Cyclosporine population pharmacokinetics in pediatric renal transplant recipients

Cyclosporine is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. To improve cyclosporine dose individualization in children, we used population pharmacokinetic modeling to study the effects of developmental, clinical, and genetic factors on cyclosporine pharmacokinetics in altogether 176 subjects (age range: 0.36–20.2 years) before and up to 16 years after renal transplantation. Pre-transplantation test doses of cyclosporine were given intravenously (3 mg/kg) and orally (10 mg/kg), on separate occasions, followed by blood sampling for 24 hours (n=175). After transplantation, in a total of 137 patients, cyclosporine concentration was quantified at trough, two hours post-dose, or with dose-interval curves. One-hundred-four of the studied patients were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. Pharmacokinetic modeling was performed with the nonlinear mixed effects modeling computer program, NONMEM. A 3-compartment population pharmacokinetic model with first order absorption without lag-time was used to describe the data. The most important covariate affecting systemic clearance and distribution volume was allometrically scaled body weight i.e. body weight**3/4 for clearance and absolute body weight for volume of distribution. The clearance adjusted by absolute body weight declined with age and pre-pubertal children (< 8 years) had an approximately 25% higher clearance/body weight (L/h/kg) than did older children. Adjustment of clearance for allometric body weight removed its relationship to age after the first year of life. This finding is consistent with a gradual reduction in relative liver size towards adult values, and a relatively constant CYP3A content in the liver from about 6–12 months of age to adulthood. The other significant covariates affecting cyclosporine clearance and volume of distribution were hematocrit, plasma cholesterol, and serum creatinine, explaining up to 20%–30% of inter-individual differences before transplantation. After transplantation, their predictive role was smaller, as the variations in hematocrit, plasma cholesterol, and serum creatinine were also smaller. Before transplantation, no clinical or demographic covariates were found to affect oral bioavailability, and no systematic age-related changes in oral bioavailability were observed. After transplantation, older children receiving cyclosporine twice daily as the gelatine capsule microemulsion formulation had an about 1.25–1.3 times higher bioavailability than did the younger children receiving the liquid microemulsion formulation thrice daily. Moreover, cyclosporine oral bioavailability increased over 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1–1.5 years. The largest cyclosporine doses were administered in the first 3–6 months after transplantation, and thereafter the single doses of cyclosporine were often smaller than 3 mg/kg. Thus, the results suggest that cyclosporine displays dose-dependent, saturable pre-systemic metabolism even at low single doses, whereas complete saturation of CYP3A4 and MDR1 (P-glycoprotein) renders cyclosporine pharmacokinetics dose-linear at higher doses. No significant associations were found between genetic polymorphisms and cyclosporine pharmacokinetics before transplantation in the whole population for which genetic data was available (n=104). However, in children older than eight years (n=22), heterozygous and homozygous carriers of the ABCB1 c.2677T or c.1236T alleles had an about 1.3 times or 1.6 times higher oral bioavailability, respectively, than did non-carriers. After transplantation, none of the ABCB1 SNPs or any other SNPs were found to be associated with cyclosporine clearance or oral bioavailability in the whole population, in the patients older than eight years, or in the patients younger than eight years. In the whole population, in those patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055C haplotype, however, the bioavailability of cyclosporine was about one tenth lower, per allele, than in non-carriers. This effect was significant also in a subgroup of patients older than eight years. Furthermore, in patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055T haplotype, the bioavailability was almost one fifth higher, per allele, than in non-carriers. It may be possible to improve individualization of cyclosporine dosing in children by accounting for the effects of developmental factors (body weight, liver size), time after transplantation, and cyclosporine dosing frequency/formulation. Further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

La experiencia de los receptores en el trasplante de órganos y tejidos

El trasplante de órganos y/o tejidos es considerado como una opción terapéutica viable para el tratamiento tanto de enfermedades crónicas o en estadios terminales, como de afectaciones no vitales, pero que generen una disminución en la calidad de vida percibida por el paciente. Este procedimiento, de carácter multidimensional, está compuesto por 3 actores principales: el donante, el órgano/tejido, y el receptor. Si bien un porcentaje significativo de investigaciones y planes de intervención han girado en torno a la dimensión biológica del trasplante, y a la promoción de la donación; el interés por la experiencia psicosocial y la calidad de vida de los receptores en este proceso ha aumentado durante la última década. En relación con esto, la presente monografía se plantea como objetivo general la exploración de la experiencia y los significados construidos por los pacientes trasplantados, a través de una revisión sistemática de la literatura sobre esta temática. Para ello, se plantearon unos objetivos específicos derivados del general, se seleccionaron términos o palabras claves por cada uno de estos, y se realizó una búsqueda en 5 bases de datos para revistas indexadas: Ebsco Host (Academic Search; y Psychology and Behavioral Sciences Collection); Proquest; Pubmed; y Science Direct. A partir de los resultados, se establece que si bien la vivencia de los receptores ha comenzado a ser investigada, aún es necesaria una mayor exploración sobre la experiencia de estos pacientes; exploración que carecería de objetivo si no se hiciera a través de las narrativas o testimonios de los mismos receptores

Uso da ciclofosfamida em modelo de imunodepressão experimental em ovinos

Cyclophosphamide (CY) was used to evaluate the effect on the immune system of sheep. Castred adult rams were divided into 3 groups, with 6 animals each one. Group I (day 0) and Group II (day 1) were treated with CY (40 mg/kg, single dose, IV), and Group III was not treated and remained as control. All groups were immunized on day 0 with B19 brucellosis vaccine. on day 6, all animals were bled and serum agglutination test for brucellosis antibodies detection was performed. During 7 days blood lymphocyte counts and electrophoresis gammaglobulin dosage were daily performed. The results showed statistical decrease of immune response. Low serum titers of brucellosis antibodies were found in Groups I and II, and lymphopenia and hypogammaglobulinemia were also found in these groups. A high mortality rate (40%) occurred in the treated animals.

Quantificação de células T regulatórias no baço e sangue de cães naturalmente infectados com Leishmania spp

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Investigação de danos visuais em pacientes diagnosticados com meningite criptocócica não associada à imunossupressão

A meningite criptocócica é uma severa doença infecciosa causada pelo Cryptococcus spp. que apresenta alta letalidade e deixa nos sobreviventes uma série de sequelas sensoriais, entre as quais estão as alterações visuais. O objetivo deste estudo foi descrever as perdas visuais sofridas por pacientes, sem história de imunossupressão, diagnosticados com meningite criptocócica, de forma a indicar um possível mecanismo e fatores de risco para essas sequelas visuais. O trabalho foi composto de um estudo de série de casos de pacientes com meningite criptocócica sem história de imunossupressão (n = 7 pacientes, n = 14 olhos) e um estudo transversal analítico de todos os casos de meningite criptocócica sem história de imunossupressão notificados em 14 anos num hospital de referência do Pará (n = 113 casos). No estudo de série de casos, as funções visuais de uma amostra de pacientes foi cuidadosamente analisada por meio de avaliação oftalmológica, testes psicofísicos e eletrofisiológicos. No estudo transversal analítico, foi realizada análise de dados de prontuário com enfoque nas alterações visuais. Observou-se que os pacientes estudados na série de casos apresentaram grave diminuição da acuidade visual e mesmo em pacientes sem queixa visual houve alteração na percepção de cor, na percepção de contraste de luminância em diferentes frequências espaciais e no campo visual. Os testes indicam comprometimento da retina central como principal desencadeadora de uma cascata de alterações que impedem o normal processamento da imagem no córtex visual. Sugere-se que lesões do nervo óptico não foram as únicas responsáveis pelas alterações visuais observadas. Os principais fatores de risco para as alterações visuais observados pelo estudo transversal analítico foram o tempo de doença antes do início do tratamento e a resposta imunológica do paciente.

Cuidados essenciais e muitas vezes negligenciados na hospitalização de pequenos animais: nutrição e analgesia

The benefits of proper nutrition and analgesia are closely linked when it comes to animals that are suffering from any illness and are hospitalized. In patients who are ill or under the stress of hospitalization, increase secretion of glucagon, catecholamines, cortisol and growth hormone antagonize the effects of insulin, leading to hyperglycemia and degradation of tissue proteins to provide substrate for gluconeogenesis. These changes result in loss of lean body mass, reflecting negatively on tissue repair processes, immune response and prognosis. Likewise, the pain induced by noxious stimulation can lead to protein catabolism, stress, immunosupression, delayed wound healing and acceleration of disease processes. This review confirms the nutrition and pain control importance in hospitalized patients, showing their physiological benefits and reduction in hospital stay when the clinician understands these benefits and the animals are treated with such care

Significado de la Leucopenia en pacientes con bacteriemia

Objetivo: Evaluar parámetros clínicos, bacteriológicos y morbimortalidad de las bacteriemias en pacientes con leucopenia (<4.000 leucocitos/mm 3) y compararlas con bacteriemias con leucocitosis (>12.000/mm3). Material y métodos: Estudio protocolizado, descriptivo y observacional en pacientes con 2 o más hemocultivos positivos para el mismo germen hospitalizados en un servicio de clínica médica desde Marzo de 1989 a Agosto de 2007. Resultados: Se identificaron 728 bacteriemias, 94 (12,91%) con leucopenia (Grupo A) y 407 (55,90%) con leucocitosis (Grupo B). La edad media fue de 55,57 años (DS±16,93) en A y de 58,40 años (DS±17,34) en B. No hubo diferencias en la permanencia media: 19,59 días (DS±18,67) en A vs 21,21 (DS±19,53) en B ni en el sexo masculino (65,96 vs 57,25%)(pNS). La adquisición nosocomial (57,44 vs 40,29%) y el foco desconocido (25,53 vs 9,33%) y abdominal (17,14 vs 9,21%) fueron más frecuentes en A (p<0.01). La comorbilidad mayor (82,98 vs 41,24%), neoplasias (45,74 vs 12,84%) y la inmunosupresión (31,91 vs 6,17%) fueron significativas en A (p<0.01). La anemia (86,17 vs 62,40%) y la trombocitopenia (84,04 vs 25,06%) predominaron en A (p<0.01). Los Bacilos Gram Negativos predominaron en A (61,71 vs 37,83%)(p<0.01) [Klebsiella (17,02 vs 9,82%) y Pseudomonas (10,64 vs 1,47%) las más frecuentes (p<0.05)] y en B fue más frecuente S. aureus (31,69 vs 11,70%)(p<0.01). La mortalidad fue de 39,36% en A y 25,30% en B (p=0.006) y se asoció en el grupo A a mayor mortalidad en las primeras 24 horas (32,43 vs 16,50%), inmunosupresión (27,02 vs 7,76%), neumococcemias (52,94 vs 23,07%), sepsis (100 vs 88,35%) y trombocitopenia (75,67 vs 30,09%)(p<0,01).- Conclusiones: Las bacteriemias en pacientes leucopénicos comparadas con aquellas con leucocitosis se asociaron significativamente a adquisición nosocomial, foco desconocido y abdominal, presencia de comorbilidad mayor, neoplasias e inmunosupresión, a bacteriemias por Klebsiella y Pseudomonas y a significativa mayor mortalidad. Palabras claves: leucopenia, bacteriemias

Esclerosis múltiple. : nuestra experiencia

Objetivos: analizar la experiencia obtenida y evaluar los resultados urodinámicos del estudio de 18 pacientes con esclerosis múltiple. Material y Métodos: se estudiaron 18 casos, valorándose la historia clínica, ecografía vesical y renal, analizándolos urodinámicamente con uroflujometría, residuo post miccional (RPM), cistotonometría y electromiografía esfinteriana. Urocultivo y antibiograma de orina. Resultados: del análisis de todas las variables se desprende que la vejiga hiperactiva se presentó en 10 casos con un predominio del síndrome frecuencia-urgencia, vejiga hipotónica-hiporrefléxica en 5 pacientes, disinergia detrusor-esfínter en 4 casos y 9 pacientes con infección urinaria que desencadenaban crisis de espasticidad. Todos fueron tratados con anticolinérgicos de acción vesical inmuno-modulación (brotes-recaídas) e inmuno-supresión en la enfermedad progresiva, de rehabilitación y terapia de apoyo psicológico. Conclusión: la vejiga hiperactiva es el tipo de consecuencia urinaria de la esclerosis en placa con los síntomas de frecuencia-urgencia y que, con tratamiento multimodal mejoran en un alto porcentaje.