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Plum is one of the most produced stone fruits worldwide. Melatonin is an environmentally eco-friendly substance that, in low concentrations, activates defence systems against biotic and abiotic stresses. This substance is considered a tool that could increase fruit quality. This study aimed to evaluate the impact of different preharvest foliar applications with different melatonin concentrations (0.1, 0.3, 0.5 mmol L−1) to enhance melatonin content and shelf life of ‘Primetime’ plum. To this purpose, two and three applications were carried out at different critical stages of fruit growth. Different quality characteristics such as size, colour, titratable acidity, total soluble solids, ripening index, respiration rate, ethylene production rate, anthocyanins and total antioxidant activity, as well as endogenous melatonin content, were tested at harvest and after 40 days of cold storage. Results showed that ‘Primetime’ plums that received 3 applications of 0.5 mmol L−1 enhanced endogenous melatonin content at harvest and showed less softening, delayed darkening, higher anthocyanin concentration and total antioxidant activity after 40 days of storage. Therefore, the concentration of 0.5 mmol L−1 melatonin in 3 applications was effective in improving the quality of ‘Primetime’ plums.

The objective of this study was to evaluate the fruit development, the quality at harvest and the shelf-life changes of three apricot cultivars—‘Spring Blush’, ‘Robada’, and ‘Kioto’—produced in the conditions of the Southwest Iberian Peninsula. Pomological characteristics and global quality (colour, firmness, total soluble solids, and total acidity) were weekly evaluated during fruit growth and ripening. Apricots were harvested at commercial ripening, and six and three days before, were tested for each harvest on the harvesting day and after three and five days of shelf-life at 20 °C, evaluating chlorophyll and carotenoids content and sensory quality. ‘Spring Blush’ was the earliest cultivar with a small calibre, and the change in colour was found to depend more on the evolution during the shelf-life than on the harvest date, although the panellists rated it well, it presented a significant lack of firmness for successful marketing. ‘Robada’ was the cultivar with the lowest evolution of colour, sugar and acid content, and it was the worst valued by tasters. In ‘Kioto’, differences in soluble solids, acidity, and colour were of high importance in the last days of development on the tree. ‘Kioto’ was the cultivar that showed the largest fruit size and colouring during the ripening on the tree, as well as the one with the highest overall quality that improves during shelf-life.

In this work it is explored a real applicability of miniaturised and portable biosensing technology for the estimation of total phenolic content in 15 different commercial beers by applying direct amperometry. Gold nanoparticles screen-printed electrodes were thoroughly modified with tyrosinase (Tyr-AuNPS-SPCEs), which was immobilised on the surface by crosslinking with glutaraldehyde. All chemical and instrumental variables involved in the electrochemical method were optimised to develop a reliable and powerful tool to estimate rapidly the content of phenolic compounds in complex beer samples. Catechol, phenol, caffeic acid and tyrosol were analysed individually using the proposed methodology and good analytical and kinetic performances were obtained. Total phenolic content in tested beers (high fermented, low fermented and non-alcoholic) were expressed as mg L−1 of tyrosol, which is one of the major phenolic compound reported in beer. Moreover, the developed amperometric methodology was successfully benchmarked against standardised Folin-Ciocalteau spectrophotometric method with a good Pearson correlation (r = 0.821, p

Aim To evaluate the effectiveness and safety of tofacitinib in ulcerative colitis [UC] in real life. Methods Patients from the prospectively maintained ENEIDA registry and treated with tofacitinib due to active UC were included. Clinical activity and effectiveness were defined based on Partial Mayo Score [PMS]. Short-term response/remission was assessed at Weeks 4, 8, and 16. Results A total of 113 patients were included. They were exposed to tofacitinib for a median time of 44 weeks. Response and remission at Week 8 were 60% and 31%, respectively. In multivariate analysis, higher PMS at Week 4 (odds ratio [OR] = 0].2; 95% confidence interval [CI] = 0].1–0.4) was the only variable associated with lower likelihood of achieving remission at Week 8. Higher PMS at Week 4 [OR = 0.5; 95% CI = 0.3–0.7] and higher PMS at Week 8 [OR = 0.2; 95% CI = 0.1–0.5] were associated with lower probability of achieving remission at Week 16. A total of 45 patients [40%] discontinued tofacitinib over time. Higher PMS at Week 8 was the only factor associated with higher tofacitinib discontinuation [hazard ratio = 1.5; 95% CI = 1.3–1.6]. A total of 34 patients had remission at Week 8; of these, 65% had relapsed 52 weeks after achieving remission; the dose was increased to 10 mg/12 h in nine patients, and five of them reached remission again. Seventeen patients had adverse events. Conclusions Tofacitinib is effective and safe in UC patients in real practice, even in a highly refractory cohort. A relevant proportion of patients discontinue the drug over time, mainly due to primary failure.

Integrating acoustic wave sensors into lab-on-a-chip (LoC) devices is a well-known challenge. We address this challenge by designing a microfluidic device housing a monolithic array of 24 high-fundamental frequency quartz crystal microbalance with dissipation (HFF-QCMD) sensors. The device features six 6-&micro, L channels of four sensors each for low-volume parallel measurements, a sealing mechanism that provides appropriate pressure control while assuring liquid confinement and maintaining good stability, and provides a mechanical, electrical, and thermal interface with the characterization electronics. We validate the device by measuring the response of the HFF-QCMD sensors to the air-to-liquid transition, for which the robust Kanazawa&ndash, Gordon&ndash, Mason theory exists, and then by studying the adsorption of model bioanalytes (neutravidin and biotinylated albumin). With these experiments, we show how the effects of the protein&ndash, surface interactions propagate within adsorbed protein multilayers, offering essentially new insight into the design of affinity-based bioanalytical sensors.

Sporadic colorectal cancer (sCRC) is the third most frequent cancer worldwide and the second most common cause of cancer-related deaths (mainly due metastatic dissemination). We investigated the immunohistochemical expression of frequently altered proteins in primary tumors from 51 patients (25 liver metastatic and 26 non-metastatic cases) with a median 103 months follow-up (103 months). We evaluated EGFR copy number (using SNP arrays and FISH) and its expression and regulation (by mRNA and miRNA arrays). We found differences between metastatic and non-metastatic sCRCs for MLH1 (p = 0.05), PMS2 (p = 0.02), CEA (p p p = 0.001), liver metastases at diagnosis (p p EGFR gene copy number- and EGFR mRNA levels. We found potential interactions of two miRNAs targeting EGFR expression, (miR-134 and miR-4328, in non-metastatic and metastatic tumors, respectively). EGFR expression was associated with a worse outcome (p = 0.005). Multivariate analysis of prognostic factors for overall survival identified that, the expression of EGFR expression (p = 0.047) and pTNM stage (p EGFR expression could be regulated by amplification or polysomies (in metastatic tumors), or miRNAs (miRNA-134, in non-metastatic tumors). EGFR expression in sCRC appears to be related to metastases and poor outcome.

Background Approximately one half of the patients with Crohn’s disease (CD) develop intestinal strictures during their lifetime. The effectiveness of currently approved drugs in fibrosis-predominant lesions is very limited. Our aim was to determine the effectiveness of anti-TNF therapy in CD complicated by symptomatic intestinal strictures in a real-world setting. Methods We included adult patients with symptomatic stricturing CD receiving their first-line anti-TNF therapy. Strictures were defined as constant luminal narrowing with pre-stenotic dilatation. We excluded those patients with previous anti-TNF exposure, surgery or endoscopic therapy of the stenosis. The effectiveness of the anti-TNF was defined as a composite outcome combining the persistence of the treatment and without dose or frequency intensification, with no new immunomodulators, surgery or endoscopic therapy during follow-up. A multivariate Cox regression was performed and the final multivariate model was determined using a backward procedure. Results A total of 262 patients from 32 sites were included (141 received infliximab and 121 adalimumab). The median number of stenosis per patient was 1 (range 1–9). The treatment was effective in 81% and 59% of patients after 6 and 12 months, respectively, while this outcome was fulfilled by 21% after a median of 40 months (IQR, 19–85). During follow-up, anti-TNF therapy required a dose or frequency adjustment in 39% of patients, 12% required a new immunomodulator or endoscopic therapy in 4%. The proportion of subjects requiring surgery was 15% and 21% after 1 and 2 years, respectively, with an overall rate of surgery of 32%. Infliximab was associated with a higher rate of surgery as compared with adalimumab (OR 1.78; 95% CI, 1,025-3,09). A shorter time since the diagnosis of CD or the stricture and the initiation of anti-TNF therapy was associated with a greater effectiveness at 6 and 12 months (HR 0.99 95% CI 0.99–1, p = 0.045; HR 0.99 95% CI 0.99–0.99, p = 0.015; HR 0.98 95% CI 0.96–0.99, p = 0.024; HR 0.99 95% CI 0.98–1.0, p = 0.046; respectively). In the survival analysis, younger age, lower albumin levels at baseline, strictures being located in the descending colon, concomitant use of mesalamine and the presence of ulcers or lymphadenopathy at the stricture were associated with lower effectiveness. The anti-TNF agent was discontinued in 131 patients (50%), and 88 subjects (34%) required a switch to a new biologic. Conclusion Anti-TNF agents are effective in approximately 20% of patients with CD complicated with symptomatic strictures. Early introduction of anti-TNF therapy improves the effectiveness in the short term in these patients. Some clinical and radiological predictors can identify patients with a lower probability of response.

Background The risk of splanic vein thrombosis (SVT) -as defined as that involving the portal vein and/or its intrahepatic branches, mesenteric, splenic and/or suprahepatic veïns is mainly observed, among others, in inflammatory abdominal conditions. Thromboembolic complications are frequent among patients with inflammatory bowel disease (IBD). However, there is little information on the prevalence, characteristics, risk factors and evolution of SVT in patients with IBD. Our aims were to describe the characteristics of SVT in patients with IBD, diagnostic explorations, treatment and evolution. Methods Retrospective, multicentre, descriptive study of the ENEIDA registry with a diagnosis of SVT. In addition to epidemiological and clinical features of IBD, we recorded specifically diagnosis, treatment, disease activity at the time of SVT and outcome of SVT. Results Over 59,000 IBD patients in the ENEIDA registry, only 49 episodes of SVT were identified (35 Crohn’s / 14 Ulcerative Colitis); 69% men, median age 42 years old, 35% smokers. 37% had a past history of surgery and/or abdominal inflammatory conditions, 16% extra-intestinal neoplasia, 23% baseline immune or hematologic conditions and 14% liver disease. Finally, 16% had a previous episode of venous thrombosis. The most frequent forms of clinical presentation were abdominal pain with/without fever (59%), and radiological findings in the setting of active IBD (25%). ST coincided with IBD activity in 76% of cases. The diagnosis of SVT was based in the findings of an abdominal CT in 82%. The most frequent localition of SVT were intrahepatic portal branches (51%) and superior mesenteric vein (47%). Only 47% had a basic aetiological study, and 37% underwent gastroscopy (median 7 months from the diagnosis of SVT) showing oesophageal varices in 67%. Anticoagulation therapy was prescribed in 94% of the episodes (74% within the first month since diagnosis), for a median of 7 months. In 90% of the cases, there was a further radiological assessment, 61% of which showing the resolution of the SVT (median of 5 months from the beginning anticoagulation treatment). Conclusion SVT seems to be a rare (or underdiagnosed) complication in IBD patients, it is mostly associated with disease activity and evolves suitably when anticoagulation therapy is suitably started.

[EN] Acoustic wave resonators have become suitable devices for a broad range of sensing applications due to their sensitivity, low cost, and integration capability, which are all factors that meet the requirements for the resonators to be used as sensing elements for portable point of care (PoC) platforms. In this work, the design, characterization, and validation of a 150 MHz high fundamental frequency quartz crystal microbalance (HFF-QCM) sensor for bio-sensing applications are introduced. Finite element method (FEM) simulations of the proposed design are in good agreement with the electrical characterization of the manufactured resonators. The sensor is also validated for bio-sensing applications. For this purpose, a specific sensor cell was designed and manufactured that addresses the critical requirements associated with this type of sensor and application. Due to the small sensing area and the sensor's fragility, these requirements include a low-volume flow chamber in the nanoliter range, and a system approach that provides the appropriate pressure control for assuring liquid confinement while maintaining the integrity of the sensor with a good base line stability and easy sensor replacement. The sensor characteristics make it suitable for consideration as the elemental part of a sensor matrix in a multichannel platform for point of care applications., This work was funded by the European Commission Horizon 2020 Programme under Grant Agreement number ICT-28-2015/687785-LIQBIOPSENS (Reliable Liquid Biopsy technology for early detection of colorectal cancer).

The present work evaluated the performance of two computer programs: Drugcalc, which utilizes the bayesian (method 1) approach and PKS, which can utilize both the non-bayesian (method 2) and bayesian (method 3) approaches. Both programs permit the introduction of serum level data obtained in both situations: steady-state and nonsteady-state. The prediction of phenytoin concentrations (n = 771) were made from steady-state (n = 378) and nonsteady-state (n = 175), and combined steady-state and nonsteady-state (n = 218) concentrations. The observed serum concentrations (at least two nonsteady-state and two steady-state per patient) were collected under routine clinical conditions in 15 patients receiving this drug. The main contribution to prediction errors is attributed to the difference between doses corresponding to the predicted and feedback serum concentrations, dD, in such a way that when the errors obtained for dD > or = 100 mg/day are excluded, the predictive performance increases significantly for all methods. In this sense, increases in precision were 87, 64, and 66% for methods 1, 2, and 3, respectively. Moreover, when dD < 100 mg/day, nonsteady-state feedback concentrations (< or = 3) only afforded clinically acceptable predictions (ME +/- SD < 3 mg/L) when they were combined with at least one steady-state datum value, and the bayesian approach was used. Despite this, for all the methods analyzed, nonsteady-state data are seen to be useful for detecting situations of potential toxicity in a significant proportion of cases (71.4-84.6%) and, when method 3 is used, may offer useful information for the adjustment of dosage schedules.

Despite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C→T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 − 0.00279·GGT)·0.602 CYP2B6*6 [G/T] ·0.354 CYP2B6*6 [T/T] ·0.793 MRP4 1497C→T , where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C→T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.

A population pharmacokinetic model for efavirenz has been developed from therapeutic drug monitoring data in human immunodeficiency virus (HIV)-positive patients by using a nonlinear mixed-effect model. The efavirenz plasma concentrations (n= 375) of 131 patients were analyzed using high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were estimated according to a one-compartment model. The effects of sex, age, total body weight, height, body mass index, and HIV treatment were analyzed. In a subgroup of 32 patients, genetic polymorphisms of the cytochrome P450 2B6 gene (CYP2B6),CYP3A4, andMDR1were also investigated. Efavirenz oral clearance and the apparent volume of distribution were 9.50 liters/h and 311 liters, respectively. The model included only the effect ofCYP2B6polymorphisms on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%. Patients showing G/T and T/TCYP2B6polymorphisms exhibited efavirenz clearances that were about 50% and 75% lower than those observed in the patients without these polymorphisms (G/G). Accordingly, to obtain EFV steady-state concentrations within the therapeutic range (1 to 4 mg/liter), it would be advisable to implement a gradual reduction in dose to 400 or 200 mg/day for patients that are intermediate or poor metabolizers, respectively. However, the remaining interindividual variability observed in the pharmacokinetic parameters of the model highlights the need for dose individualization to avoid inadequate exposure to efavirenz and suggests that these recommended doses be used with caution and confirmed by therapeutic drug monitoring and clinical efficacy. The population model can be implemented in pharmacokinetic clinical software for dosage optimization by using the Bayesian approach.

Servicio de Medicina Intensiva, Hospital de Barcelona SCIAS, Barcelona, Espana Observatori de Bio etica i Dret de la Universitat Barcelona, Barcelona, Espana Servicio Medicina Intensiva, Hospital Universitario Asociado General de Castello, Castello, Espana Servicio de Medicina Intensiva, Hospital Universitario La Fe de Valencia, Valencia, Espana Unidad de Cuidados Intensivos, Hospital General Universitario de Elche, Alicante, Espana Servicio Medicina Intensiva, Hospital San Pedro de Alc antara, C aceres, Espana Departament d’Infermeria i Fisioter apia, Universitat de les Illes Balears, Palma, Illes Balears Espana Servicio Medicina Intensiva, Hospital Arnau de Vilanova de Valencia, Valencia, Espana Servicio de Medicina Intensiva, Hospital de Sant Pau, Barcelona, Espana Servicio de Atencion al Usuario, Hospital de Sant Pau, Barcelona, Espana Servicio Medicina Intensiva y Urgencias, Consorci Hospitalari de Vic, Barcelona, Espana Coordinador de Calidad, Fundacio Hospital de l’Esperit Sant, Santa Coloma de Gramenet, Barcelona, Espana Servicio de Cuidados Cŕiticos y Urgencias, Hospital SAS de Jerez, C adiz, Espana Unidad Medicina Intensiva, Hospital de Sagunt, Valencia, Espana Unidad de medicina Intensiva, Hospital Santiago Apostol, Vitoria, Espana Coordinador GT Bio etica SEMICYUC

Introducción: el receptor del factor de crecimiento epidérmico, EGFR(HER-1), es un receptor de tirosina quinasas cuya activación permite un aumento de la proliferación celular, angiogénesis, proceso metastásico y disminución de la apoptosis celular. Nuestro objetivo es conocer el valor pronóstico de la inmunotinción de EGFR en tumores estromales gastrointestinales (GIST). Pacientes y método: estudio retrospectivo que incluye todos los GIST intervenidos quirúrgicamente entre 1995-2007 en el Servicio de Cirugía General y del Aparato Digestivo del Hospital General de Ciudad Real. Variables clínicas: edad, sexo, clínica, mortalidad, recidiva. Variables patológicas: a) macroscópicas: localización, diámetro; b) microscópicas: necrosis tumoral, índice mitótico, tipo celular; y c) inmunohistoquímicas: vimentina (V9, Dako A/s); actina del músculo liso (HHF-35, Biogenex); CD34 (QBEND/10); S100 (Policlonal Dako A/S); CD117 (c-kit Rabbit, antihuman polyclonal antibody, 1:600); PDGFR-alfa (Rabbit polyclonal antibody, 1:50, Sta. Cruz Biotechnology). Variables moleculares pronósticas: P-53, PAb240 (DakoCytomation), 1:75, Ki-67, clona MIB1 (Dako), 1:120 y EGFR pharmDx™ Dako Autostainer (Dako, Dinamarca). Criterios de malignidad: criterios de Fletcher. Resultados: entre 1995 y 2007, 35 GIST, fueron intervenidos quirúrgicamente en nuestro Servicio. Edad media: 61,11 ± 11,02, siendo mujeres en el 62,9% de los casos. Debutaron con hemorragia digestiva en un 40%. La mediana de seguimiento fue de 28 meses (3-133). La mortalidad fue de 54,3%, con recidiva del 40%. Variables morfológicas: la localización más frecuente fue gástrica, 51,4% (18). Existió necrosis tumoral en un 57,1%, 20. El patrón celular fue fusocelular en un 57,1%, y epitelioide en un 14,3%. El diámetro máximo fue de 9,58 ± 6,29. El índice mitótico por 50 campos de gran aumento fue de 13,44 ± 16,08. En un 51,45%, 18, fueron neoplasias de alto riesgo. Valores inmunohistoquímicos: CD117+, 85,7%. PDGFRA+, 85,7%. CD34+, 77,1%. EGFR+, 62,9%. S100+, 34,3%. Actina+, 20%. Vimentina+, 100%. p53+, 40%. ki67+, 10,71 ± 10,82. La expresión de EGFR no se relacionó con la recidiva y/o mortalidad del enfermo, p = 0,156, y p = 0,332, respectivamente. El índice mitótico se relacionó con la mortalidad del enfermo, p = 0,02, y recidiva neoplásica, p = 0,013. Conclusión: en nuestra muestra no existió relación entre la inmunotinción de EGFR y el pronóstico del tumor estromal gastrointestinal.

Aim and Background The efficacy and safety of rituximab plus chemo (R+chemo) for first-line and relapsed B-CLL patients(pts) have been widely investigated in clinical trials and large patient cohorts, but much less is known about whether such regimens can be effectively and safely administered to unselected pts in the community setting to reflect the routine care of B-CLL pts. Therefore, this observational study was designed to characterize the type, severity and frequency of all adverse events occurring on-treatment and in the year following rituximab infusion. A secondary objective was to assess response rate (CR/nPR/PR), duration of response, disease-free survival, overall survival, and to evaluate the relationship between various baseline markers and clinical outcome parameters in a subset of pts in each study group. Methods Data were collected prospectively from B-CLL pts, in 47 Spanish hospitals, commencing a new treatment with prescribed R+chemo in accordance with normal clinical practice at the time of enrollment. Data cut-off for this interim analysis was May 31, 2013. Results A total of 218 pts have been enrolled, 108 and 110 pts in the first-line and relapsed arm, respectively. The median age (range) of the whole series was 69 (r: 29–87) years. ECOG status varied across the two groups, with a 1 ECOG status score of 23%, and 55% of first-line and relapsed pts, respectively. In the first-line arm, 26%, 47%, and 27%, had a Binet stage of A, B and C, respectively. In the relapsed arm, 11%, 42%, and 46% had a Binet stage of A, B and C, respectively. By first-line / relapsed arm, the proportion of pts with del(11q), del(17p), and unmutated IgVH) was: 14%/15%; 17%/10%; and 10%/9%, respectively. Treated pts were categorized as receiving fludarabine/cyclophosphamide/rituximab (FCR) 60%/20%, bendamustine/rituximbab (BR) 15%/42%, chlorambucil/rituximbab (ClbR) 12%/19%, or other R-based therapy 13%/20%, in the first-line and relapsed arm, respectively. The overall response rate (ORR) in the first-line arm was as follows: BR cohort (81%; 13/16), ClbR (69%; 9/13) and FCR cohort (68%; 44/65), while in the relapsed group the ORR was higher in the ClbR cohort (55%; 11/20), followed by other R-based (48%; 10/21) and FCR cohort (43%; 9/21). Adverse events were most frequently hematologic and infusion-related and included nuetropenia (34% first-line; 28% relapsed); fever (19%; 12%); nausea (14%; 11%); lymphopenia (12%; 9%), and vomiting (11%; 8%). CTC grade 3-5 adverse events occurred in 55% of all 218 pts. Grade3 and 4 neutropenia occurred in 23% (FCR), 25%(BR) and 15% (ClbR) of first-line pts. In the relapsed group this incidence was of 14% (FCR), 16% (BR), and 25% (ClbR). The reported incidence of CTC grade 3 or 4 febtrile neutropenia (FN) in the first-line FCR, and BR cohort was of 9%, and 6%, respectively, while pts in the relapsed group the incidence of grade 3-4 FN was of 19% for FCR and 16% for BR. No FN was reported in the ClbR cohort, on both arms. Infection was reported in 61% and 17% of pts in the first-line/relapsed CFR cohort; 13% and 50% in the first-line/relapsed BR cohort, and 16% and 12% in the first-line/relapsed ClbR cohort, respectively. Treatment discontinuations due to AEs in the first-line and relapsed arm was of 12% and 9%, while treatment related mortality occurred in 3% and 4%, respectively. Conclusion In this unselected group of B-CLL patients taken from normal clinical practice, in first-line, or relapsed approach, rituximab seems an effective and relatively safe option when added to any chemotherapy regimen. Additional analysis of the whole study will give us further information on late toxicity and outcome. Disclosures: Garcia Bernaldez: Roche Pharma: Employment. Gonzalez-Grande:Roche Pharma: Employment.

e13085 Background: PM00104 (Zalypsis, Z) is a synthetic alkaloid related to Jorumycin with a strong antitumor activity against a wide variety of tumor lines. In vivo data of synergism between Z and...

The population pharmacokinetics of imipramine (IMI) and its active metabolite desipramine (DMI) have been evaluated using 177 IMI and DMI serum levels from 49 enuretic children (6-13 y) on IMI treatment. Standard two stage (STS) and maximum likelihood (ML) methods were used to estimate fixed and random effect parameters of IMI. Simultaneous estimation of the drug and metabolite parameters was carried out by the STS method. The mean value of the elimination constant of the drug and metabolite were 0.0425 h-1 and 0.0359, h-1 respectively. Significantly higher variability was found in the pharmacokinetic parameters of the metabolite. According to these estimated pharmacokinetic parameters, the recommended dose for enuretic children should be 1.7 mg.kg-1.day-1. The population pharmacokinetic parameters obtained in the study permit dosage individualisation using a bayesian algorithm.Researchers used population pharmacokinetic parameters and data on the concentration effect relationship from 49 6-13 year old children suffering from enuresis who attended an outpatient psychiatric clinic at University Clinical Hospital in Salamanca, Spain to design rational dosing guidelines of the antidepressant imipramine (IMI) for individual patients. They evaluated 177 IMI serum levels and IMI's active metabolite desipramine (DMI) serum levels. The researchers used standard 2-stage (STS) and maximum likelihood methods to conduct the population pharmacokinetic analysis of IMI. They used STS to simultaneously estimate IMI and DMI parameters. The average value of IMI's elimination constant stood at 0.0425 h-1 and that of DMI's elimination constant stood at 0.0359 h-1. The researchers observed more variability in pharmacokinetic parameters of DMI than those of IMI. Based on estimated pharmacokinetic parameters, a dose of 1.7 mg kg-1 day-1 IMI is needed in children to reach the total serum level of 80 ng/ml which was higher than the dose generally administered in clinical practice (1 mg kg-1 day-1). The researchers demonstrated that applying the population pharmacokinetic parameters to Bayesian fitting methods allows clinicians to individualize IMI dose in children.

This report compares two different methods of estimating the pharmaco-kinetic parameters of phenytoin (PHT) from steady-state serum concentration data obtained in clinical practice: the standard two-stage method (STS) and the extended least squares method (ELS). The study was carried out with the data from 27 compliant adult epileptic patients treated with PHT on a monotherapy regimen. Application of Akaike information criterion (AIC) points to a better estimation with the STS method (AIC = 268.05 for ELS; AIC = 114.13 for STS). This was confirmed by calculating the mean prediction error (mpe) and the standard deviation of EMP, which were 0.59 +/- 6.11 mg/l and -0.12 +/- 2.93 mg/l for ELS, and STS methods, respectively. Despite the well-known limitations of the STS method, a simulation study revealed that it can be successfully used when the patients to be included are selected with great care and when reliable serum concentration data are available.

2080 Background: Trabectedin (ET-743) is a marine-derived DNA and transcription interacting agent with activity in pretreated soft tissue sarcoma, breast, prostate and ovarian cancer. T is associated with 2 types of liver function alterations: a frequent acute and reversible elevation of ALT and AST and a less frequent cholestasis, usually reflected by low grade increases in alkaline phosphatase (AP) and bilirubin (B). The main predictors of dose limiting toxicity (DLT) or T-related serious adverse events appear to include elevated baseline or intercycle peaks of AP, B and ALT > 5 × ULN (Gomez J, ASCO 2000). The objectives of this trial are to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of T 3h/q3w in patients (pts) with advanced cancer and baseline liver dysfunction. Methods: All pts are stratified according to basal liver function as follows: STRATUM (S) I: ULN < AP ≤ 1.5 × ULN S II: 1.5 × ULN < AP ≤ 2.5 × ULN S III: AP > 2.5 × ULN All pts had to have AST and ALT ≤ 2.5 × ULN, albumin > 2.5 g/dl and B < 2.5 mg/dl. T concentrations in plasma are determined using a validated LC-MS/MS method. PK parameters were calculated by non-compartmental methods. Results: 32 pts were recruited.Median age: 54 years (26–76); PS≤1:28 pts; prior chemotherapy (CT): 31 pts (97%); median number of prior CT: 2 (1–6); B > ULN: 0 pts. In S I, T was administered at 1.1 mg/m2 (3 pts) and 1.3 mg/m2 (13 pts). Two DLTs were reported at 1.3 mg/m2: neutropenia G4 > 5 days with febrile neutropenia and G3 ALT not recovered by day +28. In S II no DLT occurred in 4 pts at T 0.9 mg/m2 nor 3 pts at T 1.1 mg/m2, 1 out of 4 pts at 1.3 mg/m2 suffered DLT: G3 AST not recovered by day +24. In S III one out of 2 pts at 0.9 mg/m2 had DLT: AP increase. Initial PK evaluation from S I and II (8 from each) showed a long half life (geometric mean (GM) S I: 124.6 h, S II: 118.8 h) and wide distribution (GM Vss S I: 2366 l/m2, S II: 3830 l/m2). GM clearance: 18.3 l/(hr*m2) in S I; 26.3 l/(hr*m2) in S II. Clearance is somewhat lower than in normal liver function population (GM under equal dexamethasone treatment 33.8 l/hr*m2) in study ET-B-010. Conclusions: The recommended dose (RD) of T for pts with mild AP elevations (< 1.5 ULN) and B levels < ULN is 1.3 mg/m2 3h/q3w. The study is ongoing to define the RD for S II and III [Table: see text]

2059 Background: KF is a cytotoxic cyclic peptide derived from the mollusc Elysia rufescens. Two prior phase 1 studies assessed 1 hour (h) infusions in 5-day 3-weekly and 1-day weekly schedules. Th...

The pharmacokinetics of cefoxitin have been studied in rabbit with normal renal function or with varying degress of renal impairment caused experimentally by uranyl nitrate, after i.v. administration of a single dose of 40 mg/kg. The plasma concentrations of cefoxitin 12 min after administration were 40 μg/ml in rabbits with normal renal function, and reached 36 μg/ml at 6 h in the case of terminal renal impairment. With respect to the pharmacokinetic parameters established in rabbits with normal renal function: K 12 , K 21 K e are decreased while there is an increase in t 1 2 α, t 1 2 β, V c , V p and (AUC) 0 ∞ in rabbits with induced renal impairment. Linear relationships have been established between log K e and serum creatinine. The dose percentage excreted through the kidney in normal rabbits was 85–90%. Biliary excretion of cefoxitin was increased in parallel to the increase in the degree of renal impairment, there being a linear relationship between the dose percentage excreted of the antibiotic and serum creatinine. The values of K B fell from 1.62 h −1 to 0.84 h −1 , indicating that the duration of the biliary excretion process of cefoxitin is longer in the case of severe renal impairment.

Non-compliance to dosage regimes is an important clinical problem with severe repercussions for the management of chronic illnesses requiring continued treatment. In the present study, we evaluated the degree of non-compliance in a group of 100 patients with chronic asthma undergoing continued treatment with theophylline, and the effect of the application of a monitoring programme on their degree of compliance. The evaluation was carried out by anamnesis and from the level/dose ratio. In the control group studied (n = 50) the degree of non-compliance was 44% and in the previously monitored group (n = 50) it was 18%. Serum theophylline levels in the former were: 7.6 +/- 5.8 micrograms/ml, significantly lower (P less than 0.005) than that observed in the latter: 10.1 +/- 4.0 micrograms/ml. The use of monitoring programmes can improve the degree of compliance.

The pharmacokinetics of Cefoxitin were studied in rabbits with normal renal function and with varying degrees of renal impairment induced experimentally by uranyl nitrate. All animals received a single intramuscular (i.m.) dose of 40 mg kg-1 of the antibiotic. The concentrations of Cefoxitin were determined in plasma, urine, and bile by a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. In rabbits with renal impairment there is a decrease in alpha, beta, K12, K21, Ka and an increase in Vd and the (AUC)infinity zero with respect to the values obtained for rabbits with normal renal function. Linear relationships are established between log beta and log K13 and the serum creatinine. Biliary excretion of Cefoxitin is increased in states of renal impairment. A linear relationship is established between the percentage of the dose excreted in the bile and the serum creatinine.

The serum levels of imipramine (IMI) and its active metabolite desipramine (DMI) were monitored in 90 children with primary nocturnal enuresis. Ages ranged between 5 and 14 years. Serum concentrations were determined in 21 children at 24 h after administration of a dose of 75 mg and once when steady state had been reached, 12 h after the last dose; a good correlation was seen between the total levels (IMI + DMI) on those two occasions (r = 0.81; p less than 0.01). This serves as a basis to predict the steady-state levels of IMI + DMI reached in an individual patient. In the remaining patients the serum levels of IMI + DMI were determined at steady state. Dosage regimens were adjusted individually to obtain a favorable response with regard to the frequency of enuresis and to the possible occurrence of side effects. Good correlation was established between the serum concentrations of IMI + DMI at steady state and the frequency of enuresis, with a favorable response being obtained for levels greater than 80 ng/ml. Monitoring of serum levels leads to better compliance with the regimen throughout treatment.

The pharmacokinetics of cefoxitin was studied in 6 healthy volunteers and in 5 patients with a pleural effusion after administration of a single dose of 30 mg/kg i.v. infusion. The serum and pleural fluid concentrations of cefoxitin were determined microbiologically. The elimination half-life of the antibiotic from pleural fluid in all cases was 2-3 fold longer than from serum, which shows a difference between the kinetic elimination processes of the antibiotic from the two fluids. The slow elimination of cefoxitin from pleural fluid facilitates its accumulation in this compartment during a multiple dosage regimen.

The aim of the present work was to analyse the predictive capacity of different optimization methods for carbamazepine dosage regimens according to population pharmacokinetic parameters and/or serum levels data. Calculations were performed using a multiple non-linear regression program (MULTI 2 BAYES) with two different options: (a) using the ordinary least squares methods and (b) the least squares method based on the Bayesian algorithm. The predictive capacity of the three methods was analysed comparing the serum levels values in patients predicted by each method and those observed later. The performance obtained was poor and even unacceptable when dosage prediction was based on the mean parameters of the population studied (Method A) and when only one data point relating to the serum carbamazepine levels was available (Method B). When two serum levels data were used the standard deviation of the mean prediction error was only clinically acceptable when Bayesian non-linear regression was applied (Method C). When the number of serum levels data points was 3 or 4 the errors were acceptable from a clinical point of view and no significant differences could be found between the use of the simple and Bayesian version at the same level of information.

The aim of the present study was to characterize the kinetic behavior of imipramine (IMI) and desipramine in enuretic children and to evaluate the performance of different methods for dosage prediction based on individual and/or population data. The study was carried out in 135 enuretic children (93 boys) ranging in age between 5 and 13 years undergoing treatment with IMI in variable single doses (25–75 mg/day) administered at night. Sampling time was one-half the dosage interval at steady state. The number of data available for each patient varied (1–4) and was essentially limited by clinical criteria. Pharmacokinetic calculations were performed using a simple proportional relationship (method 1) and a multiple nonlinear regression program (MULTI 2 BAYES) with two different options: using the ordinary least-squares method (method 2) and the least-squares method based on the Bayesian algorithm (method 3). The results obtained point to a coefficient of variation for the level/dose ratio of the drug (58%) that is significantly lower than that of the metabolite (101.4%). The forecasting capacity of method 1 is deficient both regarding accuracy [mean prediction error (MPE) = −5.48 \Pm 69.15] and precision (root mean squared error = 46.42 \Pm 51.39). The standard deviation of the MPE (69) makes the method unacceptable from the clinical point of view. The more information that is available concerning the serum levels, the greater are the accuracy and precision of methods (2 and 3). With the Bayesian method, less information on drug serum levels is needed to achieve clinically acceptable predictions.