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Valentina Orlando,1 Valeria Marina Monetti,1 Aida Moreno Juste,2,3 Veronica Russo,1 Sara Mucherino,1 Ugo Trama,4 Antonella Guida,5 Enrica Menditto1 1CIRFF, Center of Pharmacoeconomics, University of Naples Federico II, Naples, Italy; 2Aragon Health Sciences Institute (IACS), IIS Aragón, REDISSEC ISCIII, Zaragoza, Spain; 3Aragon Health Service (SALUD), Zaragoza, Spain; 4Regional Pharmaceutical Unit, Campania Region, Naples, Italy; 5Directorate-General for Protection of Health, Campania Region, Naples, ItalyCorrespondence: Valentina OrlandoCIRFF, Center of Pharmacoeconomics, University of Naples Federico II, Via Domenico Montesano 49, Naples 80131, ItalyTel +39 081 678657Fax +39 081 678303Email valentina.orlando@unina.itPurpose: The purpose was to analyze drug prescription and antibiotic use by age and sex in Italy’s Campania Region, and to estimate the distribution of prescription rates in children (≤ 14 years old), adults (between 15 and 65 years old), and older adults (≥ 65 years old) at a municipality level.Methods: This was a retrospective analysis of pharmacy records in Campania (Southern Italy), in 2016. Difference in antibiotic prescriptions in different age groups was assessed by prevalence rates. Age-adjusted prevalence rates were categorized into quintiles and mapped by the patient’s municipality of residence. Relationship between prevalence rates for the different age groups was estimated using the non-parametric Spearman rank correlation test.Results: There were 2,738,118 were patients with at least one antibiotic prescription. Antibiotics prescription was higher in children aged < 5 years and in the older adults aged > 70 years. Prevalence rate distribution was different among municipalities in all age groups. A positive correlation between the rank distribution of prevalence rates at municipality level was identified for children and adults (rs=0.56; P< 0.01), adults and the older adults (rs=0.79; P< 0.01), and children and the older adults (rs=0.46; P< 0.01). Among the studied age groups, the most prescribed antibiotic class was penicillin (except the older adults aged ≥ 85 years) ranging from 45% in children to 27.2% in the older adults. Fluoroquinolones were the least prescribed antibiotic class, ranging from 0.2% in children to 30.2% in the older adults.Conclusion: A considerably high use of antibiotic drugs has been detected in Campania Region, with values exceeding the regional and national average. Prescriptions at municipal level differ from one age group to another. Antibiotic use is often unjustified, and to decrease the number of prescriptions and improve their appropriateness, several measures at territorial level are recommended.Keywords: antibiotic use, drug utilization, prescription patterns, real-world data

Daria Putignano,1 Valentina Orlando,1 Valeria Marina Monetti,1 Gaetano Piccinocchi,2 Umberto Maria Musazzi,3 Roberto Piccinocchi,4 Paola Minghetti,3 Enrica Menditto1 1CIRFF, Center of Pharmacoeconomics, University of Naples Federico II, Naples, Italy; 2SIMG, Società Italiana di Medicina Generale, Florence, Italy; 3Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milan, Italy; 4University of Naples Federico II, Naples, ItalyCorrespondence: Valentina OrlandoCIRFF, Center of Pharmacoeconomics, University of Naples Federico II, Via Domenico Montesano 49, Naples 80131, ItalyTel +39 081 678657Fax +39 081 678303Email valentina.orlando@unina.itPurpose: To analyse the pattern of use and cost of antihypertensive drugs in new users in an Italian population, and explore the patient/treatment factors associated with the risk of therapy discontinuation.Patients and methods: In this retrospective study, information was collected from a population-based electronic primary-care database. Persistence with medication use 1 year from therapy initiation was evaluated for each user using the gap method. Each new user was classified according to his/her pattern of use as: “continuer”, “discontinuer” “switching” or “add-on”. A Cox regression model was used to analyse the factors influencing therapy discontinuation. Primary-care costs comprised specialists’ visits, diagnostic procedures and pharmacologic therapies.Results: Among 14,999 subjects included in persistence analyses, 55.1% of cases initially started on monotherapy were classified as discontinuers vs 36.5% of cases taking combination therapy (42.3% vs 32.7%, respectively, for free and fixed combinations, P < 0.01). Old age, high cardiovascular risk and being in receipt of fixed-combination therapy were associated with greater persistence. Overall, the primary-care cost/person/year of hypertension management was ∼€95.3 (IQR, 144.9). The monotherapy cost was €88 per patient (IQR, 132.9), and that for combination therapy was €151±148.3. The median cost/patient with a fixed combination was lower than that for a free combination (€98.4 (IQR, 155.3) and €154.9 (IQR, 182.6), respectively).Conclusion: The initial type of therapy prescribed influences persistence. Prescribing fixed combinations might be a good choice as initial therapy.Keywords: drug-utilization, adherence, fixed combination, hypertension

Francesca Guerriero,1,* Valentina Orlando,1,* Valeria Marina Monetti,1 Francesca Maria Colaccio,2 Maurizio Sessa,3,4 Cristina Scavone,3 Annalisa Capuanom3,* Enrica Menditto1,* 1Center of Pharmacoeconomics (CIRFF), University of Naples Federico II, Naples, Italy; 2Caserta Local Health Unit, Caserta, Italy; 3Department of Experimental Medicine, Section of Pharmacology, Regional Center of Pharmacovigilance, University of Campania “L. Vanvitelli”, Naples, Italy; 4Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, DK, Denmark *These authors contributed equally to this work Aim: The aim of this study was to assess the predictive role of age, gender, and number and type of co-treatments for new oral anticoagulant (NOAC) vs warfarin prescription in elderly patients naïve for the aforementioned drugs. Materials and methods: Data collected in the period from January 1, 2014, to December 31, 2014, in Caserta Local Health Unit administrative databases (Campania Region, Italy) were screened to identify new users of oral anticoagulants (OACs) who were 75 years or older and whose OAC prescriptions amounted to >90 days of treatment. Age, gender, and number and type of concomitant medications at the time of first OAC dispensation were retrieved. Multivariable logistic regression analysis was used to assess the role of the aforementioned predictors for NOAC initiation as opposed to warfarin. Results: Overall, 2,132 incident users of OAC were identified, of whom 967 met all inclusion criteria. In all, 490 subjects (50.7%) received an NOAC and 477 (49.3%) received warfarin. Age >75 years was positively associated with lower odds of NOAC initiation (OR: 0.969, 95% CI: 0.941–0.998, P=0.038). Similarly, multiple concomitant medication was negatively associated with NOAC initiation compared to warfarin (OR [five to nine drugs] group: 0.607, 95% CI: 0.432–0.852, P=0.004; OR [ten+ drugs] group: 0.372, 95% CI: 0.244–0.567, P

Enrica Menditto,1,* Caitriona Cahir,2,* Mercedes Aza-Pascual-Salcedo,3,4 Dario Bruzzese,5 Beatriz Poblador-Plou,3 Sara Malo,6 Elisio Costa,7 Francisca González-Rubio,3,4,6 Antonio Gimeno-Miguel,3 Valentina Orlando,1 Przemyslaw Kardas,8 Alexandra Prados-Torres3 1CIRFF, Center of Pharmacoeconomics, University of Naples Federico II, Naples, Italy; 2Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland; 3Aragon Health Sciences Institute (IACS), IIS Aragón, REDISSEC ISCIII, Madrid, Spain; 4Aragon Health Service (SALUD), Aragon, Spain; 5Department of Public Health, Federico II University, Naples, Italy; 6University of Zaragoza, Zaragoza, Spain; 7UCIBIO, REQUINTE, Faculty of Pharmacy, Porto4ageing Reference Site, University of Porto, Porto, Portugal; 8Department of Family Medicine, Medical University of Lodz, Lodz, Poland *These authors contributed equally to this workPurpose: The purpose of this study was to evaluate and compare medication adherence to chronic therapies in older populations across different regions in Europe.Methods: This explorative study applied a harmonized method of data extraction and analysis from pharmacy claims databases of three European countries to compare medication adherence at a cross-country level. Data were obtained for the period between January 1, 2010, and December 31, 2011. Patients (aged ≥65 years) who newly initiated to oral antidiabetics, antihyperlipidemics, or antiosteoporotics were identified and followed for over a 12-month period. Main outcome measures were medication adherence (medication possession ratio, [MPR]; implementation) and persistence on index treatment. All country-specific data sets were prepared by employing a common data input model. Outcome measures were calculated for each country and pooled using random effect models.Results: In total, 39,186 new users were analyzed. In pooled data from the three countries, suboptimal implementation (MPR 50% of older people non-adherent to antihyperlipidemics and antiosteoporotics in the three European cohorts. However, the degree of variability in adherence rates among the three countries was high. A harmonized method of data extraction and analysis across health-related database in Europe is useful to compare medication-taking behavior at a cross-country level. Keywords: drug utilization, medication adherence, medication persistence, prescribing

Veronica Russo,1,* Valeria Marina Monetti,1,* Francesca Guerriero,1 Ugo Trama,2 Antonella Guida,3 Enrica Menditto,1 Valentina Orlando1 1CIRFF, Center of Pharmacoeconomics, University of Naples Federico II, 2Regional Pharmaceutical Unit, 3Directorate-General for Protection of Health, Campania Region, Naples, Italy *These authors contributed equally to this work Purpose: The aim of this study was to analyze the geographic variation in systemic antibiotic prescription at a regional level and to explore the influence of socioeconomic and sociodemographic variables.Methods: This study was a retrospective analysis of reimbursement pharmacy records in the outpatient settings of Italy’s Campania Region in 2016. Standardized antibiotic prescription rates were calculated at municipality and Local Health Unit (LHU) level. Antibiotic consumption was analyzed as defined daily doses (DDD)/1000 inhabitants per day (DID). Logistic regression was performed to evaluate the association between antibiotic prescription and sociodemographic and socioeconomic determinants at a municipality level.Results: The average antibiotic prevalence rate was 46.8%. At LHU level, the age-adjusted prevalence rates ranged from 41.1% in Benevento to 51.0% in Naples2. Significant differences were found among municipalities, from 15.2% in Omignano (Salerno LHU [Sa-LHU]) to 61.9% in Moschiano (Avellino [Av-LHU]). The geographic distribution also showed significant differences in terms of antibiotic consumption, from 6.7 DID in Omignano to 41.6 in San Marcelino (Caserta [Ce-LHU]). Logistic regression showed that both municipality type and average annual income level were the main determinants of antibiotic prescription. Urban municipalities were more than eight times as likely to have antibiotic high prevalence rates compared to rural municipalities (adjusted odds ratio [OR]: 8.62; 95% confidence interval [CI]: 4.06–18.30, P

Francesca Guerriero, Valentina Orlando, Valeria Marina Monetti, Veronica Russo, Enrica Menditto Center of Pharmacoeconomics (CIRFF), University of Naples Federico II, Naples, Italy Purpose: The aim was to describe the current use of biological therapies among patients affected by psoriasis and to analyze a drug utilization profile in naïve patients in terms of switching and treatment costs in a Local Health Unit (LHU) of Southern Italy. Methods: We conducted an observational retrospective cohort analysis using the health-related administrative databases of a LHU in Southern Italy covering a population of about one million inhabitants. All subjects with a main or secondary diagnosis of psoriasis who received at least one prescription of biological therapies between January 1, 2010 and December 31, 2014 were analyzed. Switching rate was evaluated in naïve patients within the first year of treatment. Drug cost was calculated for all drugs prescribed and comprised both costs for psoriasis drugs and costs for other treatments. Results: About 20% of patients identified with a diagnosis of psoriasis were under treatment with biological drugs. Among 385 subjects treated with biological therapy, 51.2% were in treatment with etanercept and 33% with adalimumab. Among naïve patients, switching rate to a different biological drug, within the first year of treatment, was 7.3%. The per patient yearly drug cost was €10,536: 96.8% for psoriasis-related drugs and 3.2% for other pharmaceutical treatments. The annual average cost per patient switching from the initial treatment was €13,021, while for those who did not switch from the initial treatment, the annual average cost was €10,342, with a significant difference of about €2,680 per patient per year (p=0.002). Conclusion: Our data may be useful in exploring the dynamics that characterize the use of biological therapy within a specific context and to optimize the use of resources for a better management of the disease. Keywords: drug utilization, biological drugs, psoriasis, administrative databases, treatment cost, switch therapies

Enrica Menditto,1 Valentina Orlando,1 Silvia Coretti,2 Daria Putignano,1 Denise Fiorentino,1 Matteo Ruggeri2 1CIRFF, Center of Pharmacoeconomics, Federico II University of Naples, Naples, 2Postgraduate School of Health Economics and Management (ALTEMS), Università Cattolica del Sacro Cuore, School of Economics, Rome, Italy Background: Agency is a pervasive feature of the health care market, with doctors acting as agents for both patients and the health care system. In a context of scarce resources, doctors are required to take opportunity cost into account when prescribing treatments, while cost containment policies cannot overlook their active role in determining health care resource allocation. This paper addresses this issue, investigating the effects of cost containment measures in the market of biosimilar drugs that represent a viable and cost-saving strategy for the reduction of health care expenditure. The analysis focuses on a particular region in Italy, where several timely policies to incentivize biosimilar prescribing were launched. Methods: Drugs were identified by the anatomical therapeutic chemical classification system. Information about biosimilar drugs and their originator biological products was extracted from the IMS Health regional database. Drug consumption was expressed in terms of counting units, while expenditure was evaluated in Euro (€).The market penetration of biosimilars was analyzed by year and quarterly. Results: In the Campania region of Italy, the effects of cost containment policies, launched between 2009 and 2013, showed the prescription of biosimilars strongly increasing in 2010 until prescribing levels reached and exceeded the market share of the reference biological products in 2012. After a slight reduction, a plateau was observed at the beginning of 2013. At the same time, the use of the originator products had been decreasing until the first quarter of 2011. However, after a 1-year plateau, this trend was reversed, with a new increase in the consumption of the originators observed. Conclusion: Results show that the cost containment policies, applied to cut health expenditure "to cure and not to care", did not produce the cultural change necessary to make these policies effective in the long run. Therefore, top-down policies for cost containment are not successful; rather, a bottom-up approach based on consensus among professionals should become the preferred option. Keywords: cost containment policy, biosimilar drugs, health care expenditure, policy making

Silvia Coretti,1 Federica Romano,1 Valentina Orlando,2 Paola Codella,1 Sabrina Prete,1 Eugenio Di Brino,1 Matteo Ruggeri1 1Post-Graduate School of Economics and Management (ALTEMS), Università Cattolica del Sacro Cuore, Rome, Italy; 2Center of Pharmacoeconomics (CIRFF), Department of Pharmacy, Federico II University, Naples, Italy Background: Hepatitis C is a liver infection caused by hepatitis C virus. Its main complications are cirrhosis and liver cancer. According to the World Health Organization (WHO), more than 185 million people worldwide are infected with hepatitis C virus and, of these, 350,000 die every year. Due to the high disease prevalence and the existence of effective (and expensive) medical treatments able to dramatically change the prognosis, early detection programs can potentially prevent the development of serious chronic conditions, improve health, and save resources. Objective: To summarize the available evidence on the cost-effectiveness of screening programs for hepatitis C. Methods: A literature search was performed on PubMed and Scopus search engines. Trip database was queried to identify reports produced by the major Health Technology Assessment (HTA) agencies. Three reviewers dealt with study selection and data extraction blindly. Results: Ten papers eventually met the inclusion criteria. In studies focusing on asymptomatic cohorts of individuals at general risk the cost/quality adjusted life year of screening programs ranged between US $4,200 and $50,000/quality adjusted life year gained, while in those focusing on specific risk factors the incremental cost-effectiveness ratio ranged between $848 and $128,424/quality adjusted life year gained. Age of the target population and disease prevalence were the main cost-effectiveness drivers. Conclusion: Our results suggest that, especially in the long run, screening programs represent a cost-effective strategy for the management of hepatitis C. Keywords: hepatitis C, screening, early detection, cost-effectiveness

In this work we investigated the in vivo protective effects of Baccharis dracunculifolia leaves extract (BdE) against carbon tetrachloride (CCl4)- and acetaminophen (APAP)-induced hepatotoxicity. Total phenolic content, total flavonoid content, antioxidant DPPH radical scavenging activity, and HPLC analysis were performed. Our results showed that pretreatment with BdE significantly reduced the damage caused by CCl4 and APAP on the serum markers of hepatic injury, AST, ALT, and ALP. Results were confirmed by histopathological analysis. Phytochemical analysis, performed by HPLC, showed that BdE was rich in p-coumaric acid derivatives, caffeoylquinic acids and flavonoids. BdE also showed DPPH antioxidant activity (EC50 of 15.75 ± 0.43 μg/mL), and high total phenolic (142.90 ± 0.77 mg GAE/g) and flavonoid (51.47 ± 0.60 mg RE/g) contents. This study indicated that B. dracunculifolia leaves extract has relevant in vivo hepatoprotective properties.

The chemical composition of the essential oils obtained by hydrodistillation of different parts of Eremanthus erythropappus, including leaves, branches and inflorescences, was investigated by Gas Chromatography and Gas Chromatography/Mass Spectrometry. The antimicrobial activity of the oils was assessed by the disc diffusion and microdilution methods, while the antioxidant activity was evaluated by DPPH and reducing power tests. The main compounds found in the essential oils derived from the inflorescences and leaves were β-caryophyllene, germacrene-D, α-copaene and β-pinene. α-Bisabolol was the major component in the branches. The oils were active against Staphylococcus aureus, Streptococcus pyogenes and fungi, but not Escherichia coli and Pseudomonas aeruginosa. The MIC values ranged from 0.01 to 0.50 mg/mL. Using the DPPH test, the IC50 values ranged from 38.77 ± 0.76 to 102.24 ± 1.96 μg/mL, while the reducing power test produced IC50 values between 109.85 ± 1.68 and 169.53 ± 0.64 μg/mL. The results revealed that the E. erythropappus oils are new promising potential sources of antimicrobial and antioxidant compounds with good future practical applications for human health.

A series of recent works studying a database of chronologically sorted chess games-containing 1.4 million games played by humans between 1998 and 2007- have shown that the popularity distribution of chess game-lines follows a Zipf's law, and that time series inferred from the sequences of those game-lines exhibit long-range memory effects. The presence of Zipf's law together with long-range memory effects was observed in several systems, however, the simultaneous emergence of these two phenomena were always studied separately up to now. In this work, by making use of a variant of the Yule-Simon preferential growth model, introduced by Cattuto et al., we provide an explanation for the simultaneous emergence of Zipf's law and long-range correlations memory effects in a chess database. We find that Cattuto's Model (CM) is able to reproduce both, Zipf's law and the long-range correlations, including size-dependent scaling of the Hurst exponent for the corresponding time series. CM allows an explanation for the simultaneous emergence of these two phenomena via a preferential growth dynamics, including a memory kernel, in the popularity distribution of chess game-lines. This mechanism results in an aging process in the chess game-line choice as the database grows. Moreover, we find burstiness in the activity of subsets of the most active players, although the aggregated activity of the pool of players displays inter-event times without burstiness. We show that CM is not able to produce time series with bursty behavior providing evidence that burstiness is not required for the explanation of the long-range correlation effects in the chess database. Our results provide further evidence favoring the hypothesis that long-range correlations effects are a consequence of the aging of game-lines and not burstiness, and shed light on the mechanism that operates in the simultaneous emergence of Zipf's law and long-range correlations in a community of chess players.

ABSTRACT The present study was designed to investigate the antioxidant, antinociceptive and anti-inflammatory activities of the ethanol extract from Ageratum fastigiatum branches. Phytochemical screening and total phenol and flavonoid contents were determined. The antioxidant activity was assessed by 2,2-diphenyl-1-pycrilhydrazin (DPPH) and iron reducing power methods. The antinociceptive effect was evaluated using the acetic acid-induced writhing, formalin, hot plate and tail immersion assays; while the carrageenan-induced paw edema and pleurisy tests were performed to examine the anti-inflammatory activity against acute inflammation. The extract revealed the presence of flavonoids, tannins, coumarins, terpenes, sterols and saponins. Expressive levels of total phenols and flavonoids and a promising antioxidant effect were quantified. At the doses of 50, 100 and 200 mg/kg, the extract inhibited the writhing, reduced both phases of paw licking time and increased the reaction time on the hot plate. In the tail immersion test, the extract (50, 100 and 200 mg/kg) caused a significant inhibition of pain. In these doses, the paw edema, exudate volume and leucocyte mobilization were significantly reduced. These results suggest that A. fastigiatum can be an active source of substances with antioxidant, antinociceptive and anti-inflammatory activities, adding scientific support to the appropriate use in the Brazilian folk medicine.

Vernonia polyanthes Less. (Asteraceae), popularly known as “assa-peixe”, is a plant species used in Brazilian traditional medicine for the treatment of cutaneous damage, cicatrization, inflammation, and rheumatism. Based on these ethnopharmacological findings, the current study evaluated the topical anti-inflammatory effects of the hexane (HEVP) and ethyl acetate (EAEVP) extracts from V. polyanthes leaves in experimental models of skin inflammation. Chemical characterization was carried out by HPLC–UV/DAD analysis. Anti-inflammatory activity was evaluated using Croton oil-, arachidonic acid (AA)-, phenol-, ethyl phenylpropiolate (EPP)-, and capsaicin-induced ear edema models in mice. Histopathological evaluation and measurements of myeloperoxidase (MPO) and N-acetyl-β-d-glucosaminidase (NAG) enzymes were also performed. Rutin, luteolin, and apigenin were identified in EAEVP. Topically applied HEVP and EAEVP significantly (p < 0.05, p < 0.01 or p < 0.001) reduced edema induced by five different irritants at the doses tested (0.1, 0.5 and 1.0 mg/ear). Histopathological analysis revealed a reduction of edema, inflammatory cell infiltration, and vasodilation. In addition, the enzymes activity (MPO and NAG) in the ear tissues was reduced by the topical treatment of HEVP and EAEVP (p < 0.05, p < 0.01 or p < 0.001). The results suggest that V. polyanthes leaves are effective against cutaneous damage, which support its traditional use and open up new possibilities for the treatment of skin disorders.

Biological networks of interacting agents exhibit similar topological properties for a wide range of scales, from cellular to ecological levels, suggesting the existence of a common evolutionary origin. A general evolutionary mechanism based on global stability has been proposed recently [J I Perotti, et al., Phys. Rev. Lett. 103, 108701 (2009)]. This mechanism was incorporated into a model of a growing network of interacting agents in which each new agent's membership in the network is determined by the agent's effect on the network's global stability. In this work, we analyze different quantities that characterize the topology of the emerging networks, such as global connectivity, clustering and average nearest neighbors degree, showing that they reproduce scaling behaviors frequently observed in several biological systems. The influence of the stability selection mechanism on the dynamics associated to the resulting network, as well as the interplay between some topological and functional features are also analyzed.Received: 17 July 2010; Accepted: 27 September 2010; Edited by: D. H. Zanette; Reviewed by: V. M. Eguiluz, Inst. Fisica Interdisciplinar y Sist. Complejos, Palma de Mallorca, Spain; DOI: 10.4279/PIP.020005

O objetivo deste trabalho é estabelecer uma rotina para exame clínico e radiográfico de dentes inclusos a fim de facilitar o diagnóstico e a escolha da técnica cirúrgica indicada.

Students at a private university in southern California took part in a study focusing on high level motivation and goal commitment. Using path analysis, this study mapped out two-paths. The first path to motivation and, therefore, goal commitment was through self-efficacy. The second path to goal commitment required a more supportive course. Spiritual, peer, family and leadership support combined to create a more encouraging sequence of action toward motivation and goal dedication. There are many motivators that lead to goal completion. These motivators are generated from various influences--from peers, from family, from leaders, from faith, and from oneself. The purpose of this research is to look at motivation and goal achievement through the lens of personal motivators. The objective is to take a primarily business theory and apply it to college student marathon training.