Network coevolution drives segregation and enhances Pareto optimal equilibrium selection in coordination games.

In this work we assess the role played by the dynamical adaptation of the interactions network, among agents playing Coordination Games, in reaching global coordination and in the equilibrium selection. Specifically, we analyze a coevolution model that couples the changes in agents' actions with the network dynamics, so that while agents play the game, they are able to sever some of their current connections and connect with others. We focus on two action update rules: Replicator Dynamics (RD) and Unconditional Imitation (UI), and we define a coevolution rule in which, apart from action updates, with a certain rewiring probability p, agents unsatisfied with their current connections are able to eliminate a link and connect with a randomly chosen neighbor. We call this probability to rewire links the 'network plasticity'. We investigate a Pure Coordination Game (PCG), in which choices are equivalent, and on a General Coordination Game (GCG), for which there is a risk-dominant action and a payoff-dominant one. Changing the plasticity parameter, there is a transition from a regime in which the system fully coordinates on a single connected component to a regime in which the system fragments in two connected components, each one coordinated on a different action (either if both actions are equivalent or not). The nature of this fragmentation transition is different for different update rules. Second, we find that both for RD and UI in a GCG, there is a regime of intermediate values of plasticity, before the fragmentation transition, for which the system is able to fully coordinate on a single component network on the payoff-dominant action, i.e., coevolution enhances payoff-dominant equilibrium selection for both update rules.

Nucleophilic Reactivity at a ═CH Arm of a Lutidine-Based CNC/Rh System: Unusual Alkyne and CO2 Activation.

Reaction of an amido pincer complex [(CNC)*Rh(CO)] (1) (CNC* is the deprotonated form of CNC) with carbon dioxide gave a neutral complex [(CNC-CO2)Mes*Rh(CO)] (2), which is the result of a C-C bond-forming reaction between the deprotonated arm of the CNC* ligand and CO2. The molecular structure of 2 showed a zwitterionic complex, where the CO2 moiety is covalently connected to the former ═CH arm of the CNC* pincer ligand. The unusual structure of 1 allowed us to explore the reactivity of the CO2 moiety with selected primary amines RNH2 (benzylamine and ammonia), which afforded cationic complexes [(CNC)MesRh(CO)][HRNC(O)O] (R = Bz (3), H (4)). Compounds 3 and 4 are the result of a C-N coupling between the incoming amine and the CO2 fragment covalently connected to the pincer ligand in 2, a process that involves protonation of the "CH-CO2" fragment in 2 from the respective amines. Once revealed the nucleophilic character of the ═CH fragment in 1, we explored its reactivity with alkynes, a study that enlightened a novel reactivity trend in alkyne activation. Reaction of 1 with terminal alkynes RC≡CH (R = Ph, 2-py, 4-C6H4-CF3) yielded neutral complexes [(CNC-CH═CHR)Mes*Rh(CO)] (R = Ph (5), 2-py (6), 4-C6H4-CF3 (7)) in good yields. Deuterium labeling experiments with PhC≡CD confirmed that complex 5 is the product of a formal insertion of the alkyne into the C(sp2)-H bond of the deprotonated arm in 1. This structural proposal was further confirmed by the X-ray molecular structure of phenyl complex 5, which showed the alkyne covalently linked to the pincer ligand. Besides, this novel transformation was analyzed by DFT methods and showed a metal-ligand cooperative mechanism, based on the initial electrophilic attack of the alkyne to the ═CH arm of the CNCMes* ligand (making a new C-C bond) followed by the action of a protic base (HN(SiMe3)2), which is able to perform a proton rearrangement that leads to the final product 5.

Cost-Effectiveness Analysis of Axicabtagene Ciloleucel vs. Tisagenlecleucel for the Management of Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Spain.

The study aimed to assess the cost-effectiveness of axicabtagene ciloleucel (axi-cel) vs. tisagenlecleucel (tisa-cel) for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of systemic therapy in Spain. A lifetime partitioned survival mixture cure model, which comprises pre-progression, post-progression, and death health states, was used to estimate the accumulated costs and outcomes in terms of life years gained (LYG) and quality-adjusted life years (QALY). A matching-adjusted indirect comparison was used to reweight patient-level data from ZUMA-1, the pivotal clinical trial for axi-cel, to aggregate-level data from the pivotal tisa-cel trial, JULIET. The analysis was performed from the National Health System perspective, thus only direct costs were included. Sensitivity analyses (SA) were performed. Axi-cel yielded 2.74 incremental LYG and 2.31 additional QALY gained per patient compared to tisa-cel. Total incremental lifetime costs for axi-cel versus tisa-cel were €30,135/patient. The incremental cost-effectiveness ratio of axi-cel versus tisa-cel resulted in €10,999/LYG and the incremental cost-utility ratio in €13,049/QALY gained. SA proved robustness of the results. Considering the frequently assumed willingness-to-pay thresholds in Spain (€22,000/QALY and €60,000/QALY), axi-cel is a cost-effective treatment vs. tisa-cel for adult patients with R/R DLBCL in Spain.

Asymmetric flows and drivers of herbaceous plant invasion success among Mediterranean-climate regions.

Understanding the mechanisms that support the arrival, establishment and spread of species over an introduced range is crucial in invasion ecology. We analysed the unintentionally introduced herbaceous species that are naturalised in the five Mediterranean-climate regions. There is an asymmetry in the species flows among regions, being the Iberian Peninsula the main donor to the other regions. At interregional scale, the species' capacity to spread among regions is related to the ecological versatility of the species in the donor area (Iberian Peninsula). At intraregional scale, the species' capacity to successfully occupy a complete region first depends on the time elapsed from its introduction and afterwards on the degree of occurrence in the region of origin, which is commonly related to its chance of coming into contact with humans. Information on exotic species in their origin region provides insights into invasion process and decision-making to reduce the risks of future invasions.

The invasiveness of Hypochaeris glabra (Asteraceae): Responses in morphological and reproductive traits for exotic populations.

Scientists have been interested in many topics driven by biological invasions, such as shifts in the area of distribution of plant species and rapid evolution. Invasiveness of exotic plant species depends on variations on morphological and reproductive traits potentially associated with reproductive fitness and dispersal ability, which are expected to undergo changes during the invasion process. Numerous Asteraceae are invasive and display dimorphic fruits, resulting in a bet-hedging dispersal strategy -wind-dispersed fruits versus animal-dispersed fruits-. We explored phenotypic differentiation in seed morphology and reproductive traits of exotic (Chilean) and native (Spanish) populations of Hypochaeris glabra. We collected flower heads from five Spanish and five Chilean populations along rainfall gradients in both countries. We planted seeds from the ten populations in a common garden trial within the exotic range to explore their performance depending on the country of origin (native or exotic) and the environmental conditions at population origin (precipitation and nutrient availability). We scored plant biomass, reproductive traits and fruit dimorphism patterns. We observed a combination of bet-hedging strategy together with phenotypic differentiation. Native populations relied more on bet-hedging while exotic populations always displayed greater proportion of wind-dispersed fruits than native ones. This pattern may reflect a strategy that might entail a more efficient long distance dispersal of H. glabra seeds in the exotic range, which in turn can enhance the invasiveness of this species.

Reactivity of the parent amido complexes of iridium with olefins: C-NH2 bond formation versus C-H activation.

Herein we report on the different chemical reactivity displayed by two mononuclear terminal amido compounds depending on the nature of the coordinated diene. Hence, treatment of amido-bridged iridium complexes [{Ir(µ-NH2)(tfbb)}3] (1; tfbb = tetrafluorobenzobarrelene) with dppp (dppp = bis(diphenylphosphane)propane) leads to the rupture of the amido bridges forming the mononuclear terminal amido compound [Ir(NH2)(dppp)(tfbb)] (3) in the first stage. On changing the reaction conditions, the formation of a C-NH2 bond between the amido moiety and the coordinated diene is observed and a new dinuclear complex [{Ir(1,2-η2-4-κ-C12H8F4N)(dppp)}2(µ-dppp)] (4) has been isolated. On the contrary, the diiridium amido-bridged complex [{Ir(µ-NH2)(cod)}2] (2; cod = 1,5-cyclooctadiene) in the presence of dppb (dppb = bis(diphenylphosphane)butane) allows the isolation of a mononuclear complex [Ir(1,2,3-η3-6-κ-C8H10)H(dppb)] (5), as a consequence of the extrusion of ammonia. The monitoring of the reaction of 2 with dppb (and dppp) allowed us to detect terminal amido complexes [Ir(NH2)(P-P)(cod)] (P-P = dppb (6), dppp (7)) in solution, as confirmed by an X-ray analysis of 7. Complex 7 was observed to evolve into hydrido species 5 at room temperature. DFT studies showed that C-H bond activation occurs through the deprotonation of one methylene fragment of the cod ligand by the highly basic terminal amido moiety instead of C-H oxidative addition to the Ir(i) center.

Cost-Effectiveness and Clinical Impact of Antiviral Strategies of HBeAG-Positive and Negative Chronic Hepatitis B

ABSTRACT Introduction. Chronic hepatitis B (CHB) is associated with high burden and healthcare costs. Virologic response achieved with antivirals is associated with progression avoidance. This study aimed to estimate the efficiency and clinical impact of antiviral strategies in CHB patients. Material and methods. A Markov model estimated lifetime complications and direct costs in both, HBeAg-positive and HBeAg-negative cohorts. Strategy 1 (71% of treated population) and strategy 2 (100%), both based on pegylated interferon (peg-IFN) followed by oral tenofovir or entecavir, were compared to no treatment. Progression was based on HBV-DNA levels. Rescue therapy with oral antivirals was applied for peg-IFN failure. Disease costs (€, 2014) and utilities were obtained from literature. Results. Compared to natural history, strategy 1 increased QALY (3.98 in HBeAg-positive, 2.16 in -negative cohort). With strategy 2, survival was up to 5.60 (HBeAg-positive) and 3.05 QALY (in HBeAg-negative). The model predicted avoidance of 128 and 86 carcinomas in HBeAg-positive and -negative patients with strategy 1, and up to 181 and 121 in HBeAg-positive and -negative for strategy 2. Total cost increased up to €102,841 (strategy 1) and €105,408 (strategy 2) in HBeAg-positive, and €85,858 and €93,754 in HBeAg-negative. A€1,581/QALY gained ratio was estimated versus the natural history for both strategies. In conclusion, increasing antiviral coverage would be efficient, reducing complications.

Ecotypic differentiation and phenotypic plasticity combine to enhance the invasiveness of the most widespread daisy in Chile, Leontodon saxatilis.

Dispersal and reproductive traits of successful plant invaders are expected to undergo strong selection during biological invasions. Numerous Asteraceae are invasive and display dimorphic fruits within a single flower head, resulting in differential dispersal pathways - wind-dispersed fruits vs. non-dispersing fruits. We explored ecotypic differentiation and phenotypic plasticity of seed output and fruit dimorphisms in exotic Chilean and native Spanish populations of Leontodon saxatilis subsp. rothii. We collected flower heads from populations in Spain and Chile along a rainfall gradient. Seeds from all populations were planted in reciprocal transplant trials in Spain and Chile to explore their performance in the native and invasive range. We scored plant biomass, reproductive investment and fruit dimorphism. We observed strong plasticity, where plants grown in the invasive range had much greater biomass, flower head size and seed output, with a higher proportion of wind-dispersed fruits, than those grown in the native range. We also observed a significant ecotype effect, where the exotic populations displayed higher proportions of wind-dispersed fruits than native populations. Together, these patterns reflect a combination of phenotypic plasticity and ecotypic differentiation, indicating that Leontodon saxatilis has probably increased propagule pressure and dispersal distances in its invasive range to enhance its invasiveness.

Cost-Effectiveness and Clinical Impact of Antiviral Strategies of HBeAg-Positive and -Negative Chronic Hepatitis B.

INTRODUCTION: Chronic hepatitis B (CHB) is associated with high burden and healthcare costs. Virologic response achieved with antivirals is associated with progression avoidance. This study aimed to estimate the efficiency and clinical impact of antiviral strategies in CHB patients. MATERIAL AND METHODS: A Markov model estimated lifetime complications and direct costs in both, HBeAg-positive and HBeAg-negative cohorts. Strategy 1 (71% of treated population) and strategy 2 (100%), both based on pegylated interferon (peg-IFN) followed by oral tenofovir or entecavir, were compared to no treatment. Progression was based on HBV-DNA levels. Rescue therapy with oral antivirals was applied for peg-IFN failure. Disease costs (C, 2014) and utilities were obtained from literature. RESULTS: Compared to natural history, strategy 1 increased QALY (3.98 in HBeAg-positive, 2.16 in -negative cohort). With strategy 2, survival was up to 5.60 (HBeAg-positive) and 3.05 QALY (in HBeAg-negative). The model predicted avoidance of 128 and 86 carcinomas in HBeAg-positive and -negative patients with strategy 1, and up to 181 and 121 in HBeAg-positive and -negative for strategy 2. Total cost increased up to C102,841 (strategy 1) and C105,408 (strategy 2) in HBeAg-positive, and C85,858 and C93,754 in HBeAg-negative. A C1,581/QALY gained ratio was estimated versus the natural history for both strategies. In conclusion, increasing antiviral coverage would be efficient, reducing complications.

Nucleophilicity and P-C Bond Formation Reactions of a Terminal Phosphanido Iridium Complex.

The diiridium complex [{Ir(ABPN2)(CO)}2(µ-CO)] (1; [ABPN2](-) = [(allyl)B(Pz)2(CH2PPh2)](-)) reacts with diphenylphosphane affording [Ir(ABPN2)(CO)(H) (PPh2)] (2), the product of the oxidative addition of the P-H bond to the metal. DFT studies revealed a large contribution of the terminal phosphanido lone pair to the HOMO of 2, indicating nucleophilic character of this ligand, which is evidenced by reactions of 2 with typical electrophiles such as H(+), Me(+), and O2. Products from the reaction of 2 with methyl chloroacetate were found to be either [Ir(ABPN2)(CO)(H)(PPh2CH2CO2Me)][PF6] ([6]PF6) or [Ir(ABPN2)(CO)(Cl)(H)] (7) and the free phosphane (PPh2CH2CO2Me), both involving P-C bond formation, depending on the reaction conditions. New complexes having iridacyclophosphapentenone and iridacyclophosphapentanone moieties result from reactions of 2 with dimethyl acetylenedicarboxylate and dimethyl maleate, respectively, as a consequence of a further incorporation of the carbonyl ligand. In this line, the terminal alkyne methyl propiolate gave a mixture of a similar iridacyclophosphapentanone complex and [Ir(ABPN2){CH═C(CO2Me)-CO}{PPh2-CH═CH(CO2Me)}] (10), which bears the functionalized phosphane PPh2-CH═CH(CO2Me) and an iridacyclobutenone fragment. Related model reactions aimed to confirm mechanistic proposals are also studied.

[Cost-utility analysis of triple therapy with telaprevir in treatment-naïve hepatitis C patients]. / Análisis coste-utilidad de la triple terapia con telaprevir en pacientes con hepatitis C no tratados previamente.

INTRODUCTION: The prevalence of Hepatitis C (HCV) in Spain is 2,5%, with a high morbimortality rate. Triple therapy based on telaprevir plus peginterferon/ribavirin ([T/PR]) has demonstrated to be an effective approach in treatment-naïve G1-HCV patients. This analysis evaluated, through a Markov model, the incremental cost-effectiveness ratio of triple therapy compared to peginterferon/ ribavirin ([PR]) alone in naïve patients depending on fibrosis stage, from the Spanish Healthcare Authorities perspective. METHODS: Efficacy results and adverse events incidence were based on the combined results of ADVANCE and OPTIMIZE studies. Adverse events and disease-related costs (€, 2014) were built up from panel expert opinion except from transplant and post-transplant costs, taken from published data. Drug costs were obtained from national databases and adjusted for the mandatory deduction. Outcomes and costs were both discounted at 3%/year. RESULTS: The analysis shows higher costs and improved outcomes associated with [TR/PR] relative to [PR] alone, resulting in an incremental cost-effectiveness ratio (ICER) of €18,288/ QALY for all the cohort, €14,152QALY for moderate fibrosis, €11,364QALY for bridging fibrosis, €15,929/QALY for cirrhosis. Over a lifetime period, the use of [T/PR] could avoid 12 cirrhosis and 4 liver transplants per 1,000 patients compared to [PR] alone. The probabilistic analysis, following 10,000 Montecarlo simulations, demonstrated the probability of an ICER below a €30,000/QALY gained threshold of 69%. At a willingness- to-pay of €30,000/QALY, [T/PR] could be considered as an efficient option compared with [PR] alone for treatment-naïve genotype 1 HCV patients, over a lifetime horizon.

Introduccion: En España, con una prevalencia del 2,5%, la hepatitis C (VHC) se asocia a una elevada morbi-mortalidad. El tratamiento combinado de telaprevir y peginterferon/ribavirina ([T/PR]) es eficaz en pacientes con VHC-G1. El objetivo primario de este estudio fue evaluar la relación coste-utilidad (RCUI) de [T/PR] versus peginterferon alfa 2a/ribavirina ([PR]) en pacientes naïve VHC-G1, según el grado de fibrosis y bajo la perspectiva del sistema sanitario español. Metodología: La eficacia y la incidencia de efectos adversos (EAs) se obtuvieron de los estudios ADVANCE y OPTIMIZE. La estimación de los costes de monitorización, de manejo de EAs y de la enfermedad por estados de salud (€, 2014) fueron proporcionados por el panel de expertos, según bases de costes nacionales, excepto el coste de trasplante y post-trasplante obtenido de publicaciones. Se aplicó la deducción obligatoria a los costes farmacológicos (precio de venta del laboratorio). La tasa de descuento considerada para los costes y beneficios fue 3% anual. Resultados: [T/PR] proporcionó mejores resultados en salud (0,96 Años de Vida Ajustados por Calidad, AVAC) y mayor coste (17.495€) comparado con [PR], resultando una RCUI de [T/PR] versus [PR] de 18.288€/AVAC para toda la cohorte, 14.152€/AVAC para fibrosis moderada, 11.364€/AVAC para fibrosis en puentes y 15.929€/AVAC para cirrosis. Considerando toda la vida del paciente, [T/PR] podría evitar 12 cirrosis y 4 trasplantes cada 1.000 pacientes. Con una RCUI inferior a 30.000€/AVAC en el 69% de las simulaciones del análisis probabilístico [T/PR] sería eficiente versus [PR] en pacientes naïve, independientemente del grado de fibrosis.

Análisis coste-utilidad de la triple terapia con telaprevir en pacientes con hepatitis C no tratados previamente / Cost-utility analysis of triple therapy with telaprevir in treatment-naïve hepatitis C patients

Introducción: En España, con una prevalencia del 2,5%, la hepatitis C (VHC) se asocia a una elevada morbi-mortalidad. El tratamiento combinado de telaprevir y peginterferon/ribavirina([T/PR]) es eficaz en pacientes con VHC-G1. El objetivo primario de este estudio fue evaluar la relación coste-utilidad (RCUI) de [T/PR] versus peginterferon alfa 2a/ribavirina ([PR]) en pacientes naïve VHC-G1, según el grado de fibrosis y bajo la perspectiva del sistema sanitario español. Metodología: La eficacia y la incidencia de efectos adversos (EAs) se obtuvieron de los estudios ADVANCE y OPTIMIZE. La estimación de los costes de monitorización, de manejo de EAs y de la enfermedad por estados de salud (Euros, 2014) fueron proporcionados por el panel de expertos, según bases de costes nacionales, excepto el coste de trasplante y post-trasplante obtenido de publicaciones. Se aplicó la deducción obligatoria a los costes farmacológicos (precio de venta del laboratorio). La tasa de descuento considerada para los costes y beneficios fue 3% anual. Resultados: [T/PR] proporcionó mejores resultados en salud (0,96 Años de Vida Ajustados por Calidad, AVAC) y mayor coste (17.495 Euros) comparado con [PR], resultando una RCUI de [T/PR] versus [PR] de 18.288 Euros/AVAC para toda la cohorte, 14.152 Euros/AVAC para fibrosis moderada, 11.364 Euros/AVAC para fibrosis en puentes y 15.929 Euros/AVAC para cirrosis. Considerando toda la vida del paciente, [T/PR] podría evitar 12 cirrosis y 4 trasplantes cada 1.000 pacientes. Con una RCUI inferior a 30.000 Euros/AVAC en el 69% de las simulaciones del análisis probabilístico [T/PR] sería eficiente versus [PR] en pacientes naïve, independientemente del grado de fibrosis

Introduction: The prevalence of Hepatitis C (HCV) in Spain is 2,5%, with a high morbimortality rate. Triple therapy based on telaprevir plus peginterferon/ribavirin ([T/PR]) has demonstrated to be an effective approach in treatment-naïve G1-HCV patients. This analysis evaluated, through a Markov model, the incremental cost-effectiveness ratio of triple therapy compared to peginterferon/ribavirin ([PR]) alone in naive patients depending on fibrosis stage, from the Spanish Healthcare Authorities perspective. Methods: Efficacy results and adverse events incidence were based on the combined results of ADVANCE and OPTIMIZE studies. Adverse events and disease-related costs (Euros, 2014) were built up from panel expert opinion except from transplant and post-transplant costs, taken from published data. Drug costs were obtained from national databases and adjusted for the mandatory deduction. Outcomes and costs were both discounted at 3%/year. Results: The analysis shows higher costs and improved outcomes associated with [TR/PR] relative to [PR] alone, resulting ln an incremental cost-effectiveness ratio (ICER) of Euros 18,288/ QALY for all the cohort, Euros 14,152QALY for moderate fibrosis, Euros 11,364QALY for bridging fibrosis, Euros 15,929/QALY for cirrhosis. Over a lifetime period, the use of [T/PR] could avoid 12 cirrhosis and 4 liver transplants per 1,000 patients compared to [PR] alone. The probabilistic analysis, following 10,000 Montecarlo simulations, demonstrated the probability of an ICER below a Euros 30,000/QALY gained threshold of 69%. At a willingness-to-pay of Euros 30,000/QALY, [T/PR] could be considered as an efficient option compared with [PR] alone for treatment-naíve genotype 1 HCV patients, over a lifetime horizon

C-NH2 bond formation mediated by iridium complexes.

In the presence of phosphanes (PR3 ), the amido-bridged trinuclear complex [{Ir(µ-NH2 )(tfbb)}3 ] (tfbb=tetrafluorobenzobarrelene) transforms into mononuclear discrete compounds [Ir(1,2-η(2) -4-κ-C12 H8 F4 N)(PR3 )3 ], which are the products of the CN coupling between the amido moiety and a vinylic carbon of the diolefin. An alternative synthetic approach to these species involves the reaction of the 18 e(-) complex [Ir(Cl)(tfbb)(PMePh2 )2 ] with gaseous ammonia and additional phosphane. DFT studies show that both transformations occur through nucleophilic attack. In the first case the amido moiety attacks a diolefin coordinated to a neighboring molecule following a bimolecular mechanism induced by the highly basic NH2 moiety; the second pathway involves a direct nucleophilic attack of ammonia to a coordinated tfbb molecule.

P-H activation of secondary phosphanes on a parent amido diiridium complex.

Selected secondary phosphanes (H-PR2; R = Ph, Cy, (i)Pr) smoothly react with a parent amido-bridged diiridium cyclooctadiene complex affording mixed amido/(bis)phosphido dinuclear species. A careful investigation of the reaction profile, carried out by experimental and theoretical tools, revealed that, after an initial amido/phosphido exchange, at low temperatures a second molecule of secondary phosphane adds to the dinuclear system through an oxidative addition process leading to a hydrido amido/bis(phosphido) mixed-valence complex [Ir(III)/Ir(I)]. These species rearrange above -10 °C into the most stable isomer that arises from a migration of the hydrido moiety to one of the =CH fragments of a coordinated cod molecule, a transformation facilitated by the formation of an intermetallic bond. Further heating of these species reductively eliminates ammonia affording bis(phosphido)-metal-metal bonded complexes.

Rhodium and iridium complexes with a new scorpionate phosphane ligand.

A straightforward synthesis of a new hybrid scorpionate ligand [(allyl)2B(CH2PPh2)(Pz)](-) ([A2BPN](-)) is reported. Coordination to rhodium resulted in square-planar complexes [Rh(κ(2)-A2BPN)(L)(L')] [L = L' = (1)/2cod (1,5-cyclooctadiene), CN(t)Bu, CO (6); L = CO, L' = NH3, pyridine, PPh3, PMe3] for which spectroscopic data and the molecular structure of [Rh(κ(2)-A2BPN)(CO)PPh3] (11) indicate the ligand to be κN,κP-bound to rhodium with two dangling free allyl groups. Studies in solution point out that the six-membered Rh-N-N-B-C- P metallacycle undergoes a fast inversion in all of them. The bis(carbonyl) complex 6 easily loses a CO group to give [{Rh(A2BPN)(CO)}2], a dinuclear compound in which two mononuclear subunits are brought together by two bridging allyl groups. Coordination to iridium is dominated by a tripodal κN,κP,η(2)-C═C binding mode in the TBPY-5 complexes [Ir(κ(3)-A2BPN)(L)(L')] [L = L' = (1)/2cod (3), CN(t)Bu (5), CO (7); L = CO, L' = PPh3 (13), PMe3 (14), H2C═CH2, (17), MeO2CC≡CCO2Me (dmad, 18)], as confirmed by the single-crystal structure determination of complexes 3 and 18. A fast exchange between the two allyl arms is observed for complexes having L = L' (3, 5, and 7), while those having CO and L ligands (14, 17, and 18) were found to be nonfluxional species. An exception is complex 13, which establishes an equilibrium with the SP-4 configuration. Protonation reactions on complexes 13 and 14 with HCl yielded the hydride complex [Ir(κ(2)-A2BPN)(CO)(Cl)(H)PPh3] (15) and the C-alkyl compound [ Ir{κ(3)-(allyl)B(CH2 CHCH3)(CH2PPh2)(Pz)}(Cl)(CO)PMe3] (16), respectively. The bis(isocyanide) complex 5 reacts with dmad to form [Ir(κ(2)-A2BPN)(CN(t)Bu)2(dmad)]. On the whole, the electronic density provided to the metal by the [A2BPN](-) ligand is very sensitive to the coordination mode. The basicity of the new ligand is similar to that of the Tp(Me2) ligand in the κN,κP mode but comparable to Tp if coordinated in the κN,κP,η(2)-C═C mode.

Cost analysis of glatiramer acetate vs. fingolimod for the treatment of patients with relapsing-remitting multiple sclerosis in Spain.

BACKGROUND: Fingolimod is an innovative drug with a significant budget impact in the treatment of MS in Spain. The aim of this study was to calculate the direct cost comparison of glatiramer acetate and fingolimod for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) in Spain. METHODS: A cost analysis model was developed to compare glatiramer acetate and fingolimod, based on a 1-year time horizon. In addition to the pharmacological costs, resource use was estimated for glatiramer acetate (1 hour of training with nursing staff in self-injection techniques for subcutaneous administration) and fingolimod (vaccination for varicella-zoster virus in 5% of patients, 3 complete blood counts per year, 3 ophthalmology visits for prevention of macular edema, 3 transaminase tests to monitor liver function, and cardiovascular monitoring consisting of 1 ECG before the first fingolimod dose and at 6 hours; 1 day outpatients-hospital visit for cardiological monitoring during 6 hours on the day of the first fingolimod dose, with follow-up of blood pressure and heart rate every hour). The pharmacological costs were calculated based on the ex-factory price of the drugs evaluated, using the doses recommended in the respective Summary of Products Characteristics (SmPC). Total invoicing volume was discounted by 7.5%, as laid down in Spanish Royal Decree 8/2010. Unit costs were obtained from the e-Salud database and the drug catalog. Costs in the model are expressed in €2012. RESULTS: The cost of annual treatment was €9,439.42 for glatiramer acetate and €19,602.18 for fingolimod, yielding a cost difference of €10,162.76. Assuming a fixed budget of €100,000.00, approximately 10 patients could be treated with glatiramer acetate, compared to 5 with fingolimod. CONCLUSIONS: Fingolimod therapy requires twice the investment as glatiramer acetate.

Terminal and bridging parent amido 1,5-cyclooctadiene complexes of rhodium and iridium.

The ready availability of rare parent amido d(8) complexes of the type [{M(µ-NH2)(cod)}2] (M=Rh (1), Ir (2); cod=1,5-cyclooctadiene) through the direct use of gaseous ammonia has allowed the study of their reactivity. Both complexes 1 and 2 exchanged the di-olefines by carbon monoxide to give the dinuclear tetracarbonyl derivatives [{M(µ-NH2)(CO)2}2 ] (M=Rh or Ir). The diiridium(I) complex 2 reacted with chloroalkanes such as CH2Cl2 or CHCl3, giving the diiridium(II) products [(Cl)(cod)Ir(µ-NH2)2Ir(cod)(R)] (R=CH2Cl or CHCl2) as a result of a two-center oxidative addition and concomitant metal-metal bond formation. However, reaction with ClCH2CH2Cl afforded the symmetrical adduct [{Ir(µ-NH2)(Cl)(cod)}2] upon release of ethylene. We found that the rhodium complex 1 exchanged the di-olefines stepwise upon addition of selected phosphanes (PPh3, PMePh2, PMe2Ph) without splitting of the amido bridges, allowing the detection of mixed COD/phosphane dinuclear complexes [(cod)Rh(µ-NH2)2Rh(PR3)2], and finally the isolation of the respective tetraphosphanes [{Rh(µ-NH2)(PR3)2}2]. On the other hand, the iridium complex 2 reacted with PMe2 Ph by splitting the amido bridges and leading to the very rare terminal amido complex [Ir(cod)(NH2)(PMePh2)2]. This compound was found to be very reactive towards traces of water, giving the more stable terminal hydroxo complex [Ir(cod)(OH)(PMePh2)2]. The heterocyclic carbene IPr (IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) also split the amido bridges in complexes 1 and 2, allowing in the case of iridium to characterize in situ the terminal amido complex [Ir(cod)(IPr)(NH2)]. However, when rhodium was involved, the known hydroxo complex [Rh(cod)(IPr)(OH)] was isolated as final product. On the other hand, we tested complexes 1 and 2 as catalysts in the transfer hydrogenation of acetophenone with iPrOH without the use of any base or in the presence of Cs2CO3, finding that the iridium complex 2 is more active than the rhodium analogue 1.

Cost effectiveness of first-line oral antiviral therapies for chronic hepatitis B : a systematic review.

BACKGROUND: Chronic hepatitis B is a common, progressive disease, particularly when viral replication is detected. Oral antivirals can suppress viral replication and prevent or delay the development of cirrhosis and liver-related complications. OBJECTIVE: The aim of this study was to systematically review the quality of cost-effectiveness evidence on first-line treatment with entecavir (ETV) or tenofovir difumarate (TDF) for patients with chronic hepatitis B. METHODS: We searched electronic databases and retrieved articles published up to October 2011, in which the cost effectiveness of ETV or TDF was compared with that of other oral antivirals. The quality of the studies identified was assessed with a standard checklist for critical appraisal. RESULTS: We selected 16 original papers, all published in the last 5 years. There was a conflict of interest in 12 of the 16 studies due to sponsorship by the corresponding pharmaceutical companies. According to the validity assessment, ten studies were classified as high quality. Five studies performed a cost-effectiveness analysis comparing ETV with TDF; they concluded that TDF dominates ETV. The other 11 studies compared ETV or TDF with other strategies; all concluded that ETV and TDF are both cost-effective interventions. CONCLUSIONS: This systematic review shows that there is valid evidence suggesting that ETV and TDF are cost-effective interventions for the treatment of patients with chronic hepatitis B in many health systems. In countries where both alternatives are available, it appears that TDF dominates ETV. These results could help decision makers and clinicians to understand economic issues regarding the available drugs for first-line treatment of hepatitis B.

Budgetary impact analysis of buprenorphine-naloxone combination (Suboxone®) in Spain.

BACKGROUND: Opioid addiction is a worldwide problem. Agonist opioid treatment (AOT) is the most widespread and frequent pharmacotherapeutic approach. Methadone has been the most widely used AOT, but buprenorphine, a partial µ-opiod agonist and a κ-opiod antagonist, is fast gaining acceptance. The objective was to assess the budgetary impact in Spain of the introduction of buprenorphine-naloxone (B/N) combination. METHODS: A budgetary impact model was developed to estimate healthcare costs of the addition of B/N combination to the therapeutic arsenal for treating opioid dependent patients, during a 3-year period under the National Health System perspective. Inputs for the model were obtained from the specialized scientific literature. Detailed information concerning resource consumption (drug cost, logistics, dispensing, medical, psychiatry and pharmacy supervision, counselling and laboratory test) was obtained from a local expert panel. Costs are expressed in euros (€, 2010). RESULTS: The number of patients estimated to be prescribed B/N combination was 2,334; 2,993 and 3,589 in the first, second and third year respectively. Total budget is €85,766,129; €79,855,471 and €79,137,502 in the first, second and third year for the scenario without B/N combination. With B/N combination the total budget would be €86,589,210; €80,398,259 and €79,708,964 in the first, second and third year of the analyses. Incremental cost/patient comparing the addition of the B/N combination to the scenario only with methadone is €10.58; €6.98 and €7.34 in the first, second and third year respectively. CONCLUSION: Addition of B/N combination would imply a maximum incremental yearly cost of €10.58 per patient compared to scenario only with methadone and would provide additional benefits.