Intracellular IFN-γ and IL-2 expression monitoring as surrogate markers of the risk of acute rejection and personal drug response in de novo liver transplant recipients.

Biomarker monitoring is needed in transplantation to reflect individual response to immunosuppressive drugs and graft outcome. We evaluated intracellular expression and soluble production of interferon-(IFN)-γ and interleukin-(IL)-2 as predictive biomarkers of acute rejection (AR) and personal drug response. Pharmacokinetic-pharmacodynamic profiles were determined in 47 de novo liver recipients treated with tacrolimus, mycophenolate mofetil and prednisone. Of the 47 patients, AR occurred in nine. There were no differences in drug concentrations between rejectors and non-rejectors. A pre-transplantation cut-off value of 55.80% for %CD8(+)-IFN-γ(+) identified patients at high risk of AR with a sensitivity of 75% and a specificity of 82%. In the first week post-transplantation, patients with a % inhibition for soluble IFN-γ, %CD8(+)-IFN-γ(+) and %CD8(+)-IL2(+) lower than 40% developed AR, showing low susceptibility to immunosuppressive drugs. Therefore, effector-T-cell response monitoring may help physicians to identify personal response to treatment and patients at high risk of AR.

Descripción del proceso de certificación ISO 9001/2000 en el área de nutrición parenteral / No disponible

Objetivo: Garantizar la calidad y seguridad e incrementar la satisfacción del usuario ha llevado a organizaciones del ámbitosanitario a integrar un sistema de gestión de calidad en su estructura. Este trabajo describe el proceso de implantación dela norma UNE-EN-ISO-9001/2000 en el área de nutriciónparenteral.Método: Un grupo multidisciplinar definió el alcance de la norma, centrándose en transcripción, acondicionamiento, dispensacióny control microbiológico.Resultados: Se elaboró un procedimiento detallando secuencialmente los circuitos y actividades asociadas, el personal responsable y las pautas de actuación a seguir. Se establecieron indicadoresde calidad y de actividad.Conclusiones: Este proceso ha permitido establecer un sistema normalizado cuyos procesos están perfectamente descritos y documentados, logrando la trazabilidad y supervisión de las fases.Al no disponer de histórico de los datos actualmente obtenidos, no es posible establecer una comparación directa; por tanto, deberá analizarse su evolución en un futuro

Objective: In order to guarantee quality and safety and to increase user satisfaction, healthcare organisations have integratedquality management systems into their structures. This study describes the process for introducing the UNE-EN-ISO-9001/2000 standard in the parenteral nutrition area.Method: A multidisciplinary group established the scope of the standard, focusing on transcription, preparation, dispensation and microbiological control.Results: A detailed procedure describing the sequences of circuits and associated activities, the responsible staff and the action guidelines to be followed was established. Quality and activity markers were also established.Conclusions: This process has enabled a standard system to be implemented, with its operation perfectly described and documented, allowing its stages to be traceable and supervised. As there is no record of the data obtained beforehand, no direct comparison can be made; its evolution must therefore be analysed inthe future

Inhibitory quotient as a prognostic factor of response to a salvage antiretroviral therapy containing ritonavir-boosted saquinavir. The CIVSA Study.

BACKGROUND: The addition of a low dose of ritonavir to protease inhibitors (PIs) has become a widespread strategy to improve PI pharmacokinetics. As resistance is a major barrier to long-term suppression, in salvage therapy genotype and/or phenotype scoring is currently used to predict the response. We evaluated the relationship between the saquinavir (SQV) inhibitory quotient (IQ) (virtual and genotypic) and virological response. METHODS: Eligible patients were on a PI-containing highly active antiretroviral therapy (HAART) regimen excluding SQV and had a viral load >5000 HIV-1 RNA copies/mL. The PI was switched to SQV/ritonavir (RTV) 1000/100 mg twice a day (bid) and the same two backbone nucleoside reverse transcriptase inhibitors (NRTIs) were maintained at least until week 4, when the resistance test results became available. Genotype and virtual phenotype were determined at baseline, while the SQV trough plasma concentration was determined at week 4. RESULTS: Fifty-three patients were included in the study. Mean baseline viral load and CD4 count were 137,693 copies/mL and 263 cells/microL, respectively, the mean number of previous PIs was 2.3 and the mean number of protease gene mutations (PGMs) was 4.1. Using an on-treatment analysis, at week 16 the mean increase in CD4 count was 70.9 cells/microL, viral load was <200 copies/mL in 17 out of 37 patients (45.9%), and 30 out of 45 patients (66.7%) were considered virological responders (VRs) (viral load <200 copies/mL or viral load declined > or =1 log(10) at week 16). Median virtual phenotype was 1.3 (0.6-6.9). Baseline differences were detected between VR and non-VR populations: the mean numbers of PGMs were 3.2 and 5.8 (P<0.05), the mean numbers of SQV-associated mutations were 2 and 3.8 (P<0.05), and the mean CD4 counts were 365.9 and 184.3 cells/microL (P<0.05), respectively. Mean SQV trough concentrations at week 4 were 1.1 and 1.0 microg/mL (not significant), and mean virtual IQs were 0.7 and 0.1 (P<0.01), respectively. Multivariate analysis showed that baseline PGMs >5 or SQV-associated mutations>5, virtual phenotype, baseline viral load >50,000 copies/mL, and virtual IQ <0.5, but not genotypic IQ, were the variables independently associated with non-VR. CONCLUSION: In heavily pretreated patients, the use of SQV virtual IQ or alternatively virtual phenotype, as well as PGMs, is a useful tool for the prediction of virological response.

Pharmacokinetic interaction between rifampicin and ritonavir-boosted atazanavir in HIV-infected patients.

BACKGROUND: Tuberculosis (TB) is a common opportunistic infection among HIV-infected people, and rifampicin is an important drug for the treatment of TB. However, administration of rifampicin in combination with antiretroviral therapy, particularly protease inhibitors, is difficult because of drug-drug interactions. METHODS: We have performed a prospective study in three HIV-infected patients with TB treated with a rifampicin-containing regimen (rifampicin 600 mg per day) and antiretroviral therapy including only nucleoside reverse transcriptase inhibitors (NRTIs) plus atazanavir 300 mg once a day (qd) and ritonavir 100 mg qd, to evaluate whether the inducing effect of rifampicin on the drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 could be overcome by the inhibitory effect of ritonavir. A complete pharmacokinetic evaluation of the steady-state concentrations of atazanavir and ritonavir was performed. RESULTS: In all three cases, more than 50% of the time the atazanavir level was below the minimum recommended trough plasma level (150 ng/mL according to current pharmacokinetic guidelines) to inhibit HIV wild-type replication. CONCLUSION: These results strongly indicate that the administration of rifampicin with a combination of atazanavir 300 mg qd plus ritonavir 100 mg qd must be avoided because subtherapeutic concentrations of atazanavir are produced.

[Description of the ISO 9001/2000 certification process in the parenteral nutrition area]. / Descripción del proceso de certificación ISO 9001/2000 en el área de nutrición parenteral.

OBJECTIVE: In order to guarantee quality and safety and to increase user satisfaction, healthcare organisations have integrated quality management systems into their structures. This study describes the process for introducing the UNE-EN-ISO-9001/2000 standard in the parenteral nutrition area. METHOD: A multidisciplinary group established the scope of the standard, focusing on transcription, preparation, dispensation and microbiological control. RESULTS: A detailed procedure describing the sequences of circuits and associated activities, the responsible staff and the action guidelines to be followed was established. Quality and activity markers were also established. CONCLUSIONS: This process has enabled a standard system to be implemented, with its operation perfectly described and documented, allowing its stages to be traceable and supervised. As there is no record of the data obtained beforehand, no direct comparison can be made; its evolution must therefore be analysed in the future.

Determination of efavirenz in human plasma by high-performance liquid chromatography with ultraviolet detection.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor for the treatment of the HIV infection. A simple, high-performance liquid chromatographic method has been developed and validated for the quantitative determination of efavirenz in human plasma. The method involved solid-phase extraction of the drug and the internal standard (L-737,354) from 300 microl of human plasma. The analysis was via UV detection at 250 nm using a reversed-phase C8 analytical column and a isocratic mobile phase consisting of phosphate buffer (pH 5.75)-acetonitrile that resolved the drug and internal standard from endogenous matrix components and potential coadministered drugs. Within- and between-day precisions were less than 8.6% for all quality control samples. The lower limit of quantification was 0.1 microg/ml. Recovery of efavirenz from human plasma was greater than 83%. This validated assay is being used in pharmacokinetic studies with efavirenz.

Simultaneous determination of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma by reversed-phase high-performance liquid chromatography.

A rapid, simple and sensitive high-performance liquid chromatographic (HPLC) assay has been developed for the simultaneous quantification of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma. The method involved the solid-phase extraction of the five drugs and the internal standard (I.S., verapamil) from 400 microl of human plasma. The HPLC analysis used a reversed-phase C18 analytical column and a mobile phase consisting of a gradient with 15 mM phosphate buffer (pH 5.75)-acetonitrile and UV monitoring. The method was linear over the therapeutic concentration range for the five HIV-protease inhibitors. The accuracy of the method ranged from 98.2 to 106.7% and the precision values ranged from 1.4 to 8.1% for intra-day precision and from 3.1 to 6.4% for the inter-day values.