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 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.

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.

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.

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.

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.

Cost-effectiveness of posaconazole versus fluconazole or itraconazole in the prevention of invasive fungal infections among high-risk neutropenic patients in Spain.

BACKGROUND: We evaluated the cost-effectiveness of posaconazole compared with standard azole therapy (SAT; fluconazole or itraconazole) for the prevention of invasive fungal infections (IFI) and the reduction of overall mortality in high-risk neutropenic patients with acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS). The perspective was that of the Spanish National Health Service (NHS). METHODS: A decision-analytic model, based on a randomised phase III trial, was used to predict IFI avoided, life-years saved (LYS), total costs, and incremental cost-effectiveness ratio (ICER; incremental cost per LYS) over patients' lifetime horizon. Data for the analyses included life expectancy, procedures, and costs associated with IFI and the drugs (in euros at November 2009 values) which were obtained from the published literature and opinions of an expert committee. A probabilistic sensitivity analysis (PAS) was performed. RESULTS: Posaconazole was associated with fewer IFI (0.05 versus 0.11), increased LYS (2.52 versus 2.43), and significantly lower costs excluding costs of the underlying condition (€6,121 versus €7,928) per patient relative to SAT. There is an 85% probability that posaconazole is a cost-saving strategy compared to SAT and a 97% probability that the ICER for posaconazole relative to SAT is below the cost per LYS threshold of €30,000 currently accepted in Spain. CONCLUSIONS: Posaconazole is a cost-saving prophylactic strategy (lower costs and greater efficacy) compared with fluconazole or itraconazole in high-risk neutropenic patients.

Di-µ-methanolato-bis[(η4-tetrafluorobenzobarrelene)rhodium(I)].

The versatile synthetic precursor methanolate-bridged title rhodium complex, [Rh(2)(CH(3)O)(2)(C(12)H(6)F(4))(2)] or [Rh(µ-OCH(3))(tfbb)](2) [tfbb = tetrafluorobenzobarrelene or 3,4,5,6-tetrafluorotricyclo[6.2.2.0(2,7)]dodeca-2(7),3,5,9,11-pentaene], has been structurally characterized. The asymmetric unit contains half a molecule that can be expanded via a twofold axis. The title compound has been shown to be a dinuclear rhodium complex where each metal centre is coordinated by two O atoms from two bridging methanolate groups and by the olefinic bonds of a tfbb ligand. Comparison of the bite angles of tfbb, norbornadiene (nbd) and cyclooctadiene (cod) olefins in their η(4)-coordination to rhodium reveals similarities between the tfbb and nbd ligands, which are much more rigid than cod. The short distance found between the distorted square-planar metal centres [2.8351 (4) Å] has been related to the syn conformation of the folded core `RhORhO' ring.

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.

Chemical variability of Copaifera reticulata Ducke oleoresin.

The copaiba tree (Copaifera spp.) produces an oleoresin which is highly valued due to its medicinal properties. The chemical composition of C. reticulata oleoresin was characterized, and its variability related to seasonal variation (dry and rainy seasons), to successive extractions, and to several factors associated with tree morphometry, disease, and surrounding vegetation structure was investigated. Oleoresin was collected from 24 C. reticulata individuals between October 2006 and March 2008. For seven individuals, oleoresin was extracted for a second time between three and nine months after the first extraction. For each tree, several morphometric variables, viz., the presence of termites, vines, and holes as well as the soil type and surrounding vegetation structure, were recorded. The chemical composition and concentration of the main volatile compounds were identified by GC/MS. Almost 100% of the constituents were sesquiterpenes, the three main ones being ß-caryophyllene, trans-α-bergamotene, and ß-bisabolene. A classification analysis separated the C. reticulata individuals in two main groups and further divided one of the main groups in two subgroups, which were defined by different concentrations of the three main compounds. The results showed high intra-population variability in the composition and concentration of sesquiterpenes, this being comparable to the interspecific variability. It was not possible to determine a clear influence of environmental, morphometrical, and structural factors on the oleoresin composition, although some compounds varied according to the soil type, the volume of oleoresin extracted, and the crown surface.

Suboxone (buprenorphine/naloxone) as an agonist opioid treatment in Spain: a budgetary impact analysis.

OBJECTIVE: To evaluate the economic impact of buprenorphine/naloxone (B/N) as an agonist opioid treatment for opiate dependence. METHODS: A budgetary impact analysis model was designed to calculate the annual costs (drugs and associated costs) to the Spanish National Healthcare System of methadone versus B/N. Data for the model were obtained from official databases and expert panel opinion. RESULTS: It was estimated that 86,017 patients would be in an agonist opioid treatment program each of the 3 years of the study. No increase in the number of patients is expected with the introduction of B/N combination. The budgetary impact (drugs and associated costs) for agonist opiate treatment in the first year of the study would be 89.53 million EUR. In the first year of B/N use, the budgetary impact would rise by 4.39 million EUR (4.6% of the total impact), with an incremental cost of 0.79 million EUR (0.9% of the total impact). The budgetary increase would be 0.6% (0.48 million EUR increase) and 0.6% (0.49 million EUR increase) in the second and third years of use, respectively. The mean cost per patient in the first year with and without B/N would be EUR 1,050 and 1,041, respectively. The most influential variables in the sensitivity analysis were logistics and production costs of methadone and the percentage use of B/N. CONCLUSION: With an additional cost of only EUR 9 per patient, B/N is an efficient addition to the therapeutic arsenal in the drug treatment of opiate dependence, particularly when considering clinical aspects of novel pharmacotherapy.

Global spending on orphan drugs in France, Germany, the UK, Italy and Spain during 2007.

BACKGROUND: Orphan drugs are indicated for the treatment of rare diseases which, in the EU, are defined as those with a prevalence of <5 per 10000 inhabitants. Characteristically, these diseases negatively affect health-related quality of life and may be life threatening. The EU has passed legislation to encourage pharmaceutical companies to invest in research programmes into rare diseases, with the aim of developing new, safe and effective orphan drugs. OBJECTIVES: To describe the status of orphan drugs in five countries in the EU (France, Germany, the UK, Italy and Spain), estimate the mean annual cost per patient and indication of these orphan drugs, and determine the associated cost of these drugs in comparison with overall spending on drugs in each country (year 2007 values). METHODS: The analysis was limited solely to costs of orphan drugs with sales data available for 2007. The mean annual cost per patient was estimated using recommended regimens for maintenance dose and duration from the summary of product characteristics. Likewise, the ratio between annual costs per patient for treatment of each disease and its prevalence was calculated. Sales data were available for at least one of the countries studied for 38 of the 44 orphan drugs authorized by the European Medicines Agency. Only 21 products had data available for all five countries studied. RESULTS: Germany was the country with access to the largest number of orphan drugs (36), followed by the UK (34), Spain (28), France (27) and Italy (25). The mean annual cost per patient and indication of the 38 orphan drugs on the market ranged widely from €331 to €337,501. It appears that orphan drugs indicated to treat diseases with a prevalence of <2 per 10000 inhabitants have higher annual per-patient costs than those indicated to treat diseases with a higher prevalence. The percentage of total drug spending accounted for by orphan drugs in 2007 was 1.7% in France, 2.1% in Germany, 1.0% in the UK, 1.5% in Italy and 2.0% in Spain, with an average overall percentage of 1.7% for these five countries. CONCLUSIONS: In 2007, spending on orphan drugs in five European countries was acceptable in terms of the percentage of these countries' overall drug expenditure. Mean annual costs per patient of orphan drugs varied widely, with costs being related to the prevalence of the disease for which the product is indicated.

Modeling the cost-effectiveness of different oral antiviral therapies in patients with chronic hepatitis B.

BACKGROUND/AIMS: Chronic hepatitis B (CHB) is a common disease associated with high morbidity, mortality and impact on healthcare costs. Several oral antiviral therapies can lead to complete virologic response, which is associated with prevention of disease progression. The aim of this study was to estimate the cost-effectiveness of the oral antiviral treatments lamivudine, adefovir, telbivudine, entecavir and tenofovir, in patients with CHB. METHODS: A Markov model was used to project the lifetime complications and costs in cohorts of both HBeAg-positive and HBeAg-negative CHB patients treated with one of the above drugs or no treatment. Rescue therapy with two different combination therapies (adefovir plus lamivudine or tenofovir plus entecavir) with their corresponding costs and efficacy rates was also considered. The probabilities of disease progression were based on serum HBV DNA levels. Disease and complication costs were assessed using the perspective of the Spanish National Health System. RESULTS: The highest rate of virologic response was obtained with tenofovir, and this translated to its higher life years saved (LYS) and quality adjusted life years (QALY) compared with the rest of the alternatives in HBeAg-positive and HBeAg-negative patients. Tenofovir is associated with lower costs and higher efficacy over entecavir, telbivudine and adefovir in HBeAg-positive patients, and telbivudine and entecavir in HBeAg-negative patients. The incremental cost-effectiveness ratios with respect to the rest of the alternatives are below the common reference efficiency threshold of 30,000 euro per LYS/QALY. CONCLUSION: In chronic HBV infected patients, tenofovir is a cost-effective or even cost-saving strategy compared with other available treatment options for CHB.

Infliximab maintenance therapy is associated with decreases in direct resource use in patients with luminal or fistulizing Crohn's disease.

GOALS: To estimate the impact of infliximab (IFX) maintenance therapy on the use of hospital resources in patients with Crohn's disease (CD). STUDY: Medical records of patients treated with IFX maintenance therapy (5 mg/kg body weight; intravenous infusion) for luminal (L) or fistulizing (F) CD at 13 hospitals were retrospectively reviewed. Patients were assessed as their own controls. Use of CD-related healthcare resources was recorded comparing 1-year periods before and after first IFX infusion (pre-IFX and post-IFX). RESULTS: One hundred fifty-three CD patients (n=84 L; 69 F) fulfilled the inclusion criteria. Mean number of IFX infusions was 7/y with an average of 335 mg/infusion dose/patient. During the pre-IFX period, 55% of patients needed hospitalization versus 31% in the post-IFX period (P<0.001). Mean inpatient stay was 11.3 d/y [11.2 (L), 11.5 (F)] for the pre-IFX period, and 6.3 d/y [6.2 (L), 6.3 (F)] in the post-IFX period (P<0.001). Surgery was required in 24% patients in the pre-IFX period and in 11% post-IFX (P<0.001). There were no significant changes in the incidence of outpatient visits although emergency room visits fell significantly. CONCLUSIONS: Maintenance IFX in CD patients is associated with decreases in the use and length of hospitalizations and the need for surgery in clinical practice.

[Budget impact of a set-dose combination of efavirenz-emtricitabine-tenofovir in the treatment of patients infected with HIV-1]. / Impacto presupuestario de una combinación a dosis fija de efavirenz-emtricitabina-tenofovir para tratamiento de pacientes infectados por el virus de la inmunodeficiencia humana tipo 1.

OBJECTIVE: Estimate the budgetary impact of using a set-dose combination of efavirenz-emtricitabine-tenofovir for the Spanish health care system's treatment of patients infected with HIV-1, while evaluating repercussions for each autonomous community in 2008. METHODS: We developed a budgetary impact model with pharmacological costs for the different currently available treatment options, based on GeSida's recommended guidelines for treating HIV-positive patients. The model defines five possible scenarios in which various possibilities for substituting different drug cocktails with the efavirenz-emtricitabine-enofovir combination are contemplated. RESULTS: The investment per patient on a national level amounts to euro7,989 in the base scenario (without considering the availability of the efavirenz-emtricitabine-tenofovir combination) and to euro7,997, euro8,424, euro7,830, euro8,375 and euro8,527 for scenario 1 (substitution of recommended drugs with efavirenz, emtricitabine and tenofovir or efavirenz, lamivudine and tenofovir); scenario 2 (substitution of recommended drugs with efavirenz); scenario 3 (substitution of recommended drugs with tenofovir); scenario 4 (substitution of recommended drugs with tenoforvir or zidovudine) and scenario 5 (total substitution), respectively. Compared with the base scenario this means increments of 0.11 %, 5.45 %, -1.99 %, 4.83 % and 6.73 % for scenarios 1, 2, 3, 4 and 5. CONCLUSION: Use of a set combination of efavirenz, emtricitabine and tenofovir to treat adult patients with the HIV-1 virus would lead to slight surpluses or even budgetary savings by decreasing the number of daily doses, which could increase patients' quality of life and help them stay on the treatment properly.

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.