Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy.

Efficacy and toxicity of anthracycline treatment in acute myeloid leukemia (AML) is mediated by reactive oxygen species (ROS). NADPH oxidase is the major endogenous source of ROS and a key mediator of oxidative cardiac damage. The impact of NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112, RAC2:rs13058338) was evaluated in 225 adult de novo AML patients. Variant alleles of NCF4 and RAC2 were related to higher complete remission (P=0.035, P=0.016), and CYBA homozygous variant showed lower overall survival with recessive model (P=0.045). Anthracycline-induced cardiotoxicity was associated to NCF4 homozygous variant (P=0.012) and CYBA heterozygous genotype (P=0.027). Novel associations were found between variant allele of CYBA and lower lung and gastrointestinal toxicities, and a protective effect in nephrotoxicity and RAC2 homozygous variant. Moreover, RAC2 homozygous variant was related to delayed thrombocytopenia recovery. This study supports the interest of NADPH oxidase polymorphisms regarding efficacy and toxicity of AML induction therapy, in a coherent integrated manner.

Haemodialysis significantly reduces serum levetiracetam levels inducing epileptic seizures: Case report.

WHAT IS KNOWN AND OBJECTIVE: Levetiracetam is used in the treatment of some forms of epilepsy. In renal impairment and patients on chronic haemodialysis, dose adjustment is required. We report a case. CASE DESCRIPTION: This case report describes a woman on levetiracetam treatment who presented with generalized tonic-clonic seizures during a haemodialysis session. We report on treatment adjustment and on the impact of dialysis on levetiracetam levels. WHAT IS NEW AND CONCLUSION: Haemodialysis reduces serum levetiracetam concentration and can lead to subtherapeutic levels. Close monitoring is necessary when dialysis is used on patients receiving anticonvulsant drugs that are extensively eliminated by the procedure.

A systematic review and meta-analysis of the impact of WT1 polymorphism rs16754 in the effectiveness of standard chemotherapy in patients with acute myeloid leukemia.

The polymorphism rs16754 of the WT1 gene has been described as a possible prognostic marker in different acute myeloid leukemia (AML) cohorts; however, it is not supported by all the studies. We performed the first meta-analysis evaluating the effect of this polymorphism upon the effectiveness of standard AML therapy. Fourteen cohort studies were included (3618 patients). Patients with the variant allele showed a significant higher overall survival (OS) at 5 years (OR:1.24, 95% CI: 1.06-1.45, P=0.007, with dominant model). WT1 did not influence complete remission, but a higher disease-free survival was observed with the variant allele. In the subgroup analysis, Caucasians, pediatric and patients treated with idarubicin and etoposide carrying the variant allele showed consistent results in OS, whereas patients with cytogenetically normal AML did not show differences. To verify the effect of this polymorphism upon other outcomes, studies in larger and multiracial populations are needed.

Influence of ABCB1 polymorphisms upon the effectiveness of standard treatment for acute myeloid leukemia: a systematic review and meta-analysis of observational studies.

The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.

Defining well-being in psoriasis: A Delphi consensus among healthcare professionals and patients.

Psoriasis is a chronic skin disease that negatively impacts on patient's life. A holistic approach integrating well-being assessment could improve disease management. Since a consensus definition of well-being in psoriasis is not available, we aim to achieve a multidisciplinary consensus on well-being definition and its components. A literature review and consultation with psoriasis patients facilitated the design of a two-round Delphi questionnaire targeting healthcare professionals and psoriasis patients. A total of 261 panellists (65.1% patients with psoriasis, 34.9% healthcare professionals) agreed on the dimensions and components that should integrate the concept of well-being: emotional dimension (78.9%) [stress (83.9%), mood disturbance (85.1%), body image (83.9%), stigma/shame (75.1%), self-esteem (77.4%) and coping/resilience (81.2%)], physical dimension (82.0%) [sleep quality (81.6%), pain/discomfort (80.8%), itching (83.5%), extracutaneous manifestations (82.8%), lesions in visible areas (84.3%), lesions in functional areas (85.8%), and sex life (78.2%)], social dimension (79.5%) [social relationships (80.8%), leisure/recreational activities (80.3%), support from family/friends (76.6%) and work/academic life (76.5%)], and satisfaction with disease management (78.5%) [treatment (78.2%), information received (75.6%) and medical care provided by the dermatologist (80.1%)]. This well-being definition reflects patients' needs and concerns. Therefore, addressing them in psoriasis will optimise management, contributing to better outcomes and restoring normalcy to the patient's life.

Cost-effectiveness of Cladribine Tablets and fingolimod in the treatment of relapsing multiple sclerosis with high disease activity in Spain.

OBJECTIVE: To estimate the cost-effectiveness of Cladribine Tablets in the treatment of relapsing multiple sclerosis (RMS) with high disease activity compared with fingolimod, from the perspective of the National Health System (NHS) in Spain. METHODS: A Markov model was developed. The annual transition probabilities, were adjusted to patients with RMS with high disease activity. The effect of the treatments compared on the Expanded Disability Status Scale (EDSS) was modeled by hazard ratios for the confirmed progression of disability. The annual relapse rate and the probability of suffering adverse reactions were obtained from a meta-analysis and the literature. The derived costs were calculated from Spanish unit costs. The utilities were obtained from the CLARITY clinical trial and the literature. Deterministic and probabilistic sensitivity analyzes were performed. RESULTS: Cladribine tablets was the dominant treatment: lower costs (-86,536 €) and more effective (+1.11 quality-adjusted life years - QALYs) compared to fingolimod. The probability that Cladribine Tablets was cost-effective compared to fingolimod ranged between 94.6% and 96.1% for willingness to pay from € 20,000 to € 30,000 per QALY gained. CONCLUSIONS: Cladribine Tablets is a cost-effective treatment, compared to fingolimod, for the treatment of RMS with high disease activity. EXPERT OPINION: According to the present study, compared to fingolimod, treatment with Cladribine Tablets of relapsing multiple sclerosis with high disease activity is an option that could generate savings for the Spanish National Health System, with a considerable gain in QALYs. Cladribine Tablets is considered cost-effective and dominant (less costs and more effectiveness) than fingolimod treatment option in this population.

Bayesian pharmacokinetic-guided prophylaxis with recombinant factor VIII in severe or moderate haemophilia A.

INTRODUCTION: Personalised pharmacokinetics (PK) using Bayesian analysis with limited sampling is assumed to help to optimise prophylaxis in haemophilia A (HA) patients. MATERIALS AND METHODS: Our prospective, observational study analysed the influence of PK parameters on clinical variables (bleeding rates, joint status, adherence, and consumption) using myPKFiT® in a cohort of twenty-one severe and moderate HA patients on prophylaxis with recombinant FVIII (Advate®) in two periods of one year, the first before PK-based tailoring and the second after PK-guided prophylaxis. Intra-individual and inter-individual coefficients of variation (CV) of half-life (t1/2) were calculated. RESULTS: A total of 73 PK estimations were performed in both periods, resulting in 17.2% inter-individual CV in mean t1/2, and 4.9% intra-individual CV. Before PK-based tailoring a significant association between joint bleeds and t1/2 was found (P = 0.010), especially in patients with short t1/2. This finding was reproduced (P = 0.013) after withdrawal of two patients with bleeding phenotype related to their advanced arthropathy but normal t1/2 and trough levels. Patients with joint bleeds weighed less (P = 0.039) and required higher doses (P = 0.032) than patients with zero joint bleeds. These associations were not observed in the second period after the adoption of PK-guided prophylaxis. There were no differences between the two periods, although a tendency to fewer spontaneous bleeds was suggested after PK-based tailoring. CONCLUSIONS: PK-guided prophylaxis facilitates an adequate level of bleeding control in patients with HA, maintaining clinical variables and patient convenience in an integrative manner, without increasing FVIII consumption.

[Antimicrobial stewardship programme implementation in a medical ward]. / Implantación de un programa de optimización y uso racional de antimicrobianos en un modelo de área clínica médica.

OBJECTIVE: Antimicrobial stewardship programmes (ASP) have proven to be effective tools for reducing the use of antimicrobials. The purpose of the study is to evaluate the effect of an ASP implantation in a medical Ward. METHODS: Prospective intervention study in a medical ward with a heterogeneous composition. In September 2014, an ASP based on prospective audits was implemented. Antimicrobial consumption and the length of stay and mortality in all patients admitted, as well as in the main infections present in the unit, were compared before and after two years of the ASP implementation. RESULTS: A total of 378 infectious episodes of 335 pa-tients were evaluated in 168 meetings. The prescriber ac-cepted 92.3% of the suggestions. The consumption of an-timicrobials reviewed was reduced from 31.3 to 17.6 DDD / 100-stays (ß =-0.40, P = 0.015). The average cost per income was reduced from € 161.4 to € 123.3 (-23.6%). No differences were found in total length of stay or mortality. There were no changes in the incidence of Clostridium difficile infection or candidemia between the two periods. There were no significant differences in length of stay or mortality in total bacteremia, candidemia, and urinary tract infections caused by multiresistant bacteria. CONCLUSIONS: The implementation of an ASP in a heterogeneous medical ward significantly reduces the use of antimicrobials in a short time horizon without adversely affecting the evolution of the patients..

The view of experts on initiatives to be undertaken to promote equity in the access to orphan drugs and specialised care for rare diseases in Spain: A Delphi consensus.

OBJECTIVES: To reach a consensus amongst experts on the most feasible actions to be undertaken to facilitate patient access to specialised care and orphan drugs (OD) in the public health sector in Spain. METHODS: Two Delphi rounds were completed. The questionnaire was based on a literature review and 2 focus groups. Agreement was sought on the desire (D) and prognosis (P) for the implementation within the next 5 years, on a 5-point Likert scale. Consensus was reached when ≥75% participants chose agreement (1-2) or disagreement options (4-5). RESULTS: 82 experts on rare disease (RD) participated. Agreement on the D and P was reached in 66.07% statements: OD pricing review [absence of clinical effectiveness (D:85.37%; P:85.90%), target population increase (D:79.27%; P:91.03%)]; reference team definition of referral protocols and clinical practice guidelines (D: 97.56%; P: 89.74%); and a unified, usable, etiology-based registry (D:97.56%; P:84.62%). D and P assessment diverged in 32.14% items: creation of a specific funding system for OD (D: 97.56%; P: 60.25%); and a network of medical teams to coordinate the care of RD patients (D: 99%; P: 62%). CONCLUSIONS: The results have shown the need to promote dialogue between stakeholders, introduce European recommendation to national and regional Spanish policies and set up priorities and undertake actions to drive relevant changes in current medical practice in managing RD patients.

[Cefditoren pivoxil: A new oral cephalosporin for skin, soft tissue and respiratory tract infections]. / Cefditoren pivoxilo: una nueva cefalosporina oral para infecciones de vias respiratorias y de piel y tejidos blandos.

Cefditoren pivoxil, a new-third generation cephalosporin antibiotic that has recently been granted approval in Spain, shows important activity over a large part of the pathogens causing skin, soft tissue and respiratory tract infections, including Gram-negative and Gram-positive bacteria. Cefditoren has also been shown to be stable against hydrolysis by many common beta-lactamases. Data from in vitro studies and clinical trials show this antibiotic as an oral formulation with an intrinsic activity against Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae equivalent to that of other third-generation cephalosporins administered via parenteral, like cefotaxime or ceftriaxone, thereby placing its maximal benefits mainly in the treatment of ambulatory infections. This paper reviews the main characteristics of cefditoren pivoxil (spectrum of activity, chemical structure, mechanism of action, pharmacokinetics, adverse effects and clinical efficacy) and attempts to find its place in current antibiotic therapeutics.

[Risk sharing agreements: with orphan drugs?]. / Contratos de riesgo compartido, ¿con medicamentos huérfanos?

OBJECTIVE: To summarize available information on share risk agreements (RSA) with orphan drugs (OD). METHODS: A bibliographic search was carried out in MEDLINE, EMBASE and INAHTA using 19 keywords and combinations thereof. Papers published as original, narrative and systematic reviews, editorials, commentaries, letters to the Editor, and special articles were included and reviewed. Public or private institutional reports or documents found in Google that contained relevant information were also reviewed. RESULTS: experience gained so far with RSA is scant. No published rigorous evaluations of outcomes of these agreements were found. It seems, however, that OD are suitable for introduction in clinical practice by means of RSA. There are two main types of RSA: financially based, and performance-outcome based. A number of theoretical advantages of SRA are described, as well as hurdles that hinder their design, implementation, and followup, and thus endangering their success. Very few RSA have clearly succeed so far. CONCLUSIONS: If thoroughly managed, RSA may reasonably contribute to value-based pricing of OD, improve their pharmacovigilance, knowledge about their comparative effectiveness, and to reducing uncertainty and its consequences on patients, industry, payers and clinicians. There are technical groups that can bring the essential knowledge to manage RSA in Spain. The challenge now is to be able to harmonize their assessments and appraisals, to put in motion the mechanisms needed to overcome those hurdles, and to provide them adequate political and institutional support.

Clinical interest of pharmacogenetic polymorphisms in the immunosuppressive treatment after heart transplantation.

In the transplantation field, genetic changes in a single nucleotide in the genes responsible for the transport and metabolism of an immunosuppressive drug may modify the response of the patient. The aim of this study was to evaluate the effect of single nucleotide polymorphisms (SNPs) in heart transplant recipients and their donors in association with tacrolimus and cyclosporine blood levels during the first 2 weeks after transplantation. A total of 18 blood samples from heart transplant recipients and their donors (n=36) were analyzed using Sequenom to characterize the more relevant SNPs of the ABCB1 and CYP3A5 genes for correlation with C0 (trough concentration) drug blood levels. Differences between groups were evaluated with two-way analysis of variance (ANOVA) and Bonferroni post-test. In agreement with theoretical predictions, the wild type genotype in ABCB1 SNPs (CC) tended to stabilize drug levels within the therapeutic range, whereas the T variant induced a 79% mean increase in blood levels among heterozygous (CT) and 100% among homozygous (TT) recipients. These results agreed with the mean levels in various recipient/donor populations, finding significant differences between them (P<.001 in CC vs CT and P<.01 in CT vs TT), as well as a certain influence of the donor genotype.

Selection of optimal prophylactic aminoglycoside dosage in cancer patients: population pharmacokinetic approaches.

We report an alternative dose-finding approach for the selection of optimal prophylactic aminoglycoside dosage in specific (sub)populations of patients. Relative a priori utility of several intervals of gentamicin or tobramycin (AMG) peak and trough serum levels were assigned by a group of pharmacokinetics experts, assuming prophylactic administration for laryngectomy interventions. A group of 27 adult patients, with normal renal function, undergoing elective surgery for laryngeal problems and treated prophylactically with gentamicin (80 mg t.i.d.) or tobramycin (100 mg t.i.d.) was studied. Two blood samples (peak and trough) were drawn at steady-state for AMG assay. Three different methods, standard two-stage (STS), extended least-squares non-linear regression [MULTI(ELS)] and non-parametric expected maximization (NEPM), were used to estimate the pharmacokinetic (PK) population parameters. PK simulations were applied to estimate the AMG steady-state concentrations from the PK population parameters. From these data, relative utility values were calculated, allowing the selection of the optimal dosage schedule for this group of patients. There were no statistically significant differences between the PK population estimates as generated by the three methods. Using the STS estimates, the simulation of several dosages indicated that the optimal dosage is 170 mg every 8 h. Conversely, using the individual PK parameters and the mean AMG levels simulated from them, the dose with best relative utility is 130 mg every 8 h. This important difference points out the relevance of the use of relative utilities for the AMG serum concentrations in the selection of optimal a priori dosage. We propose the use of 120 mg every 8 h as the safer dose for our population. Further studies are needed to validate this proposal in patients similar to ours.

Phenolic constituents of Phenax angustifolius.

Fractionation of an ethanolic extract of the leaves of Phenax angustifolius has resulted in the isolation of two new lignans, 2-hydroxy-2-(3',4'-dihydroxyphenyl)methyl-3-(3' ',4' '-dimethoxyphenyl)methyl-gamma-butyrolactone (1) and 2-hydroxy-2-(4'-O-beta-D-glucopyranosyl-3'-hydroxyphenyl)methyl-3-(3' ',4' '-dimethoxyphenyl)methyl-gamma-butyrolactone (2), and three known compounds, vitexin, isovitexin, and quercetin 3-O-alpha-L-rhamnopyranoside. The structures of 1 and 2 were determined using spectroscopic methods.

Therapeutic drug monitoring of tobramycin: once-daily versus twice-daily dosage schedules.

OBJECTIVE: To evaluate the effect of dosage regimen (once-daily vs. twice-daily) of tobramicyn on steady-state serum concentrations and toxicity. MATERIALS AND METHODS: Patients undergoing treatment with i.v. tobramycin (4 mg/kg/day) were randomised to two groups. Group OD (n = 22) received a once-daily dose of tobramycin and group TD (n = 21) received the same dose divided into two doses daily. Tobramycin serum concentrations (peak and trough) were measured by enzyme multiplied immunoassay. The renal and auditory functions of the patients were monitored before, during and immediately after treatment. RESULTS: The two groups were comparable with respect to sex, age, body weight and renal function. No statistically significant differences were found in mean daily dose, duration of treatment, or cumulative dose. Trough concentrations were < 2 g/ml in the two groups (100%). Peak concentrations were > 6 microg/ml in 100% of the OD group and in 67% of the TD group (P< 0.01). Mean peak concentrations were markedly different: 11.00+/-2.89 microg/ml in OD vs. 6.53+/-1.45 microg/ml in TD (P< 0.01). The pharmacokinetics parameters were: Ke, (0.15+/-0.03/h in OD vs. 0.24+/-0.06/h in TD), t1/2, (4.95+/-1.41 h in OD vs. 3.07+/-0.71 h in TD), Vd (0.35+/-0.11 l/kg in OD vs. 0.33+/-0.09 l/kg in TD), Cl (0.86+/-0.29 ml/min/kg in OD vs. 1.28+/-0.33 ml/min/kg in TD). Increased serum creatinine was observed in 73% of patients in OD versus 57% of patients in TD, without evidence of nephrotoxicity. In TD group, three patients developed decreased auditory function, of which one presented with an auditory loss of -30 dB, whereas in the OD group only one patient presented decreased auditory function. CONCLUSION: This small study suggests that a once-daily dosing regimen of tobramycin is at least as effective as and is no more and possibly less toxic than the twice-daily regimen. Using a single-dose therapy, peak concentration determination is not necessary, only trough samples should be monitored to ensure levels below 2 microg/ml.