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1.
Transplantation ; 91(7): 779-85, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21297553

RESUMO

BACKGROUND: Efficacy and safety of an intensified dosing (ID) regimen of enteric-coated mycophenolate sodium (EC-MPS), which achieves higher mycophenolic acid exposure early posttransplantation, were evaluated in comparison with a standard dosing (SD) regimen. METHODS: In total, 128 de novo kidney transplant recipients treated with basiliximab induction, cyclosporine A, and steroids were randomized (1:1) to receive EC-MPS as SD (1440 mg/day; n=65) or ID (days 0-14: 2880 mg/day; days 15-42: 2160 mg/day; followed by 1440 mg/day; n=63). Efficacy parameters, safety, and tolerability were assessed over a 6-month study period. The primary endpoint was mean time to first occurrence of treatment failure. RESULTS: Mean time to treatment failure was 130 days (95% confidence interval [CI]: 81-n/a) in the ID group versus 114 days (95% CI: 15-155) in the SD group (P=0.36). Similar percentages (ID 30.2%; SD 36.9%) experienced treatment failure. Biopsy-proven acute rejection occurred in 2 (3.2%) ID versus 11 (16.9%) SD patients (P<0.001). Three (2.3%) deaths (2 SD, 1 ID) and five (3.9%) graft losses (3 SD, 2 ID) occurred. Renal function, incidence of infection, and hematologic disorders were comparable in both study cohorts. Gastrointestinal disorders occurred in 51 (81.0%) ID and 49 (75.4%) SD patients with overall similar tolerability as assessed by the Gastrointestinal Symptom Rating Scale. CONCLUSION: In this exploratory study, the EC-MPS ID regimen reduced the incidence of rejection and showed a comparable safety and tolerability profile to SD. Further examination of this approach in a larger patient cohort is now warranted to confirm these findings.


Assuntos
Transplante de Rim , Ácido Micofenólico/administração & dosagem , Adulto , Idoso , Feminino , Rejeição de Enxerto , Humanos , Imunossupressores/administração & dosagem , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Estudos Prospectivos , Comprimidos com Revestimento Entérico
2.
Clin J Am Soc Nephrol ; 5(3): 503-11, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20150450

RESUMO

BACKGROUND AND OBJECTIVES: Adequate early mycophenolic acid (MPA) exposure is an important determinant for effective rejection prophylaxis. This pharmacokinetic study investigated whether an intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) could achieve higher mycophenolic acid (MPA) exposure early after transplantation versus a standard dosing regimen. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: De novo kidney transplant recipients (n = 75) who were treated with basiliximab induction and cyclosporine were randomly assigned to receive EC-MPS as either standard dosing (1440 mg/d; n = 37) or intensified dosing (days 0 through 14: 2880 mg/d; days 15 through 42: 2160 mg/d; followed by 1440 mg/d; n = 38). Full 12-hour pharmacokinetic and pharmacodynamic profiles were taken at six time points during the first 3 months. Exploratory analysis of inosine monophosphate dehydrogenase (IMPDH) activity was also performed for better understanding of the pharmacokinetic-pharmacodynamic relationship between MPA exposure and IMPDH activity in the early posttransplantation period. Preliminary efficacy parameters, safety, and tolerability were assessed. RESULTS: Exposure to MPA was significantly higher on days 3 and 10 after transplantation in the intensified versus standard EC-MPS group, with 52.9 versus 22.2% (P < 0.05) of patients reaching MPA exposure >40 mg/h per L in the first week. The intensified regimen resulted in significantly lower IMPDH activity on day 3 after transplantation, and the overall safety was comparable for both groups. CONCLUSIONS: These pharmacokinetic and safety data support further research on the hypothesis that early adequate MPA exposure could improve clinical outcome.


Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Transplante de Rim , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , Administração Oral , Adulto , Anticorpos Monoclonais/administração & dosagem , Área Sob a Curva , Basiliximab , Distribuição de Qui-Quadrado , Ciclosporina/administração & dosagem , Quimioterapia Combinada , Estudos de Viabilidade , Feminino , Alemanha , Rejeição de Enxerto/imunologia , Humanos , IMP Desidrogenase/sangue , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Projetos Piloto , Estudos Prospectivos , Proteínas Recombinantes de Fusão/administração & dosagem , Comprimidos com Revestimento Entérico , Fatores de Tempo , Resultado do Tratamento
3.
Neuropeptides ; 43(6): 483-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19864020

RESUMO

Nitric oxide (NO) donors induce delayed headaches in migraineurs. In a corresponding rat model NO donors cause delayed ongoing activity in central trigeminal neurons which process intracranial afferent input. Cellular models indicate that NO may increase the release or production of calcitonin gene-related peptide (CGRP), a key mediator in primary headaches. CGRP release from intact isolated trigeminal ganglia of adult male Wistar rats was investigated in vitro. Exposure to high NO donor concentrations did not affect basal or stimulated CGRP release. After a two hour infusion of the NO donor glyceroltrinitrate (250microg/kg/h), however, inflammatory mediators-induced CGRP release was 80% higher compared to control animals. Administration of the soluble guanylate cyclase inhibitor ODQ or the application of 8Br-cGMP revealed a cGMP-independent mechanism. In four groups of separate experiments total mRNA was extracted from rat trigeminal ganglia up to 6h after glyceroltrinitrate or saline infusion. Gene expression of CGRP and the CGRP-receptor components, receptor activity-modifying protein 1, receptor component protein and calcitonin receptor-like receptor was measured by quantitative RT-PCR. Glyceroltrinitrate infusion did not change mRNA levels of these genes compared to infusion of saline. The present data suggest that prolonged increase in NO levels facilitates stimulated CGRP release from trigeminal ganglion neurons. The underlying mechanism appears to be independent of the cGMP pathway and not to interact with CGRP in the trigeminal ganglion. Delayed headaches induced by NO may change CGRP or CGRP-receptor expression.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Nitroglicerina/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/fisiologia , Vasodilatadores/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genética , Gânglio Trigeminal/citologia
4.
J Am Soc Nephrol ; 19(7): 1371-8, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18400940

RESUMO

Increasing evidence indicates that inflammation of visceral organs is significantly affected by the autonomic nervous system. Such neuroimmune interactions have not been studied in the kidney. Here, we show that the rat kidney is innervated by both tyrosine hydroxylase-positive sympathetic efferent nerve fibers and calcitonin gene-related peptide-positive primary afferent nerve fibers, both of which are found in proximity to macrophages and dendritic cells. Complete surgical bilateral renal denervation was performed 2 d before glomerulonephritis was induced by injecting the monoclonal anti-Thy-1.1 antibody OX-7. Denervation significantly reduced albuminuria, mesangiolysis, formation of microaneurysms, deposition of glomerular collagen IV, and expression of TGF-beta compared with sham-operated controls. Accordingly, inflammation, identified by accumulation of interstitial macrophages and renal expression of TNF-alpha, and mesangial cell proliferation were significantly reduced. These findings indicate that autonomic renal denervation ameliorates and, by inference, innervation exacerbates acute inflammation in the kidney; therefore, neurotransmitters or neuropeptides and their receptors might represent novel targets for the treatment of acute glomerulonephritis.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Glomerulonefrite/fisiopatologia , Rim/inervação , Animais , Denervação , Glomerulonefrite/patologia , Rim/patologia , Ratos , Ratos Sprague-Dawley , Antígenos Thy-1/imunologia
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