Prioritization of high-cost new drugs for HCV: making sustainability ethical

Hepatitis C virus (HCV) infection is a major health problem worldwide. Chronic HCV infection may in the long run cause cirrhosis, hepatic decompensation and hepatocellular carcinoma, with an ultimate disease burden of at least 350,000 deaths per year worldwide. The new generation of highly effective direct acting antivirals (DAA) to treat HCV infection brings major promises to infected patients in terms of exceedingly high rates of sustained virological response (SVR) but also of tolerability, allowing even the sickest patients to be treated. Even in the face of the excellent safety and efficacy and wide theoretical applicability of these regimens, their introduction is currently facing cost and access issues denying their use to many patients in need. Health systems in all countries are facing a huge problem of distributive justice, since while they should guarantee individual rights, among which the right to health in its broader sense, therefore not limited to healing, but extended to quality of life, they must also grant equal access to the healthcare resources and keep the distribution system sustainable. In the face of a disease with a relatively unpredictable course, where many but not of all chronically infected will eventually die of liver disease, selective allocation of this costly resource is debatable. In most countries the favorite solution has been a stratification of patients for prioritization of treatment, which means allowing Interferon-free DAA treatment only in patients with advanced fibrosis or cirrhosis, while keeping on hold persons with lesser stages of liver disease. In this report, we will perform an ethical assessment addressing the issues linked to access to new therapies, prioritization and eligibility criteria, analyzing the meaning of the term “distributive justice” and the different approaches that can guide us (individualistic libertarianism, social utilitarianism and egalitarianism) on this specific matter. Even if over time the price of new DAA will be reduced through competition and eventual patent expiration, the phenomenon of high drug costs will go on in the next decades and we need adequate tools to face the problems of distributive justice that come with it

β-Caryophyllene Counteracts Chemoresistance Induced by Cigarette Smoke in Triple-Negative Breast Cancer MDA-MB-468 Cells

Exposure to cigarette smoke (CS) has been associated with an increased risk of fatal breast cancers and recurrence, along with chemoresistance and chemotherapy impairment. This strengthens the interest in chemopreventive agents to be exploited both in healthy and oncological subjects to prevent or repair CS damage. In the present study, we evaluated the chemopreventive properties of the natural sesquiterpene beta-caryophyllene towards the damage induced by cigarette smoke condensate (CSC) in triple negative breast cancer MDA-MB-468 cells. Particularly, we assessed the ability of the sesquiterpene to interfere with the mechanisms exploited by CSC to promote cell survival and chemoresistance, including genomic instability, cell cycle progress, autophagy/apoptosis, cell migration and related pathways. beta-Caryophyllene was found to be able to increase the CSC-induced death of MDA-MB-468 cells, likely triggering oxidative stress, cell cycle arrest and apoptosis; moreover, it hindered cell recovery, autophagy activation and cell migration; at last, a marked inhibition of the signal transducer and activator of transcription 3 (STAT3) activation was highlighted: this could represent a key mechanism of the chemoprevention by beta-caryophyllene. Although further studies are required to confirm the in vivo efficacy of beta-caryophyllene, the present results suggest a novel strategy to reduce the harmful effect of smoke in cancer patients and to improve the survival expectations in breast cancer women

A comparative analysis of punicalagin interaction with PDIA1 and PDIA3 by biochemical and computational approaches

In a previous work, it was shown that punicalagin, an active ingredient of pomegranate, is able to bind to PDIA3 and inhibit its disulfide reductase activity. Here we provide evidence that punicalagin can also bind to PDIA1, the main expressed form of protein disulfide isomerase (PDI). In this comparative study, the affinity and the effect of punicalagin binding on each protein were evaluated, and a computational approach was used to identify putative binding sites. Punicalagin binds to either PDIA1 or PDIA3 with a similar affinity, but the inhibition efficacy on protein reductase activity is higher for PDIA3. Additionally, punicalagin differently affects the thermal denaturation profile of both proteins. Molecular docking and molecular dynamics simulations led to propose a punicalagin binding mode on PDIA1 and PDIA3, identifying the binding sites at the redox domains a’ in two different pockets, suggesting different effects of punicalagin on proteins’ structure. This study provides insights to develop punicalagin-based ligands, to set up a rational design for PDIA3 selective inhibitors, and to dissect the molecular determinant to modulate the protein activity

focus on practice\u201d - clinical ethics consultation on an orthotopic liver transplantation case.

The contribution describes a case report addressed in 2011 by the clinical ethics consultation service team of the Institute ofBioethics and Medical Humanities at the \u201cAgostino Gemelli\u201d School of Medicine of the Universit\ue0 Cattolica del Sacro Cuore, Rome (Italy). The clinical case regards ethical dilemmas about the patient\u2019s prospects for receiving an orthotopic liver transplant, because she was a non-resident and lacked a caregiver to assist her during the follow-up period, as well as a place to stay after liver transplant surger

Bio\ue9tica cl\uednica. Lineamientos sobre el inicio y la suspensi\uf3n del tramatiento de hemodi\ue1lisis

La decisi\uf3n sobre el acceso o la suspensi\uf3n del tratamiento mediante di\ue1lisis en pacientes con insuficiencia renal cr\uf3nica (lrc) actualmente gira en torno al reconocimiento de aquellos pacientes para los cuales no est\ue1 indicado. Por tanto, la cuesti\uf3n inicial seg\ufan la cual era necesario asegurar el tratamiento a todos los numerosos pacientes que de ello habr\uedan podido obtener un beneficio, ha sido alternada por un problema opuesto: individualizar, entre los muchos candidatos a la di\ue1lisis, aquellos que no obtendr\uedan un beneficio apreciable. Ah\ued donde, de hecho, el tratamiento no es capaz de ofrecer los beneficios m\ue9dicos esperados, configurando una verdadera y propia futilidad m\ue9dica o bien, ah\ued donde el peso impuesto por el tratamiento (efectos colaterales, com plicaciones, etc.) supere los beneficios que esto es capaz de ofrecer al paciente, es \ue9ticamente apropiado no iniciar (o eventualmente suspender) el tratamiento mismo