1、Multiple Sclerosis and Currently Available Treatments in the USMichelle Rainka, Pharm.D., CCRPDent InstituteUniversity at Bmmrainkabuffalo.eduCopyright : Reproduction of these slides is prohibited without permission of the author,“Multiple”- multiple areas of lost myelin“Sclerosis”- ScarringMS is a
2、chronic autoimmune inflammatory diseaseAffects Central Nervous System (brain, spinal chord and optic nerves),Multiple Sclerosis,International Journal of MS Care,Multiple Sclerosis,Multiple Sclerosis,A chronic, autoimmune disease Affects central nervous system the myelin sheath covering of nerve fibe
3、rs in the brain and spinal cordImpairs the nerves ability to send electrical impulses,MS Statistics,Approximately 400,000 Americans are diagnosed with MS Affects 2.5 million people worldwideSymptom onset and diagnosis occur typically between the ages of 20-502.5:1 women:man ratioPeople of Northern E
4、uropean 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 any other raceFound in people who live in temperate climatesOnset o
5、ccurs between ages of 20 and 40,http:/ of MS,Muscle weaknessVisual symptomsBlurry visionDouble visionUnsteady gait/balance issuesPain/ParesthesiasEmotional/Cognitive disturbancesShort term memory lossInability to concentrate,FatigueSexual DysfunctionSpeechSwallowingAbnormal sensationsTinglingNumbnes
6、sSensitivity to heatBladder and bowel problemsFrequencyLoss of control,Multiple Sclerosis Kurtzke disability status scale1 No disability & minimal neurologic sign2 Minimal disability - slight weakness or stiffness, mild disturbance of gait or mild visual disturbance3 Moderate disability - monoparesi
7、s (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 Relatively severe disability, but fully ambula
8、tory 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 involves walking unaided up to 500 meters6 Ne
9、eds 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 effective use of arms9 Helpless and b
10、edridden10 Death due to MS - results from respiratory paralysis, coma of uncertain origin, or following repeated or prolonged epileptic seizures,Diagnosing MS,A diagnosis by exclusion eliminate other disease states that may explain symptoms before suggesting MSPatients undergo clinical, laboratory (
11、hematology and CSF panels), and imaging studies to confirm diagnosis,Diagnosis 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 abnormal
12、ities 1 attack, clinical evidence of 2 separate lesions & CSF abnormalities 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 p
13、eriventricular Lesions 6 mm diameter or greater Ovoid lesions, oriented perpendicular to ventricles Corpus callosum lesions Brainstem lesions Open ring appearance of gadolinium enhancement,The axial T2WI shows peri-ventricular flame-shaped hyperintense areas,MRI Imaging,Normal Brain,Patient with MS,
14、MS Lesions “Dawsons Fingers”,MS Lesions in Spine,Cerebral Spinal Fluid Studies Strongly 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 c
15、hains Oligoclonal bands,Relapsing-Remitting MS (RRMS),Most common, affecting 85% of patients.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. Contrast
16、ed by symptom-free periods, known as remissions, where the patients symptoms partially or completely 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 RRMSI
17、ncidence has since decreasedThis disease course is steadily progressing.Can present with or without 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 no
18、t effective at treating this type of disease.,Progressive-Relapsing MS (PRMS),Relatively rare, affecting 5% of 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
19、therapy.,Treatment,Not a known cureTreatment aimed at controlling symptoms and maintaining functionDisease modifying therapyTreatment of RelapsesMedications depending on the symptomsPhysical therapySpeech therapyPlanned exercise programs in early course of disease,Treatment for Acute Exacerbation: A
20、cute severe attack Corticosteroids A hormone that stimulates the body to make its own hormone and improve its immune system ; Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.Methylprednisone (Solumedrol): 1 gram iv i
21、nfusion 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 infection,Treatment for Acute Exacerbation: Acute seve
22、re attack Corticotropin Acthar gel:Adrenocorticotropic hormone 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 weeks,Currently Available Disease Modifying Trea
23、tments,KM. 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. ,Interferon beta,Mechanism of Action = Specific interferon-induced proteins and mechanisms by whi
24、ch 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 of major histocompatibility complex gene produ
25、ction on antigen presenting glial cells.May also suppress T cell proliferation and decrease blood brain barrier permeability,Intramuscular injection given once weeklyDose: 30 mcgPregnancy Category C,Subcutaneous injection given three times a weekDose: 22 or 44 mcg Pregnancy Category C,Interferon bet
26、a-1b,Subcutaneous injection given every other dayDose: 250 mcg achieved over a 6 week titrationPregnancy Category C,Betaseron,Rebif,Avonex,Interferon beta-1aAvailable in three forms:,Interferon beta Side Effects,FLU LIKE SYMPTOMS! Up to 60% of patients.Pre-medicate before injection and the day follo
27、wing with Ibuprofen or Acetaminophen to decrease these symptoms.Will dissipate with continued use.Generally worse in females and those with lower body weight.FeverChillsHeadacheChest pain,Injection site reactionsErythemaInflammationPainSkin discoloration/swellingDepressionMyalgiaArthralgiaAstheniaMa
28、laiseDiaphoresisMyastheniaAbdominal pain,Glatiramer acetate,Mechanism 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-specific suppressor T-cells
29、 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 lymphocytes and decre
30、ase inflammation, demyelination, and axon damage.Available as CopaxoneSubcutaneous injection given once dailyDose = 20 mgPregnancy Category B,Glatiramer acetate Side Effects,INJECTION SITE REACTION!Indurations, masses, and welts from injections may last for days after administration.PainErythemaInfl
31、ammationUrticariaTransient flushingVasodilitation,Chest tightness and/or chest painAstheniaNausea/vomitingPainArthralgiaAnxietyPalpitationsDyspneaConstriction of the throat,Natalizumab,Mechanism of Action = Antagonizes 4-integrin of the adhesion molecule very late activating antigen (VLA)-4 on leuko
32、cytes.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 tissueAvailable a
33、s TysabriA humanized monoclonal antibody.Intravenous infusion given once every 4 weeksDose = 300 mgPregnancy Category C,Tysabri,In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration ac
34、ross 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-integrin expressed
35、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 into brain
36、parenchyma and reduction of plaque formation, detected by MRI following repeated administration of natalizumab.,Natalizumab PML,Progressive Multifocal Leukoencephalopathy (PML) is a sometimes fatal viral opportunistic infection that has been observed in patients receiving natalizumab. Results from a
37、ctivation 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
38、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 Fumarate,Natalizumab Side Effects,Infusion reaction including hypersensitivity reactionsRespiratory tract
39、infectionUrinary tract infectionDepressionHeadacheFatigueDiarrheaCholelithiasisArthralgiaPML,Mitoxantrone,Mechanism 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
40、 presentationPro-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 D,M
41、itoxantrone Side Effects,CardiotoxicityBone marrow suppressionHemoglobin levels, white blood cell count, and platelet counts must be measured before each infusionStomatitis, esophagitis, oral ulcerationNausea/vomitingAlopeciaHeadacheFatigueHepatic dysfunction,Fingolimod (Gilenya),Mechanism of Action
42、 = Acts on the sphingosine-1-phosphate (S1P) receptors S1P1 and S1P3-5 on the surface of lymphocytesDepletes both CD4+ and CD8+ T lymphocytes in the blood stream, up to 75% below baseline.CD4+ cells are decreased to a greater extent than CD8+ cells. Inhibits lymphocyte release from lymphatic organs
43、decreasing overall numbers in circulation,Fingolimod,Fingolimod has been assessed as an oral therapy for RRMS and SPMSDose = 0. 5 mg QDsignificantly reduced gadolinium-enhancing lesions, relapse rate compared to both placebo and Avonex, and demonstrated significantly less loss in brain volume,38,Cli
44、nical Pharmacology,800 patients in Pharmacology studies using 0.125 to 40 mg doseHigh oral bioavailability with no food effectMetabolized by cytochrome CyP450-4F2; no DDI; no toxic metabolitesT1/2 of 6-9 days No dose adjustment (renal, hepatic dysfunction; age, gender, race),Reduced lymphocyte count
45、: 70% reduction at 0.5 mg steady stateHeart rate decrease on day 1, attenuates over timeMild-moderate decrease in FEV1 at high dose (5.0 mg),First Dose Monitoring,ECG needed before initiatingMonitor hourly for 6 hrs post 1st dose for bradycardiatake HR and BPContinue observing if bpm45 or if HR is s
46、till at lowest point post dose at 6 hoursRepeat 1st dose monitoring if patient misses 1 day in first 2 weeks, 7 days in 3rd and 4th weeks, or 14 days after 1 month,Fingolimod Side Effects,NasopharyngitisHeadacheInfluenzaLymphopeniaLeukopeniaUpper respiratory tract infectionMacular edemaChanges in FE
47、V1Increase in BPHypertensionElevation in LFTsDose-dependent effects include transient heart rate reduction on treatment initiation, small increase in blood pressure, liver enzyme elevations, macular edema,Teriflunomide (Aubagio),Mechanism of Action = Blocks pyrimidine synthesis in rapidly dividing c
48、ells, inhibits protein tyrosine-kinase and cyclo-oxygenase-2 activity, and decreases the ability of antigen presenting cells to activate T-cells.active metabolite of leflunomide that has antiproliferative and anti-inflammatory activity. inhibits the mitochondrial enzymatic activity of dihydroorotate
49、 dehydrogenase. Dihydroorotate dehydrogenase functions as the rate-limiting enzyme in de novo pyrimidine synthesis. Inhibition of pyrimidine synthesis selectively produces a cytostatic effect on proliferating T and B lymphocytes in the periphery, while avoiding undue cytotoxicity to other cell types
50、. 5 ,6 Teriflunomide effectively reduces B-lymphocyte proliferation by direct suppression of dihydroorotate dehydrogenase and reduction of lipopolysaccharide-induced proliferation via the secretion of immunoglobulin M from B cells. Additionally, independent of teriflunomide activity, B-cell prolifer
51、ation is suppressed by an interleukin 4 class switch into immunoglobulin G1. The interaction between B and T lymphocytes is effectively inhibited by teriflunomide; thus, blockade of T lymphocyte dependent antibody production occurs.Has been studied as an oral therapy for RRMS and SPMS - Doses = 7 and 14 mg,
