DOCSLIB.ORG

Pharmacology in Childhood Arterial Ischemic Stroke Catherine Amlie-Lefond, MD,* and Joan Cox Gill, MD†

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pharmacology in Childhood Arterial Ischemic Stroke Catherine Amlie-Lefond, MD,* and Joan Cox Gill, MD† Pharmacology in Childhood Arterial Ischemic Stroke Catherine Amlie-Lefond, MD,* and Joan Cox Gill, MD† In recent years, there has been increasing recognition of the impact of childhood stroke and interest in the role of drugs in the acute, chronic, and prophylactic management of this condition. Most treatment strategies are based on studies in adults with stroke, and the relative infrequency of stroke and the heterogeneity of etiologies in childhood compared with adults present significant challenges in study design for childhood stroke studies. The presence of thrombophilia has been associated with stroke in children, strengthening the concept that antithrombotic, antiplatelet, and even thrombolytic agents have a role in stroke treatment and prevention. There are several potential roles for drugs in the treatment of childhood stroke including hyperacute therapy, antithrombotic medication, antiplatelet medication, and disease-specific medications. Herein, we review the use and rationale of these medications in childhood arterial ischemic stroke. Semin Pediatr Neurol 17:237-244 © 2010 Published by Elsevier Inc. fter arterial ischemic stroke (AIS), 10% of children will There is great variability in the use of antithrombotic and Adie, and 70% will be left with neurologic deficit;1-3 of the antiplatelet drugs after acute childhood AIS. Among 661 chil- survivors, approximately 15% to 20% will have further dren with AIS reported to the International Pediatric Stroke strokes.4,5 However, despite such compelling numbers, opti- Study, acute treatment consisted of anticoagulation alone in mal treatments for acute stroke and prophylaxis of children at 27%, antiplatelet therapy alone in 28%, and a combination of high risk for initial or recurrent strokes are largely unknown. anticoagulation and antiplatelet therapy in 16% of patients. An- In recent years, there has been increasing recognition of ticoagulation was more likely to be used in children with dissec- the impact of pediatric stroke and interest in the role of drugs tion and cardiac disease and less likely to be used in those with in the acute, chronic, and prophylactic management of stroke SCD and in those enrolled in centers in the United States.15 in childhood. Most treatment strategies are based on studies in There are several potential roles for drugs in the treatment adults with stroke. Other than the use of transfusions to of childhood stroke. Tissue plasminogen activator (tPA) as a prevent stroke in high-risk patients with sickle cell disease hyperacute therapy has revolutionized the approach to (SCD), randomized controlled studies have not been com- stroke in adults; however, it is not known if tPA is safe or pleted in children. The relative infrequency of stroke and the efficacious in childhood stroke. Antithrombotic medication heterogeneity of etiologies in childhood compared with is frequently used early while evaluation for an embolic adults present significant challenges in study design for source is ongoing and is used in children believed to be at childhood stroke studies. The presence of thrombophilia has high risk of recurrent embolic events. Aspirin is the most been associated with stroke in children,6-11 strengthening the common antiplatelet medication used to prevent recurrent concept that antithrombotic, antiplatelet, and even thrombo- stroke in childhood, but other antiplatelet medications are lytic agents have a role in stroke treatment and prevention. being used more often for children who continue to have Nonetheless, the developmental nature of the hemostatic and ischemic events despite aspirin. Finally, disease-specific 12-14 fibrinolytic systems limits generalization of safety and medications are being developed for use in children with efficacy data from adult studies of acute and prophylactic stroke caused by specific modifiable underlying etiologies, stroke interventions to children. such as the use of hydroxyurea in SCD and folic acid in hyperhomocysteinemia. From the *Department of Neurology, Medical College of Wisconsin, Mil- waukee, WI. †Departments of Pediatrics and Epidemiology, Medical College of Wisconsin, Hyperacute Therapy Blood Center Children’s Research Institute of Wisconsin, Milwaukee, WI. Address reprint requests to Catherine Amlie-Lefond, MD, Department of in Childhood Stroke Neurology, Medical College of Wisconsin, 9000 West Wisconsin Ave- nue, CHW CCC, Suite C540, Milwaukee, WI 53201. E-mail: KLefond@ Plasminogen activators are serine proteases that convert the mcw.edu inactive zymogen, plasminogen, to active plasmin, which in 1071-9091/10/$-see front matter © 2010 Published by Elsevier Inc. 237 doi:10.1016/j.spen.2010.10.006 238 C. Amlie-Lefond and J. Cox Gill Table 1 Plasminogen Activators22 Agent Source Clinical Experience Streptokinase Extracellular metalloenzyme produced by Most widely used fibrinolytic, especially for myocardial invasive bacteria infarction Staphylokinase Extracellular metalloenzyme produced by Phase II for myocardial infarction completed invasive bacteria Urokinase Isolated from human neonatal kidney cell Symptomatic intracranial hemorrhage in 10.9% when cultures given within 6 h23 tPA Recombinant human tPA Beneficial at 0-4.5 hours when given at 0.9 mg/kg over 1h16,21 Desmoteplase DSPA␣1 plasminogen activator from No benefit in stroke when given 3-9 h after stroke saliva of vampire bats, may be less onset25 neurotoxic than tPA because it does not interact with the NMDA receptor24 Reteplase Recombinant nonglycolsylated form of Can be given as 2 boluses human tPA Tenecteplase Genetically modified recombinant tPA Can be given as single bolus turn degrades fibrin, a structural protein of clots, to fibrin age 16 to 49 years showed that none of the 48 patients de- degradation products. tPA is used acutely to lyse intracere- veloped SICH and that these patients benefited from intrave- bral clots and restore blood flow to brain parenchyma, nous thrombolysis, suggesting that tPA may be safer in thereby salvaging tissue that is not yet infarcted. Intravenous younger patients than older ones.26 tPA at a dose of 0.9 mg/kg (maximum total dose 90 mg) with Children are increasingly receiving tPA, despite the lack of 10% given as a bolus over the first minute and the rest given safety and efficacy data.27 The 2008 American Heart Associ- over the next hour is Food and Drug Administration ap- ation (AHA) guidelines for “Management of Stroke in Infants proved for use in adults within 3 hours of stroke onset. It and Children” state that “Until there are additional published improves outcome at 3 months with an odds ratio of 1.7 (P ϭ safety and efficacy data, tPA generally is not recommended .008) for a favorable outcome.16 The benefits appear to be for children with AIS outside a clinical trial (Class III, Level of reduced and offset by bleeding complications if given beyond evidence C). However, there was no consensus about the use 3 hours17,18 but may be beneficial in selected patients.19,20 In of tPA in older adolescents who otherwise meet standard the European Cooperative Acute Stroke Study (ECASS) III, adult tPA eligibility criteria.”28 intravenous tPA at a dose of 0.9 mg/kg was shown to be The developmental nature of the fibrinolytic system is now beneficial in adults with AIS and National Institutes of Health universally recognized.12-14 Plasminogen concentrations are ap- Stroke Scale Յ25 when initiated at 3 to 4.5 hours after stroke proximately 50% of adult values at birth but reach adult values onset; the rate of symptomatic intracranial hemorrhage by 1 year of age. The blood concentration and stimulated release (SICH) was 2.4%.21 A recent American Heart Association/ of endogenous tPA also show maturational differences. From 1 American Stroke Association advisory recommends ex- to 16 years of age, baseline tPA concentrations in blood are tending the time window for intravenous tPA to 4.5 hours about 50% lower than in adults. A study of females aged 14 to 18 (Table 1).22 years showed that teenagers have lower venocclusive stimulated The first generation of thrombolytic plasminogen activa- fibrinolytic activity (50%-70%) compared with adult men and tors (streptokinase, staphylokinase, and urokinase) are sys- women.29 Plasminogen activator inhibitor-1 (PAI-1) binds with temic plasminogen activators that result in widespread plas- tPA, thereby inhibiting tPA’s activity and influencing tPA’s he- min production in the circulation, with consumption and patic clearance. PAI-1 concentrations overall are increased in loss of circulating plasminogen, fibrinogen, and plasmin in- children compared with adults. Furthermore, the ratio of tPA to hibitors. The second-generation thombolytic, tPA, targets the PAI-1 is reversed throughout childhood compared with adults. plasminogen activator to the fibrin clot and is considered In contrast, plasminogen and its inactivating protein, ␣2-anti- “clot specific,” with more limited systemic plasmin genera- plasmin (␣2-AP), do not change significantly between 1 year tion. The third-generation plasminogen activators (desmote- and adulthood; however, there are no data regarding changes in plase, reteplase, tenecteplase, and so on) have improved concentration of these proteins during acute stroke in children. properties, such as longer half-life allowing for bolus admin- The lower baseline levels of tPA and increased PAI-1 concentra- istration before arrival at the hospital, and, in the case of tions, which suggest a less active innate fibrinolytic system in desmoteplase, possibly less neurotoxicity but have clot spec- children,
Load more

Recommended publications
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • Desmoteplase for Acute Ischaemic Stroke
    Desmoteplase for acute ischaemic stroke September 2011 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research September 2011 Desmoteplase for acute ischaemic stroke Target group • Acute ischaemic stroke – within 3 to 9 hours of the onset of symptoms. Technology description Desmoteplase (LU-AE-03329) is a recombinant fibrin-specific plasminogen activator derived from the saliva of the vampire bat, Desmodus rotundus. It catalyses the conversion of plasminogen to plasmin, the enzyme responsible for breaking down fibrin blood clots. Structurally, desmoteplase is very similar to human tissue-type plasminogen activator (tPA), but its activity is 200 times more fibrin-specific than tPA. It therefore does not cause systemic plasminogen activation and fibrinogen depletion. Desmoteplase is intended to be used for the treatment of patients with acute ischaemic stroke in the extended time window of 3 to 9 hours after the onset of symptoms. It is administered as an IV bolus at 90µg/kg (dose used in ongoing phase III clinical trials). Innovation and/or advantages If licensed, desmoteplase would extend the time window for thrombolysis in acute stroke from 3 hours to 9 hours. In addition, because it is highly fibrin-specific it may not have some of the negative effects of tPA (like systemic plasminogen activation and neurotoxicity).
    [Show full text]
  • Supplemental Material Liu Page 1
    Supplementary material Stroke Vasc Neurol Supplemental Material Liu Page 1 Supplemental Material Chinese Stroke Association Guidelines for Clinical Management of Cerebrovascular Disorders Executive Summary and 2019 Update of Clinical Management of Ischemic Cerebrovascular Diseases Liu L, et al. Stroke Vasc Neurol 2020; 5:e000378. doi: 10.1136/svn-2020-000378 Supplementary material Stroke Vasc Neurol Supplemental Material Liu Page 2 Section 1 Definitions associated with ischemic cerebrovascular diseases. The definitions of ischemic cerebrovascular disease are shown in Table 1. Section 2 Emergency assessment and diagnosis of ischemic stroke patients Please refer to Figure 1 for details of the management process for ischemic stroke patients in the acute phase. I. First assessment of emergency (I) Medical history collection Acute ischemic stroke (AIS) patients suffer from acute onset. It is very important to inquire about the time of occurrence of symptoms, onset characteristics and progress, including symptom persistence, fluctuations and relief. If the disease starts onset during sleep, the time when the patient's last normal performance should be recorded. These patients may also get sick shortly before waking up, and the onset time is uncertain, but clinically the final normal time should still be calculated as the last normal time [1-2]. Using MRI to screen wake-up stroke patients who are not suitable for thrombectomy, intravenous thrombolysis helps patients get good prognosis [3]. Before the occurrence of current symptoms, some patients will have similar TIA symptoms that can be relieved automatically. The time window for thrombolytic therapy is calculated based on the occurrence time of current symptoms. The inquiry about whether there are causes related to haemorrhagic stroke before the occurrence of symptoms, such as emotional excitement, intense exercise, sudden change of body position, excessive blood pressure reduction, as well as whether there is a history of Liu L, et al.
    [Show full text]
  • 5Emerging Stroke Tx Copy
    3/5/18 Outline ■ Thrombolytic therapy EMERGING THERAPY IN ■ Mechanical Thrombectomy STROKE MEDICINE ■ Antiplatelet drug 7th MAR 2018 ■ Anticoagulant drug Assist.Prof. Kannikar Kongbunkiat, MD ■ Other management Neurology division, Internal medicine department, Srinagarind Hospital, Faculty of Medicine, KhonKaen University North-Eastern Stroke Research Group Outline Thrombolytic therapy st ■ Thrombolytic therapy ■ 1 generation – Streptokinase, Urokinase ■ Mechanical Thrombectomy ■ 2nd generation ■ Antiplatelet drug – Prourokinase ■ Anticoagulant drug – Alteplase (r-tPA)** (NIND, ECLASSIII ,etc. FDA approved for IV) ■ Other management ■ 3rd & 4th generation – Staphylokinase, Reteplase, Monteplase, – Lanoteplase, Ancrod – Desmoteplase, Tenecteplase Desmoteplase vs Placebo Desmoteplase in Acute Ischemic Stroke (DIAS) - Extended time window to 3-9 hr - Desmoteplase or placebo, given as a single iv bolus injection. desmoteplase was beneficial for pts w/ proximal arterial occlusion Phase III study - Japanese pts - Asia and Europe Pt w/ perfusion/diffusion - North and Latin mismatch is associated America and with a higher rate of supported an excellent Europe reperfusion and better safety profile with the 90 clinical outcome than μg/kg dose. placebo DIAS-J DIAS DIAS-3 DIAS-2 DEDAS DIAS-4 2005 2009 2015 2016 1 3/5/18 DIAS-3 desmoteplase was as safe as placebo, but without clinical benefit. Pooled DIAS-3, DIAS-4, and DIAS-J patient data Terminated the DIAS-4 trial after the enrollment of 270/400 pts, because the goal of 2 positive trials could
    [Show full text]
  • Imaging and Treatment of Patients with Acute Stroke: an Evidence-Based Review
    Published April 18, 2013 as 10.3174/ajnr.A3518 REVIEW ARTICLE Imaging and Treatment of Patients with Acute Stroke: An Evidence-Based Review P.C. Sanelli, J.B. Sykes, A.L. Ford, J.-M. Lee, K.D. Vo, and D.K. Hallam ABSTRACT SUMMARY: Evidence-based medicine has emerged as a valuable tool to guide clinical decision-making, by summarizing the best possible evidence for both diagnostic and treatment strategies. Imaging plays a critical role in the evaluation and treatment of patients with acute ischemic stroke, especially those who are being considered for thrombolytic or endovascular therapy. Time from stroke-symptom onset to treatment is a strong predictor of long-term functional outcome after stroke. Therefore, imaging and treatment decisions must occur rapidly in this setting, while minimizing unnecessary delays in treatment. The aim of this review was to summarize the best available evidence for the diagnostic and therapeutic management of patients with acute ischemic stroke. ABBREVIATIONS: DPM ϭ diffusion-perfusion mismatch; IA ϭ intra-arterial; ICH ϭ intracranial hemorrhage; r-proUK ϭ recombinant prourokinase; TIMI ϭ Thrombolysis in Myocardial Infarction n this era of health care reform and cost containment, major con- The aim of this review is to summarize the best available evi- Icerns have been raised regarding inappropriate medical expendi- dence for the diagnostic and therapeutic management of patients tures and the lack of data to support the necessity of such high levels with acute ischemic stroke. The first part of this review synthesizes of health care spending. It is becoming ever more difficult to justify the most current evidence on the appropriate indications and diagnostic imaging and other medical procedures with anecdotal ev- modalities to consider in the diagnostic work-up of patients with idence, expert opinion, or experience.
    [Show full text]
  • Drugs Affecting Coagulation
    PHARMACOLOGY Drugs affecting Learning objectives coagulation After reading this article, you should be able to: C outline the process of coagulation Balraj Appadu C compare and contrast the different drugs used for Katrina Barber anticoagulation C evaluate anticoagulant drugs and their uses in patients under- going surgery Abstract For more than half a century, heparin and vitamin K antagonists have defined anticoagulant therapy in both the short-term and long-term leading to dissolution (lysis) and restoration of blood flow to the management of thrombotic diseases. However, the limitations of organs. these traditional anticoagulants have prompted the development of new drugs. In the past 15 years new agents with improved safety pro- First-generation agents fi le and greater ease of use that target almost every step of the coag- Streptokinase is a non-enzymatic protein produced by b-hae- ulation cascade have been developed. These include factor Xa molytic streptococci. It activates the fibrinolytic system indi- inhibitors and direct thrombin inhibitors. The mechanism of action of rectly, binding to human plasminogen and forming a 1:1 ‘ ’ these new anticoagulants and also the older agents are reviewed in stoichiometric complex, which converts plasminogen into this article. plasmin. It is associated with allergic reactions and can stimulate Keywords ADP receptor antagonists; dabigatran; fondaparinux; the production of anti-streptococcal antibodies. For this reason, glycoprotein IIb/IIIa antagonists; heparin; rivaroxaban; warfarin repeat doses should be avoided. Urokinase is a trypsin-like serine protease composed of two Royal College of Anaesthetists CPD Matrix: A102 polypeptide chains connected by a disulphide bridge. It activates plasminogen directly, converting it to active plasmin.
    [Show full text]
  • AHA/ASA Guideline
    Jauch et al Early Management of Acute Ischemic Stroke 1 AHA/ASA Guideline lww Guidelines for the Early Management of Patients With Acute STR Ischemic Stroke: Executive Summary 202623 A Guideline for Healthcare Professionals From the American Heart AQ1 Jauch et al Early Management of Acute Ischemic Stroke Association/American Stroke Association The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Endorsed by the American Association of Neurological Surgeons and Congress of Neurological Surgeons Edward C. Jauch, MD, MS, FAHA, Chair; Jeffrey L. Saver, MD, FAHA, Vice Chair; Harold P. Adams, Jr, MD, FAHA; Askiel Bruno, MD, MS; J.J. (Buddy) Connors, MD; Bart M. Demaerschalk, MD, MSc; Pooja Khatri, MD, MSc, FAHA; Paul W. McMullan, Jr, MD, FAHA; Adnan I. Qureshi, MD, FAHA; Kenneth Rosenfield, MD, FAHA; Phillip A. Scott, MD, FAHA; Debbie R. Summers, RN, MSN, FAHA; David Z. Wang, DO, FAHA; Max Wintermark, MD; Howard Yonas, MD; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Peripheral Vascular Disease, and Council on Clinical Cardiology his publication, “Guidelines for the Early Management of stroke care. This document addresses opportunities for optimal TPatients With Acute Ischemic Stroke,” from the American stroke care in the acute phase of the acute ischemic stroke. Heart Association/American Stroke Association (AHA/ASA) The goal of these guidelines is to further reduce the morbid- is an overview of the current evidence and management rec- ity and mortality associated with stroke. The guidelines sup- ommendations for evaluation and treatment of adults with port the overarching concept of stroke systems of care and acute ischemic stroke.
    [Show full text]
  • Multimodal Imaging Using Ct, Mri, and Angiography in Stroke
    1/18/2014 MULTIMODAL IMAGING USING CT, MRI, AND ANGIOGRAPHY IN STROKE Jefferson T Miley MD Seton Brain and Spine Institute Department of Neurology UT-Southwestern Austin Outline Focus of Imaging on Acute Ischemic Stroke Physiology Basics Imaging Computerized Tomography NCCT CT-Perfusion Magnetic Resonance Imaging DWI PWI FLAIR Digital Subtraction Angiography Conclusions Physiology CBF = CBV/MTT Benign oligemia; >17 mL/100 g per minute Penumbra 17 to 10 mL/100 g per minute infarct core 10mL/100 g per minute Latchaw RE, Yonas H, Hunter GJ, Yuh WT, et al. Guidelines and recommendations for perfusion imaging in cerebral ischemia:a scientific statement for healthcare professionals by the writing group on perfusion imaging, from the Council on Cardiovascular Radiology of the American Heart Association. Stroke. 2003;34: 1084–1104. 1 1/18/2014 Oligemia? Penumbra? Infarct? infarct core 10mL/100 g per minute Imaging Tools DWI FLAIR CT Penumbra 10-17 mL/100 g per min Imaging: CTP MRP PET Xe-CT 2 1/18/2014 Benign oligemia; >17 mL/100 g per min CBV CBF = CBV/MTT CBV= mL/100g of brain MTT Time 3 1/18/2014 Summary AUC=CBV MRI DWI DWI lesions are regions of cytotoxic edema which proceed to infarction Lesions can reverse if reperfusion is achieved Median reversal DWI volume 43% in DEFUSE trial Reversibility correlates with good clinical outcome Jean-Marc Olivot, MD, PhD; Michael Mlynash, MD, MS; Vincent N. Thijs, MD, PhD, et al. Relationships Between Cerebral Perfusion and Reversibility of Acute Diffusion Lesions in DEFUSE Insights from RADAR. Stroke. 2009;40:1692-1697.
    [Show full text]
  • International Nonproprietary Names (Inn) for Biological and Biotechnological Substances
    INN Working Document 05.179 Distr.: GENERAL ENGLISH ONLY 15/06/2006 INTERNATIONAL NONPROPRIETARY NAMES (INN) FOR BIOLOGICAL AND BIOTECHNOLOGICAL SUBSTANCES (A REVIEW) Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines (QSM) Medicines Policy and Standards (PSM) Department CONTENTS 0. INTRODUCTION…………………………………….........................................................................................v 1. PHARMACOLOGICAL CLASSIFICATION OF BIOLOGICAL AND BIOTECHNOLOGICAL SUBSTANCES……………………………………................................1 2. CURRENT STATUS OF EXISTING STEMS OR SYSTEMS FOR BIOLOGICAL AND BIOTECHNOLOGICAL SUBSTANCES…………………….3 2.1 Groups with respective stems ……………………………………………………………………3 2.2 Groups with respective pre-stems………………………………………………………………4 2.3 Groups with INN schemes………………………………………………………………………….4 2.4 Groups without respective stems / pre-stems and without INN schemes…..4 3. GENERAL POLICIES FOR BIOLOGICAL AND BIOTECHNOLOGICAL SUBSTANCES……………………………………………………………………………………………………...5 3.1 General policies for blood products……………………………………………………………5 3.2 General policies for fusion proteins……………………………………………………………5 3.3 General policies for gene therapy products………………………………………………..5 3.4 General policies for glycosylated and non-glycosylated compounds………...6 3.5 General policies for immunoglobulins……………………………………………………….7 3.6 General polices for monoclonal antibodies………………………………………………..7 3.7 General polices for skin substitutes……………………………………………………………9 3.8 General policies for transgenic products……………………………………………………9
    [Show full text]
  • (INN) for Biological and Biotechnological Substances
    WHO/EMP/RHT/TSN/2019.1 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) 2019 WHO/EMP/RHT/TSN/2019.1 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) 2019 International Nonproprietary Names (INN) Programme Technologies Standards and Norms (TSN) Regulation of Medicines and other Health Technologies (RHT) Essential Medicines and Health Products (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) FORMER DOCUMENT NUMBER: INN Working Document 05.179 © World Health Organization 2019 All rights reserved. Publications of the World Health Organization are available on the WHO website (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
    [Show full text]
  • Does Diffusion-Weighted Imaging Represent the Ischemic Core? an Evidence-Based Systematic ORIGINAL RESEARCH Review
    Published April 8, 2009 as 10.3174/ajnr.A1547 Does Diffusion-Weighted Imaging Represent the Ischemic Core? An Evidence-Based Systematic ORIGINAL RESEARCH Review P.G. Kranz BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) hyperintensity is hypothesized to J.D. Eastwood represent irreversibly infracted tissue (ischemic core) in the setting of acute stroke. Measurement of the ischemic core has implications for both prognosis and therapy. We wished to assess the level of evidence in the literature supporting this hypothesis. MATERIALS AND METHODS: We performed a systematic review of the literature relating to tissue outcomes of DWI hyperintense stroke lesions in humans. The methodologic rigor of studies was evaluated by using criteria set out by the Oxford Centre for Evidence-Based Medicine. Data from individual studies were also analyzed to determine the prevalence of patients demonstrating lesion progression, no change, or lesion regression compared with follow-up imaging. RESULTS: Limited numbers of highly methodologically rigorous studies (Oxford levels 1 and 2) were available. There was great variability in observed rates of DWI lesion reversal (0%–83%), with a surprisingly high mean rate of DWI lesion reversal (24% of pooled patients). Many studies did not include sufficient data to determine the precise prevalence of DWI lesion growth or reversal. CONCLUSIONS: The available tissue-outcome evidence supporting the hypothesis that DWI is a surrogate marker for ischemic core in humans is troublingly inconsistent and merits an overall grade D based on the criteria set out by the Oxford Centre for Evidence-Based Medicine. dentifying threatened but still-viable brain tissue in patients falsely appears to exceed the accepted limit.
    [Show full text]
  • Thrombolysis for Acute Ischemic Stroke: Does It Work?—The Con Position
    EDITORIAL COMMENTARY Thrombolysis for acute ischemic stroke: does it work?—the con position Chris Johnstone*† Thrombolysis for acute ischemic stroke (AIS) has (n = 16–57), and two had unacceptably poor metho- become mainstream therapy, despite the scientific evi- dological quality. The Cochrane authors acknowledged dence rather than because of it. Careful scrutiny of the and measured the high level of heterogeneity in their literature demonstrates that it has proven harm but no choice of studies (I2 = 39%) but did not modify their clear benefit, because of the sheer paucity of hard evi- conclusion. Therefore, there are only 11 large (n ≥ 100) dence supporting its use. There are only two large RCTs of reasonable quality and homogeneous metho- randomized controlled trials (RCTs) showing benefit dology (Table 1, including the International Stroke for thrombolysis, and nine large RCTs that failed to Trial [IST-3], which was published after the Cochrane show any significant difference to placebo (four were Review). If the likelihood of a good outcome (mRS ≥ 3) stopped early due to excess harm). This is in stark is recalculated using only these 11 trials (I2 = 5%), contrast to the clear mortality benefit for thrombolysis thrombolysis is favoured with OR = 0.87 (95% con- in six out of eight large RCT for myocardial infarction.1 fidence interval [CI] = 0.79–0.96) but with a CI close to Both systematic and non-systematic reviews of throm- 1.0 and a number needed to treat (NNT) of 29. Even if bolysis for AIS are severely biased by the inappropriate the statistical significance is real, the clinical significance inclusion of heterogeneous studies, to the extent that is doubtful.
    [Show full text]