Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases.

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.

Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases.

The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure-activity relationships and structure-property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.

Perfil epidemiológico y patrón de sensibilidad de aislamientos causantes de infección fúngica invasora frente a aislamientos fúngicos de colonización en pacientes críticos no neutropénicos / Epidemiological profile and sensitivity pattern of isolates causing invasive fungal infection vs. colonizing isolates in non-neutropenic critically ill patients

Antecedentes. Los pacientes ingresados en unidades de críticos suelen presentar un importante número de aislamientos fúngicos, responsables, en ocasiones, de infecciones fúngicas invasoras (IFI). Objetivos. Describir el perfil epidemiológico y patrón de sensibilidad antifúngica de los aislamientos fúngicos en nuestra unidad, e identificar los principales factores de riesgo relacionados con el desarrollo de la IFI. Métodos. Se realizó un estudio de cohortes, descriptivo y retrospectivo de pacientes ingresados en una unidad de críticos polivalente de un hospital universitario, con aislamiento al menos de una especie fúngica en cultivo de muestras biológicas, en un periodo de 48 meses. Resultados. Se estudiaron 232 pacientes, de los que 20 desarrollaron IFI. Los sujetos del grupo con IFI presentaron mayor mortalidad y puntuación en la escala de estratificación Candida score 48h previas al diagnóstico clínico. Los factores de riesgo asociados al desarrollo de IFI fueron la existencia de enfermedad pulmonar obstructiva crónica (EPOC), la cirugía digestiva, la nutrición parenteral total y la corticoterapia sistémica prolongada. La especie fúngica predominante en ambos grupos fue Candida albicans, con una resistencia global a fluconazol e itraconazol del 1,94%. Conclusiones. La especies del género Candida no-C. albicans tuvieron una baja incidencia. La tasa de resistencia a azoles para C. albicans fue similar a la de series en similar contexto clínico. Se identifican como factores de riesgo asociados al desarrollo de IFI los antecedentes de cirugía digestiva y de EPOC, así como el tratamiento prolongado con corticoides y la administración de nutrición parenteral(AU)

Background. Patients admitted to critical care units can be infected with a large number of fungal isolates that are occasionally responsible for invasive fungal infections (IFI). Aims. To describe the epidemiological profile and antifungal susceptibility patterns of fungal isolates in our unit, and to identify key risk factors associated with the development of IFI. Methods. A descriptive cohort and retrospective study with patients admitted to a polyvalent Critical Care Unit of a university hospital was carried out. The isolation of at least one fungal species in a culture of biological samples, over a period of 48 months was considered. Results. Twenty patients out of 232 developed IFI. Patients in the IFI group had a higher mortality and higher Candida score value 48h prior to clinical diagnosis. Risk factors associated with the development of IFI were chronic obstructive pulmonary disease, gastrointestinal surgery, total parenteral nutrition, and prolonged systemic corticosteroid therapy. The predominant fungal species in both groups was Candida albicans, with global resistance to fluconazole and itraconazole of 1.94%. Conclusions. We found a low incidence of species of Candida non-C. albicans in our unit. The rate of resistance to azoles in C. albicans was similar to that of larger series. Gastrointestinal surgery, COPD, prolonged treatment with corticosteroids, and parenteral nutrition administration are risk factors associated with the development of IFI(AU)

[Epidemiological profile and sensitivity pattern of isolates causing invasive fungal infection vs. colonizing isolates in non-neutropenic critically ill patients]. / Perfil epidemiológico y patrón de sensibilidad de aislamientos causantes de infección fúngica invasora frente a aislamientos fúngicos de colonización en pacientes críticos no neutropénicos.

BACKGROUND: Patients admitted to critical care units can be infected with a large number of fungal isolates that are occasionally responsible for invasive fungal infections (IFI). AIMS: To describe the epidemiological profile and antifungal susceptibility patterns of fungal isolates in our unit, and to identify key risk factors associated with the development of IFI. METHODS: A descriptive cohort and retrospective study with patients admitted to a polyvalent Critical Care Unit of a university hospital was carried out. The isolation of at least one fungal species in a culture of biological samples, over a period of 48 months was considered. RESULTS: Twenty patients out of 232 developed IFI. Patients in the IFI group had a higher mortality and higher Candida score value 48 h prior to clinical diagnosis. Risk factors associated with the development of IFI were chronic obstructive pulmonary disease, gastrointestinal surgery, total parenteral nutrition, and prolonged systemic corticosteroid therapy. The predominant fungal species in both groups was Candida albicans, with global resistance to fluconazole and itraconazole of 1.94%. CONCLUSIONS: We found a low incidence of species of Candida non-C. albicans in our unit. The rate of resistance to azoles in C. albicans was similar to that of larger series. Gastrointestinal surgery, COPD, prolonged treatment with corticosteroids, and parenteral nutrition administration are risk factors associated with the development of IFI.

Sirolimus-Eluting Stents vs Uncoated Stents for the Treatment of Proximal Left Anterior Descending Coronary Artery Stenosis.

Sirolimus-eluting stents (SES) have demonstrated low incidence of target vessel revascularizations in several anatomic scenarios, including proximal left anterior descending coronary artery (pLAD) lesions. The aim of present study was to compare the efficacy of SES with bare metal stents (BMS) for the treatment of such lesions. 96 patients with severe pLAD stenosis treated with SES were included. Clinical follow-up were performed during a 24 month period. A 98 patient sample with pLAD lesions treated with BMS was taken as control group. Death, angiographic restenosis, new target lesion revascularization (TLR) and target vessel failure (TVF) were registered. Clinical, angiographic and procedural variables were analysed to identify predictors of TVF and TLR. Angiographic procedural success was 100% in SES group vs 99% in BMS group (p=1.0). At 2.5 years, the cumulative rate of TVF was 9.4% in SES group vs 16.3% in BMS group (p=0.15), and the rate of TLR was 5.2% in SES group vs 12.2% in control group (p=0.08). The probabilities of cumulative TVF and TLR free survival were in BMS group 83.7% and 87.8%, and in SES group 90.6% and 94.8%, respectively. After multivariate analysis only SES utilization was found as independent protective factor against TVF and TLR (HR 0.38, 95%CI [0.15-0.94] p=0.037 and HR 0.21, 95%CI [0.06-0.66] p=0.008, respectively), and diabetes as independent predictor of TFV and TLR (HR 2.37, 95%CI [1.07-5.24] p=0.034 and HR 3.57, 95%CI [1.29-9.87] p=0.014, respectively). This study demonstrates that SES utilization is safe and effective in the tretament of pLAD lesions with a better clinical outcome than BMS in a long-term follow-up.

Two-year follow-up of sirolimus-eluting stents for the treatment of proximal left anterior descending coronary artery stenosis.

INTRODUCTION: Sirolimus-eluting stents (SES) have demonstrated low target vessel revascularizations and low incidence of angiographic restenosis in several clinical scenarios. The aim of the present study was to assess the efficacy and safety of SES for the treatment of proximal left anterior descending coronary artery (pLAD) lesions. METHODS: Ninety-six patients with severe pLAD stenosis were enrolled. Angiographic and clinical follow-up were performed at 6 and 24 months, respectively. Death, myocardial infarction (MI), new target lesion revascularization (TLR), and target vessel failure (TVF) were registered. Clinical, angiographic, and procedural variables were analyzed to identify predictors of restenosis. RESULTS: Mean clinical follow-up was 858+/-158 days (26.5+/-8.3 months). Angiographic procedural success was 100%. Angiographic follow-up showed 8.4% of binary restenosis without edge-restenosis phenomenon. Late loss was 0.15+/-0.65 mm; 15.6% of patients had an adverse cardiac event, with 1% of death, 5.2% of MI, 6.3% of TLR, and 9.4% of TVF. At 2 years, the probabilities of cumulative TVF- and TLR-free survival were 90.6% and 93.7%, respectively. Interestingly, no adverse cardiac events were registered between the first and second years. Female gender (OR 10.7 CI 95%[1.7-66.7]) and in-stent restenosis (OR 8.2, CI 95%[1.2-56.4]) were found as independent predictors of binary restenosis. Advanced chronic renal failure showed a strong trend toward worse outcome in terms of binary restenosis (P=0.063). CONCLUSIONS: SES for the treatment of pLAD stenosis proved safe and effective in a long-term follow-up with low incidence of adverse cardiac events and restenosis. Female gender and in-stent restenosis were predictors of binary restenosis.

Are there ethnic differences in the circadian variation in onset of acute myocardial infarction? A comparison of 3 ethnic groups in Birmingham, UK and Alicante, Spain.

We hypothesised that ethnicity may influence the circadian pattern in acute myocardial infarction (MI), in view of the potential differences in genetic background, cardiovascular risk factors and cultural habits. To test our hypothesis, we studied 340 consecutive acute MI patients (268 males; mean age 61.6+/-12.3 years) from two different city-centre teaching hospitals in Birmingham (United Kingdom) and Alicante (Spain). A different circadian rhythm in MI onset was observed between the ethnic groups (p=0.001), with a significantly higher number of acute MI onset occurring between midnight and noon in British Caucasians and Indo-Asians. In contrast, Mediterranean Caucasians showed the converse circadian pattern, with most of the acute MI events happened between noon and midnight. Indo-Asian patients were the youngest patient group and showed the highest prevalence of diabetes and increased body mass index. Mediterranean patients had the highest prevalence of smokers but their mean serum cholesterol was the lowest. No differences in sex, blood pressure, height and weight were observed. In conclusion, this study has shown a different circadian rhythm in acute MI onset between 3 ethnic groups from two different city-centre teaching hospitals in Birmingham (United Kingdom) and Alicante (Spain) and, for the first time, provide data in the Indo-Asian population. Further studies are required to determine the pathophysiological mechanism(s) underlying these differences.

A pharmacogenetic effect of factor XIII valine 34 leucine polymorphism on fibrinolytic therapy for acute myocardial infarction.

OBJECTIVES: The aim of this study was to evaluate the pharmacogenetic role of the factor XIII (FXIII) valine 34 leucine (Val34Leu) polymorphism in the fibrinolytic therapy of acute myocardial infarction (MI). BACKGROUND: Fibrinolytic therapy is an established treatment for acute MI, but up to 40% of treated patients do not achieve optimal tissue reperfusion. The FXIII Val34Leu polymorphism is one of the most relevant functional polymorphisms described in the haemostatic system. The common Leu34 allele associates with an increased FXIII-transglutaminase activity, which results in an increased and faster rate of fibrin stabilization. METHODS: We genotyped this polymorphism in 293 consecutive MI patients (62 +/- 12 years; 231 males) from two different European populations. All patients were treated with standard doses of fibrinolytic drugs. Noninvasive assessment of the efficacy of coronary fibrinolysis was evaluated by serial electrocardiograms and creatine kinase time-activity curves. The clinical outcome was also re-evaluated at 24 h (death, reinfarction, or urgent revascularization). RESULTS: Multivariate analysis showed that Leu34 carriers displayed a significantly less efficient fibrinolysis than carriers of Val/Val genotype (p = 0.021; odds ratio [OR] 1.90, 95% confidence interval [CI] 1.10 to 3.28). At 24 h, Leu34 allele carriers had the worst outcome (p = 0.006; OR 2.14, 95% CI 1.25 to 3.68). Interestingly, the combination of the Leu34 allele and nonsmoking status increased the risk of non-reperfusion criteria (p = 0.003, OR 3.77), and worse outcomes at 24 h (p = 0.001, OR 4.55). CONCLUSIONS: In a large cohort of nonselected and consecutive acute MI patients from two different European populations, we show clinical evidence that the presence of the Leu34 allele reduces the efficacy of fibrinolytic therapy.