First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade \u3e 1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (\u3e 9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Retinitis pigmentosa: Revisión bibliográfica

La retinitis pigmentosa es la degeneración hereditaria más frecuente en retina, caracterizada por una progresiva alteración de los fotorreceptores. La prevalencia de RP es de entre 1/3.000 a 1/5.000 aprox. Los primeros síntomas visuales que experimentan los pacientes con RP son la ceguera nocturna y la pérdida de campo visual periférico. La visión central suele mantenerse preservada hasta fases avanzadas de la enfermedad. Los signos oftalmoscópicos más comunes son la presencia de espículas óseas, atenuación de los vasos y palidez cérea del disco óptico. Los principales exámenes clínicos utilizados para el diagnóstico de la enfermedad incluyen la medida de campo visual, ERG, adaptación a la oscuridad, AFG y OCT. Aunque existen grandes avances en el conocimiento de la enfermedad, aún no se ha conseguido ningún tratamiento eficaz que permita restablecer la visión o interrumpir el curso natural de su evolución, siendo necesario el conocimiento del profesional sobre esta enfermedad, sus signos y síntomas clínicos, para poder realizar una detección precoz.No data (2013

Why Does Extracellular Potassium Rise in Acute Ischemia? Insights from Computational Smilations

[EN] Hyperkalemia, acidosis and hypoxia are the three main components of acute myocardial ischemia. In particular, the increase of extracellular K+ concentration (hyperkalemia), has been proved to be very proarrhythmic because it sets the stage for ventricular fibrillation. However, the intimate mechanisms remain partially unknown. The aim of this work was to investigate, using computational simulation, the relationship between the different phases of hiperkalemia, the activity of the ion channels and the changes related to the action potential in the absence of coronary flow. Our results show that the partial inhibition of the sodium-potassium pump is the main cause of extracellular potassium accumulation. However, the cause of the plateau phase could be due to the appearance of action potential alternans, which reduces the net potassium efflux and limits the increase of extracellular potassium concentration.This work was partially supported by the "Programa Salvador de Madariaga 2018" of the Spanish Ministry of Science, Innovation and Universities (Grant Reference PRX18/00489).González-Ascaso, A.; Olcina, P.; Garcia-Daras, M.; Rodriguez Matas, JF.; Ferrero De Loma-Osorio, JM. (2019). Why Does Extracellular Potassium Rise in Acute Ischemia? Insights from Computational Smilations. IEEE. 1-4. https://doi.org/10.22489/CinC.2019.088S1

Interaction of Specialized Cardiac Conduction System With Antiarrhythmic Drugs: A Simulation Study

[EN] The use of antiarrhythmic drugs is common to treat heart rhythm disorders. Computational modeling and simulation are promising tools that could be used to investigate the effects of specific drugs on cardiac electrophysiology. In this paper, we study the multiscale effects of dofetilide, a drug that blocks IKr, from cellular to organ level paying special attention to its effect on heart structures, in particular the specialized cardiac conduction system (CCS). We include a model of the CCS in a patient-specific anatomical ventricular model and study the drug effects in simulations with and without a CCS. Results confirmed the expected effects of dofetilide at cellular level, increasing the action potential duration, and at organ level, prolonging the QT segment. Notable differences are shown between models with and without the CCS on action potential duration distributions. These techniques show the importance of heart heterogeneity and the global effects of the interaction of drugs with cardiac structures. © 2006 IEEE.This work was supported in part by the Ministry of Science and Innovation, TEC-2008-02090 (FPI grant BES-2009-016071), in part by the Programa de Apoyo a la Investigacion y Desarrollo (PAID-06-09-2843) de la Universitat Politecnica de Valencia, and in part by the Direccion General de Politica Cientifica de la Generalitat Valenciana (GV/2010/078). Asterisk indicates corresponding author.Dux-Santoy Hurtado, L.; Sebastián Aguilar, R.; Felix-Rodriguez, J.; Ferrero De Loma-Osorio, JM.; Saiz Rodríguez, FJ. (2011). Interaction of Specialized Cardiac Conduction System With Antiarrhythmic Drugs: A Simulation Study. IEEE Transactions on Biomedical Engineering. 58(12):3475-3478. https://doi.org/10.1109/TBME.2011.2165213S34753478581