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Background: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. Methods: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term "Disseminated intravascular coagulation". A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. Results: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08–1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38–2.27) and 2.02 (1.57–2.61), respectively. Conclusion: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy. [ABSTRACT FROM AUTHOR]

Rotaviruses (RVs) are the most common cause of severe diarrheal disease. To date two rotavirus oral vaccines are licensed: Rotarix and Rotateq. Our aim was to contribute to the post-marketing evaluation of these vaccines safety profile. We collected all RV vaccines-related reports of Adverse Events Following Immunization (AEFI) in US Vaccine Adverse Events Reporting System (VAERS) and VigiBase between January 2007 and December 2017. A disproportionality analysis using Reporting Odds Ratio (ROR) was performed. A total of 17,750 reports in VAERS and 6,358 in VigiBase were retrieved. In VAERS, 86.2% of the reports concerned RotaTeq, whereas in VigiBase 67.7% of them involved Rotarix. Across the databases, diarrhea (1,672 events in VAERS, 1,961 in VigiBase) and vomiting (1,746 in VAERS, 1,508 in VigiBase) were the most reported AEFIs. Noteworthy, the RV vaccines-intussusception pair showed a ROR greater than 20 in both databases. Some new potential safety signals emerged such as fontanelle bulging, hypotonic-hyporesponsive episode, livedo reticularis, and opisthotonus. Overall, our data show that most of the reported AEFIs are listed in the Summary of Product Characteristics (SPCs). However, there remains the need to investigate the potential safety signals arose from this analysis, in order to complete the description of the AEFIs. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this multicenter prospective study was to evaluate efficacy and safety of biosimilar erythropoiesis-stimulating agents (ESAs) vs originator, based on data from clinical practice in patients with chronic kidney disease (CKD).Methods: We collected data of the patients with diagnosis of CKD on conservative treatment from nine Italian structures. Patients were enrolled applying different exclusion criteria, and various individual parameters were registered at the beginning for descriptive analysis. Patients were treated with epoetin alfa, beta, and darbepoetin as originator and epoetin zeta as biosimilar. Hemoglobin levels have been analyzed at baseline and after 3, 6, and 12 months. Descriptive statistics were used to analyze the results.Results: At baseline, 47 patients were in the biosimilar group and 57 in the originator; the basal level of hemoglobin was similar between the groups (mean Hb 9.4 and 9.3 g/dL, respectively). Median age, weight, and comorbidities were almost comparable. After 3 months, 44 patients remained in the biosimilar group and 48 in the originator; hemoglobin increase was significantly greater in patients treated with biosimilar [absolute increase 1.6 vs 1.0 g/dL, p < 0.001]. After 6 and 12 months, number of patients fall furthermore. Hemoglobin levels increased more in the biosimilar group after 6 months (2.1 vs 1.1 g/dL, p < 0.001) and 12 months (2.0 vs 1.0 g/dL, p < 0.001).Conclusions: Biosimilar ESAs have similar risk/benefit profile compared to originators. Our data are in agreement with relevant scientific literature and, on the other hand, they are in contrast with common thought that considers biosimilar less efficacious and less safe than originators. [ABSTRACT FROM AUTHOR]

Purpose: An analysis of Italian spontaneous adverse drug reactions (ADR) reporting database highlighted a potential association between hypothermia and ibuprofen in children. Hypothermia is defined as a core body temperature of 35 °C (95 °F). Ibuprofen is the most prescribed NSAID for the treatment of fever and moderate pain in children. We aimed to analyze the cases of ibuprofen-associated hypothermia retrieved in the Italian database in order to contribute to the discussion on this potential association. Methods: We extracted all suspected cases of ibuprofen-associated hypothermia from the Italian spontaneous reporting database and from VigiBase up to December 2015. We considered the proportional reporting ratio (PRR) as a measure of disproportionality for the Italian cases and the information component (IC) for the reports from VigiBase. We performed a case-by-case analysis to exclude duplicates. Results: Nineteen cases of hypothermia associated with ibuprofen use were retrieved from the Italian spontaneous reporting database (PRR 19.8, CI 95 %, 12.0-32.9). The reports concerned ten females and nine males with an average age of 2.5 years. Up to 31 December 2015, 168 cases of hypothermia associated with ibuprofen were reported to VigiBase, with an IC of 2.05 (IC, 1.82). Among these, 126 cases involved children (49 % males) with an average age of 4.4 years. Conclusions: Although the risk of this ADR is unknown so far, the widespread use of this drug recommends the need for further studies to better characterize this possible association. Clinicians and pharmacists but also parents should be aware that this risk is theoretical as not yet been confirmed. [ABSTRACT FROM AUTHOR]

Objective: To identify safety signals concerning the association between the use of various drug classes and the onset of progressive multifocal leukoencephalopathy (PML).Methods: All reports containing suspected or interacting PML-related or leukoencephalopathy-related drugs, held in the World Health Organization spontaneous individual case safety reports database as at 1 September 2014, were retrieved. We identified safety signals by analysing the drug-reaction pairs, using the reporting odds ratio as a measure of disproportionality. A safety signal was defined if a drug was reported more than twice in PML cases with a reporting odds ratio >2 and a lower 95 % confidence limit >1.Results: We retrieved 2452 reports associated with PML (N = 1612), leukoencephalopathy (N = 835) or both (N = 5), corresponding to 343 different drugs. PML was reported similarly in male and female adults (18-64 years), and almost 30 % of the cases had a fatal outcome. The most frequent Anatomical Therapeutic Chemical (ATC) classification groups concerned antineoplastic agents (23.5 %), antivirals for systemic use (10.1 %) or immunostimulants (4.6 %). Significant disproportionality was found for 88 drugs in the overall analysis (of cases with 'progressive multifocal leukoencephalopathy' or 'leukoencephalopathy' as the Preferred Term), and a new safety signal was identified for 59 active substances (e.g. muromonab-CD3, basiliximab and antithymocyte Ig), as no information on a possible risk of PML was acknowledged in their Summary of Product Characteristics documents. Some safety signals were confirmed also after sensitivity analysis adjustment for several confounding factors (underlying diseases and considering only 'progressive multifocal leukoencephalopathy' as the Preferred Term).Conclusion: We report a possible association between several drugs and PML that has not been previously described. In addition, we have confirmed previously reported signals in a number of drugs. We highlight the need for follow-up by regulatory agencies. [ABSTRACT FROM AUTHOR]

Purpose: Causes of ARF are numerous including drugs. In 2012, spontaneous reporting showed a possible association between dronedarone and ARF. To further investigate such association, a retrospective cohort study on health-service claim databases was performed taking amiodarone as comparison. Methods: All patients receiving new prescription of amiodarone or dronedarone between September 2010 and December 2012 were selected. Cox regression models to estimate the hazard ratios (HRs), with 95 % confidence intervals (CIs), for dronedarone versus amiodarone were performed. HRs were calculated: (i) for the entire cohort; (ii) for matched cohorts using propensity score; (iii) and high-dimensional propensity score. Results: New users without previous episodes of ARF were 56,739 and 1761 on dronedarone and 54,978 on amiodarone. After 1:1 matching for propensity score, new users with dronedarone and amiodarone were 1467 and 1467, respectively. The cumulative incidence rate of ARF was 1.6 % (95 % CI 0.7-3.6 %) among dronedarone group and 2.3 % (1.0-5.1 %) among amiodarone group ( p from log rank test = 0.4884). The unadjusted HR of ARF was 0.34 (0.18-0.64) in dronedarone new users compared to amiodarone; in propensity score matched cohort, it was 0.75 (0.26-2.16), and in high-dimensional propensity score, it was 0.83 (0.25-2.73). Conclusions: This large community-based study did not confirm the signal of an increased nephrotoxicity from dronedarone compared to amiodarone. Nevertheless, given the increasing number of reports collected from pharmacovigilance databases worldwide on this association, it is advisable for clinicians and patients to be aware of the possible kidney damage due to dronedarone in order to improve clinical outcomes with early intervention. [ABSTRACT FROM AUTHOR]

Purpose: Osteoporosis is a chronic disease of the bone, whose incidence increases progressively with aging. The main consequences of osteoporosis are fragility fractures, which have considerable medical, social, and economic implications. Adequate treatment of osteoporosis must be considered as a compelling public health intervention. Bisphosphonates (BPs) represent the most significant advance in this field in the past decade, and they are widely used in the treatment of osteoporosis. However, evidence for their effectiveness is limited to secondary prevention, whereas their effect in primary prevention is uncertain and needs further investigation. Methods: Using administrative data collected in the 'Biphosphonates Efficacy-Safety Tradeoff' (BEST) study, a nested case-control study was conducted by including 56,058 participants, aged 55 years who were started on oral BPs from 2003 to 2005. Cases were the 1,710 participants who were hospitalized for osteoporotic fractures until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio of fracture associated with categories of treatment duration. Results: Compared with participants assuming BPs for less than 1 year, those who remained on therapy for at least 2 years had a 21 % (95 % confidence interval (CI) 7 to 33 %) fracture risk reduction. Conclusion: This study provides evidence that BPs, dispensed for primary prevention of osteoporotic fractures, are associated with a reduced risk of osteoporotic fractures after at least 2 years of treatment. [ABSTRACT FROM AUTHOR]

Purpose: Underreporting is a major limitation of spontaneous reporting systems for suspected adverse drug reactions (ADRs). Several interventions to increase the ADR reporting rate have been proposed, but their efficacy remains poorly investigated. Methods: This was a questionnaire study aimed at assessing the knowledge, attitudes, and behavior of general practitioners (GPs) regarding ADR reporting and at evaluating whether a monthly e-mail-based newsletter on drug safety could affect the rate and the quality of the ADR reports submitted by these GPs. Three local health authorities (LHAs) of the Emilia-Romagna region were chosen on the basis of their ADR reporting rate during the period preceding the study: Rimini (high), Ferrara (average), and Piacenza (low reporting rate). All GPs ( n = 737) associated with these three LHAs were recruited. The pooled number of ADR reports sent by GPs in the remaining seven LHAs of the region was used as controls. The study covered a period of 3 years and was divided into: (1) identification of the reasons leading to underreporting through a questionnaire (Phase I); (2) the intervention, i.e., sending a newsletter for a 10-month period (Phase II); (3) evaluation of the intervention outcomes during the 10 months following the period in which the newsletter had been received (Phase III). Results: Among GPs involved, 22.8 % returned the questionnaire. Over 94 % of the respondents considered the spontaneous reporting of suspected ADRs to be part of their professional obligations, but only 6.5 % had submitted at least one report in the previous 6 months. Following the completion of Phase II, the overall number of reports coming from the LHAs subjected to the intervention rose by 49.2 % compared to 2009, while the number of reports coming from the control LHAs increased by 8.8 %. Rimini and Piacenza showed a 200 % increase in the number of ADR reports submitted by GPs, while the number of ADR reported submitted by the control group decreased by 25.5 %. In 2011, the number of overall ADRs reports from the LHAs subjected to the intervention decreased by 6.8 %; this decrease reached 50.0 % of the GPs. Control HLAs showed an overall decline of 4.3 %, while the total number of ADRs from GPs increased by 63.3 %. Ferrara was excluded from the analysis due to confounding factors. Conclusions: The periodic e-mail update on the safety of drugs represents an effective and inexpensive way to raise the awareness of GPs on the importance of spontaneous ADR reporting. Since the outcome of the intervention seemed to disappear after the intervention was stopped, there appears to be a need to adopt a policy of regular updates and educational strategies for health professionals. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the incidence, prevalence, and patterns of triptan use with a special focus on patients who also received cardiovascular drugs, considered as a deviation from appropriate triptan use. Methods: We collected data on prescriptions reimbursed in between 2006 and 2008 in an Italian region. Patients receiving at least one prescription of triptans from January to December 2007 were divided in two populations: new users (without triptan prescriptions in 2006), and already in treatment. All patients were followed for 12 months in terms of both triptan use and cardiovascular coprescriptions. Results: One-year prevalence of triptan use was 0.8%, whereas the incidence was 0.4%. New users accounted for 47.5% of total users (34,915). The percentages of very frequent users (>120 and >180 dosage unit per year) were about double among those already in treatment (26.6% and 15.3%, respectively) and new users (1% and 0.3%; p < 0.01). Patients starting with the lowest dose of tablet formulation were more likely to interrupt therapy after their first prescription ( p < 0.01). Many users aged >65 received concomitant cardiovascular therapies: 36.6% among new users and 64.3% for already in treatment ( p < 0.01). In both groups, about 5% of elderly patients received coprescriptions, suggesting a high deviation from appropriate triptan use. Conclusions: A higher percentage of very frequent users was detected in patients already in treatment compared with new users. Moreover, the percentage of nonnegligible triptan recipients were in age groups for which the drug is not recommended by the product label (≤18 years and >65) and who had cardiovascular coprescriptions suggestive of vasoconstrictive risk. [ABSTRACT FROM AUTHOR]

Purpose: In the general population, lack of adherence to statin therapy remains a widespread phenomenon and an important matter of concern both in terms of cost-effectiveness and risk-benefit profile. This study aimed to evaluate the occurrence of cardiovascular events in Italian statin recipients, focussing on the relationship between degree of adherence to therapy and occurrence of events in a 3-year follow-up. Methods: Our cohort consisted of all patients from Emilia Romagna (4,027,275 inhabitants) who received statin prescriptions in January-February 2005 and who were followed for up to 36 months for cardiovascular hospital admission (i.e. coronary disease, cerebrovascular accidents, peripheral arthropathy), adherence to statin treatment (proportion of days covered: ≥80%) and use of other cardiovascular drugs. The relationship between adherence and cardiovascular events was analysed by multivariate logistic regression; age, sex, other cardiovascular drugs and previous events were covariates of the model. Results: Patients non-adherent to a statin regimen over the 3-year period (76% of the cohort) had higher odds of events, irrespective of risk factors, by more than 40% when compared with adherent patients. Odds of events were in particular: strongly non-adherent, adjOR = 1.19 (CI95% 1.15-1.23), slightly non-adherent, adjOR = 1.25 (1.21-1.30), highly variable in the amount of statins received, adjOR = 1.69 (1.62-1.77). Conclusions: This study shows the key role of adherence to statins in cardiovascular prevention at any level of risk. Appropriateness of statin use needs not only careful selection of patients to be treated, but also cooperation between patient and physician to ensure continued drug use whenever treatment is appropriate. [ABSTRACT FROM AUTHOR]

Background: The reporting of adverse drug reactions (ADRs) is the mainstay of post-marketing surveillance systems. Under-reporting and selective reporting are considered the main limitations of a spontaneous reporting-based pharmacovigilance system. However, excessive reporting induced by external events may also impair signal detection by increasing the noise level.Objective: The aim of this study was to examine the influence of regulatory measures and other external factors on the rate of ADR reporting in Italy, focusing on four situations occurring in the last 10 years: ACE inhibitor-induced cough; HMG-CoA reductase inhibitors ('statins') and rhabdomyolysis; nimesulide and hepatic toxicity; and cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') and increase in cardiovascular risk.Methods: The study was based on data from spontaneous reporting in six Italian regions collected from January 1995 to December 2005. We analysed a 10-year period as a reasonable time interval around the four situations of interest, highlighting the influence of regulatory measures on the rate of ADR reporting (number of reports per million inhabitants). Chi-squared tests were used to assess the statistical significance of any changes in ADR reporting. Drug sales data were also studied to examine possible changes in drug use. Sales data were expressed as daily defined dose per 1000 inhabitants per day.Results: ACE inhibitors: a 5-fold increase in the reporting rate of ACE inhibitor-induced cough was observed in 1998 and 1999 following a restriction on reimbursement for angiotensin receptor blockers introduced in 1998 and removed at the end of 1999. Statins: after the withdrawal of cerivastatin in 2001, the ADR reporting rate increased more than 4-fold, with musculoskeletal ADRs representing about 60% of all the ADRs reported in that year, and progressively decreased in the following years. Nimesulide: an increase in hepatic ADR reporting was observed after withdrawal of the drug from the Finnish and Spanish markets in 2002. Coxibs: no important changes in the rate of cardiovascular events reporting in the period 2000-4 were observed. In 2005, after the withdrawal of rofecoxib in September 2004, both the ADR reporting rate and sales of the drug decreased drastically.Conclusion: Our data suggest that spontaneous ADR reporting can be influenced in different ways by external events. Our data emphasize the need for educational initiatives aimed at increasing the doctor's and patient's awareness of the usefulness and the limitations of spontaneous reporting in the pharmacovigilance system. Such initiatives should use appropriate risk communication strategies in order to avoid unnecessary alarm, which could cause unjustified interruption of therapies or misplaced confidence in new drugs. [ABSTRACT FROM AUTHOR]

To evaluate the pattern of use of statins in the Emilia Romagna Region, with a focus on the therapeutic regimens and the patient’s risk profile as predictors of adherence to therapy. Methods All patients from Emilia Romagna (4,027,275 inhabitants) receiving statin prescriptions in Janurary–February 2005 were selected and observed for 12 months in terms of their statin regimen and use of other drugs for cardiovascular risk prevention. Previous hospital admissions for major cardiovascular events were also obtained. Adherence to statins was evaluated in terms of coverage (covered: ≥300 tablets/year). The relationship between coverage and risk profile (age, sex, other cardiovascular drugs, previous cardiovascular events and choice of drugs/dosages) was analysed by multivariate logistic regression. Results Among the 137,217 patients receiving at least one prescription in the observation period, the rate of coverage was 46%. Coverage was statistically higher in patients with a previous hospital admission (secondary prevention) [Odds ratio (OR) 1.19; 95% confidence interval (95% CI) 1.16, 1.22], in those concomitantly treated with three to four different cardiovascular drugs (OR 2.77; 95% CI 2.66, 2.89). The coverage was also statistically higher in patients aged 50–69 years (OR 1.14; 95% CI 1.08, 1.20) and among males (OR 1.21; 95% CI 1.18, 1.23). Conclusions Less than half of patients receiving statin therapy took their medication daily, with a coverage only slightly higher in patients at higher cardiovascular risk. Three-quarters of the patients received statin therapy in primary prevention, whereas the benefits of statins are documented mostly for patients in secondary prevention. These findings strengthen the need to sensitise physicians and patients to the correct use of statins. [ABSTRACT FROM AUTHOR]

Adverse drug reactions (ADRs) can involve all tissues and organs. Liver injuries are considered among the most serious and are a cause for concern among physicians and patients. To assess the extent of drug-induced liver injuries in Italy we compared the number of cases of hepatic ADRs with reports of all other drug-related reactions present in the same database. Spontaneous reports from six Italian Regions collected from January 1990 to May 2005 were analysed. Adverse reactions were classified according to WHO Adverse Reaction Terminology for causality assessment, and only those with “certain”, “probable” or “possible” causality assessment were included. Association between drugs and hepatic ADRs was assessed using the case/non case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. On May 2005, the database contained 35,767 ADR reports, of which 11,829 were excluded because they were unclassifiable or unlikely in terms of causality assessment. Therefore, the analysis was carried out on 23,938 reports, of which 1,069 concerned hepatic ADRs (cases) and 22,869 concerned non-cases. The proportion of serious ADRs was about 40% in the overall database, and about 74% among cases. The drug classes with the highest number of cases were statins (ROR = 2.9, 95% CI 2.4–3.5), antiplatelet agents (ROR = 3.5; 95% CI 2.6–4.6), NSAIDs (ROR = 2.9; 95% CI 2.1–3.9) and macrolides (ROR = 1.7; 95% CI 1.2–2.3). Hepatic adverse drug reactions remain a serious concern for several drugs widely used in clinical practice. Monitoring hepatic enzymes on a monthly basis for the first 6 months of treatment has been suggested for patients taking medications known to be hepatotoxic. A better knowledge of the epidemiology and mechanisms of hepatic ADRs may contribute to minimising their occurrence. [ABSTRACT FROM AUTHOR]

Background: In a previous questionnaire-based survey, we found extensive use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects with risk factors for serious gastrointestinal complications. Aim: This study focused on the use of NSAIDs in subjects who reported either (a) pre-existing disorders which would have required caution in using NSAIDs (e.g. dyspepsia/heartburn or peptic ulcer) or (b) co-medication with drugs having a high risk of interacting with NSAIDs. Methods: Between March and September 2002, 65 general practitioners (GPs) submitted a validated self-administered questionnaire on health status and drug use to 3,250 subjects (age ≥18 years, stratified by sex and age). The questionnaire was divided into three parts: (1) sociodemographic information, (2) symptoms/illnesses (in the previous 6 months) and (3) drugs taken during the previous week. Results: Of the 2,738 subjects who filled in the questionnaire (84% of responders), 633 (23%) used NSAIDs and, among them, 114 (18%) were chronic users. Among the subjects reporting dyspepsia/heartburn or ulcer (n=909 of 2,738), 24% were occasional NSAID users and 6% chronic users. Of the chronic NSAID users reporting gastrointestinal symptoms, 35% also used a drug for acid-related disorders, but only 14% used daily a proton pump inhibitor (PPI). One hundred six subjects used concomitantly more than one NSAID. Eighteen percent of the subjects using corticosteroids also reported NSAID use; similar proportions were seen in subjects using selective serotonin reuptake inhibitor (SSRI) antidepressants or calcium channel blockers, whereas 6% of the subjects with oral anticoagulants used NSAIDs. Conclusions: Our study shows that NSAIDs are frequently used in patients with upper gastrointestinal complaints or in combination with potentially interacting medications. Adverse effects and untoward drug interactions should be monitored in patients treated with NSAIDs in order to minimise their occurrence. [ABSTRACT FROM AUTHOR]

Background: Antihypertensive agents are among the most used therapeutic classes. The approach to the pharmacological treatment of hypertension is guided by international recommendations and adherence to treatment is known to result in effective prevention of cardiovascular risk. Aim: The aim of this study was to evaluate the pattern of use of antihypertensive agents in general practice in terms of drug choice for the initial treatment of hypertension and adherence to treatments among newly recruited patients. Methods: We collected the data of all antihypertensive drugs prescribed by general practitioners (GPs) and reimbursed between January 1998 and December 2002 by a Local Health Authority of Emilia Romagna (Ravenna district, 350,000 inhabitants). We selected subjects aged 40 years and older, permanently living in the area during the whole period of the study, who received their first prescription of antihypertensives between January and December 1999, with no prescription of antihypertensive agents in the previous year. For each patient, we documented the starting regimen and evaluated adherence to treatment in terms of persistence during the years (patients were defined persistent if they received at least one prescription per year) and in terms of daily coverage (patients were defined covered if they received an amount of drugs consistent with a daily treatment). Finally, switches or addition of other therapeutic classes during the 3-year period were identified. Results: A cohort of 6,043 subjects receiving their first antihypertensive treatment in 1999 was obtained. Regarding the starting regimen, monotherapies with angiotensin converting enzyme inhibitors (n=1,597; 26%) or calcium channel blockers (n=1126; 19%) were the most frequently prescribed. Of the patients, 21% started with a drug combination regimen. Regarding adherence to treatment, 18% of the cohort received only one prescription throughout the 3 years, 13% received more than one prescription but stopped the therapy during the first year, 69% were persistent during the second year and 60% also during the third year. Only 34% were covered during the first year and 24% also during the second year, whereas only 20% of the patients resulted covered throughout the 3 years. Among persistent patients, 41% maintained the same antihypertensive regimen throughout the 3 years, 25% added other drugs to the initial treatment and 34% switched to completely different regimens. Conclusions: Our findings reflect the lack of convergence among guidelines on the drug class(es) to be considered as first choice in the initial treatment of hypertension. Although an intervention in this field may have important implications in terms of cost savings, the ongoing debate does not allow us to draw definite conclusions on whether measures should be taken by the National Health Authority. However, the lack of adherence to antihypertensive treatment is undoubtedly a matter of concern for public health and should be addressed with appropriate interventions. [ABSTRACT FROM AUTHOR]

Background: Non-steroidal anti-inflammatory drugs (NSAJDs) are among the most widely used medicines in the developed countries. The most important adverse reactions involve the upper gastrointestinal tract and can be life threatening. A detailed knowledge of the pattern of use of NSAJDs may help doctors in advising their patients about appropriateness and safety of use. Aim: The aim of the present survey was to evaluate the prevalence and pattern of NSAJD use in the general population, as well as the main characteristics of NSAJD users. Methods: Between March and September 2002, a self- administered questionnaire was submitted to a random sample, stratified by gender and age, representative of the Italian adult population (n = 3,250). The questionnaire was divided into three parts regarding: (1) sociodemographic information, (2) symptoms/illnesses and (3) any drug taken during the previous week and the corresponding purpose. A statistical analysis (logistic regression) was performed. Results: Of the 2,738 subjects who filled in the questionnaire, 65 % took at least one drug in the previous week and, among them, 35% used NSAIDs (top drug class; n = 633). Of the NSAID users, 20% were ≥65 years of age and 18% were chronic users (daily or frequent use for more than 6 months). NSAID use was significantly higher in women, both for overall and chronic use. The older age groups showed an increasing risk of chronic NSAJD use. Among NSAJDs, nimesulide was the most used compound (35%) followed by acetylsalicylic acid (14%) and ibuprofen (11%). The main reasons for NSAJD use, as reported by subjects, were: headache (25%), osteoarticular pain (19%), unspecified pain (15%) and osteoarthrosis (9%). More than 50% of all the NSAJDs were prescribed by physicians (general practitioner, specialist, hospital physician), whereas about 44% were taken as self-treatment or following the advice of a pharmacist, relative/friend, etc. Conclusions: Our study confirms that NSAJDs are widely used in the Italian general population and that, in most cases, they are used in accordance with their approved indications. However, their large and often chronic use in the elderly, as well as the high frequency of self-treatment, recommends a higher awareness by all physicians. [ABSTRACT FROM AUTHOR]

Background. Italy is reported to have a relatively low consumption of antidepressants. This is probably due to the fact that until 2000 antidepressants were reimbursed with some restrictions. Aim. To describe the pattern of use of antidepressants in primary care in Italy, after admission of selective serotonin reuptake inhibitors (SSRIs) for reimbursement without restrictions. Methods. We collected prescription data of antidepressants (ATC code: N06) reimbursed between January 1999 and March 2002 from three local health authorities in Emilia Romagna. Then, we calculated the prevalence of use for the different therapeutic classes of antidepressants, by age and gender. Moreover, after selecting a cohort of incident adult patients to follow for 6 months after the first prescription, we analysed the continuity, the average daily doses and the average duration of treatment. Results. Out of 1000 subjects, 78 received at least one prescription of antidepressants in 1 year. The prevalence of use increased with age from 43 to 136/1000. Women used antidepressants more frequently than men, with a ratio varying from 1.6 to 2, depending on age. SSRIs were the most used drugs (63%), and their prevalence of use diminished with age; on the contrary, use of mianserine and trazodone increased with age, and that of the other antidepressants did not vary. About 60% of the subjects received occasional prescriptions. Continuous treatment was more frequent with SSRIs and in subjects older than 34 years. Daily doses were higher in patients receiving newer drugs (0.9–1 DDD per day), and lower in patients receiving the older agents (0.3–0.4 DDD per day). The average daily doses were usually lower than those recommended for the treatment of the major depression, especially for tricyclics, trazodone and reboxetine. Overall, doses were within the recommended range in about 75% of recipients of newer antidepressants (i.e., SSRIs, venlafaxine, mirtazapine and reboxetine), and in less than 30% of recipients of older drugs (i.e., tricyclics, trazodone and mianserine). In 59% of subjects receiving continuous treatment, the duration of the therapeutic course was at least 6 months. Conclusions. We found a high prevalence of use of antidepressants in primary care with a frequency of occasional use higher than in other countries. Only rarely were doses and duration of treatment consistent with recommendations for treatment of depression. Recipients of newer drugs received doses consistent with a use for major depression more frequently than others; however, rates of 6 month duration did not differ among drug classes. [ABSTRACT FROM AUTHOR]

Several studies have indicated that the D2 dopamine receptors mediate the antidopaminergic activity of the neuroleptics; nevertheless, the selective blocker (−)-sulpiride weakly inhibits dopamine-mediated behaviour. The present study investigated whether the concomitant injection of doses of the D1 antagonist SCH 23390, which by themselves are without effect, would enable (−)-sulpiride to express fully neuroleptic activity in the rat. The benzamide YM 09151-2 that strongly inhibits dopamine-mediated behaviour was also studied. Rats receiving different doses of (−)-sulpiride, YM 09151-2 and SCH 23390 given alone or in combination were tested for exploratory activity, apomorphine-induced stereotyped behaviour and hyperactivity elicited by the D2 agonist LY 171555. When given alone, (−)-sulpiride (10, 20 and 40 mg/kg IP) had no effect on exploratory activity and stereotypy. When (−)-sulpiride was administered in combination with an ineffective dose of SCH 23390 (5 μg/kg) both responses were significantly inhibited. The combined administration of subthreshold doses of (−)-sulpiride (2.5 mg/kg) and SCH 23390 (2.5 μg/kg) significantly inhibited hypermotility induced by LY 171555. Moreover, the combined administration of ineffective doses of YM 09151-2 with subthreshold doses of SCH 23390 strongly inhibited all the behavioural responses. The results indicate that SCH 23390 allowed (−)-sulpiride to exhibit a wider spectrum of neuroleptic activity and potentiated the antidopaminergic activity of YM 09151-2. [ABSTRACT FROM AUTHOR]

The selective D1 receptor stimulant SKF 38393 dose-dependently increased grooming time in rats without affecting locomotor activity or eliciting stereotyped behaviour. The selective D2 receptor agonist LY 171555 induced a dose-dependent increase in rat motility, a marked decrease in grooming time and a low occurrence of stereotyped behaviour. Concurrent administration of the two selective agonists induced high-degree stereotyped responses and reductions in locomotor and grooming behaviours. Rats withdrawn from repeated treatment with the selective D1 receptor blocker SCH 23390 (0.05 mg/kg twice daily for 21 days; 7 days of washout) did not exhibit any change of locomotor and grooming responses to threshold doses of LY 171555 and SKF 38393 given alone or in combination. On the contrary, a significantly greater occurrence of high-degree stereotyped responses to the combination of the two selective agonists was observed. The data support the view that D1 and D2 receptors have a cooperative role in the generation of stereotypies and suggest that D1 receptor supersensitivity needs D2 stimulation to be revealed. [ABSTRACT FROM AUTHOR]

This study proposes a method capable of separating the pharmacodynamic from the pharmacokinetic component in the methamphetamine (MA) hyperactivity potentiation induced by antidepressants. Several antidepressants and neuroleptics, other centrally-acting drugs and the inhibitor of hepatic drug metabolism SKF 525-A were studied. The motility counts taken between 10 and 20 min after MA injection were considered as an index of pharmacodynamic interaction and the whole duration of the hyperactivity syndrome as an index of pharmacokinetic interaction. The duration of MA effect was prolonged by some of the drugs studied and left unchanged by the others regardless of their clinical classification. On the contrary, our evaluation of the intensity of MA effect produced a sharp differentiation between classical neuroleptics and typical antidepressants: the former antagonized and the latter potentiated MA peak intensity. Only the D-2 blocking neuroleptics sulpiride and tiapride potentiated MA intensity. Regarding the specificity of our model, none of the compounds known to be devoid of clinical antidepressant or antipsychotic activity interacted with MA in such a way as to be included in either category. As to the sensitivity of the test, two 'false negatives' were obtained: the neuroleptic clozapine and the antidepressant mianserin. Such exceptions were discussed taking into account their peculiar mechanisms of action. [ABSTRACT FROM AUTHOR]

A critical dose of apomorphine (300 μg/kg SC) given immediately before placing rats into a novel environment produced a diphasic motility response (initial sedation followed by enhanced locomotion). Various neuroleptics having different clinical and/or pharmacological profiles were studied by using such a model. (−)-Sulpiride and sultopride preferentially antagonized apomorphine inhibition; haloperidol and tiapride antagonized both phases of apomorphine response at similar doses; chlorpromazine, fluphenazine, thioridazine, metoclopramide and SCH 23390 preferentially antagonized apomorphine stimulation. The results are discussed in terms of the dopamine receptor subtypes involved in the two phases of apomorphine effect. Apomorphine stimulation can be antagonized by D-1 as well as D-2 receptor blockade. A higher affinity for D-2 receptors seems a necessary requisite for the antagonism of apomorphine inhibition; moreover, the ability of neuroleptics to antagonize apomorphine inhibition seems to depend on the ratio of their presynaptic versus postsynaptic D-2 activity. [ABSTRACT FROM AUTHOR]

The atypical neuroleptic sulpiride is also prescribed for depression because of its activating effect. However, such an effect does not necessarily imply an action identical to that of classical antidepressants, and a laboratory comparison of the neuroleptic and antidepressant activities of sulpiride may contribute to a better definition of its psychotherapeutic profile. Sulpiride isomers were studied in the rat in four behavioural models of depression which are thought to be influenced by neuroleptics in different ways. Desipramine (imipramine) and haloperidol were employed in each test as a standard antidepressant and neuroleptic, respectively. The four tests were: 1) prevention of apomorphine-induced sedation: 2) antagonism of apomorphine-induced hypothermia; 3) behavioural despair (swim test); 4) learned helplessness (FR2 lever pressing escape). Desipramine ameliorated behaviour in all tests; haloperidol ameliorated the response to test 1, influenced that to test 2 in a neuroleptic-like way and worsened the responses to tests 3 and 4.(-)-Sulpiride worked in a similar way to haloperidol in all tests.(+)-Sulpiride significantly and dose-dependently ameliorated the responses to test 3 and was inactive in the others. No conclusion was drawn from test 1 owing to its lack of specificity; the results of the remaining tests indicated a neuroleptic profile of (-)-sulpiride and suggested a potential 'antidepressant' activity of (+)-sulpiride which merits further investigation. [ABSTRACT FROM AUTHOR]

Combined treatment with (-)-sulpiride plus a low dose of the D1 receptor antagonist SCH 23390, unlike (-)-sulpiride given alone, blocked rat striatal dopaminergic transmission. Five days after the withdrawal of 21-day repeated administration of the combined treatment, no increase in apomorphine-induced stereotyped behaviour was observed. The results suggest that the combination of a D2 blocker and a low dose of a D1 blocker produces a wider spectrum of neuroleptic activity without an overt risk of inducing dopaminergic behavioural supersensitivity. [ABSTRACT FROM AUTHOR]