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Background REM sleep behaviour disorder (RBD) is a common non-motor feature of Parkinson's disease (PD). Cannabidiol (CBD) is one of the main non-psychoactive components of Cannabis sativa and may represent an alternative route for treating RBD. Objective This study assessed the efficacy and safety of CBD for RBD in PD. Methods We conducted a phase II/III, double-blind, placebo-controlled clinical trial in 33 patients with RBD and PD. Patients were randomized 1:1 to CBD in doses of 75 to 300mg or matched capsules placebo and were followed up for 14 weeks. The primary outcomes were the frequency of nights with RBD, CGI-I, and CGI-S. Results CBD showed no difference to placebo for primary outcomes. Regarding secondary outcomes, we observed a significant improvement in average sleep satisfaction from the 4th to 8th week in the CBD versus placebo group with P = 0.049 and P = 0.038, respectively. Conclusion CBD, as an adjunct therapy, showed no reduction in RBD manifestations in PD patients. A transient improvement in sleep satisfaction with a dose of 300mg has been noted. © 2021 International Parkinson and Movement Disorder Society.

Made available in DSpace on 2022-04-28T19:47:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-10 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The antidepressant effect of ketamine has been widely acknowledged and the use of one of its enantiomers, S-ketamine (esketamine), has recently been approved for the clinical management of treatment-resistant depression. As with ketamine, the non-selective opioid receptor-interacting drug buprenorphine is reported to have antidepressant and anxiolytic properties in humans and rodents. Given the fact that antidepressant drugs are also first line treatment for panic disorder, it is surprising that the potential panicolytic effect of these compounds has been scarcely (ketamine), or not yet (buprenorphine) investigated. We here evaluated the effects of ketamine (the racemic mixture), esketamine, and buprenorphine in male Wistar rats submitted to a panicogenic challenge: acute exposure to hypoxia (7% O2). We observed that esketamine (20 mg/kg), but not ketamine, decreased the number of escape attempts made during hypoxia, and this effect could be observed even 7 days after the drug administration. A panicolytic-like effect was also observed with MK801, which like esketamine, antagonizes NMDA glutamate receptors. Buprenorphine (0.3 mg/kg) also impaired hypoxia-induced escape, an effect blocked by the non-selective opioid receptor antagonist naloxone, indicating an interaction with classical ligand sites, such as µ and kappa receptors, but not with nociception/orphanin FQ receptors. Altogether, the results suggest that esketamine and buprenorphine cause rapid-onset panicolytic-like effects, and may be alternatives for treating panic disorder, particularly in patients who are refractory to standard pharmacological treatment. Department of Pharmacology School of Medicine of Ribeirão Preto University of São Paulo Department of Biomolecular Sciences School of Pharmaceutical Sciences University of São Paulo Aarhus Institute of Advanced Studies (AIAS) Aarhus University Behavioural Neurosciences Institute (INeC) Department of Pharmacology and Therapeutics State University of Maringá (UEM) Department of Biological Sciences School of Sciences São Paulo State University (UNESP) Department of Biological Sciences School of Sciences São Paulo State University (UNESP) CNPq: 142509/2018-3 FAPESP: 2018/00153-5

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti–PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.

Infection by the hepatitis C virus (HCV) generates inflammatory response selectively modulating cytochrome P450 protein (CYP) activities. This study assessed the effect of chronic hepatitis C on CYP2C19 activity in patients with HCV.Patients with HCV infection (n = 23) at different fibrosis stages were allocated into groups 1 (F0/F1 and F2, mild to moderate fibrosis) and 2 (F3 and F4, advanced fibrosis stages). Phase 1 was conducted before the treatment with direct-acting antivirals (DAAs) and phase 2 after the sustained virological response. Participants were administered 2 mg of a single oral dose of omeprazole (OME) as probe drug in both phases. Metabolic ratios (MRs) (plasma samples collected at 4 h after OME administration) were calculated by dividing plasma concentrations of 5-hydroxyomeprazole by OME.The MRs for group 1 were 0.45 (0.34-0.60, 90% confidence interval) and 0.69 (0.50-0.96) for phases 1 and 2, respectively, while the MRs for group 2 were 0.25 (0.21-0.31) and 0.41 (0.30-0.56) for phases 1 and 2, respectively. MRs were different (P .05) between phases 1 and 2 for both groups, as well as between groups 1 and 2 in phase 1, but not in phase 2 (P .05).Both groups presented different MRs before and after treatment with DAAs, evidencing that CYP2C19 inhibition during inflammation was at least partially reversed after DAA treatment. Groups 1 and 2 were also found to be different in phase 1 but not phase 2, showing that CYP2C19 metabolic activity does not differ between groups after DAA treatment.

Autophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

Clinical question What is the role of drugs in preventing covid-19? Why does this matter? There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. Recommendations The second version of this living guideline reiterates the previous strong recommendation against the use of hydroxychloroquine and includes a new conditional recommendation against the use of tixagevimab-cilgavimab in individuals who do not have covid-19. How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provides methodological support. A living systematic review with network analysis informs the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produces recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the recommendations The living network meta-analysis informing this guideline included 12 trials (8379 participants) comparing hydroxychloroquine to standard care/placebo, and one trial (5197 participants) comparing tixagevimab-cilgavimab to standard care/placebo. When moving from evidence to the continued strong recommendation against the use of hydroxychloroquine, the GDG emphasised additional evidence suggesting no or little effect on mortality and hospital admission, and an increased risk of adverse effects. For the new conditional recommendation against the use of tixagevimab-cilgavimab, the GDG emphasised in vitro evidence reducing the applicability of available trial data. While trial results demonstrated modest reduction in the occurrence of laboratory confirmed symptomatic covid-19, lack of in vitro neutralisation of new SARS-CoV-2 sub-lineages was considered to have rendered these results obsolete. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. Readers note This is the second version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19 and living guidance regarding covid-19 related clinical management. When citing this article, please consider adding the update number and date of access for clarity.

Post-traumatic stress disorder is a common condition that affects millions of people across the world. Up to date recommendations based on the best available evidence are vital to prevent and treat this debilitating condition. In this issue, we are bringing together a series of systematic reviews and meta-analyses that underpinned the development of the 2018 International Society for Traumatic Stress Studies Guidelines. The strongest evidence was found for psychological treatments for PTSD, in particular for cognitive behavioural therapy with a trauma focus (CBT-TF)(generic), cognitive processing therapy (CPT), cognitive therapy (CT), eye movement desensitisation and reprocessing (EMDR) and prolonged exposure (PE). For the subgroup of military personnel and veterans, results were less impressive. Dropout from trauma-focused psychological treatments was higher than for other forms of psychological treatment for PTSD in adults. For early interventions, CBT-TF, CT and EMDR were recommended. With regard to pharmacological approaches, a number of them were effective but with a low effect size. Of the pharmacologically assisted psychotherapies, MDMA-assisted psychotherapy was promising. Six complementary and alternative approaches showed emerging evidence. We now have an evidence base for a diverse range of pharmacological, psychological and other approaches that should facilitate their implementation and lead to the more effective management of people affected by traumatic events., HIGHLIGHTS • A diverse range of pharmacological, psychological and other approaches now have an evidence base for the prevention and treatment of PTSD.• This editorial introduces the EJPT special issue that considers these interventions and their relative strengths in more detail.

Vasoplegic syndrome (VS) comprises a constellation of concurrent signs and symptoms: hypotension, high cardiac index, low systemic vascular resistance, low filling pressures, the tendency to occur diffuse bleeding, and sustained hypotension. All of these parameters may persist even despite the use of high doses of vasoconstrictor amines. VS arises from vasoplegic endothelial dysfunction with excessive release of nitric oxide by polymorphonuclear leukocytes mediated by the nitric oxide synthase’s inducible form and is associated with systemic inflammatory reaction and high morbimortality. The achievements regarding the treatment of VS with methylene blue (MB) are a valuable Brazilian contribution to cardiac surgery. The present text review was designed to deliver the accumulated knowledge in the past ten years of employing MB to treat VS after cardiac surgery. Considering that we have already published two papers describing acquired experiences and concepts after 15 and 20 years, now, as we achieve the 30-year mark, we compose a trilogy.

Cell senescence is a process that causes growth arrest and the release of a senescence associated secretory phenotype (SASP), characterized by secretion of chemokines, cytokines, cell growth factors and metalloproteases, leading to a tissue condition that may precipitate cancers and neurodegenerative processes. With the recent pandemic of coronavirus, senolytic drugs are being considered as possible therapeutic tools to reduce the virulence of SARS-CoV-2. In the last few years, our research group showed that lithium carbonate at microdose levels was able to stabilize memory and change neuropathological characteristics of Alzheimer's disease (AD). In the present work, we present evidence that low-dose lithium can reduce the SASP of human iPSCs-derived astrocytes following acute treatment, suggesting that microdose lithium could protect cells from senescence and development of aging-related conditions. With the present findings, a perspective of the potential use of low-dose lithium in old patients from the "high risk group" for COVID-19 (with hypertension, diabetes and chronic obstructive pulmonary disease) is presented.

Background Two-drug regimens (2DR) to treat HIV infection have the potential to reduce long-term toxicity and increase therapeutic options for people living with HIV (PLHIV). Prior phase III trials, SWORD-1 and SWORD-2, as well as GEMINI-1 and GEMINI-2, have demonstrated that a dolutegravir-based 2DR is as effective as three-or four-drug regimens among virologically suppressed patients. Limited information exists, however, on patient and provider experiences with 2DR to inform roll-out and integration into routine clinical care. Methods We conducted 39 in-depth interviews with PLHIV currently on 2DR in the context of routine care and 8 of their clinical care providers in the United States (U.S.) and Spain. Participants included 33 male and 6 female PLHIV and 8 providers. Interview topics explored perceptions of and experiences with 2DR compared to prior anti-retroviral regimens (ARVs), side effects, patient satisfaction, and clinical performance. Interviews were audio-recorded, transcribed and analyzed using thematic content analysis. Results Participants viewed 2DR as a significant and positive advance, in terms of its ability to effectively treat HIV with reduced toxicity and essentially no reported side effects. Patients noted the central role providers played in the decision to switch to a 2DR regimen and, among U. S. participants, the importance of insurance coverage making this preferred option feasible. Patients aynd providers agreed that a 2DR regimen would be appropriate for any PLHIV regardless of whether they were treatment naive or had significant experience with ARVs. Conclusions Participants' experiences with a 2DR regimen were positive with no participants, reporting side effects and all reporting continued viral suppression. Providers valued the reduced toxicity offered by 2DR and served as the primary gateway to a transition to 2DR for patients in both settings. This study provides a foundation for further research on the transition to 2DR regimens in other populations and contexts including low- and middle-income settings., This study was funded by ViiV Healthcare (www.viivhealthcare.com) and ViiV Healthcare was involved in the study design, decision to publish, and preparation of the manuscript. Additional support was provided by ViiV Healthcare in the form of a contract to the American University which supported a portion of salaries for WD,AM, TK, and DK.

Purpose To evaluate the gene expression of peroxisome proliferator activated receptors gamma (PPARG) in colorectal tumors and to correlate this data with clinical variables of the patients. Methods We analyzed the gene expression of PPARG in 50 samples of colorectal tumors using real-time reverse transcription polymerase chain reaction, and 20 adjacent normal tissue samples as control. The results of these quantifications were correlated with the respective patients’ medical records’ clinical information. Results PPARG expression was not different in the tumor tissue compared to the control tissue. Patients older than 60 years, histological type with mucinous differentiation, more advanced staging at the time of diagnosis, and patients who evolved with recurrence of the disease or death did not present higher PPARG expression. Conclusion Expression of PPARGD was not associated with worse prognosis.

Factors related to the discrepancy between patient-perceived and actual disease control remain unclear. Identifying patients at risk of overestimation of asthma control remains elusive. This study aimed to (i) investigate the relationship between patient-reported and actual level of asthma control (ii), compare the characteristics between patients who believe their asthma is well controlled that accurately report 'well-controlled' asthma with those that do not, and (iii) identify factors associated with inaccurately reported 'well-controlled' asthma. A historical, multinational, cross-sectional study using data from the iHARP (initiative Helping Asthma in Real-life Patients) review service for adults with asthma prescribed fixed-dose combination therapy. Data from 4274 patients were analysed. A major discrepancy between patient-reported and Global Initiative for Asthma defined asthma control was detected; 71.1% of patients who reported 'well-controlled' asthma were inaccurate in their perception despite receiving regular maintenance therapy. Significant differences were noted in age, gender, body mass index, education level, medication use, side effects, attitudes to preventer inhaler use, inhaler technique review and respiratory specialist review between patients who accurately reported 'wellcontrolled' asthma and those who did not. Independent risk factors associated with inaccurately reported 'well-controlled' asthma were: having taken a maximum of 5-12 puffs or more of reliever inhaler on at least one day within the previous 4 weeks; being female; having seen a respiratory specialist more than a year ago (rather than in the previous year); and having required oral corticosteroids for worsening asthma in the previous year. The study highlighted the significant hidden burden associated with under-recognition of poor asthma control, on the part of the patient and the need for targeted interventions designed to address the continuing discrepancy between perceived and actual disease control., The International Primary Care Respiratory Group (IPCRG) has facilitated the publication of this paper. The iHARP database was funded by unrestricted grants from Mundipharma International Limited and Optimum Patient Care Global Ltd, which is a social enterprise that focuses on quality improvement in clinical practice. The sponsor was not involved in data analysis or the interpretation of the results.

Objective Our objective was to assess the effect of sublingual fentanyl tablets (SFTs) on pain relief, quality of life, and adverse effects in patients with cancer pain, according to cancer stage and background opioid regimen. Methods Subgroup analyses from a recently completed study were performed according to cancer stage (locally advanced cancer [LAC] vs. metastatic cancer) and most frequent background opioid medication (fentanyl vs. oxycodone/naloxone). The efficacy and safety of SFTs were evaluated, recording pain intensity (PI), onset of pain relief, and adverse events (AEs). Health status was assessed with the Short Form 12, version 2 (SF-12v2) questionnaire and the Hospital Anxiety and Depression Scale (anxiety subscale [HADS-A] and depression subscale [HADS-D]). Results In total, 54 (67.5%) patients had LAC and 26 (32.5%) had metastatic cancer. The oxycodone/naloxone group included 39 patients (48.1%) and the fentanyl group 29 (35.8%). In all subgroups, pain relief was achieved within 5 min in an increasing number of individuals over time; at the end of the study, PI values decreased (PI-end: 44.4% for LAC vs. 57.9% for metastatic cancer; 44.4% for fentanyl vs. 38.6% for oxycodone/naloxone). HADS and mental component summary (MCS) SF-12v2 scores significantly improved in the LAC group (HADS-A 9.44-8.04; HADS-D 10.46-8.15; MCS 44.69-45.94) and in the fentanyl group (HADS-A 10.05-8.33; HADS-D 11.95-8.76; MCS 44.38-47.19). AEs were reported in few patients and were mostly mild. Conclusions Exploratory subgroup analyses show the efficacy and safety of SFTs for the treatment of breakthrough pain in patients with cancer, regardless of their cancer stage and background opioid medication., This work was supported by Kyowa Kirin Farmaceutica SLU. The authors received research funding from Kyowa Kirin Farmaceutica SLU for this study.

Resumen El adecuado tratamiento de la diabetes mellitus tipo 2 (DM2) incluye la alimentación saludable y el ejercicio (150 min/semana) como pilares básicos. Para el tratamiento farmacológico, la metformina es el fármaco de elección inicial, salvo contraindicación o intolerancia; en caso de mal control, se dispone de 8 familias terapéuticas (6 orales y 2 inyectables) como posibles combinaciones. Se presenta un algoritmo y unas recomendaciones para el tratamiento de la DM2. En prevención secundaria cardiovascular se recomienda asociar un inhibidor del cotransportador sodio-glucosa tipo 2 (iSGLT2) o un agonista del receptor de glucagon-like peptide-1 (arGLP1) en pacientes con obesidad. En prevención primaria, si el paciente presenta obesidad o sobrepeso la metformina deberá combinarse con iSGLT2, arGLP1 o inhibidores de la dipeptidilpeptidasa tipo 4 (iDPP4). Si el paciente no presenta obesidad, podrán emplearse los iDPP4, los iSGLT2 o la gliclazida, sulfonilurea recomendada por su menor tendencia a la hipoglucemia.

Background The economic feasibility of pharmacotherapeutic empowerment of patients with type 2 diabetes mellitus (DM2) is still not well established. Objectives To evaluate the cost-effectiveness of an individual pharmacotherapeutic empowerment strategy (IPES) for patients with DM2. Methods This is a cost-effectiveness study nested in a non-randomized clinical trial with patients ≥18 years of age, of both genders, with low and moderate cardiovascular risks. This study was carried out from the perspective of the municipal health system of Divinópolis in Minas Gerais state, and compared patients submitted to an IPES and patients who received only traditional care, 1 year before the beginning of the intervention (baseline) and 1 year after its completion (follow-up). The costs of the services offered by the municipality were computed, and in the intervention group IPES costs were included. Glycated hemoglobin (A1c) was the effectiveness parameter adopted. Cost-effectiveness ratio analyses, incremental cost-effectiveness ratio (ICER), and sensitivity analysis were performed. Results In the analysis of cost-effectiveness, it is observed that a reduction of 0.359 in A1c costs US$708.47 in the intervention group and a reduction of 0.170 costs US$1927.13 in the control group. Thus, the ICER is US$387.66 per patient/year. In the sensitivity analysis, it was observed that the IPES was dominant in 19.8% of the simulated scenarios and cost-effective in 80.2%. Conclusions The IPES is an alternative that presents economic feasibility for the municipal public health system scenario. The absence of randomization in patient selection is a limitation of this study. Antecedentes A viabilidade econômica da capacitação farmacoterapêutica de pacientes com diabetes mellitus tipo 2 (DM2) ainda não está bem estabelecida. Objetivos Avaliar o custo-efetividade de uma estratégia individual de capacitação farmacoterapêutica (EPI) para pacientes com DM2. Métodos Trata-se de um estudo de custo-efetividade aninhado em um ensaio clínico não randomizado com pacientes ≥18 anos, de ambos os sexos, com risco cardiovascular baixo e moderado. Este estudo foi realizado na perspectiva da rede municipal de saúde de Divinópolis em Minas Gerais, e comparou pacientes submetidos a IPES e pacientes que receberam apenas cuidados tradicionais, 1 ano antes do início da intervenção (linha de base) e 1 ano após sua conclusão (acompanhamento). Foram computados os custos dos serviços oferecidos pelo município, e no grupo de intervenção os custos do IPES foram incluídos. A hemoglobina glicada (A1c) foi o parâmetro de efetividade adotado. Foram realizadas análises de relação custo-efetividade, relação custo-efetividade incremental (ICER) e análise de sensibilidade. Resultados Na análise de custo-efetividade, observa-se que uma redução de 0,359 na A1c custa US$ 708,47 no grupo intervenção e uma redução de 0,170 custa US$ 1927,13 no grupo controle. Assim, o ICER é de US$ 387,66 por paciente/ano. Na análise de sensibilidade, observou-se que o IPES foi dominante em 19,8% dos cenários simulados e custo-benefício em 80,2%. Conclusões O IPES é uma alternativa que apresenta viabilidade econômica para o cenário do sistema público municipal de saúde. A ausência de randomização na seleção dos pacientes é uma limitação deste estudo.

Background and aims Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r +/- DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015. Material and methods Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records. Results Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan (R), 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient ' s decision. Conclusions These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials., MCL has served as consultant for AbbVie, MSD, Janssen, BMS and Gilead; MRB has received grant research from Gilead Science, and speaker fees from AbbVie, Gilead and MSD; MR has received speaker fees from AbbVie; MD has received grant support and consultancy fees from AbbVie, Bayer, Bristol-Myers Squibb, Gilead and Merck, Sharp & Dhome; FGR has served as speaker for AbbVie, Gilead and BMS; MLM has served as a speaker for AbbVie, BMS, Gilead, Janssen, MSD and ViiV; as a consultant for AbbVie, BMS and Janssen and has received research funding from FIPSE 36465/03, FIPSE 36680/07.-NEAT IG5 (NEAT is a project funded by the European Union under the 6th Framework programme) contract number LSHP-CT-2006-037570; MAC has served as a consultant for Gilead and and ViiV healthcare, and has received speaker fees from Janssens, Gilead, ViiV Healthcare; MMA reports personal fees from ViiV Healthcare, Gilead Sciences, Merck, Janssen, AbbVie and ABBOTT Laboratories, outside the submitted work; AR has received consultancy and speaker fees from AbbVie, Gilead Sciences and Merck Sharp & Dohme; JM has received honoraria, speaker fees, consultant fees or funds for research from AbbVie, BMS, Boehringer-Ingelheim, Gilead, Janssen, MSD, Roche and ViiV; EGP has received speaker fees from AbbVie and Gilead; LGB has served as consultant for AbbVie and Intercept and has received speaker fees from Gilead and MSD; AA, RMG, CB, TAE, MLG, BPL, IC, SB, LB, JGS, MJP, IMG, LM, IdlS, ML and JEL don't have a financial interest or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this paper; CdA and AM are paid employees of AbbVie and may hold stock or options. The specific roles of these authors are articulated in the 'author contributions' section. The design, study conduct, and financial support for the study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the manuscript.

[Aim] We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain., [Material and methods] Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven “National HCV plan.” Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded., [Results] Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8–97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of −2.2% (90% CI, −4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p, [Conclusions] Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV., The design, study conduct, and financial support for the study were provided by AbbVie (https://www.abbvie.com/).

Detrimental drug-drug interactions (DDIs) in Diabetic patients could be from the simultaneous use of multiple drugs, polypharmacy. Brazilian public health studies evaluating the practical knowledge about drug interactions are scarce. This study's objective is to identify drug interactions and prevalence of detrimental DDIs in diabetic patients attending Brazilian basic health system clinics. Methods Patients using insulin between the age of 18–90 years were selected to complete the MedTake questionnaire, to evaluate the indication, dosage, regimen and drug interaction. The MedTake test was employed. For each medicine, the test was scored as the percentage of correct actions and compared with printed instructions one single researcher downloaded all the data was from the municipality's computerized system. Results The median age of recruits was 60.2 ± 14.3 and MedTake test scores were low 60.3 ± 20. One hundred patients missed the correct dose question, 40 missed why they were prescribed the drug, indication and 65 missed the therapeutic regimen. These diabetes patients did not know the DDIs between insulin combined with other medicines. Drugs that had more interaction with insulin were: acetylsalicylic acid (40%), enalapril (18%), losartan (32%) and hydrochlorothiazide (23%). Conclusions Diabetes patients without practical knowledge about insulin interacting with other pharmaceutical drugs that can produce DDIs with other medicines illustrates a need to develop education programs for diabetics.

Enterococcus faecalis infective endocarditis (EFIE) is a severe disease of increasing incidence. The objective was to analyze whether the outcome of patients with native valve EFIE (NVEFIE) treated with a short course of ampicillin plus ceftriaxone (4wAC) was similar to patients treated according to international guidelines (6wAC). Between January 2008 and June 2018, 1,978 consecutive patients with definite native valve IE were prospectively included in a national registry. Outcomes of patients with NVEFIE treated with 4wAC were compared to those of patients who received 6wAC. Three hundred and twenty-two patients (16.3%) had NVEFIE. One hundred and eighty-three (56.8%) received AC. Thirty-nine patients (21.3%) were treated with 4wAC for four weeks and 70 patients (38.3%) with 6wAC. There were no differences in age or comorbidity. Patients treated 6wAC presented a longer duration of symptoms before diagnosis (21 days, IQR 7-60 days vs. 7 days, IQR 1-22 days; p = 0.002). Six patients presented perivalvular abscess and all of these received 6wAC. Surgery was performed on 14 patients (35.9%) 4wAC and 34 patients (48.6%) 6wAC (p = 0.201). In-hospital mortality, one-year mortality and relapses among 4wAC and 6wAC patients were 10.3% vs. 11.4% (p = 0.851); 17.9% vs. 21.4% (p = 0.682) and 5.1% vs. 4.3% (p = 0.833), respectively. In conclusion, a four-week course of AC may be considered as an alternative regimen in NVEFIE, notably in patients with shorter duration of symptoms and those without perivalvular abscess. These results support the performance of a randomized clinical trial to evaluate the efficacy of this short regimen., This work was supported in part by the “Fondo de Investigaciones Sanitarias” (FIS) grant 17/01251 from the “Instituto de Salud Carlos III”, Madrid, Spain awarded to JMM. JMM received a personal 80:20 research grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–19. JMP was member of the Endocarditis Team of the Hospital Clinic of Barcelona, Spain when this project was approved by the GAMES Steering Committee.’

Objective The objective of this study was to characterise international trends in the use of psychotropic medication, psychological therapies, and novel therapies used to treat obsessive–compulsive disorder (OCD). Methods Researchers in the field of OCD were invited to contribute summary statistics on the characteristics of their samples. Consistency of summary statistics across countries was evaluated. Results The study surveyed 19 expert centres from 15 countries (Argentina, Australia, Brazil, China, Germany, Greece, India, Italy, Japan, Mexico, Portugal, South Africa, Spain, the United Kingdom, and the United States) providing a total sample of 7,340 participants. Fluoxetine (n = 972; 13.2%) and fluvoxamine (n = 913; 12.4%) were the most commonly used selective serotonin reuptake inhibitor medications. Risperidone (n = 428; 7.3%) and aripiprazole (n = 415; 7.1%) were the most commonly used antipsychotic agents. Neurostimulation techniques such as transcranial magnetic stimulation, deep brain stimulation, gamma knife surgery, and psychosurgery were used in less than 1% of the sample. There was significant variation in the use and accessibility of exposure and response prevention for OCD. Conclusions The variation between countries in treatments used for OCD needs further evaluation. Exposure and response prevention is not used as frequently as guidelines suggest and appears difficult to access in most countries. Updated treatment guidelines are recommended., Author V. B. would like to acknowledge all the staff at the numerous research centres throughout the world and their participants who contributed valuable data to this large data base. V. B. would also like toacknowledge Prof. Naomi Fineberg and the International College of Obsessive‐Compulsive Spectrum Disorders (ICOCS) who supportedthis project by circulating his invitation to participate in the surveyto its members.This study was sponsored by Nepean Medical Research Founda-tion Grant, Pfizer Neuroscience Grant, National Natural Science Foun-dation of China (Grant 81371340), and Spanish MINECO GrantPSI2013‐44733‐R.

Hypertrophic cardiomyopathy is an inherited cardiac disease and a major cause of heart failure and sudden death. Although it was first described more than 50 years ago, sarcomeric hypertrophic cardiomyopathy still lacks a disease-specific treatment: the drugs routinely used alleviate symptoms but do not prevent or revert the phenotype. With recent advances in knowledge of the genetics and pathophysiology of hypertrophic cardiomyopathy, new genetic and pharmacological approaches have recently been identified and studied that, by influencing different pathways involved in this disease, have the potential to function as disease-modifying therapies. These promising new pharmacological and genetic therapies will be the focus of this review. Resumo: A miocardiopatia hipertrófica é uma doença cardíaca hereditária e uma causa major de insuficiência cardíaca e morte súbita. Apesar de descrita há mais de 50 anos, a miocardiopatia hipertrófica sarcomérica ainda não apresenta uma terapêutica farmacológica especifica de doença: os fármacos utilizados por rotina oferecem alívio sintomático mas não previnem ou revertem o fenótipo característico. Os avanços no conhecimento relativo à genética e fisiopatologia da miocardiopatia hipertrófica permitiram, recentemente, descobrir e estudar novas abordagens genéticas e farmacológicas que, ao influenciar diferentes vias envolvidas nesta doença, têm o potencial de funcionar como terapêuticas modificadoras. Estas novas e promissoras terapêuticas são o foco desta revisão.

Aims To describe the prevalence and associated factors of inappropriate doses of direct oral anticoagulants (DOAC) in a national registry of patients of real clinical practice. Methods and results Five hundred and thirty outpatients with atrial fibrillation treated with DOAC were included in a prospective, national, multicentre study. The appropriateness of the doses of DOAC was defined according to the recommendations of the European Heart Rhythm Association. Mean age was 73 ± 9 years, with a 46% of women. Two hundred and sixty-seven patients were prescribed dabigatran, 190 rivaroxaban, and 73 apixaban. A total of 172 patients (32%) did not receive the appropriate dose: 93 patients received a lower dose (18%) and 79 patients a higher dose (15%). In the comparisons among the subgroups of inappropriately low, appropriate, and inappropriately high dose, we observed significant trends to older age (69 ± 8 years vs. 73 ± 10 years vs. 77 ± 6 years), more frequent female sex (37% vs. 46% vs. 59%), antiplatelet drugs (5% vs. 8% vs. 25%), rivaroxaban (14% vs. 38% vs. 53%), and apixaban use (5% vs. 15% vs. 19%), higher CHAD2DS2-VASc (3.00 ± 1.38 vs. 3.58 ± 1.67 vs. 4.59 ± 1.44) and HAS-BLED scores (1.83 ± 0.87 vs. 1.92 ± 1.07 vs. 2.47 ± 1.13), lower body mass index (30 ± 6 kg/m2 vs. 29 ± 4 kg/m2 vs. 28 ± 4 kg/m2) and glomerular filtration rate (74 ± 27 mL/min vs. 70 ± 22 mL/min vs. 63 ± 16 mL/min), and lower frequency of dabigatran use (81% vs. 47% vs. 28%) (all comparisons P ≤ 0.01). Conclusion In this real-life study, 32% of patients received an inappropriate dose of DOAC. Several clinical factors can identify patients at risk of this situation. Sin financiación 5.047 JCR (2018) Q1, 30/136 Cardiac & Cardiovascular Systems 2.612 SJR (2018) Q1, 27/365 Cardiology and Cardiovascular Medicine, 7/108 Physiology (medical) No data IDR 2018 UEM

This study aims to characterize the drugs used in a Portuguese Neonatal Intensive Unit Care, assess the rate of off-label or unlicensed drugs use according to the information available in the Summary of Product Characteristics and compare results between preterm and full-term neonates.A 6-month period retrospective cross-sectional study was conducted in our Neonatal Intensive Unit Care in 2013. Prescribed drugs data were recorded and compared with the paediatric information contained in drugs Summary of Product Characteristics.We analyzed 1011 prescriptions of 84 active substances, made in 218 admissions. In 42.9% of the cases, medicines were used according to Summary of Product Characteristics information; 27.9% of drugs were approved for neonatal period but used in an off-label manner; off-label drugs for neonates were used in 10.1%, whereas those with undetermined approval state and contraindicated were used 6.0% and 8.7% of the cases, respectively. Unlicensed prescriptions accounted for 4.4% of total. Preterm received a higher rate of drugs used according to Summary of Product Characteristics (p0.0001), whereas full-term received more off-label drugs for dose/frequency (p0.0001) and contra-indicated for neonates (p0.012).Preterm neonates received a higher median number of drugs, since they stayed longer in the unit. The main reason for off-label prescribing was the use of doses/frequencies of administration different from those stated in the Summary of Product Characteristics, suggesting that updating these documents is necessary. Manipulation of medicines is one of the causes for unlicensed drugs use, emphasizing the lack of appropriate formulations for neonatal age.Progresses have been made to reduce the risks of off-label/unlicensed prescriptions, but competent authorities must continue their efforts to develop safer and more effective drugs for neonatal period.Introdução: Este estudo pretende caracterizar os medicamentos usados numa Unidade de Cuidados Intensivos Neonatais portuguesa, avaliar a frequência do uso de fármacos off-label ou não licenciados de acordo com a informação disponível no Resumo das Caraterísticas do Medicamento e comparar resultados entre recém-nascidos prematuros e de termo.Material e Métodos: Um estudo retrospetivo transversal foi conduzido na nossa Unidade de Cuidados Intensivos Neonatais no primeiro semestre de 2013. Os dados das prescrições realizadas foram comparados com a informação pediátrica contida nos Resumos das Caraterísticas do Medicamento.Resultados: Analisámos 1011 prescrições respeitantes a 84 substâncias ativas, feitas em 218 admissões. Em 42,9% dos casos, os fármacos foram usados de acordo com a informação do Resumo das Caraterísticas do Medicamento; 27,9% dos fármacos eram aprovados para o período neonatal mas usados de forma off-label; medicamentos off-label para a idade neonatal foram usados em 10,1%, enquanto aqueles com estado de aprovação indeterminado ou contraindicados foram usados em 6,0% e 8,7% dos casos, respetivamente. As prescrições não licenciadas representaram 4,4% do total. Os recém-nascidos pré-termo receberam uma taxa superiorde fármacos usados de acordo com o Resumo das Caraterísticas do Medicamento (plt; 0,0001), enquanto os de termo receberam mais fármacos off-label para dose/frequência (plt; 0,0001) e contraindicados para recém-nascidos (plt; 0,012).Discussão: Os prematuros receberam um número mediano de fármacos superior, o que se relaciona com o seu internamento mais prolongado. A principal razão para prescrições off-label foi a utilização de doses/frequências de administração diferentes das referidas no Resumo das Caraterísticas do Medicamento, reforçando a necessidade de atualização destes documentos. A manipulação dosmedicamentos é uma das causas para o seu uso não licenciado, enfatizando a falta de formulações apropriadas à idade neonatal.Conclusão: Têm sido feitos progressos para reduzir os riscos destas prescrições off-label/não licenciadas, mas esforços para o desenvolvimento de medicamentos mais seguros e eficazes para este período devem continuar a ser envidados.

AIM To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM. METHODS This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed. RESULTS Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA (HBV-DNA) remained undetectable, all patients remained HBeAg negative, and hepatitis B surface antigen (HBsAg) positive. Alanine aminotransferase (ALT) values at the end of the study were similar in the 2 groups (25.1 +/- 7.65, TDF vs 24.22 +/- 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects (AEs) (53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively (P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment ((sic)4943 +/- 1059 vs (sic)5811 +/- 1538, respectively, P < 0.001). CONCLUSION TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.

Objectives: Antibiotic resistance is a major public health concern and is greatly exacerbated by inappropriate antibiotic use at a community level. The aim of this study was to ascertain which attitudes of community pharmacists were related to inappropriate antibiotic dispensing. Methods: We conducted a cross-sectional study of community pharmacists in a region situated in northern Spain (n = 393). Personal interviews were conducted using a self-administered questionnaire. The degree of agreement with each item of knowledge and attitude was measured using an unnumbered, horizontal visual analogue scale, with replies being scored from 0 (total disagreement) to 10 (total agreement). The data were analysed using logistic regression. Results: Of the total of 286 pharmacists (72.8%) who completed the questionnaire, 185 (64.7%) acknowledged having undertaken dispensing of antibiotics without a medical prescription (DAwMP). Attitudes such as patient complacency, external responsibility, indifference and insufficient knowledge were shown to be related to DAwMP. In contrast, no association was found with any of the pharmacists' personal or professional traits. Conclusions: This study confirms that, albeit unlawful, DAwMP is a common practice in Spanish pharmacies. DAwMP was seen to be usually associated with some of the attitudes evaluated. Fondo de Investigación Sanitaria

Drug resistance is a common concern for the development of novel antiviral, antimicrobial and anticancer therapies. To overcome this problem, several strategies have been developed, many of which involving the theme of this review, the use of structure-based drug design (SBDD) approaches. These include the successful design of new compounds that target resistant mutant proteins, as well as the development of drugs that target multiple proteins involved in specific biochemical pathways. Finally, drug resistance can also be considered in the early stages of drug discovery, through the use of strategies to delay the development of resistance. The purpose of this brief review is to underline the usefulness of SBDD approaches based on case studies, highlighting present challenges and opportunities in drug design.

Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HRþ) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemo-therapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2þ) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HRþ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field. RESUMO O câncer de mama é o mais comum, e a principal causa de mortalidade por câncer em mulheres de todo o mundo. Os tumores com receptor hormonal (RH) positivo representam o tipo mais comum desta doença. O benefício e as taxas de resposta à quimioterapia neoadjuvante variam de acordo com a expressão de RH, sendo mais baixa nos tumores luminais em comparação com tumores HER2 positivos ou triplo-negativos. A hormonioterapia neoadjuvante, uma opção para pacientes selecionados com tumores RH positivo localmente avançados, apresenta melhor perfil de tolerabilidade e segurança, e está associada com benefícios adicionais, como baixo custo e fácil acesso. Estes fatores são relevantes, uma vez que 70% das mortes por câncer de mama acontecem em mulheres de países pobres ou em desenvolvimento. Além disso, a hormonioterapia neoadjuvante vem sendo explorada como uma ferramenta científica, ao possibilitar o estudo de biomarcadores que podem predizer desfechos tanto para pacientes individuais quanto para ensaios clínicos em adjuvância. Este artigo de revisão detalha o conhecimento atual e as evidências mais relevantes sobre hormonioterapia neoadjuvante em câncer de mama, assim como perspectivas futuras nesta área.

Introduction: Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC + pegylated interferon-alpha 2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. Methods: This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. Results: From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). Conclusions: Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC + PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferonfree therapies are not available yet., Funded by Merck: BOC-HIV Study.Maria Martinez-Rebollar is funded by a grant Sara Borrell, CM13-00123, from Instituto de Salud Carlos III, Ministerio Economia y Competitividad. - Other authors declare no other conflict of interest.

Allergen immunotherapy has proved effective in the treatment of various allergies, but whether the clinical benefits outweigh the economic costs has been little evaluated.To explore the economic consequences of immunotherapy in asthma, rhinitis and dermatitis.Descriptive study. Patients with at least 18 months' follow-up were selected, whose medical history allowed evaluation of drugs received, manner of use, check-ups, treatment changes, reasons for these, and so on. Patients were classified according to whether they received drug treatment + immunotherapy (active group) or drug therapy alone (control group).1848 patients were included: 648 in the active group and 1200 in the control. Immunotherapy increased the cost of treatment during the first few months, but after 9 to 12 months drug treatment decreased significantly compared to the control group. In patients with asthma or various diseases, immunotherapy reduced costs of treatment (p0.05). The active group saw fewer relapses at 18 months (p0.05).Allergen immunotherapy allows the sustained reduction in drug treatment, with medium-term financial savings for the patient and the health system.Antecedentes: La inmunoterapia con alérgenos ha demostrado ser efectiva en el tratamiento de diversas alergias, pero poco se ha evaluado si los beneficios clínicos compensan los costos económicos. Objetivo: Explorar las consecuencias económicas de la inmunoterapia en asma, rinitis y dermatitis. Métodos: Estudio retrospectivo analítico. Se seleccionaron pacientes con seguimiento por al menos 18 meses, cuya historia clínica permitiera evaluar los medicamentos recibidos, forma de uso, citas de control, cambios en el tratamiento, motivos de estos, etcétera. Los pacientes fueron clasificados de acuerdo a si recibieron tratamiento farmacológico + inmunoterapia (grupo activo) o solo tratamiento farmacológico (grupo control). Resultados: 1848 pacientes fueron incluidos: 648 en el grupo activo y 1200 en el control. La inmunoterapia aumentó el costo del tratamiento durante los primeros meses, pero después de 9 a 12 meses disminuyó significativamente el tratamiento farmacológico en comparación con el grupo control. En los pacientes con asma o varias enfermedades, la inmunoterapia redujo los costos del tratamiento (p0.05). En el grupo activo se observó menos recaídas a los 18 meses (p0.05). Conclusión: La inmunoterapia con alérgenos permite la reducción sostenida del tratamiento farmacológico, con ahorro económico a mediano plazo para el paciente y el sistema de salud.

Population aging increases the prevalence of chronic and multiple morbid illnesses and increases the consumption of multiple medications and related problems accordingly. It is reported that 50% of dispensed medications are consumed by older adults; in fact, 80% of older adults take at least one medication daily and 75% do not inform their doctor that they are using unconventional treatments. Appropriate medication prescription to older adults is challenging and it requires the consideration of risks and benefits of the indicated medications, for which clear evidence of their efficacy is often lacking due to the limited inclusion of elderly populations in randomized clinical trials on which clinical guides are based for chronic disease management. However, general guidelines and recommendations must be comprehensively implemented and supported by a multidisciplinary team whenever pharmacological management is provided for older adults. Here we focus on promoting proper prescriptions according to evidence-based recommendations to reduce inappropriate prescriptions, polypharmacy, and self-medication. El envejecimiento de la población tiene como consecuencia incrementos en la prevalencia de enfermedades crónicas y de multimorbilidad, en el consumo de múltiples fármacos y los problemas relacionados con los mismos. Se reporta que más del 50% de todos los medicamentos expendidos son consumidos por adultos mayores; más del 80% de las personas adultas mayores toman al menos una medicación diaria y 75% no informa a su médico que usa tratamientos no convencionales. Prescribir de forma apropiada en el adulto mayor es un trabajo difícil que requiere considerar un balance entre los riesgos y beneficios de las medicinas indicadas, las cuales suelen no tener una evidencia clara de su eficacia, dada la poca representatividad de la población adulta mayor en los ensayos clínicos randomizados sobre los cuales se basan las guías clínicas para el manejo de las enfermedades crónicas, condiciones altamente prevalentes en la población adulta mayor. Sin embargo, existen directrices y recomendaciones generales que deben de aplicarse de forma integral, apoyados por un equipo multidisciplinario, toda vez que se realice un manejo farmacológico en el adulto mayor. En este artículo, nos enfocamos en promover la prescripción adecuada sobre la base de recomendaciones basadas en evidencia para disminuir la medicación inapropiada, la polifarmacia y la automedicación.

Objectives: To describe the baseline date and drugs therapy changes during treatment optimization in patients with heart failure with depressed systolic function included in the EFICAR study. Design: Multicenter randomized clinical trial. Location: Seven Health Centers. Participants: 150 patients (ICFSD) age 68 +/- 10 years, 77% male. Measurements: Sociodemographic variables, comorbidities (Charlson index), functional capacity and quality of life. Drug therapy optimization was performed. Results: The main etiology was ischemic heart disease (45%), with 89% in functional class II. The Charlson index was 2.03 +/- 1.05. The ejection fraction mean was 37% +/- 8, 19% with ejection fraction < 30%. With the stress test 6.3 +/- 1.6 mean was reached, with the 6 minutes test 446 78 meters and the chair test 13.7 +/- 4.4 seconds. The overall quality of life with ejection fraction was 22.8 +/- 18.7 and with the Short Form-36 Health Survey, physical health 43.3 +/- 8.4 and mental health 50.1 +/- 10.6. After optimizing the treatment, the percentage of patients on drugs therapy and the dose of angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists and beta-blockers were not changed. Conclusions: The majority of the subjects are in functional class II, with functional capacity and quality of life decresed and comorbidity index high. A protocolized drug therapy adjustment did not increase the dose or number of patients with effective drugs for heart failure with depressed systolic function

The use of progestogen-only contraceptives may cause a change in bleeding pattern, which is a common cause of discontinuation of these methods. Co-administration with some antiretroviral therapies (ART) changes the bioavailability of the etonogestrel (ENG)-releasing contraceptive implant, possibly affecting the bleeding pattern. Bleeding patterns were evaluated in HIV-positive users of the ENG implant co-administered with two common ART regimens.Forty-five HIV-positive women who wished to use an ENG implant were included in this study: 15 had received zidovudine/lamivudine (AZT/3TC) + lopinavir/ritonavir (LPV/r) for ≥3 months (LPV/r-based ART group), 15 had received AZT/3TC + efavirenz (EFV) for ≥3 months (EFV-based ART group), and 15 had not received ART (non-ART group). Bleeding patterns were evaluated at 3 and 6 months after implant placement using a standard bleeding calendar.Amenorrhoea and infrequent bleeding rates were higher in the LPV/r-based ART group (50% and 36%, respectively) than in the other groups (non-ART group, 36% and 29%, respectively; EFV-based ART group, 7% and 14.5%, respectively; p = 0.01). The EFV-based ART group more frequently had regular bleeding (71.5%) compared with the other groups (LPV/r-based ART group, 7%; non-ART group, 21%; p = 0.01). The proportions of women with frequent and prolonged bleeding were similar (p 0.05) in the three groups.The co-administration of EFV-based or LPV/r-based ART with the ENG implant affected the expected bleeding patterns during use of the implant, although unfavourable bleeding (frequent and prolonged) was not associated with the medications under evaluation.

12 p., BACKGROUND Elevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol increase the risk of cardiovascular disease. Lowering both should reduce the risk of cardiovascular events substantially. METHODS In a trial with 2-by-2 factorial design, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to rosuvastatin (10 mg perday) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. In the analyses reported here, we compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included heart failure, cardiac arrest, or revascularization. The median follow-up was 5.6 years. RESULTS The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P=0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P=0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of discontinuation of the trial regimen was similar in the two groups. CONCLUSIONS The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.)

The present study developed an experimental metronidazole-based gel and evaluated its efficacy for the adjuvant treatment of chronic periodontitis. Sixteen patients were randomly allocated into two groups of eight subjects according to the following proposed treatments: (1) scaling and root planing (active control) or (2) scaling and root planing and direct periodontal intrapocket application of 15% metronidazole-based gel in two sites (≥5 mm in depth) (experimental group). Potential changes in the subgingival microbiota were assessed using a DNA Checkerboard method at three proposed times: baseline and following 7 or 30 days of drug administration. High-performance liquid chromatography (HPLC) monitored metronidazole concentrations in the crevicular fluid during treatment. The metronidazole experimental group presented lower bacterial counts than the control group at the three evaluated times (p

Parkinson's disease is characterized by alterations in the gait pattern that may increase the risk of falls. Variations in the gait pattern cannot be objectively measured in clinical examination, so it is necessary to adapt devices to measure objectively, valid and replicable changes in gait patterns that are part of the evolution of the disease and / or pharmacotherapy. In an interdisciplinary effort, we developed the “e-Motion Capture System” software, which is able to calculate motor (cadence, stride and step length) and spatiotemporal (velocity and acceleration) parameters that affect quality of life in patients with Parkinson's disease. In this paper, we show results of the comparison between our e-Motion software and a benchmark reference, multiple-camera 3D motion capture system to track a gait pattern. This analysis was performed to compare the spatial locations of the ankles of a volunteer under indoor controlled conditions. Our results for the comparison between e-Motion and the 3D motion capture system show excellent agreement.

Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients.Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent.Forty-one patients (26women/15 men) were recruited. They had a mean age of 34.414 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2-6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3-47.5] mg/day at ANK onset to 5 [0-10] at 12 months. After a median [IQR] follow-up of 16 [5-50] months, the most important side effects were cutaneous manifestations (n=8), mild leukopenia (n=3), myopathy (n=1), and infections (n=5).ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations., Dr MAG-G received grants/research supports from Abbott, MSD, and Roche, and had consultation fees/participation in company sponsored speaker?s bureau from Abbott, Pfizer, Roche, Janssen, Lilly, Bristol-Meiers, and MSD.; Dr FO-S received grants/research supports from Abbvie.; This work was also partially supported by RETICS Programs, RD08/0075 (RIER), and RD12/0009/0013 from Instituto de Salud Carlos III (ISCIII) (Spain).

Background. Paraoxonase-1 (PON1) activity is suggested to be altered in individuals infected with human immunodeficiency virus type-1 (HIV-1). We investigated PON1 activity in individuals receiving different regimens of highly active antiretroviral therapy (HAART).Methods. PON1 activity was evaluated in 91 HIV-1 seronegative and 624 HIV-1 infected individuals (115 were not undergoing therapy (ART-naïve), and 509 were receiving HAART). HIV-1 infected individuals were treated with the following: efavirenz (EFV;n=195) or nevirapine (NVP;n=95) or lopinavir/ritonavir (LOP/r;n=219). Serum levels of total cholesterol (TC), HDL, and low-density lipoprotein (LDL) fractions and the atherogenic indices (AI, TC : HDL, and LDL : HDL ratios) were determined.Results. PON1 activity (U/L) was lower in the ART-naïve group compared with the other groups. PON1 activity correlated with CD4+ T-cell number of ART-naïve group (r=0,121;P=0,014). The LOP/r group showed a reduction in HDL and an increase in AI (TC : HDL ratio) in comparison with other groups.Conclusion. PON1 activity was reduced in untreated individuals, but not in individuals receiving HAART. PON1 activity correlated with the number of CD4+ T-cells. The findings suggest that the activity of PON1 is associated with the immune status of HIV-1 infected individuals.

Background: Organ transplants in elderly recipients have increased over the past few years. This situation poses specific problems both in terms of organs and recipients; therefore, immunosuppressant regimens must be adapted accordingly. A previous study demonstrated good initial results in kidney transplant cases in which older donors and recipients (average ages of 64.4 years and 61.3 years) had received initial immunosuppressant therapy with daclizumab and mycophenolate mofetil as well as delayed introduction of reduced-dose tacrolimus. In this study we reviewed the long-term results in the same group of patients. Methods: An observational, retrospective multicentre study carried out at a national level to determine survival rates and renal function in 126 patients included in the initial study (127 patients who survived the first year with a functioning graft, 123 treated according to protocol). We gathered data from the 2nd to the 6th year for 120, 118, 113, 102 and 62 patients, respectively. The evolution of renal function, relevant clinical data, and safety profiles were also analysed. Results: After five years, most patients continued with the initial immunosuppressant regimen: 92% tacrolimus and 80% mycophenolate mofetil; 48% had abandoned steroids and proliferation signal inhibitors had been introduced in 3%. Patient and graft survival (adjusted for patient death) after five years was 93.1% and 93.8%, respectively. The main cause of death was neoplasia (in 7 out of 10 cases) whilst graft loss was mainly due to death with a functioning graft. The other causes of death were 2 acute myocardial infarctions and a gastrointestinal haemorrhage. Renal function was moderately but significantly reduced with the passing of time (P

Background: The aim of the study was to determine the most common pharmacological strategies used in the management of major depressive disorder (MDD) after an inadequate response to first-line antidepressant treatment in clinical practice. Methods: Multicenter, non-interventional study in adult outpatients with a DSM-IV-TR diagnosis of MDD and inadequate response to first-line antidepressant medication. Multiple logistic regression analyses were performed to identify independent factors associated with the adoption of a specific second-line strategy. Results: A total of 273 patients were analyzed (mean age: 46.8 years, 67.8% female). Baseline mean Montgomery-Asberg Depression Rating Scale total score was 32.1 (95% CI 31.2-32.9). The most common strategies were: switching antidepressant medication (39.6%), augmentation (18.8%), and combination therapy (17.9%). Atypical antipsychotic drugs were the most commonly used agent for augmenting antidepressant effect. The presence of psychotic symptoms and the number of previous major depressive episodes were associated with the adoption of augmenting strategy (OR = 3.2 and 1.2, respectively). Conclusion: The switch to another antidepressant agent was the most common second-line therapeutic approach. Psychiatrists chose augmentation based on a worse patients' clinical profile (number of previous episodes and presence of psychotic symptoms)., This study was sponsored by AstraZeneca Spain. EM and JM are employees of AstraZeneca Spain. JLG was an employee of AstraZeneca Spain when the study was designed and the data were collected. MAG is an employee of Quintiles Spain. MG-T has no conflict of interest to declare.

Background: The recently observed association between the APOC3-related rs10892151 polymorphism and serum triglyceride levels has prompted us the possibility to explore whether this genetic variant may play a major role in human immunodeficiency virus (HIV)/antiretroviral therapy-induced dyslipidemia. Methods: We determined the rs10892151 genotype distribution and serum apolipoprotein (apo) C-III concentration in a group of HIV-infected patients (n = 208) and in a group of age and sex-matched healthy volunteers (n = 200). Circulating lipid and lipoprotein levels were followed for 12 months after antiretroviral treatment initiation in the HIV-infected group. Results: There were no significant variations in the frequency of the A allele between the healthy and HIV-infected groups (7.5 vs. 8.6%, respectively; p = 0.7); additionally, the A allele was not related to serum apo C-III concentration. However, among patients receiving protease inhibitor ( PI) treatment, carriers of the A allele had significantly increased serum triglyceride (5.76 +/- 2.54 mmol/L) and total cholesterol (6.63 +/- 2.85 mmol/L) concentrations together with depressed levels of HDL-cholesterol (0.75 +/- 0.3 mmol/L) when compared with patients not carrying the allele (2.43 +/- 1.32, 5.2 +/- 2.17 and 1.24 +/- 0.4 mmol/L, respectively) at the end of the study. This effect was only evident for HDL-cholesterol concentration when patients were treated with non-nucleoside reverse transcriptase inhibitors (1.05 +/- 0.4 vs. 1.28 +/- 0.4 mmol/L). Conclusions: The A allelic variant of the rs10892151 polymorphism is not associated with serum apo C-III concentration, but predisposes HIV-infected patients to less favorable lipid profile, particularly in those patients treated with PIs., This work was financially supported by the Fondo de Investigacion Sanitaria (FIS PI08/1032).

This Galician consensus statement is a joint oncologists/cardiologists initiative indented to establish basic recommendations on how to prevent and to manage the cardiotoxicity in breast cancer with the aim of ensuring an optimal cardiovascular care of these patients. A clinical screening of the patients before treatment is recommended to stratify them into a determined risk group based on their intrinsic cardiovascular risk factors and those extrinsic arose from breast cancer therapy, thereby providing individualized preventive and monitoring measures. Suitable initial and ongoing assessments for patients with low and moderate/high risk and planned treatment with anthracyclines and trastuzumab are given; also, measures aimed at preventing and correcting any modifiable risk factor are pointed out . TEVA Farma España

OBJECTIVE: This study assesses the relationship between sleep disturbances (SD) and attention-deficit and hyperactivity disorder (ADHD) to characterize clinical features and associated problems. METHOD: The medical records of 50 children and adolescents ranging in age from 4 to 17 years with ADHD without the diagnosis of mental retardation or pervasive developmental disorders were reviewed. RESULTS: Significant relationships were found between SD and drug therapy (p