Dissertations / Theses on the topic 'Johnson Syndrome'

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.<br>Stevens - Johnson syndrome and Toxic Epidermal Necrolysis Syndrome are rare, but serious conditions affecting skin and mucous membranes that are primarily treated with supportive care. Other more specific therapies have limited evidence to support the benefit of their use; one such treatment is intravenous immunoglobulin (IVIG). The use of IVIG in the treatment of these syndromes remain controversial due to mixed results demonstrated in the literature, and at present is not considered a component of the standard of care. This study seeks to provide additional data regarding the efficacy of IVIG treatment on mortality in a small cohort of patients presenting with these syndromes at a regional burn center over a 10-year period; data was retrospectively collected from patient medical records. On analysis of this data, IVIG use showed a potential, but not significant. improvement on mortality in comparison to the non-treatment group. Compared with the non-treatment group, odds ratios for death were 0.81 (95% CI 0.3-2.0) for IVIG. There is ultimately no new evidence that the benefit of IVIG in the treatment of Stevens - Johnson syndrome and Toxic Epidermal Necrolysis Syndrome is anything more than potential. Further investigation should include a rigorous analysis and comparison of different dosing regimens.

Intrdodução: As terapias com anticonvulsivantes de anel aromático (ACA) são freqüentemente associadas a reações adversas. No entanto, reações de hipersensibilidade (RH) não-imediatas (tardias) a estes fármacos são raras, imprevisíveis e geralmente relacionadas à alta morbidade e mortalidade. Foi demonstrado que estas RH aos ACA estão fortemente associadas ao Antígenio de Leucócitos Humanos (HLA)-B*1502 em pacientes chineses e ao HLA-A*3101 em caucasianos. Polimorfismos de genes do metabolismo do Citocromo P450 (CYP)2C9 foram mais associados a estas reações em pacientes orientais. Objetivo: Nosso objetivo é analisar a associação das reações de hipersensibilidade a anticonvulsivantes de anel aromático com os polimorfismos descritos e de interesse, bem como realizar a tipificação de HLA em uma população de São Paulo, Brasil. Métodos: Estudo tipo caso-controle com genotipagem dos polimorfismos de interesse por reação em cadeia da polimerase (PCR) em tempo real e tificação de HLA A, B, C, DRB, DQA, DQB por PCR seguido de deteção utilizando método LuminexR. A avaliação fenotípica se baseou em sistemas de escores padronizados, utilizando um questionário adaptado da ENDA (Rede Européia de Alergia a Medicamentos), em registros médicos e no acompanhamento clínico. O teste de contato com o medicamento suspeito foi realizado de acordo com as recomendações da ENDA, nos pacientes que apresentaram reação. Resultados: Foram estudados 506 pacientes, 65% do gênero feminino e a idade média foi de 43,6 anos. Oitenta por cento era de etnia mista. Polimorfismos de HLA-A*3101, HLA-B*1502, CYP2C9, CYP2C19 e CYP3A5 foram analisados de 55 indivíduos com reações de hipersensibilidade (RH) a antiepilépticos, de 85 tolerantes e de 366 controles sadios. Dos 55 casos foram validados como RH, 32 apresentaram Reação a Drogas com eosinofilia e sintomas sistêmicos (DRESS), 12 Síndrome de Stevens-Johnson (SSJ) e 11 exantema maculo-papular. De todos os 46 testes de contato com medicamento, 29 (63%) foram positivos, tanto em SSJ como em DRESS. Houve associação significativa entre polimorfismo de HLA-A*1502 e casos. Nenhum de nossos grupos de estudo apresentou associação positiva com polimorfismos de HLAA* 3101. Verificamos uma forte associação entre a atividade normal do CYP3A5 e indivíduos tolerantes quando comparado com casos (p = 0,0002, OR = 4,8). A tipificação de HLA demonstrou associação significante de HLA-A*31, HLA-A*74, HLA-B*35 e HLA-B*53 com reações graves aos ACA e de HLA-B*44 e HLA-C*03 com indivíduos tolerantes. Conclusão: Estes resultados sugere fortemente a existência de fatores genéticos de risco e/ou de proteção a RH a ACA em indivíduos brasileiros, mas não devem ser considerados de forma isolada. Assim, a relevância deste estudo extrapola o objetivo de estudo caso-controle e sugere um modelo como forma de prevenção primária às RH aos ACA.<br>Background: Antiepileptics with aromatic ring (AAR) therapies are frequently associated with adverse reactions. Nevertheless non-immediate (late) hypersensitivity reactions (HR) to these drugs are rare, unpredictable and usually related with high morbidity and mortality. A strong pharmacogenetic association has been reported in Chinese patients with these HR and Human Leukocyte Antigen (HLA)-B*1502 and with HLA- A*3101 in caucasians. Polymorphism of genes of P450 Cytocrome (CYP)2C9 has been related to these reactions in patients of oriental origin. Objective: Our aim is to analyze the association between hypersensitivity reactions due to AAR and the described polymorphisms, as well as perform the typification of HLA in a population of São Paulo, Brazil. Methods: Case-control study genotyping the polymorphisms of interest by polymerase chain reaction (PCR) real time and typifying HLA A, B, C, DRB, DQA, DQB by PCR followed by LuminexR .The phenotype evaluation was based on standardized scoring systems using an adapted ENDA (European Network of Drug Allergy) questionnaire, medical records and on the clinical follow-up in our Allergy Clinic. The patch test with the culprit drug was performed in patients who experienced HR according to the ENDA recommendations. Results: We studied 506 subjects, 65% female and mean age was 43,6 years. Eighty percent had mixed ethnicity. Polymorphisms of HLA-B*1502, HLA- A*3101, CYP2C9, CYP2C19 e CYP3A5 were studied in 55 subjects with antiepileptics HR, 85 tolerants, and 366 control subjects. Of 55 cases were validated as AHR, 32 presented Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), 12 Stevens-Johnson Syndrome (SJS) and 11 maculopapular exanthema. Of all 46 drug patch tests, 29 (63%) were positive, in both SJS and DRESS. A significant association between polymorphism of HLA-A*1502 and cases was found. None of our study groups presented positive association with HLA-A*3101 polymorphisms. We found a strong association between the normal activity of CYP3A5 and tolerants subjects when compared to HR (p=0.0002, OR=4.8). The HLA typification showed a significant association between HLA-A*31, HLA-A*74, HLAB* 35 e HLA-B*53 and severe AAR reactions and HLA-B*44 and HLA-C*03 in tolerants subjects. Conclusion: These results strongly suggests the existence of genetic risk and/or protective factors to the development of HR to AAR AAR in Brazilian subjects, but it should not be considered in a isolated manner. So, the relevance of this study extrapolates the aim of a case-control study and suggests a system of primary prevention to HR due to AAR

碩士<br>國立臺灣科技大學<br>工業管理系<br>104<br>Stevens-Johnson syndrome (SJS), a form of toxic epidermal necrolysis, is a lifethreatening skin condition, in which cell death causes the epidermis to separate from the dermis. There are many factors cause SJS, most of SJS cases are caused by using improper drugs. The drugs which cause SJS are used in various medical fields. However, very few physician are familiar with all these drugs, so there are many cases when physician is not aware about the drugs causing SJS. This study uses 1-year data of Taiwan’s NHIRD (National Health Insurance Research Database) to find the sequential pattern of medical specialties and their prescription for SJS patients. Two sequential patterns mining algorithms, GSP and PrefixSpan are used to find patterns. The research results could be use as medical reference.

碩士<br>國立臺灣科技大學<br>工業管理系<br>99<br>In clinical practice, a severe illness might be the result of an untoward reaction to the pharmacological treatment for another disease. For instance, Stevens-Johnson syndrome (SJS) can be caused by antibiotics; nonsteroidal anti-inflammatory drugs; antiepileptics; antugout agents; and cardiovascular drugs, as well as the drugs for local use in ophthalmology and dermatology. Since there are so many drugs covering various different medical fields, very few physicians are familiar with all the potential drugs that can cause SJS. Hence new cases or even recurrent cases of drug-induced SJS are still reported from time to time. Currently in Taiwan, the causal relations between physicians’ prescription behaviors and the occurrence of SJS are not clear. Therefore, in this research, by applying the SJS cases data from National Health Insurance database, a pharmacological treatment mining approach is proposed to investigate physicians’ prescription behaviors before and after the occurrence of SJS. This research will describe the behavior of pharmacological treatment by the rule-based classification method. A matrix will be used to specify the pharmacological record for each SJS case. Then, a modified F-measure will be used to measure the similarity between each pair of matrices. The measured data will be used to cluster the cases. For each group of cases, its frequent item sets will be mined and the behavior pattern of the pharmacological treatment will be identified.

碩士<br>國立臺灣大學<br>微生物學研究所<br>94<br>Stevens-Johnson Syndrome (SJS) is a severe, life-threatening cutaneous adverse reaction, most often caused by medication. Growing evidence indicates that CD8+ cytotoxic T lymphocytes, which can be activated by specific antigen-MHC complex expressed on the surface of antigen-presenting cells (APC), are involved in the pathogenesis of SJS. In our previous studies, we found that SJS induced by carbamazepine (CBZ), a commonly prescribed anticonvulsant, is strongly associated with HLA-B*1502 allele. Because specific T cell receptor (TCR) recognition of drug-bound peptide-MHC complex is likely to be driven by HLA-B*1502 with CBZ-bound endogenous peptides, we hypothesized that T cell populations having restricted TCR usage that recognized the CBZ modified antigens may be selected during the course of the disease in the SJS patients. My thesis is therefore to aim at analyzing TCR usage of CBZ-specific T cells in PBMC or blister cells from CBZ-SJS patients. To examine if CBZ-SJS patients share common T-cell receptor usage, I first enriched drug-specific T cells from PBMC and blister cells of patients by co-culturing with irradiated autologous EBV- transformed B cells and CBZ major metabolite, 10,11-epoxide CBZ. There was a biased reactivity of the T cells after co-culturing for 3 to 5 weeks, with CD8+ T cells increasing 1.8 to 7.5 times (from average 30% to average 90%) in three CBZ-SJS PBMC and to 85.43% in one CBZ-SJS blister, which were detected by FLOW cytometry. The mRNAs of these T cells were extracted by Trizol reagent and reverse-transcripted into cDNA. These cDNAs were used to detect both α-chain and β-chain TCR phenotype by PCR with 47 sequence specific primers for different TCRV gene types. The PCR result showed a selected pattern of these biased T cells that were composed of restricted T cell gene types comparing to normal control or patient before co-culturing. After cloning and sequencing the transcripts of each TCRV gene type, the gene rearrangement and the amino acid sequences of each TCR were analyzed IMGT website. The result showed that there was preferential TCRAV and TCRBV gene usage in the SJS patients. Among four CBZ-SJS patients, TRAV14 and TRBV3-1*01 are shared by three patients, while TRAV19*01 and TRBV7-8*03/D1*01/J2-7*01 and TRAV17*01 and TRBV28*01/D1*01/ J1-1*01 are shared by two patients. This finding suggests selective activation of T cells in the pathogenesis of CBZ-SJS. More samples and further functional studies are needed to demonstrate that these TCRs are indeed involved in the induction of T cell activation.

博士<br>國立陽明大學<br>生化暨分子生物研究所<br>100<br>Increasing studies revealed that HLA alleles are the major genetic determinants of drug hypersensitivity; however, the underlying molecular mechanism remains unclear. Here, we adopt the HLA-B*1502 genetic predisposition to carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) as a model to study the pathological role of HLA in delayed-type drug hypersensitivity. We in vitro expanded CBZ-specific cytotoxic T lymphocytes (CTLs) from CBZ-SJS/TEN patients and analyzed the interaction between HLA-B and CBZ/analogs by CTLs response, surface plasmon resonance, peptide binding assay, site-direct mutagenesis, and computer modeling. The majority of aromatic anti epileptic drugs (AEDs)-specific T cells generated from CBZ-SJS/TEN patients was CD8+ cytotoxic T lymphocyte (CTL) with massive expression of cytolytic components, such as granulysin, perforin, and granzyme B. The endogenous peptides-loaded HLA-B*1502 molecule presented aromatic AEDs to CTLs without the involvement of intracellular drug metabolism or antigen processing. The HLA-B*1502/peptide/??m protein complex showed binding affinity toward chemicals sharing 5-carboxamide on the tricyclic ring as CBZ. However, modifications of the ring structure of CBZ altered HLA-B*1502 binding and CTLs response. In addition to HLA-B*1502, other HLA-B75 members could also present CBZ to activate CTLs, whereas members of HLA-B62 and B72 could not. Three residues (Asn63, Ile95, and Leu156) in the peptide-binding groove of HLA-B*1502 were involved in CBZ presentation and CTLs activation. In particular, Asn63 shared by members of B75 was the key residue. Computer simulations revealed a preferred molecular conformation of 5-carboxamide group of CBZ and the side chain of Arg62 on the B pocket of HLA-B*1502. Besides, Asn63 also responded to the interaction between HLA-B*1502 and PHT or LTG. In conclusion, this study demonstrates a direct interaction of HLA with drugs, provides a detailed molecular mechanism of HLA-B*1502-associated drug hypersensitivity, and has clinical correlations for CBZ-induced SJS/TEN and the cross-reactivity to aromatic AEDs.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina<br>Stevens-Johnson syndrome and toxic epidermal necrolysis are part of a spectrum of rare but acute and potentially life-threatening mucocutaneous reactions. The vast majority of cases are caused by medication, with allopurinol, non-steroidal anti-inflammatory drugs, antibiotics and anticonvulsants as the most frequently involved drugs. Generally, the reaction occurs within 7-21 days of the onset of drug administration.The main manifestation of SJS/TEN is a painful erythema with extensive exfoliation of the epidermis with mucosal involvement, mainly oral, ocular and genital. Distinction between SJS and TEN is based on the extent of skin detachment with <10% of the total body surface for SJS, while TEN involves exfoliation > 30% of the body surface. Between 10-30% it is considered a "SJS/TEN overlap". The percentage of body area that suffers detachment is directly related to the mortality rate, which varies from 1-5% in SJS, up to 25-35% in TEN.Exfoliation of the epidermis occurs due to extensive apoptosis of keratinocytes mediated by inflammatory and apoptotic mediators, such as granulysin, and by the interaction of the Fas receptor and its ligand FasL. The physiopathological basis of the disease remains controversial, with several studies pointing to the great importance and intervention of granulysin and involvement of specific T lymphocytes.The ideal treatment involves the identification and immediate withdrawal of the causative drug associated with supportive therapy, preferably in an intensive care unit. It’s of great importance to perform the diagnosis at an early stage in order to avoid its progression. The most appropriate pharmacological treatment still lacks scientific validation, however, recent studies point to the growing benefit of using cyclosporine as the first line therapy. Other immunomodulatory options include the use of intravenous immunoglobulin and corticosteroids.<br>A Síndrome de Stevens-Johnson e Necrólise epidérmica tóxica fazem parte do espectro de reacções mucocutâneas raras, porém agudas e potencialmente fatais. A grande maioria dos casos é de causa medicamentosa, sendo os medicamentos mais frequentemente envolvidos o alopurinol, anti-inflamatórios não esteróides, antibióticos e anticonvulsivantes. Geralmente, a reacção ocorre num intervalo de 7-21 dias após início da toma do medicamento.A principal manifestação da SJS/TEN é um eritema doloroso com exfoliação extensa da epiderme com afecção das mucosas, maioritariamente oral, ocular e genital. A distinção entre SJS e TEN é efectuada com base na extensão do descolamento epidérmico, sendo a SJS caracterizada por afectar <10% da superfície corporal, enquanto que a TEN implica exfoliação >30% da superfície corporal. Entre 10-30% fala-se de “SJS-TEN overlap”. A percentagem de área corporal afectada encontra-se directamente relacionada com a mortalidade. A SJS apresenta uma taxa de mortalidade de 1-5%, enquanto que a TEN apresenta uma taxa de mortalidade entre 25-35%.O descolamento epidérmico ocorre devido a uma extensa apoptose dos queratinócitos mediada por mediadores inflamatórios e apoptóticos, como a granulisina, e pela interacção entre o receptor Fas e o seu ligando FasL. A base fisiopatológica da doença ainda permanece controversa, com vários estudos apontando para a maior importância e intervenção da granulisina e de linfócitos T específicos.O tratamento ideal passa pela identificação e cessação imediata do medicamento causador associado a terapia de suporte, de preferência numa unidade de cuidados intensivos, sendo importante efectuar o diagnóstico numa fase precoce de modo a evitar a sua progressão. O tratamento farmacológico mais adequado ainda carece de validação científica, no entanto, estudos recentes apontam para o crescente benefício da utilização de ciclosporina como primeira linha. Outras opções imunomoduladoras passam pela utilização de imunoglobulina intravenosa e corticosteróides.

Inherited disorders of bilirubin metabolism - hereditary hyperbilirubinemias - are metabolic disorders manifested in early childhood. Unconjugated hyperbilirubinemias result from the defect of the enzyme uridine diphosphoglucuronosyltransferase (UGT1A1). UGT1A1 mediates the conjugation of bilirubin with glucuronid acid in hepatocytes and its elimination to water soluble compound. In the next step of bilirubin degradation the transport of conjugated bilirubin from hepatocyte into the bile occure. It is caused by the ATP dependent transporters ABCC2, ATP1B1 and OATP1B3. Mutations in the genes coding the bilirubin transporters results in conjugated hyperbilirubinemia Dubin-Johnson or Rotor syndrome. This study is focused on unconjugated hyperbilirubinemia in adolescents including the non-typical manifestations and the defects of ABCC2 transporter and their phenotype in humans.

碩士<br>國立臺灣大學<br>微生物學研究所<br>94<br>Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are related life-threatening cutaneous adverse reactions most often caused by medication. Carbamazepine (CBZ), a commonly prescribed anticonvulsant, is the number one culprit drug associated with SJS in Taiwan, accounts for 25% of all drug-induced SJS. Susceptibility to drug induced idiosyncratic reactions is thought to be genetically determined and immune-mediated. Previous studies suggest that the pathogenesis of the severe cutaneous adverse drug reactions involves MHC-restricted presentation of a drug or its metabolites for T-cell activation. However, the specific MHC molecules involved are not known until our study of carbamazepine-induced SJS/TEN in which we identified HLA-B*1502 as the MHC molecule. To further investigate the pathogenesis mechanism, we hypothesized that CBZ or its metabolites bind to endogenous proteins through processing and complexed with HLA-B*1502 or directly bind to the HLA-B*1502-bound peptides, which are then recognized by T-lymphocytes. The specific aims of my thesis are: 1. Establishment of the soluble HLA-B*1502-producing stable clones. 2. Identification of the peptides bind to the HLA-B*1502. 3. Identification of the drug-modified peptides involved in CBZ-SJS. Using soluble HLA-B*1502 molecule as a bait, I identified over 100 peptides bind to the HLA-B*1502. An unusual and an unique feature of these peptides were that many of these endogenous bound peptides (up to 20.9 %) contained polyproline, ranged from 4 to 9 continuous proline residues, but typically 6, 7 or 8 proline residues in the peptides. There were a total of 38 different proline-rich peptides been identified. Among these peptides, the existence of continuous proline residues in the center was a consistent finding; amino acid residues at the N- or C- terminal of peptides were variable. Interestingly, in the presence of CBZ, these proline-rich peptides decreased dramatically. We hypothesized that CBZ may bind to the polyproline peptides covalently, which modify them to become unnatural peptides thus unable to be recognized as the proline-rich peptides under analysis of LC/MS/MS and SEQUEST program. Further functional studies will be needed to demonstrate that these CBZ-modified peptides are indeed involved in the induction of T cell activation in both drug and peptide-specific manners. This is the first study in identification of the MHC-bound peptides associated with adverse drug reactions. The discovery opened a door to understanding the complete mechanism of this life-threatening condition.

碩士<br>高雄醫學大學<br>藥學研究所碩士在職專班<br>98<br>Background/Aim: Combination of some drugs would cause interactions between drugs, and this kind of interactions could lead to side effect. So far, there were less related reports about SJS in combination of drugs. Therefore, we study the relationship between drug combination and mortal of SJS that to prevent SIS which lead to death by retrospective study. Methods: This longitude and retrospective study uses mortality cases that diagnoses as ICD-9-CM 695.1 from NHI from 1999 to 2008. Statistical comparisons of the results were made using analysis of variance (ANOVA), independent-samples T test, Odds Ratio (OR), and Relative risk (RR). Therefore, the relationship between combination of SJS drugs and mortality could be found. Results: Possibility relation with drugs combination and mortality : Allopurinol and ampicillin (p=0.049)、Carbamazepine and sulfamethoxazole/TMP (p＜0.000)、carbamazepine and phenytoin (p＜0.000)、sulfamethoxazole/TMP and phenytoin (p=0.015)、Sulfadoxine and Piroxicam (p=0.045)、Henobarbital and Cephalexin (p＜0.000)、Ampicillin and Erythromycin (p＜0.000)、Erythromycin and Minocycline (p＜0.000)、Vancomycin and Ethambutol (p＜0.000)。 Conclusion： Stop to take any possible drugs when SJS occurred and then give supported cure. Exception of SJS patient who should prevented contact with this kind of drugs again; any possible combination of SJS drugs should also be noticed. Key Words：Adverse Drug Reaction、Stevens-Johnson Syndrome、Toxic Epidermal Necrolysis、Drug Interaction、Allergy

碩士<br>國立臺灣科技大學<br>工業管理系<br>100<br>Complications of drug therapy are the most common type of adverse events in hospitalized patients. The example includes Stevens-Johnson syndrome (SJS), a life-threatening skin reactions to medications. Since drugs are the important causes of SJS, the first and most important step in treating SJS is to discontinue any medication that may be causing it. But the potential drugs that may lead SJS spread extensively in various medical fields and very few physicians are familiar with all these drugs. There is a case when physician is not aware about the drugs causing SJS, the physician failed to identify the “must be discontinued drugs” and treat the patient with more antibiotics which make the SJS patient’s condition worse. This condition makes the patient re-hospitalized for treating SJS. Currently in Taiwan, the emergence of re-hospitalization case in SJS patients has not yet known. Motivating by recent study that successfully defined six kinds of prescription behavior that commonly acted by physicians in treating SJS patient, this study, by taking the same SJS case data from Taiwan’s National Health Insurance database, proposes a data mining approach to investigate association pattern between drugs within these prescription behavior that may affect the occurrence of re-hospitalization case in SJS. This study will first classify prescription history of re-hospitalized patients through rule-based classification method. Secondly, using the basic properties of prescription behavior identify drug’s association pattern. Then, pair of drugs will be generated by employing A-priori algorithm and its degree of association will be obtained by using selected objective measure. Finally, by listing and ranking up this pair of drugs based on its degree of association, it can assist physician in prescribing drugs to increase the awareness and reduce recurrence and re-hospitalization case in SJS patients.

碩士<br>國立臺灣科技大學<br>工業管理系<br>105<br>With plenty of convenient medical resources, it is easy for patients to see a doctor in several hospitals with the same disease or let patients get duplicated medication or interactions between multiple drugs. On the other hand, in the investigation of Taiwan Drug relief system, it indicated that Stevens Johnson Syndrome (shortly as SJS in the following paper) was the main case for application. Therefore, the aim of this study is to use the time interval sequential pattern to explore the patients’ medication sequence and length of stays before suffering Steven Johnson Syndrome. However, the conventional sequential pattern mining methods only provide the chronological order but it will ignore the time-interval between the items. For this reason, using the approach to mine the patients who got SJS, it might lead to neglecting the interactions between the medicines which would cause an increase in morbidity of SJS. Consequently, the research of this study will consider the influences of time interval in the above methods to discuss the time-interval sequential pattern of patients who suffered from SJS. This research has retrieved patients’ medical records from Taiwan National Health Insurance Research Database and connected the relative data for preprocessing. To easily analyze the data, pharmacological classification, admission and discharge were classified and coded. In addition, K-means approach was initially adopted to analyze the time interval between taking medicines and length of stays to categorize in consecutive days. After that, we can apply high frequency pattern from the database to discover correlation between receiving medicines and length of stays with time interval sequential pattern. The results of the research can be regards as a reference for medical decision making and a benefit to the potential patients.

博士<br>國立臺灣大學<br>微生物學研究所<br>100<br>Drug hypersensitivity remains a major clinical problem. Stevens-Johnson syndrome (SJS) and the related disease toxic epidermal necrolysis (TEN) are life-threatening drug hypersensitivities with robust immune responses to drugs. Despite the strong genetic association between HLA-B*1502 and carbamazepine (CBZ)-induced SJS/TEN, it is not known whether particular T-cell receptor (TCR) repertoires participate in the recognition of small drug-peptide-HLA complexes in T cell-mediated drug hypersensitivity. Using the strong HLA predisposition in CBZ-SJS as a model, we studied the diversity of the TCR repertoire involved in drug hypersensitivity. Upon in vitro CBZ stimulation, CBZ-specific CD8+ T cells isolated from CBZ-SJS patients could be expanded, activated with release of interferon-γ and granulysin, and exhibited strong cytotoxicity. CDR3 spectratyping of drug-enriched CD8+ T cells revealed common, restricted TCR repertoire usages that were VB-11 skewed in all 8 CBZ-SJS patients examined. CDR3 sequence analysis confirmed this oligoclonality and identified VB-11-ISGSY as the most predominant clonotype. This clonotype was present in 16 of 19 (84%) SJS patients, absent in all 17 tolerant patients, and present at low frequency in normal individuals (4 of 29, 14.8%); all study subjects were HLA-B*1502 carriers. Moreover, CBZ-specific cytotoxicity could be primed in vitro in those normal individuals with disease-specific clonotypes; this cytotoxicity could be blocked by an anti-TCR VB-11 antibody. Thus, this study establishes the key role of the T cell receptor in the pathogenic mechanism of SJS/TEN, explains why some HLA-B*1502 positive individuals are tolerant to CBZ, and provides a potential therapeutic target for SJS/TEN.

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia<br>A base da intervenção médica é a utilização de medicamentos que estão muitas vezes associados a complicações inerentes ao seu uso, sendo uma das principais causas da ocorrência de eventos adversos nos cuidados de saúde.A definição de RAM é vaga. Deve esclarecer-se que não são resultantes apenas da “utilização autorizada de um medicamento em doses normais, mas também dos erros terapêuticos e das utilizações fora dos termos da autorização de introdução no mercado, incluindo a utilização indevida e abusiva do mesmo”, como referido na diretiva 2010/84/UE.Para a presente análise de reações de hipersensibilidade a medicamentos, os dados recolhidos pertencem a um período de janeiro de 2009 a dezembro de 2014 e foram cedidos pela Unidade de Farmacovigilância de Coimbra. Para a sua recolha foi utilizado o Medical Dictionary for Regulatory Activities (MedDRA) query (versão 17.1). MedDRA é um dicionário de terminologia médica desenvolvido na década de 1990 pela International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).Foram reportadas um total de 1278 notificações de RAM, das quais 3 relativas a SJS (prevalência de 0,23%), 2 relativas a NET (prevalência de 0,16%), 7 relativas a DRESS (prevalência de 0,55%) e 2 relativas a DILI (prevalência de 0,16%).Concluindo, unidades de farmacovigilância, como a UFC, onde são reportadas reações adversas a medicamentos representam uma fonte muito importante de informação da segurança dos medicamentos após a sua introdução no mercado e o seu uso sob condições não controladas. Desta forma é possível concluir à cerca da segurança dos medicamentos para a população, procedendo à sua retirada do mercado se assim for necessário.<br>The basis of medical intervention is the use of medications that are often associated with the inherent complications to their use, being one of the main causes of the occurrence of adverse events in health care.The definition of RAM is vague. It should be made clear that they are not only a result of “(...) the authorised use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorisation, including the misuse and abuse of the medicinal product (...)", as referred to in Directive 2010/84/EU.For the present analysis of hypersensitivity reactions to medications, the collected data belong to a period from january 2009 to december 2014 and were ceded by the Pharmacovigilance Unit of Coimbra. The Medical Dictionary for Regulatory Activities (MedDRA) query (version 17.1) was used for its collection. MedDRA was developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), in the late 1990s.A total of 1278 notifications of RAM were reported, of which 3 on the SJS (prevalence of 0.23%), 2 on the NET (prevalence of 0.16%), 7 concerning DRESS (prevalence of 0.55%) and 2 relating to DILI (prevalence of 0.16%).In conclusion, pharmacovigilance units, such as the Pharmacovigilance Unit of Coimbra, where adverse drug reactions are reported represent a very important source of drug safety information after their placing on the market and their use under uncontrolled conditions. In this way, it is possible to conclude about the drug safety for the population and to remove them from the market if necessary.