Amyloid-beta immunotherapy: the hope for Alzheimer disease? / Inmunoterapia beta-amiloide: ¿la esperanza para la enfermedad de Alzheimer?

Abstract Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

Resumen La enfermedad de Alzheimer (EA) es la forma más frecuente de demencia de inicio en el adulto, caracterizada por un deterioro progresivo en la cognición y la memoria. No hay cura para la enfermedad y los tratamientos actuales son sólo sintomáticos. El descubrimiento de fármacos es un proceso costoso y que consume mucho tiempo; en la última década no se han encontrado nuevos fármacos para la EA a pesar de los esfuerzos de la comunidad científica y las compañías farmacéuticas. La inmunoterapia contra Aβ es uno de los enfoques más prometedores para modificar el curso de la EA. Esta estrategia terapéutica utiliza péptidos sintéticos o anticuerpos monoclonales (mAb) para disminuir la carga de Aβ en el cerebro y retardar la progresión de la enfermedad. Por lo tanto, este artículo discutirá los principales aspectos de la neuropatogénesis de la EA, el tratamiento farmacológico clásico, así como la inmunización activa y pasiva describiendo los prototipos de fármacos evaluados en diferentes ensayos clínicos.

Improvement of erectile dysfunction by the active pepide from urechis unicinctus by high temperature/pressure and ultra - wave assisted lysis in streptozotocin induced diabetic rats

ABSTRACT Introduction: We investigate the effect of active peptide from Urechis unicinctus (UU) by high temperature/pressure and ultra-wave assisted lysis on erectile dysfunction in streptozotocin-induced diabetic rats. Materials and Methods: Forty 12-week-old Sprague-Dawley rats were used in this study. Diabetes was induced by a one-time intraperitoneal injection of streptozotocin (50mg/kg). One week later, the diabetic rats were randomly divided into four groups: normal control, untreated diabetes control, and groups treated with 100 or 500mg/kg/d UU peptide. Rats were fed with UU peptide by intragastric administration for 8 weeks. After 8 weeks, penile hemodynamic function was evaluated in all groups by measuring the intracavernosal pressure after electrostimulating the cavernous nerve. Nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) activities were measured and endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) protein expression was determined by Western blot. Results: Maximum intracavernosal pressure in diabetic control rats decreased significantly compared to normal control rats, and was increased significantly compared to untreated diabetic rats after UU peptide supplementation. Treatment with the higher dose of UU peptide significantly increased the NO and cGMP levels compared with the diabetic control group. Decreased activity and expression eNOS and nNOS were found in the diabetic rats compared with the normal control group. Decreased eNOS and nNOS in diabetic rats were improved by UU peptide administration. Conclusions: Active peptide from UU ameliorates erectile function in a streptozotocin induced diabetic rat model of erectile dysfunction.

Gene mutations of platelet glycoproteins and response to tirofiban in acute coronary syndrome / Mutações gênicas das glicoproteínas plaquetárias e resposta ao tirofiban na síndrome coronariana aguda

CONTEXT AND OBJECTIVES: Glycoprotein inhibitors (abciximab, eptifibatide and tirofiban) are used in patients with unstable angina and non-ST-segment elevation myocardial infarction before percutaneous coronary intervention. Of these, tirofiban is the least effective. We hypothesized that the response to tirofiban might be associated with glycoprotein gene mutations. DESIGN AND SETTING: Prospective study at Emergency Unit, Heart Institute (InCor), University of São Paulo. METHOD: Intrahospital evolution and platelet aggregation in response to tirofiban were analyzed in relation to four glycoprotein mutations in 50 patients indicated for percutaneous coronary intervention: 17 (34%) with unstable angina and 33 (66%) with non-ST-segment elevation myocardial infarction. Platelet aggregation was analyzed using the Born method. Blood samples were obtained before and one hour after tirofiban infusion. Glycoproteins Ia (807C/T ), Ib (Thr/Met) , IIb (Ile/Ser ) and IIIa (PIA ) were the mutations selected. RESULTS: Hypertension, dyslipidemia, diabetes, smoking, previous coronary artery disease and stroke were similar between the groups. Mutant glycoprotein IIIa genotypes had lower platelet aggregation before tirofiban administration than that of the wild genotype (41.0% ± 22.1% versus 55.9% ± 20.8%; P = 0.035). Mutant glycoprotein IIIa genotypes correlated moderately with lower platelet inhibition (r = -0.31; P = 0.030). After tirofiban administration, platelet glycoprotein Ia, Ib, IIb and IIIa mutations did not influence the degree of inhibition of platelet aggregation or intrahospital mortality. CONCLUSIONS: Mutations of glycoproteins Ia, Ib, IIb and IIIa did not influence platelet aggregation in response to tirofiban in patients with unstable angina and non-ST-segment elevation myocardial infarction.

RESUMO CONTEXTO E OBJETIVOS: Inibidores da glicoproteína (abciximab, eptifibatide, tirofiban) são utilizados em pacientes com angina instável e infarto do miocárdio sem elevação do segmento ST (IAMSSST) antes da intervenção coronária percutânea. Dentre eles, o tirofiban é o menos eficaz. Nossa hipótese é que a resposta ao tirofiban possa estar associada a mutações no gene da glicoproteína. DESENHO E LOCAL: Estudo prospectivo na Unidade de Emergência do Instituto do Coração (InCor), Universidade de São Paulo (USP). MÉTODOS: Foram analisadas a evolução intra-hospitalar e agregabilidade plaquetária em resposta ao tirofiban de 4 mutações da glicoproteína em 50 pacientes com indicação para intervenção coronária percutânea, 17 (34%) com angina instável e 33 (66%) com IAMSSST. A agregação plaquetária foi analisada pelo método de Born. Amostras de sangue foram obtidas antes e uma hora após infusão do tirofiban. As glicoproteínas Ia (807C/T ), Ib (Thr/Met ), IIb (Ile/Ser ) e IIIa (PIA ) foram as mutações selecionadas. RESULTADOS: Hipertensão, dislipidemia, diabetes, tabagismo, doença coronariana e acidente vascular cerebral prévios foram semelhantes entre os grupos. Observou-se menor agregabilidade plaquetária dos genótipos mutantes da glicoproteína IIIa antes da administração de tirofiban do genótipo selvagem (41% ± 22% versus 56% ± 21%; P = 0,035). Genótipos mutantes da glicoproteína IIIa correlacionaram-se moderadamente com menor inibição plaquetária (r = -0,31; P = 0,030). Após a administração tirofiban, as mutações das glicoproteínas Ia, Ib, IIb, e IIIa não influenciaram o grau de inibição da agregação plaquetária e mortalidade intra-hospitalar. CONCLUSÕES: Mutações das glicoproteínas Ia, Ib, IIb e IIIa não influenciaram a agregação plaquetária em resposta ao tirofiban nos pacientes com angina instável e IAMSSST.

Pesticide exposure and health conditions of terrestrial pesticide applicators in Córdoba Province, Argentina / Exposición a plaguicidas y condiciones de salud de agroaplicadores terrestres de la Provincia de Córdoba, Argentina / Exposição aos agrotóxicos e condições de saúde dos aplicadores de pesticidas da Província de Córdoba, Argentina

Agricultural workers represent a population that is highly vulnerable to the toxic effects of pesticide exposure. This cross sectional study aimed to describe the health conditions of terrestrial pesticide applicators in Córdoba Province, Argentina, their work practices and socio-demographic characteristics, by means of a standardized self-administered questionnaire (n = 880). A descriptive analysis reported a high prevalence of occasional or frequent symptoms: 47.4% had symptoms of irritation, 35.5% fatigue, 40.4% headache and 27.6% nervousness or depression. Using logistic regression models, risk and protective factors were found for symptoms of irritation, medical consultation and hospitalization. Among the occupational exposure variables, marital status, length of time in the job, low level of protection with regard to the use of personal protective equipment, combined use of different pesticides and the application of the insecticide endosulfan, were associated with a higher frequency of reported symptoms and higher consultation rates and hospitalization.

Los trabajadores agrícolas son una población altamente vulnerable a los efectos tóxicos de la exposición a plaguicidas. Con el objetivo de describir las condiciones de salud de agroaplicadores terrestres de plaguicidas de la Provincia de Córdoba, Argentina, sus prácticas laborales y características sociodemográficas, se realizó un estudio transversal, mediante cuestionario (n = 880). Un análisis descriptivo reportó alta prevalencia de sintomatología ocasional o frecuente: 47,4% síntomas irritativos, 35,5% cansancio, 40,4% cefalea y 27,6% ansiedad o depresión. Mediante modelos logísticos se detectaron factores protectores y de riesgo que explican la presencia de síntomas irritativos, la consulta médica y la hospitalización. El estado civil, la antigüedad en la tarea, el nivel de protección considerando uso de equipo de protección personal, la exposición múltiple a plaguicidas y la aplicación del insecticida endosulfán, se asociaron a mayor frecuencia de reporte de síntomas, consultas médicas y hospitalizaciones por causas relacionadas con la exposición a plaguicidas.

Os trabalhadores agrícolas são uma população altamente vulnerável aos efeitos tóxicos da exposição a pesticidas. Este estudo transversal teve o objetivo de descrever as condições de saúde de aplicadores terrestres de pesticidas da Província de Córdoba, Argentina, suas práticas de trabalho e características sociodemográficas, por meio de um questionário padronizado autoadministrado (n = 880). A análise descritiva relatou alta prevalência de sintomas ocasionais ou frequentes: 47,4% sintomas irritativos, 35,5% fadiga, 40,4% dor de cabeça e 27,6% ansiedade ou depressão. Mediante modelos logísticos foram detectados os fatores protetores e do risco que explicam a presença de sintomas irritativos, consulta médica e hospitalização. O estado civil, anos de trabalho, o nível de proteção considerando o uso de equipamentos de proteção individual, a exposição a vários pesticidas e aplicação do inseticida endosulfan, foram associados com maior frequência de sintomas, consultas médicas e hospitalização por causas relacionadas à exposição ao agrotóxico.

Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease / Exenatide melhora o diabetes tipo 2 de ocorrência concomitante com doença hepática gordurosa não alcoólica

OBJECTIVE: To investigate the effects of exenatide on blood glucose, body weight and hepatic enzymes in patients with type 2 diabetes mellitus (T2DM) and concomitant non-alcoholic fatty liver disease (NAFLD). SUBJECTS AND METHODS: One hundred and seventeen patients with T2DM and NAFLD were randomly divided into exenatide group and metformin group. Patients were treated with exenatide and metformin, respectively, for 12 weeks. RESULTS: After 12 weeks of treatment, body weight, body mass index (BMI), waist-to-hip ratio, HbA1c, FPG, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were significantly reduced, and the AST/ALT ratio and adiponectin were markedly increased in both groups. BMI, waist-to-hip ratio, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were markedly lower, and AST/ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group. CONCLUSION: Compared with metformin, exenatide is better to control blood glucose, reduces body weight and improves hepatic enzymes, attenuating NAFLD in patients with T2DM concomitant with NAFLD.

OBJETIVO: Investigar os efeitos do exenatide sobre a glicose sérica, peso corporal e enzimas hepáticas em pacientes com diabetes melito tipo 2 (T2DM) e doença hepática gordurosa não alcoólica (DHGNA). SUJEITOS E MÉTODOS: Um total de 117 pacientes com T2DM e DHGNA foi aleatoriamente separado em dois grupos, um tratado com exenatide e um tratado com metformina. Os pacientes foram tratados por 12 semanas. RESULTADOS: Após 12 semanas de tratamento, o peso corporal, índice de massa corporal (IMC), relação cintura-quadril, HbA1c, FPG, glicose pós-prandial, ALT, AST, γ-GT e proteína C-reativa foram significativamente reduzidos, e a relação AST/ALT e a adiponectina aumentaram marcadamente nos dois grupos. O IMC, relação cintura-quadril, glicose pós-prandial, ALT, AST, γ-GT e proteína C-reativa foram marcadamente menores, e a relação AST/ALT e a adiponectina foram dramaticamente mais altas no grupo tratado com exenatide do que no grupo tratado com metformina. CONCLUSÃO: Comparado com a metformina, o exenatide controla melhor a glicose sérica, reduz o peso corporal e melhora as enzimas hepáticas, atenuando a DHGNA em pacientes com T2DM de ocorrência concomitante com a DHGNA.

Clinical response to interferon beta and glatiramer acetate in multiple sclerosis patients: a Brazilian cohort / Resposta terapêutica ao interferon beta e ao acetato de glatiramer em pacientes com esclerose múltipla: estudo de uma coorte brasileira

INTRODUCTION: Many patients with multiple sclerosis (MS) are currently receiving treatment with interferon beta (IFNb) and glatiramer acetate (GA). Identifying nonresponders patients is important to define therapy strategies. Several criteria for treatment response to IFNb and GA have been proposed. OBJECTIVE: It was to investigate the response to treatment with IFNb-1a, IFNb-1b and GA among relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: We analyzed treatment response to IFNb and GA in ninety-one RRMS patients followed for at least one year. Clinical response was established by clinical criteria based on relapses, disability progression or both. RESULTS: We observed a proportion of nonresponders, ranging from 3.3 to 42.9%, depending on the stringency of the criteria used. CONCLUSIONS: Our sample of Brazilian patients with MS has similarities when compared to other studies and there was no statistically significant difference regarding age, gender, ethnicity or disease duration between responders and nonresponders.

INTRODUÇÃO: Muitos pacientes com esclerose múltipla (EM) estão atualmente recebendo tratamento com interferon beta (IFNb) e acetato de glatiramer (AG). Identificar pacientes não respondedores é importante para definir estratégias terapêuticas. Foram propostos vários critérios para definir a resposta ao tratamento com IFNb e AG. OBJETIVO: Foi investigar a resposta ao tratamento com IFNb-1a, IFNb-1b e AG entre pacientes com esclerose múltipla remitente-recorrente (EMRR). MÉTODOS: Analisamos a resposta ao tratamento com IFNb e AG em 91 pacientes com EMRR acompanhados por um período de pelo menos um ano. A resposta clínica foi estabelecida por critérios baseados em surtos, progressão da incapacidade ou ambos. RESULTADOS: Observamos uma proporção de não respondedores que variou de 3,3 a 42,9%, dependendo do rigor do critério utilizado. CONCLUSÕES: Nossa amostra de pacientes brasileiros com EM tem semelhanças quando comparada a outros estudos e não apresentou diferença estatisticamente significativa entre respondedores e não respondedores com relação à idade, sexo, etnia ou duração da doença.

Avaliação do efeito de implantes subgengivais do polímero ELVAX com equistatina. Estudo microscópico em dentes de ratos extraídos e reimplantados / Evaluation of the effect of subgingival implants of polymer ELVAX with echistatin: microscopic study on rats' extracted and reimplanted teeth

O presente trabalho investigou microscopicamente o efeito da equistatina sobre o processo reabsortivo de dentes incisivos superiores de ratos, extraídos e reimplantados. Foram utilizados 42 animais, divididos em grupos com e sem equistatina. Os tempos extra-alveolares dos dentes foram de 30 e 60 minutos e os períodos experimentais pós-cirúrgicos foram 15, 60 e 90 dias. Os espécimes obtidos foram processados e corados em H.E. para observar os processos biológicos presentes. Os eventos microscópicos foram avaliados por dois examinadores, de modo quantitativo histomorfométrico e descritivo, de acordo com o tipo de infiltrado e intensidade da reação inflamatória; com o tipo, extensão e localização de reabsorção dentária; e presença de anquilose alveolodentária. O nível de concordância entre examinadores, determinado pelo índice Kappa, revelou-se quase perfeito para todas as variáveis avaliadas. A comparação entre os grupos testes e controle para as variáveis apresentadas foi feita por meio do teste Mann-Whitney e mostrou não haver diferença estatística entre a administração de equistatina e tempo extra-alveolar em relação à intensidade inflamatória nas diferentes porções radiculares. Quanto ao tipo de reabsorção estabelecida, notou-se que a presença de reabsorção inflamatória foi significativamente maior (p<0,05) no grupo controle nos tempos de 30 e 60 minutos no período pós-cirúrgico de 15 dias. A anquilose alveolodentária também esteve significativamente mais presente no grupo tratado com equistatina com 30 minutos extra-alveolar e 15 dias de período experimental. Houve, ainda, mais anquilose alveolodentária no grupo controle de 60 minutos extra-alveolar, com o período experimental de 60 dias. No período experimental de 90 dias todos os espécimes avaliados apresentaram processos reabsortivos inflamatórios e ausência de anquilose alveolodentária. O teste Kruskall-Wallis avaliou as diferenças significantes entre grupos, em relação à intensidade inflamatória por...

This study aimed to microscopically investigate the effect on the dental resorptive process of subgingival implants of ELVAX polymer with peptide echistatin in reimplantation of upper incisors in rats. For this purpose, 42 animals were used and divided into groups with and without echistatin. Extra alveolar socket period was 30 and 60 minutes and post-surgical experimental periods were 15, 60 and 90 days. Specimens were processed and stained with H.E. to observe the biological processes in the area. The microscopic events were evaluated by two examiners. Quantitative histomorphometric and descriptive evaluation of the events were performed according to the presence, type and location of the inflammatory response, incidence of resorptions or dental ankylosis. The level of agreement between examiners determined by the Kappa index, proved to be almost perfect for all variables. The comparison between the experimental and control groups for the variables presented was performed using the Mann-Whitney test and showed no statistical difference between the administration of echistatin and extra alveolar socket period relative to the inflammatory intensity in different portions of the root. Regarding the type of resorption established, it was noted that the presence of inflammatory resorption was significantly higher (p<0.05) in the control group on days 30 and 60 minutes in the postoperative period of 15 days. Dental ankylosis was also significantly more prevalent in the group treated with echistatin in extra alveolar socket period of 30 minutes and 15-day trial period. There was even more dental ankylosis in control group with 60 minutes of extra alveolar socket, with the trial period of 60 days. In the trial period of 90 days all specimens studied featured inflammatory resorptives processes and absence of dental ankylosis. The Kruskal-Wallis test assessed significant differences between groups in relation to the intensity of...

Avaliação do efeito de implantes subgengivais do polímero ELVAX com equistatina. Estudo microscópico em dentes de ratos extraídos e reimplantados / Evaluation of the effect of subgingival implants of polymer ELVAX with echistatin: microscopic study on rats' extracted and reimplanted teeth

O presente trabalho investigou microscopicamente o efeito da equistatina sobre o processo reabsortivo de dentes incisivos superiores de ratos, extraídos e reimplantados. Foram utilizados 42 animais, divididos em grupos com e sem equistatina. Os tempos extra-alveolares dos dentes foram de 30 e 60 minutos e os períodos experimentais pós-cirúrgicos foram 15, 60 e 90 dias. Os espécimes obtidos foram processados e corados em H.E. para observar os processos biológicos presentes. Os eventos microscópicos foram avaliados por dois examinadores, de modo quantitativo histomorfométrico e descritivo, de acordo com o tipo de infiltrado e intensidade da reação inflamatória; com o tipo, extensão e localização de reabsorção dentária; e presença de anquilose alveolodentária. O nível de concordância entre examinadores, determinado pelo índice Kappa, revelou-se quase perfeito para todas as variáveis avaliadas. A comparação entre os grupos testes e controle para as variáveis apresentadas foi feita por meio do teste Mann-Whitney e mostrou não haver diferença estatística entre a administração de equistatina e tempo extra-alveolar em relação à intensidade inflamatória nas diferentes porções radiculares. Quanto ao tipo de reabsorção estabelecida, notou-se que a presença de reabsorção inflamatória foi significativamente maior (p<0,05) no grupo controle nos tempos de 30 e 60 minutos no período pós-cirúrgico de 15 dias. A anquilose alveolodentária também esteve significativamente mais presente no grupo tratado com equistatina com 30 minutos extra-alveolar e 15 dias de período experimental. Houve, ainda, mais anquilose alveolodentária no grupo controle de 60 minutos extra-alveolar, com o período experimental de 60 dias. No período experimental de 90 dias todos os espécimes avaliados apresentaram processos reabsortivos inflamatórios e ausência de anquilose alveolodentária. O teste Kruskall-Wallis avaliou as diferenças significantes entre grupos, em relação à intensidade inflamatória por...

This study aimed to microscopically investigate the effect on the dental resorptive process of subgingival implants of ELVAX polymer with peptide echistatin in reimplantation of upper incisors in rats. For this purpose, 42 animals were used and divided into groups with and without echistatin. Extra alveolar socket period was 30 and 60 minutes and post-surgical experimental periods were 15, 60 and 90 days. Specimens were processed and stained with H.E. to observe the biological processes in the area. The microscopic events were evaluated by two examiners. Quantitative histomorphometric and descriptive evaluation of the events were performed according to the presence, type and location of the inflammatory response, incidence of resorptions or dental ankylosis. The level of agreement between examiners determined by the Kappa index, proved to be almost perfect for all variables. The comparison between the experimental and control groups for the variables presented was performed using the Mann-Whitney test and showed no statistical difference between the administration of echistatin and extra alveolar socket period relative to the inflammatory intensity in different portions of the root. Regarding the type of resorption established, it was noted that the presence of inflammatory resorption was significantly higher (p<0.05) in the control group on days 30 and 60 minutes in the postoperative period of 15 days. Dental ankylosis was also significantly more prevalent in the group treated with echistatin in extra alveolar socket period of 30 minutes and 15-day trial period. There was even more dental ankylosis in control group with 60 minutes of extra alveolar socket, with the trial period of 60 days. In the trial period of 90 days all specimens studied featured inflammatory resorptives processes and absence of dental ankylosis. The Kruskal-Wallis test assessed significant differences between groups in relation to the intensity of...

Exendin-4 improves resistance to Listeria monocytogenes infection in diabetic db/db mice

The incidence of diabetes mellitus is increasing among companion animals. This disease has similar characteristics in both humans and animals. Diabetes is frequently identified as an independent risk factor for infections associated with increased mortality. In the present study, homozygous diabetic (db/db) mice were infected with Listeria (L.) monocytogenes and then treated with the anti-diabetic drug exendin-4, a glucagon-like peptide 1 analogue. In aged db/db mice, decreased CD11b+ macrophage populations with higher lipid content and lower phagocytic activity were observed. Exendin-4 lowered high lipid levels and enhanced phagocytosis in macrophages from db/db mice infected with L. monocytogenes. Exendin-4 also ameliorated obesity and hyperglycemia, and improved ex vivo bacteria clearance by macrophages in the animals. Liver histology examined during L. monocytogenes infection indicated that abscess formation was much milder in exendin-4-treated db/db mice than in the control animals. Moreover, mechanistic studies demonstrated that expression of ATP binding cassette transporter 1, a sterol transporter, was higher in macrophages isolated from the exendin-4-treated db/db mice. Overall, our results suggest that exendin-4 decreases the risk of infection in diabetic animals by modifying the interaction between intracellular lipids and phagocytic macrophages.

Classical immunomodulatory therapy in multiple sclerosis: how it acts, how it works / Terapêutica imunomoduladora clássica na esclerose múltipla: como atua, como funciona

Interferon beta (IFNβ) and glatiramer acetate (GA) were the first immunomodulators approved to the treatment of relapsing-remitting multiple sclerosis (MS) and clinically isolated syndromes. Despite the enlargement of the therapeutic armamentarium, IFNβ and GA remain the most widely drugs and the therapeutic mainstay of MS. OBJECTIVE: To review the mechanisms of action of IFNβ and GA and main clinical results in MS. RESULTS: IFNβ modulates T and B-cell activity and has effects on the blood-brain barrier. The well proved mechanism of GA is an immune deviation by inducing expression of anti-inflammatory cytokines. Some authors favor the neuroprotective role of both molecules. Clinical trials showed a 30 percent reduction on the annualized relapse rate and of T2 lesions on magnetic resonance. CONCLUSION: Although the precise mechanisms how IFNβ and GA achieve their therapeutics effects remain unclear, these drugs have recognized beneficial effects and possess good safety and tolerability profiles. The large clinical experience in treating MS patients with these drugs along almost two decades deserves to be emphasized, at a time where the appearance of drugs with more selective mechanisms of action, but potentially less safer, pave the way to a better selection of the most appropriate individualized treatment.

O interferão beta (IFNβ) e o acetato de glatirâmero (GA) foram os primeiros imunomoduladores aprovados para o tratamento da esclerose múltipla (EM) surto-remissão e doentes com síndromes clinicamente isoladas. Apesar do alargamento do armamentário terapêutico, o IFNβ e o GA continuam a ser os medicamentos mais usados na EM. OBJETIVO: Rever os mecanismos de acção do IFNβ e do GA e os principais resultados na clínica. RESULTADOS: O IFNβ modula a actividade das células T e B e tem efeitos sobre a barreira hemato-encefálica. O mecanismo melhor comprovado do GA é o desvio imune através da indução da expressão de citocinas. Alguns autores favorecem ainda um papel neuroprotetor para ambos. Os ensaios clínicos mostraram diminuição da taxa anualizada de surtos de 30 por cento e das lesões em T2 na ressonância magnética. CONCLUSÃO: Embora os mecanismos pelos quais o IFNβ e o GA atingem os seus efeitos terapêuticos continuem a ser pouco claros, estes fármacos possuem efeitos benéficos reconhecidos e bons perfis de segurança e tolerabilidade. A grande experiência clínica no tratamento da EM com estes fármacos ao longo de quase duas décadas merece ser destacada, numa altura em que o aparecimento de novos fármacos com mecanismos de acção mais seletivos, mas potencialmente menos seguros, possibilitarão melhor seleção e individualização do tratamento.

Programa piloto para pacientes beneficiarios de Fonasa, que padecen esclerosis multiple: tratamiento con inmunomoduladores en el sistema público de salud de Chile: Informe del primer año, 10 de julio 2008-30 de Junio 2009 / Pilot national treatment program for multiple sclerosis patients belonging to the public health care system of Chile (FONASA) with immunomodulating disease-modifying therapies: first year report from July 2008 to June 2009

Multiple Sclerosis (MS) is a chronic disease of the central nervous system. It is manifested in the young adult who presents at the beginning alternation between transient neurological dysfunction and normality, followed by a progressive level of disability. MS affects the quality of life in the young adults in their full productive and creative age limiting not only in their personal lives but also affects to the whole society in terms of "dreams and life projects". Besides, this illness also influences the family group who has to assume progressively the help and care for the patient. In healthcare aspect MS implies intensive and progressive resources. In Chile, although we don't have epidemiological studies that indicate which is the MS prevalence it exist a projection that states 14 per 100.000 inhabitants. Considering a population of 16.5 million of inhabitants our expectative of patients with MS is of 2310 cases in our country. The MS immunomodulating injectable disease-modifying therapies are of high cost and were not available in a regular way in the state health care system of Chile (FONASA) that attends the 70 percent of the population; the other 30 percent has different private health insurances. In 2008 the ministry of health decided to initiate and pilot (exploratory) program which had a great meaning and impact concerning to start offering immunomodulating therapies to relapsing remitting MS, for patients belonging to FONASA system. The pilot program was thought with a double mission, on the one hand to achieve that a very limited group of MS patients belonging to FONASA system (80 cases) from all over the country had access to immunomodulating injectable disease-modifying therapies of high cost in a regular way. The second objective was to obtain clinical and epidemiological information which let us to evaluate the clinical and administrative obstacles generated by the incorporation of this treatment in the public health...

Introducción El presente documento corresponde al informe del primer año de trabajo operativo del "Programa piloto de tratamiento con inmunomoduladores, para pacientes beneficiarios de Fonasa1, que padecen esclerosis múltiple (EM)", elaborado por el equipo del centro de referencia nacional, para este programa, con sede en el Servicio de Neurología del Complejo Asistencial Barros Luco (CABL) del SSMS2. Dado su origen no incluye antecedentes del proceso de gestión ni toma de decisiones del nivel Minsal3 o Fonasa. Este trabajo, no es ni aspira ser: un ensayo clínico, una guía de práctica clínica, una revisión bibliográfica, ni una puesta al día sobre el tratamiento de la Esclerosis Múltiple (EM), es simplemente el informe anual de un centro de referencia, para una tarea específica, a la autoridad ministerial competente. El informe incluye algunos antecedentes generales y referencias presentadas como "notas al pie", sólo para contextualizar la información presentada4. La EM es una enfermedad crónica del SNC, de origen incierto, inmunológicamente mediada, bien definida en sus características inmunopatogénicas, patológicas, imagenológicas y clínicas. Se expresa en el adulto joven, quien presenta inicialmente alternancia entre disfunción neurológica transitoria y normalidad y cuya progresión determina múltiples efectos discapacitantes. La EM afecta la calidad de vida de adultos jóvenes en plena edad productiva y creativa limitando tanto los "sueños y proyectos de vida" como el desarrollo laboral, social y afectivo. Además trasciende al grupo familiar, cuando deben asumir la asistencia del paciente. En lo sanitario, la EM, genera uso intensivo y progresivo de recursos. Las terapias inmunomoduladores para la EM, que tienen la posibilidad de detener o reducir la evolución de la modalidad recurrente remitente de la EM, no se encontraban disponibles en forma regular en el sector público de salud de nuestro país, por esto el presente programa piloto...

Some arachnidan peptides with potential medical application

The search for new active drugs that can alleviate or cure different diseases is a constant challenge to researchers in the biological area and to the pharmaceutical industry. Historically, research has focused on the study of substances from plants. More recently, however, animal venoms have been attracting attention and studies have been successful in addressing treatment of accidents. Furthermore, venoms and their toxins have been considered good tools for prospecting for new active drugs or models for new therapeutic drugs. In this review, we discuss some possibilities of using different toxins, especially those from arachnid venoms, which have shown some potential application in diseases involving pain, hypertension, epilepsy and erectile dysfunction. A new generation of drugs is likely to emerge from peptides, including those found in animal venoms.

Clinical features of multiple sclerosis in the south of Brazil: a partial analysis / Características clínicas da esclerose múltipla no sul do Brasil: uma análise parcial

There are no published studies on the characteristics of multiple sclerosis (MS) patients from the south of Brazil. OBJECTIVE: To identify the clinical features of a series of MS patients and to compare to other Brazilian series. METHOD: Retrospective study with 67 patients followed in The MS Reference Center - RS, Brazil during the year of 2008. We analyzed demographic and clinical data. RESULTS: Most were women (74.6 percent), the general average age was 43.5 years old, and the general average EDSS score was 4.1. Of those patients, 81.8 percent had relapsing-remitting MS. Sexual dysfunction prevalence was 31.1 percent in men and 68.9 percent in women (p<0.01). We found a positive correlation (Spearman=0.444, p<0.05) between EDSS and depressive symptoms. CONCLUSION: This study showed a very similar sample compared to other states of Brazil. Moreover, there was found a high prevalence of sexual dysfunction and a straight relation between EDSS and depressive symptoms.

Não há dados publicados sobre as características clínicas da esclerose múltipla (EM) no estado do Rio Grande do Sul (RS). OBJETIVO: Identificar e comparar as características clínicas de uma série de pacientes com EM no RS com as de outras séries nacionais. MÉTODO: Foram coletados e avaliados dados demográficos e clínicos de 67 pacientes atendidos em nosso centro. RESULTADOS: Houve predomínio de mulheres (74,6 por cento), idade média geral foi de 43,5 anos e EDSS médio de 4,1. O tipo surto-remissão correpondeu a 81,8 por cento. A prevalência de disfunção sexual foi de 31,1 por cento nos homens e 68,9 por cento nas mulheres (p<0,01). Encontrou-se correlação de 0,444 (p<0,05) entre depressão e EDSS. CONCLUSÃO: Este estudo demonstrou uma amostra semelhante às demais amostras brasileiras, apresentando, adicionalmente, elevada prevalência de sintomas sexuais e a estreita associação entre depressão e o grau de incapacidade.

Ensayos clínicos de exenatida y su rol en el tratamiento de la diabetes tipo 2 / Exenatide trials for the treatment of type 2 diabetes

La diabetes mellitus tipo 2 es una enfermedad metabólica crónica, frecuente y progresiva, responsable del 90% de los casos de diabetes a nivel mundial. Aproximadamente el 60% de los individuos que padecen este desorden no alcanzan niveles óptimos de hemoglobina glicosilada, a pesar de la disponibilidad de numerosas alternativas terapéuticas. Los dos objetivos más importantes a cumplir en el manejo actual de la diabetes tipo 2 son la capacidad de los agentes antidiabéticos de exhibir eficacia prolongada y la capacidad de preservar la función de las células beta pancreáticas. El efecto incretina se encuentra reducido en pacientes con diabetes tipo 2. Exenatida pertenece a un nuevo grupo de drogas antidiabéticas que mejoran el control de la glucemia en estos pacientes a través de mecanismos fisiológicos glucorregulatorios que mejoran el efecto incretina. Los ensayos clínicos fase III con exenatida demostraron una reducción media de aproximadamente el 1% en los valores de hemoglobina glicosilada. Los datos a largo plazo de estudios de extensión no controlados indican una mejoría sostenida en los niveles de hemoglobina glicosilada y una reducción progresiva del peso luego de 3 años de tratamiento con esta droga. La droga es generalmente bien tolerada y los efectos adversos más frecuentes son los gastrointestinales, con una intensidad leve a moderada. El objetivo de esta revisión es analizar la evidencia publicada hasta la fecha sobre la eficacia y tolerabilidad del tratamiento con exenatida y su rol en el tratamiento de la diabetes tipo 2.

Type 2 diabetes mellitus is a common, chronic and progressive metabolic disorder, which accounts for 90% of diabetes cases worldwide. Approximately 60% of individuals with the disease do not achieve target glycosylated hemoglobin levels, despite the availability of many antidiabetic agents. The two most important needs in the present management of diabetes are the ability of antidiabetic agents to exhibit prolonged efficacy in reducing hyperglycemia and to preserve beta-cell function. The incretin effect appears to be reduced in patients with type 2 diabetes. Exenatide is the first in a novel class of antidiabetic drugs that improves glycemic control in patients with type 2 diabetes through several physiological glucoregulatory mechanisms which improve the incretin effect. Overall, mean glycosylated hemoglobin (HbA1c) reductions achieved in the exenatide phase III clinical trials were in the order of 1%. Long-term data from the uncontrolled open-label extension studies indicate that adjunctive exenatide therapy leads to sustained improvements in HbA1c and progressive weight loss for at least 3 years. The drug is generally well tolerated. The most common adverse events were gastrointestinal in nature and mild to moderate in severity. The objective of this review is to discuss the available published evidence on exenatide therapeutic efficacy and tolerability, and the role of this new drug in the treatment of type 2 diabetes.

The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model

The immunomodulador glatiramer acetate (GA) has been shown to significantly reduce the severity of symptoms during the course of multiple sclerosis and in its animal model - experimental autoimmune encephalomyelitis (EAE). Since GA may influence the response of non-neuronal cells in the spinal cord, it is possible that, to some extent, this drug affects the synaptic changes induced during the exacerbation of EAE. In the present study, we investigated whether GA has a positive influence on the loss of inputs to the motoneurons during the course of EAE in rats. Lewis rats were subjected to EAE associated with GA or placebo treatment. The animals were sacrificed after 15 days of treatment and the spinal cords processed for immunohistochemical analysis and transmission electron microscopy. A correlation between the synaptic changes and glial activation was obtained by performing labeling of synaptophysin and glial fibrillary acidic protein using immunohistochemical analysis. Ultrastructural analysis of the terminals apposed to alpha motoneurons was also performed by electron transmission microscopy. Interestingly, although the GA treatment preserved synaptophysin labeling, it did not significantly reduce the glial reaction, indicating that inflammatory activity was still present. Also, ultrastructural analysis showed that GA treatment significantly prevented retraction of both F and S type terminals compared to placebo. The present results indicate that the immunomodulator GA has an influence on the stability of nerve terminals in the spinal cord, which in turn may contribute to its neuroprotective effects during the course of multiple sclerosis.

Identification of bradykinin: related peptides from Phyllomedusa nordestina skin secretion using electrospray ionization tandem mass spectrometry after a single-step liquid chromatography

Amphibian skin secretions are a source of potential new drugs with medical and biotechnological applications. Rich in peptides produced by holocrine-type serous glands in the integument, these secretions play different roles, either in the regulation of physiological skin functions or in the defense against predators or microorganisms. The aim of the present work was to identify novel peptides with bradykinin-like structure and/or activity present in the skin of Phyllomedusa nordestina. In order to achieve this goal, the crude skin secretion of this frog was pre-fractionated by solid phase extraction and separated by reversed-phase chromatography. The fractions were screened for low-molecular-mass peptides and sequenced by mass spectrometry. It was possible to identify three novel bradykinin-related peptides, namely: KPLWRL-NH2 (Pnor 3), RPLSWLPK (Pnor 5) and VPPKGVSM (Pnor 7) presenting vascular activities as assessed by intravital microscopy. Pnor 3 and Pnor 7 were able to induce vasodilation. On the other hand, Pnor 5 was a potent vasoconstrictor. These effects were reproduced by their synthetic analogues.

Incretin mimetics and dipeptidyl peptidase-4 inhibitors: innovative treatment therapies for type 2 diabetes / Incretinomiméticos e inibidores da dipeptidil peptidase-4: terapias inovadoras para o tratamento do diabetes tipo 2

The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inhibitors reduce elevated A1C, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. Collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with T2DM.

É previsto que a prevalência de diabetes e a intolerância à glicose aumente dramaticamente ao longo das próximas duas décadas. As terapias clínicas para diabetes melito tipo 2 (DM2) têm tradicionalmente incluído modificação do estilo de vida, agentes antidiabéticos orais e, por último, o início da insulina. Neste artigo, revisamos os resultados dos estudos clínicos de duas terapias inovadoras no tratamento do DM2 baseadas nos efeitos glicorregulatórios dos hormônios incretina. Os incretinomiméticos são medicamentos peptídeos que mimetizam várias das ações do peptídeo semelhante ao glucagon-1 (GLP-1) e têm demonstrado reduzir níveis de hemoglobina glicada (A1C) em pacientes com DM2. Adicionalmente, incretinomiméticos reduzem as glicemias pós-prandial e de jejum, suprimem a liberação elevada do glucagon, e são associados com redução de peso. Os inibidores da dipeptidil peptidase-4 (DPP-4) aumentam os níveis de GLP-1 endógeno pela inibição da degradação enzimática do GLP-1. Estudos clínicos em pacientes com DM2 têm demonstrado que inibidores da DPP-4 reduzem A1C elevada, reduzem as glicemias pós-prandial e de jejum, suprimem a liberação elevada do glucagon e são neutros quanto ao peso. Coletivamente, estas novas medicações, administradas em combinação com outros agentes antidiabéticos, como metformina, sulfoniluréias e/ou tiazolidinedionas (TZDs), podem ajudar a recuperar a homeostase glicêmica de pacientes com DM2 não-controlados.

Exenatide: uso en humanos / Exenatide: use in humans

El exenatide es el primer agonista sintético del receptor de GLP-1 (glucagon-like peptide 1) aprobado para el tratamiento de pacientes con diabetes tipo 2. La multiplicidad de efectos que produce sobre el metabolismo de la glucosa, el apetito y el peso corporal, así como su capacidad potencial para mantener la masa de células β, lo convierten en una alternativa terapéutica atractiva. El presente artículo pretende revisar la información existente sobre la farmacocinética, farmacodinamia, efectividad y seguridad del exenatide en humanos, derivada de los primeros estudios de fase I y II y de los ensayos clínicos controlados que condujeron a la aprobación de su uso clínico como terapia de combinación con sulfonilureas y metformina.

Exenatide is the first synthetic agonist of the GLP-1 (glucagon-like peptide 1) receptor approved for clinical use in patients with type 2 diabetes. The multiplicity of its effects over glucose metabolism, appetite, body weight and its potential capacity to preserve the ?cell mass, makes it an attractive therapeutic alternative. This article attempts to review the current literature on pharmacokinetics, pharmacodynamics, efficacy, and safety of exenatide in humans, derived from the early phase I and II studies, and from the clinical controlled trials that led to its approval for clinical use as a combination therapy with sulphonylureas and metformin.