RESUMO
The non-operative management of hemodynamically stable patients with liver trauma has become the standard of care. Non-operative treatment has a success rate of >80%. In the majority of cases of hemodynamic instability or high grade liver injuries, however, a surgical approach is necessary. As for conservative treatment of liver trauma the surveillance of patients in the ICU is of utmost importance. Repeat CT scans are only necessary in patients with high grade injuries or in case of complications. Interventional procedures, such as the endoscopic retrograde cholangiopancreatography in cases of biliary complications or angiography for vascular complications, are increasingly being used in order to avoid surgery. The success rates of non-operative strategies have been improving continuously over the last decades.
Assuntos
Traumatismos Abdominais/diagnóstico por imagem , Traumatismos Abdominais/terapia , Fígado/diagnóstico por imagem , Fígado/lesões , Traumatismos Abdominais/complicações , Traumatismos Abdominais/cirurgia , Colangiopancreatografia Retrógrada Endoscópica , Embolização Terapêutica , Endoscopia , Vesícula Biliar/lesões , Doenças da Vesícula Biliar/diagnóstico por imagem , Hemodinâmica , Humanos , Peritonite/diagnóstico por imagem , Peritonite/terapia , Stents , Tomografia Computadorizada por Raios X/métodosRESUMO
Sometimes intravenous administration of cyclosporine (CsA) is essential before oral administration is possible. There are only a few reports available on the interindividual variability of CsA metabolism and different metabolite pattern depending on intravenous versus oral administration of CsA in heart transplant (HTx) patients. For effective inhibition of calcineurin we used a short infusion reaching peak concentrations after 2 hours. In a prospective cross-over study we compared the pharmacokinetics of CsA and its metabolites after oral (2.0 mg/kg body weight) versus intravenous (0.7 mg/kg body weight; 2-hour infusion) CsA administration (single test dose) in 7 pre-HTx patients. The pharmacokinetic parameters of CsA and its metabolites were analyzed using high-pressure liquid chromatography. The pharmacokinetic parameter area under the concentration time curve (AUC(0-infinity)) of CsA after intravenous administration was significantly lower (2903 ng*h*mL(-1)) than that after oral administration (4344 ng*h*mL(-1); P=.01). Peak concentrations, time to peak concentration, and terminal elimination half life were not significantly different. Short-time infusion of CsA resulted in a significant decrease in the AUC of the metabolites AM1 (3-fold), AM9 (10-fold), and AM1c (3-fold). A 2-hour infusion of CsA is just as effective as oral administration and the reduced amount of metabolites is advantageous for the patient.
Assuntos
Ciclosporina/farmacocinética , Transplante de Coração/imunologia , Administração Oral , Adulto , Idoso , Estudos Cross-Over , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Estudos ProspectivosRESUMO
We describe a case of a 39-year-old male, who initially presented with severe muscle pain, fever, shortness of breath and tachycardia. He was admitted to hospital with suspected myocarditis. The next days he developed a generalized icterus and acute renal failure. Suspecting leptospirosis an intravenous therapy with penicillin was started. Due to pulmonary and circulatory insufficiency intensive care was necessary. In course the patient developed all known manifestations of leptospirosis including, cardiac arrhythmia and asystolia due to AV-block III degrees, recurrent atelectases of the lungs, hyperbilirubinemia, thrombocytopenia, hepatitis, pancreatitis, very severe rhabdomyolysis and polyradiculitis with areflexia and tetraplegia. Additionally, the patient had a transient hyperthyreosis, which has not been described in the literature so far. After 33 days the patient left the intensive care unit and was discharged out of hospital a fortnight later. 4 weeks later he was able to return to work. The only residuum of this illness is a partial paresis of his right quadriceps muscle.
Assuntos
Insuficiência de Múltiplos Órgãos/diagnóstico , Doença de Weil/diagnóstico , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/terapia , Adulto , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Cuidados Críticos , Bloqueio Cardíaco/diagnóstico , Bloqueio Cardíaco/terapia , Hepatite/diagnóstico , Hepatite/terapia , Humanos , Hipertireoidismo/diagnóstico , Hipertireoidismo/terapia , Masculino , Insuficiência de Múltiplos Órgãos/terapia , Atelectasia Pulmonar/diagnóstico , Atelectasia Pulmonar/terapia , Quadriplegia/diagnóstico , Quadriplegia/terapia , Viagem , Doença de Weil/terapia , Doença de Weil/transmissãoRESUMO
We developed a universal LC-mass spectrometry assay with automated online extraction (LC/LC-MS) to quantify the immunosuppressants cyclosporine, tacrolimus, sirolimus and SDZ-RAD alone or in combination in whole blood. After protein precipitation, samples were loaded on a C18 extraction column, were washed and, after activation of the column-switching valve, were backflushed onto the C8 analytical column. [M+Na]+ ions were detected in the selected ion mode. For tacrolimus, sirolimus and SDZ-RAD, the assay was linear from 0.25 to 100 microg/l and for cyclosporine from 7.5 to 1250 microg/l (all r2>0.99). Analytical recovery was >85% and, in general, inter-day, intra-day variability for precision and accuracy were <10%.
Assuntos
Cromatografia Líquida/métodos , Imunossupressores/sangue , Espectrometria de Massas/métodos , Automação , Calibragem , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIMS: The aim of the study was to investigate the pharmacokinetics and metabolism of the new immunosuppressant SDZ RAD during concomitant therapy with cyclosporin in stable renal transplant patients. Furthermore, we studied the influence of SDZ RAD on the pharmacokinetics of cyclosporin at steady state levels. METHODS: SDZ RAD was administered orally in different doses (0.25-15 mg day-1) to seven patients, who were on standard cyclosporin-based immunosuppression. The blood concentrations of both drugs including their main groups of metabolites were measured simultaneously by LC/electrospray-mass spectrometry. RESULTS: The mean area under the blood concentration-time curve to 12 h (AUC(0,12 h)) was 4244 +/- 1311 microg l-1 h for cyclosporin before SDZ RAD treatment and 4683 +/- 1174 microg l-1 h (P = 0.106) on the day of SDZ RAD treatment (95% CI for difference -126, 1003). On both study days Cmax, and tmax of cyclosporin were not significantly different. The metabolite pattern of cyclosporin did not change. The pharmacokinetic data of SDZ RAD dose-normalized to 1 mg SDZ RAD were as follows: AUC(0,24 h): 35.4 +/- 13.1 microg l-1 h, Cmax: 7.9 +/- 2.7 microg l-1 and tmax: 1.5 +/- 0.9 h. The metabolites of SDZ RAD found in blood were hydroxy-SDZ RAD, dihydroxy-SDZ RAD, demethyl-SDZ RAD, and a ring-opened form of SDZ RAD. CONCLUSIONS: A single dose of SDZ RAD did not influence significantly the pharmacokinetics of cyclosporin. The most important metabolite of SDZ RAD was the hydroxy-SDZ RAD, its AUC(0,24 h) being nearly half that of the parent compound SDZ RAD.
Assuntos
Ciclosporina/farmacocinética , Imunossupressores/farmacologia , Transplante de Rim , Sirolimo/análogos & derivados , Sirolimo/farmacocinética , Administração Oral , Adulto , Cromatografia Líquida , Ensaios Clínicos Fase I como Assunto , Ciclosporina/sangue , Ciclosporina/metabolismo , Ciclosporinas/sangue , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Everolimo , Feminino , Humanos , Hidroxilação , Imunossupressores/sangue , Imunossupressores/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Sirolimo/sangue , Sirolimo/metabolismo , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
PURPOSE: In patients undergoing cytokine therapy, systemically applied interleukin-2 (IL-2) and/or interferon-alpha (IFN-alpha) have been reported to induce thyroid dysfunction as well as thyroid autoantibodies. We analyzed the correlation of thyroid autoimmunity with HLA phenotype, various other autoimmune parameters, and patient survival. PATIENTS AND METHODS: For this purpose, antithyroglobulin autoantibodies, antimicrosomal thyroid autoantibodies, thyroglobulin receptor autoantibodies, thyroid dysfunction, and multiple clinical parameters were determined in 329 unselected patients with metastatic renal cell cancer before and after systemic IL-2 and IFN-alpha2 therapy. For statistical analysis, we used both univariate and multivariate Cox proportional hazards models and the two-tailed Fisher's exact test. RESULTS: Antithyroglobulin autoantibodies and antimicrosomal thyroid autoantibodies were detected in 60 patients (18%); positive autoantibody titers of various other autoimmune parameters were statistically unrelated. The presence of thyroid autoantibodies was correlated with prolonged survival (P<.0001). There was a statistically significant difference in frequencies of HLA-Cw7 expression between thyroid autoantibody-positive and -negative patients (P< or =.05), and the Cw7 expression was associated with prolonged overall survival (P = .009). CONCLUSION: The evaluation of thyroid autoantibodies during cytokine therapy could be a useful prognostic marker for patients with renal cell carcinoma who benefit from cytokine treatment. IL-2- and IFN-alpha2-induced tumor control and prolonged survival may require breaking of immunologic tolerance against self-antigens.
Assuntos
Autoimunidade/efeitos dos fármacos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Adulto , Idoso , Anticorpos Antineoplásicos/sangue , Autoanticorpos/sangue , Carcinoma de Células Renais/secundário , Feminino , Antígenos HLA/imunologia , Humanos , Imunoterapia , Interleucina-2/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Análise de Sobrevida , Doenças da Glândula Tireoide/etiologia , Doenças da Glândula Tireoide/imunologiaRESUMO
An analytic technique using liquid chromatography (LC) coupled with electrospray-mass spectrometry (ESI-MS) has been developed for the simultaneous determination of the new immunosuppressant SDZ RAD (40-O-[2-hydroxy)ethylrapamycin) and cyclosporine (Cs), including their metabolites in blood. With the time-sparing, automated on-line extraction technique, the recovery of SDZ RAD averaged 95% and that of Cs, 94%. The calibration lines were linear from 0.5 to 100 microg/L (r2 = 0.99) for SDZ RAD and from 10 to 1,000 microg/L (r2 = 0.99) for Cs. The method has been tested on blood samples from renal transplant recipients taken between 1 and 5 hours after oral SDZ RAD and Cs administration. In blood, we found the following metabolites: Hydroxy-SDZ RAD, dihydroxy-SDZ RAD, demethyl-SDZ RAD, and the ring-opened form of SDZ RAD. The main metabolite of SDZ RAD in blood was hydroxy-SDZ RAD. This novel LC/ESI-MS technique provided an excellent method for simultaneous quantitative monitoring of SDZ RAD and Cs, including their relevant groups of metabolites in patients treated simultaneously with these immunosuppressants.
Assuntos
Ciclosporina/sangue , Imunossupressores/sangue , Sirolimo/análogos & derivados , Cromatografia Líquida de Alta Pressão , Ciclosporina/metabolismo , Everolimo , Humanos , Imunossupressores/metabolismo , Espectrometria de Massas , Sirolimo/sangue , Sirolimo/metabolismoRESUMO
We developed a sensitive and specific semi-automated liquid chromatography-electrospray mass spectrometric (HPLC-ESI-MS) assay for the simultaneous quantification of sirolimus and ciclosporin in blood. Following a simple protein precipitation step, the supernatants were injected into the HPLC system and extracted on-line. After column switching, the analytes were backflushed from the extraction column onto the analytical narrow-bore column and eluted into the ESI-MS system. The assay was linear from 0.4 to 100 microg/l sirolimus and from 2 to 1500 microg/l ciclosporin. The mean recoveries of sirolimus and ciclosporin were 98 and 96%, respectively. The mean interday precision/accuracy was 8.6%/-4.8% for sirolimus and 9.3%/-2.9% for ciclosporin.
Assuntos
Ciclosporina/sangue , Imunossupressores/sangue , Sirolimo/sangue , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Espectrometria de Massas , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
SDZ RAD [40-O-(2-hydroxyethyl)rapamycin] is a macrolide immunosuppressant that is currently under clinical investigation after organ transplantation. The elucidation of its metabolic pathway is essential to improve the understanding of its therapeutic potentials and safety. In this article we describe investigations on the structural identification of some major metabolites of the drug produced by human liver microsomes in vitro. The principles described may be generally applicable for the structural elucidation of complex compound mixtures in biological matrices. Under the conditions of electron impact ionization, SDZ RAD undergoes extensive fragmentation and no information sufficient for structural elucidation is obtained. Therefore, mass spectrometry based on soft electrospray ionization (ESI) in conjunction with collision-induced fragmentation was the method of choice. High-performance liquid chromatography coupled to an ESI mass spectrometer resulted in separation and identification of 16-O-demethyl-SDZ RAD, the ring-opened form of SDZ RAD, and its dehydrate. Additionally, we characterized several demethylated and hydroxylated metabolites.
Assuntos
Imunossupressores/química , Imunossupressores/metabolismo , Sirolimo/análogos & derivados , Cromatografia Líquida de Alta Pressão , Everolimo , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Técnicas In Vitro , Espectrometria de Massas , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Sirolimo/química , Sirolimo/metabolismoRESUMO
AIMS: The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin-2 (rhIL-2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens. METHODS: RhIL-2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20 x 10(6) IU m(-2) once daily and group B 10 x 10(6) IU m(-2) twice daily (every 12 h). Additionally, in all patients the influence of soluble interleukin-2 receptor (sIL-2R) on the pharmacokinetics of rhIL-2 was investigated. RESULTS: The mean area under the serum concentration-time curve to 24 h (AUC(0,24 h)) was 627 IU ml(-1) h in treatment group A and 1130 IU ml(-1) h (P=0.029) in treatment group B. In both study groups Cmax and AUC(0,12 h) were not significantly different. Seventy-two hours after the beginning of s.c. rhIL-2 therapy the sIL-2R increased significantly (P=0.016), and sIL-2R levels over 1200 pmol l(-1) seemed to reduce the AUC. CONCLUSIONS: In patients with metastatic renal cell cancer administration of 20 x 10(6) IU m(-2) of rhIL-2 s.c. in two daily doses (10 x 10(6) IU m(-2) every 12 h) provides better bioavailability and is preferable to the single dose administration.
Assuntos
Carcinoma de Células Renais/terapia , Interleucina-2/farmacocinética , Neoplasias Renais/terapia , Idoso , Disponibilidade Biológica , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Interleucina-2/administração & dosagem , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinéticaRESUMO
A new analytical method to quantify 40-O-(2-hydroxyethyl)rapamycin (SDZ RAD) and cyclosporine (Cs) simultaneously in blood is presented. The combination of an on-line solid-phase extraction step with an HPLC system coupled to an electrospray mass spectrometer gave excellent specificity, sensitivity, and reproducibility. Aliquots of deproteinized blood samples were injected into the HPLC system and extracted on-line, using a conventional C18 guard column. The extract was eluted from the guard column in the backflush mode and injected into the liquid chromatography-mass spectrometry system. The calibration functions for SDZ RAD and Cs extracted from blood with added analyte were linear from 0.15 to 30 microg/L (r2 = 0.999) and from 1.5 to 1000 microg/L (r2 = 0.999), respectively. The CVs of peak areas were 6.2% at 10 microg/L SDZ RAD (n = 6) and 6.2% at 100 microg/L Cs (n = 6). Recovery ranged from 84.3% to 102.3% for SDZ RAD and from 81.7% to 92.2% for Cs. The lower limit of detection for both drugs was 0.05 microg/L. A rate of four samples per hour was maintained during the consecutive analysis of SDZ RAD and Cs in >500 blood samples with one single extraction and analytical column. The method described is a powerful tool for the simultaneous determination of SDZ RAD and Cs in blood. It works without time-consuming sample preparation steps and with excellent reproducibility. Because of the detection performance of electrospray mass spectrometry, this system offers flexibility in the working range, which is essential for therapeutic drug monitoring under different conditions.