1、多发性硬化英文“Multiple”-multiple areas of lost myelin“Sclerosis”-ScarringMS is a chronic autoimmune inflammatory diseaseAffects Central Nervous System(brain,spinal chord and optic nerves)Multiple SclerosisInternational Journal of MS CareMultiple SclerosisMultiple Sclerosis A chronic,autoimmune disease Aff
2、ects central nervous system the myelin sheath covering of nerve fibers in the brain and spinal cord Impairs the nerves ability to send electrical impulsesMS StatisticsApproximately 400,000 Americans are diagnosed with MS Affects 2.5 million people worldwideSymptom onset and diagnosis occur typically
3、 between the ages of 20-502.5:1 women:man ratioPeople of Northern European descent are afflicted most commonlyMore common above 40 latitude in areas like western New York.Women are 2 times more likely to get the disease(i.e.2 women for every 1 men)More common in Northern European descendants than an
4、y other raceFound in people who live in temperate climatesOnset occurs between ages of 20 and 40http:/ of MSMuscle weaknessVisual symptomsBlurry visionDouble visionUnsteady gait/balance issuesPain/ParesthesiasEmotional/Cognitive disturbancesShort term memory lossInability to concentrateFatigueSexual
5、 DysfunctionSpeechSwallowingAbnormal sensationsTinglingNumbnessSensitivity to heatBladder and bowel problemsFrequencyLoss of controlMultiple Sclerosis Kurtzke disability status scale1 No disability&minimal neurologic sign2 Minimal disability-slight weakness or stiffness,mild disturbance of gait or m
6、ild visual disturbance3 Moderate disability-monoparesis(partial or incomplete paralysis affecting one or part of one extremity)mild hemiparesis(slight paralysis affecting one side of body)moderate ataxia,disturbing sensory loss,prominent urinary or eye symptom,or a combination of lesser dysfunction4
7、 Relatively severe disability,but fully ambulatory without aid,self sufficient and able to be up and about 12 hours a day,does not prevent the ability to work or carry on normal living activities,excluding sexual dysfunction5 Disability is severe enough to preclude working,maximal motor function inv
8、olves walking unaided up to 500 meters6 Needs assistance walking,for example a cane,crutches,or braces7 Essentially restricted to a wheelchair but able to wheel oneself and enter and leave the chair without assistance8 Essentially restricted to bed or a chair,retains many self care functions and has
9、 effective use of arms9 Helpless and bedridden10 Death due to MS-results from respiratory paralysis,coma of uncertain origin,or following repeated or prolonged epileptic seizuresAcute severe attackStudies in animals and in vitro systems suggest that upon its administration,glatiramer acetate-specifi
10、c suppressor T-cells are induced and activated in the periphery.CarbamazepineAdditionally,independent of teriflunomide activity,B-cell proliferation is suppressed by an interleukin 4 class switch into immunoglobulin G1.Affects Central Nervous System(brain,spinal chord and optic nerves)Mechanism of A
11、ction=Blocks pyrimidine synthesis in rapidly dividing cells,inhibits protein tyrosine-kinase and cyclo-oxygenase-2 activity,and decreases the ability of antigen presenting cells to activate T-cells.Relatively rare,affecting 10%of patients.Sensitivity to heatThe annualized relapse rate of teriflunomi
12、de patients was 0.DalfampridineAlemtuzumab(Lemtrada)Impairs the nerves ability to send electrical impulsesPerform baseline and yearly skin exams.Pain/ParesthesiasIntramuscular or Subcutaneously:80 to 120 units/day for 2 to 3 weeks“Sclerosis”-Scarring2 women for every 1 men)Pharmacotherapy:A Pathophy
13、siologic Approach 7th ed.Detected in semen contraception for men.Transient eosinopheliaDiagnosing MSA diagnosis by exclusion eliminate other disease states that may explain symptoms before suggesting MSPatients undergo clinical,laboratory(hematology and CSF panels),and imaging studies to confirm dia
14、gnosisDiagnosis by Poser Criteria Clinically definite MS 2 attacks and clinical evidence of 2 separate lesions Laboratory supported Definite MS 2 attacks,either clinical or paraclinical evidence of 1 lesion,and CSF immunologic abnormalities 1 attack,clinical evidence of 2 separate lesions&CSF abnorm
15、alities 1 attack,clinical evidence of 1 and paraclinical evidence of another separate lesion,&CSF abnormalities MRI MRI findings that strongly suggestive of MS 4 or more white matter lesions(each 3mm)3 white matter lesions,1 periventricular Lesions 6 mm diameter or greater Ovoid lesions,oriented per
16、pendicular to ventricles Corpus callosum lesions Brainstem lesions Open ring appearance of gadolinium enhancementThe axial T2WI shows peri-ventricular flame-shaped hyperintense areas MRI ImagingNormal BrainPatient with MSMS Lesions“Dawsons Fingers”MS Lesions in SpineCerebral Spinal Fluid Studies Str
17、ongly suggestive of MS Normal Red Blood Cells and glucose Normal or mildly elevated protein 5-20 mononuclear cells/ul Intrathecal IgG synthesis Increased IgG index or 24 hour synthesis rate Increased free kappa light chains Oligoclonal bandsRelapsing-Remitting MS(RRMS)Most common,affecting 85%of pat
18、ients.Patients experience worsening of pre-existing symptoms or onset of new symptoms for periods of greater than 48 hours without concomitant fever,known as relapses,flare-ups,or exacerbations,of MS.Contrasted by symptom-free periods,known as remissions,where the patients symptoms partially or comp
19、letely disappear.Secondary-Progressive MS(SPMS)A progression of RRMSMore common before advent of disease-modifying medicationsApproximately 50%of patients progressed to SPMS after 10-15 years with RRMSIncidence has since decreasedThis disease course is steadily progressing.Can present with or withou
20、t clear-cut relapses.Primary-Progressive MS(PPMS)Relatively rare,affecting 10%of patients.Disease course is characterized by steady decline,without clear-cut relapses.Medications are generally not effective at treating this type of disease.Progressive-Relapsing MS(PRMS)Relatively rare,affecting 5%of
21、 patients.Steady disease progression,in addition to clear-cut periods of exacerbations of MS.Patients can be treated for relapses with steroids,however disease will progress regardless of therapy.TreatmentNot a known cureTreatment aimed at controlling symptoms and maintaining functionDisease modifyi
22、ng therapyTreatment of RelapsesMedications depending on the symptomsPhysical therapySpeech therapyPlanned exercise programs in early course of disease Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.Methylprednisone(
23、Solumedrol):1 gram iv infusion per day x 3 to 5 days -may be followed by oral Prednisone taper 60 mg qd x 7 days,then 60 mg qod x 7 days,then 40 mg qod x 7 days,then 20 mg qod x 7 days,then stop H2 blocker/PPI for ulcer prophylaxis Monitor blood glucose Watch for infectionAdrenocorticotropic hormone
24、 stimulates the adrenal cortex to secrete adrenal steroids(including cortisol),weakly androgenic substances,and aldosteroneIntramuscular or Subcutaneously:80 to 120 units/day for 2 to 3 weeksprevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissueThe PO bioavaila
25、bility single dose healthy,fasted patients is 100%,peak 1 to 2 hours.Multiple SclerosisIntramuscular injection given once weeklyClinically definite MSNatalizumab Side EffectsLamotrigineSensitivity to heatAntihistamines and/or antipyretics may also be considered.binds to the 4-subunit of 41 and 47 in
26、tegrins expressed on the surface of all leukocytes except neutrophils,and inhibits the 4-mediated adhesion of leukocytes to their counter-receptor(s).Adrenocorticotropic hormone stimulates the adrenal cortex to secrete adrenal steroids(including cortisol),weakly androgenic substances,and aldosterone
27、1 attack,clinical evidence of 2 separate lesions&CSF abnormalities 1 attack,2 attacks,either clinical or paraclinical evidence of 1 lesion,and CSF immunologic abnormalitiesprevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissueThe PO bioavailability single dose
28、healthy,fasted patients is 100%,peak 1 to 2 hours.Disease course is characterized by steady decline,without clear-cut relapses.Signs/symptoms of PMLDecreased leukocyte migrationApproximately 50%of patients progressed to SPMS after 10-15 years with RRMSMild-moderate decrease in FEV1 at high dose(5.No
29、t a known cureCurrently Available Disease Modifying TreatmentsKM.Gawronski et al.Treatment Options for Multiple Sclerosis:Current and Emerging TherapiesPharmacotherapy.2010;30(9):916-927.Dipiro et al.Pharmacotherapy:A Pathophysiologic Approach 7th ed.2008 Interferon betaMechanism of Action=Specific
30、interferon-induced proteins and mechanisms by which interferon beta exerts its effects in MS have not been fully defined.It may augment suppressor T-cell function;may decrease interferon gamma secretion by activated lymphocytes;may decrease macrophage activating effect;may down-regulate expression o
31、f major histocompatibility complex gene production on antigen presenting glial cells.May also suppress T cell proliferation and decrease blood brain barrier permeabilityIntramuscular injection given once weeklyDose:30 mcgPregnancy Category CSubcutaneous injection given three times a weekDose:22 or 4
32、4 mcg Pregnancy Category CInterferon beta-1bSubcutaneous injection given every other dayDose:250 mcg achieved over a 6 week titrationPregnancy Category CBetaseronRebifAvonexInterferon beta-1aAvailable in three forms:Interferon beta Side EffectsFLU LIKE SYMPTOMS!Up to 60%of patients.Pre-medicate befo
33、re injection and the day following with Ibuprofen or Acetaminophen to decrease these symptoms.Will dissipate with continued use.Generally worse in females and those with lower body weight.FeverChillsHeadacheChest painInjection site reactionsErythemaInflammationPainSkin discoloration/swellingDepressi
34、onMyalgiaArthralgiaAstheniaMalaiseDiaphoresisMyastheniaAbdominal painGlatiramer acetateMechanism of Action=Not fully known,thought to be related to alteration of T-cell activation and differentiation.Studies in animals and in vitro systems suggest that upon its administration,glatiramer acetate-spec
35、ific suppressor T-cells are induced and activated in the periphery.May mimic antigenic properties of myelin basic protein;May bind to Major histocompatibility complex class II receptors and inhibit binding of myelin basic protein peptides to T cell receptor complexes;May induce Th2 antiinflammatory
36、lymphocytes and decrease inflammation,demyelination,and axon damage.Available as CopaxoneSubcutaneous injection given once dailyDose=20 mgPregnancy Category BGlatiramer acetate Side EffectsINJECTION SITE REACTION!Indurations,masses,and welts from injections may last for days after administration.Pai
37、nErythemaInflammationUrticariaTransient flushingVasodilitationChest tightness and/or chest painAstheniaNausea/vomitingPainArthralgiaAnxietyPalpitationsDyspneaConstriction of the throatNatalizumabMechanism of Action=Antagonizes 4-integrin of the adhesion molecule very late activating antigen(VLA)-4 o
38、n leukocytes.binds to the 4-subunit of 41 and 47 integrins expressed on the surface of all leukocytes except neutrophils,and inhibits the 4-mediated adhesion of leukocytes to their counter-receptor(s).prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissueAvaila
39、ble as TysabriA humanized monoclonal antibody.Intravenous infusion given once every 4 weeksDose=300 mgPregnancy Category CMore common before advent of disease-modifying medicationsDetected in semen contraception for men.Contraindicated:History of seizure;Moderate to severe renal impairmentSigns/symp
40、toms of PML56 compared to 0.Interferon beta-1bHas been studied as an oral therapy for RRMS and SPMS -Doses=7 and 14 mgSymptom onset and diagnosis occur typically between the ages of 20-50GI SYMPTOMS!80%of patients were free from relapse,compared to 52%treated with interferon-1aCan present with or wi
41、thout clear-cut relapses.Dose:10 mg BID-Tablets should only be taken whole;do not divide,crush,chew,or dissolve.Pro-inflammatory cytokine expressionStomatitis,esophagitis,oral ulcerationNatalizumab Side EffectsIncreases in LFTsProgressive Multifocal Leukoencephalopathy(PML)is a sometimes fatal viral
42、 opportunistic infection that has been observed in patients receiving natalizumab.Without 8 mo-2 yearsClinical PharmacologyDextroamphetamineTysabriIn multiple sclerosis,lesions are believed to occur when activated inflammatory cells,including T lymphocytes,cross the blood-brain barrier(BBB).Leukocyt
43、e migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall.The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of 41-integr
44、in expressed by inflammatory cells with VCAM-1 on vascular endothelial cells,and with connecting segment 1 and/or osteopontin expressed by parenchymal cells in the brain.Data from an experimental autoimmune encephalitis animal model of multiple sclerosis demonstrate reduction of leukocyte migration
45、into brain parenchyma and reduction of plaque formation,detected by MRI following repeated administration of natalizumab.Natalizumab PMLProgressive Multifocal Leukoencephalopathy(PML)is a sometimes fatal viral opportunistic infection that has been observed in patients receiving natalizumab.Results f
46、rom activation of the latent John Cunningham polyomavirus in immunocompromised patients.PML is a demyelinating disease similar to MS,causing impairment of the transmission of nerve impulses,however once myelin is lost in PML,it cannot be regained.Due to PML,there is a TOUCH Prescribing Program where
47、 patients,prescribers,and infusion centers must be registered to monitor for the development of this condition.Note:PML has now also been seen in patients treated with Fingolimod and Dimethyl FumarateNatalizumab Side EffectsInfusion reaction including hypersensitivity reactionsRespiratory tract infe
48、ctionUrinary tract infectionDepressionHeadacheFatigueDiarrheaCholelithiasisArthralgiaPMLMitoxantroneMechanism of Action=Intercalates with DNA strands causing breaks,and inhibits DNA repair through topoisomerase II.Affects rapidly dividing cells secondary effects on the immune systemAntigen presentat
49、ionPro-inflammatory cytokine expressionDecreased leukocyte migrationAvailable as NovantroneAn immunosuppressive agent chemically related to doxorubicin and daunorubicin Intravenous infusion given once every 3 monthsDose=12 mg/m2 Cumulative lifetime dose of 100 mg/m2Pregnancy Category DMitoxantrone S
50、ide EffectsCardiotoxicityBone marrow suppressionHemoglobin levels,white blood cell count,and platelet counts must be measured before each infusionStomatitis,esophagitis,oral ulcerationNausea/vomitingAlopeciaHeadacheFatigueHepatic dysfunctionFingolimod(Gilenya)Mechanism of Action=Acts on the sphingos
