The endless frontier? The recent increase of R&D productivity in pharmaceuticals

Background: Studies on the early 2000s documented increasing attrition rates and duration of clinical trials, leading to a representation of a "productivity crisis" in pharmaceutical research and development (R&D). In this paper, we produce a new set of analyses for the last decade and report a recent increase of R&D productivity within the industry. Methods: We use an extensive data set on the development history of more than 50,000 projects between 1990 and 2017, which we integrate with data on sales, patents, and anagraphical information on each institution involved. We devise an indicator to quantify the novelty of each project, based on its set of mechanisms of action. Results: First, we investigate how R&D projects are allocated across therapeutic areas and find a polarization towards high uncertainty/high potential reward indications, with a strong focus on oncology. Second, we find that attrition rates have been decreasing at all stages of clinical research in recent years. In parallel, for each phase, we observe a significant reduction of time required to identify projects to be discontinued. Moreover, our analysis shows that more recent successful R&D projects are increasingly based on novel mechanisms of action and target novel indications, which are characterized by relatively small patient populations. Third, we find that the number of R&D projects on advanced therapies is also growing. Finally, we investigate the relative contribution to productivity variations of different types of institutions along the drug development process, with a specific focus on the distinction between the roles of Originators and Developers of R&D projects. We document that in the last decade Originator-Developer collaborations in which biotech companies act as Developers have been growing in importance. Moreover, we show that biotechnology companies have reached levels of productivity in project development that are equivalent to those of large pharmaceutical companies. Conclusions: Our study reports on the state of R&D productivity in the bio-pharmaceutical industry, finding several signals of an improving performance, with R&D projects becoming more targeted and novel in terms of indications and mechanisms of action

Second Order Nonlinear Optical Properties of 4-Styrylpyridines Axially Coordinated to A4 ZnII Porphyrins: A Comparative Experimental and Theoretical Investigation

In this research, two 4-styrylpyridines carrying an acceptor \u2013NO2 (L1) or a donor \u2013NMe2 group (L2) were axially coordinated to A4 ZnII porphyrins displaying in 5,10,15,20 meso position aryl moieties with remarkable electron withdrawing properties (pentafluorophenyl (TFP)), and with moderate to strong electron donor properties (phenyl (TPP) < 3,5-di-tert-butylphenyl (TBP) < bis(4-tert-butylphenyl)aniline) (TNP)). The second order nonlinear optical (NLO) properties of the resulting complexes were measured in CHCl3 solution by the Electric-Field-Induced Second Harmonic generation technique, and the quadratic hyperpolarizabilities \u3b2\u3bb were compared to the Density Functional Theory (DFT)-calculated scalar quantities \u3b2||. Our combined experimental and theoretical approach shows that different interactions are involved in the NLO response of L1- and L2-substituted A4 ZnII porphyrins, suggesting a role of backdonation-type mechanisms in the determination of the negative sign of Electric-Field-Induced Second Harmonic generation (EFISH) \u3b2\u3bb, and a not negligible third order contribution for L1-carrying complexes

A chiral bis(salicylaldiminato)zinc(ii) complex with second-order nonlinear optical and luminescent properties in solution

Whereas there is an increasing amount of reports on the second-order nonlinear optical (NLO) and luminescence properties of tetradentate [N2O2] Schiff base-zinc complexes, the study of zinc complexes having two bidentate [NO] Schiff-base ligands is relatively unexplored from an NLO point of view. This work puts in evidence that the known chiral bis(2-[(R)-(+)-1-phenylethyliminomethyl]phenolato-N, O)zinc(II) complex is a fascinating multifunctional molecular inorganic-organic hybrid material characterized by interesting second-order NLO and luminescent properties in solution. The emissive properties of the organic 2-(R)-(+)-1-phenylethyliminomethyl]phenol proligand are greatly enhanced upon coordination to the inorganic Zn(II) center

Ferrocene-quinoxaline Y-shaped chromophores as fascinating second-order NLO building blocks for long lasting highly active SHG polymeric films

The first example of a Y-shaped ferrocene quinoxaline derivative with a surprisingly high and stable second harmonic generation (SHG) response in composite polymeric films is reported. The interesting quadratic hyperpolarizability values of different substituted Y-shaped chromophores are also investigated in solution by the EFISH technique

Tuberculosis/HIV/AIDS coinfection in Porto Alegre, RS/Brazil - invisibility and silencing of the most affected groups

OBJECTIVE: To analyze how belonging to certain social groups contributes to constituting the vulnerabilities associated with illnesses due to tuberculosis/HIV/AIDS coinfection. METHODOLOGYThis is a qualitative study carried out in the city of Porto Alegre, state of Rio Grande do Sul, in regions of high social vulnerability. Twenty coinfected people were interviewed in specialized health services between August and December 2016. The analysis was based on the frameworks The Sound of Silence and Vulnerability and Human Rights. RESULTS: Socioeconomic conditions were decisive for the constitution of the vulnerability conditions. Processes of people invisibilization, and the silencing of their voices, in a scenario marked by economic, racial and gender inequalities, contributed for their health needs not to be understood and effectively taken into account in the services actions. FINAL CONSIDERATIONS: The more effective strategies are to legitimize voices and to understand the needs of those affected by coinfection, the greater the chances that programmatic responses to the problem will be successful

Intrinsic and Extrinsic Heavy-Atom Effects on the Multifaceted Emissive Behavior of Cyclic Triimidazole

Considering that heavy halogen atoms can be used to tune the emissive properties of organic luminogens, the understanding of their role in photophysics is fundamental for materials engineering. Here, the extrinsic and intrinsic heavy-atom effects on the photophysics of organic crystals were separately evaluated by comparing cyclic triimidazole (TT) with its monoiodo derivative (TTI) and its co-crystal with diiodotetrafluorobenzene (TTCo). Crystals of TT showed room-temperature ultralong phosphorescence (RTUP) originated from H-aggregation. TTI and TTCo displayed two additional long-lived components, the origin of which is elucidated through single-crystal X-ray and DFT/TDDFT studies. The results highlight the different effects of the I atom on the three phosphorescent emissions. Intrinsic heavy-atom effects play a major role on molecular phosphorescence, which is displayed at room temperature only for TTI. The H-aggregate RTUP and the I c5 c5 c5N XB-induced (XB=halogen bond) phosphorescence on the other side depend only on packing features

Basilar Artery Changes in Fabry Disease

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Zinc(II) as a versatile template for efficient dipolar and octupolar second-order nonlinear optical molecular materials

This short review outlines the main results obtained in the field of molecular materials based on zinc coordination compounds for second-order nonlinear optics. It presents an overview of the main classes of second-order nonlinear optical (NLO) active complexes bearing monodentate, bidentate, tridentate, or tetradentate \u3d5-delocalized ligands such as substituted stilbazoles, bipyridines, phenanthrolines, terpyridines, and Schiff bases. Macrocyclic ligands such as porphyrins and phthalocyanines are not covered. This paper shows how coordination to the Zn(II) center of \u3c0-delocalized nitrogen donor ligands produces a significant enhancement of their quadratic hyperpolarizability. Dipolar complexes are mainly presented, but octupolar zinc complexes are also presented. The coverage is mainly focused on NLO properties that are measured at the molecular level, working in solution, by means of the electric field-induced second harmonic generation (EFISH) or the hyper-Rayleigh scattering (HRS) techniques

Fluorine-induced J-aggregation enhances emissive properties of a new NLO push–pull chromophore

A new fluorinated push–pull chromophore with good second-order NLO properties even in concentrated solution shows solid state intermolecular aryl–fluoroaryl interactions leading to J-aggregates with intense solid state luminescence