Cassia angustifolia and tacrolimus interaction in a liver transplant patient, a case report.

Cassia angustifolia is a species of plant from the Senna family that has traditionally been used as a laxative in different herbal products and commercial medicines. Even though there are few documented drug-plant interactions, the use of C. angustifolia with different drugs may have additive effects, such as with other laxatives or potassium-depleting diuretics. Its use also increases peristalsis which, may reduce drug absorption. The combination with digoxin has been associated with an increased risk of digoxin toxicity, probably due to an increase in plasma digoxin concentrations and hypokalaemia. We present a case with supratherapeutic trough concentration of tacrolimus, an immunosuppressive agent, and a herbal product in a liver transplant patient after concomitant intake of tacrolimus and a herbal product based on C. angustifolia, suggesting a possible drug-lant interaction through by P-glycoprotein. We observed an increase in the patient's blood concentration 2.8-fold and the area under the curve at steady state 2.1-fold. This interaction could be of clinical relevance, given the dose-dependent side effects of tacrolimus, such as nephrotoxicity, neurotoxicity, hypertension, hyperglycaemia, or electrolyte alterations.

Population Pharmacokinetic Model of Adalimumab Based on Prior Information Using Real World Data.

Adalimumab is a fully human monoclonal antibody used for the treatment of inflammatory bowel disease (IBD). Due to its considerably variable pharmacokinetics and the risk of developing antibodies against adalimumab, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to develop a population pharmacokinetic (PopPK) model of adalimumab for patients with IBD based on a literature model (reference model) to be used in the clinical setting. A retrospective observational study with 54 IBD patients was used to develop two different PopPK models based on the reference model. One of the developed models estimated the pharmacokinetic population parameters (estimated model), and the other model incorporated informative priors (prior model). The models were evaluated with bias and imprecision. Clinical impact was also assessed, evaluating the differences in dose interventions. The developed models included the albumin as a continuous covariate on apparent clearance. The prior model was superior to the estimated model in terms of bias, imprecision and clinical impact on the target population. In conclusion, the prior model adequately characterized adalimumab PK in the studied population and was better than the reference model in terms of predictive performance and clinical impact.

Incidence of Lymphoproliferative Disorders After Renal Transplantation is Down, but the Poor Prognosis Remains. Multicenter 32-Year Cohort Study.

BACKGROUND: Post-transplant lymphoproliferative disorders represent rare but serious complications of kidney transplantation. METHODS: We assessed incidence, risk factors, and outcomes in 21,546 patients receiving grafts between 1990 and 2009. Data were compared by decade of transplant (1990-1999 vs 2000-2009). Patients were followed for at least 12 years over a 32-year study period. RESULTS: In total, 331 patients (1.5%) developed PTLD: 189 of 9740 transplanted in the first decade, and 142 of 11,806 in the second. Incidence decreased significantly (19.40 vs12.02 cases/1000 patients; P < .001). Mean age at diagnosis was 50.2 years (standard deviation 14.7), and the median time from transplant to PTLD diagnosis was 48 months (interquartile range, 14.7-77.5), with no difference between cohorts. The origin of PTLD was mostly (86%) B-cell proliferation. No classical risk factors were reported in 31.7% of affected patients. Compared with 2000 to 2009, in 1990 to 1999 there was a higher frequency of induction therapy (P = .023) and detection of the Epstein-Barr virus in lymphoproliferative tissue (71.3% vs 52.7% P = .019). After diagnosis, 1- and 5-year patient survival was 51% and 38%. Graft survival was 48% and 33%. Survival was stable throughout the study period. CONCLUSION: Post-transplant lymphoproliferative disorders have a low and decreasing incidence, but the poor prognosis has not changed.

Cost-Effectiveness of Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease: A Systematic Review.

Infliximab and adalimumab are monoclonal antibodies against tumor necrosis factor (anti-TNF) used to manage inflammatory bowel disease (IBD). Therapeutic Drug Monitoring (TDM) has been proven to prevent immunogenicity, to achieve better long-term clinical results and to save costs in IBD treatment. The aim of this study was to conduct a systematic review on cost-effectiveness analyses of studies that apply TDM of anti-TNF in IBD and to provide a critical analysis of the best scientific knowledge available in the literature. The quality of the included studies was assessed using Consolidated Health Economic Evaluation Reporting Standards (CHEERS). Cost-effectiveness of the TDM strategies was presented as total costs, cost savings, quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER). Thirteen studies that examined the health economics of TDM of anti-TNF in IBD from 2013 to 2021 were included. Eight of them (61.5%) achieved a score between 17 and 23 on the CHEERS checklist. The comparison between the TDM strategy and an empirical strategy was cost saving. The ICER between reactive TDM and an empirical strategy was dominated (favorable) by reactive TDM, whereas the ICER value for proactive TDM compared to an empirical strategy ranged from EUR 56,845 to 3,901,554. This systematic review demonstrated that a TDM strategy is cost-effective or cost-saving in IBD.

Textbook outcome among patients undergoing enhanced recovery after liver transplantation stratified by risk. A single-center retrospective observational cohort study.

BACKGROUND & AIMS: Liver transplantation (LT) is one of the most complex surgical procedures. Enhanced recovery after surgery (ERAS) aims to reduce the risk of postoperative complications. When patients achieve all desirable outcomes after a procedure, they are considered to have experienced a textbook outcome (TO). METHODS: Two cohorts of patients undergoing low (n = 101) or medium risk (n = 15) LT were identified. The remaining patients (n = 65) were grouped separately. The ERAS protocol included pre-, intra-, and post-operative steps. TO was defined as the absence of complications, prolonged length of hospital stays, readmission and mortality during the first 90 days. RESULTS: One third of patients who underwent ERAS after LT experienced a TO. On multivariable analysis, age (OR, 1.05 [95% CI, 1.01-1.09]; P = .02), and having hepatocellular carcinoma (OR, 2.83 [95% CI, 1.37-6.03]; P = .005) were individually associated with a greater probability of achieving a TO. Belonging to the cohorts of medium risk or outside the selection criteria was associated with a lower probability of achieving a TO (OR, 0.46 [96% CI, 0.22-0.93]; P = .03). Patients less likely to experience TO required more hospital resources. Patients who achieved TO were more likely to remain free of chronic kidney disease (achieved TO, 83.8% [82.7-85.6]; failed TO, 67.9% [66.9-70.2]; P < .05). Tacrolimus dose and trough levels were similar. CONCLUSIONS: A novel finding of our study is that short and medium-term kidney function is better preserved in patients who experience a TO. Better kidney function of patients who achieve TO is not due to lower tacrolimus dosage.

There Are 33,784 Functioning Kidney Grafts in Spain: Who Monitors Them and How?

BACKGROUND: As of December 31, 2018, Spain's National Transplant Organization estimated that there were 61,764 people under renal replacement therapy across the country. Of this population, 33,784 (54.7%) had a functioning kidney graft. METHODS: Through the use of a survey to all Spanish hospitals involved in kidney transplantations, we studied the distribution of these recipients nationally, along with who was monitoring them and how. Data collected include the ratio of recipients to transplant nephrologists, median number of recipients followed in each center, and median number of transplant nephrologists per hospital. Of the 806 centers in the Spanish hospital network, 43 (5.3%) were involved in kidney transplants, including 39 transplant hospitals and 4 associated hospitals. The median number of transplants per center was 800 (interquartile range [IQR] = 510-1200). There were 3 nephrologists (IQR 2-5), and the ratio of recipients to transplant nephrologists was 270 (IQR = 190-323). RESULTS: There were no significant differences in these data between autonomous communities, except in the case of the Canary Islands, which had a significantly lower ratio of recipients to transplant nephrologists (146; IQR = 100-185) compared with the rest of the country (ratio 277; IQR = 207-329; P < .001). Of the 39 hospitals, 29 (74.4%) referred patients to centers that did not perform transplants. CONCLUSIONS: All in all, few Spanish hospitals perform kidney transplants. The ratio of recipients to transplant nephrologists is very high, compelling most hospitals to refer patients to nontransplant hospitals for follow-up. There are important differences in the distribution of recipients in hospitals in the Canary Islands vs the rest of the country, a difference that is undoubtedly attributable to its geographic peculiarities.

Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease.

Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target.

Fast-Track Liver Transplantation: Six-year Prospective Cohort Study with an Enhanced Recovery After Surgery (ERAS) Protocol.

INTRODUCTION: Enhanced recovery after surgery (ERAS) has been shown to facilitate discharge, decrease length of stay, improve outcomes and reduce costs. We used this concept to design a comprehensive fast-track pathway (OR-to-discharge) before starting our liver transplant activity and then applied this protocol prospectively to every patient undergoing liver transplantation at our institution, monitoring the results periodically. We now report our first six years results. PATIENTS AND METHODS: Prospective cohort study of all the liver transplants performed at our institution for the first six years. Balanced general anesthesia, fluid restriction, thromboelastometry, inferior vena cava preservation and temporary portocaval shunt were strategies common to all cases. Standard immunosuppression administered included steroids, tacrolimus (delayed in the setting of renal impairment, with basiliximab induction added) and mycophenolate mofetil. Tacrolimus dosing was adjusted using a Bayesian estimation methodology. Oral intake and ambulation were started early. RESULTS: A total of 240 transplants were performed in 236 patients (191♂/45♀) over 74 months, mean age 56.3±9.6 years, raw MELD score 15.5±7.7. Predominant etiologies were alcohol (n = 136) and HCV (n = 82), with hepatocellular carcinoma present in 129 (54.7%). Nine patients received combined liver and kidney transplants. The mean operating time was 315±64 min with cold ischemia times of 279±88 min. Thirty-one patients (13.1%) were transfused in the OR (2.4±1.2 units of PRBC). Extubation was immediate (< 30 min) in all but four patients. Median ICU length of stay was 12.7 hours, and median post-transplant hospital stay was 4 days (2-76) with 30 patients (13.8%) going home by day 2, 87 (39.9%) by day 3, and 133 (61%) by day 4, defining our fast-track group. Thirty-day-readmission rate (34.9%) was significantly lower (28.6% vs. 44.7% p=0.015) in the fast-track group. Patient survival was 86.8% at 1 year and 78.6% at five years. CONCLUSION: Fast-Tracking of Liver Transplant patients is feasible and can be applied as the standard of care.

Population pharmacokinetics models of sirolimus in renal transplant patients: A systematic review.

OBJECTIVE: Sirolimus is used in the immunosuppressive therapeutic treatment  of kidney transplant patients. The high pharmacokinetic variability of sirolimus  makes pharmacokinetic monitoring and dosage individualization of  mmunosuppressive therapy a key process to achieve better efficacy results.  The availability of a population pharmacokinetic model can be used to provide  better pharmacokinetic adjustment of plasma concentrations of sirolimus and  thus achieve greater clinical benefit. METHOD: We conducted a systematic review of the literature available in the  Medline, Embase, and Scopus databases to identify and subsequently analyze  population pharmacokinetic models of orally administered sirolimus in adult  patients after kidney transplant. The descriptors used MeSH were kidney  transplantation, pharmacokinetics, and sirolimus. The following variables from  the selected studies were assessed: study population, immunosuppressive  treatment, blood sampling times, covariates analyzed, type of pharmacokinetic  model, computer software used, estimated pharmacokinetic  parameters, interindividual variability of pharmacokinetic parameters, residual  variability and mathematical equations of the pharmacokinetic model. RESULTS: A total of 548 results were obtained, excluding 175 records that were  identified in more than one database. Finally, seven articles that  et  the inclusion criteria were selected. Most of the pharmacokinetic models found fit a two-compartment model. The interindividual variability of sirolimus  was explained by covariates such as age, weight, liver function, cyclosporine exposure and dose, sirolimus doses, CYP3A5 genetic  olymorphisms, serum creatinine, and concomitant treatment. CONCLUSIONS: The two-compartment model was the pharmacokinetic model of  choice in most of the selected studies. The interindividual variability of the  pharmacokinetic parameters of sirolimus is explained by demographic, clinical,  genetic, and biochemical variables. The availability of pharmacokinetic models  of sirolimus can assist in optimizing therapy in patients after kidney transplant.

OBJETIVO: Sirólimus es un fármaco utilizado en los esquemas terapéuticos inmunosupresores en pacientes con trasplante renal. La elevada  variabilidad farmacocinética de sirólimus hace que la monitorización  farmacocinética y la individualización posológica de la terapia inmunosupresora sea un proceso crucial para conseguir mejores resultados de  eficacia. La disponibilidad de un modelo farmacocinético poblacional permite  realizar un mejor ajuste farmacocinético de las concentraciones plasmáticas de  sirólimus y así conseguir un mayor beneficio clínico.Método: Se realizó un análisis sistemático de la literatura disponible en las  bases de datos Medline, Embase y Scopus para identificar y posteriormente analizar los modelos farmacocinéticos poblacionales de  irólimus administrado por vía oral en pacientes adultos con trasplante renal. Se utilizaron como descriptores MeSH: kidney transplantation, pharmacokinetic  y sirolimus. De cada artículo seleccionado se evaluó: la  población a estudio, el esquema de tratamiento inmunosupresor, los tiempos  de muestreo de las extracciones de sangre, las covariables analizadas, el tipo  de modelo farmacocinético, el programa informático utilizado, los parámetros  armacocinéticos estimados, la variabilidad interindividual de  los parámetros  farmacocinéticos, la variabilidad residual y las ecuaciones matemáticas del  modelo farmacocinético. RESULTADOS: Se obtuvieron un total de 548 resultados, excluyendo 175  registros tras identificarse en más de una base de datos. Finalmente se  seleccionaron siete artículos que cumplían los criterios de inclusión. La mayoría  de los modelos farmacocinéticos encontrados siguen un modelo  bicompartimental. Covariables como edad, peso, función hepática, exposición y  dosis de ciclosporina, dosis de sirólimus, polimorfismos genéticos del  CYP3A5, creatinina sérica y tratamiento concomitante explican la variabilidad  interindividual de sirólimus. CONCLUSIONES: El modelo bicompartimental fue el modelo farmacocinético de  elección en la mayoría de los estudios seleccionados. La variabilidad interindividual de los parámetros farmacocinéticos de sirólimus se explica por variables demográficas, clínicas, genéticas y bioquímicas. La disponibilidad de modelos farmacocinéticos de sirólimus permiten  ndividualizar la terapia en pacientes con trasplante renal.

Enhanced recovery after low- and medium-risk liver transplantation. A single-center prospective observational cohort study.

BACKGROUND & AIMS: Few studies have fully applied an enhanced recovery after surgery (ERAS) protocol to liver transplantation (LT). Our aim was to assess the effects of a comprehensive ERAS protocol in our cohort of low- and medium-risk LT patients. METHODS: The ERAS protocol included pre-, intra-, and post-operative steps. During the five-year study period, 181 LT were performed in our institution. Two cohorts were identified: low risk patients (n = 101) had a laboratory model for end-stage liver disease (MELD) score of 20 points or less at the time of LT, received a liver from a donor after brain death, and had a balance of risk score of 9 points or less; medium-risk patients (n = 15) had identical characteristics except for a higher MELD score (21-30 points). In addition, we analyzed the remaining patients (n = 65) who were transplanted over the same study period separately using the ERAS protocol. RESULTS: The low-risk cohort showed a low need for packed red blood cells transfusion (median: 0 units) and renal replacement therapy (1%), as well as a short length of stay both in the intensive care unit (13 h) and in the hospital (4 days); morbidity during one-year follow-up, and probability of surviving to one year (89.30%) and five years (76.99%) were in line with well-established reference data. Similar findings were observed in the medium-risk cohort. CONCLUSIONS: This single-center prospective observational cohort study provides evidence that ERAS is feasible and safe for low- and medium-risk LT.

Pre-emptive deceased-donor kidney transplant: A matched cohort study. / Una aproximación al trasplante renal anticipado de donante cadáver. Estudio de cohortes emparejadas.

INTRODUCTION: Currently, kidney transplantation is the treatment of choice for patients with kidney disease who require replacement therapy. Dialysis is a necessary step, but not mandatory prior to transplantation. There is the possibility of pre-emptive transplantation or transplantation in pre-dialysis, that is, without previous dialysis. The aim of the present study is to evaluate the result of our experience with a pre-emptive kidney transplant from a deceased donor. MATERIALS AND METHODS: Retrospective, observational, matched cohort study. We compared 66 pre-emptive with 66 non pre-emptive recipients, who received a first renal graft performed at our centre, matched by age and gender of donors and recipients, time of transplant, immunological risk, immunosuppression and cold ischaemia time. Early graft loss, incidence of acute rejection, delayed graft function, renal function at 12 and 36 months and graft and recipient survival were assessed in this period. RESULTS: The percentage of recipients who presented early graft loss, delayed graft function and acute rejection was similar in both groups. No differences were observed in their renal function at 12 and 36 months after transplantation, as well as the actuarial survival of patients (P=0.801) and grafts (P=0.693) in the studied period. The total calculated cost of the period on dialysis for the control group was 8,033,893.16 euros. CONCLUSIONS: Pre-emptive transplantation can yield comparable outcomes to those for post-dialysis kidney transplantation, and results in better quality of life for patients with end-stage kidney disease, as well as a reduced cost.

Envarsus, a novelty for transplant nephrologists: Observational retrospective study. / Envarsus, una novedad para los nefrólogos del trasplante: estudio observacional retrospectivo.

The aim of this study was to evaluate the trough concentrations (Cptrough) and the tacrolimus dosage regimen after the conversion of Prograf or Advagraf to Envarsus (new pharmaceutical form with MeltDose technology that improves the absorption of fat-soluble drugs) in patients with stable renal transplantation, and their renal function. We selected stable renal transplant patients who were converted to Envarsus. Two periods were defined: Baseline and Conversion (Envarsus) and they were stratified according to the pharmaceutical form used in the Baseline period. Sixty-one patients were included (24 with Advagraf and 37 with Prograf), with an average age of 52years. The mean post-transplant time at the time of conversion to Envarsus was 76.3months and the mean follow-up in the Baseline and Conversion period was 10.1months and 11.6months, respectively. In the Prograf and Envarsus group, the Cptrough medians were 6.6 vs 6.4 ng/mL (P=.636), with a mean daily dose that decreased significantly from 3mg to 2mg (P<.001), respectively, maintaining the filtration rate. The median Cptrough values in the Advagraf and Envarsus groups were 5.7ng/mL and 6.3ng/mL (P=.07), with a median daily dose of 7mg and 4mg (P<.001), respectively, and the same renal function. In stable renal transplant patients, the conversion from Advagraf to Envarsus has allowed the dose of tacrolimus to be reduced by 42.9% and, in the case of Prograf, by 33.3%, maintaining similar Cptrough values, without renal function being altered.

Bacterial DNA translocation contributes to systemic inflammation and to minor changes in the clinical outcome of liver transplantation.

Bacterial (bact)DNA is an immunogenic product that frequently translocates into the blood in cirrhosis. We evaluated bactDNA clearance in patients undergoing liver transplantation (LT) and its association with inflammation and clinically relevant complications. We prospectively included patients consecutively admitted for LT in a one-year follow-up study. We evaluated bactDNA before and during the first month after LT, quantifying cytokine response at 30 days. One hundred patients were included. BactDNA was present in the blood of twenty-six patients undergoing LT. Twenty-four of these showed bactDNA in the portal vein, matching peripheral blood-identified bactDNA in 18 cases. Thirty-four patients showed bactDNA in blood during the first month after LT. Median TNF-α and IL-6 levels one month after LT were significantly increased in patients with versus without bactDNA. Serum TNF-α at baseline was an independent risk factor for bactDNA translocation during the first month after LT in the multivariate analysis (Odds ratio (OR) 1.14 [1.04 to 1.29], P = 0.015). One-year readmission was independently associated with the presence of bactDNA during the first month after LT (Hazard ratio (HR) 2.75 [1.39 to 5.45], P = 0.004). The presence of bactDNA in the blood of LT recipients was not shown to have any impact on complications such as death, graft rejection, bacterial or CMV infections. The rate of bactDNA translocation persists during the first month after LT and contributes to sustained inflammation. This is associated with an increased rate of readmissions in the one-year clinical outcome after LT.

Efficacy and safety of high-flow nasal cannula oxygen therapy in patients with acute heart failure. / Efectividad y seguridad de la terapia de alto flujo con cánulas nasales en pacientes con insuficiencia cardiaca aguda.

OBJECTIVES: To evaluate the efficacy and safety of high-flow nasal cannula (HFNC) oxygen therapy in patients in acute respiratory failure due to acute heart failure (AHF) refractory to conventional oxygen therapy or noninvasive ventilation. METHODS: Prospective observational study of patients with AHF and respiratory failure attended in an emergency department whose condition worsened after they were admitted to a short-stay unit, leading to use of HFNCs. Efficacy was assessed using a modified Borg dyspnea scale and oxygenation variables on discharge from the emergency department. Data were recorded after 24 hours on conventional oxygen therapy and after 60 and 120 minutes and 24 hours of HFNC therapy. Safety outcomes were the degree of patient comfort and the frequency of adverse events. RESULTS: Prospective observational study of patients with AHF and respiratory failure attended in an emergency department whose condition worsened after they were admitted to a short-stay unit, leading to use of HFNCs. Efficacy was assessed using a modified Borg dyspnea scale and oxygenation variables on discharge from the emergency department. Data were recorded after 24 hours on conventional oxygen therapy and after 60 and 120 minutes and 24 hours of HFNC therapy. Safety outcomes were the degree of patient comfort and the frequency of adverse events. CONCLUSION: HFNC oxygen therapy offers a treatment alternative for patients with acute respiratory failure due to AHF.

OBJETIVOS: Valorar la eficacia y seguridad de la terapia de alto flujo con cánulas nasales (TAFCN) en pacientes con insuficiencia respiratoria aguda (IRA) secundaria a insuficiencia cardiaca aguda (ICA) y refractaria al tratamiento con oxigenoterapia convencional o ventilación no invasiva. METODOS: Estudio observacional prospectivo de pacientes con ICA e IRA atendidos en un servicio de urgencias, con ingreso posterior en una unidad de corta estancia, que, tras 24 horas presentaron empeoramiento y a los que se administró TAFCN. Para evaluar la eficacia se utilizó la escala de disnea modificada de Borg y la oxigenación al alta de urgencias, a las 24 h de tratamiento con oxigenación convencional y a los 60, 120 minutos y 24 h de iniciada la TAFCN. Para evaluar la seguridad se midió grado de confort y eventos adversos producidos. RESULTADOS: Se recogieron 44 pacientes con edad media de 84 (7) años, 75 % mujeres. El uso de la TAFCN supuso una mejoría significativa en los parámetros clínicos y gasométricos (basal, 60 min, 120 min y 24 h), en la escala de disnea y confort, oximetría y cociente de oxigenación y una disminución de la frecuencia respiratoria (p < 0,05). No hubo cambios significativos en la presión arterial de dióxido de carbono. El efecto secundario más frecuente fue el calor (20,4%). CONCLUSIONES: La TAFCN es una alternativa para el tratamiento de los pacientes con IRA secundaria a ICA.

Suitability of the AUC Ratio as an Indicator of the Pharmacokinetic Advantage in HIPEC.

The purpose of this study was to evaluate the area under the concentration-time curve (AUC) ratio as an optimal indicator of the pharmacokinetic advantage during hyperthermic intraperitoneal perioperative chemotherapy. The impact on the AUC ratio on the variables related to the calculation of systemic drug exposure, instillation time, and peripheral drug distribution was evaluated through simulations as well as through a retrospective analysis of studies published in the literature. Both model simulations and the retrospective analysis showed that the 3 variables evaluated had an impact on the AUC ratio value if the complete systemic exposure was not fully considered. However, when that complete systemic exposure was considered, none of these variables affected the AUC ratio value. AUC ratio is not a characteristic parameter of a drug if the calculated systemic drug exposure is not complete. Thus, AUC ratio is not valid for comparing the pharmacokinetic advantage of 2 drugs, and it should not be employed to prove whether a drug can be used in hyperthermic intraperitoneal perioperative chemotherapy safely with regard to toxicity. As an alternative, the study of the absorption rate constant and the bioavailability are proposed as the true and independent parameters that reflect the amount of drug absorbed.

Impact of Laparotomy and Intraperitoneal Hyperthermic Instillation (LIHI) on the oxaliplatin pharmacokinetics after intravenous administration in Wistar rats.

PURPOSE: In peritoneal metastasis condition, the fact that most of the disease is limited to the peritoneal cavity laid the foundations for a surgical treatment, including intraperitoneal hyperthermic chemotherapy (HIPEC). The aim of this study was to evaluate the impact of the surgical procedures implied in open HIPEC technique, referred to laparotomy procedures followed by an intraperitoneal hyperthermic instillation (LIHI) on oxaliplatin tissue distribution and elimination. To delimit the influence of this procedure alone, oxaliplatin was administered as an intravenous (iv) bolus in both groups. METHODS: An experimental model in Wistar rats was employed, and LIHI was evaluated as a dichotomous covariate by using a population pharmacokinetic (PK) approach. Rats were randomized in two groups receiving 1.5 mg iv oxaliplatin alone or 1.5 mg iv oxaliplatin under LIHI conditions, carrying out a hyperthermic 5% dextrose instillation. The oxaliplatin plasma concentrations were characterized by an open two-compartment PK model. RESULTS: Results concluded that surgical conditions affect the oxaliplatin elimination and distribution from blood to peripheral tissues, increasing the systemic drug exposure. Concretely, oxaliplatin peripheral volume of distribution, and clearance decreased by 48.6% and 55.3%, respectively, compared to the control group that resulted in a two-fold increase of the area under the concentration time curve. CONCLUSIONS: Comparison in clinical practice of oxaliplatin PK parameters obtained after iv administrations with those obtained after HIPEC interventions must be done carefully. This would limit the use of iv PK parameters to simulate new scenarios for oxaliplatin in HIPEC.

PEG-Interferon-α ribavirin-induced HCV viral clearance: a pharmacogenetic multicenter Spanish study.

OBJECTIVE: Dual PEGylated interferon-α (PEG-IFN) and ribavirin therapy has been the main hepatitis C virus (HCV) treatment of the last decade. Current direct-acting antiviral agents have improved the outcome of therapy but also have increased the cost and management complexity of treatment. The current study analyzes host genetics, viral and clinical predictors of sustained viral response (SVR) to dual PEG-IFN and ribavirin therapy in a representative Spanish population. METHODS: Observational prospective multicentre pharmacogenetic cohort study conducted in 12 different hospitals of 12 different Spanish regions. A total of 98 patients with SVR and 106 with non-SVR in response to PEG-IFN and ribavirin therapy were included. 33 single nucleotide polymorphisms located in 24 different genes related with inflammatory, immune and virus response were selected. Clinical and viral data were also analyzed as candidate of SVR predictors. RESULTS: IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) and TNFRSF1B (rs1061622) genotypes, as well as TNFRSF1B/IL-10/TNFα (-308) non-TTG and TNFRSF1B/IL- 10/IL-4 non-TTC haplotypes together with lower age, lower basal HCV RNA load, higher basal serum LDL cholesterol values, VHC genotypes 2 and 3 and basal low grade fibrosis 0-2 were associated with a SVR in the univariate analysis. Independent predictors of SVR in the multivariate analysis were IL-28B rs12979860 CC, TNFRSF1B/IL-10/IL-4 non-TTC along with low baseline HCV RNA load and HCV genotypes 2 and 3. CONCLUSIONS: IL-28B rs12979860 CC, TNFRSF1B/ IL-10/ IL-4 non-TTC haplotype, low baseline HCV RNA load and HCV genotypes 2 and 3 may help to predict successful outcome to PEG-IFN/ribavirin therapy in Spanish population.

Objetivo: El interferon-pegilado (IFN-PEG) junto a ribavirina ha sido el principal tratamiento de la infeccion por el virus de la hepatitis C (VHC) de la ultima decada. Los agentes antivirales de accion directa actuales han mejorado los resultados de la terapia, pero tambien han aumentado el costo y la gestion de la complejidad del tratamiento. El presente estudio analiza factores geneticos de los pacientes, asi como predictores virales y clinicos de respuesta sostenida viral (RSV) al tratamiento con IFN-PEG y ribavirina en poblacion Espanola. Métodos: Estudio farmacogenetico, multicentrico, prospectivo, observacional de cohortes realizado en 12 hospitales diferentes de 12 comunidades autonomas diferentes. Se incluyeron un total de 98 pacientes con RVS y 106 sin SVR al tratamiento con IFNPEG y ribavirina. Se seleccionaron 33 polimorfismos de nucleotido unico ubicados en 24 genes diferentes relacionados con la respuesta inflamatoria, inmunologica y viral. Los datos clinicos y virales tambien se analizaron como candidatos predictores de RVS. Resultados: Los genotipos IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) y TNFRSF1B (rs1061622), asi como los haplotipos TNFRSF1B / IL-10 / TNF(-308) no-TTG y TNFRSF1B / IL-10 / IL-4 no-TTC junto con la menor edad, menor carga de ARN-VHC basal, valores elevados de colesterol LDL en suero basal, genotipos VHC2 y 3 y bajo grado de fibrosis basal (0-2) se asociaron con una RVS en el analisis univariante. Los predictores independientes de RVS en el analisis multivariante fueron el genotipo IL-28B rs12979860 CC, el haplotipo TNFRSF1B / IL-10 / IL-4 no-TTC junto con los bajos niveles basales de VHCARN y los genotipos virales VHC2 y 3. Conclusiones: El genotipo IL-28B rs12979860 CC, el haplotipo TNFRSF1B / IL-10 / IL-4 haplotipos no-TTC, la carga viral basal baja y los genotipos del VHC2 y 3 pueden ayudar a predecir una buena respuesta a la terapia con IFN-PEG y ribavirina en poblacion espanola.

Medication list assessment in Spanish hospital emergency departments.

BACKGROUND: Medication errors lead to morbidity and mortality among emergency department (ED) patients. An inaccurate medication history is one of the underlying causes of these errors. OBJECTIVES: This study was performed to determine the prevalence of patients with discrepancies between the medical list information contained in the clinical history compiled on admission to the ED and the list of medications patients are actually taking, to characterize the discrepancies found, and to analyze whether certain factors are associated with the risk of discrepancies. METHODS: We conducted a cross-sectional, descriptive, observational, multicenter study with an analytic component in the EDs of 11 hospitals in Spain. We compared pharmacist-obtained medication lists (PML) with ED-obtained medication lists (EDML). Discrepancy was defined as one or more differences (in drug or dosage or route of administration) between the EDML and PML. The endpoints were the proportion of patients with discrepancies in their home medical lists, and the prevalence of certain factors among patients with discrepancies and those without. RESULTS: We detected 1476 discrepancies in 387 patients; no discrepancies were found in 20.7%. The most frequent discrepancies involved incomplete information (44.2%) and omission (41.8%). In the bivariate analysis, age, number of medications, and Charlson comorbidity score were significantly associated with discrepancy. In the multivariate analysis, number of medications and hospital were the variables associated with discrepancy. CONCLUSIONS: The EDML differed from the list of medications patients were actually taking in 79.3% of cases. Incomplete information and omission were the most frequent discrepancies. Age, number of medications, and comorbidities were related to the risk of discrepancies.