Pharmacology
`and Therapeutics
`
`Principles to Practice
`
`Scott A. Waldman, MD, PhD, FCP
`Past President, American Society for Clinical Pharmacology and Therapeutics
`Samuel M.V. Hamilton Professor of Medicine
`Professor of Pharmacology and Experimental Therapeutics and Medicine
`Chair, Department of Pharmacology and Experimental Therapeutics
`Director, Division of Clinical Pharmacology, Department of Medicine
`Director, Gastrointestinal Malignancies Program, Kimmel Cancer Center
`Director, NIH Training Program in “Clinical Pharmacology”
`Thomas Jefferson University
`Philadelphia, Pennsylvania
`
`Andre Terzic, MD, PhD
`Past President, American Society for Clinical Pharmacology and Therapeutics
`Marriott Family Professor of Cardiovascular Research
`Professor of Medicine and Pharmacology, Medical Genetics
`Director, Marriott Heart Disease Research Program
`Director, NIH Training Program in “Cardiovasology”
`Mayo Clinic Associate Director for Research
`Co-Director, Mayo Clinic Center for Individualized Medicine
`Mayo Clinic
`Rochester, Minnesota
`
`EyNGT a)Sk
`
`Bee <<: a
`
` Merck 2005
`
`Merck 2005
`TWi v Merck
`TWi v Merck
`IPR2023-00049
`IPR2023-00049
`
`

`

`SAUNDERS
`ELSEVIER
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`PHARMACOLOGY AND THERAPEUTICS: PRINCIPLES TO PRACTICE
`Copyright © 2009 by Saunders, an imprintof Elsevier Inc.
`
`ISBN: 978-1-4160-3291-
`Expert Consult: 978-1-4160-329]-
`Expert Consult Premium: 978-1-4160-6098-
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`Library of Congress Cataloging-in-Publication Data
`Pharmacology and therapeutics : principles to practice / [edited by] Scott A. Waldman, Andre Terzic.—ist ed.
`cm.
`ISBN 978-1-4160-3291-5
`Il. Terzic, Andre.
`[. Waldman, Scott A.
`1. Pharmacology.
`2. Chemotherapy.
`[DNLM:
`|. Pharmacology, Clinical—methods.
`2. Drug Therapy. QV 38 P53603 2008)
`RM300.P5193 2008
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`a Or MID
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`

`

`1
`Principles,
`PHARMACOTHERAPEUTIC CONTINUUM:
`ENGINEERING THE FUTURE OF INDIVIDUALIZED
`MEDICINE,
`3
`
`SECTION 1
`
`Pharmacotherapeutic
`Continuum,
`7
`
`4 DRUG DISCOVERY,
`Patrick Vallance
`
`7
`
`2 DRUG DEVELOPMENT,
`Steven Ryder and Ethan Weiner
`
`15
`
`Robert G. Sharrar, Linda S Hostelley.
`
`and Filip Musser
`
`3 REGULATIONS AND eeaeLEE 29
`4 acme‘BASED DRUG UTILIZATION,
`41
`SECTION 2 Molecular Pharmacology,
`51
`5 DRUG-BECERTOR INTERACTIONS,
`51
`6 SIGNAL TRANSDUCTION,
`67
`Philip B. Wedegaertner
`
`+A Waidma
`
`16 HETEROGENEITY OF DRUG RESPONSES AND
`INDIVIDUALIZATION OF ao 225
`Kirchheiner
`and Matthias Schwe
`
`239
`47 PEDIATRIC PHARMACOLOGY,
`Kathleen A Neville, Michael
`J. Blake, Michael D Reed, and
`Gregory L. Kearns
`
`18 SEX DIFFERENCES IN PHARMACOLOGY,
`Jean Gray
`
`251
`
`19 PHARMACOLOGY ACROSS THE AGING
`CONTINUUM,
`257
`Naomi Gronich and Darrell
`
`R. Abernethy
`
`20 ADVERSE DRUG REACTIONS AND
`INTERACTIONS,
`265
`Shiwew-Mei Huang, Lawrence J, Lesko, and Robert Temple
`
`21 THERAPEUTIC DRUG MONITORING,
`Michael
`C. Milone and Lesle M. Shaw
`
`275
`
`289
`Practice,
`SECTION 5S Cardiovascular Therapeutics,
`
`291
`
`291
`22 HYPERTENSION,
`ean-Luc Eighoz:, Michel Azizi, and Prerre-Frangois Plouin
`
`83
`
`303
`23 DYSLIPIDEMIAS,
`Matthew $. Murphy and Timothy O'Brien
`
`7 CELL CYCLE PHARMACOLOGY,
`ANTIPROLIFERATION, AND APOPTOSIS,
`Sarah A. Holstein and Raymond J. Hon
`SECTION 3 Systems Pharmacology,
`8 NEUROTRANSMITTERS,
`91
`Eduardo £. Benarroch
`
`91
`
`9 AUTONOMIC PHARMACOLOGY,
`Anastasios Lymperopoulos and Walter J Koch
`40 FLUID AND ELECTROLYTE HOMEOSTASIS,
`Bruce C. Kone
`
`115
`
`141
`
`11.
`
`INFLAMMATION AND
`IMMUNOMODULATION,
`Laurence J, Egan
`173
`412 PHARMACOBIOLOGY OF INFECTIONS,
`Dionissios Neofytos, Claudine El-Beyrouty, and Joseph A. DeSimone,Jr
`SECTION 4 Clinical Pharmacology,
`193
`
`157
`
`13 PHARMACOKINETICS,
`Arthur J. Atkinson, Jr
`
`193
`
`14 PHARMACODYNAMICS,
`Richard L. Lalonde
`
`203
`
`15 PHARMACOGENETICS AND
`PHARMACOGENOMICS,
`219
`Richard Weinshilbourm
`
`24 CORONARY ARTERY DISEASE,
`Arshad Jahangir and Vigar Maria
`
`321
`
`367
`25 RHYTHM DISORDERS,
`Dawood Darbar and Dan M. Roden
`
`26 HEART FAILURE,
`Arthur M, Feldman
`
`389
`
`SECTION 6 Pulmonary Therapeutics,
`
`401
`
`27 PULMONARY ARTERIAL HYPERTENSION,
`Azad Raiesdana and Joseph Loscalzo
`
`401
`
`28 ASTHMA AND CHRONIC OBSTRUCTIVE
`PULMONARYDISEASE,
`417
`Walter K. Kraft and Frank T Leone
`
`SECTION 7 Renal Therapeutics, 435
`
`29 RENAL INSUFFICIENCY,
`Kumar Sharma
`
`435
`
`445
`30 VOIDING DYSFUNCTION,
`Alan ) Wein, Rajiv Saini, and David R. Staskin
`
`SECTION 8 Gastroenterologic Therapeutics, 457
`31 ACID REFLUX AND ULCER DISEASE,
`457
`Alex Mejia and Walter K. Kraft
`
`xvii
`
`

`

`XVili
`
`=Contents
`
`475
`32 MOTILITY DISORDERS,
`Michael Camillen and Viola Andresen
`
`53 DEPRESSION AND BIPOLAR DISORDERS,
`Wade Berrettini
`
`787
`
`54 PSYCHOSIS AND SCHIZOPHRENIA,
`797
`487
`33 INFLAMMATORY BOWEL DISEASES,
`ege!, Mary E Dankert, and Je
`
`Laurence|Egan and Christian Maaser
`
`55 DRUG ADDICTION,
`817
`505
`34 HEPATIC CIRRHOSIS,
`Doo-Sup
`Choi, Victor M Karpyak, Mark
`
`WietorJ.Navarro, Simona Rossi, and Ste
`Dame! K. Hall-Flavin,
`and David A. M
`
`35 INFECTIOUS HEPATITIS,
`na Ross:
`Steven K. Hernmne, Sim
`
`527
`and Victor
`
`J, Navarro
`
`SECTION 9 Endocrinologic Therapeutics,
`
`549
`
`36 OBESITY AND NUTRITION,
`Robert F Kushner
`
`549
`
`557
`37 DIABETES MELLITUS,
`Robert A. Rizza and Adnan Vella
`
`38 DISORDERS OF THE THYROID,
`Helen L Baron and Peter A Singer
`
`571
`
`39 DISORDERS OF CALCIUM METABOLISM AND
`BONE MINERALIZATION,
`587
`Bart
`L. Clarke and Sundeep Khosla
`
`40 DISORDERS OF THE HYPOTHALAMIC-PITUITARY
`AXIS,
`611
`Run Yu and Gienn D Braunstein
`
`41 ADRENAL DISORDERS,
`Lise Hamaker and Serge Jabbour
`
`623
`
`631
`42 REPRODUCTIVE HEALTH,
`Dale W. Stovall and Jerome F. Strauss, Ill
`
`SECTION 10 Neuropharmacologic
`Therapeutics,
`641
`
`43 ALZHEIMER'S DISEASE AND DEMENTIAS,
`Wael N. Haidar and Ronald C. Petersen
`
`641
`
`44 PARKINSON'S DISEASE,
`Ludy Shih and Daniel Tarsy
`
`651
`
`45 SEIZURE DISORDERS,
`Scott Mintzer
`
`663
`
`685
`46 MULTIPLE SCLEROSIS,
`Benjamin M. Greenberg, John N. Ratchford, and Peter A. Calabresi
`
`703
`47 DYSAUTONOMIAS,
`Kyoko Sato, André Diedrich, and David Robertson
`
`48 HEADACHE,
`Alfredo Bianchi
`
`719
`
`743
`49 STROKE,
`RodneyBell, Kiwon Lee, Carissa Pineda, and David Brock
`
`SECTION 11 Psychopharmacologic
`Therapeutics,
`753
`50 OBSESSIVE-COMPULSIVE DISORDERS,
`Datin D. Dougherty and Michael A. Jenike
`
`753
`
`51 ATTENTION-DEFICIT/HYPERACTIVITY
`DISORDER,
`759
`David A. Mrazek and Kathryn M. Schak
`
`769
`52 ANXIETY,
`Chi-Un Pae and Ashwin A. Patkar
`
`56 NICOTINE DEPENDENCE,
`Neal
`lL Benowitz
`
`837
`
`57 INSOMNIA (NARCOLEPSY)-RELATED
`DISORDERS,
`849
`Teofilo Lee-Chiong and James F Pagel
`
`SECTION 12 Ophthalmologic Therapeutics,
`
`857
`
`58 DRUGS IN OPHTHALMOLOGY,
`Douglas | Rhee and William S$. Tasman
`
`857
`
`SECTION 13 Anesthesia,
`
`863
`
`59 LOCAL ANESTHESIA,
`John
`E Tetzlaft
`
`863
`
`60 GENERAL ANESTHESIA AND SEDATION,
`joseph F Foss and Marco A. Maurtua
`
`873
`
`883
`61 TREATMENT OF PAIN,
`Kishor Gandhi,
`James W. Heitz, and Eugene R. Viscus
`
`SECTION 14 Hematologic Therapeutics,
`
`895
`
`62 ANEMIAS AND CYTOPENIAS,
`Nandi J. Reddy and Lionel D. Lewis
`
`895
`
`63 DISORDERS OF HEMOSTASIS AND
`THROMBOSIS, 909
`Erev E. Tubb and Steven E. McKenzie
`
`SECTION 15 Oncologic Therapeutics,
`64 LUNG CANCER,
`921
`Sarah A. Holstein and Raymond J. Hohl
`
`921
`
`933
`65 BREAST CANCER,
`Vivek Roy and Edith A. Perez
`
`66 HEMATOLOGIC MALIGNANCIES,
`Jasmine Nabi and Raymond J. Hohl
`
`945
`
`951
`67 PROSTATE CANCER,
`Sarah A. Holstein and Raymond J. Hohl
`
`959
`68 COLON CANCER,
`Muhammad Wasif Saif and Robert B. Diasio
`
`969
`69 MELANOMA,
`Jasmine Nabi and Raymond J, Hohl
`
`SECTION 16 Dermatologic Therapeutics,
`70 ACNE,
`973
`Joseph Genebriera and Mark Davis
`
`973
`
`983
`71 PSORIASIS,
`Mark R. Pittelkow and Joseph Genebriera
`
`72 DERMATITIS,
`Mark Davis
`
`1007
`
`

`

`SECTION 17 Rheumatologic Therapeutics,
`
`1015
`
`85 SEXUALLY TRANSMITTED DISEASES,
`Kristine E
`Johnson and Anne M Rompalo
`
`1201
`
`1015
`73 OSTEOARTHRITIS,
`William F Harvey and DavidJ,Hunter
`SECTION 19 Practical Therapeutics,
`1213
`86 MEDICAL TOXICOLOGY AND ANTIDOTES,
`Thomas P Moyer
`
`74 RHEUMATOID ARTHRITIS,
`Rechard MM Keatina
`
`1025
`
`1213
`
`Contents
`
`xix
`
`1039
`75 GOUT,
`Michael P Keith, William Ro Gilliland, and Kathleen Uhl
`
`87 OVER-THE-COUNTER MEDICATIONS,
`Barbara A Levey
`
`1221
`
`1047
`76 SYSTEMIC LUPUS ERYTHEMATOSUS,
`Wiliam R. Gilliiand, Michael P Keith, and Kathleen Uh
`
`8B PRESCRIPTION AND ORDER WRITING,
`Carol L Beck
`
`1225
`
`SECTION 18 Therapy of Infectious
`Diseases,
`1063
`
`77 ~INFLUENZA AND VIRAL RESPIRATORY
`INFECTIONS,
`1063
`Joseph P Lynch,
`
`tl
`
`78 COMMUNITY-ACQUIRED PNEUMONIA,
`Andrew R. Haas and Paul
`E Marik
`
`1081
`
`79 TUBERCULOSIS,
`Ying Zhang
`
`1089
`
`1109
`80 BACTERIAL MENINGITIS,
`Diederik van de Beek, Martyn VWerstelt, and Jan
`
`de Gans
`
`1121
`81 ENDOCARDITIS,
`Lisa G. Winston, Dame! Deck, and Ann F Bolger
`
`1141
`82 MALARIA,
`Myaing Nyunt and Christopher V. Plowe
`
`83 PROTOZOAN AND HELMINTHIC
`INFECTIONS,
`1171
`Enc R. Houp! and Omer Chaudhry
`
`84 HIV INFECTIONS AND AIDS,
`Paul & Pham and Charlies W Flexner
`
`1187
`
`89 PHARMACY AND THERAPEUTICS COMMITTEES
`AND THE HOSPITAL FORMULARY,
`1233
`Joseph $ Bertino,
`Jr
`SECTION 20 Emerging Therapeutics,
`90 COMPLEMENTARYAND ALTERNATIVE
`MEDICINE, NUTRACEUTICALS, AND DIETARY
`SUPPLEMENTS,
`1237
`Christine A. Haller
`
`1237
`
`1247
`91 VACCINES,
`Paul V Targonski, Inna G. Ovsyannikova, Pritish K. Tosh,
`Robert M. Jacobson, and Gregory A. Poland
`
`1269
`92 TRANSPLANT MEDICINE,
`Mark Chaballa, JoanneFilicko-O’Hara, Dorothy Holt, Adam M. Frank,
`John L. Wagner, Dolores Grosso, and Neal Flomenberg
`
`1295
`93 GENE THERAPY,
`Stephen J. Russell and Kah Whye Peng
`
`94 REGENERATIVE MEDICINE AND STEM CELL
`THERAPEUTICS,
`1317
`Timothy J. Nelson, Atta Behfar, and Andre Terzic
`
`INDEX,
`
`1333
`
`

`

`
`
`
`
`MULTIPLE SCLEROSIS
`
`Benjamin M. Greenberg, John N. Ratchford, and Peter A. Calabresi
`
`OVERVIEW 685
`INTRODUCTION 685
`Epidemiology 685
`Genetics
`685
`Clinical Features
`Diagnosis
`686
`PATHOPHYSIOLOGY 687
`THERAPEUTICS AND CLINICAL
`PHARMACOLOGY 689
`Goals of Therapy 689
`Therapeutics by Class
`
`689
`
`685
`
`689
`Immunomodulators
`691
`Immunosuppressants
`Therapeutic Approach 692
`Treatment with DMT: Patient
`Selection and Initiation
`692
`First-Line Treatment for RRMS
`Treatments Helpful in SPMS
`Treatments Helpful in PPMS
`Definition of Treatment Failure
`Management of Breakthrough
`Disease Activity
`695
`
`693
`694
`695
`695
`
`Management of Acute
`Relapses
`695
`Treatments Helpful for Common
`MS-Related Symptoms 696
`Treatment Considerations Related
`to Pregnancy
`697
`Treating the Pediatric MS
`Patient
`697
`Emerging Targets and
`Therapeutics
`698
`
`OVERVIEW
`
`Multiple sclerosis (MS) is a complex disease of the central nervous
`system (CNS) with the potential to cause significant physical and emo-
`tional disability. Approximately 350,000 Americansare currently diag-
`nosed with MS, and the direct and indirect costs associated with the
`disease are about $14 billion per year.’ MS is the most common non-
`traumatic cause of neurologic disability in early to middle adulthood.
`There is an inherentvariability from patient to patient with regard to
`disease course and severity. Some patients experience frequent exacer-
`bations with escalating disability while others have a relatively benign
`course. Most commonly the disease begins with episodic relapses that
`are separated byperiods of remission. [n the later stages of the disease,
`many patients will develop slowly progressive neurologic disability.
`Most evidence points to an immune-mediated pathophysiology involv-
`ing B and T lymphocytes, macrophages, and microglia. According to
`this hypothesis, an autoimmuneresponse against CNS myelin is initi-
`ated, leading to demyelination and axonal injury. To date, the most
`effective therapies have been immunosuppressant and immunomodu-
`latory drugs. While none of the approaches can be described as cura-
`tive, the presently approved drugs haveled to significant reductionsin
`relapse rates and disability.
`
`INTRODUCTION
`Epidemiology
`Thetypical age of onset for MS is between 20 and 40, The disease is
`unusual before adolescence, but onset has been described as young as
`age 2 and as old as age 74. The ratio of affected women to menis
`between 1,7; 1 and 2.5: 1, although the ratio is more even at older ages
`of onset. Several
`important epidemiologic observations have been
`made about the geographic distribution of MS. In both the northern
`and southern hemispheres, the prevalenceofthe disease increases with
`increasing distance from the equator. There is also a difference in risk
`for different ethnic groups,
`independent
`oflatitude. For example,
`England and Japanare at the samelatitude, but the prevalence of MS
`differs significantly in the two countries (85 per 100,000 for England
`versus 1.4 per 100,000 in Japan). Caucasians tend to have the highest
`risk, while lower risk is seen in people of African or Asian descent. The
`highest prevalence is seen in the northern United States, southern
`Canada, northern Europe, and southern Australia. The southern
`United States and southern Europe have a moderate prevalence. The
`
`lowest prevalence is seen in Japan, China, Latin America, and equato-
`rial Africa. Migration studies have also added to our understanding of
`the relationship between geography and risk of MS. Children born to
`parents who migrated from a low- to a high-risk area had an increase
`in their risk of developing MS, andvice versa.’ By analyzing the ages
`of migrants, it was suggested that one’s environmentalrisk was deter-
`mined by about age 15.° This has led to hypotheses that the risk of MS
`is partly determined byviral exposures during childhood. Recent data
`suggest that
`the incidence of MS may be increasing, especially in
`women, although issues regarding ascertainment and diagnosis make
`these studies challenging.
`
`Genetics
`
`In addition to environmental factors, genetics influences the risk of
`developing MS. Family clusters are known to occur. Twin studies have
`found that the monozygotic twin of an MS patient has about a 30%
`chance of developing MS. Dizygotic twinshavea risk thatis similar to
`that of any sibling of an MS patient, about 2% to 5%. The risk in
`children of MS patientsis slightly lower than for siblings. Second- and
`third-degree relatives of an MS patient also carry some elevated risk.
`Genetic studies have found the strongest association with the major
`histocompatibility complex (MHC),particularly the HLA-DRB] locus,
`More recently, two additional genes were identified in genome-wide
`scans, the interleukin-2 receptor alpha gene and the interleukin-7
`receptor alpha gene. Thefact thatall three genes are part of the immune
`system serves as an important confirmation of the autoimmunenature
`of this disease.
`
`Clinical Features
`
`MS has classically been separated into four different subtypes: relaps-
`ing-remitting, secondary progressive, primary progressive, and pro-
`gressive relapsing MS (Fig. 46-1). Relapsing-remitting MS (RRMS)is
`the most commonclinical subtype, representing about 85% of patients
`at diagnosis.It is marked by intermittent exacerbations that may partly
`or completely resolve over weeks to months. These relapses are sepa-
`rated by periods ofclinical stability. However, patients may continue
`to experience symptoms from prior relapses that healed incompletely.
`After a variable period of time, a majority of RRMS patients will enter
`a secondary progressive phase of the disease (SPMS). SPMS patients
`experience a slowly progressive worsening ofdisability that may or may
`not have superimposed relapses. About 10% to 15% of patients will
`
`685
`
`

`

`686
`
`Section 10 Neuropharmacologic Therapeutics
`
`have a primaryprogressive course (PPMS), marked byslowly progres-
`sive worsening from the outset without relapses. A small number of
`patients are labeled as having progressive relapsing MS. These patients
`begin with a progressive course but develop one or more relapses.
`Patients who have had a single demyelinating event, but do notyet
`meet criteria for MS, are referred to as having a clinically isolated
`syndrome.
`MS can present with a large number of symptomspossiblyreferable
`to the CNS. The symptoms maybe transient and often difficult to
`describe. Classic MS symptomsinclude unilateral blurred vision with
`browpain onlateral eye movement, weakness, numbness, paresthesias,
`pain,
`imbalance, double vision, bladder and bowel dysfunction,
`impaired coordination, fatigue, depression, cognitive impairment, heat
`intolerance, and sexual dysfunction. On exam, commonsigns include
`visual
`impairment, brainstem dysfunction, nystagmus, dysarthria,
`spasticity, hyperreflexia, weakness, sensoryloss, and ataxia. Several
`paroxysmal phenomena can be associated with MS, including tonic
`
`D
`
`FIGURE 46-1 © A diagrammatic representation of disability by time for
`different subtypes of MS, A, Relapsing-remitting MS. B, Secondary
`progressive MS. C, Primary progressive MS. D, Progressive relapsing MS.
`
`spasms, trigeminal neuralgia, and myokymia. Newclinical symptoms
`are thought to result from new areasofinflammation and demyelin-
`ation, while the acquisition of long-term disability is more related to
`axonal damage.**
`
`Diagnosis
`The diagnosis of MS can be challenging as there is no single test with
`adequate sensitivity or specificity and there are several potential
`mimics. MS wasclassically diagnosed by the identification of lesions
`attributable to the CNS white matter that were separated in time and
`space with objective findings on neurologic exam and nobetter expla-
`nation.” However, the advent of magnetic resonance imaging (MRI)
`has significantly changed howthe diagnosis is made. Currently, the
`most widely used diagnostic criteria are the McDonald criteria, which
`werelast revised in 2005 (Table 46-1).’ These criteria endorsed the use
`of MRI as a surrogate marker for defining separation in time and
`space,
`Brain MRI in MS classically showslesions that are hyperintense on
`2-weighted sequences(Fig. 46-2). Lesions are frequentlyin the peri-
`ventricular white matter, often extending perpendicular to the ven-
`tricle. Lesionsof the corpuscallosum are common in MS,as are lesions
`in the subcortical white matter, cerebellum, brainstem,and spinal cord.
`Newer imaging techniquesare also identifying an increased number of
`lesionsin the cortex. Acute lesions will often enhance with gadolinium,
`indicating active inflammation with blood-brain barrier (BBB) break-
`down. Areas of hypointensity on Tl sequences are also seen. T1
`hypointensityis observed transiently in acute lesions. However, when
`it is present chronically, it likely represents an area ofsignificant axonal
`damage.Disability correlates more strongly with the T] hypointensity
`volume than the volume of T2 hyperintensities. With time, the accu-
`mulating axonal damage will often manifest as global cerebral atrophy.
`Only about 5% to 10%of lesions seen on MRIare associated with
`clinical symptoms. Gray matter lesions are also common in MS, but
`are not well seen on conventional MRI.
`
`Clinical Presentation
`2 or more attacks; objective clinical evidence of 2 or
`morelesions
`
`Additional Data Needed for MS Diagnosis
`* None
`
`2 or more attacks; objective clinical evidence of 1
`lesion
`
`Dissemination in space, demonstrated by:
`—MRI
`or
`
`1 attack; objective clinical evidence of 2 or more
`lesions
`
`1 attack; objective clinical evidence of 1 lesion
`(monosymptomatic presentation; clinically isolated
`syndrome)
`
`Insidious neurologic progression suggestive of MS
`
`—2 or more MRi-detected lesions consistent with MS plus positive CSF
`or
`
`—Await further clinical attack implicating a different site
`Dissemination in time, demonstrated by:
`—MRI
`or
`Second clinical attack
`
`.
`
`.
`
`Dissemination in space, demonstrated by:
`—MRI
`or
`—2 or more MRI-detected lesions consistent with MS plus positive CSF
`and
`Dissemination in time, demonstrated by:
`—MRI
`or
`Second clinical attack
`andOneyear of disease progression (retrospectively or prospectively determined)
`Twoout of three of the following:
`a. Positive brain MRI (9 T2 lesions or 4 or more T2 lesions with positive visual
`evoked potentials)
`b. Positive spinal cord MRI (2 or more focal T2 lesions)
`c. Positive CSF
`
`CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis.
`From Polman CH, Reingold SC, Edan G, et al, Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neural 2005;58;840-846.
`
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`Chapter 46 Multiple Sclerosis
`
`687
`
`FIGURE 46-2 * Brain MRI of a patient with MS. A, Axial fluid-attenuated inversion recovery (FLAIR) image showing multiple hyperintensities. B, Axial T1-
`weighted image at the samelevel. Some of the areas of FLAIR hyperintensity are also hypointense on T1-weighted images. C, Sagittal FLAIR image showing
`periventricular hyperintensities
`
`In the past, a cerebrospinal fluid (CSF) exam was a commonpart of
`the MS diagnosis. The presence of an elevated protein, oligoclonal
`bands, or an elevated immunoglobulin G index is supportive of the
`diagnosis. Although CSF analysis is still important in some cases to
`rule out other diagnoses such as infections, it
`is often unnecessaryin
`routine cases. Evoked potentials ofthe visual, auditory, or somatosen-
`sory pathways canbe helpful in somecases to detect subclinical lesions
`that cannot be seen on MRI.
`
`PATHOPHYSIOLOGY
`
`==q
`
`significantly restricts the diffusion of molecules from the periphery
`into the CNS. Disruption of the BBB by immunecells in MS is respon-
`sible for gadolinium-enhancing lesions on MRI and“attacks” in MS
`patients. Lymphocytes are able to migrate across the BBBvia a series
`of adhesion molecule interactions. Critical to this process is a connec-
`tion between verylate antigen-4 (VLA-4) on lymphocytes and mono-
`cytes andits ligands vascular cell adhesion molecule-1 (VCAM-1) on
`endothelial cells and fibronectin in the basement membrane."
`Pre-
`sumably, once effector cells from the immune system have gained
`access to the CNS,
`theysecrete a cascade of cytokines that lead to
`demyelination and ultimately axonal damage (Fig. 46-3).
`Numerous studies have analyzed the relative role that CD4* and
`Classically, MS has been described as an immune-mediated demyelin-
`CD8&" Tcells play in disease pathogenesis. Epidemiologic studies and
`ating disease affecting the brain, spinal cord, and optic nerves.” Recent
`mouse models have linked MS to MHC class II genes, which present
`research has reemphasized the concomitant presence of both gray
`antigens to CD4* Tcells.'** Thus, CD4* T cells have been ofinterest
`matter pathologyand extensive axonal damage inthebrains ofpatients
`for years. The production of tumor necrosis factor (TNF) from CD4*
`diagnosed with MS."'" The exact cause(s) of MS have not been deter-
`T cells correlates with the number of T2-hyperintense lesions on
`mined, but
`a combination of genetic and environmental
`factors
`MRI.” While autoreactive T cells have been identified in patients with
`coalesces in somepeople to lead to demyelination and axonal damage.
`MS andin healthyvolunteers, the CD4° T cells are functionallydiffer-
`One theoryis that certain viruses may share sequence homologywith
`myelin proteins and, through molecular mimicry, mediate aberrant
`ent in patients with MS. Specifically, they tend to be more differenti-
`activation ofcross-reactive T cells. Viruses mayalso cause bystander
`ated and havea higher level of T helper cell type 1 (Th1) phenotypes
`a]
`in patients with MS compared to controls."* Yet, therapy directed
`activation throughrelease of cytokines orstimulation of antigen-pre-
`=7
`wu
`senting cells. It
`is possible that MS is actually a syndrome ofvarious
`against CD4° T cells made only a small difference in patients treated
`related diseases that cause episodic demyelination and neuronal
`in clinicaltrials." Therapythat depleted both CD4" and CD8* Tcells,
`however, led to a reductionin disease activity.'"?' The role of T helper
`damage. Four pathologic subtypes of MS have been described, as dis-
`cussedlater, confirminga variety of immunopathogenetic mechanisms
`type 17 (Th17) cells in MS is less clear. This newly described subset of
`involved in different types of MS. While most of these types have an
`Tcells has been implicated in an animal model of MS, experimental
`immune-mediated component, there are some aspects of MS that may
`autoimmune encephalomyelitis, and interleukin (IL)-17 expression
`can be seen in MS brain-infiltrating cells.
`be independent of the immune system. For example, the degeneration
`of chronically demyelinated axons that occurs in the secondarypro-
`Several studies have identified the potential role of CD8* T cells in
`MS. Genetic studies have implicated various MHC class I genes as
`gressive phase ofthe disease appears to be noninflammatory. To date,
`being associated with increased risk of MS while some MHC class |
`the only successful treatment strategies for MS have involved immu-
`genes are protective.’ Persistence of autoreactive CD8* T cells in the
`nomodulatory or immunosuppressive approaches, supporting the role
`CSFofpatients with MS has beendescribed.” In mouse studies, CD8"
`that the immunesystemplays. Moreover, these therapies generally are
`T cells have been shown to potentiate immune-mediated demyeli-
`effective only during the relapsing-remitting phase, the most inflam-
`nating disease.” Yet,
`there are also data that suggest a possible
`matoryphase ofthe disease.
`Pathologic examination of the CNS in patients with MS typically
`neuroprotective role for self-reactive CD8° Tcells.“ While CD4° T
`cell production of TNF-a has correlated with the number of T2-
`identifies an inflammatory response involving cellular and humoral
`immune systems. Whether or not the immunesystem begins by rec-
`hyperintense lesions on MRI, certain CD8* T cell populations have
`beennegatively correlated with T1-hypointense lesions.'*~”
`ognizing a foreign antigen and thenstrays against self or begins by
`In onestudy, a systematic review ofbiopsies and autopsy specimens
`recognizing self-antigens is unknown. Fundamental
`to the classic
`from MS patients identified fourdistinct pathologic patterns.” Two
`description of MS pathogenesis is the inappropriate disruption of the
`BBB. Normally, the BBB is composed ofspecialized endothelial cells
`patterns were noteworthy for T-cell
`infiltrates and preservation of
`with an intricate network of tight
`junctions. Functionally, the BBB
`oligodendrocytes, with one pattern additionally having deposition of
`
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`688
`
`Section 10 Neuropharmacologic Therapeutics
`
`
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`Microglia
`
`
`
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`CD8+T cell
`—.
`
`Oligodendrocyte
`
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`Granzyme B
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`TNFB
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`CD4+ Thift
`Astrocyte
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`NMDA/AMPAreceptors
`FIGURE 46-3 * Pathogenesis of MS.
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`antibodies and complement. A third pattern was notable for a T-cell
`infiltrate without antibodydeposition, but there was a loss of myelin-
`associated glycoprotein in tissues and oligodendrocyte apoptosis with
`preserved myelin around veins and venules. Finally, the fourth pattern
`was notable for T-cell
`inflammation, but also oligodendrocyte cell
`death, This research identified heterogeneous pathology between
`patients with MS, but the findings within each individual patient were
`homogeneous. Presumably, these patterns represent various forms of
`MS,but only one form is occurring in anygiven patient at one time.
`However, the selection bias that is inherent in this study (patients
`presenting for biopsy or autopsy) could account for someof the homo-
`geneity, and other groups have not confirmed these patterns in their
`MSbraintissue examinations.
`Clinically, patients may experience new symptomsin the setting of
`new inflammation and demyelination affecting clinically eloquent
`parts of the CNS. Often the inflammation resolves partly, and there
`can be partial remyelination with varying degrees ofgliotic scarring
`and axonal damage. Muchofthe disease accumulatesin a silent manner
`and is not evident until compensatory mechanisms begin to break
`down, years into the disease process. Thus, progression of disability
`occurs slowly with time but becomes most noticeable after years
`of accumulated axonal damage.’ Therapeutic possibilities include
`immunomodulatory, immunosuppressive, neuroprotective, and neu-
`roreparative strategies.
`
`THERAPEUTICS AND CLINICAL
`PHARMACOLOGY
`Goals of Therapy
`There are two types of therapies for MS: disease-modifying therapies
`(DMTs) and symptomatic treatments. All of the DMTs currently
`approved bythe U.S. Food and Drug Administration (FDA) for MS act
`by immunomodulation or immunosuppression. These treatments are
`effective at reducing the frequencyofdisease relapses and decreasing
`the numberofnewlesions seen on MRI in RRMS. Somehavealso been
`shown to delay the accumulation ofdisability. While these immuno-
`modulatory treatments are beneficial in relapsing-remitting patients,
`they have not been proven effective in SPMS or PPMS. Immuno-
`modulation is probably ineffective in progressive MS because the nerve
`damage in these groups is less dependent on inflammation. Conse-
`quently,
`there is a major need for treatments for progressive MS
`patients.
`While the DMTs decrease the incidence of newrelapses, they are not
`helpful in repairing damage that has already occurred. Prior relapses
`often leave patients with residual symptoms. A number of medications
`are available to help these MS-related symptoms. Alleviating pain,
`spasticity, bladder dysfunction, depression, and anxiety makes up a
`significant portion of the care offered to patients with MS.
`
`Therapeutics by Class
`Immunomodulators
`
`Interferons. Thefirst drug specifically approved foruse in relapsing
`MS wasinterferon beta-1b (Betaseron in North America/Betaferon in
`Europe), Subsequent to that, two different preparations ofinterferon
`beta-1a were released (Avonex and Rebif). While the interferon beta-la
`preparations are identical to human interferon-f in terms of amino
`acid sequence and glycosylation, interferon beta-1b is produced in
`bacterial cells, has a few amino acid changes, andis not glycosylated.
`All of the interferons are FDA approved for RRMS andare therefore
`not recommended for PPMS or SPMS withoutrelapses.
`Mechanism ofAction. A variety of mechanismsof action have been
`proposed for beta interferons. First, immunologically, there is a down-
`regulation of CD80" B cells in patients treated with interferon beta.”
`This protein is responsible for co-stimulation of T cells and leads to
`Th1-type cytokinesecretion. Interferon beta also suppresses the expres-
`sion of interferon-y-induced MHC class II antigens on antigen-
`presentingcells."’”' Several studies have demonstrated a direct effect
`
`Chapter 46 Multiple Sclerosis
`
`689
`
`on Tcells, including suppression of matrix metalloproteinases (MMPs)
`and promotionofthe production of anti-inflammatorycytokines such
`as IL-4 and IL-10.*“* These processes complementeachother andlead
`to an overall