70 Premier HMO, Sharp Silver 70 Premier HMO AI-AN, Sharp Silver 73 Performance HMO, Sharp Silver 73 Premier HMO, Sharp Silver 87 Performance HMO, Sharp Silver 87 Premier HMO, Sharp Silver 94 Performance HMO, Sharp Silver 94 Premier HMO, Sharp Bronze 60 Performance HMO, Sharp Bronze 60 Performance HMO AI-AN, Sharp Bronze 60 Premier HDHP HMO, Sharp Bronze 60 Premier HDHP HMO AI-AN, Sharp Minimum Coverage Performance HMO, Sharp $0 Cost Share Performance HMO AI-AN, Sharp $0 Cost Share Premier HMO AI-AN, Sharp Silver 70 Off Exchange Performance HMO, Sharp Silver 70 Off Exchange Premier HMO, Sharp Performance Platinum 90 HMO 0/15 + Child Dental, Sharp Premier Platinum 90 HMO 0/20 + Child Dental, Sharp Performance Gold 80 HMO 350 /25 + Child Dental, Sharp Premier Gold 80 HMO 250/35 + Child Dental, Sharp Performance Silver 70 HMO 2250/50 + Child Dental, Sharp Premier Silver 70 HMO 2250/55 + Child Dental, Sharp Premier Silver 70 HDHP HMO 2500/20% + Child Dental, Sharp Performance Bronze 60 HMO 6300/65 + Child Dental, Sharp Premier Bronze 60 HDHP HMO
    [Show full text]
  • Cvs Caremark ® Maintenance Drug List
    CVS CAREMARK® MAINTENANCE DRUG LIST EFFECTIVE AS OF 03/03/2021 Maintenance drugs are prescriptions commonly used to treat conditions that are considered chronic or long-term. These conditions usually require regular, daily use of medicines. Examples of maintenance drugs are those used to treat high blood pressure, heart disease, asthma and diabetes. Due to the large number of available medicines, this list is not all inclusive. Please note that this list does not guarantee coverage and is subject to change. Your prescription benefit plan may not cover certain products or categories, regardless of their appearance on this list. Where a generic is available, it is listed by the generic name. If no generic is available, then the brand name appears. This list represents brand products in CAPS and generic products in lower case italics. If you have questions about your prescription benefits, please log on to your account at Caremark.com or call Customer Care at the number on your ID card. Allergies pentoxifylline Depression desloratidine prasugrel bupropion levocetirizine ticlopidine citalopram ZONTIVITY desvenlafaxine Alzheimer’s Disease duloxetine donepezil Cancer escitalopram galantamine anastrozole fluoxetine memantine exemestane fluvoxamine rivastigmine letrozole mirtazapine NAMZARIC tamoxifen nefazodone toremifene paroxetine Antipsychotics sertraline trazodone Aripiprazole Contraceptives venlafaxine brexipiprazole ethinyl estradiol-desogestrel APLENZIN loxapine ethinyl estradiol-drospirenone FETZIMA olanzapine ethinyl estradiol-ethynodiol
    [Show full text]
  • Skeletal Muscle Relaxants Review 05/31/2010
    Skeletal Muscle Relaxants Review 05/31/2010 Copyright © 2007 – 2010 by Provider Synergies, L.L.C. All rights reserved. Printed in the United States of America. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage and retrieval system without the express written consent of Provider Synergies, L.L.C. All requests for permission should be mailed to: Attention: Copyright Administrator Intellectual Property Department Provider Synergies, L.L.C 10101 Alliance Road, Suite 201 Cincinnati, Ohio 45242 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended
    [Show full text]
  • Voltage-Gated Sodium Channels and Blockers: an Overview and Where Will They Go?*
    Current Medical Science 39(6):863-873,2019 DOICurrent https://doi.org/10.1007/s11596-019-2117-0 Medical Science 39(6):2019 863 Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?* Zhi-mei LI1, Li-xia CHEN2#, Hua LI1# 1Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 2Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China Huazhong University of Science and Technology 2019 Summary: Voltage-gated sodium (Nav) channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization. Mutations in Nav channels are associated with a variety of channelopathies, which makes them relevant targets for pharmaceutical intervention. So far, the cryoelectron microscopic structure of the human Nav1.2, Nav1.4, and Nav1.7 has been reported, which sheds light on the molecular basis of functional mechanism of Nav channels and provides a path toward structure-based drug discovery. In this review, we focus on the recent advances in the structure, molecular mechanism and modulation of Nav channels, and state updated sodium channel blockers for the treatment of pathophysiology disorders and briefly discuss where the blockers may be developed in the future. Key words: voltage-gated sodium channels; blockers; Nav channel structures; channelopathies Life did not come into existence until living In this review, we focus on voltage-gated organisms were enclosed by one or more membranes sodium (Nav) channels, which selectively conduct which cut them off from the chaotic world at a sodium ions movement in response to variations of molecular level.
    [Show full text]
  • Randomized Study of Dofetilide, Quinidine, Ranolazine, and Verapamil
    Clinical Trial nature publishing group CLINICAL TRIAL see COMMENTARY page 534 Differentiating Drug-Induced Multichannel Block on the Electrocardiogram: Randomized Study of Dofetilide, Quinidine, Ranolazine, and Verapamil L Johannesen1,2, J Vicente1,3, JW Mason4, C Sanabria4, K Waite-Labott4, M Hong5, P Guo5, J Lin5, JS Sørensen6, L Galeotti1, J Florian6, M Ugander1,2, N Stockbridge7 and DG Strauss1,2 Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J–Tpeak) and late repolarization (global Tpeak–Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology. Fourteen drugs have been removed from the market worldwide and/or sodium channels (inward currents). The most notable because they increase the risk for torsade de pointes,1 a ven- example is amiodarone, which causes substantial QT prolonga- tricular arrhythmia that can cause sudden cardiac death.
    [Show full text]
  • August 2021 California Signaturevalue 4 Tier HMO Formulary
    Pharmacy | Formulary | California 2021 California SignatureValue 4-Tier HMO Formulary Please note: This Formulary is accurate as of August 1, 2021 and is subject to change after this date. All previous versions of this Formulary are no longer in effect. Your estimated coverage and copay/coinsurance may vary based on the benefit plan you choose and the effective date of the plan. This Formulary can also be accessed online at myuhc.com > Pharmacy Information > Prescription Drug Lists > California plans > SignatureValue HMO plans. Plan-specific coverage documents may be accessed online at uhc.com/statedruglists > Small Group Plans > California. If you are a UnitedHealthcare member, please register or log on to myuhc.com, or call the toll-free number on your health plan ID card to find pharmacy information specific to your benefit plan. This Formulary is applicable to the following health insurance products offered by UnitedHealthcare: • SignatureValue • SignatureValue Advantage • SignatureValue Alliance • SignatureValue Flex • SignatureValue Focus • SignatureValue Harmony • SignatureValue Performance Updated 6/17/2021 6/21 © 2021 United HealthCare Services, Inc. All Rights Reserved. WF3890815-N Contents At UnitedHealthcare, we want to help you better understand your medication options. ..................................................... 3 How do I use my Formulary? ............................................. 4 What are tiers? ........................................................ 5 When does the Formulary change? ........................................ 5 Utilization Management Programs ......................................... 6 Your Right to Request Access to a Non-formulary Drug ....................... 6 Requesting a Prior Authorization or Step Therapy Exception ................... 7 How do I locate and fill a prescription through a retail network pharmacy? . 7 How do I locate and fill a prescription through the mail order pharmacy? . 7 How do I locate and fill a prescription at a specialty pharmacy? ...............
    [Show full text]
  • 291 BCBSA Reference Number: 5.01.16 NCD/LCD: N/A
    Medical Policy Intravenous Anesthetics for the Treatment of Chronic Pain Table of Contents • Policy: Commercial • Coding Information • Information Pertaining to All Policies • Policy: Medicare • Description • References • Authorization Information • Policy History Policy Number: 291 BCBSA Reference Number: 5.01.16 NCD/LCD: N/A Related Policies • Repetitive transcranial magnetic stimulation (rTMS), #297 • Esketamine Nasal Spray (SpravatoTM) and Intravenous Ketamine for Treatment-Resistant Depression, #087 Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity Medicare HMO BlueSM and Medicare PPO BlueSM Members Intravenous infusion of anesthetics (eg, ketamine or lidocaine) for the treatment of chronic pain, including, but not limited to chronic neuropathic pain, chronic daily headache, and fibromyalgia, is INVESTIGATIONAL. Prior Authorization Information Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient. Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient. Outpatient Commercial Managed Care (HMO and POS) This is not a covered service. Commercial PPO and Indemnity This is not a covered service. Medicare HMO BlueSM This is not a covered service. Medicare PPO BlueSM This is not a covered service. 1 CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member. Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.
    [Show full text]
  • North Carolina Division of Medical Assistance North
    North Carolina Division of Medical Assistance North Carolina Medicaid and Health Choice Preferred Drug List (PDL) Effective January 15, 2018 Trial and failure of two preferred drugs are required unless otherwise indicated. Not all therapeutic drug classes are included on the PDL. All drugs in the classes not included are considered preferred. In addition to trial and failure criteria, clinical criteria (indicated in RED) may also apply. Drugs requiring prior authorization, clinical criteria and prior authorization request forms can be found at: www.nctracks.nc.gov/content/public/providers/pharmacy/pa-drugs-criteria-new-format.html More information on the PDL can be found at: http://www.ncdhhs.gov/dma/pharmacy/index.htm ALZHEIMER’S AGENTS Preferred Non-Preferred donepezil 5mg, 10mg tablets / ODT (generic for Aricept® / ODT) Aricept® ODT / Tablets Exelon® Patch donepezil 23mg tablets (generic for Aricept®) memantine tablet / titration pack (generic for Namenda®) Exelon® Capsule Namenda® Solution galantamine ER capsule / solution / tablet (generic for Razadyne® / ER) rivastigmine capsules (generic for Exelon®) memantine solution (oral) (generic for Namenda® Solution) Namenda® Titration Pack / XR Capsule / XR Titration Pack Namenda® Tablet Namzaric™ Solution (Oral) rivastigmine (Trandsderm) (generic for Exelon® Patch) Razadyne® ER Capsule / Tablet ANALGESICS OPIOID ANALGESICS Long Acting Clinical criteria apply to all drugs in this class Preferred Non-Preferred Arymo® ER Butrans® Patch Avinza® Capsule Embeda® ER Capsule Belbuca (Buccal) fentanyl
    [Show full text]
  • MEXITIL® (Mexiletine Hydrochloride, USP) Is an Orally Active Antiarrhythmic Agent Available As 150 Mg, 200 Mg and 250 Mg Capsules
    ® Mexitil (mexiletine hydrochloride, USP) Capsules of 150 mg, 200 mg and 250 mg Oral Antiarrhythmic Prescribing Information DESCRIPTION MEXITIL® (mexiletine hydrochloride, USP) is an orally active antiarrhythmic agent available as 150 mg, 200 mg and 250 mg capsules. 100 mg of mexiletine hydrochloride is equivalent to 83.31 mg of mexiletine base. It is a white to off-white crystalline powder with slightly bitter taste, freely soluble in water and in alcohol. MEXITIL has a pKa of 9.2. Chemically, MEXITIL is 1-methyl-2-(2, 6-xylyloxy) ethylamine hydrochloride and has the following structural formula: C11 H17 NO•HCl mexiletine hydrochloride, USP Mol. Wt. 215.73 (MEXITIL) MEXITIL capsules contain the following excipients: colloidal silicon dioxide, corn starch, magnesium stearate, titanium dioxide, gelatin, pharmaceutical glaze, simethicone, FD&C Red No. 40, and FD&C Blue No. 1; the MEXITIL 150 mg and 250 mg capsules also contain FD&C Yellow No. 10 and D&C Red No. 28. MEXITIL capsules may contain one or more of the following components: sodium lauryl sulfate, lecithin, shellac, and FD&C Blue No. 1 Aluminum Lake. CLINICAL PHARMACOLOGY Mechanism of Action MEXITIL (mexiletine hydrochloride, USP) is a local anesthetic, antiarrhythmic agent, structurally similar to lidocaine, but orally active. In animal studies, MEXITIL has been shown to be effective in the suppression of induced ventricular arrhythmias, including those induced by glycoside toxicity and coronary artery ligation. MEXITIL, like lidocaine, inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. MEXITIL decreased the effective refractory period (ERP) in Purkinje fibers.
    [Show full text]
  • NCT02523690 IRB00072940 Evaluating Muscle
    NCT02523690 IRB00072940 Evaluating Muscle Weakness Improvement With Lorcaserin in ICU (EMILI) Protocol Version: February 10, 2017 (Date in header of protocol, 8/1/2016 was inadvertently not updated) Date: 1 August 2016 Principal Investigator: Dale Needham, MD PhD Application Number: IRB00072940 JHM IRB - eForm A – Protocol Use the section headings to write the JHM IRB eForm A, inserting the appropriate material in each. If a section is not applicable, leave heading in and insert N/A. When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at the top of JHM IRB eForm A. *************************************************************************************************** 1) Abstract (Provide no more than a one page research abstract briefly stating the problem, the research hypothesis, and the importance of the research.) It was recently discovery that patients recovering from sepsis/critical illness have great difficulty recruiting motor units to generate muscle force. Prior to this discovery, the primary etiology of muscle weakness in these patients was thought to be muscle disease (myopathy) and degeneration of peripheral nerve (neuropathy). However, since motor units are composed of a group of muscle fibers contacted by a single motor neuron arising from the spinal cord, these new findings suggested a problem within the spinal cord as the primary cause of weakness in affected patients. Consistent with these clinical findings in critically ill patients, there is a profound deficit in the excitability of motor neurons in the spinal cord of septic rats. Studies characterizing the impaired excitability in rat motor neurons point to a specific deficit in a slowly inactivating type of sodium current (i.e., the persistent sodium current).
    [Show full text]