Drugs used in multiple sclerosis and amyotrophic lateral sclerosis

Transcription

1 Drugs used in multiple sclerosis and amyotrophic lateral sclerosis 1

2 Multiple sclerosis Multiple sclerosis is a chronic disease which involves demyelination of nerve fibres. Its first symptoms are the slowing down and the atrophy of nerve transmission. Patients with MS suffer from paraparesis, disorders of balance and coordination, dysesthesia, dysuria, dyschezia, disorders of vision, depression, pain of the trigeminal nerve mainly and other nerves, migraine and thinking disorders. Epileptic seizures are rarely observed. 2

3 Multiple sclerosis It is believed that the basis of multiple sclerosis may be: immunological disorders viral infections and bacterial infections environmental factors 3

4 Epidemiology. The number of people with MS is million (approx. 30 per 100,000) globally, with rate varying widely in different regions: In Africa less than 0.5 per 100,000 In south East Asia 2.8 per 100,000 In the Americas 8.3 per 100,000 In Europe 80 per 100,000 4

5 Multiple sclerosis Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for therapeutic decisions. In 1996 the United States National Multiple Sclerosis Society standardized four subtype definitions: 5

6 Progressive-relapsing multiple sclerosis Steady decline since onset superimposed attacks Secondary progressive multiple sclerosis Initial relapsing-remiting multiple sclerosis that suddenly begins to have decline without periods of remission. Primary progressive multiple sclerosis Steady increase in disability without attacks. Relapsing-remitting multiple sclerosis Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission. 6

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8 Disease-modifying treatments Disease-modifying treatments for relapsing-remitting MS (RRMS) include: interferon 1a (AVONEX i.m, REBIF subcutaneously, CinnoVex i.m.) interferon 1b (BETAFERON, BETASERON, EXTAVIA s.c.) glatiramer acetate (COPAXONE s.c.) mitoxantron (NOVANTRON iv, only in USA) natalizumab (TYSABRI i.v) fingolimod (GILENYA orally) teriflunomide (AUBAGIO orally) Emerging agents for RRMS that have shown promise in phase 2 trials include alemtuzumab (trade name Campath), daclizumab (trade name Zenapax), rituximab, dirucotide, cladribine, dimethyl fumarate, estriol, laquinimod, minocycline, statins, 8 temsirolimus.

9 Interferons Mechanism of action Interferon beta balances the expression of pro- and anti-inflammatory agents in the brain and reduces the number of inflammatory cells that cross the blood brain barrier. Overall therapy with interferon beta leads to a reduction of neuron inflammation. Moreover, it is also thaught to increase the production on nerve growth factor and consequently improve neuronal survival. 9

10 Glatiramer acetate (COPAXONE) Glatiramer acetate (COPAXONE) is a polymer of L-glutamic acid, L-alanine, L-lysine, L-tyrosine in the form of acetates. It is believed that this drug creates a cross reaction with the basic protein of myelin at humoral and cellular levels and it shows high affinity for particles of the second class histocompatibility MHC antigen. It removes from second class MHC bonds such proteins as the basic protein of myelin (MBP), the myelinic glycoprotein of oligodendrites (MOG) and proteolipid protein (PLP). 10

11 Glatiramer acetate (COPAXONE) The bonding of drugs with the second class MHC slows down the progression of MS as a result of: induction of specific suppressor T lymphocytes inhibition of specific effector T lymphocytes. Glatiramer acetate is administered subcutaneously to patients with MS to diminish the frequency of disease bouts. The following adverse effects may appear during therapy: reddening, pain, local irritation or edema in the place of injection allergic reactions (rarely) angiectasia, tachycardia, headache and dizziness, dyspnea, nausea, rigor, weakness, arthralgia, tremor and excessive sweating. 11

12 Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. Natalizumab was approved in 2004 by the U.S. Food and Drug Administration (FDA). It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy (PML) when administered in combination with interferon beta-1a, another immunosuppressive drug often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. In the European Union, it has been approved for human use only for the treatment of multiple sclerosis and only then as a monotherapy because the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by 12 the deceased customers.

13 Mechanism of action Natalizumab is a humanized monoclonal antibody against alpha-4 (α4) integrin, the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for white blood cells to move into organs; natalizumab's mechanism of action is believed to be the inhibition these immune cells from crossing blood vessel walls to reach affected organs. 13

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15 Fingolimod, GILENYA (was approved in 2010 by the U.S. Food and Drug Administration (FDA), in 2011 in UE and in 2013 in Poland). It is pro-drugs, which is phosphorylated by sphingosine kinase to its active form, phosphorylated fingolimod (fingolimod-p). H 2 N OH OH H 3 C Fingolimod sphingosine kinase 2 H 3 C (S)-Fingolimod-P H 2 N OH O P OH OH O 15

16 NH 2 H 3 C OH Sphingosine OH NH 2 H 3 C Sphingosine-1-phosphate OH O P OH O OH Mechanism of action. Fingolimod and fingolimod-phoshate (fingolimod-p) are structural analogues of sphingosine and sphingosine-1-phosphate (S1P), respectively. Sphingosine is a membrane component in all cells and constitutes 25% of the lipid in the myelin sheath. S1P regulates cell proliferation, movement and survival and vascular maturatation, and has pronounced effects on immune function and lymphocytes trafficking. 16

17 Sphingosine-1-phosphate binds to a family of 5G protein-coupled receptors (S1P 1-5 ). The expression and type of S1P receptor varies between different cell lineages (S1P 1-3 ). Receptors are widely expressed in the immune, central nervous and cardiovascular systems, with S1P 1 also being the predominant S1P receptor expressed on T and B lymphocytes. S1P 4 is specifically expressed in lymphoid tissue and S1P 5 is predominantly expressed in CNS white matter. In normal immune function, when an activating antigen is encountered in the lymph modes, S1P receptors on T cells are transiently downregulated, and the egress from the lymph nodes is blocked. Following T-cell activation in the node, T cells respond to an S1P concentration gradient between lymphoid tissue and bodily fluid and T cells are returned to the circulation and reach the site of inflamation. 17

18 Fingolimod-P acts as an agonist at S1P receptors in a wide variety of tissues and cell types. It is active at S1P 1, S1P 3, S1P 4 and S1P 5 receptors. In lymphocytes, fingolimod-p binds to S1P receptors and acts as a functional antagonist. It binds and stimulates the receptor, which results in internalization and degradation of the receptor. This reduces the responsiveness of T cells to the egress signal S1P. Immunomodulatory effects of fingolimod blockade of lymphocyte egress from lymph node (e.g. Th17 cell) Potential effects of fingolimod on the blood-brain barrier - promotion of adherent junction assembly - decreased permeability of the blood-brain barrier Potential CNS effects of fingolimod - differentiation and protection of OLGs/OLG precursor cells - increased remyelination 18

19 Sfingozyna S1P S1P 1 S1P 1 (S)-Fingolimodo-P Fingolimod G 1 G Kinaza sfingozynowa Kinaza sfingozynowa Ujemna regulacja S1P 1 Transport limfocytów na zewnątrz wtórnej tkanki limfatycznej i grasicy Hamowanie transportu limfocytów zależnego od S1P/S1P 1 19

20 Indication. GILENYA is a prescription medicine used to treat relapsing forms of MS in adults. GILENYA can decrease the number of MS relapses. GILENYA does not cure MS but it can help down the physical problems that MS causes. 20

21 Side effects. Gilenya may causes serious side effects such as: Slow heart, especially after your first doses Increased risk of serious infections Macular edema, a vision problem that can cause some of the same vision symptoms as an MS attack (optic neuritis) or no symptoms. Breading problems Liver problems Increasses in blood pressure GILLENYA may harm your unborn baby. 21

22 N H N CH 3 Teriflunomid AUBAGIO tablets F F F O OH On 21 March 2013, the Commitee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product AUBAGIO 14 mg film-coated tablet intended for the treatment of multiple sclerosis. Mechanism of action Teriflunomide is a selective immunosuppressant with anti-inflammatory properties. The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood, but it is known to reduce the proliferation of lymphocytes by blocking the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH). 22

23 Indication Treatment of adult patient with relapsing remitting MS Side effect The most common side effect are upper respiratory tract infections, urinary tract infections, diarrhoea, nausea, paraesthesia (pins and needles), alopecia (loss of hair) and increase in the liver enzyme alanine aminotransferase. 23

24 OH O HN H N OH Mitoxantrone is an anthracenedione (not an anthracycline) antineoplastic agent. Mitoxantrone is also used to treat multiple sclerosis (MS), most notably the subset known as secondary progressive MS. Mitoxantrone will not cure multiple sclerosis, but is effective in slowing the progression of secondary progressive MS and extending the time between relapses in relapsing-remitting MS and progressive relapsing MS. OH O HN N H OH 24

25 Mechanism of action Mitoxantrone is a type II topoisomerase inhibitor; it disrupts DNA synthesis and DNA repair in both healthy cells and cancer cells. It also engages in intercalation. 25

26 Side effects As other drugs in its class, mitoxantrone may cause several adverse reactions of varying severity, such as nausea, vomiting, hair loss, heart damage, and immunosuppression. Some side effects may have delayed onset. Cardiomyopathy is a particularly concerning effect as it is irreversible; regular monitoring with echocardiograms or MUGA scans is recommended for people taking mitoxantrone. 26

27 Glycocorticosteroids in acute attacks To relieve a bout of multiple sclerosis, methylprednisolone is used as a drug of choice. It is administered in a dosage of 1 g by slow intravenous infusion, repeated for at least 3 days, depending on the intensity of the disease. After that the dosage is gradually decreased during the next 10 days. In the case of less intense bouts oral administration of glycocorticosteroids is recommended. 27

28 The symptomatic treatment of MS The objectives of the symptomatic treatment of MS are to: rectify muscular tone diminish the fatigability of muscles relieve disorders of the urinary and intestinal systems act antipsychotically facilitate and normalize sleep prevent epileptic seizures. 28

29 Rehabilitation and diet Movement rehabilitation has an influence on the efficiency of the patient s movements and also on his or her general feeling. It should be conducted by an experienced therapist. Because of muscle fatigability, which increases at higher temperatures, cooling therapy and swimming in water at a temperature lower than the temperature of the body is recommended. 29

30 Rehabilitation and diet Also an appropriate diet plays an important role. Consumption of large amounts of meat has a negative impact but eating fish, green and red vegetables has a protective influence. A diet rich in unsaturated fatty acids helps the destroyed myelin sheath to regenerate. Antioxidants have the same effect. It is thought that growth factors facilitate nerve transmission. 30

31 Amyotrophic lateral sclerosis (SLA sclerosis lateralis amyotrophica) Amyotrophic lateral sclerosis affects both central and peripheral motor neurons. This disease is also called Lou Gehrig s disease and Charcot s syndrome. This disease of motor neurons involves damage of the extrapyramidal system, the motor neurons of cranial nerves and the cells of the anterior horn of the spinal cord. In contrast to MS, pathological symptoms are not observed in the sensory system or in the muscle of the eyeball. 31

32 Amyotrophic lateral sclerosis (SLA sclerosis lateralis amyotrophica) Several clinical forms of the disease of motor neurons are distinquished. The most common of them is characterized by progressive and irreversible degeneration of the cells of the anterior horn of the spinal cord, flaccid paresis of upper limbs and spasticity of lower limbs, progressive muscular atrophy and bulbar paralysis. Seven out of a hundred thousand individuals suffer from SLA, usually between ages 40 and 70. It is more widespread among men than women. 32

33 Amyotrophic lateral sclerosis (SLA sclerosis lateralis amyotrophica) At present this disease is progressive and incurable and causes the death of 50% of patients within 3 years. 25% of patients survive 5 years and 10% about 10 years. First, the progressive asymmetric weakness of limb muscles occurs. Finally, the paralysis of all four limbs is observed. As paralysis intensifies, the following are also observed: speech disorder, dysphagia and other vegetative symptoms such as sialorrhea, dyspnea, sleep disorder and depression. The atrophy of respiratory muscles is the direct cause of the death of patients who die without losing consciousness. 33

34 Amyotrophic lateral sclerosis (SLA sclerosis lateralis amyotrophica) In 90% of cases this disease is sporadic. 5-10% of SLA cases are familial and are caused by the genetic defect of chromosome 21. Then the probability that an off spring will develop SLA is 50%. It is believed that the defect of chromosome 21 is responsible for the synthesis of an incorrect form of superoxide dysmutase. Under normal conditions this enzyme protects motor neurons from free radicals. 34

35 Amyotrophic lateral sclerosis (SLA sclerosis lateralis amyotrophica) The cause of SLA has not been explained yet. According to one hypothesis, SLA may be caused by the excess of glutamic acid in the CNS. The level of this acid is regulated by the protein EAAT2. It is suspected that in a person with SLA this protein does not function properly because of a mutation in the gene responsible for its synthesis. At present SLA is incurable. 35

36 Drugs used in the treatment of SLA The only drug registered by FDA (1995) and in Poland (1992) is riluzole. Riluzole inhibits the release of glutamate. It prolongs life and delays the necessity of mechanical ventilation in patients with SLA. It is the most effective at the early stage of the disease. After oral administration it is rapidly and almost completely absorbed from the gastrointestinal tract. Biological availability of this drug is 60 ± 18%. Fatty foods increase the rate and degree of absorption. F 3 CO S N NH 2 Riluzole, RILUTEK 36

37 Drugs used in the treatment of SLA Riluzole is distributed in the whole body and permeates through the blood-brain barrier. It binds with plasma proteins at a ratio of 97%. Riluzole is rapidly metabolized in the liver due to the presence of the isoenzyme CYP1A2. The biological half-life of riluzole in the elimination phase is 9-15 h. It is eliminated mainly in urine as metabolites. The adverse effects may involve: weakness, nausea, a transient decrease in the activity of ALAT, headache and vertigo, abdominal pain, vomiting, tachycardia, somnolence and paresthesia. 37

38 The future of SLA treatment A recombination form of a glial cell-line-derived neurotrophic factor, which protects motor neurons, is in the first phase of clinical trials. Other experimental preparations are a brain-derived neurotrophic factor (BDNF) for intrathecal administration and Myothrophin, a recombined insulin-like growth factor (IGF-1), also called somatomedine C. It is believed that Myothrophin protects neurons and stimulates their regeneration. 38

39 The future of SLA treatment Another drug undergoing tests is SR57746A. This compound may imitate or stimulate the synthesis of natural neurotrophic factors such as NGF (nerve growth factor) or BDNF. Gabapentin used as anticonvulsant, is in the third phase of clinical trials (an anticonvulsant that is a structural analogue of -aminobutyric acid, used as adjunctive therapy in the treatment of partial seizures; administered orally). Gabapentin inhibits the action of glutamate like Riluzole, but at synapse level. The use of allopurinol and hydroxychloroquine is also being considered. These drugs are already used to treat other diseases. 39