Kuwait Pharmacy Bulletin DRUG INFORMATION FOR THE HEALTH PROFESSIONAL

Vol 17. No 3 Autumn 2013 ISSN 1028-0480

Multiple Sclerosis: the viral link and anti- body-based therapies

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination; lymphocytes and macrophages are drawn to the fibers of the white matter and start attacking the myelin sheath and killing the oligodendrocytes. This inflammatory response leads to either par- tial or complete demyelination, resulting in formation of scars and le- sions. MS affects women more than men. Although the exact cause remains unclear, genetic factors as well as environmental triggers may be involved. Viruses such as Epstein-Barr Virus (EBV) and human herpes virus-6 (HHV-6) are strongly associated with the pathogenicity of this disease in genetically predisposed individuals. Symptoms depend on the affected area of the CNS with optic neuritis and motor disturbance as early symptoms. Despite the fact that there is no cure, disease modifying drugs are used to reduce relapses, progression rate, and number of brain lesions. These include β , glatiramer acetate and mitoxantrone. In addition, there are al- so a number of monoclonal such as , and ; with the only FDA approved one being . Other antibodies still under investigation are , ofatumumab and AIN457.

Diagnosis and disease course can last from days to months. As RRMS progresses, it becomes secondary pro- To reveal the demyelination, cerebrospinal fluid gressive (SPMS) (second type). Only partial recov- (CSF) test should show increased levels of IgG. ery occurs after relapses in patients with SPMS. MRI is also per- Moreover, SPMS formed to reveal worsens on a slow any lesions during steady state. the diagnosis (1). The third type is called As the disease pro- primary progressive gresses, axons are MS (PPMS) and is also destroyed due characterized by a to death of oli- slowly progressive godendrocytes course without any which are responsi- period of remission. ble for nourishing The last type is pro- the axons with insulin like growth factor and brain gressive relapsing (PRMS) which is rare. Disease derived neutrophic factor. This process is termed progression rate is Wallerian degeneration. higher in adults. In this issue MS is divided into four types (1,2) depending on However, children its severity and disease progression. The first and experience a higher most common is relapsing remitting MS (RRMS) rate of relapse. Multiple Sclerosis 1 Test your knowledge 8 which appears to be experienced by all patients. Topical issues 9 This type has acute onset and is characterized by Viral links and FDA reviews & approvals 11 recovery periods folowing relapses which may last causes New Drug approvals 16 for days, weeks or even months, while remission

2 Kuwait Pharmacy Bulletin Autumn 2013

logical damage of the oligodendrocytes, which in That monozygotic twins show only 30% concord- turn may cause demyelination. Moreover, during ance in the incidence of this disease (3-5) supports exacerbations, a rise in anti-EBV early was the theory of environmental triggers such as virus- observed, which means reactivation of the virus es. Furthermore, CSF tests show increased levels leading to recruitment of T-cells.. (6) of IgG and oligodendrocytes. These markers are 2- Epitopic mimicry seen in infectious diseases such as neurosyphilis Anti-EBV killer T-cells are misguided to killing and cryptococcalmeningitis. both the virus and destroying an epitope of a protein Additionally, a number of demyelinating diseas- component in the myelin sheath, (MBP) (7). The es are caused by viruses (6). A study on mice also reason behind this is that the virus’s protein resem- concluded that MS can be induced by a virus. In bles one of the myelin sheath components. This

addition, upper respiratory tract infections are epitopic mimicry explains the autoimmunity of the linked to increase in the rate of exacerbations epi- disease (8). However, MS may not be induced by sodes as well as their severity (3). this mechanism alone; it needs to be followed by In the last decade a number of viruses such as non-specific immune response to initiate the dis- measles, rubella, and herpes (3,7,5) have been im- ease. plicated. EBV can induce\trigger MS as evidenced by increased levels of antibodies specific to this HHV-6 virus, EBV DNA in serum, and anti-EBV killer T- HHV-6 DNA was detected in MS plaques in the cells (9). Human herpes virus-6 (HHV-6) has also brain (6). Infections caused by this virus may result been detected in patients’ brain (6). in neurological complications and epilepsy. Howev- er, HHV-6 remains controversial as cause or trigger EBV for MS as studies have failed to show the ability of This virus can hide in the to trig- this virus to activate MBP-reactive T cells (11). Its ger an inflammatory response that is responsible mechanism in causing MS is thought to be by either for demyelination (10). Patients who are affected molecular mimicry as EBV, direct cytopathic action by EBV have a higher rate of developing MS ei- or virus reactivation. ther immediately or after a period of virus expo- sure (8,9). Furthermore, people who are exposed to EBV are twice as likely as healthy individuals to Treatment develop MS (8). Moreover, there is an association between disease progression and anti-EBV anti- MS therapy is composed of three categories: exacer- bodies (3). This virus may induce or trigger MS by bations therapy including steroids and plasmaphere- the following mechanisms: sis; symptomatic therapy including baclofen for 1- Reactivation of the virus muscle spasm, sildenafil for sexual dysfunction, and Activation of the virus may also trigger immuno-

Vol 17, No 3 Drug Information For The Health Professional 3 amitriptylin for depression; and disease modifying therapy. Disease modifying drugs (DMDs) are Teriflunomide is another oral immunomodulator classified into immunomodulators, immunosup- used for RRMS (20, 21). It is the second oral medi- pressants and monoclonal antibodies. cation approved by FDA after because of its cardiovascular risks. Although beta IFNs and A. Immunomodulators glatiramer acetate are used for clinical isolated syn- Immunomodulators are considered first line thera- drome, teriflunomide is the first drug that shows de- py. They include beta interferons (beta IFN-1a and laying in the progression to the clinically definite 1b) and glatiramer acetate, which is composed of MS. This drug is used to reduce number of relapses aminoacid polymers (12). They reduce the number and to slow the progression of MS. It reversibly in- of lesions when MRI is performed, and are used hibits dihydrorotate dehydrogenase, which has a for RRMS (13). Both agents are used for clinically role in DNA replication, thus, reducing T- and B- isolated syndrome (13-15). cell proliferation. Liver toxicity and teratogenicity Clinically isolated syndrome means the first at- are the major side effects. To avoid hepatotoxicity, tack, which is not yet a definite MS and is con- patients should undergo monthly liver function tests firmed only when the second attack occurs. Β IFNs for the first six months (21,22). are thought to act by decreasing the interaction be- tween immune cells with other foreign cells, thus decreasing the inflammation which leads to demy- Dimethyl fumarate is the third oral drug approved elination (16). by FDA to treat MS. It is taken twice daily. It is Liver dysfunction and thrombocytopenia are con- used for patients with RRMS. It works by decreas- traindications for these drugs. Side effects include ing the number of immune cells, particularly lym- reaction at the site of injection and liver damage. phocytes. Infection, as a result of its mechanism of Unlike glatiramer acetate, IFNs may show flu-like action, GIT disturbance and flushing are the most symptoms (14). To overcome this side effect, acet- common adverse events (23). aminophen or ibuprofen should be taken prior to the (13). B. Immunosuppressants: Each one of these agents has a different frequen- Mitoxantrone is an FDA approved immunosuppres- cy of administration. Glatiramer acetate is injected sant for MS (16). This antineoplastic drug acts on T- daily via subcutaneous injection while beta IFNs cells and B-cells by destruction of their DNA and are administered subcutaneously, either three times RNA leading to suppression of immune system ac- per week or every other day. Another beta IFN tivity (15, 24). It is used for RRMS, PRMS and preparation can be given intramuscularly weekly SPMS but not for PPMS. Serious side effects, main- (16). ly cardiotoxicity confine this medication to only the The main drawbacks for using immunomodula- severe stage of MS based on MRI results. Assessing tors are their variable effectiveness and cost. Fur- baseline left ventricular function before starting this thermore, the risks of prolonged usage are not medication is essential (15). Mitoxantrone may also known yet (13, 14). cause secondary acute myelogenous leukemia The following three drugs are oral immunomod- (AML) (12,15) and infection. Bone marrow sup- ulators used in MS: pression, thrombocytopenia and are contra- indications. Fingolimod Finglolimod slows the progression and reduces the C. Monoclonal antibodies: number of relapses (17). It works by modifying a Monoclonal antibodies are becoming increasing sphingosine 1-phosphate receptor leading to en- popular in treating MS. To overcome immunogenic- trapments of T-cells and B-cells in the lymph ity, humanized or chimeric monoclonal antibodies nodes (17). It is an oral drug taken once daily. It is are utilised. This process is carried out by attaching also indicated for RRMS when treatment with gla- a small portion of a mouse monoclonal , tiramer acetate or inteferons is ineffective (18). which is needed to recognize the targeted antigen, to This medication costs more than other therapies a human antibody backbone. Super-humanized and requires monitoring of heart function after the monoclonal antibodies are similar to chimeric mon- first dose for 6 h, because of bradycardia risk oclonal antibodies, but with attachment of a smaller (17,19).

4 Kuwait Pharmacy Bulletin Autumn 2013 part of the mouse antibody to a whole human anti- clonal antibody that is body framework. used to treat leukemia Variation of dosage forms can also help in re- (28, 33). It is used ducing immunogenicity. For example, the intrave- nowadays for patients nous form produces less immune reaction than the with RRMS when first subcutaneous one. However, infusion reaction is line therapy has failed another problem. (25, 26) Treatment with mono- (34). Reduction in the clonal antibodies should only be considered for relapsing rate to 50% patients who have severe progression despite the compared to beta use of first line therapy immunomodulators (27). IFNs and decreasing Antibodies used in MS include natalizumab, the progression of the alemtuzumab, daclizumab and rituximab. Only disease have been observed (28,33). Moreover, the natalizumab is FDA approved and licensed while number of new lesions of patients with secondary alemtuzumab and daclizumab are in phase III and progressive MS using this medication is reduced rituximab still in phase II. (28) (33). The mechanism of action of this drug is by binding Natalizumab to CD52, and killing T-cells in order to prevent them This is prescribed for patients who have had at from entering into the CNS and initiate damage to the least two severe attacks in one year with signifi- myelin sheath. This drug is given for five days intra- cant rise in the number of lesions on MRI (29, 30) venously and then after one year for three days. Com- and for patients who suffer from relapses despite mon side effects are infusion reactions which can be the use of IFNs or glatiramer acetate (29, 31). It prevented by pre-treatment with steroids or antihista- reduces the number of relapses by around 60-70%, mines, hyperthyroidism e.g. Graves’ disease, and idi- as well as lesions and rate of disease progression opathic thrombocytopenia purpura (ITP) (35). (29,31,32). Natalizumab is given as 300 mg intravenously Daclizumab every 28 days (30). This drug works by binding to Daclizumab is used to treat RRMS and SPMS in pa- alpha-4 on the surface of lymphocytes, tients who failed to respond to beta IFNs or glati- thus preventing immune cells from passing into ramer acetate (36,37). It decreases the rate of pro- the CNS (29). It is approved as monotherapy. gression and number of relapses. Additionally, it re- Common side effects include dizziness, infec- duces the number of new lesions as indicated by tions and skin rash. One of the most serious infec- MRI. Daclizumab is injected via monthly subcutane- tions is progressive multifocal leukoencephalopa- ous injections. This medication acts by binding to the thy (PML). This fatal complication is caused by tac-epitop on the -2 receptor (IL-2) against JC virus (29,31). the CD25 receptor on the surface of T-cells. Dacli- Several risk factors include previous exposure to zumab is designed to inhibit further inflammation, JC virus, prior immunosuppressant treatment, and leading to protection of the myelin sheath against T- duration of natalizumab exposure. If a patient is cells. Daclizumab also activates the natural T-cell on steroids or other immunomodulators they killers (37-39). Some side effects such as fatigue and should stop taking them for at least one month be- GIT disturbance may occur. Monotherapy shows fore starting natalizumab monotherapy. To re- similar efficacy to combination therapy with beta duce natalizumab induced PML risk, patients IFNs. should go through a drug holiday of 3-4 months after a year of taking natalizumab, but this comes Rituximab with a risk of MS rebound. Longer half-lives and A chimeric used to treat non- slower clearance are achieved with higher doses. Hodgkins lymphoma, rituximab targets CD20 antigen Natalizumab is used for RRMS and not for pa- on B-cells. It decreases the number of B as well as T- tients with progressive form of MS. However, re- cells in the cerebrospinal fluid and reduces the num- cent studies showed an improvement in patients ber of new lesions as well as relapses in patients with with SPMS. (32) RRMS but is not effective for patients with PPMS. Improvement is seen after the first dose as indicated Alemtuzumab by MRI. It is only administered intravenously. Com- Alemtuzumab is another super-humanised mono- mon side effects include progressive multifocal leu-

Vol 17, No 3 Drug Information For The Health Professional 5 koencephalopathy (PML) and infusion reaction. and reducing the relapsing rate (31). In addition, it (40, 41) can be used in the progressive form of MS (32). When alemtuzumab was compared to β IFNs, Pregnancy and MS treatment alemtuzumab was associated with greater reduction in rate of disability and decreased number of relapses Pregnant women experience reduced number of (28,33). relapses, and stabilization of the disease. This is explained by the increased production of cortico- Indication steroids and some natural immunosuppressants β interferons and glatiramer acetate are considered during pregnancy. However, rate of relapses may first line therapy for patients with RRMS as well as increase significantly in the first three months af- patients with clinically isolated syndrome (13-15). ter delivery when compared to its rate before ges- Although mitoxantrone is used in progressive form of tation. Long term disability progression is not af- MS, it comes with serious side effects like cardiotox- fected by pregnancy. Glatiramer acetate, β IFNs, icity and acute myelogenous leukemia. Natalizumab,

fingolimod, teriflunomide, mitoxantrone, natali- alemtuzumab, and daclizumab can be taken in case of zumab, and rituximab should be discontinued dur- a more progressive form of MS like SPMS ing pregnancy. Intravenous steroids can be used in (32,33,36,37). case of relapse. (42) Routes of administration Monoclonal antibodies vs DMDs All monoclonal antibodies, glatiramer acetate, and β IFNs are taken via injections; either subcutaneously like daclizumab or via infusion like natalizumab, DMDs include immunomodulators such as beta alemtuzumab and rituximab. In contrast, there are IFNs and glatiramer acetate, immunosuppressants three oral medications, such as fingolimod, terifluno- like mitoxantrone and the new oral DMDs fin- mide, and dimethyl fumarate, which may be prefera- golimod, teriflunomid and dimethyl fumarate. ble to patients. DMDs reduce relapse rate and progression of the disease, as well as number of new lesions. Com- pared to monoclonal antibodies, they may differ in Safety terms of efficacy, indication, route of administra- There is a risk of PML with natalizumab. It should be tion and safety profile. prescribed only for patients who test negative for JC- virus before initiating therapy (43). Alemtuzumab is associated with rare side effects like thyroid disorders Efficacy and idiopathic thrombocytopenia purpura (28,33,35). In terms of efficacy, natalizumab is more effective In contrast, β IFNs and glatiramer acetate cause liver than β IFNs in slowing the progression of disease

6 Kuwait Pharmacy Bulletin Autumn 2013 dysfunction and infusion reaction. Fingolimod in reduced relapse rate as well as 24% reduction in may affect the heart, while teriflunomide may the progression of the disease (47). cause liver damage. Mitoxantrone is associated Moreover, add on daclizumab therapy in patients with cardiotoxicity (12,15). Although monoclonal receiving β IFNs showed reduced number of new antibodies seem to be the most effective approach, lesions as indicated by MRI when compared to the risk of immunogenicity is considered as a monotherapy. problem. Other approaches New Therapeutic approaches A number of strategies have been described (44).Vaccines work by decreasing the production of These include new monoclonal antibodies, combi- T-cells and also reducing body response to these nation therapy, vaccination, stem cell treatment, cells. Stem cells transplantation is another way of transdermal patch, vitamin D supplements, mino- treating MS patients but is still under investigation. cycline, statins, and . Myelin peptides have been studied for administra- tion in patients with RRMS through transdermal A. New monoclonal antibodies patches. The results showed reduced relapse, pro- Monoclonal antibodies are becoming a new prom- gression and lesions. ising approach for treating patients with MS. Na- Low levels of vitamin D increase the risk of MS. talizumab is the only FDA approved one. There In animal models, vitamin D supplements showed are three new monoclonal antibodies under study; reduced relapse by suppressing T-cells. However, ocrelizumab, ofatumumab and AIN457 (44). trials on humans have not been conducted. Minocy- cline is an oral antibiotic that showed immunomod- Ocrelizumab is a super-humanized intravenously ulatory and neuroprotective action. administered monoclonal antibody working simi- Simvastain may be beneficial for patients with larly to rituximab. It binds to the CD20 antigen on SPMS; further investigations are needed . the surface of B-cells. Ocrelizumab showed re- Sphingosine 1-phosphate receptor modulators duced brain lesions and relapse rate in a small work in an action similar to fingolimod by altering group of patients with RRMS as well as PPMS. It sphingosine 1-phosphate receptors. There are three was associated with mild infusion reaction. new drugs under investigation: , ponesi- mod, and ONO-4641. All of them showed promis- Ofatumumab is another super-humanized mono- ing results. clonal antibody that works similarly to rituximab Laquinimod and cladribine are new immunomod- and ocrelizumab. It is directed against the CD20 ulators. Laquinimod works by a neuroprotective ef- antigen. This new drug showed reduced number of fect, while cladribine showed reduction in relapse lesions when tested on patients with RRMS. rate, progression of the disease, and number of le- AIN457 works by binding to (IL- sions for patients with RRMS. 17). In this way, it reduces recruitment of T-cells. It is being tested for treating patients with RRMS. Conclusion

Combination therapy Research in MS is evolving rapidly, but there still Combination therapy is becoming a new approach remains no cure. A number of disease modifying for MS. Combining glatiramer acetate with β IFNs agents are used to control the disease. Combination showed reduced lesions and reduced relapsing rate therapy of monoclonal antibodies with other agents when compared to either agent alone. Relapsing can reduce relapse rate and generally shows greater rate was reduced when the two drugs were com- efficacy. New therapeutic approaches are also show- bined when compared to IFNs alone. However, ing promising results. In less than 10 years, a num- monotherapy with glatiramer acetate showed the ber of new drugs have been developed with proven same relapsing rate and sdisease progression as the ability to alter the natural history of MS and miti- combined therapy (45,46). In terms of disease pro- gate the disease. These advances have completely gression, there were no differences whether these altered the clinician's approach to the patient with drugs were used together or as monotherapy MS and have renewed hope for the ultimate cure of Combining natalizumab and β IFNs has resulted this debilitating disease.

Vol 17, No 3 Drug Information For The Health Professional 7

References 18. Fingolimod. (2012). Retrieved from http:/www.nlm.nih. gov/medlineplus/druginfo/meds/a611006.html 19. Multiple sclerosis (relapsing-remitting) - fingolimod 1. Multiple Sclerosis Information Trust (2008). What is multi- (ta254). (2012). Technology appraisals, Retrieved from ple sclerosis? Retrieved from http://www.multsclerosis.org/ http://guidance.nice.org.uk/TA254 whatisms.html 20. Jeffrey, S. (2012). Fda approvals: Teriflunomide for re- 2. Mayo Foundation for Medical Education and Research lapsing multiple sclerosis. Retrieved from http:// (MFMER). (2012). Multiple sclerosis. Retrieved from www.medscape.org/viewarticle/770215 http://www.mayoclinic.com/health/multiple-sclerosis/ 21. Aubagio (teriflunomide) tablet, film coated . (2012). Re- DS00188 trieved from http://dailymed.nlm.nih.gov/dailymed/ 3. Moyer, P., & Stratmoen, J. (2002). Finding the viral link to drugInfo.cfm?id=77152 ms: Progress and challenges reportedon the research trail. 22. 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Monoclonal antibodies: A new 6. Delbue, S., Carluccio, S., & Ferrante, P. (2012). The long way to treat ms. Retrieved from http:/www.unitedspinal. and evolving relationship between viruses and multiple org/msscene/2008/05/28/monoclonal-antibodies-a-new- sclerosis. Future Virology, 7(9), 871-883. Retrieved from way-to-treat-ms/ http://www.medscape.com/viewarticle/771891 26. Helliwell, C. L., & Coles, A. J. (2009). Monoclonal anti- 7. Khan, O. (2003). A viral link to ms?. Retrieved from http:// bodies in multiple sclerosis treatment: Current and future www.medscape.com/viewarticle/452102 steps. TherAdvNeurolDisord, 2(4), 195–203. Retrieved 8. Multiple Sclerosis Information Trust (2011). Epstein-barr from http://www.ncbi.nlm.nih.gov/pmc/articles/ virus. Retrieved from http://www.mult-sclerosis.org/ PMC3002635/ EpsteinBarrvirus.html 27. Rose, J. (2008). Monoclonal antibody treatment in ms. Re- 9. National Multiple Sclerosis Society. (n.d.). Viruses. Re- trieved from http://www.va.gov/MS/articles/ trieved from http://www.nationalmssociety.org/about- Monoclonal_Antibody_Treatment_for_MS.asp multiple-sclerosis/what-we-know-about-ms/what-causes- 28. Multiple Sclerosis Society. (2013). Alemtuzumab (campath ms/viruses/index.aspx 1-h, lemtrada). Retrieved from http:/www.mssociety.org. 10. Blanchard RN., K. (2012). Ms, virus link shown in new uk/ms-research/new-and-potential-treatments/alemtuzumab findings. Retrieved from http:/www.emaxhealth.com/ -campath 1020/ms-virus-link-shown-new-findings 29. Natalizumab (tysabri). (2013). Retrieved from http:// 11. Multiple Sclerosis Information Trust (2011). Human her- www.mstrust.org.uk/atoz/natalizumab-tysabri.jsp pes virus 6. Retrieved from http://www.mult-sclerosis.org/ 30. Natalizumab for the treatment of adults with highly active HumanHerpesVirus6.html relapsing–remitting multiple sclerosis . NICE technology 12. Olek, M. (2013). treatment of relapsing-remitting multiple appraisal guidance. (2007). Retrieved from http:// sclerosis in adults. Retrieved from http:/www.uptodate. publications.nice.org.uk/natalizumab-for-the-treatment-of- com/contents/treatment-of-relapsing-remitting-multiple- adults-with-highly-active-relapsingremitting-multiple- sclerosis-in-adults sclerosis-ta127/the-technology 13. Interferon beta for multiple sclerosis. (2010). Retrieved 31. Olek, M. (2013). Natalizumab for relapsing-remitting mul- from http://www.webmd.com/multiple-sclerosis/interferon tiple sclerosis in adults. Retrieved from http:// -beta-for-multiple-sclerosis www.uptodate.com/contents/natalizumab-for-relapsing- 14. Glatiramer for multiple sclerosis. (2010). Retrieved from remitting-multiple-sclerosis-in-adults http://www.webmd.com/multiple-sclerosis/glatiramer- 32. Anderson, P. (2012). Promising results for natalizumab in acetate-for-multiple-sclerosis progressive ms. Retrieved from http://www.medscape.com/ 15. National multiple Sclerosis society. (n.d.). Novantrone viewarticle/772939 (mitoxantrone). Retrieved from http:/www.nationalmssoci 33. Multiple Sclerosis Trust. (2012). Alemtuzumab (campath, ety.org/about-multiple-sclerosis/what-we-know-about-ms/ lemtrada). Retrieved from http://www.mstrust.org.uk/ treatments/medications/mitoxantrone/index.aspx research/drugsindevelopment/alemtuzumab.jsp 16. Dangond, F. (2007). Understanding multiple sclerosis 34. Coles AJ, Twyman CL, Arnold DL, et al. (2012). medications. Retrieved from http: www.emedicinehealth. Alemtuzumab for patients with relapsing multiple sclerosis com/understanding_multiple_sclerosis_medications/ after disease-modifying therapy: A randomised controlled page6_em.htm phase 3 trial. Lancet, 380(9856), 1829-39. Retrieved from 17. National Multiple Sclerosis Society. (n.d.). Fingolimod. http://www.ncbi.nlm.nih.gov/pubmed/23122650 Retrieved from http://www.nationalmssociety.org/about- 35. Button, T., & Coles, A. (2012). Alemtuzumab for the treat- multiple-sclerosis/what-we-know-about-ms/treatments/ ment of multiple sclerosis. Future Neurology, 5(2), 177- medications/fingolimod/index.aspx 188. Retrieved from http://www.medscape.com/

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viewarticle/718543_2 talizumab therapy. Medscape Neurology , Retrieved from 36. Multiple Sclerosis Society. (n.d.). Daclizumab. Retrieved http://www.medscape.com/viewarticle/767165 from http://www.mssociety.org.uk/ms-research/new-and- 44. Krieger, S., & Schneider, D. (2013). Ms research update. potential-treatments/daclizumab Retrieved from http://www.mymsaa.org/publications/ 37. Multiple Sclerosis Ttrust. (2013). Daclizumab. Retrieved msresearch-update-2013 from http://www.mstrust.org.uk/research drugsindevelop- 45. Wilner, A., & Lublin, F. (2012). Combo therapy in ms: ment/daclizumab.jsp Ready or not?. Medscape Neurology, Retrieved from http:// 38. Bielekova, B. (2013). Daclizumab therapy for multiple www.medscape.com/viewarticle/773288 sclerosis. Neurotherapeutics, 10(1), 55-67. Retrieved from 46. Jeffrey, S. (2013). Extension combirx data show no benefit http://www.ncbi.nlm.nih.gov/pubmed/23055048 of combined ms drugs. Retrieved from http:// 39. Schippling, S., & Martin, R. (2008). Spotlight on anti- www.medscape.com/viewarticle/781153 cd25: Daclizumab. The International MS Journal, 15, 94– 47. Rudick, R., Stuart, W., Calabresi, P., et al. (2006). Natali- 98. Retrieved from http://www.msforumonline.net/journal/ zumab plus interferon beta-1a for relapsing multiple sclero- download/20081594.pdf sis. New England Journal of Medicine, 354, 911-923. Re- 40. Multiple sclerosis discovery forum. (2013). Rituximab. trieved from http://www.nejm.org/doi/full/10.1056/ Retrieved from http://www.msdiscovery.org/research- NEJMoa044396 resources/drug-pipeline/229-rituximab 41. RxList. (2012). Rituxan. Retrieved from http:/www.rxlist. com/rituxan-drug/warnings-precautions.htm Haya Khalid Al Braiki 42. National Multiple sclerosis society. (n.d.). Pregnancy and Final Year student, 2013 reproductive issues. Retrieved from http:/www.national Faculty of Pharmacy, mssociety.org/living-with-multiple-sclerosis/healthy- living/pregnancy/index.aspx Kuwait University 43. Wilner, A., &Leist, W. (2012). The art and science of na- (Edited by Leyla Sharaf)

TEST YOUR KNOWLEDGE Answers to MCQs on back

1) Which of the following is the only FDA Is there a problem? approved monoclonal antibody used in the management of multiple sclerosis? A 30 year old pregnant patient was prescribed the drug given in the a) Ocrelizumab prescription for high cholesterol. Is b) Ofatumumab there any major error? c) Natalizumab d) Alemtuzumab KOL HOSPITAL e) Daclizumab

Patient Name: Mrs. Fatima Beevi Age: 30

2) Which of the following is an oral years

immunomodulator used in MS? Address: Street No.11 a) beta IFN-1a Rx b) beta IFN-1b Atorvastatin 10mg tablet c) Glatiramer acetate One tablet once a day d) Fingolimod Send one pack e) All of the above

Dr. TXC 3) Which drug is a sphingosine 1-phosphate Signature Date: 21/09/13 receptor modulator that works similar to

fingolimod? a) Laquinimod Answer b) Cladribine Atorvastatin should be avoided in c) Mitoxantrone d) Ofatumumab pregnancy. e) (Source: British National Formulary)

Vol 17, No 3 Drug Information For The Health Professional 9 TOPICAL ISSUES AND CONTROVERSIES

Poor people have a higher risk for colorectal cancer

People with a relatively low socioeconomic status account for a disproportionate number of colorectal cancers in the United States. Now, for the first time, a large prospective, observational study at University of Pennsylvania Perelman School of Medicine in Philadelphia has shed light on the de- gree to which behaviour and body mass contribute to this disparity. This study showed that over one third of the ex- cess risk of invasive adenocarcinoma of the colon and rectum resulting from low socioeconomic sta- tus could be explained by differences in behavioral risk factors, particularly in an unhealthy diet. In addition to diet, they found that physical inactivity, smoking and being overweight are likely contribu- tors to this risk. education and risk for colorectal cancer, and be- In their study, the authors looked at health behav- tween 8.6% and 15.3% of the association between iours, obesity and colorectal cancer risk among neighbourhood status and risk for colorectal cancer. Americans of all socioeconomic statuses. They Diet was found to have the biggest impact of all the used the National Institutes of Health-AARP Diet health behaviours. and Health Study as their data source. Specifically, Overall, the combination of health behaviours and they looked at middle-aged and elderly people body mass index (BMI) explained approximately from 6 states (California, Florida, Louisiana, New 43.9% (95% confidence interval [CI], 35.1% to Jersey, North Carolina, and Pennsylvania) and 2 57.9%) of the association between risk for colorectal metropolitan areas (Atlanta, Georgia and Detroit, cancer and education and 36.2% (95% CI, 28.0% to Michigan). All of the participants enrolled in the 51.2%) of the association between the risk and study in 1995/96 and were followed through 2006. neighbourhood socioeconomic status. Health behaviours of the participants were deter- In short, somewhere between one third and nearly mined using questionnaires. Of the 506,488 study one half of colorectal cancers among either low- participants, 7676 developed colorectal cancer dur- income or less-than-high-school-educated Ameri- ing the 10-year follow-up period. cans might be attributable to obesity and unhealthy

behaviours. However, some experts not involved Class and behaviour, and body mass with the study, do not find these results to be a cause The authors evaluated the socioeconomic status of for despair. Instead, the study "demonstrates the in- the participants in 2 ways: by census-tract data, tricate interplay" of socioeconomic and behavioural which revealed "neighborhood socioeconomic sta- factors affecting colorectal cancer risk. They believe tus," and by self-reported educational level (less that public health practitioners can learn from these than high school vs high school and above). On the results. The study underscores the need for more basis of data from other studies on colorectal can- effective public health strategies to improve nutri- cer and behaviour, they used statistical modeling to tion and physical activity and thereby curb the rising estimate the likely percentage of colorectal cancers tide of obesity, particularly for those with less edu- mediated by behavioural risk factors. They found cation and in disadvantaged communities. that differences in socioeconomic status in the re- ported levels of physical inactivity, unhealthy diet, Colon cancer by location smoking, and unhealthy weight each explained be- The study accounted for the anatomic location of the tween 11.3% and 21.6% of the association between

10 Kuwait Pharmacy Bulletin Autumn 2013 participants' cancers (proximal colon, distal colon, be more effective in reducing cancer incidence and or rectum). The health behaviours and BMI ex- mortality in the distal colon and rectum than in the plained 95% of the association between education proximal colon. Thus, this finding might have an and the incidence of proximal colon cancer, but easy explanation. Because adults who are less edu- only 38% of the association between education cated and from less affluent communities are less and distal cancer and 24% of that between educa- likely to be screened, the greater effectiveness of tion and rectal cancer. That is a dramatic differ- screening for distal colorectal cancer may explain ence. However, these contrasting results for proxi- why socioeconomic gradients were much steeper for mal and more distal cancers might "reflect the im- these anatomic sites than for proximal cancer. pact of an important omitted variable- colorectal cancer screening by socioeconomic status." Source: http://www.medscape.com/viewarticle/77035 5? Colorectal cancer screening has been shown to src=nldne

Combinations of antibiotics and non-antibiotic drugs

Antimicrobial resistance is on the rise, evidenced gesting that these could be used to target specific in- by greater use of "last resort" antibiotics such as fectious bacteria and leave the rest of a patient's mi- vancomycin and recent epidemics of antibiotic- crobial flora alone. resistant diseases, including tuberculosis and The researchers further examined loperamide, an MRSA. opioid anti-diarrheal agent marketed as Imodium, For decades, researchers and clinicians have which inhibited 99% of P. aeruginosa and 70% of E. been combining antibiotics to increase their effica- coli growth when combined with minocycline in the cy against such resistant bacteria, but those obvi- initial screen, though it had no antibacterial function ous efforts don't go far enough. on its own. They found that it disrupts the electron So G Wright and his team potential across bacterial mem- (Ejim et al, Nature Chemical Biology, branes, effectively weakening the doi:10.1038/nchembio. 559, 2011) cell and giving the minocycline a decided to broaden the search. way in. They focused on minocycline, an antibiotic that inhibits pro- Mark Riddle of the Naval Medical tein synthesis, frequently used Research Center's Enteric Diseases in the 1950s and 1960s until Department had previously found bacteria developed resistance. that treating diarrheal infections They screened minocycline with a combination of loperamide in combination with more than and antibiotics resolved patients' 1,000 previously approved bio- symptoms significantly faster. He active drug compounds - most assumed that this was "likely due to of which had no known antibiotic function - the loperamide helping with the symptoms, while the against three common and often resistant bacteria: antibiotics worked on eradicating the infection….But Pseudomonas aeruginosa, Escherichia coli, and this study opens up the thinking that maybe there are Staphylococcus aureus. some other mechanisms that it would have in syner- The screen showed that a total of 69 compounds gising with antibacterial drugs." never before used to treat bacterial infections that, Many questions remain, of course, such as how when combined with minocycline, decreased bac- well the drug combinations will be absorbed by the terial growth by at least 45%- significantly more body. But Wright is optimistic that finding new uses than when treated with only the antibiotic. One for old drugs will give less-effective antibiotics a finding that surprised the researchers was that second wind. many of the compound combinations inhibited on- ly one of the three bacterial species tested, sug-

Vol 17, No 3 Drug Information For The Health Professional 11 FDA DRUG NEWS FDA Reviews and approvals In 2010, the FDA published the following reviews, stroke asso- updates and new drug approvals: ciated with its use for Brand Name Change weight loss. The brand name for dexlansoprazole was changed from KAPIDEX to DEXILANT to avoid name Updates confusion with CASODEX, (bicalutamide).  Tamper- resistant OxyContin (oxycodone) formulation: is Obsolete Indications intended to prevent the medication from being cut,  Bevacizumab does not appear to prolong sur- broken, chewed, crushed or dissolved to release vival or slow disease progression in patients with medication more rapidly than intended. metastatic breast cancer, so the FDA has proposed  Update on the Clinical Impact of USP Heparin withdrawing this indication for the drug. Potency Reduction: The 10% decrease in anticoagu-  Dolasetron can increase the risk of torsades de lation activity of heparin products manufactured un- pointes and is no longer recommended for chemo- der the USP standard may warrant adjustments in therapy-induced nausea and vomiting. heparin dosage and monitoring in the following situ-  Quinine can cause life-threatening thrombocy- ations: i), extracorporeal membrane oxygenation in topenia, hemolytic-uremic syndrome, and throm- pediatric patients, ii), cardiopulmonary bypass, and iii), treatment or prevention of life-threatening botic thrombocytopenic purpura. Quinine is no thrombosis. longer recommended for the off-label use for leg cramps. “Re-purposed” drugs Four established drugs were approved for new pur- Marketed unapproved drugs poses or as novel formulations for established pur- FDA granted market approval to 2 previously un- poses. approved marketed drugs. The newly licensed ver- sions are morphine sulfate oral solution concen- Licensed vaccines and biologics trate (20 mg/ml) and pancrelipase (PANCREAZE).  A photodynamic imaging agent, hexaminolevuli-

nate hydrochloride (CYSVIEW), was licensed for Market withdrawals/suspensions the detection of superficial bladder cancer during  Gemtuzumab a monoclonal antibody, was with- cystoscopy. drawn from the US market due to a lack of survival  Human papillomavirus (HPV) vaccine benefit for patients with acute myeloid leukemia. (Gardasil) licensure was extended for children and Generic manufacturers have been informed of young adults aged 9 to 26 years to include the pre- FDA’s recommendation for healthcare profession- vention of anal cancer and associated precancerous als to stop prescribing the drug. lesions due to HPV types 6, 11, 16, and 18.  Propoxyphene was withdrawn from the US  A fourth alpha1-proteinase inhibitor (Glassia) market due to evidence of risk for serious heart was licensed for treatment of emphysema due to rhythm abnormalities. congenital deficiency of alpha1-antitrypsin.  Rosiglitazone has been suspended from market-  A new 13-valent pneumococcal conjugate vac- ing in Europe and placed on a restricted distribu- cine (Prevnar 13) was licensed to prevent invasive tion status in the US due to increased cardiovascu- pneumococcal disease and otitis media in children lar risk. aged 6-weeks to 5-years old.  Sibutramine was withdrawn from the US mar-  The first RANK ligand inhibitor, denosumab ket due to increased risks for heart attack and (PROLIA, XGEVA), was licensed for prevention of

12 Kuwait Pharmacy Bulletin Autumn 2013 skeletal fractures and pain in patients with bone function, hepatic dysfunction, hypertension and metastases from solid tumors (XGEVA) and for hepatotoxicity. Women of childbearing potential postmenopausal osteoporosis (PROLIA). should use effective contraception to avoid pregnan-  An autologous cellular immunotherapy, sip- cy during, and extending for 2 months after its dis- uleucel-T (PROVENGE) was licensed for the continuation. Untoward reactions may also occur in treatment of metastatic hormone-refractory pros- patients receiving antiarrhythmic drugs, beta- tate cancer. blockers, calcium channel blockers, antihypertensive  An absorbable fibrin sealant patch drugs, drugs for heart failure, ketoconazole, live at- (TACHOSIL) was licensed for use as an adjunct tenuated vaccines, antineoplastics, immunosuppres- to hemostasis in cardiovascular surgery when con- sives, immune modulators, and antigenic testing trol of bleeding by suture, ligature or cautery, is concurrently with fingolimod and for up to 2 months ineffective or impractical. after its discontinuation. The recommended dose of  Velaglucerase alfa (VPRIV), a glucocerebro- fingolimod is 0.5 mg orally once daily. Patients side-specific enzyme, was licensed for long-term should have baseline laboratories drawn before start- replacement treatment of type 1 Gaucher disease. ing therapy and should be monitored for bradycardia for 6 hours after the first dose. Anticancer agent derived from marine  Tesamorelin (EGRIFTA) is a GHRH analog ap- invertebrates proved for reducing visceral adipose tissue in pa- tients with HIV-associated lipohypertrophy.  Eribulin (HALAVEN), an antimitotic indicated Tesamorelin is administered subcutaneously once for breast cancer, is the first drug derived from the daily. The drug is contraindicated in patients with sea sponge, Halichondria okadai. disruption of the hypothalamic-pituitary axis, active malignancy, and during pregnancy. Adverse effects Orphan drugs include fluid retention, hemoglobin A1c elevation,  Carglumic acid (CARBAGLU) is an analogue glucose intolerance, development of diabetes, injec- of N-acetylglutamate (NAG). NAG is the product tion site reactions, and hypersensitivity reactions. of N-acetylglutamate synthase (NAGS). NAGS Tesamorelin induces growth hormone secretion from deficiency is a very rare genetic disorder charac- the pituitary which results in insulin-like growth hor- terized by hyperammonemia, encephalopathy, and mone 1 secretion from the liver and peripheral tis- respiratory alkalosis, and is frequently fatal within sues. the first days-to-hours after birth. Carglumic acid Careful monitoring of patients receiving concomi- is used to decrease the frequency of hyperammo- tant therapy with CYP450 substrates is warranted, nemic crises and reduces the associated neurotoxi- particularly patients receiving chronic corticoster- city. Concomitant therapy with other ammonia oids and glucocorticoids. The reduction was sustain- lowering strategies is recommended. able for up to a year of treatment with regain of the  Collagenase clostridium histolyticum fat lost upon its discontinuation. The magnitude of (XIAFLEX) is used to treat Dupuytren disease. fat loss with tesamorelin is similar to diet and exer- Up to three repeat injections per palpable cord cise. may be administered if needed. Common side ef-  (ACTEMRA) is the 9th immuno- fects are: tendon ruptures, pain, swelling, bruising, modulator approved for rheumatoid arthritis. It is the and bleeding at the injection site, hypersensitivity first-in-class anti- (IL-6) receptor mono- reactions and risk of fainting during the post- clonal antibody. Tocilizumab is indicated for once-a- injection finger extension procedure. month intravenous infusion, with or without metho- trexate, for patients who have failed therapy with “First in class” medicines one or more TNF antagonists. Adverse effects in-  Fingolimod (GILENYA) is the first oral medi- clude: infusion reactions, development of neutraliz- cation for multiple sclerosis marketed in the US. It ing antibodies, hypersensitivity reactions, elevation is superior over interferon beta-1a over the course of the risk for serious infections and reactivation of of 12 months of study. 2.Side effects include: latent infections, and risk of malignancy, hyper- bradycardia, heart block, , lipidemia, gastrointestinal perforation, and symp- lymphoma, serious infection, macular edema, toms of demyelinating disorders. change in visual acuity, reduction in pulmonary Tocilizumab may result in a shift in the expression

Vol 17, No 3 Drug Information For The Health Professional 13 3 of hepatic CYP450 enzymes and may lead to clin- nist effects. Ulipristal is approved as a 30 mg single- ically significant drug interactions with narrow dose emergency contraceptive. Ulipristal is only therapeutic index substrates of these isozymes. available by prescription and can be taken up to 5 Decrease in rheumatoid factor, erythrocyte sedi- days after unprotected intercourse. Common adverse mentation rate and serum amyloid A levels but reactions are: headache, abdominal pain, nausea, increase in hemoglobin values are noted. Its half- dysmenorrhea, fatigue, dizziness, and a one-time dis- life for elimination is 11-12 days. Tocilizumab is ruption to the menstrual cycle length. Ulipristal may the first biologic to demonstrate superiority over reduce the efficacy of regular hormonal contracep- . tives. It is metabolized by CYP3A4 to mono- and di-  Ulipristal (ELLA) is the first progesterone re- demethylated metabolites. Its mechanism of action is ceptor modulator with antagonist and partial ago- ovulation delay or inhibition.

Self subscribing for patients ?

Prescription and non-prescription drugs call or other communication with the practitioner. In contrast, non-prescription drugs (OTC products) can Under the Federal Food, Drug, and Cosmetic Act be purchased by consumers in pharmacies, super- (FD Act), the US FDA approves new drugs either markets, and other retail establishments without the as prescription or non- need for a prescription. prescription. A drug must be Currently, consumers can pur- dispensed by prescription if, chase non-prescription drugs from “because of its toxicity or oth- a retailer for diseases or conditions er potentiality for harmful ef- that do not meet the statutory crite- fect, or the method of its use, ria for prescription products and or the collateral measures nec- that are safe and effective for use essary to its use, it is not safe in self-medication as directed in for use except under the super- the labeling. Generally, OTC prod- vision of a practitioner li- ucts: 1), are available to treat dis- censed by law to administer eases or conditions that can be self such drug.” FDA has consid- -diagnosed without a prior interac- erable latitude in determining tion with a practitioner, 2), are not whether the information sub- associated with toxicities that re- mitted as part of a new drug quire an evaluation of the benefits application (NDA) is suffi- and risks by a practitioner; and 3), cient to ensure that a drug is do not require a practitioner's input safe for use under its proposed for use. labeling. FDA also makes a determination under as to whether the product Under-treatment of diseases and other ef- meets the criteria for prescription-only dispensing. fects on the health care system Prescription drugs are dispensed upon receipt of a prescription from a practitioner licensed by law Under-treatment of many common diseases or con- to administer the drug (which may include health ditions in the US is a well recognised public health care professionals such as physicians, nurse practi- problem. Increasing the number of people who are tioners, physician's assistants, and others whom able to obtain for the first time and those who con- we will refer to here as practitioners or prescrib- tinue on necessary drug therapy could provide im- ers). In many instances, a patient has to obtain at proved health outcomes. least the initial prescription, and in some cases, The requirement to obtain a prescription for appro- prescription refills, from a practitioner through an priate medication (and to make one or more visits to in person interaction. Obtaining a refill for other a practitioner) may contribute to under-treatment of prescription drugs involves at least a telephone certain common medical conditions including hyper-

14 Kuwait Pharmacy Bulletin Autumn 2013 lipidemia (high cholesterol), hypertension (high care costs. blood pressure), migraine headaches, and asthma. For instance, some consumers do not seek neces- New paradigm sary medical care, which may include prescription FDA is considering whether medications for certain drug therapy, because of the cost and time required diseases or conditions that would otherwise be to visit a health care practitioner for an initial diag- available only by prescription could be made availa- nosis and an initial prescription. Some patients ble without a prescription with certain conditions of who obtain an initial prescription do not continue safe use. For example, some conditions of safe use on necessary medication because they would need could be designed to assist patients in self-selection to make additional visits to a health care practition- of an appropriate medication or provide for follow- er for a prescription refill after any refills author- up monitoring during continued use. The conditions ized by the initial prescription have been used or of use could include requiring pharmacist interven- the time during which they can be filled has ex- tion to ensure appropriate nonprescription use. Ad- pired. Some prescription medications require rou- ditionally, conditions of safe use could involve the tine monitoring through the prescribing practition- use of innovative technologies, such as diagnostics er such as blood tests to assist in the diagnosis of a approved or cleared by FDA for use in the pharma- condition, or to determine whether or how well the cy or other setting. medication is work- FDA is aware that industry is ing, or to adjust the developing new technologies dose. that consumers could use to self- FDA believes that screen for a particular disease or some of these visits condition and determine wheth- could be eliminated er a particular medication is ap- by making certain propriate for them. For example, prescription medica- kiosks or other technological tions available with- aids in pharmacies or on the In- out a prescription but ternet could lead consumers with certain other through an algorithm for a par- conditions of safe use ticular drug product. Such an that would ensure algorithm could consist of a se- they could be used ries of questions that help con- safely and effectively sumers properly self-diagnose certain medical con- without the initial involvement of a health care ditions, or determine whether specific medication practitioner. In some cases, a visit to a practitioner warnings contraindicate their use of a drug product. would be required for the initial prescription, but a In addition, for some drug products that require an certain number of refills could be authorized be- initial prescription, the product could be made avail- yond those that would normally be authorised able as a nonprescription product with a condition without a return visit under specialized conditions of safe use for the purpose of product refills. of safe use. This paradigm might be useful for cer- In addition, some drug products that would other- tain rescue medicines, such as inhalers used to treat wise require a prescription could be approved as asthma or epinephrine for allergic reactions, that nonprescription drug products with some type of patients need to keep on hand for use in emergen- pharmacist intervention as their condition of safe cies. use. For example, some diseases or conditions might In addition to improved health outcomes for con- require confirmation of a diagnosis or routine moni- sumers staying on their medications, the time and toring using a diagnostic test (e.g., a blood test for attention that physicians and other health care pro- cholesterol levels or liver function) that could be viders expend on routine tasks related to prescrip- available in a pharmacy. A pharmacist, or consum- tion refills reduces the time that they are available er, could then use the results to determine whether to attend to more seriously ill patients. Eliminating use of a certain drug product is appropriate. or reducing the number of routine visits could free Other potential roles for the pharmacist include up prescribers to spend time with more seriously ill assessing whether the consumer has any conditions patients, reduce the burdens on the already over- or other risk factors that would indicate that the drug burdened health care system, and reduce health

Vol 17, No 3 Drug Information For The Health Professional 15 should not be used, or assisting the consumer in to demonstrate that certain drugs could be used safe- choosing between various drug products. For ly and effectively in the nonprescription setting with drugs that require use of a diagnostic test, creating conditions of safe use. Depending upon the situation, a pathway for nonprescription use may result in applications for approval of non-prescription prod- the development by industry of diagnostics suita- ucts with conditions of safe use may need to include ble for use by the patient or a pharmacy profes- patient studies (e.g., self-selection studies, label sional. comprehension studies, and actual use studies) to FDA is also considering whether the same drug demonstrate that the drug would be safe and effec- product could be simultaneously available as both tive under the specified conditions. When a device, a prescription and nonprescription product with e.g., diagnostic test or computer algorithm, is neces- conditions of safe use. Dual availability could sary as a condition of safe use, evidence may need to help ensure greater access to needed medications be submitted demonstrating that it will perform its by making obtaining them more flexible. Consum- intended function and can be appropriately adminis- ers could choose to continue seeing their health tered in the particular setting in which it will be used. care practitioner to diagnose diseases or condi- Certain classes of drugs may be appropriate candi- tions and obtain prescriptions, and when their lo- dates for non-prescription use under this new para- cal retail establishment is not equipped to offer the digm, but FDA would need to evaluate each NDA, nonprescription product with conditions of safe use. Other consumers could take advantage of the Source: https://www.federalregister.gov/articles/201 ability to obtain nonprescription products with 2/02/28/2012-4597/using-innovative-technologies-and- conditions of safe use where they are available. other-conditions-of-safe-use-to-expand-which-drug- FDA, by means of Public Hearings, is seeking products-can-be input on what types of evidence would be needed

IN THE NEWS

Fighting Type 1 diabetes with tuberculosis vaccine

Researchers at the Immunobiology laboratory at U.S. FDA, is called bacille Calmette-Guerin (BCG), Massachusetts General Hospital in Boston con- and has been used against tuberculosis for about 90 ducted a small trial of a vaccine that has already years. been approved for tuberculosis and found that the BCG also is used as a treatment for bladder cancer. vaccine can kill the autoimmune cells that are ac- The vaccine works by increasing levels of tumor ne- tive players in type 1 diabetes. There were no crosis factor (TNF). High doses of TNF can be toxic, changes however, in the need for insulin among but the vaccine doesn't appear to raise levels of TNF those with longstanding diabetes who received the too high. According to the U.S. Centers for Disease vaccine. Control and Prevention, the only groups that should- Two vaccines, given four weeks apart, caused n't receive the live vaccine are those whose immune the death of bad T-cells according to the study au- systems are compromised, such as people who have thor. They found that the good regulatory T-cells HIV or people who have received an organ trans- came on and the pancreas went on briefly. This plant. The CDC also recommends against giving the was in people who were 15 years out from their vaccine to pregnant women because it hasn't been type 1 diagnosis. This doesn't mean that people well-studied in this population. were discarding their insulin syringes. But the ex- In 2001, this team tested a similar substance in citing part of this study is that even decades after mice and found that it destroyed the harmful T-cells the disease begins, the cells in the pancreas can and allowed the insulin-producing cells in the pan- regain function albeit briefly. creas to regenerate and produce insulin. They then The vaccine, which has been approved by the wanted to know if such regeneration can take place

16 Kuwait Pharmacy Bulletin Autumn 2013 in humans with type 1 diabetes if the immune- One expert said the finding was important, but system attack that causes type 1 diabetes in the first many questions remain. This study shows that by place was stopped. To answer that question, they increasing TNF, they can induce the death of the recruited six people with type 1 diabetes who were auto-reactive T-cells that destroy the cells that make randomly assigned to receive two injections of ei- insulin, and they transiently increase C-peptide lev- ther the vaccine or a pla- els - but what hap- cebo, and they were pens after 20 weeks? compared to one control Another question group without diabetes is how often would and one with the disease. they need to give The average duration of this vaccine? Some type 1 diabetes at the be- experts are also con- ginning of the study was cerned about wheth- 15.3 years, and the aver- er increasing the age age of those with di- levels of TNF in the abetes was 35. During body may have long the 20-week study, two -term effects, if it's out of the three people given repeatedly. treated with BCG had Some would like to evidence of bad T-cell know whether this death and increases in could be used in the levels of protective T children. -cells. They also showed However, experts an elevation in levels of a substance called C- believe that this is an important research that will peptide that indicates insulin production. It was not help in the understanding of the pathophysiology of clear why BCG didn't appear to help one of those type 1 diabetes. treated with it, but at the end of the study, the indi- BCG has an excellent safety record, and has been vidual's level of C-peptide began to increase. given to billions of adults and children worldwide to It's not yet certain whether more frequent doses or prevent tuberculosis. The authors of the study are higher doses would be needed to restore more pan- currently developing phase II trials to test using creatic function, but it may matter how long some- higher levels of the vaccine. one has had the disease. However, according to the authors, no matter how Source : http://www.drugs.com/news/tb-vaccine- long someone has had the disease, they'll likely get promising-new-way-fight-type-1-diabetes- some function back. Any restoration of C-peptide 39728.html helps to prevent diabetes complications.

Correct answers: Answers to: Test your knowledge 1-c; 2-d; 3-e

The Kuwait Pharmacy Bulletin (ISSN 1028-0480) is published quarterly by the Faculty of Pharmacy, Kuwait University, and when available includes a list of recently approved drugs from the MOH. It aims to provide instructive reviews and topical news items on a range of drug related issues. It is widely distributed free within the university, to hospitals, polyclinics & private pharmacies as well as to other universities within the Gulf & Middle East region. The information in this bulletin does not necessarily reflect the views of the editorship, nor should it be taken as an endorsement of any product that is mentioned herein. Articles are generally adapted from literature sources and rewritten or occasionally reproduced with permission from the appropriate sources. Readers wishing their own copy may ask to be added to the mailing list by contacting the Executive Editor.

Executive Editor: Yunus Luqmani. Assistant Editors: Leyla Hasan Sharaf, Samuel Koshy

Editorial Office: Faculty of Pharmacy, Health Sciences Centre, Kuwait University, PO Box 24923 Safat, 13110 Kuwait,