RESUMO
The Seismic Experiment for Interior Structure (SEIS) of the InSight mission to Mars, has been providing direct information on Martian interior structure and dynamics of that planet since it landed. Compared to seismic recordings on Earth, ground motion measurements acquired by SEIS on Mars are made under dramatically different ambient noise conditions, but include idiosyncratic signals that arise from coupling between different InSight sensors and spacecraft components. This work is to synthesize what is known about these signal types, illustrate how they can manifest in waveforms and noise correlations, and present pitfalls in structural interpretations based on standard seismic analysis methods. We show that glitches, a type of prominent transient signal, can produce artifacts in ambient noise correlations. Sustained signals that vary in frequency, such as lander modes which are affected by variations in temperature and wind conditions over the course of the Martian Sol, can also contaminate ambient noise results. Therefore, both types of signals have the potential to bias interpretation in terms of subsurface layering. We illustrate that signal processing in the presence of identified nonseismic signals must be informed by an understanding of the underlying physical processes in order for high fidelity waveforms of ground motion to be extracted. While the origins of most idiosyncratic signals are well understood, the 2.4 Hz resonance remains debated and the literature does not contain an explanation of its fine spectral structure. Even though the selection of idiosyncratic signal types discussed in this paper may not be exhaustive, we provide guidance on best practices for enhancing the robustness of structural interpretations.
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OBJECTIVES: Implement a sensitive UHPLC method for the assay of ganciclovir in human plasma. DESIGN AND METHODS: We developed and validated a chromatographic method coupled to ultraviolet detection for quantification of ganciclovir, with a short run time using a small volume of human plasma. Comparison of system performance was made with respect to analysis time, efficiency and sensitivity. RESULTS: Correlation coefficients (r) of the calibration curves ranged from 0.999744 to 0.999784. Within-day and between-day imprecision and inaccuracy, specificity and recovery were also evaluated for validation. The method was precise and accurate and the retention time was 0.7 min. The calibration curves were linear between 0.5 and 30 µg/mL. There was a good correlation between HPLC and UHPLC techniques. CONCLUSIONS: We developed a method that is currently applied in a clinical study assessing GCV plasma concentration variability after ganciclovir and valganciclovir administration.
Assuntos
Antivirais/sangue , Ganciclovir/sangue , Calibragem , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Espectrofotometria UltravioletaRESUMO
Oral (p.o.) or intravenous (IV) ganciclovir (GCV) has been the first-line agent for prevention and treatment of cytomegalovirus (CMV) infection and disease in solid organ transplantation (SOT). The introduction of p.o. valganciclovir, with higher bioavailability than p.o. GCV, has proven to be a suitable approach toward outpatient p.o. therapy for CMV infection/disease. The present single-arm, exploratory pilot trial performed with 21 patients investigates the efficacy and safety of a short therapeutic course (21 days) based on an initial IV treatment with GCV (5 mg/kg twice daily, for 5 days) followed by p.o. valganciclovir (900 mg twice daily, for 16 days) for CMV infection/disease in SOT patients. In all cases, doses were adjusted for renal function. Moreover, the study allowed comparison of exposure to GCV after p.o. valganciclovir with respect to IV GCV in the same patients. Response to treatment was monitored until day 180. Viral load eradication was achieved in 66.7% of patients, on day 21. Although not statistically significant, a trend was seen toward increased persistence of viral load on day 21 for patients with donor positive/recipient negative CMV serostatus or receiving either anti-rejection therapy or polyclonal anti-thymocyte globulin. CMV clinical infection recurred in 14.3% of patients, with higher recurrence rates in patients with risk factors for persistence of viremia. Exposures to GCV after using IV GCV or p.o. valganciclovir showed comparable values (P=0.054). This short course, combining initial IV GCV and subsequent p.o. valganciclovir, may provide effective exposure and therapeutic response in the treatment of CMV infection in SOT patients with adequate drug exposure and with the additional potential benefit of shortening the length of hospital stay, which may result in cost reduction and improved patient comfort.
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Antivirais , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Transplante de Órgãos/efeitos adversos , Administração Oral , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacologia , Antivirais/uso terapêutico , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Esquema de Medicação , Quimioterapia Combinada , Feminino , Ganciclovir/administração & dosagem , Ganciclovir/efeitos adversos , Ganciclovir/farmacocinética , Ganciclovir/uso terapêutico , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , ValganciclovirRESUMO
A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CL(CR)) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49.(CL(CR)/57) liter/h (57 was the mean population value of CL(CR)); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h(-1); bioavailability was 0.825; and lag time was 0.382 h. The CL(CR) was the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure.
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Antivirais/farmacocinética , Ganciclovir/análogos & derivados , Ganciclovir/farmacocinética , Transplante de Órgãos/efeitos adversos , Administração Oral , Adulto , Idoso , Área Sob a Curva , Infecções por Citomegalovirus/tratamento farmacológico , Feminino , Ganciclovir/administração & dosagem , Humanos , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Estudos Prospectivos , ValganciclovirRESUMO
OBJECTIVE: Our aim was to assess our experience with the use and management of everolimus after orthotopic liver transplantation (OLT). MATERIALS AND METHODS: Among the 759 patients who underwent transplantation from 1988 to 2008, 25 (3.2%) received immunosuppression with everolimus. Their mean age was 55.6 years. We analyzed indications for use, time between transplantation and introduction of everolimus, as well as its efficacy, side effects, and patient survival. RESULTS: The indications for everolimus treatment were: extended hepatocellular carcinoma (HCC) in the explanted liver (n = 6; 24%); HCC recurrence during follow-up (n = 4; 16%); de novo tumor (n = 6; 24%); refractory rejection (n = 3; 12%); side effects of calcineurin inhibitors (CNI; n = 3; 12%); and other causes (n = 3; 12%). Mean time between OLT and everolimus treatment was 40 +/- 33 months (range, 10 days-178 months). Mean follow-up after conversion was 10 +/- 9 months (range, 1.5-25 months). More than half of the patients resolved the event for which the drug was indicated: 75% of patients with refractory rejection; 60% of those with renal insufficiency; and 100% of those converted for neurotoxicity or hepatotoxicity. Two patients with recurrent HCC and 1 with extended HCC died at a mean time of 10.5 months. The 6 cases of de novo tumors were operated and are healthy. Side effects were dyslipidemia in 8 and infection in 2. Five patients (20%) discontinued the drug. CONCLUSIONS: In the early posttransplantation period, everolimus is indicated for refractory rejection or as prophylaxis for recurrence of extended tumors. In any time but especially in the late period, everolimus is indicated for patients with serious side effects due to a CNI or to a de novo tumor.
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Imunossupressores/uso terapêutico , Transplante de Fígado/imunologia , Sirolimo/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/cirurgia , Everolimo , Feminino , Seguimentos , Humanos , Imunossupressores/efeitos adversos , Cirrose Hepática Alcoólica/cirurgia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva , Estudos Retrospectivos , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Análise de Sobrevida , Sobreviventes , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico , Fatores de TempoRESUMO
UNLABELLED: Preemptive therapy with ganciclovir has been recommended in the pediatric liver transplant strategy to avoid the development of posttransplant lymphoproliferative disorder (PTLD) from an high Epstein-Barr virus (EBV) is detected. We sought viral load to analyze the response to preemptive therapy with valganciclovir (VGC) in children with liver transplantations and an high quantitative EBV-PCR. METHODS: From June 2005 to December 2007, we tested 979 EBV-PCR among 80 pediatric liver transplant recipients, from those 21/80 PCR were tested from the date of transplantation and 59/80 belonged to the historical cohort (7/59 had a prior history of PTLD). Patients were divided into 2 groups depending upon whether they did (n = 22) or did not (n = 19) receive VGC treatment. The response to VGC was considered complete, if the PCR was negative at 30 and 60 days of treatment; and partial, when the PCR decreased at least 50%. Ganciclovir blood levels tested in 109 cases instances and correlated with the EBV-PCR. RESULTS: A total of 369 (33%) positive PCR were detected in 36/80 patients (mean, 75,000 copies; range = 5000-4,200,000). Among the 22 episodes treated for 30 days, 34% showed complete responses, 41%, partial, and 23%, no response. Among the non-treated group the rates were 6%, 25%, and 68%, respectively (P = .01). However, no differences were observed among those episodes treated for 60 days. At the administered doses, hardly any patient reached the recommended ganciclovir therapeutic level at 2 hours (6 micro/mL). However, the mean PCR was lower when the ganciclovir levels were greater than 4 mg/L when compared with lower levels (P = .03). CONCLUSION: After 30 days of treatment there was a response to VGC in the EBV viral load. There was high interpatient variability of ganciclovir serum concentrations, suggesting the need for pharmacokinetic monitoring to optimize treatment. There was a relationship between the concentration of ganciclovir and the EBV viral load.
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Antivirais/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Ganciclovir/análogos & derivados , Herpesvirus Humano 4/genética , Transplante de Fígado/métodos , Criança , Estudos de Coortes , Infecções por Vírus Epstein-Barr/genética , Ganciclovir/uso terapêutico , Genoma Viral/efeitos dos fármacos , Herpesvirus Humano 4/efeitos dos fármacos , Humanos , Transplante de Fígado/efeitos adversos , Reação em Cadeia da Polimerase/efeitos dos fármacos , Reação em Cadeia da Polimerase/métodos , Estudos Retrospectivos , Valganciclovir , Carga ViralRESUMO
BACKGROUND: Studies of mycophenolate mofetil (MMF) in primary glomerulonephritis have varied in their inclusion criteria, regimen and follow-up compromising assessments of efficacy and optimal dose. METHOD: This multicentre study analysed the safety and efficacy of MMF monotherapy in a large cohort with primary glomerulonephritis that was resistant to other conventional therapies. A total of 98 patients with biopsy-proven primary glomerulonephritis resistant to other drugs received MMF monotherapy for 1 year. Primary outcome measures were urinary protein excretion and the number of patients with complete or partial remission of proteinuria. Secondary analyses were time to remission and changes in the slope of creatinine clearance. RESULTS: Fifty-four percent of the patients achieved either complete or partial remission of proteinuria with no significant differences between glomerulonephritis types. Median (range) dose of MMF was 2 g/day (1.5-2 g/day) Mean (SD) treatment time to remission was 141.5 (+/-61.1) days with no significant differences between glomerulonephritis types. Serum albumin increased (P<0.01), whereas proteinuria (P<0.01) serum LDL-cholesterol (P<0.01) and mean blood pressure (P<0.05) decreased post-treatment. No significant changes were observed in glomerular filtration rate (GFR), serum creatinine or slopes of GFR. The reduction of urinary protein excretion was significantly higher in patients with basal nephrotic proteinuria and preserved renal function; it did not arise from an increased dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, since, among responders, mean blood pressure significantly decreased and the number of anti-hypertensive drugs could be reduced. CONCLUSIONS: MMF monotherapy causes a moderate decrease in proteinuria in >50% of the patients who do not have other treatment options. The response to therapy is largely influenced by a preserved renal function and requires sustained MMF treatment.
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Glomerulonefrite/tratamento farmacológico , Imunossupressores/uso terapêutico , Ácido Micofenólico/análogos & derivados , Terapia de Salvação/métodos , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Creatinina/sangue , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glomerulonefrite/complicações , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Resultado do TratamentoRESUMO
OBJECTIVE: To describe the quality of professional life (QPL) as perceived by primary care workers and to measure the organizational climate (OC). To identify the influence of OC on QPL and the variables that explain this relationship. DESIGN: Cross-sectional study. SETTING: Primary care centres in the Menorca Health Area (Balearic Islands, Spain). PATIENTS: One hundred and sixty six primary care, including health-workers and others. MAIN MEASUREMENTS: Two anonymous, self-administered, PC-validated questionnaires were filled in: QPL-35 (dimensions: perception of demands, support from managers, and motivation) and OC (dimensions: team-work, cohesion, and commitment). Age, seniority, professional group, job relationship, and the health centre were analysed. RESULTS: Positive answers: 67.4%. Average QPL was 5.78, lower for older workers and higher among those perceiving more cohesion. Average score for perceived demands was 5.53, higher among physicians and less if there is high commitment. Support from managers was 4.9, positively associated with cohesion and team-work and negatively associated with permanent workers and clerical staff. Intrinsic motivation was 7.43, greater if commitment was higher. Regardless of age, professional category and seniority, there was a significant association between OC and QPL (strongest in the motivation [r2=0.26] and managerial support [r2=0.476] dimensions). CONCLUSIONS: OC influences QPL, especially in motivation and managerial support. Commitment enhances motivation and perception of demands. Where there is better cohesion and team-work, the manager s support is also rated more highly.
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Pessoal de Saúde , Satisfação no Emprego , Política Organizacional , Adulto , Estudos Transversais , Humanos , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To determine the mean time per meeting--visit--and per problem attended to in the doctor's office and their distribution according to the care procedure during the visit. DESIGN: Prospective study of the direct encounter in the doctor's office with a third person as timer. SETTING. Three doctors at 2 family medicine clinics (each with a list of about 2500 health cards). PARTICIPANTS: 316 health problems attended to in 289 direct encounters in the doctor's office. Main measurements. Total time according to type of direct encounter in the doctor's office and problem addressed. Determination of the time spent on each stage of the encounter. RESULTS: Mean time per direct encounter in the doctor's office of 9.1 minutes, and mean time per problem attended of 7.4 minutes, with a range from 76 seconds to 25 minutes. 84% were spontaneous visits, 13.5% were scheduled and 2.5% could not be put off/were urgent. Problems were mainly bureaucratic in 17% of cases, organic in 77.4 and psycho-social-family in 5.6%. Mean time devoted to advice and treatment was 2.4 minutes; that devoted to explanation of the problem, 18.3 seconds. The times varied according to the kind of problem, the doctor and the sex and age of the patient. CONCLUSIONS: Distribution of time during the medical visit depends on the kind of problem involved. The doctor and the age and sex of the patient also affect the question. The short time spent on the explanation of the problem suggests that the period for active listening should be extended.
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Medicina de Família e Comunidade , Visita a Consultório Médico/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Atenção Primária à Saúde , Estudos Prospectivos , Fatores de TempoRESUMO
The aim of this study was to determine whether cyclosporine levels predose (C0) and at two hours postdose (C2) were higher among patients presenting with cytomegalovirus (CMV) infection or disease. Between days 40 and 365 posttransplantation serial C0 and C2 levels were measured in 15 lung transplant recipients. Nine developed 13 episodes of CMV infection or disease. Both C0 and C2 levels were higher during CMV infection or disease episodes. Eleven of the 13 CMV episodes (84%) displayed C0 >220 ng/mL and none had C0 <200 ng/mL. For C2, 11 of 13 CMV episodes (84%) showed C2 >1200 ng/mL and none had C2 <1000 ng/mL. Among determinations that did not coincide with a CMV episode, 7 of 21 (33%) showed C0 >220 and 9 of 21 (42%) showed C2 >1200, respectively (P<.05). In conclusion, cyclosporine blood levels are higher among patients presenting with CMV infection or disease.
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Ciclosporina/sangue , Infecções por Citomegalovirus/epidemiologia , Imunossupressores/sangue , Transplante de Pulmão/imunologia , Adulto , Ciclosporina/farmacocinética , Ciclosporina/uso terapêutico , Infecções por Citomegalovirus/sangue , Feminino , Seguimentos , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Incidência , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Complicações Pós-Operatórias/virologia , Fatores de TempoRESUMO
To determine whether rifampicin reduces serum concentrations of nevirapine and whether nevirapine modifies serum concentrations of rifampicin, levels of these agents were determined at steady state by high-performance liquid chromatography in 10 HIV-infected patients with tuberculosis. The median area under the curve (AUC) 0-12h of nevirapine before and after rifampicin was 56.2 and 32.8 microg/ml per hour, respectively ( p =.04). This represents a 31% reduction in serum nevirapine concentrations. The C(max) decreased from 5.6 to 4.5 microg/ml ( p =.04), which represented a 36% reduction. A 21% decrease in the C(min) was not statistically significant. Exposure to rifampicin did not significantly differ between those patients who were receiving and were not receiving nevirapine. However, our study shows that rifampicin reduces serum exposure to nevirapine. The clinical implications for this reduction remain to be established. Given that the lowest trough serum concentration of nevirapine exceeded by more than 40 times the protein binding adjusted median infective dose (IC(50)) of wild-type HIV in all patients, we suggest that there is no need to increase nevirapine dosage when it is given with rifampicin.
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Fármacos Anti-HIV/farmacocinética , Antibióticos Antituberculose/farmacocinética , Infecções por HIV/metabolismo , Nevirapina/farmacocinética , Rifampina/farmacocinética , Tuberculose/metabolismo , Cromatografia Líquida de Alta Pressão , Interações Medicamentosas , Infecções por HIV/complicações , Humanos , Nevirapina/sangue , Rifampina/sangue , Tuberculose/complicaçõesRESUMO
To determine whether rifampin reduces concentrations of trimethoprim (TMP) and sulfamethoxazole (SMX) in serum of human immunodeficiency virus (HIV)-infected persons, levels of these agents were determined by high-performance liquid chromatography before and after more than 12 days of standard antituberculosis treatment for 10 patients who had been taking one double-strength tablet of co-trimoxazole once daily for more than 1 month. Statistically significant, 47 and 23% decreases in TMP and SMX mean areas under the concentration-time curve from 0 to 24 h (AUC(0-24)), respectively, were observed after administration of rifampin. N-Acetyl-SMX profiles without and with rifampin were similar. The steady-state AUC(0-24) metabolite/parent drug ratio increased by 32% with rifampin administration. Our study shows that rifampin reduces profiles of TMP and SMX in serum of HIV-infected patients.
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Anti-Infecciosos/farmacocinética , Antibióticos Antituberculose/efeitos adversos , Infecções por HIV/metabolismo , Rifampina/efeitos adversos , Combinação Trimetoprima e Sulfametoxazol/farmacocinética , Adulto , Anti-Infecciosos/sangue , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Interações Medicamentosas , Feminino , Humanos , Masculino , Combinação Trimetoprima e Sulfametoxazol/sangueAssuntos
Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Fígado/fisiologia , Tacrolimo/uso terapêutico , Administração Oral , Ciclosporina/administração & dosagem , Infecções por Citomegalovirus/epidemiologia , Quimioterapia Combinada , Rejeição de Enxerto/epidemiologia , Hepatite C/epidemiologia , Humanos , Imunossupressores/administração & dosagem , Transplante de Fígado/imunologia , Transplante de Fígado/mortalidade , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Recidiva , Reoperação , Estudos Retrospectivos , Taxa de Sobrevida , Tacrolimo/administração & dosagem , Fatores de TempoRESUMO
With the aim of investigating home therapy for enterococcal endocarditis, we compared the efficacy of teicoplanin combined with gentamicin given once a day or in three daily doses (t.i.d.) with the standard treatment, ampicillin plus gentamicin administered t.i.d., for treating experimental enterococcal endocarditis. The antibiotics were administered by using "human-like pharmacokinetics" (H-L), i.e, pharmacokinetics like those in humans, that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 10(8) CFU of Enterococcus faecalis EF91 (MICs and MBCs of ampicillin, gentamicin, and teicoplanin, 0.5 and 32, 16 and 32, and 0.5 and 1 microg/ml, respectively) and were treated for 3 days with ampicillin H-L at 2 g every 4 h plus gentamicin H-L at 1 mg/kg every 8 h, or teicoplanin H-L at 10 mg/kg every 24 h, alone or combined with gentamicin, administered at dose of H-L at 1 mg/kg every 8 h or H-L at 4.5 mg/kg every 24 h. The results of therapy for experimental endocarditis due to EF91 showed that teicoplanin alone was as effective as ampicillin alone in reducing the bacterial load (P > 0.05). The combination of ampicillin or teicoplanin with gentamicin was more effective than the administration of both drugs alone in reducing the log(10)CFU/gram of aortic vegetation (P < 0.01 and P < 0.05, respectively). Teicoplanin plus gentamicin H-L at 4.5 mg/kg, both administered every 24 h, showed an efficacy equal to the "gold standard," ampicillin plus gentamicin H-L at 1 mg/kg t.i.d. (P > 0.05). Increasing the interval of administration of gentamicin to a single daily dose combined with teicoplanin resulted in a reduction of bacteria in the vegetations equivalent to that achieved with the recommended regimen of ampicillin plus thrice-daily gentamicin in the treatment of experimental endocarditis due to E. faecalis. Teicoplanin plus gentamicin, both administered once a day, may be useful home therapy for selected cases of enterococcal endocarditis.
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Endocardite Bacteriana/tratamento farmacológico , Enterococcus faecalis/efeitos dos fármacos , Gentamicinas/uso terapêutico , Teicoplanina/uso terapêutico , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Endocardite Bacteriana/metabolismo , Gentamicinas/farmacocinética , Gentamicinas/farmacologia , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Coelhos , Teicoplanina/farmacocinética , Teicoplanina/farmacologia , Resultado do TratamentoRESUMO
Nevirapine is an antiretroviral agent belonging to the class of non-nucleoside reverse transcriptase inhibitors. We describe a fast, simple isocratic reversed-phase high-performance liquid chromatography method with a 30-mm long column for assaying nevirapine in human serum. After deproteinization of 200 microl serum samples with 50% trichloroacetic acid, the supernatant was injected into a reversed-phase C18 column, using 10 mM phosphate buffer (pH 5)-acetonitrile (82:18, v/v) as the mobile phase. Peak detection was performed at 240 nm. Nevirapine retention time was 2 min. The method was validated over 0.1-10 microg/ml and the assay was linear over this concentration range (r2>0.998). Within- and between-day precisions were less than 5.4%. The lower limit of quantification was 0.1 microg/ml. Nevirapine in human serum samples was stable for 2 days at 20-25 degrees C, 15 days at 4 degrees C and 3 months at -20 degrees C.
Assuntos
Fármacos Anti-HIV/sangue , Cromatografia Líquida de Alta Pressão/métodos , Nevirapina/sangue , Inibidores da Transcriptase Reversa/sangue , Calibragem , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria UltravioletaRESUMO
Mycophenolate mofetil (MMF) in combination with cyclosporine (CsA) or Tacrolimus (TAC) has been show to be a potent immunosuppressive agent. The authors assessed the mycophenolic acid (MPA) plasma levels achieved in clinical practice and evaluated the effect of concomitant administration of CsA and TAC . One hundred forty transplant patients (kidney: 120 and lung: 20) received a triple immunosuppression regimen of CsA or TAC, prednisone and MMF. Twenty-two renal transplant patients received double therapy with MMF and prednisone. There was no correlation between MMF dose and MPA trough concentrations (r = -0.0657). The medians (range) of the MPA dose-to-concentration ratio (D/C) in the CsA and TAC groups were 0.90 (0.11-8.33) and 0.56 (0.11-14.3), respectively (p < 0.0001). According to the post transplant period (1-3, 4-6 and >6 months), D/C values were significantly lower in patients receiving MMF and TAC than those receiving MMF and CsA in all three periods. MPA levels in patients treated with MMF and CsA were significantly lower than those obtained in double therapy. The D/C ratio in CsA-treated patients, increased significantly (p = 0.0005) when CsA level increased. There was no relationship between D/C ratio and TAC blood concentrations. These results suggest that CsA exerts an influence on MPA trough levels, although further work is required to characterize the mechanism of interaction.
Assuntos
Imunossupressores/sangue , Ácido Micofenólico/sangue , Adulto , Idoso , Ciclosporina/efeitos adversos , Interações Medicamentosas , Feminino , Humanos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/farmacocinética , Tacrolimo/efeitos adversosRESUMO
Mycophenolate mofetil is a highly effective immunosuppressant drug used in the prophylaxis of organ rejection in combination with cyclosporine or tacrolimus and corticosteroids. The present study is a retrospective data analysis of the routinely estimated mycophenolic acid plasma trough levels in 60 transplant patients (kidney, n = 49; lung, n = 11) receiving mycophenolate mofetil in combination with prednisone and cyclosporine (n = 45) or tacrolimus (n = 15). Coadministration of cyclosporine instead of tacrolimus resulted in a significant increase of median (range) of the ratio of dose-to-concentration 0.92 (0.11-8.33) (n=167) versus 0.38 (0.11-14.28) (n = 66); P < 0.0001. No correlation was seen between mycophenolate mofetil dose and mycophenolic acid trough concentrations. The dose-to-concentration in cyclosporine-treated patients increased significantly (P<0.0001) as the cyclosporine level increased, suggesting a possible interaction between mycophenolate mofetil and cyclosporine. No correlation was seen between dose-to-concentration and tacrolimus blood levels (P x 0.215). Further studies are necessary to investigate this issue.
Assuntos
Ciclosporina/farmacologia , Imunossupressores/farmacocinética , Transplante de Rim , Transplante de Pulmão , Ácido Micofenólico/análogos & derivados , Tacrolimo/farmacologia , Adulto , Idoso , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/sangue , Ácido Micofenólico/farmacocinética , Estudos RetrospectivosRESUMO
A rapid high-performance liquid chromatographic method was developed using a short silica column (30 mm x 4.6 mm) with an aqueous methanol mobile phase consisting of methanol-water-NH4H2PO4 (94:5.96:0.04) adjusted to a final apparent pH of 5.0 and pumped at a flow-rate of 1 ml/min. Ultraviolet detection was carried out at a wavelength of 280 nm, and serum samples were prepared for HPLC analysis by extraction into dichloromethane after basification. Lamotrigine was eluted at 0.96 min. Within-day variation of the method was 4.46% at 0.75 microg/ml and 2.37% at 6.0 microg/ml, and day-to-day variation was 9.10% at 0.75 microg/ml and 7.28% at 6.0 microg/ml.
Assuntos
Anticonvulsivantes/sangue , Cromatografia Líquida de Alta Pressão/métodos , Triazinas/sangue , Humanos , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Lamotrigina , Metanol , Cloreto de Metileno , Controle de Qualidade , Sensibilidade e Especificidade , ÁguaRESUMO
The aim of the Multicentric Liver Transplant Spanish Study was to evaluate tacrolimus therapy at the reduced, initial oral dose of 0.1 mg/kg per day to maintain the immunosuppressive potency of the drug and to avoid toxicity. The dosage of tacrolimus (D), the trough blood concentrations (C), and the evolution of the ratio (D/C) were followed up for 2 years after transplantation in 50 adult patients (38 men, 12 women) undergoing liver allograft transplantation. A total of 1732 samples were analyzed using the IMx tacrolimus method. The overall mean+/-SD concentrations were 10.84 ng/ml+/-5.32 ng/ml. During the first month, the median of the tacrolimus levels was 8.40 ng/ml, and 73.1% of the analyzed samples were within the established therapeutic range. The median oral tacrolimus dose was progressively reduced from 0.12 mg/kg per day during the first month to 0.058 mg/kg per day at the end of study period. A significant negative association was observed between the ratio of D/C and the post-transplantation period (r=-0.3624; p < 0.001). The median D/C ratio ranged from 0.0144 at the end of the first month to 0.0053 at 1 year. Significant declines in D/C were observed after the first and the third months after transplantation. The decrease in corticosteroid doses and the increase in serum albumin may explain the reduction in clearance with time.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Fígado/imunologia , Tacrolimo/uso terapêutico , Adulto , Idoso , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Espanha , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Fatores de TempoRESUMO
Tacrolimus is a potent immunosuppressive drug successfully used for baseline and rescue immunosuppression in patients after liver and kidney transplantation. Data from several clinical trials have demonstrated the efficacy of tacrolimus in the prevention of allograft rejection, even at lower concentrations in the therapeutic range (5-15 microg/L). In fact, some patients with tacrolimus levels at less than 5 microg/L have excellent hepatic or kidney function. The limit of detection of the IMx Tacrolimus I assay (TAC I; Abbott Laboratories, IL) is only 5 microg/L and that of the lower tacrolimus calibrator is 10 microg/L. The second-generation assay uses the same monoclonal antibody and the same IMx technology but offers improved sensitivity, with a dynamic range from 0 microg/L to 30 microg/L (lower calibrator, 3 microg/L). The aim of this multicenter study was to evaluate the new IMx Tacrolimus II assay (TAC II) by assessing its precision, sensitivity, performance, and correlation degree relative to the IMx TAC I assay. The study was performed at three centers in Spain. The within-run coefficients of variation (CVs) obtained for the new assay, using each of the trilevel controls in replicates of 20 during 3 consecutive days, were 8.06%, 4.38% and 5.09% at 5 microg/L, 11 microg/L, and 22 microg/L, respectively. The corresponding between-run CVs obtained measuring each of the three controls in duplicate on 10 consecutive days were 9.54%, 6.38% and 5.75%. The limit of detection, with 97.5% confidence, was 1.22 microg/L. TAC II results (Y) were compared with those from the original TAC I assay (X) analyzing 293 whole blood samples from liver (n=145) and kidney (n=148) transplant recipients. The correlation study with patient samples (using the Passing-Bablock method) was y=1.056, x + 0.017, r=0.927. No statistically significant differences were observed between assays (TAC I versus TAC II) in the mean values obtained for total patients (9.89+/-5.42 microg/L versus 10.49+/-5.63 microg/L), liver patients (9.16+/-4.79 microg/L versus 10.00+/-5.20 microg/L), and kidney patients (10.62+/-5.87 micro g/L versus 10.98+/-5.99 microg/L). The new IMx TAC II assay demonstrated the same precision and accuracy that characterized the original assay but showed improved sensitivity to the demands of tacrolimus monitoring in the lower therapeutic range of drug concentrations.