Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

PhD / The aims of this study were to test the efficacy of immunoglobulin and its Fab and Fc fragment in the treatment of experimental autoimmune neuritis (EAN) in Lewis rats, to investigate which portion of immunoglobulin is operative in the effect of IVIg, and to clarify the possible mechanisms by which immunoglobulin exerts its action in the treatment of rats EAN. EAN was induced by immunization with whole bovine peripheral nerve myelin. The immunized rats were randomized into groups, assessed clinically, electrophysiologically, and histologically, and intravenously injected with normal saline, albumin, human IVIg preparation, purified Fab or Fc fragments. The treatment efficacy was compared between normal saline and albumin groups, albumin and IVIg groups, albumin and Fab groups, albumin and Fc groups, Fab and Fc groups, Fab and IVIg groups, and Fc and IVIg groups. Methods of myelin isolation, antibody purification, and Western blot techniques were also applied. The results revealed that treatment with Fc fragment and IVIg at the onset of signs of disease effectively prevented further progression of disease, shortened disease duration, and facilitating recovery from illness as shown in clinical, electrophysiological and histological parameters. In the study which the efficacy of albumin and IVIg was compared, 5 out of 17 rats (29%) in the albumin group and 12 out of 17 (71%) in the IVIg group completely recovered from the clinical disease by day 30. The animals receiving IVIg treatment exhibited lower clinical scores, less prolongation of S wave latencies, better maintained S wave amplitudes, less reduction of distal motor NCVs, better maintained distal and proximal CMAP amplitudes, and lower histological grades. In the study which the efficacy of albumin, Fab fragment, Fc fragment, and IVIg was compared, 0 out of 8 (0%) in the albumin group, 1 out of 8 (13%) in the Fab group, 4 out of 8 (50%) in the Fc group, and 6 out of 9 (67%) rats in the IgG group completely recovered from the clinical disease by day 30. The animals receiving Fc fragment and IVIg treatment exhibited lower clinical scores, less prominent weight loss, less prolongation of S wave latencies, better maintained S wave amplitudes, less reduction of distal motor NCVs, better maintained distal and proximal CMAP amplitudes, and lower histological grades.

PhD / The aims of this study were to test the efficacy of immunoglobulin and its Fab and Fc fragment in the treatment of experimental autoimmune neuritis (EAN) in Lewis rats, to investigate which portion of immunoglobulin is operative in the effect of IVIg, and to clarify the possible mechanisms by which immunoglobulin exerts its action in the treatment of rats EAN. EAN was induced by immunization with whole bovine peripheral nerve myelin. The immunized rats were randomized into groups, assessed clinically, electrophysiologically, and histologically, and intravenously injected with normal saline, albumin, human IVIg preparation, purified Fab or Fc fragments. The treatment efficacy was compared between normal saline and albumin groups, albumin and IVIg groups, albumin and Fab groups, albumin and Fc groups, Fab and Fc groups, Fab and IVIg groups, and Fc and IVIg groups. Methods of myelin isolation, antibody purification, and Western blot techniques were also applied. The results revealed that treatment with Fc fragment and IVIg at the onset of signs of disease effectively prevented further progression of disease, shortened disease duration, and facilitating recovery from illness as shown in clinical, electrophysiological and histological parameters. In the study which the efficacy of albumin and IVIg was compared, 5 out of 17 rats (29%) in the albumin group and 12 out of 17 (71%) in the IVIg group completely recovered from the clinical disease by day 30. The animals receiving IVIg treatment exhibited lower clinical scores, less prolongation of S wave latencies, better maintained S wave amplitudes, less reduction of distal motor NCVs, better maintained distal and proximal CMAP amplitudes, and lower histological grades. In the study which the efficacy of albumin, Fab fragment, Fc fragment, and IVIg was compared, 0 out of 8 (0%) in the albumin group, 1 out of 8 (13%) in the Fab group, 4 out of 8 (50%) in the Fc group, and 6 out of 9 (67%) rats in the IgG group completely recovered from the clinical disease by day 30. The animals receiving Fc fragment and IVIg treatment exhibited lower clinical scores, less prominent weight loss, less prolongation of S wave latencies, better maintained S wave amplitudes, less reduction of distal motor NCVs, better maintained distal and proximal CMAP amplitudes, and lower histological grades.

The current Coronavirus disease 2019 (COVID-19) outbreak, caused by a virus called severe acute respiratory syndrome 2 (SARS-CoV-2), has become a global health emergency. Recent findings in case studies assert that the transmigration of SARS-CoV-2 to the nervous system implicates severe neurotropic pathologies, including the onset of the rare autoimmune disease called Guillain-Barré syndrome (GBS). GBS is recognized as several disorders characterized by immune-mediated polyradiculoneuropathy, which is typically preceded by an infection or other immune stimulation. The symptoms of GBS initially present as acute symmetrical ascending paresthesia, weakness, and paralysis. This meta-analysis serves to help understand the predisposing factors (such as gender, age, comorbidities) and the clinical features of COVID-19- induced GBS. Most patients affected were 40 years or older and comprised 78.2% of all the cases. Males comprised most of the cases (62.8%; n=76). The patient mortality was 9.1%, intensive care unit (ICU) admission was 46.6%, and the need for mechanical ventilation was 35.8%. It was found that concomitant GBS and COVID-19 patients most often presented with increased cerebral spinal fluid (CSF) protein levels (88%; n=106), hyporeflexia or areflexia (87.6%) (n=106), lower limb strength and sensation impairment (91.7%; n=111), upper limb strength and sensation impairment (83.5; n=101), and somatic sensation impairment (73.6%; n=89). It is postulated that COVID-19 triggers the onset of GBS through a “cytokine release storm” (CRS) that occurs in the early stages of the disease. The same cytokines and chemokines involved in this CRS caused by COVID-19 contribute to the onset of GBS. Predisposing factors which influence this concomitance include male gender and older age. Most of the reported symptoms included abnormal limb functions (including paresthesia, weakness, and paralysis) and absent or weak deep tendon reflexes. The most common variant of GBS observed was AIDP, and the most significant laboratory finding among patients was high CSF protein levels.

Objetivo: Comparar as relações de custo-efetividade de duas terapias, Imunoglubulina Intravenosa (IgIV) e Plasmaferese (PE), no tratamento da Síndrome de Guillain-Barré sob a perspectiva do sistema público (SUS). O objetivo secundário foi avaliar a adesão às recomendações da Comissão de Medicamentos do HCPA Métodos: estudo transversal com análise econômica de pacientes tratados por Síndrome de Guillain-Barré no período de junho de 2003 a junho de 2008 no Hospital de Clínicas de Porto Alegre (HCPA). Foi realizada análise de custo-efetividade do emprego de IgIV e de PE nestes pacientes, pelo método de minimização de custos, considerando-se somente os custos diretos sanitários, fornecidos pelo sistema gerencial da instituição . Foram excluídos os pacientes que usaram outro tipo de tratamento associado ou isolado. Coletaram-se os dados através da revisão dos prontuários. A gravidade da doença na internação foi classificada como: doença leve, quando caminhar foi possível; doença moderada, quando caminhar foi impossível; doença grave, quando os pacientes necessitaram de ventilação assistida. A incapacidade na alta foi estabelecida pela escala de sete pontos de Hughes. A adesão às recomendações da Comissão de Medicamentos do HCPA, objetivo secundário, foi avaliada através da dose e o esquema de prescrição da IgIV. Resultados: Vinte e cinco participantes (2 a 70 anos) foram incluídos no estudo, cinco tratados com PE, empregando-se Albumina Humana como substituto do plasma, e 20 tratados com IgIV. O custo total do tratamento de um paciente com PE foi R$10.603,88 (± 2.978,12) e o de um que recebeu IgIV foi R$ 32.103,00 (± 21.454,24). O custo total da internação foi de R$45.027,14 (± 32.750,45) para os tratados com PE e de R$ 60.844,28 (±48.590,52) para os que receberam IgIV. Em relação ao desfecho clínico principal, melhora na escala de incapacidade de sete pontos, após o tratamento com uma das alternativas escolhida, a mediana dos pacientes que internaram com grau de gravidade 3 e que foram tratados com PE foi igual a dos que receberam IgIV. Em relação à permanência hospitalar, permanência em UTI e dias de Ventilação Mecânica, não houve diferença estatisticamente significativa entre os dois tratamentos. Conclusões: Quando comparados os custos médios das duas opções terapêuticas, uma delas aparece claramente com menor custo. Quando comparados os desfechos, após o emprego de cada opção terapêutica, estes não revelam diferença. Concluímos que, no HCPA, a opção pelo procedimento Plasmaferese é mais custo efetiva do que o emprego da IgIV. / Objectives: To compare the cost-effectiveness of two distinct therapies, Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE) in the treatment of Guillain-Barré Syndrome, concerning the public health care system. Compliance to the guidelines of the Pharmacy and Therapeutics Committee of the Hospital de Clínicas de Porto Alegre was a secondary objective. Methods: A cross-sectional, economical analysis was conducted, including patients treated for GBS in the period from June, 2003 through June, 2008 in Hospital de Clínicas de Porto Alegre (HCPA). The cost-effectiveness of the use of IVIg and PE in such patients was studied through the cost minimization method, considering direct medical costs only (2008 currency), yield by the management of the institution. Patients receiving treatments other than PE or IVIg were excluded. Data were collected by chart reviews. Severity of disease on admittance was classified as follows: mild disease, when the patient was able to walk; moderate disease, when the patient was unable to walk, and severe disease, when assisted ventilation was required. Disability on discharge was established by the 7-point scale of Hughes. Compliance to the guidelines of the Pharmacy and Therapeutics Committee was evaluated through the dose and prescription scheme of IVIg. Results: Twenty-five participants (2 to 70 years of age) were included in the study, 5 were submitted to treatment with PE, using human albumin as replacement for plasma, and 20 were treated with IVIg. The total treatment cost for PE in a single patient was US$6,058.85 (±1,701.78 SD), and the same expense for IVIg was US$18,344.57 (± 12,259.56 SD) (p = 0.035). Total inpatient cost was US$25,729.79 (± 18,714.54 SD) in the PE group, and US$34,768.16 (±27,766.01 SD) (p=0.530) in the IVIg group. The main clinical outcome was improvement in the 7-point disability grade scale. The median of that measure in patients admitted with a severity grade 3 treated either with PE and IVIg was the same. Secondary outcomes, such as in-hospital stay, ICU stay, and number of days on mechanical ventilation revealed no statistically significant difference between treatments. Conclusions: As the mean expenses of both therapeutic options are compared, one clearly stands-out as less onerous. Clinical outcomes, when compared, reveal no statistical difference after each treatment. We concluded that, in HCPA, plasma exchange is more cost-effective than intravenous immunoglobulin.

Objetivo: Comparar as relações de custo-efetividade de duas terapias, Imunoglubulina Intravenosa (IgIV) e Plasmaferese (PE), no tratamento da Síndrome de Guillain-Barré sob a perspectiva do sistema público (SUS). O objetivo secundário foi avaliar a adesão às recomendações da Comissão de Medicamentos do HCPA Métodos: estudo transversal com análise econômica de pacientes tratados por Síndrome de Guillain-Barré no período de junho de 2003 a junho de 2008 no Hospital de Clínicas de Porto Alegre (HCPA). Foi realizada análise de custo-efetividade do emprego de IgIV e de PE nestes pacientes, pelo método de minimização de custos, considerando-se somente os custos diretos sanitários, fornecidos pelo sistema gerencial da instituição . Foram excluídos os pacientes que usaram outro tipo de tratamento associado ou isolado. Coletaram-se os dados através da revisão dos prontuários. A gravidade da doença na internação foi classificada como: doença leve, quando caminhar foi possível; doença moderada, quando caminhar foi impossível; doença grave, quando os pacientes necessitaram de ventilação assistida. A incapacidade na alta foi estabelecida pela escala de sete pontos de Hughes. A adesão às recomendações da Comissão de Medicamentos do HCPA, objetivo secundário, foi avaliada através da dose e o esquema de prescrição da IgIV. Resultados: Vinte e cinco participantes (2 a 70 anos) foram incluídos no estudo, cinco tratados com PE, empregando-se Albumina Humana como substituto do plasma, e 20 tratados com IgIV. O custo total do tratamento de um paciente com PE foi R$10.603,88 (± 2.978,12) e o de um que recebeu IgIV foi R$ 32.103,00 (± 21.454,24). O custo total da internação foi de R$45.027,14 (± 32.750,45) para os tratados com PE e de R$ 60.844,28 (±48.590,52) para os que receberam IgIV. Em relação ao desfecho clínico principal, melhora na escala de incapacidade de sete pontos, após o tratamento com uma das alternativas escolhida, a mediana dos pacientes que internaram com grau de gravidade 3 e que foram tratados com PE foi igual a dos que receberam IgIV. Em relação à permanência hospitalar, permanência em UTI e dias de Ventilação Mecânica, não houve diferença estatisticamente significativa entre os dois tratamentos. Conclusões: Quando comparados os custos médios das duas opções terapêuticas, uma delas aparece claramente com menor custo. Quando comparados os desfechos, após o emprego de cada opção terapêutica, estes não revelam diferença. Concluímos que, no HCPA, a opção pelo procedimento Plasmaferese é mais custo efetiva do que o emprego da IgIV. / Objectives: To compare the cost-effectiveness of two distinct therapies, Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE) in the treatment of Guillain-Barré Syndrome, concerning the public health care system. Compliance to the guidelines of the Pharmacy and Therapeutics Committee of the Hospital de Clínicas de Porto Alegre was a secondary objective. Methods: A cross-sectional, economical analysis was conducted, including patients treated for GBS in the period from June, 2003 through June, 2008 in Hospital de Clínicas de Porto Alegre (HCPA). The cost-effectiveness of the use of IVIg and PE in such patients was studied through the cost minimization method, considering direct medical costs only (2008 currency), yield by the management of the institution. Patients receiving treatments other than PE or IVIg were excluded. Data were collected by chart reviews. Severity of disease on admittance was classified as follows: mild disease, when the patient was able to walk; moderate disease, when the patient was unable to walk, and severe disease, when assisted ventilation was required. Disability on discharge was established by the 7-point scale of Hughes. Compliance to the guidelines of the Pharmacy and Therapeutics Committee was evaluated through the dose and prescription scheme of IVIg. Results: Twenty-five participants (2 to 70 years of age) were included in the study, 5 were submitted to treatment with PE, using human albumin as replacement for plasma, and 20 were treated with IVIg. The total treatment cost for PE in a single patient was US$6,058.85 (±1,701.78 SD), and the same expense for IVIg was US$18,344.57 (± 12,259.56 SD) (p = 0.035). Total inpatient cost was US$25,729.79 (± 18,714.54 SD) in the PE group, and US$34,768.16 (±27,766.01 SD) (p=0.530) in the IVIg group. The main clinical outcome was improvement in the 7-point disability grade scale. The median of that measure in patients admitted with a severity grade 3 treated either with PE and IVIg was the same. Secondary outcomes, such as in-hospital stay, ICU stay, and number of days on mechanical ventilation revealed no statistically significant difference between treatments. Conclusions: As the mean expenses of both therapeutic options are compared, one clearly stands-out as less onerous. Clinical outcomes, when compared, reveal no statistical difference after each treatment. We concluded that, in HCPA, plasma exchange is more cost-effective than intravenous immunoglobulin.

Objetivo: Comparar as relações de custo-efetividade de duas terapias, Imunoglubulina Intravenosa (IgIV) e Plasmaferese (PE), no tratamento da Síndrome de Guillain-Barré sob a perspectiva do sistema público (SUS). O objetivo secundário foi avaliar a adesão às recomendações da Comissão de Medicamentos do HCPA Métodos: estudo transversal com análise econômica de pacientes tratados por Síndrome de Guillain-Barré no período de junho de 2003 a junho de 2008 no Hospital de Clínicas de Porto Alegre (HCPA). Foi realizada análise de custo-efetividade do emprego de IgIV e de PE nestes pacientes, pelo método de minimização de custos, considerando-se somente os custos diretos sanitários, fornecidos pelo sistema gerencial da instituição . Foram excluídos os pacientes que usaram outro tipo de tratamento associado ou isolado. Coletaram-se os dados através da revisão dos prontuários. A gravidade da doença na internação foi classificada como: doença leve, quando caminhar foi possível; doença moderada, quando caminhar foi impossível; doença grave, quando os pacientes necessitaram de ventilação assistida. A incapacidade na alta foi estabelecida pela escala de sete pontos de Hughes. A adesão às recomendações da Comissão de Medicamentos do HCPA, objetivo secundário, foi avaliada através da dose e o esquema de prescrição da IgIV. Resultados: Vinte e cinco participantes (2 a 70 anos) foram incluídos no estudo, cinco tratados com PE, empregando-se Albumina Humana como substituto do plasma, e 20 tratados com IgIV. O custo total do tratamento de um paciente com PE foi R$10.603,88 (± 2.978,12) e o de um que recebeu IgIV foi R$ 32.103,00 (± 21.454,24). O custo total da internação foi de R$45.027,14 (± 32.750,45) para os tratados com PE e de R$ 60.844,28 (±48.590,52) para os que receberam IgIV. Em relação ao desfecho clínico principal, melhora na escala de incapacidade de sete pontos, após o tratamento com uma das alternativas escolhida, a mediana dos pacientes que internaram com grau de gravidade 3 e que foram tratados com PE foi igual a dos que receberam IgIV. Em relação à permanência hospitalar, permanência em UTI e dias de Ventilação Mecânica, não houve diferença estatisticamente significativa entre os dois tratamentos. Conclusões: Quando comparados os custos médios das duas opções terapêuticas, uma delas aparece claramente com menor custo. Quando comparados os desfechos, após o emprego de cada opção terapêutica, estes não revelam diferença. Concluímos que, no HCPA, a opção pelo procedimento Plasmaferese é mais custo efetiva do que o emprego da IgIV. / Objectives: To compare the cost-effectiveness of two distinct therapies, Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE) in the treatment of Guillain-Barré Syndrome, concerning the public health care system. Compliance to the guidelines of the Pharmacy and Therapeutics Committee of the Hospital de Clínicas de Porto Alegre was a secondary objective. Methods: A cross-sectional, economical analysis was conducted, including patients treated for GBS in the period from June, 2003 through June, 2008 in Hospital de Clínicas de Porto Alegre (HCPA). The cost-effectiveness of the use of IVIg and PE in such patients was studied through the cost minimization method, considering direct medical costs only (2008 currency), yield by the management of the institution. Patients receiving treatments other than PE or IVIg were excluded. Data were collected by chart reviews. Severity of disease on admittance was classified as follows: mild disease, when the patient was able to walk; moderate disease, when the patient was unable to walk, and severe disease, when assisted ventilation was required. Disability on discharge was established by the 7-point scale of Hughes. Compliance to the guidelines of the Pharmacy and Therapeutics Committee was evaluated through the dose and prescription scheme of IVIg. Results: Twenty-five participants (2 to 70 years of age) were included in the study, 5 were submitted to treatment with PE, using human albumin as replacement for plasma, and 20 were treated with IVIg. The total treatment cost for PE in a single patient was US$6,058.85 (±1,701.78 SD), and the same expense for IVIg was US$18,344.57 (± 12,259.56 SD) (p = 0.035). Total inpatient cost was US$25,729.79 (± 18,714.54 SD) in the PE group, and US$34,768.16 (±27,766.01 SD) (p=0.530) in the IVIg group. The main clinical outcome was improvement in the 7-point disability grade scale. The median of that measure in patients admitted with a severity grade 3 treated either with PE and IVIg was the same. Secondary outcomes, such as in-hospital stay, ICU stay, and number of days on mechanical ventilation revealed no statistically significant difference between treatments. Conclusions: As the mean expenses of both therapeutic options are compared, one clearly stands-out as less onerous. Clinical outcomes, when compared, reveal no statistical difference after each treatment. We concluded that, in HCPA, plasma exchange is more cost-effective than intravenous immunoglobulin.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.

Orientador: Leonilda Maria Barbosa dos Santos / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-07T03:41:32Z (GMT). No. of bitstreams: 1 Castro_FabianoRobertode_M.pdf: 943470 bytes, checksum: 271c21deb3b25015f9737d33adf49814 (MD5) Previous issue date: 2006 / Resumo: A Síndrome de Guillain-Barré (SGB) é uma doença desmielinizante do sistema nervoso periférico (SNP). Baseado principalmente nas similaridades clínicas e histopatológicas a Neurite Experimental Auto-imune (EAN) tem sido extensivamente usada como modelo de estudo da SGB. A EAN é uma doença auto-imune, que pode ser experimentalmente induzida em ratos geneticamente suscetíveis através da imunização com os componentes da mielina de nervos periféricos tais como os peptídeos P0 e P2 , ou ainda por transferência adotiva de lifócitos T CD4+ do tipo Th1. Diferentes tentativas de tratamentos para a SGB têm sido estudadas, dentre elas pode-se citar a plasmaferese, o uso de anticorpos monoclonais, administração de corticóides e a imunossupressão global através da administração de intérferon ß. A utilização de venenos totais de serpentes, ou frações deles, já demonstrou bons resultados na tentativa de tratamento de alguns modelos de doenças auto-imunes como a diabetes auto-imune insulino dependente, lúpus e encefalomielite experimental auto-imune (EAE). No presente trabalho foi estudado o efeito de uma fração do veneno da cascavel sul americana Crotalus durissus terrificus (Cdt), a crotapotina, no modelo de EAN. São apresentadas evidências de que tanto a administração intraperitoneal (IP) como a oral de crotapotina reduz significativamente a gravidade da EAN induzida em ratos Lewis, associada a um significativo declínio na resposta proliferativa das células T neuritogênicas, assim como diminuição de infiltrados de células mononucleares no nervo ciático dos os animais / Abstract: Biomedical research in which venom components are being investigated for their potential as novel therapeutic agents has emerged as an interesting option. Crotapotin which is a fraction of the venom of the rattlesnake Crotalus durissus terrificus, has been described as an antinflammatory that acts on the innate arm of the immune response. Here we have demonstrated that intraperitoneal (IP), as well as oral administration of crotapotin significantly reduces the severity of experimental autoimmune neuritis (EAN), an experimental model for Guillain-Barré Syndrome. The reduction of the severity of the disease is associated with a reduction in the mononuclear cells infiltrating in the sciatic nerve and a significant decrease in the lymphocyte proliferative response to neuritogenic peptide / Mestrado / Ciencias Basicas / Mestre em Clinica Medica