Introdução. As hemisferectomias são cirurgias utilizadas há décadas para se tratar epilepsias refratárias à medicação anticonvulsivante. Embora o controle das crises seja satisfatório, a morbidade, per e pós-operatória, ainda é considerada um importante fator limitante à sua utilização. Dessa maneira, compreender as complicações mais comuns do procedimento, e os fatores que as influenciam, é essencial para se estabelecer o melhor uso para a técnica. Métodos. Foram coletados dados de 30 pacientes, operados por seis cirurgiões no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período entre 1980 e 2003. Foram realizadas 11 hemisferectomias com a abordagem de Rasmussen, três hemisferectomias anatômicas, nove hemisferectomias funcionais extraventriculares e sete hemisferotomias. Foram estudados cinco grupo de pacientes de acordo com a fisiopatologia da doença de base: Dezesseis pacientes eram portadores de Síndrome de Rasmussen, dois da Síndrome de Sturge-Weber, quatro de malformações corticais, dois de lesões sequelares e seis de cistos porencefálicos. Os fatores de morbidade foram avaliados dentro de rês perspectivas: 1- da doença de base; 2- da técnica utilizada; e 3- do fator humano. Resultados. Nossos dados mostraram ausência de diferença estatisticamente significativa entre as técnicas cirúrgicas empregadas nos itens: tempo cirúrgico; tempo de internação na unidade de terapia intensiva; queda da hemoglobina; volume de hemoderivados transfundidos e febre no pós-operatório. Presença de leucograma acima de 15.000 leucócitos/mm3 no pós-operatório imediato foi associada a estadias mais longas na unidade de terapia intensiva A média diária de temperatura dos pacientes, mostrou temperaturas acima de 38º C entre o terceiro e sexto dia pós-operatório. Pacientes com hemimegalencefalia apresentaram temperaturas mais elevadas quando comparados com os portadores de cistos porencefálicos. Doenças com maior manto cortical contribuíram para aumentar o tempo cirúrgico, embora o fator humano tenha sido decisivo nesse item. Ao comparar nossos achados com os da literatura, vimos que os pacientes submetidos à hemisferectomia anatômica apresentaram no pós-operatório temperaturas mais elevadas e reação inflamatória liquórica mais intensa que os submetidos a técnicas de desconexão hemisférica, no entanto, a importância desse dado necessita ser estabelecida. Conclusões: O principal fator de morbidade nas hemisferectomias é a doença de base, assim, os dados presentes na literatura, incluindo nossa casuística, não nos permite concluir que uma técnica seja superior à outra ou que as técnicas desconectivas sejam melhores que as ressectivas / Hemispherectomy has been the treatment of choice in some sorts of refractory epilepsies for decades. Although surgery results in satisfactory control of seizures, its morbidity remains a major concern. Thus, understanding most common complications, as well as the factors that contribute to it, becomes an essential step to learn the limits on technique applications. Methods. Hospital charts from 30 patients operated on by six different surgeons at the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo from 1980 to 2003 were reviewed. Eleven functional hemispherectomies using Rasmussen approach, three anatomical hemispherectomies, nine extraventricular functional hemispherectomies, and seven hemispherotomies were included in this study. Sixteen patients presented with Rasmussen Syndrome, two Sturge-Weber Syndrome, four cortical malformations, two hemispheric lesions, and six porencephalic cysts. Morbidity was evaluated from three different perspectives 1- background disease, 2- employed technique, and 3- human factor. Results: our data presented no statistical difference among the employed techniques regarding 1- surgical time, 2- intensive care unit time, 3- per and postoperative fall of hemoglobin, 4- blood transfusion volume, and 5- postoperative axilar temperature variation. Patients that presented over 15,000 leucocytes per mm3 stayed longer at the intensive care unit, regardless of the surgical technique employed. Daily average temperatures varied around 38 degrees Celsius from the third to the sixth postoperative day. Patients with hemimegalencephaly had higher postoperative axilar temperatures when compared to those with porencephaly. Thicker cortical mantle contributed to increase surgical time, though human factor also showed to be important in this item. Comparing data from this study and the literature disclosed that patients undergoing anatomical hemispherectomies presented an inflammatory response in the cerebrospinal fluid more evident than those submitted to cerebral disconnection, although the importance of this finding is still elusive. Conclusions: The main factors of morbidity in the hemispherectomy are the background disease and patient\'s peculiarities, therefore, it is not reasonable to infer that there is a superior technique or that hemisphere disconnection is better than removal

Hin-Chung Chu. / Thesis submitted in: July 2002. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 281-306). / Abstracts in English and Chinese. / Cover (English & Chinese version) --- p.I / 中文封面 --- p.II / Abstract (English version) --- p.III-IV / 中藥不良反應論文摘要 --- p.V / Acknowledgements --- p.VI / Abbreviations --- p.VII-VIII / Publication in press --- p.IX / Content --- p.X-XV / Lists of Table --- p.XVI / Chapter Chapter 1 --- Introduction --- p.1-3 / Chapter Chapter 2 --- Chinese herbal medicines used in Hong Kong. --- p.4-15 / Chapter 2.1 --- Overview --- p.4-5 / Chapter 2.2 --- The Policy In Hong Kong -- Past And Present --- p.5-1 / Chapter 2.3 --- The Preparatory Committee on Chinese Medicine (PCCM) --- p.7-8 / Chapter 2.4 --- The Chinese Medicine Council of Hong Kong --- p.8-10 / Chapter 2.5 --- Development of Standards --- p.10 / Chapter 2.6 --- Development of Centres of Good Clinical Practice --- p.10-11 / Chapter 2.7 --- Establishment of a Good System of Education and Training --- p.11 / Chapter 2.8 --- Investigation of Suspected Herbal Toxicity Cases --- p.12-13 / Chapter 2.8.1 --- Herbal Safety Surveillance --- p.13-14 / Chapter 2.9 --- Conclusion --- p.14-15 / Chapter Chapter 3 --- Herbal medicines used in other countries --- p.16-45 / Chapter 3.1 --- Overview --- p.16 / Chapter 3.2 --- China --- p.16-19 / Chapter 3.3 --- Macau --- p.22-23 / Chapter 3.4 --- Taiwan --- p.23-26 / Chapter 3.5 --- Japan --- p.27-30 / Chapter 3.6 --- Singapore --- p.30-31 / Chapter 3.7 --- Australia --- p.31-34 / Chapter 3.8 --- Others Asian countries --- p.35 / Chapter 3.9 --- USA --- p.35-39 / Chapter 3.10 --- United Kingdom --- p.39-41 / Chapter 3.11 --- Europe --- p.41-43 / Chapter 3.12 --- Germany --- p.43-45 / Chapter Chapter 4 --- Adverse reaction -- General Aspect --- p.46-63 / Chapter 4.1 --- Overview --- p.46 / Chapter 4.2 --- Traditional Chinese medicine --- p.47-49 / Chapter 4.2.1 --- Compound Prescriptions to Reduce Toxicity --- p.50 / Chapter 4.2.2 --- Processing Of Chinese Herbs --- p.50-51 / Chapter 4.2.2.1 --- The Aims of Herbal Drug Processing --- p.51-52 / Chapter 4.2.2.2 --- The Methods of Herbal Drug Processing --- p.52 / Chapter 4.2.2.3 --- External processing (simple treatment by trimming) --- p.52-53 / Chapter 4.2.2.4 --- Water processing --- p.53-54 / Chapter 4.2.2.5 --- Fire processing --- p.54 / Chapter 4.2.2.6 --- Water-fire processing --- p.54-55 / Chapter 4.2.2.7 --- Other methods --- p.55 / Chapter 4.3 --- Practical Problem in Traditional Chinese Medicine --- p.55-57 / Chapter 4.4 --- Evaluation of herbal adverse reactions --- p.57 / Chapter 4.4.1 --- Type A reactions --- p.57 / Chapter 4.4.2 --- Type B reactions --- p.58 / Chapter 4.4.3 --- Type C reactions --- p.58 / Chapter 4.4.4 --- Type D reactions --- p.58 / Chapter 4.5 --- Chinese Proprietary medicine --- p.58-59 / Chapter 4.6 --- Potential Risks for Herbal Adverse Reaction --- p.59 / Chapter 4.6.1 --- Misidentification --- p.59-60 / Chapter 4.6.2 --- Lack of standardisation --- p.60 / Chapter 4.6.3 --- Contamination --- p.60 / Chapter 4.6.4 --- Incorrect preparation / dosage --- p.60 / Chapter 4.6.5 --- Excessive dosage --- p.60-61 / Chapter 4.6.6 --- Individual errors --- p.61 / Chapter 4.6.7 --- Individual response --- p.61 / Chapter 4.6.8 --- Unqualified Herbal Practitioner with Wrong Prescription --- p.61-62 / Chapter 4.6.9 --- Interaction with Western medicine --- p.62 / Chapter 4.6.10 --- Prolonged Usage --- p.62 / Chapter 4.6.11. --- Coexisting disease --- p.62-63 / Chapter 4.7 --- Conclusion --- p.63 / Chapter Chapter 5 --- "Substitution, Adulteration or Misusing with Toxic Herbs" --- p.64-84 / Chapter 5.1 --- Overview --- p.64-65 / Chapter 5.2 --- Adulteration by Guijiu --- p.65-68 / Chapter 5.3 --- Anticholinergic reactions Caused by <Yangjinhua> --- p.69-74 / Chapter 5.4 --- Overdosage --- p.74 / Chapter 5.4.1 --- Overdose of Aconitine --- p.74-78 / Chapter 5.4.2 --- Overdose of Liquorice ('Gancao') --- p.78-80 / Chapter 5.4.3 --- Overdose of <Chansu> --- p.80 / Chapter 5.5 --- Misusing - Personal abuse --- p.80 / Chapter 5.5.1 --- <Banmao> --- p.80-81 / Chapter 5.6 --- Discussion --- p.81-84 / Chapter 5.7 --- Conclusion --- p.84 / Chapter Chapter 6 --- Chinese Patent Medicine - General Aspect --- p.85-112 / Chapter 6.1 --- Chinese Patent Medicine --- p.85 / Chapter 6.1.1 --- Introduction --- p.85-87 / Chapter 6.1.2 --- Herbal Injection and Infusion --- p.87-88 / Chapter 6.1.2.1 --- Variety & Processing --- p.88 / Chapter 6.1.2.2 --- Stabilization --- p.88-89 / Chapter 6.1.2.3 --- The Molecular Size --- p.89-90 / Chapter 6.1.3 --- Adverse Reactions Caused by Chinese Proprietary Medicines --- p.90 / Chapter 6.1.3.1 --- Aconitine poisoning --- p.90 / Chapter 6.1.3.2 --- Nan Lien Chui Fong Toukuwan' --- p.90-91 / Chapter 6.1.3.3 --- Jin Bu Huan' --- p.91 / Chapter 6.1.3.4 --- Baoyingdan' --- p.91 / Chapter 6.1.4 --- Heavy metals in CPM --- p.91 / Chapter 6.1.5 --- The Necessarity to Develop Randomise Herbal Clinical Trial. --- p.91-92 / Chapter 6.1.6 --- Recommendation --- p.92-93 / Chapter 6.1.7 --- Conclusion --- p.93-94 / Chapter 6.2 --- Adulteration by synthetic therapeutic substances --- p.95-104 / Chapter 6.2.1 --- The Experiences in China --- p.91-99 / Chapter 6.2.2 --- The Experiences in Hong Kong --- p.99-101 / Chapter 6.2.3 --- The Experience in Taiwan --- p.101-102 / Chapter 6.2.4 --- Discussion --- p.102-104 / Chapter 6.3 --- Oil of Wintergreen (Methyl salicylate) --- p.104-112 / Chapter 6.3.1 --- Overview --- p.104-111 / Chapter 6.3.2 --- Prevention --- p.111-112 / Chapter Chapter 7 --- Adverse effects of Ginseng. --- p.113-123 / Chapter 7.1 --- Overview --- p.113 / Chapter 7.2 --- Botany --- p.113-114 / Chapter 7.3 --- Pharmacological Effects --- p.114-115 / Chapter 7.4 --- Adverse reaction of Ginseng --- p.115 / Chapter 7.4.1 --- Overdosage --- p.115-116 / Chapter 7.4.2 --- Substitution with cheaper and more toxic herbs --- p.116-121 / Chapter 7.5 --- Drug - herb Interaction --- p.121-122 / Chapter 7.6 --- Conclusion --- p.123 / Chapter Chapter 8 --- Herbal Medicines With Cardiovascular Adverse Reactions --- p.124-123 / Chapter 8.1 --- Overview --- p.124 / Chapter 8.2 --- Hypertension --- p.124 / Chapter 8.3 --- Atherosclerosis --- p.124-125 / Chapter 8.4 --- Arrhythmias --- p.125-126 / Chapter 8.5 --- Cardic Failure --- p.126 / Chapter 8.6 --- Angia Pectoris --- p.126 / Chapter 8.7 --- Thromboembolic Disorders --- p.126-127 / Chapter 8.8 --- Discussion --- p.127-128 / Chapter 8.8.1 --- Herbal Medicine Used in Cardiovascular System --- p.131 / Chapter 8.8.1.1 --- Ginseng --- p.131-133 / Chapter 8.8.1.2 --- Ma huang (Ephedra sinica) --- p.133-136 / Chapter 8.8.1.3 --- Yellow oleander (Thevetia neriifolia) --- p.136-137 / Chapter 8.8.1.4 --- Stephania tetrandra --- p.137-138 / Chapter 8.8.1.5 --- Danshen (Salvia miltiorrhiza) --- p.138 / Chapter 8.8.1.8 --- Ginkgo biloba --- p.138-140 / Chapter 8.8.1.9 --- Dong Quai (Angelicae Sinensis) --- p.140-141 / Chapter 8.8.1.10 --- Licorice (Glycyrrhiza Glabra) --- p.141-143 / Chapter 8.8.1.11 --- Berberine --- p.143 / Chapter 8.8.2 --- Potential Problem Caused by Chinese Proprietary Medicine --- p.143-144 / Chapter 8.9 --- Other Herbal Adverse Effects And Drug Interaction --- p.144-145 / Chapter 8.10 --- Conclusion --- p.145 / Chapter Chapter 9 --- Review of the Adverse Reactions to herbal treatments of Obesity --- p.146-150 / Chapter 9.1 --- Overview --- p.146 / Chapter 9.2 --- Combined With Unknown medication --- p.146-147 / Chapter 9.3 --- Dietary Supplements and Herbal Preparations --- p.147-149 / Chapter 9.4 --- Conclusion --- p.149-150 / Chapter Chapter 10 --- Adverse Effects of CHM used for Diabetes --- p.151-159 / Chapter 10.1 --- Introduction --- p.151 / Chapter 10.2 --- Traditional Chinese medicine used in Diabetes --- p.151 / Chapter 10.3 --- Adverse Reaction of Alternative Diabetic Treatment --- p.152-158 / Chapter 10.4 --- Conclusion --- p.159 / Chapter Chapter 11 --- Review of Herbal Hepatotoxicity --- p.160-194 / Chapter 11.1 --- Introduction --- p.160-161 / Chapter 11.2 --- Drug-induced hepatic injury --- p.161-163 / Chapter 11.3 --- Types of Liver Injury --- p.163 / Chapter 11.3.1 --- Pyrrolizidine alkaloid (PA) --- p.163 / Chapter 11.4 --- Hepatotoxicity Herbs --- p.163 / Chapter 11.4.1 --- Tripterygium wilfordii --- p.163-164 / Chapter 11.4.2 --- Rhizoma Discoreae Bulbiferae --- p.164-165 / Chapter 11.5 --- Consumption of Insect herbs --- p.165 / Chapter 11.6 --- Hepatotoxicity Cause by Chinese Proprietary Medicine --- p.165-166 / Chapter 11.6.1 --- Jin Bu Huan --- p.166-168 / Chapter 11.6.2 --- Chi R Yun (Breynia officinalis) --- p.168 / Chapter 11.6.3 --- Sho-saiko-to --- p.168-169 / Chapter 11.6.4 --- Shou-Wu-Pian --- p.169-171 / Chapter 11.7 --- Importance of Drug-Herb and Herb-Herb Interactions --- p.171-172 / Chapter 11.8 --- Diagnosis of Herbal Hepatotoxicity --- p.172-173 / Chapter 11.9 --- Recomandation --- p.173-174 / Chapter 11.10 --- Conclusion --- p.175 / Table --- p.176-180 / Chapter Chapter 12 --- Review of Herbal Nephropathy --- p.181-194 / Chapter 12.1 --- Introduction --- p.181 / Chapter 12.2 --- Aristolochia acids (AA) --- p.181-183 / Chapter 12.2.1 --- Intoxication of Aristolochia in Worldwide --- p.183-184 / Chapter 12.2.2 --- Morphological findings --- p.184-185 / Chapter 12.2.3 --- Carcinogenic --- p.185-187 / Chapter 12.3 --- MuTong (Aristolochia manshuriensis) --- p.187-188 / Chapter 12.4 --- Ma-dou-ling (Fructus Aristolochiae) --- p.188 / Chapter 12.5 --- Tripterygium wilfordii --- p.188-189 / Chapter 12.6 --- Gastrodia Elata --- p.189 / Chapter 12.7 --- Licorice (Glycyrrhiza glabra) --- p.190-191 / Chapter 12.8 --- Hippocampus (Sea Horse) --- p.191 / Chapter 12.9 --- Milabris Phanalerata --- p.191-192 / Chapter 12.10 --- Chinese Proprietary Medicine --- p.192-193 / Chapter 12.11 --- Conclusion --- p.193-194 / Chapter Chapter 13 --- Adverse Reaction of Herbal Medicine in Dermatology. --- p.195-217 / Chapter 13.1 --- Overview --- p.195-196 / Chapter 13.2 --- Chinese Herbal Medicine Used in Psoriasis --- p.196 / Chapter 13.2.1 --- Tripterygium wilfordii --- p.197 / Chapter 13.2.2 --- Radix Angelicae pubescentis and Radix Angelicae dahuricae --- p.197-198 / Chapter 13.2.3 --- Radix macrotomiae seu Lithospermi Injection --- p.198 / Chapter 13.3 --- Chinese Herbal Decoction For Atopic Dermatitis --- p.198-200 / Chapter 13.3.1 --- Tea Extracts --- p.200-201 / Chapter 13.4 --- Potential Adverse Effect with Herbal Medicine --- p.201 / Chapter 13.4.1 --- Allergic skin reactions --- p.201-202 / Chapter 13.4.2 --- Stevens-Johnson syndrome --- p.202 / Chapter 13.4.3 --- Photosensitization --- p.202-204 / Chapter 13.4.4 --- Pellagra --- p.204 / Chapter 13.4.5 --- Hepatotoxic Effects --- p.204-205 / Chapter 13.4.6 --- Others Adverse Reaction --- p.205 / Chapter 13.4.7 --- Potential Adverse Reaction Caused by Interactions --- p.205 / Chapter 13.5 --- Potential Adverse Reaction Caused by Contamination of Herbal Product --- p.206 / Chapter 13.5.1 --- Herbal creams adulterated with corticosteroids --- p.206-207 / Chapter 13.5.2 --- Arsenic dermatoses --- p.207 / Chapter 13.5.3 --- Mercury poisoning --- p.207-208 / Table --- p.208-211 / Chapter 13.6 --- Dermatological Adverse Reaction Caused by Herbs --- p.211 / Chapter 13.7 --- Contact Dermatitis Caused by CPM --- p.211-212 / Chapter 13.7.1 --- Liushenwan' --- p.211-212 / Chapter 13.7.2 --- Heiguiyou' --- p.212 / Chapter 13.7.3 --- 101 Hair Regrowth Liniment' --- p.212-213 / Chapter 13.7.4 --- Zhenggushui' --- p.213 / Chapter 13.7.5 --- Tiedayaoiing' --- p.213-214 / Table --- p.214-215 / Chapter 13.8 --- Non-dermatological adverse effects of systemic herbal treatments used for dermatological conditions --- p.215-216 / Chapter 13.9 --- Conclusion --- p.216-217 / Chapter Chapter 14 --- "Chinese Herbal Medicine in Pregnancy, Infants & Children," --- p.218-229 / Chapter 14.1 --- Overview --- p.218-219 / Chapter 14.2 --- Asian Cultures for Pregnancy --- p.219-223 / Chapter 14.3 --- Teratogenic Herbs --- p.224-225 / Chapter 14.4 --- Chinese proprietary medicines --- p.225 / Chapter 14.4.1 --- "“Tse Koo Choy""" --- p.225-226 / Chapter 14.4.2 --- "“Lu Shen Wan""" --- p.226 / Chapter 14.4.3 --- "“Po Ying Pills""" --- p.226-227 / Chapter 14.4.4 --- """Jin Bu Huan Toxicity"" in Children" --- p.227 / Chapter 14.6 --- Topical Preparations --- p.227-228 / Chapter 14.7 --- Dietary supplement --- p.228-229 / Chapter 14.8 --- Conclusion --- p.229 / Chapter Chapter 15 --- Heavy metals poisoning in traditional Chinese medicines. --- p.230-251 / Chapter 15.1 --- Introduction --- p.230-232 / Chapter 15.2 --- LEAD --- p.232 / Chapter 15.2.1 --- Overview --- p.232 / Chapter 15.2.2 --- Poisoning Cases of Boa Ning Dan --- p.233-235 / Chapter 15.2.3 --- Lead Poisoning in Worldwide --- p.235-238 / Chapter 15.3 --- MERCURY --- p.238 / Chapter 15.3.1 --- Overview --- p.238-239 / Chapter 15.3.2 --- Cinnabar --- p.239-240 / Chapter 15.3.3 --- Presentation --- p.240-241 / Chapter 15.3.4 --- Poisoning Cases --- p.241-242 / Chapter 15.4 --- ARSENIC --- p.242 / Chapter 15.4.1 --- Overview --- p.242-243 / Chapter 15.4.2 --- Arsenic toxicity --- p.243-244 / Chapter 15.4.3 --- The toxicologic mechanisms of inorganic arsenic --- p.244-246 / Chapter 15.4.4 --- Poisoning Cases --- p.246 / Chapter 15.4.5 --- Discussion --- p.247-248 / Chapter 15.5 --- Conclusion --- p.248 / Table --- p.249-251 / Chapter Chapter 16 --- Herb - Drug Interactions --- p.252-269 / Chapter 16.1 --- Overview --- p.252-254 / Chapter 16.2 --- Effects of Herb-drug interactions --- p.255 / Chapter 16.2.1 --- Gastrointestinal system --- p.255-256 / Chapter 16.2.2 --- Cardiovascular system --- p.256 / Chapter 16.2.3 --- Central nervous system --- p.257 / Chapter 16.2.4 --- Endocrine system --- p.257 / Chapter 16.3 --- Reason regard to herb-drug interactions --- p.257 / Chapter 16.3.1 --- Lack of Knowledge About Herbs --- p.257 / Chapter 16.3.2 --- Mislabelling or Adulteration --- p.258 / Chapter 16.3.3 --- Lack of Patient Communication About Use of Botanicals --- p.258 / Chapter 16.3.4 --- Lack of Practitioner Knowledge About Potential Interactions --- p.258 / Chapter 16.4 --- Metabolism of Herb-Drug Interaction --- p.258-259 / Chapter 16.5 --- Pharmacologic Interactions --- p.259-260 / Chapter 16.5.1 --- Interaction with Antibiotics --- p.260 / Chapter 16.5.2 --- Interaction with Nonsteroidal Anti-inflammatory Drugs --- p.260-261 / Chapter 16.5.3 --- Interaction with Sedatives --- p.261-262 / Chapter 16.5.4 --- Interaction with Anticoagulants --- p.262-263 / Chapter 16.5.5 --- Interaction with Anti-hypertensives and Diuretics --- p.263 / Chapter 16.5.6 --- Interaction with Spironolactone --- p.264 / Chapter 16.5.7 --- Interaction with Corticosteroids and Cyclosporine --- p.264-265 / Chapter 16.5.8 --- Interaction with Estrogen Replacement Therapy --- p.265 / Chapter 16.5.9 --- Interactions Between Natural Product and Drug --- p.265-266 / Chapter 16.6 --- Herb-to-Herb Interactions --- p.266-267 / Chapter 16.7 --- Conclusion --- p.268-269 / Chapter Chapter 17 --- Recommendation --- p.270-264 / Chapter 17.1 --- Overview --- p.270 / Chapter 17.2 --- The need to evaluate the clinical effectiveness of traditional Chinese medicine --- p.270-271 / Chapter 17.3 --- For the Pharmaceutical Industries --- p.211-212 / Chapter 17.4 --- For the physicians & patient --- p.272-274 / Conclusion --- p.274 / Chapter Chapter 18 --- Conclusion --- p.275-280 / Chapter Chapter 19 --- Reference --- p.281-306

O Tacrolimus é uma potente droga imunossupressora introduzida no transplante cardíaco no início da década de 90. Pacientes com rejeição refratária ou intolerância à ciclosporina podem responder à terapia de resgate com o tacrolimus. Os objetivos deste estudo foram: avaliar a evolução clínica das crianças submetidas ao transplante cardíaco que necessitaram da conversão de ciclosporina para tacrolimus por rejeição refratária, tardia ou efeitos adversos de difícil controle; avaliar a incidência de rejeição após a conversão para o tacrolimus e comparar a sobrevida dos pacientes em uso de tacrolimus e ciclosporina. Realizou-se estudo coorte, observacional, prospectivo, em 28 crianças submetidas ao transplante cardíaco no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e que foram submetidas à conversão da ciclosporina ao tacrolimus, no período de julho de 1999 a dezembro de 2009. Avaliou-se a incidência de episódios de rejeição e a sobrevida após a conversão. Realizou-se, também, a comparação entre os pacientes em uso de tacrolimus e os pacientes que permaneceram em uso de ciclosporina submetidos ao transplante cardíaco no mesmo período. A idade média no momento do transplante foi de 5,3 anos, e no momento da conversão de 8,2 anos. As causas de conversão foram efeitos adversos em 50% dos pacientes, rejeição tardia em 32% e rejeição refratária em 18%. O tempo médio de conversão e seguimento foram 36 meses e 74 meses, respectivamente. Observou-se resolução completa dos episódios de rejeição refratária e melhora dos efeitos adversos em todos os pacientes. A taxa de incidência (x100) de episódios de rejeição antes da conversão foi de 7,98 e após a conversão foi de 2,11 (p=0,0001). A taxa de episódios de infecção antes da conversão foi de 5,89 e após a conversão 4,18 (p=0,023). Pela análise das complicações pré e pós-conversão ao tacrolimus, não se evidenciou diferença estatisticamente significativa em relação a incidência de tumor, insuficiência renal, hipertensão arterial sistêmica, dislipidemia, litíase biliar, diabetes melito, anemia, alterações neurológicas, hirsutismo e hiperplasia gengival. Houve maior prevalência da doença vascular do enxerto após conversão para tacrolimus (p=0,004). Ao se comparar os pacientes com tacrolimus e os com ciclosporina, identificou-se diminuição significativa na taxa de incidência de episódios de rejeição (p=0,001), e na taxa de incidência de episódios de infecção (p=0,002), nos pacientes em uso de tacrolimus. Os pacientes convertidos ao tacrolimus apresentaram menor incidência de complicações neurológicas, hirsutismo e hiperplasia gengival, porém maior prevalência de anemia. Em relação à sobrevida, observou-se uma mortalidade de 25% nos pacientes em uso de tacrolimus, após um período médio de conversão de sessenta meses. Três óbitos foram secundários à rejeição, dos quais apenas um, no primeiro ano de transplante. Evidenciou-se menor sobrevida nos pacientes em uso de ciclosporina. O estudo clínico das crianças submetidas ao transplante cardíaco e que necessitaram de conversão do esquema de imunossupressão permitiu concluir que o tacrolimus foi eficaz como terapia de resgate para rejeição refratária e constitui opção terapêutica como droga imunossupressora de manutenção na faixa etária pediátrica / Tacrolimus is a potent calcineurin inhibitor that was introduced in heart transplantation therapy in the early 1990s. Organ transplant recipients with refractory rejection or intolerance to conventional immunosuppressant may respond to rescue therapy with tacrolimus. The aim of this study was to evaluate the clinical outcome of children undergoing heart transplantation who required conversion from a cyclosporine to a tacrolimus-based immunosuppressive regimen due to refractory rejection, late rejection or cyclosporine intolerance. We performed a prospective observational cohort study in 28 children who underwent cardiac transplantation at the Heart Institute (InCor) University of São Paulo Medical School and who required conversion from July 1999 to December 2009. The clinical outcome of the patients was evaluated after tacrolimus conversion. We also compared the patients on tacrolimus to the patients who remained on cyclosporine, and who had undergone heart transplantation during the same period. The mean age at the time of transplantation was 5.3 years and 8.2 years at the time of conversion. The causes of conversion were adverse side effects in 50% of patients, late rejection in 32% and refractory rejection in 18%. The mean time from heart transplant to conversion was 36 months and the mean follow-up period was 74 months. We observed complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (x100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (p = <0.0001). The rate of infectious episodes before conversion was 5.89 and after conversion was 4.18 (p = 0.023). There was no statistically significant difference in relation to tumor, renal failure requiring dialysis, systemic arterial hypertension, dyslipidemia, gallstones, diabetes mellitus, anemia, neurological complications, hirsutism and gingival hyperplasia after conversion. A significant incidence of cardiac allograft vasculopathy after conversion to tacrolimus was found (p = 0.004). When comparing patients on tacrolimus to patients on cyclosporine, there was a significant decrease in the incidence of rejection (p = 0.001), and infectious episodes (p = 0.002) in patients using tacrolimus. Patients converted to tacrolimus when compared to patients on cyclosporine had lower neurological complications, hirsutism and gingival hyperplasia, but higher prevalence of anemia. There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. Three deaths were secondary to rejection, and only one in the first year after transplant. Patients using tacrolimus showed greater survival rate when compared to patients taking cyclosporine. The clinical outcome of children undergoing heart transplantation and who required conversion of immunosuppressive regimen allowed us to conclude that tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option in pediatric patients

Introdução: Na fase pré-comercialização, os ensaios clínicos randomizados (ECRs) constituem-se em ferramenta primordial no acúmulo de informação sobre a segurança de um medicamento. Recomendações têm sido publicadas no sentido de que a informação sobre eventos adversos seja adequadamente descrita nesses estudos. Na fase pós-comercialização, vigilância ativa e passiva complementam-se e relatos de caso de reações adversas a medicamentos (RAMs) publicados em revistas médicas deveriam contribuir no processo de geração de sinal, alertando o meio científico e auxiliando na adoção de medidas pelas agências regulatórias de medicamentos. Seu impacto, no entanto, é incerto, seja na geração de estudos confirmatórios ou incorporação das RAMs em fontes de informação sobre medicamentos utilizadas na prática médica. Objetivo: avaliar, em revistas de alto impacto da área médica: 1) a adoção das recomendações da versão do CONSORT “Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement” e das recomendações propostas por outros autores em ECRs envolvendo medicamentos publicados em 2009; 2) o impacto de relatos de caso de RAMs novas publicados em 1998, através da geração de estudos controlados confirmatórios e inclusão na base de dados MICROMEDEX e no British National Formulary (BNF). Metodologia: Através de buscas no Medline, foram selecionados todos os ECRs envolvendo medicamentos publicados em 2009 nas revistas British Medical Journal, The Journal of The American Medical Association, The Lancet e The New England Journal of Medicine e os relatos de caso publicados em 1998 nas revistas Annals of Internal Medicine, Archives of Internal Medicine, The Journal of the American Medical Association e New England Journal of Medicine. Baseando-se nas recomendações propostas por Ioannidis e Lau e na versão ampliada do CONSORT, as informações sobre eventos adversos foram extraídas dos ECRs. O impacto dos relatos de caso foi avaliado através da geração de estudos controlados confirmatórios publicados em revistas indexadas no Medline e/ou EMBASE e da incorporação da informação na base de dados MICROMEDEX e no BNF. Resultados: Dos 122 ECRs analisados, 32,8% objetivaram avaliar desfechos de segurança do medicamento em questão (posicionando-se a este respeito na introdução), 72,1% mencionaram riscos no título ou resumo; 10,7% esclareceram como a informação sobre riscos foi coletada; 46,7% apresentaram as frequências dos eventos adversos, separando-os por tipo e braço do estudo e especificando se algum tipo de evento adverso não ocorreu; e 18,0% apresentaram discussão balanceada sobre riscos e benefícios. Dos 32 relatos de caso de RAMs novas avaliados, verificou-se a inclusão da RAM em questão no MICROMEDEX em 16 (50%) relatos de caso e, no BNF, em 10 (32,1%). Observou-se geração de estudos controlados confirmatórios para 4 (12,5%) relatos. Conclusões: Informações importantes sobre eventos adversos permanecem insuficientemente atendidas em ECRs. Relatos de caso publicados em revistas médicas desempenham papel importante no processo de geração de sinal, impactando relativamente na geração de estudos confirmatórios e em fontes de informação da prática médica. / Introduction: In pre-commercialization phase, randomized clinical trials (RCTs) represent an essential tool for obtaining information on drug safety. Recommendations have been published so that the information about adverse events is properly described in these studies. In the pre-commercialization phase, active and passive vigilance complement one another, and case reports of adverse reactions to drugs (ADRs) published in medical journals should contribute for the process of sign generation, making the scientific world alert and supporting the adoption of measures by the regulatory drug agencies. Its impact, nonetheless, remains uncertain, both regarding the generation of confirmation studies and the ADR acceptance in the drug information sources used in the medical practice. This study aims at assessing, in highly-impacting medical journals: the compliance with the recommendations from the CONSORT version ‘Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement’ , as well as with the ones proposed by other authors in RCTs involving drugs, published in 2009; the impact of new ADR case reports published in 1998, through carrying out controlled confirmation studies and including them in the MICROMEDEX databank and in the British National Formulary (BNF). Methodology: Through Medline search, all the RCTs involving drugs published in 2009 in the journals British Medical Journal, The Journal of The American Medical Association, The Lancet and The New England Journal of Medicine were chosen. The same was done for the case reports published in 1998 in the Annals of Internal Medicine, Archives of Internal Medicine, The Journal of the American Medical Association and New England Journal of Medicine. Based on the recommendations proposed by Ioannidis and Lau and in the CONSORT comprehensive version, the information on adverse events was extracted from the RCTs. The impact of the case reports was assessed through carrying out controlled confirmation studies published in journals indexed in the Medline and/or EMBASE and the inclusion of this information in the MICROMEDEX databank and the BNF. Outcomes: Among the 122 RCTs analyzed, 72.1% mentioned risks in the title or abstract; 10.7% explained how information on risks had been collected; 46.7% presented adverse event frequency, sorting them by kind and study ramification, and also specifying whether some kind of adverse event had not occurred; and 18.0% presented a balanced discussion on risks and benefits. Among the 32 new ADR case reports analyzed, it was verified that these ADRs were included in the MICROMEDEX in 16 (50%) of the case reports, and in the BNF in 10 (32.1%). It was observed that controlled confirmation studies were designed for 4 (12.5%) of these studies. Conclusions: Relevant information on adverse events remains insufficient in RCTs. Case reports published in medical journals play an important part in the sign generating process, and they also relatively impact the carrying out of confirmation studies and the information sources of the medical practice.

O Tacrolimus é uma potente droga imunossupressora introduzida no transplante cardíaco no início da década de 90. Pacientes com rejeição refratária ou intolerância à ciclosporina podem responder à terapia de resgate com o tacrolimus. Os objetivos deste estudo foram: avaliar a evolução clínica das crianças submetidas ao transplante cardíaco que necessitaram da conversão de ciclosporina para tacrolimus por rejeição refratária, tardia ou efeitos adversos de difícil controle; avaliar a incidência de rejeição após a conversão para o tacrolimus e comparar a sobrevida dos pacientes em uso de tacrolimus e ciclosporina. Realizou-se estudo coorte, observacional, prospectivo, em 28 crianças submetidas ao transplante cardíaco no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e que foram submetidas à conversão da ciclosporina ao tacrolimus, no período de julho de 1999 a dezembro de 2009. Avaliou-se a incidência de episódios de rejeição e a sobrevida após a conversão. Realizou-se, também, a comparação entre os pacientes em uso de tacrolimus e os pacientes que permaneceram em uso de ciclosporina submetidos ao transplante cardíaco no mesmo período. A idade média no momento do transplante foi de 5,3 anos, e no momento da conversão de 8,2 anos. As causas de conversão foram efeitos adversos em 50% dos pacientes, rejeição tardia em 32% e rejeição refratária em 18%. O tempo médio de conversão e seguimento foram 36 meses e 74 meses, respectivamente. Observou-se resolução completa dos episódios de rejeição refratária e melhora dos efeitos adversos em todos os pacientes. A taxa de incidência (x100) de episódios de rejeição antes da conversão foi de 7,98 e após a conversão foi de 2,11 (p=0,0001). A taxa de episódios de infecção antes da conversão foi de 5,89 e após a conversão 4,18 (p=0,023). Pela análise das complicações pré e pós-conversão ao tacrolimus, não se evidenciou diferença estatisticamente significativa em relação a incidência de tumor, insuficiência renal, hipertensão arterial sistêmica, dislipidemia, litíase biliar, diabetes melito, anemia, alterações neurológicas, hirsutismo e hiperplasia gengival. Houve maior prevalência da doença vascular do enxerto após conversão para tacrolimus (p=0,004). Ao se comparar os pacientes com tacrolimus e os com ciclosporina, identificou-se diminuição significativa na taxa de incidência de episódios de rejeição (p=0,001), e na taxa de incidência de episódios de infecção (p=0,002), nos pacientes em uso de tacrolimus. Os pacientes convertidos ao tacrolimus apresentaram menor incidência de complicações neurológicas, hirsutismo e hiperplasia gengival, porém maior prevalência de anemia. Em relação à sobrevida, observou-se uma mortalidade de 25% nos pacientes em uso de tacrolimus, após um período médio de conversão de sessenta meses. Três óbitos foram secundários à rejeição, dos quais apenas um, no primeiro ano de transplante. Evidenciou-se menor sobrevida nos pacientes em uso de ciclosporina. O estudo clínico das crianças submetidas ao transplante cardíaco e que necessitaram de conversão do esquema de imunossupressão permitiu concluir que o tacrolimus foi eficaz como terapia de resgate para rejeição refratária e constitui opção terapêutica como droga imunossupressora de manutenção na faixa etária pediátrica / Tacrolimus is a potent calcineurin inhibitor that was introduced in heart transplantation therapy in the early 1990s. Organ transplant recipients with refractory rejection or intolerance to conventional immunosuppressant may respond to rescue therapy with tacrolimus. The aim of this study was to evaluate the clinical outcome of children undergoing heart transplantation who required conversion from a cyclosporine to a tacrolimus-based immunosuppressive regimen due to refractory rejection, late rejection or cyclosporine intolerance. We performed a prospective observational cohort study in 28 children who underwent cardiac transplantation at the Heart Institute (InCor) University of São Paulo Medical School and who required conversion from July 1999 to December 2009. The clinical outcome of the patients was evaluated after tacrolimus conversion. We also compared the patients on tacrolimus to the patients who remained on cyclosporine, and who had undergone heart transplantation during the same period. The mean age at the time of transplantation was 5.3 years and 8.2 years at the time of conversion. The causes of conversion were adverse side effects in 50% of patients, late rejection in 32% and refractory rejection in 18%. The mean time from heart transplant to conversion was 36 months and the mean follow-up period was 74 months. We observed complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (x100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (p = <0.0001). The rate of infectious episodes before conversion was 5.89 and after conversion was 4.18 (p = 0.023). There was no statistically significant difference in relation to tumor, renal failure requiring dialysis, systemic arterial hypertension, dyslipidemia, gallstones, diabetes mellitus, anemia, neurological complications, hirsutism and gingival hyperplasia after conversion. A significant incidence of cardiac allograft vasculopathy after conversion to tacrolimus was found (p = 0.004). When comparing patients on tacrolimus to patients on cyclosporine, there was a significant decrease in the incidence of rejection (p = 0.001), and infectious episodes (p = 0.002) in patients using tacrolimus. Patients converted to tacrolimus when compared to patients on cyclosporine had lower neurological complications, hirsutism and gingival hyperplasia, but higher prevalence of anemia. There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. Three deaths were secondary to rejection, and only one in the first year after transplant. Patients using tacrolimus showed greater survival rate when compared to patients taking cyclosporine. The clinical outcome of children undergoing heart transplantation and who required conversion of immunosuppressive regimen allowed us to conclude that tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option in pediatric patients

It is now generally acknowledged that particulate air pollution can cause respiratory symptoms and that indoor dust particles may be associated with mucous membrane irritation and odour annoyance. One reason for this may be that dust particles adsorb large quantities of gases and other volatile compounds. It is therefore important to be able to determine the chemical compounds adsorbed onto indoor dust particles. In this thesis, a new technique was developed that can analyse chemical compounds in indoor dust particles in a simple yet accurate way. In its basic configuration, it comprises a one stage thermal desorption oven, a gas flow cell with a miniaturized GC column, and a nitrogen-flushed photo diode array (PDA) detector for fast UV spectra recording. The dust sample is thermally desorbed in the oven and the released compounds are flushed onto the GC column by means of a carrier gas stream; the separated compounds are then registered by the PDA detector and identified by their characteristic gas-phase UV spectra. Using this set-up, a number of volatile organic as well as inorganic compounds were identified in indoor dust particles, e.g. nitric oxide, ammonia, hydrogen sulphide, pyridine, 2-furaldehyde, 2-methylfuran, and isoprene. Moreover, acrylate monomers were identified in dust samples from a secondary school with problems due to powdering floor polish. An instrumental set-up with higher performance was achieved by interfacing the gas flow cell to a capillary GC column. When airborne indoor dust samples were analysed by this system and by GC-MS under similar conditions of thermal desorption (150 °C) and GC separation, the two analytical systems were found to be complementary. GC-UV together with GC-MS was thus demonstrated to be considerably more powerful than GC-MS alone for the analysis of volatile organic compounds (VOC) in indoor dust. When airborne dust samples from damp (n=9) and control (n=9) residences were analysed for VOC and microorganisms, identifications made by culture and microscopy of the major moulds found, i.e. Aspergillus, Cladosporium and Penicillum, coincided with the identification of VOC known to be produced by these species. A number of additional VOC were also found, some of which may be irritating to the skin, eyes or respiratory tract if present at higher concentrations. Quantitative GC-UV analysis of indoor dust from 389 residences in Sweden showed that the VOC found at the highest concentrations were saturated aldehydes (C5-C10), furfuryl alcohol, 2,6-di-tert-butyl-4-methylphenol, 2-furaldehyde, and benzaldehyde. Alkenals were also found, notably 2-butenal (crotonaldehyde), 2-methyl-propenal (methacrolein), hexenal, heptenal, octenal, and nonenal. GC-UV was also applied (together with GC-MS) to determine VOC in dust from residences of 198 children with symptoms of asthma and/or allergy (cases) and from residences of 202 children without symptoms (controls). The mean concentration of nicotine was found to be significantly higher in dust from case residences, while the mean concentrations of hexane, nonanal, octane, 2-pentylfuran and tridecanol were significantly higher in dust from control residences. In a stepwise logistic regression model, nicotine, hexanal, furfuryl alcohol, nonane, butanol, and octenal showed increased relative risks, expressed as odds ratios comparing cases with controls. By contrast, benzaldehyde, nonanal, butenal, hexane, tridecanol, and pentylfuran showed decreased relative risks. These findings point to the possibility that not only environmental tobacco smoke but also other emissions in the indoor environment may be linked to the increased prevalence of asthma and/or allergy in children. It is concluded that GC-UV may be used as an alternative or complement to GC-MS for measuring chemicals in indoor dust, thus improving the survey and control of human exposure to particle-bound toxicants and other chemicals. / Copyright Agreement: Figure 3 included in the PDF file abowe is the exclusive property of SAGE Publications (http://www.sagepublications.com/), or its licensors and is protected by copyright and other intellectual property laws. The download of the file(s) is intended for the User's personal and noncommercial use. Any other use of the download of the Work is strictly prohibited. User may not modify, publish, transmit, participate in the transfer or sale of, reproduce, create derivative works (including coursepacks) from, distribute, perform, display, or in any way exploit any of the content of the file(s) in whole or in part. Permission may be sought for further use from Sage Publications Ltd, Rights and Permissions Department, 1 Oliver's Yard, 55 City Road, London EC1Y 1SP Fax: +44 (020) 7324-8600. By downloading the file(s), the User acknowledges and agrees to these terms.

Myelin and oligodendrocytes (OLGs) are the apparent targets of the immune-mediated injury that underlies the development of multiple sclerosis (M8). Recovery from M8 clinical relapses likely reflects remyelination attributed to recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), rather than to new process formation by previously myelinating OLGs. Newly emerging M8-directed immuno-modulatory therapies (statins and FTY720) can readily cross the blood-brain barrier and have been shown to impact signaling pathways implicated in cytoskeletal regulation, differentiation, migration, and survival; these are cellular events presumably important for myelin integrity and remyelination. / Statins inhibit the production of cholesterol (concentrated in the myelin membrane) and isoprenoids (post-translational attachments regulating the functions of proteins such as the Rho GTPases). We showed that treatment of human and rodent-derived OPCs with lipophilic statins induced an initial process extension associated with enhanced differentiation and impaired spontaneous migration, whereas prolonged treatment induced process retraction and cell death. Rodent and human mature OLGs demonstrated similar cytoskeletal and survival responses. Chronic simvastatin therapy of mice inhibited remyelination following demyelination induced by the OLG toxin, cuprizone, attributed to a block in OPC differentiation and consequent decrease in mature OLGs. Even fully myelinated animals treated with simvastatin over the long-term demonstrated a decrease in myelin in the brain by maintaining oligodendroglial cells in the pre-OLG state and preventing continual replacement of mature OLGs. / FTY720 is an agonist of G-protein-coupled receptors S1P1, 3, 4, and 5, that are associated with distinct receptor isotype-selective activation of Rho GTPases. In human OPCs, FTY720 could induce initial S1P3/5-dependent process retraction associated with an inhibition of differentiation, and subsequent S1P1-dependent process extension. Mature OLGs showed a dose-dependent cyclic modulation of process extension and retraction was observed over time. Both human OPCs and OLGs were rescued by FTY720 under death-promoting environments. Both cell types also demonstrated a cyclic and reciprocal modulation of S1P1 and S1P5 mRNA levels, reflected in the recurring receptor isotype-dependent functional responses over time. Studies using organotypic cerebellar slice cultures demonstrated that FTY720 did not impact myelin integrity under basal conditions, yet accelerated remyelination following lysolecithin-induced demyelination. Both treatment regimens were associated with an extension of OPC and mature OLG processes. / Our observations demonstrate that drug concentrations used to modulate immune function can have differential dose and time-dependent effects on OPCs, OLGs, as well as on myelin and remyelination processes. Our findings indicate the need to monitor the effects of putative immuno-modulatory therapies on myelin-related processes in MS patients.

Whereas first line therapy for chronic obstructive pulmonary disease (COPD) usually includes a short-acting bronchodilator, there are suggestions that these agents may increase the risk of cardiac arrhythmias. In this thesis, we first assessed the risks associated with short-acting beta-agonists (SABA), long-acting beta-agonists (LABA), ipratropium bromide (IB), and methyl xanthines (MX) within a cohort of COPD patients using the health databases of Saskatchewan. In order to confirm these findings and to address some methodological issues we then replicated this analysis within a larger cohort of patients using the health databases of Quebec. / Our first study cohort consisted of 6,018 adults aged 55 and older, newly treated with bronchodilator medications. We found that new users of both IB and LABA increased the risk of arrhythmia (RR 2.39 [95% CI 1.42-4.05] and (RR 4.55 [95% CI 1.43-14.45] respectively). When the cohort was restricted by excluding subjects who had recently either been hospitalised or experienced an exacerbation, the elevated risk associated with the new use of IB persisted (RR 3.65 [95% CI 1.72-7.74]), an effect was detected with new use of MX (RR 5.17 [95% CI 1.38-19.30]), but there was insufficient power to detect an effect associated with the new use of LABA. / Due to both power issues and the limited availability of LABA within the Saskatchewan data, we replicated the analysis in a larger new-user cohort of 76,661 Quebec adults aged 67 and over. This study confirmed our earlier results, with an elevated risk of arrhythmia associated with the new use of both IB and LABA (RR 1.43 [95% CI 1.08-1.88]) and (RR 1.54 [95% CI 1.00-2.36]) respectively, as well as with new use of SABA (RR 1.28 [95% CI 1.02-1.61]). Finally, using marginal structural models, we demonstrated that both exacerbations of COPD as well as minor non-event arrhythmias were moderate time-dependent confounders within this setting. / In conclusion, we found that new use of bronchodilators in COPD, particularly IB and LABA, was associated with an increase in the risk of cardiac arrhythmias. We also demonstrated the method by which the time-dependent confounder status of specific model covariates may be evaluated.

Many epidemiological studies assess the effects of time-dependent exposures, where both the exposure status and its intensity vary over time. The analysis of such studies poses the challenge of modelling the association between complex time-dependent drug exposure and the risk, especially given the uncertainty about the etiological relevance of doses taken in different time periods. / To address this challenge, I developed a flexible method for modelling cumulative effects of time-varying exposures, weighted by recency, represented by time-dependent covariates in the Cox proportional hazards model. The function that assigns weights to doses taken in the past is estimated using cubic regression splines. Models with different number of knots and constraints are estimated. Bootstrap techniques are used to obtain pointwise confidence bands around the weight functions, accounting for both the sampling variation of the regression coefficients, and the uncertainty at the model selection stage, i.e. the additional variance due to a posteriori selection of the number of knots. / To assess the method in simulations, I had to develop and validate a novel algorithm to generate event times conditional on time-dependent covariates and compared it with the algorithms available in the literature. The proposed algorithm extends a previously proposed permutational algorithm to include a rejection sampler. While all the algorithms generated data sets that, once analyzed, provided virtually unbiased estimates with comparable variances, the algorithm that I proposed reduced the computational time by more than 50 per cent relative to alternative methods. I used simulations to systematically investigate the properties of the weighted cumulative dose method. Six different weight functions were considered. Simulations showed that in most situations, the proposed method was able to capture the shape of the true weight functions and to produce estimates of the magnitude of the exposure effect on the risk that were close to those used to generate the data. I finally illustrated the use of the weighted cumulative dose modelling by reassessing the association between the use of selected benzodiazepines and fall-related injuries, using administrative data on a cohort of elderly who initiated their use of benzodiazepines between 1990 and 2004.

Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 113-119.