O efeito do tratamento com rapamicina em órgãos linfoides de camundongos propensos à senescência acelerada / The effect of rapamycin treatment on lymphoid organs of senescence accelerated mice prone

Envelhecer compreende um fenômeno complexo, natural e irreversível, que submete o organismo a inúmeras alterações nos processos biológicos, fisiológicos, ambientais, psicológicos, comportamentais e sociais. Esse processo é caracterizado por um declínio gradual dos mecanismos homeostáticos do organismo, intimamente relacionados com o estado senescente. A senescência, quando diz respeito ao sistema imunológico, é denominada de imunossenescência, que pode ser definida como uma parada estável do ciclo celular associada a mudanças, com uma resposta que limita a proliferação de células envelhecidas ou danificadas. A autofagia está diretamente relacionada com a manutenção do fenótipo senescente, em que a atividade autofágica exerce um papel essencial e ativo na influência da biossíntese de proteínas e organelas. Essa via é regulada naturalmente pela proteína mTOR e quimicamente pelo fármaco rapamicina. Assim, pretendemos investigar: (1) as alterações no perfil corporal e hematimêtrico dos animais ao longo do tratamento com rapamicina; (2) avaliar o perfil de citocinas; (3) observar as modificações histológicas em órgãos linfoides primários e secundário; (4) analisar as populações de células linfoides e mieloides; e (5) avaliar a capacidade proliferativa de linfócitos in vitro. Camundongos SAMP-8 e SAMR-1 foram tratados com rapamicina durante dois meses. A mensuração da massa corporal e análises hematológicas foram realizadas antes e durante o tratamento. Amostras de soro, medula óssea, timo e baço foram analisados em ensaios de ELISA, histologia, população e subpopulações de células. Alterações na massa corporal, parâmetros hematológicos e celularidade de células foram nítidas entre os dois modelos utilizados. Diferenças também foram percebidas na detecção de citocinas IL-1ß. IL-6 e TNF-α, com resultados significantes nas amostras de baço, timo e medula óssea. As citocinas IL-7 e IL-15 apresentaram diferenças de secreção entre os grupos, sendo a primeira maior detectada em camundongos com senescência acelerada tratados com rapamicina. Em nossa análise histológica observamos que os camundongos SAM-P8 apresentaram involução tímica. E nas subpopulações de linfócitos T do baço, células TCD4+ e TCD8+ estavam, respectivamente, em maior e menor quantidade nos camundongos SAM-P8 tratados com rapamicina. Dessa forma, o camundongo da linhagem SAM-P8 é um excelente modelo para se estudar as alterações da senescência, em que o mesmo apresenta características fisiológicas distintas dos camundongos utilizados como controle (SAM-R1). Além disso, verificamos que a dose de rapamicina empregada não desencadeou alterações que pudessem comprometer a resposta imunológica desses camundongos, bem como na possibilidade de atuar na resposta contra os efeitos complexos do envelhecimento

Aging comprises a complex, natural, and irreversible phenomenon, which subjects the organism to countless alterations in biological, physiological, environmental, psychological, behavioral, and social processes. This process is characterized by a gradual decline in the organism's homeostatic mechanisms, closely related to senescence effects. Senescence, when it concerns the immune system, is called immunosenescence, which can be defined as a stable cell cycle arrest associated with changes and is a response that limits the proliferation of aged or damaged cells. Autophagy is a genetically regulated, conserved cellular process and a metabolic pathway essential for maintaining cellular homeostasis, which plays a constitutive and active role in controlling the biosynthesis of proteins and organelles. This pathway is regulated naturally by mTOR or chemically by the drug rapamycin, having a direct relationship with cellular homeostasis and maintenance of the senescent phenotype. Thus, we intend to investigate: (1) the changes in the body and hematimetic profile of the animals throughout the rapamycin treatment; (2) evaluate the cytokine profile; (3) observe histological changes in primary and secondary lymphoid organs; (4) analyze lymphoid and myeloid cell populations; and (5) evaluate the proliferative capacity of lymphocytes in vitro. SAMP-8 and SAMR-1 mice were treated with rapamycin for two months. Body mass measurement and hematological analyses were performed before and during treatment. Serum, bone marrow, thymus and spleen samples were analyzed in ELISA assays, histology, cell population and subpopulations. Changes in body mass, hematological parameters, and cellularity were clear between the two models used. Differences were also noticed in the detection of cytokines IL-1ß. IL-6 and TNF-α, with significant results in the spleen, thymus and bone marrow samples. The cytokines IL-7 and IL-15 showed differences in secretion between groups, the former being higher detected in mice with accelerated senescence treated with rapamycin. In our histological analysis we observed that SAM-P8 mice showed thymic involution. And in the spleen T-lymphocyte subpopulations, TCD4+ and TCD8+ cells were, respectively, in higher and lower quantities in SAM-P8 mice treated with rapamycin. Thus, the SAM-P8 mouse is an excellent model to study the changes of senescence, since it presents physiological characteristics different from the control mice (SAM-R1). Furthermore, we verified that the dose of rapamycin used did not trigger changes that could compromise the immune response of these mice, as well as the possibility of acting in the modulatory response against the complex effects of aging

Vascular endothelial growth factor induces inflammatory injury of pancreatic tissue by activating autophagy in hyperlipidemic acute pancreatitis rats / 生理学报

This study was to investigate the changes of autophagy in pancreatic tissue cells from hyperlipidemic acute pancreatitis (HLAP) rats and the molecular mechanism of autophagy to induce inflammatory injury in pancreatic tissue cells. Male Sprague Dawley (SD) rats were intraperitoneally injected with caerulein to establish acute pancreatitis (AP) model and then given a high fat diet to further prepare HLAP model. The HLAP rats were treated with autophagy inducer rapamycin or inhibitor 3-methyladenine. Pancreatic acinar (AR42J) cells were treated with caerulein to establish HLAP cell model. The HLAP cell model were treated with rapamycin or transfected with vascular endothelial growth factor (VEGF) siRNA. The inflammatory factors in serum and cell culture supernatant were detected by ELISA method. The histopathological changes of pancreatic tissue were observed by HE staining. The changes of ultrastructure and autophagy in pancreatic tissue were observed by electron microscopy. The expression levels of Beclin-1, microtubule- associated protein light chain 3-II (LC3-II), mammalian target of rapamycin complex 1 (mTORC1), and VEGF were measured by immunohistochemistry and Western blot. The results showed that, compared with control group, the autophagy levels and inflammatory injury of pancreatic tissue cells from HLAP model rats were obviously increased, and these changes were aggravated by rapamycin treatment, but alleviated by 3-methyladenine treatment. In HLAP cell model, rapamycin aggravated the autophagy levels and inflammatory injury, whereas VEGF siRNA transfection increased mTORC1 protein expression, thus alleviating the autophagy and inflammatory injury of HLAP cell model. These results suggest that VEGF-induced autophagy plays a key role in HLAP pancreatic tissue cell injury, and interference with VEGF-mTORC1 pathway can reduce the autophagy levels and alleviate the inflammatory injury. The present study provides a new target for prevention and treatment of HLAP.

Effectiveness and Safety of Biolimus A9™-Eluting stEnt in Patients with AcUTe Coronary sYndrome; A Multicenter, Observational Study (BEAUTY Study)

PURPOSE: This study sought to determine the 1-year clinical effectiveness and safety of a biodegradable, polymer-containing Biolimus A9™-eluting stent (BES) in Korean patients with acute coronary syndrome (ACS). MATERIALS AND METHODS: A total of 1000 ACS patients with 1251 lesions who underwent implantation of BESs at 22 centers in Korea were enrolled between May 2011 and July 2013. We assessed major adverse cardiac events (MACE) defined as the composite of cardiac death, non-fatal myocardial infarction (MI), and clinical-driven target vessel revascularization at 12 months. RESULTS: Patient mean age was 62.6±11.4 years. 72.8% of the patients were male, 28.5% had diabetes, 32.8% had multi-vessel disease (MVD), and 47.9% presented with acute MI (AMI). The mean global registry of acute coronary events risk score of all patients was 103.0±27.6. The number of stents per patient was 1.3±0.6. The incidences of MACE and definite stent thrombosis at 12 months were 3.9% and 0.2%, respectively. On multivariate Cox-regression analysis, age ≥65 years was identified as an independent predictors of 1-year MACE (hazard ratio=2.474; 95% confidence interval=1.202−5.091). Subgroup analyses revealed no significant differences in the incidence of MACE between patients with and without diabetes (4.3% vs. 3.7%, p=0.667), between those who presented with and without AMI (4.4% vs. 3.4%, p=0.403), and between those with and without MVD (4.6% vs. 3.5%, p=0.387). CONCLUSION: Our study demonstrated excellent 1-year clinical outcomes of BES implantation in patients at low-risk for ACS.

Uso de sirolimus en pacientes pediátricos con poliquistosis renal autosómica dominante / Use of sirolimus in pediatric patients with autosomal dominant polycystic kidney disease

La poliquistosis renal autosómica dominante (PQRAD) se caracteriza por la aparición de quistes renales. Objetivos: Evaluar el crecimiento del volumen renal y de los quistes en los pacientes tratados con sirolimus, en comparación con aquellos que reciben el tratamiento habitual para la PQRAD; evaluar la aparición de efectos adversos relacionados con el uso de sirolimus; evaluar los cambios en la presión arterial, la proteinuria y el filtrado glomerular (FG) estimado. Materiales y métodos: Durante 24 meses se asignaron al azar 12 pacientes con PQRAD a un grupo de tratamiento con sirolimus (6 pacientes recibieron sirolimus 2 a 3 mg/m2/día, con un máximo de 5 mg/día) o a un grupo control (bajo tratamiento habitual). Resultados: De los 12 pacientes, los 6 pertenecientes al grupo de tratamiento con sirolimus tuvieron, al final del estudio, un aumento del volumen renal total y del volumen quístico del 13% y el 32%, respectivamente. En el grupo control, los 6 pacientes restantes tuvieron aumentos del 11% y el 23%, respectivamente. El FG fue normal para ambos grupos. La proteinuria para los grupos de sirolimus y control fue inicialmente 7.3 mg/m2/h y 6 mg/m2/h, respectivamente. Al finalizar el estudio era normal para ambos grupos. Tres pacientes tenían hipertensión arterial, pero a los 24 meses la presión arterial fue normal. Los efectos adversos observados fueron: anemia, diarrea y úlceras bucales. Conclusiones: El sirolimus no disminuyó el volumen renal ni el quístico. No hubo un aumento significativo en la proteinuria o una disminución en el FG. La media de la presión arterial se mantuvo normal.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the develop-ment of kidney cysts. Objectives: To assess the growth of kidney and cystic volume in patients treated with rapamycin compared with patients receiving the usual treatment for ADPKD; assess the occurrence of adverse effects associated with the use of sirolimus; evaluate changes in blood pressure, proteinuria and estimated glomerular filtration rate (eGFR). Materials and methods: For a 24-month period, 12 patients with ADPKD were randomly allocated to a sirolimus group (6 patients, received rapamycin, 2-3 mg/m2/day, max. 5 mg/day) and the other 6 patients were allocated to a control group (receiving conventional treatment). Results: Out of the 12 patients, the 6 patients in the sirolimus group had a total increase in kidney and cystic volume of 13% and 32%, respectively, by the end of the study. In the control group, the other 6 patients had increases of 11% and 23%, respectively. eGFR was normal in both groups. Baseline proteinuria was 7.3 mg/m2/hour and 6 mg/m2/hour in the sirolimus- and control groups, respectively. By the end of the study, it was normal in both groups. Three patients had high blood pressure at baseline, but it was normalized at 24 months. Adverse effects were: anemia, diarr-hea, and mouth sores. Conclusions: Sirolimus did not reduce kidney and cystic volume. No significant increase in proteinuria or decrease in eGFR were observed. Mean blood pressure remained normal.

Efeitos de compostos naturais, sintéticos e da fototerapia antifúngica sobre Candida tropicalis resistente ao fluconazol / Effects of natural compounds, synthetic and herbal medicine on Candida tropicalis antifungal fluconazole-resistant

A candidíase é uma infecção oportunista provocada por diversas espécies de fungos do gênero Candida, frequentemente encontrados integrando a microbiota, da superfície cutânea, no trato gastrointestinal e cavidades mucosas do ser humano desde o seu nascimento. A incidência das infecções fúngicas sistêmicas têm aumentado consideravelmente nas últimas décadas em função do grande número de pacientes com SIDA, a grande quantidade de transplantes e condições crônicas como o câncer, a terapia prolongada com imunossupressores e o uso de agentes corticosteroides. Além disso, a exposição prolongada aos antifúngicos azólicos promove a seleção de patógenos resistentes. No presente estudo avaliou-se a atividade antifúngica do complexo Rutênio-pirocatecol (RPC) frente a um isolado clinico de Candida tropicalis resistente ao fluconazol. A metodologia empregada para os testes de susceptibilidade foi de acordo com o documento M27-A3 do National Committee for Clinical Laboratory Standards (NCCLS, 2008). Esplenócitos de camundongos Balb/c foram obtidos de forma asséptica para avaliar a citotoxicidade do composto para células de mamíferos. O estresse oxidativo promovido pelo composto foi avaliado através da reação ao ácido tiobarbitúrico (TBARS) e ensaios de fluorescência com a sonda diclorodihidrofluoresceína diacetato (DCFH2DA). O Calcofluor White foi empregado para avaliar a integridade da parede celular. A análise ultraestrutural foi realizada através da microscopia eletrônica de varredura e transmissão. Os resultados encontrados para os testes de atividade antifúngica foram analisados através do teste estatístico ANOVA e pós-teste Dunnett. Os resultados encontrados para os testes de atividade antifúngica do RPC mostraram uma Concentração Inibitória de 50% (IC50) de 20,3 μM, enquanto em esplesnócitos a concentração efetiva de 50% foi de 325 μM mostrando um índice de seletividade igual a 16...

Candidiasis is an opportunistic infection caused by several species of fungi of the genus Candida, often found is the microbiota, on the skin, gastrointestinal tract and mucous cavities of the human beings birth. The incidence of systemic fungal infections have increased considerably in recent decades due to the large number of AIDS patients, the large number of transplants and chronic conditions such as cancer, prolonged therapy promotes the selection of resistant pathogen with immunosuppressant and corticosteroid agents. Also prolonged exposure azole antifungals to make them strong candidates for patients resistance. In the present study we evaluated the antifungal activity of Ruthenium-pyrocatechol complex (RPC) against a clinical isolate of Candida tropicalis resistant to fluconazole. The methodology for susceptibility testing was in accordance with the M27-A3 document of there National Committee for Clinical Laboratory Standards (NCCLS, 2008). Splenocytes from Balb/c mice were obtained aseptically to evaluate the cytotoxicity of the compound to mammalian cells. Oxidative stress caused by the compound was assessed by reaction to thiobarbituric acid (TBARS) and fluorescence assays with the probe diclorodihidrofluoresceína diacetate (DCFH2DA). The Calcofluor White was used to evaluate the integrity of the cell wall. The ultrastructural analysis was performed by scanning and transmission electron microscopy. The results for the antifungal activity tests were analyzed using ANOVA and pos-test Dunnett test statistic. The results for the tests of antifungal activity of the RPC showed a 50% inhibitory concentration (IC50) of 20.3 μM while in splenocytes the 50% effective concentration was 325 μM showing a selectivity index of 16...

Zotarolimus-eluting stent-induced hypersensitivity pneumonitis

No abstract available.

Safety and Efficacy of Overlapping Homogenous Drug-Eluting Stents in Patients with Acute Myocardial Infarction: Results from Korea Acute Myocardial Infarction Registry

The aim of this study was to compare safety and efficacy of 4 homogenous overlapping drug-eluting stents (DES) in acute myocardial infarction (AMI) patients. We selected 1,349 consecutive patients (62.1 +/- 14.9 yr, 69.4% male) who received homogenous overlapping DESs in diffuse de novo coronary lesions from Korea Acute Myocardial Infarction Registry from April 2006 through September 2010. They were divided into 4 groups based on type of DES implanted - Paclitaxel (PES), Sirolimus (SES), Zotarolimus (ZES) and Everolimus (EES)-eluting stents. Primary endpoint was 12-month MACE. We also studied EES versus other DESs (PES + SES + ZES). Mean stent length was 26.2 +/- 7.5 mm and mean stent diameter was 3.1 +/- 0.4 mm. Average number of stents used per vessel was 2.2 +/- 0.5. Incidence of major adverse cardiac events (MACE) in PES, SES, ZES, and EES groups were 9.5%, 9.2%, 7.5%, and 3.8%, respectively (P = 0.013). In EES group, overall MACE and repeat revascularization were lowest, and no incidence of stent thrombosis was observed. Non-fatal MI was highest in PES, almost similar in SES and EES with no incidence in ZES group (P = 0.044). Cox proportional hazard analysis revealed no differences in the incidence of primary endpoint (P = 0.409). This study shows no significant differences in 12-month MACE among 4 groups.

Safety and Efficacy of Overlapping Homogenous Drug-Eluting Stents in Patients with Acute Myocardial Infarction: Results from Korea Acute Myocardial Infarction Registry

The aim of this study was to compare safety and efficacy of 4 homogenous overlapping drug-eluting stents (DES) in acute myocardial infarction (AMI) patients. We selected 1,349 consecutive patients (62.1 +/- 14.9 yr, 69.4% male) who received homogenous overlapping DESs in diffuse de novo coronary lesions from Korea Acute Myocardial Infarction Registry from April 2006 through September 2010. They were divided into 4 groups based on type of DES implanted - Paclitaxel (PES), Sirolimus (SES), Zotarolimus (ZES) and Everolimus (EES)-eluting stents. Primary endpoint was 12-month MACE. We also studied EES versus other DESs (PES + SES + ZES). Mean stent length was 26.2 +/- 7.5 mm and mean stent diameter was 3.1 +/- 0.4 mm. Average number of stents used per vessel was 2.2 +/- 0.5. Incidence of major adverse cardiac events (MACE) in PES, SES, ZES, and EES groups were 9.5%, 9.2%, 7.5%, and 3.8%, respectively (P = 0.013). In EES group, overall MACE and repeat revascularization were lowest, and no incidence of stent thrombosis was observed. Non-fatal MI was highest in PES, almost similar in SES and EES with no incidence in ZES group (P = 0.044). Cox proportional hazard analysis revealed no differences in the incidence of primary endpoint (P = 0.409). This study shows no significant differences in 12-month MACE among 4 groups.

Desfechos clínicos por região geográfica em pacientes com implante de stent eluidor de Zotarolimus / Clinical outcomes by geographic region for patients implanted with the zotarolimus-eluting stent / Desenlaces clínicos por región geográfica en pacientes con implante de Stent liberador de Zotarolimus

FUNDAMENTO: Diferenças entre regiões geográficas em relação à características de pacientes e desfechos, particularmente em síndromes coronarianas agudas, tem sido demonstradas em testes clínicos. Os desfechos clínicos após intervenções coronarianas percutâneas com o stent eluidor de Zotarolimus em uma população real foram analisados com o tempo. OBJETIVO: A influência da localização geográfica sobre os desfechos clínicos com o stent eluidor de Zotarolimus foi avaliada em três regiões: Pacífico Asiático, Europa e América Latina. MÉTODOS: Um total de 8.314 pacientes (6.572 da Europa, 1.522 do Pacífico Asiático e 220 da América Latina) foram acompanhados por 1 ano; 2.116 desses (1.613, 316, e 187, respectivamente) foram acompanhados por 2 anos. Características dos pacientes e lesões, terapia antiplaquetária dupla e desfechos clínicos foram comparados entre a América Latina e as outras duas regiões. RESULTADOS: Os pacientes da América Latina apresentavam a maior proporção de fatores de risco e infarto do miocárdio prévio. O uso da terapia antiplaquetária dupla declinou rapidamente na América Latina, de 44,9 por cento em 6 meses para 22,5 por cento em 1 ano e 7,8 por cento em 2 anos (Europa: 87,4 por cento, 61,5 por cento, 19,7 por cento; Pacífico Asiático: 82,4 por cento, 67,0 por cento, 45,7 por cento, respectivamente). Não houve diferenças significantes entre a América Latina e a Europa ou Pacífico Asiático para qualquer desfecho em qualquer ponto do tempo. A incidência de trombose de stent provável e definitiva pelo Academic Research Consortium foi baixa (<1,2 por cento) entre todos os pacientes em 1 ano e 2 anos. CONCLUSÃO: Os desfechos clínicos foram comparáveis entre os pacientes da América Latina e Europa, e América Latina e Pacífico Asiático, a despeito dos subgrupos clínicos menos favoráveis na América Latina, perfil de risco mais elevado e menor uso acentuado de terapia antiplaquetária dupla com o tempo.

BACKGROUND: Differences between geographic regions in patient characteristics and outcomes, particularly for acute coronary syndromes, have been demonstrated in clinical trials. Clinical outcomes after percutaneous coronary interventions with the Zotarolimus-eluting stent in a real-world population were assessed over time. OBJECTIVE: The influence of geographic location on clinical outcomes with the Zotarolimus-eluting stent was assessed in 3 regions: Asia Pacific, Europe, and Latin America. METHODS: A total of 8,314 patients (6,572 Europe, 1,522 Asia Pacific, and 220 Latin America) were followed for 1 year; 2,116 of these (1,613, 316, and 187, respectively) were followed for 2 years. Patient and lesion characteristics, dual antiplatelet therapy, and clinical outcomes were compared between Latin America and the other regions. RESULTS: Patients in Latin America had the highest proportions of risk factors and prior myocardial infarction. Dual antiplatelet therapy usage rapidly declined in Latin America, from 44.9 percent at 6 months to 22.5 percent at 1 year and 7.8 percent at 2 years (Europe: 87.4 percent, 61.5 percent, 19.7 percent; Asia Pacific: 82.4 percent, 67.0 percent, 45.7 percent). There were no significant differences between Latin America and Europe or Asia Pacific for any outcome at either time point. The incidence of Academic Research Consortium definite and probable stent thrombosis was low (<1.2 percent) among all patients at 1 year and 2 years. CONCLUSION: Clinical outcomes were comparable between patients in Latin America and Europe, and Latin America and Asia Pacific, despite less favorable clinical subsets in Latin America, a higher risk profile, and markedly lower use of dual antiplatelet therapy over time.

FUNDAMENTO: Las diferencias entre las regiones geográficas en relación con las características de pacientes y desenlaces, sobre todo en los síndromes coronarios agudos se ha demostrado en ensayos clínicos. Los desenlaces clínicos después de las intervenciones coronarias percutáneas con stent liberador de zotarolimus en una población real se analizaron a través del tiempo. Objetivos: La influencia de la ubicación geográfica sobre los desenlaces clínicos con el stent liberador de zotarolimus se evaluó en tres regiones: Pacífico Asiático, Europa y América Latina. MÉTODOS: A total of 8,314 patients (6.572 Europe, 1.522 Asia Pacific, and 220 Latin America) were followed for 1 year; 2.116 of these (1.613, 316, and 187, respectively) were followed for 2 years. Patient and lesion characteristics, dual antiplatelet therapy, and clinical outcomes were compared between Latin America and the other regions. RESULTADOS: Los pacientes en América Latina tuvieron la mayor proporción de factores de riesgo e infarto de miocardio previo. Hubo un rápido descenso en el uso de la terapia antiplaquetaria en América Latina, el 44,9 por ciento en 6 meses para 22,5 por ciento en 1 año y 7,8 por ciento en 2 años (Europa: un 87,4 por ciento, un 61,5 por ciento, un 19,7 por ciento; Pacífico Asiático: un 82,4 por ciento, un 67,0 por ciento, un 45,7 por ciento, respectivamente). No hubo diferencias significativas entre América Latina y Europa o Pacífico Asiático para cualquier desenlace en cualquier momento. La incidencia de trombosis de stent probable y definitiva por el Academic Research Consortium fue baja (< 1,2 por ciento) entre todos los pacientes en 1 año y 2 años. CONCLUSIONES: Los desenlaces clínicos fueron comparables entre los pacientes de América Latina y Europa, y América Latina y Pacífico Asiático, pese a los subgrupos clínicos menos favorables en América Latina, perfil de riesgo más elevado y menor uso acentuado de terapia antiplaquetaria doble con el ...

Trastorno linfoproliferativo post trasplante renal en un niño / Lymphoproliferative disorders after renal transplantation in a child

Post transplant lymphoproliferative disorder (PTLD) is the commonest form of post transplant malignancy in children. The incidence in renal transplant recipients varies between 2 percent-4 percent. They are characterized by uncontrolled B lymphocyte proliferation, in most cases driven by Epstein Barr virus (EBV). They are more common in younger children, EBV seronegative patients and those who receive aggressive immunosuppression. PTLD commonly presents in an unspecific form and it requires high suspicion rate for its diagnosis, especially in children with risk factors. We report a twelve year-old girl who developed fever, sore throat and lymph node enlargement, six months after receiving a renal allograft. Laboratory assessment and imaging studies were compatible with PTLD, which was confirmed by biopsy. Treatment was reduction of immunosuppression and surveillance. The patient had a favorable evolution.

Testing intravitreal toxicity of rapamycin in rabbit eyes / Toxicidade intravítrea da rapamicina em olhos de coelhos

PURPOSE: To evaluate retinal toxicity of varying doses of rapamycin when injected intravitreally in rabbits. Rapamycin is a potent immunosuppressive agent with significant antitumor and antiangiogenic properties, clinically approved for prevention of organ transplant rejection. METHODS: Twelve New Zealand albino rabbits were divided into four groups. Four different doses of rapamycin were prepared in 0.1 ml: 20 µg, 50 µg, 200 µg, and 1000 µg. Each concentration was injected in one eye of three rabbits, and 0.1 ml volume of sterile BSS was injected into the contralateral eye of the three rabbits. Slit-lamp and fundoscopic examinations were performed and the animals were observed for 2 weeks for signs of infection, inflammation, and toxicity. A baseline ERG was performed before drug treatment and at day 14, after which the rabbits were euthanized. Histology of the enucleated eyes was studied to look for retinal toxicity. RESULTS: ERG results showed some decrease in scotopic response; however this was not dose related. ERG results were normal at 20 µg. Histological results showed no retinal toxicity in all groups. CONCLUSION: Although ERG changes were identified at dosages between 50-1000 µg, the histology of all groups up to 1000 µg did not show any discernable abnormalities.

OBJETIVO: Avaliar a toxicidade da injeção intravítrea de diferentes doses de rapamicina para a retina de coelhos. Rapamicina é uma potente droga imunossupressora aprovada clinicamente para a prevenção da rejeição de transplantes de orgãos. MÉTODOS: Doze coelhos albinos da Nova Zelândia foram usados neste estudo. Foram divididos em quatro grupos. Quatro diferentes doses de rapamicina foram preparadas nas seguintes concentrações: 20 µg, 50 µg, 200 µg, 1000 µg. Foram realizadas injeções intravítreas de 0,1 ml de cada concentração em um olho de três coelhos e 0,1 ml de solução salina foi injetada no olho contralateral de cada coelho. Foram realizadas biomicroscopia e fundoscopia e observamos sinais de inflamação, infecção ou toxicidade durante duas semanas. Fizemos um ERG antes do tratamento e outro 14 dias depois da injeção intravítrea. Os animais foram sacrificados, fizemos a enucleação dos olhos e preparamos o tecido para a avaliação histológica. RESULTADOS: Os resultados do ERG e da histologia demonstraram diminuição da resposta escotópica, entretanto essa diminuiçãão foi dose dependente. A histologia foi normal em todos os grupos. CONCLUSÃO: A injeção intravítrea de rapamicina levou a alterações eletrorretinográficas nos grupos de 50-1000 µg, entretanto a histologia foi normal em todos os grupos até 1000 µg.

Preclinical and early clinical experience with a biodegradable polymer-based, rapamycin-eluting, Indian drug-eluting coronary stent: the BIO-RAPID study.

OBJECTIVE: To evaluate the performance of a biodegradable polymer based rapamycin-eluting coronary stent in a porcine model and demonstrate its safety and efficacy in the treatment of patients with de novo coronary stenosis. BACKGROUND: The indefinite presence of the polymer after the implantation of drug-eluting stents may initiate and sustain inflammation and contribute to the occurrence of late complications. METHODS: Seven study stents and 5 polymer-coated (control) stents were implanted in porcine carotid arteries. Histomorphometric analysis was performed 8 weeks after stent implantation. After establishing the safety of the stent in the animal model, a single-center, non-randomized study in patients with de novo coronary artery lesions was performed. Forty-nine stents were implanted in 43 patients. The 6-month clinical follow-up was 91% (39/43) and angiographic follow-up was 67% (29/43). The primary safety endpoint was the occurrence of 30-day major adverse cardiovascular events (MACE) and the principal efficacy endpoint was the 6-month angiographic late loss and binary restenosis rate. RESULTS: In the porcine model, the study stent showed acceptably low injury, inflammation and fibrin scores. There was a quantitative reduction in neointimal hyperplasia which was not statistically different from the control stent. However, in the first-in-man evaluation, there was significant suppression of intimal growth as evidenced by an angiographic late loss of 0.28 +/- 0.45 mm at 6 months. The restenosis rate was 10.3% (3/297). There was no death, stent thrombosis or myocardial infarction at 30 days or at 6 months. The 6-month target lesion revascularization rate was 3.47 percent; (1/29). CONCLUSION: This preclinical and early clinical experience demonstrates the safety and efficacy of a novel biodegradable polymer-based rapamycin-eluting coronary stent.

Sirolimus en trasplante de órgano sólido pediátrico: Experiencia en 5 casos / Use of Sirolimus in five pediatric patients undergoing solid organ transplantation

Sirolimus (SRL) is an immunosuppressive drug increasingly used in children undergoing solid organ transplantation. SRL does not cause glucose intolerance, hypertension, nephrotoxicity or neurotoxicity offering significant potential advantages over calceneurin inhibitors (CM). Aim: To report five children treated with SRL. Material and methods: A retrospective review of four children undergoing orthotopic liver transplantation (OLT) and one undergoing renal transplantation with recurrent acute rejection (RAR), chronic rejection (CR) or toxicity due to CM, treated with SRL between June 2001 and November 2006. Results: As primary immunosuppressive therapy, all patients received 3 drugs: CM (Tacrolimus (FK) or Cyclosporine), mycophenolate mofetil and steroids. Mean age at treatment with SRL was 98 months. Children undergoing OLT had a ¡ate introduction of SRL (mean time after OLT: 37 months), and mean follow-up was 24 months. In this group rescue indications of SRL were RAR in one, CR in one, thrombotic thrombocytopenic purpura (TTP) in one, food allergy in one and other CM toxicity in three. Only one did not experience adverse events due to SRL, but no one required discontinuation of SRL. There were remissions of RAR, CR, TTP and food allergy. The patient with RT was switched from FK to SRL at day 18th after RT, but he had severe neutropenia that led to discontinuation of SRL. Conclusions: SRL may be useful in pediatric solid organ transplant recipients suffering from RAR, CR, TTP, food allergy and CM toxicity. Careful attention should be directed to detect side effects and avoid severe complications.

Evolução clínica tardia dos stents farmacológicos: segurança e eficácia até cinco anos do registro DESIRE / Long-term clinical outcomes of drug eluting stents: safety and efficacy up to five years of the DESIRE registry

Fundamentos: A expansão das indicações para o uso dos stents farmacológicos liberadores de sirolimus e de paclitaxel lesões de complexidade crescente e populações com perfil clínico muito diferente daquele dos estudos randomizados fundamentais. O registro DESIRE foi idealizado para monitorar a efetividade e a segurança institucional dos stents farmacológicos disponíveis pra uso clínico desde 2002, em nosso meio. Método e Resultados: Entre maio/2002 e março/2007, foram incluídos 2.043 pacientes (P) tratados com maior ou menor Cypher ou Taxus, no Hospital do Coração da Associação do Sanatório Sírio, em São Paulo - SP. A média das idades foi de 63,8 mais ou menos 11,3 anos, 76,6 por cento eram do sexo masculino e 28,49 por cento eram diabéticos. Um total de 2.415 lesõs foram tratadas, sendo implantados 2.983 stents: 2.608 Cypher e 375 Taxus. as tromboses agudas/subagudas (menor ou igual 30 dias),...

Background: Indications for the implantation of sirolimusand paclitaxel-eluting stents are expanding and include complex lesions and subsets of patients with clinical and demographic characteristics very different from those of early pivotal randomized trials. The DESIRE Registry was planned to monitor the safety of both Cypher® and Taxus® stent available in Brazil since 2002. Methods and Results: From May 2002 through March 2007, 2043 patients treated with one or more than one stent (either Cypher® or Taxus®) at Hospital do Coração da Associação do Sanatório Sírio were included in this Registry. Mean age was 63.8 (11.3) years; 76.6% were male and 28.4% had diabetes. A total of 2,415 lesions were treated and 2,983 stents were implanted: 2,608 Cypher® and 375 Taxus®. Acute and subacute (≤30 days); late thrombosis (31 days - 360 days) and very late thrombosis (>360 days) occurred in 0.34%, 0.73% and 0.34% of the patients, adding up to a 1.42% overall rate. Likewise, the major adverse cardiac event rate was low and added up to 8.6% (154 patients), including: 45 (2.51%) cardiac deaths; 50 (2.8%) myocardial infarctions and 59 (3.3%) of additional revascularizations...

Análise comparativa do segmento de "ovelapping" dos stents liberadores de sirolimus e paclitaxel / Comparative analysis of the overlapping segment of sirolimus-versus paclitaxel-eluting stents

Introdução: No tratamento de obstruções coronárias longas e complexas recomenda-se cobertura total da lesão. Quando mais de um stent é implantado, torna-se mandatário um "overlapping" ou sobreposição dos stents para evitar espaços não cobertos entre eles. Há pouca evidência na literatura sobre a eficácia e segurança de se realizar sobreposição de stents liberadores de sirolimus (Cypher, SES) e paclitaxel (Taxus, SEP). Objetivo: Avaliar, por meio de estudo seriado com ultra-sonografia intravascular (USIC), a eficácia na redução da proliferação neointimal e as mudanças na parede vascular no segmento com sobreposição de stents farmacológicos SES e SEP. Método: Um total de 52 pacientes (72 lesões) foram prospectivamente incluídos nesta análise e randomizados para tratamento percutâneo com implante de SES ou SEP. Cartoze pacientes do grupo SES e 12 do grupo SEP apresentaram segmentos de sobreposição. Angiografia Coronária quantitativa e USIC foram realizados imediatamente após o implante dos stents e repetidos após oito meses. Resultados: Ambos os grupos apresentavam características clínicas e angiográficas basais...

Introduction: To treat long complex coronary obstructions, total lesion coverage is recommended. When more than one stent is deployed an overlap segment is mandatory to avoid uncovered gaps between stents. There is no data comparing Sirolimus- (SES) versus Paclitaxel-eluting stents (PES) at overlapping segments in regards to neointimal inhibition or toxic effects on the vessel wall. Objective: To evaluate, by means of serial intravascular ultrasound (IVUS), the efficacy in reducing neointimal proliferation and the vessel changes in the overlapping segment comparing these two drug-eluting stents. Method: Fifty-two patients with 72 de novo coronary lesions were randomized for SES or PES. Fourteen patients in the SES Group and twelve in the PES Group had overlapping segments. Quantitative coronary angiography and IVUS were performed at the time of the procedure and at 8 months follow-up. Results: No significant baseline differences were identified between the 2 groups. The mean stent/lesion ratios were similar (1.74 ± 0.89 for SES vs. 2.01 ± 0.92 for PES; p= 0.47). SES and PES were comparable in reducing neointima hyperplasia in the overlapping zone (neointima volume 2.24 ± 0.9 mm3 after SES vs. 2.53 ± 1.5 mm3 after PES; p=0.1 and % neointima obstruction of 18.15 ± 8.5% after SES vs. 26.7 ± 16.8% after PES; p=0.1). There was no positive remodeling in the overlapping segment for both groups (expansion ratio 0.74 ± 0.18 vs. 0.76 ± 0.14, respectively; p=0.74). Other IVUS volumetric measurements were also equivalent between the two cohorts. Conclusion: In our preliminary experience, overlapping of DESs proved...

Relationship of cyclosporin and sirolimus blood concentrations regarding the incidence and severity of hyperlipidemia after kidney transplantation

The influence of drug concentrations on the development of persistent posttransplant hyperlipidemia was investigated in 82 patients who received cyclosporin A (CsA) and prednisone plus sirolimus (SRL) (52) or azathioprine (AZA) (30) during the first year after transplantation. Blood levels of CsA and SRL, daily doses of AZA and prednisone, and cholesterol, triglyceride, and glucose concentrations were determined during each visit (pretransplant and 30, 60, 90, 120, 180, and 360 days posttransplant). Persistent hyperlipidemia was defined as one-year average steady-state cholesterol (CavCHOL) or triglyceride (CavTG) concentrations above 240 and 200 mg/dL, respectively. Mean cholesterol and triglyceride concentrations increased after transplantation (P < 0.01) and were higher in patients receiving SRL compared to AZA (P < 0.001). Patients receiving SRL showed a significantly higher number of cholesterol (>229 or >274 mg/dL) and triglyceride (>198 or >282 mg/dL) determinations in the upper interquartile ranges. CsA and SRL interquartile ranges correlated with cholesterol concentrations (P = 0.001) whereas only SRL interquartile ranges correlated with triglyceride concentrations (P < 0.0001). Only pretransplant cholesterol concentration >205 mg/dL was independently associated with development of persistent hypercholesterolemia (CavCHOL >240 mg/dL, relative risk (RR) = 20, CI 3.8-104.6, P = 0.0004) whereas pretransplant triglyceride concentration >150 mg/dL (RR = 7.2, CI 1.6-32.4, P = 0.01) or >211 mg/dL (RR = 19.8, CI 3.6-107.9, P = 0.0006) and use of SRL (RR = 3, CI 1.0-8.8, P = 0.0049) were independently associated with development of persistent hypertriglyceridemia (CavTG >200 mg/dL). Persistent hypercholesterolemia was more frequent among patients with higher pretransplant cholesterol concentrations and was dependent on both CsA and SRL concentrations. Persistent hypertriglyceridemia was more frequent among patients with higher pretransplant triglyceride concentrations and was dependent on SRL concentrations.

Aneurisma de artéria coronária um ano e cinco meses pós-implante de stent com eluicão de sirolimus / Coronary artery aneurysm one year and five months after sirolimus-eluting stent placement

Paciente de 52 anos de idade, do sexo masculino, com diagnóstico de angina instável pós-infarto. A angiografia coronariana revelou obstrucão luminal de 90 por cento no terco médio da artéria coronária direita e de 90 por cento no ramo marginal da artéria circunflexa. Após o uso de clopidogrel 300 mg associado ao ácido acetilsalicílico, o paciente foi submetido a implante de stent com eluicão de sirolimus (CYPHER; Johnson&Johnson-Cordis) 2,5 x 18 mm, na lesão do ramo marginal esquerdo. Após um ano e cinco meses do implante do stent CYPHER, foi observada em nova angiografia a presenca de aneurisma coronariano intra-stent, no ramo marginal esquerdo. O presente relato sugere que o implante de stent coronariano revestido com sirolimus pode ocasionar, tardiamente, a formacão de aneurisma da artéria coronária.

Estudo experimental da nefotoxicidade aguda do sirolimus: estudos in vitro e in vivo / Sirolimus acute nephrotoxicity: in vitro and in vivo studies

Avaliou-se os efeitos do Sirolimus (SIRO 3mg/kg/diaVO) isoladamente e associado a Ciclosporina A (CsA 3mg/kg/dia SC) em túbulos renais proximais isolados (TP) e sobre a função renal de ratos Wistar normais e submetidos à isquemia renal (30 min). SIRO não apresentou efeito tóxico em TP e nem potencializou a toxicidade da CsA. SIRO não afetou a recuperação da filtração glomerular (FG) após isquemia e foi capaz de prevenir a diminuição da FG induzida pela CsA, a despeito da persistência da vasoconstrição e maior infiltrado inflamatório /The effects of sirolimus (SIRO 3 mg/kg/day PO) alone or associated with ciclosporine (CsA 3 mg/kg/day SC) were evaluated in isolated proximal tubules suspensions (PT) and in control and ischemic (30 min) Wistar rats. SIRO was neither toxic to PT nor affected CsA toxicity. SIRO did not affect glomerular filtration rate (GFR) recovery after ischemia and it prevented CsA induced aggravation despite persistence of vasoconstriction and greater inflammatory infiltrate...