"Success fee" represents an effective strategy to promote value-based pricing, making available to patients a rapid access to innovative and expensive therapies, with an affordable impact on drug expenditure and, simultaneously, ensuring third-party payers to share with manufacturers the risk deriving from uncertain safety and effectiveness.
NAD is an essential coenzyme involved in numerous metabolic pathways. Its principal role is in redox reactions, and as such it is not heavily "consumed" by cells. Yet a number of signaling pathways that bring about its consumption have recently emerged. This has brought about the hypothesis that the enzymes that lead to its biosynthesis may be targets for anticancer therapy. In particular, inhibition of the enzyme nicotinamide phosphoribosyl transferase has been shown to be an effective treatment in a number of preclinical studies, and two lead molecules [N-[4-(1-benzoyl-4-piperidinyl)butyl]-3-(3-pyridinyl)-2E-propenamide (FK866) and (E)-1-[6-(4-chlorophenoxy)hexyl]-2-cyano-3-(pyridin-4-yl)guanidine (CHS 828)] have now entered preclinical trials. Yet, the full potential of these drugs is still unclear. In the present study we have investigated the role of FK866 in neuroblastoma cell lines. We now confirm that FK866 alone in neuroblastoma cells induces autophagy, and its effects are potentiated by chloroquine and antagonized by 3-methyladenine or by down-regulating autophagy-related protein 7. Autophagy, in this model, seems to be crucial for FK866-induced cell death. On the other hand, a striking potentiation of the effects of cisplatin and etoposide is given by cotreatment of cells with ineffective concentrations of FK866 (1 nM). The effect of etoposide on DNA damage is potentiated by FK866 treatment, whereas the effect of FK866 on cytosolic NAD depletion is potentiated by etoposide. Even more strikingly, cotreatment with etoposide/cisplatin and FK866 unmasks an effect on mitochondrial NAD depletion.
This method may be considered a tool for the evaluation of appropriateness of price proposed at negotiation and could represent a reliable resource for decision-making. Furthermore, this analysis suggests that most recently approved cancer drugs in Italy do not fulfill price adequacy.
Intravitreal injections of TA may offer certain advantages over the standard of care for ocular inflammatory diseases, especially in the early stage of follow-up. However, it is necessary to take into account risks and benefits of TA treatment for ocular inflammatory diseases due to possible ocular hypertension elicited, in general, by intravitreal injection of corticosteroids.
Factor VIII belongs to the coagulation cascade and is expressed as a long pre-protein (mature form, 2351 amino acids long). FVIII is deficient or defective in hemophilic A patients, who need to be treated with hemoderivatives or recombinant FVIII substitutes, i.e., biologic drugs. The interaction between FVIII and von Willebrand factor (VWF) influences the pharmacokinetics of FVIII medications. In vivo, full-length FVIII (FL-FVIII) is secreted in a plasma-inactive form, which includes the B domain, which is then proteolyzed by thrombin protease activity, leading to an inactive plasma intermediate. In this work, we analyzed through a computational approach the binding of VWF with two structure models of FVIII (secreted full-length with B domain, and B domain-deleted FVIII). We included in our analysis the atomic model of efanesoctocog alfa, a novel and investigational recombinant FVIII medication, in which the VWF is covalently linked to FVIII. We carried out a structural analysis of VWF/FVIII interfaces by means of protein–protein docking, PISA (Proteins, Interfaces, Structures and Assemblies), and protein contact networks (PCN) analyses. Accordingly, our computational approaches to previously published experimental data demonstrated that the domains A3-C1 of B domain-deleted FVIII (BDD-FVIII) is the preferential binding site for VWF. Overall, our computational approach applied to topological analysis of protein–protein interface can be aimed at the rational design of biologic drugs other than FVIII medications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.