多发性硬化英文概要课件

Multiple Sclerosis and Currently Available Treatments in the US Michelle Rainka, Pharm.D., CCRP Dent Institute University at Buffalo Copyright : Reproduction of these slides is prohibited without permission of the author “Multiple”- multiple areas of lost myelin “Sclerosis”- Scarring MS is a chronic autoimmune inflammatory disease Affects 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 fibers in the brain and spinal cord Impairs the nerves ability to send electrical impulses MS Statistics Approximately 400,000 Americans are diagnosed with MS Affects 2.5 million people worldwide Symptom onset and diagnosis occur typically between the ages of 20-50 2.5:1 women:man ratio People of Northern European descent are afflicted most commonly More 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 race Found in people who live in temperate climates Onset occurs between ages of 20 and 40 http:/multiplesclerosis.n et/what-is-ms/statistics/ Symptoms of MS Muscle weakness Visual symptoms Blurry vision Double vision Unsteady gait/balance issues Pain/Paresthesias Emotional/Cognitive disturbances Short term memory loss Inability to concentrate Fatigue Sexual Dysfunction Speech Swallowing Abnormal sensations Tingling Numbness Sensitivity to heat Bladder and bowel problems Frequency Loss of control Multiple Sclerosis Kurtzke disability status scale 1 No disability system ; Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability. Methylprednisone (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 infection Treatment for Acute Exacerbation:Treatment for Acute Exacerbation: Acute severe attack Acute severe attack CorticotropinCorticotropin ActharActhar gel: gel: Adrenocorticotropic hormone stimulates the adrenal cortex to secrete adrenal steroids (including cortisol), weakly androgenic substances, and aldosterone Intramuscular or Subcutaneously: 80 to 120 units/day for 2 to 3 weeks CURRENTLY AVAILABLE DISEASE MODIFYING TREATMENTS KM. Gawronski et al. Treatment Options for Multiple Sclerosis: Current and Emerging Therapies Pharmacotherapy. 2010;30(9):916-927. Dipiro et al. Pharmacotherapy: A Pathophysiologic Approach 7th ed. 2008 Interferon beta Mechanism of Action = Specific 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 of major histocompatibility complex gene production on antigen presenting glial cells. May also suppress T cell proliferation and decrease blood brain barrier permeability Intramuscular injection given once weekly Dose: 30 mcg Pregnancy Category C Subcutaneous injection given three times a week Dose: 22 or 44 mcg Pregnancy Category C Interferon beta-1b Subcutaneous injection given every other day Dose: 250 mcg achieved over a 6 week titration Pregnancy Category C Betaseron RebifAvonex Interferon beta-1a Available in three forms: Interferon beta Side Effects FLU LIKE SYMPTOMS! Up to 60% of patients. Pre-medicate before 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. Fever Chills Headache Chest pain Injection site reactions Erythema Inflammation Pain Skin discoloration/swelling Depression Myalgia Arthralgia Asthenia Malaise Diaphoresis Myasthenia Abdominal 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 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 decrease inflammation, demyelination, and axon damage. Available as Copaxone Subcutaneous injection given once daily Dose = 20 mg Pregnancy Category B Glatiramer acetate Side Effects INJECTION SITE REACTION! Indurations, masses, and welts from injections may last for days after administration. Pain Erythema Inflammation Urticaria Transient flushing Vasodilitation Chest tightness and/or chest pain Asthenia Nausea/vomiting Pain Arthralgia Anxiety Palpitations Dyspnea Constriction of the throat Natalizumab Mechanism of Action = Antagonizes 4-integrin of the adhesion molecule very late activating antigen (VLA)-4 on 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 tissue Available as Tysabri A humanized monoclonal antibody. Intravenous infusion given once every 4 weeks Dose = 300 mg Pregnancy 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 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-integrin 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 into brain 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 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 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 reactions Respiratory tract infection Urinary tract infection Depression Headache Fatigue Diarrhea Cholelithiasis Arthralgia PML 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 system Antigen presentation Pro-inflammatory cytokine expression Decreased leukocyte migration Available as Novantrone An immunosuppressive agent chemically related to doxorubicin and daunorubicin Intravenous infusion given once every 3 months Dose = 12 mg/m2 Cumulative lifetime dose of 100 mg/m2 Pregnancy Category D Mitoxantrone Side Effects Cardiotoxicity Bone marrow suppression Hemoglobin levels, white blood cell count, and platelet counts must be measured before each infusion Stomatitis, esophagitis, oral ulceration Nausea/vomiting Alopecia Headache Fatigue Hepatic dysfunction Fingolimod (Gilenya) Mechanism of Action = Acts on the sphingosine-1- phosphate (S1P) receptors S1P1 and S1P3-5 on the surface of lymphocytes Depletes 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 decreasing overall numbers in circulation Fingolimod Fingolimod has been assessed as an oral therapy for RRMS and SPMS Dose = 0. 5 mg QD significantly reduced gadolinium-enhancing lesions, relapse rate compared to both placebo and Avonex, and demonstrated significantly less loss in brain volume 36 Clinical Pharmacology 800 patient