Infrared Spectroscopy of Gas-Phase MnxOy(CO2)z+ Complexes.

The interaction of manganese oxide clusters MnxOy+ (x = 2-5, y ≥ x) with CO2 is studied via infrared multiple-photon dissociation spectroscopy (IR-MPD) in the spectral region of 630-1860 cm-1. Along with vibrational modes of the manganese oxide cluster core, two bands are observed around 1200-1450 cm-1 and they are assigned to the characteristic Fermi resonance of CO2 arising from anharmonic coupling between the symmetric stretch vibration and the overtone of the bending mode. The spectral position of the lower frequency band depends on the cluster size and the number of adsorbed CO2 molecules, whereas the higher frequency band is largely unaffected. Despite these effects, the observation of the Fermi dyad indicates only a small perturbation of the CO2 molecule. This finding is confirmed by the theoretical investigation of Mn2O2(CO2)+ revealing only small orbital mixing between the dimanganese oxide cluster and CO2, indicative of mainly electrostatic interaction.

Infrared photodissociation spectroscopy of di-manganese oxide cluster cations.

Infrared multiple-photon dissociation (IR-MPD) spectroscopy and density functional theory (DFT) calculations have been employed to elucidate the geometric structure of a series of di-manganese oxide clusters Mn2Ox+ (x = 4-7). The theoretical exploration predicts that all investigated clusters contain a rhombus-like Mn2O2 core with up to four, terminally bound, oxygen atoms. The short Mn-O bond length of the terminal oxygen atoms of ≤1.58 Å indicates triple bond character instead of oxyl radical formation. However, the IR-MPD spectra reveal that higher energy isomers with up to two O2 molecules η2-coordinated to the cluster core can be kinetically trapped under the given experimental conditions. In these complexes, all O2 units are activated to superoxide species. In addition, the sequential increase of the oxygen content in the cluster allows for a controlled increase of the positive charge localized on the Mn atoms reaching a maximum for Mn2O7+.

Innovations in pharmaceutical policies and learnings for sustainable access to affordable medicines.

Sustainable access to affordable medicines remains a public health issue globally, including for high-income countries. To foster the debate on avenues for the future, the fifth PPRI Conference held in Vienna on 25 and 26 April 2024 will offer a forum for the debate on innovating pharmaceutical policymaking to develop and implement futureproof policy options, which are able to address current and future challenges. The Conference invites a broad audience of stakeholders, including researchers, policymakers, payers, patients, industry and health professionals. The conference topics are organised in three strands: Strand 1 on 'Local challenges, global learnings' aims to contribute to lively discussions on the implementation of pharmaceutical policies across the globe. Best-practice examples will be presented, supplemented by case studies of less effective policies which can offer rich learnings. Strand 2 on 'Strengthening the evidence base' is the place for presentations and discussions on topics such as health technology assessments, managed entry agreements and real-world data. Strand 3 'Futureproofing pharmaceutical policies' is particularly dedicated to explore innovation in policymaking to achieve sustainable access to affordable medicines.

The role of discounts and loss leaders in medicine procurement in Austrian hospitals - a primary survey of official and actual medicine prices.

BACKGROUND: Knowledge about the prices of medicines used in hospitals, particularly the actually achieved ones, is scant. There are indications of large discounts and the provision of medicines cost-free to Austrian hospitals. The study aims to survey the official and actual prices of medicines procured by Austrian hospitals and to compare them to the out-patient prices. METHODS: Primary price collection of the official hospital list prices and the actually achieved prices for 12 active ingredients as of the end of September 2009 in five general hospitals in Austria and analysis of the 15 most commonly used presentations. RESULTS: The official hospital list prices per unit differed considerably (from 1,500 Euro for an oncology medicine to 0.20 Euro for a generic cardiovascular medicine). For eight on-patent medicines (indications: oncology, anti-inflammatory, neurology-multiple sclerosis and blood) actual hospital medicine prices equaled the list prices (seven medicines) or were lower (one medicine) in four hospitals, whereas one hospital always reported higher actual prices due to the application of a wholesale mark-up. The actual hospital prices of seven medicines (cardiology and immunomodulation) were below the official hospital prices in all hospitals; of these all cardiovascular medicines were provided free-of-charge. Hospital prices were always lower than out-patient prices (pharmacy retail price net and reimbursement price). CONCLUSION: The results suggest little headroom for hospitals to negotiate price reductions for "monopoly products", i.e. medicines with no therapeutic alternative. Discounts and cost-free provision (loss leaders) appear to be granted for products of strategic importance for suppliers, e.g. cardiovascular medicines, whose treatment tends to be continued in primary care after discharge of the patient.

Species-specific patterns in fecal glucocorticoid and androgen levels in zoo-living orangutans (Pongo spp.).

In contrast to most primate species, including the other great apes, orangutans maintain a fission-fusion social system in the wild without being part of a stable community. In zoos, however, they are kept in permanent groups, usually consisting of one adult male and several females. In zoo orangutans, we predict higher levels of glucocorticoids and androgens in the Bornean species compared to its congener from Sumatra, due to the much more solitary lifestyle of Bornean orangutans and the apparent higher frequency of male aggression directed towards females in this species in the wild. To compare hormone levels of the two orangutan species, we validated a fecal glucocorticoid and a fecal androgen assay. Subsequently, fecal samples from a total of 73 female and 38 male orangutans housed in 29 European zoos were analyzed to investigate the effect of species, social group size, age and (for female glucocorticoid levels) reproductive state and the presence of adult males on fecal hormone metabolite concentrations. The results of linear mixed effect models indicate that both male and female Bornean orangutans show a steeper increase in glucocorticoid levels with increasing group size than Sumatran orangutans. We therefore conclude that Sumatran zoo orangutans are better able to adjust to social housing conditions than their Bornean congeners. In addition, our analyses reveal higher glucocorticoid levels in lactating females of both species compared to non-lactating and juvenile females. Concerning androgen levels in males, our analyses revealed significantly higher concentrations in Bornean than Sumatran orangutans. These differences in both glucocorticoid and androgen output between the two species of orangutan are presumably linked to ecological and behavioral differences and could possibly be attributed to phenotypic plasticity. However, given that we found interspecific differences in hormone excretion in captivity, where both species live under very similar conditions, we conclude that this variation has a genetic basis.

Size, Stoichiometry, Dimensionality, and Ca Doping of Manganese Oxide-Based Water Oxidation Clusters: An Oxyl/Hydroxy Mechanism for Oxygen-Oxygen Coupling.

Gas-phase ion-trap reactivity experiments and density functional simulations reveal that water oxidation to H2O2 mediated by (calcium) manganese oxide clusters proceeds via formation of a terminal oxyl radical followed by oxyl/hydroxy O-O coupling. This mechanism is predicted to be energetically feasible for Mn2Oy+ (y = 2-4) and the binary CaMn3O4+, in agreement with the experimental observations. In contrast, the reaction does not proceed for the tetramanganese oxides Mn4Oy+ (y = 4-6) under these experimental conditions. This is attributed to the high fluxionality of the tetramanganese clusters, resulting in the instability of the terminal oxyl radical as well as an energetically unfavorable change of the spin state required for H2O2 formation. Ca doping, yielding a symmetry-broken lower-symmetry three-dimensional (3D) CaMn3O4+ cluster, results in structural stabilization of the oxyl radical configuration, accompanied by a favorable coupling between potential energy surfaces with different spin states, thus enabling the cluster-mediated water oxidation reaction and H2O2 formation.

Addressing the medicines access challenge through balance, evidence, collaboration and transparency: key take-away lessons of the 4th PPRI Conference.

The 4th PPRI Conference, held in Vienna in October 2019, addressed issues related to equitable and affordable access to medicines. A multi-stakeholder audience from around the globe discussed solutions and best practice models for current challenges such as high-priced medicines, limitations of current pricing and reimbursement policies and tight budgets for health technologies. A multi-faceted approach (so-called balance, evidence, collaboration and transparency/BECT strategy) was also discussed. This includes an improved balance of different interests and policy areas, generation of relevant evidence, collaboration between countries and stakeholders, and transparency, and was considered as the most promising pathway for the future.

Evolution of Average European Medicine Prices: Implications for the Methodology of External Price Referencing.

BACKGROUND: There are indications of staggered market entry of medicines in the national markets, with medicines being marketed first in countries with high prices. This study aimed to analyse the availability and evolution of medicine prices in the European Union (EU). METHODS: This research was performed for an illustrative sample of five medicines (abiraterone, emtricitabine/rilpivirine/tenofovir disoproxil, fingolimod, linagliptin and sofosbuvir) in 27 EU Member States. Price data at 6, 12, 18, 36 and 60 months after marketing authorisation were retrieved from national administrative price databases and registers accessible through the Pharma Price Information service. RESULTS: In the first year after marketing authorisation, price data for the selected medicines were only available in a small number of EU Member States-usually high-income countries. Availability increased over time. However, some countries, for instance Central and Eastern Europe, had price data available only several years after marketing authorisation. The average European price of the surveyed medicines decreased by at least 7.1% between 6 months and 3 years and at least 9.5% between 6 months and 5 years after marketing authorisation. Price data availability in lower-income countries at later stages, and price decreases in some countries, appear to be major reasons for the reductions in average prices. CONCLUSIONS: If policymakers aim to apply the pricing policy of external price referencing (i.e. price setting based on prices in other countries) for cost-containment purposes, they are recommended to undertake continuous price revisions over the years.

Price comparison of high-cost originator medicines in European countries.

BACKGROUND: In recent years, high-cost medicines have increasingly been challenging the public health budget in all countries including high-income economies. In this context, this study aims to survey, analyze and compare prices of medicines that likely contribute to high expenditure for the public payers in high-income countries. METHODS: We chose the following 16 European countries: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, the Netherlands, Portugal, Sweden, Slovakia, Spain and United Kingdom. The ex-factory price data of 30 medicines in these countries were collected in national databases accessible through the Pharmaceutical Price Information (PPI) service of Gesundheit Österreich GmbH (Austrian Public Health Institute). RESULTS: The ex-factory prices (median) per unit (e.g. per tablet, vial) ranged from 10.67 cent (levodopa + decarboxylase inhibitor) to 17,000 euro (ipilimumab). A total of 53% of the medicines surveyed had a unit ex-factory price (median) above 200 Euro. For two thirds of the medicines, price differences between the highest-priced country and lowest-priced country ranged between 25 and 100%; the remaining medicines, mainly low-priced medicines, had higher price differential, up to 251%. Medicines with unit prices of a few euros or less were medicines for the treatment of diseases in the nervous system (anti-depressants, medicines to treat Parkinson and for the management of neuropathic pain), of obstructive airway diseases and cardio-vascular medicines (lipid modifying agents). High-priced medicines were particularly cancer medicines. CONCLUSION: Medicine prices of Greece, Hungary, Slovakia and UK were frequently at the lower end, German and Swedish, as well as Danish and Irish prices at the upper end. For high-priced medicines, actual paid prices are likely to be lower due to confidential discounts and similar funding arrangements between industry and public payers. Pricing authorities refer to the higher undiscounted prices when they use price data from other countries for their pricing decisions.

Policy interventions related to medicines: Survey of measures taken in European countries during 2010-2015.

BACKGROUND: Policy-makers can use a menu of pharmaceutical policy options. This study aimed to survey these measures that were implemented in European countries between 2010 and 2015. METHODS: We did bi-annual surveys with competent authorities of the Pharmaceutical Pricing and Reimbursement Information network. Additionally, we consulted posters produced by members of this network as well as further published literature. Information on 32 European countries (all European Union Member States excluding Luxembourg; Iceland, Norway, Serbia, Switzerland, Turkey) was included. RESULTS: 557 measures were reported between January 2010 and December 2015. The most frequently mentioned measure was price reductions and price freezes, followed by changes in patient co-payments, modifications related to the reimbursement lists and changes in distribution remuneration. Most policy measures were identified in Portugal, Greece, Belgium, France, the Czech Republic, Iceland, Spain and Germany. 22% of the measures surveyed could be classified as austerity. CONCLUSIONS: Countries that were strongly hit by the financial crisis implemented most policy changes, usually aiming to generate savings and briefly after the emergence of the crisis. Improvements in the economic situation tended to lead to an easing of austerity measures. Countries also implemented policies that aimed to enhance enforcement of existing measures and increase efficiency.

Pharmaceutical policies in a crisis? Challenges and solutions identified at the PPRI Conference.

In October 2015, the third international Pharmaceutical Pricing and Reimbursement Information (PPRI) Conference was held in Vienna to foster discussion on challenges in pricing and reimbursement policies for medicines. The research presented highlighted that commonly used pharmaceutical pricing and reimbursement policies are not sufficiently effective to address current challenges. Conference participants called for fundamental reforms to ensure access to medicines, particularly to new and potentially more effective and/or safe medicines, while safeguarding the financial sustainability of health systems and working towards universal health coverage.

Discounts and rebates granted to public payers for medicines in European countries.

OBJECTIVE: The objective of this study was to provide an overview about the existence and types of discounts and rebates granted to public payers by the pharmaceutical industry in European countries. METHODS: Data were collected via a questionnaire in spring 2011. Officials from public authorities for pharmaceutical pricing and reimbursement represented in the PPRI (Pharmaceutical Pricing and Reimbursement Information) network provided the information and reviewed the compilation. RESULTS: Information is available from 31 European countries. Discounts and rebates granted to public payers by pharmaceutical industry were reported for 25 European countries. Such discounts exist both in the in- and out-patient sectors in 21 countries and in the in-patient sector only in four countries. Six countries reported not having any regulations or agreements regarding the discounts and rebates granted by industry. The most common discounts and rebates are price reductions and refunds linked to sales volume but types such as in-kind support, price-volume and risk-sharing agreements are also in place. A mix of various types of discounts and rebates is common. Many of these arrangements are confidential. Differences regarding types, the organizational and legal framework, validity and frequency of updates and the amount of the discounts and rebates granted exist among the surveyed countries. CONCLUSIONS: In Europe, discounts and rebates on medicines granted by pharmaceutical industry to public payers are common tools to contain public pharmaceutical expenditure. They appear to be used as a complimentary measure when price regulation does not achieve the desired results and in the few European countries with no or limited price regulation. The confidential character of many of these arrangements impedes transparency and may lead to a distortion of medicines prices. An analysis of the impact on these measures is recommended.

Pharmaceutical policies in European countries in response to the global financial crisis.

OBJECTIVE: The objective of this paper is to analyze which pharmaceutical policies European countries applied during the global financial crisis. METHODS: We undertook a survey with officials from public authorities for pharmaceutical pricing and reimbursement of 33 European countries represented in the PPRI (Pharmaceutical Pricing and Reimbursement Information) network based on a questionnaire. The survey was launched in September 2010 and repeated in February 2011 to obtain updated information. RESULTS: During the survey period from January 2010 to February 2011, 89 measures were identified in 23 of the 33 countries surveyed which were implemented to contain public medicines expenditure. Price reductions, changes in the co-payments, in the VAT rates on medicines and in the distribution margins were among the most common measures. More than a dozen countries reported measures under discussion or planned, for the remaining year 2011 and beyond. The largest number of measures were implemented in Iceland, the Baltic states (Estonia, Latvia, Lithuania), Greece, Spain and Portugal, which were hit by the crisis at different times. CONCLUSIONS: Cost-containment has been an issue for high-income countries in Europe - no matter if hit by the crisis or not. In recent months, changes in pharmaceutical policies were reported from 23 European countries. Measures which can be implemented rather swiftly (e.g. price cuts, changes in co-payments and VAT rates on medicines) were among the most frequent measures. While the "crisis countries" (e.g. Baltic states, Greece, Spain) reacted with a bundle of measures, reforms in other countries (e.g. Poland, Germany) were not directly linked to the crisis, but also aimed at containing public spending. Since further reforms are under way, we recommend that the monitoring exercise is continued.

Asthma intervention program prevents readmissions in high healthcare users.

The largest portion of the cost for asthma healthcare is due to hospitalizations. Improved methods of healthcare delivery for patients with asthma are needed to prevent readmissions. From 1996 to 1999, 96 adult subjects (predominantly young African American women) hospitalized with an asthma exacerbation, who had a history of frequent healthcare use, were randomized to an asthma nurse specialist intervention (n = 50) or a usual care group (n = 46) for 6 months. Our aim was to decrease rates of readmissions within 6 months of hospital discharge, to reduce cost, and to improve health-related quality of life. Our results demonstrate a 60% reduction in total hospitalizations (31 readmissions in the intervention group and 71 in the control group, p = 0.04), with no significant change in emergency department visits. Readmissions for asthma were reduced by 54% (21 vs. 42 in the control group; p = 0.04). We found a marked reduction in lost work or school days: 246 versus 1040 days in the control group (p = 0.02). The intervention resulted in a substantial reduction in direct and indirect healthcare costs, saving US dollars 6462 per patient (p = 0.03). A brief intervention program focusing on high healthcare users with asthma can result in improved asthma control and reduced hospital use with substantial cost savings.