Cardiovascular complications and drug prescriptions in subjects with and without diabetes in a Northern region of Italy, in 2002 and 2012.

BACKGROUND AND AIMS: In contrast to the well-documented global prevalence of diabetes, much less is known about the epidemiology of cardiovascular (CV) complications in recent years. We describe the incidence of major CV events, deaths and drug prescribing patterns from 2002 to 2012 in subjects with (DM) or without diabetes mellitus (No DM). METHODS AND RESULTS: Subjects and outcomes were identified using linkable health administrative databases of Lombardy, a region in Northern Italy. A logistic regression model was used to compare myocardial infarction (MI), stroke, major amputation and death between DM and No DM in 2002 and 2012 and between the two index years in each population. The interaction between years and diabetes was introduced in the model. From 2002 to 2012 the incidence of major CV complications and death fell in both groups with a larger reduction among DM only for CV events: OR (95% CI) for the interaction 0.86 (0.79-0.93) for MI, 0.89 (0.82-0.96) for stroke, 0.78 (0.57-1.06) for major amputations. CV prevention drugs rose considerably from 2002 to 2012 particularly in DM and a switch towards safer antihyperglycemic drugs was also observed. CONCLUSIONS: Major CV complications and death declined from 2002 to 2012 in both DM and No DM. This might be due to a larger increase in prescriptions of CV drugs in DM and a relevant change toward recommended antihyperglycemic drugs.

Lithium use from 2000 to 2010 in Italy: a population-based study.

INTRODUCTION: Lithium is a highly specific and evidence-supported drug for the acute and maintenance treatment of bipolar disorder. METHODS: The purpose of this study was to calculate the prevalence and incidence of lithium use and to investigate the prescribing patterns of other mood-stabilizing agents in lithium users. We analyzed lithium utilization from 2000 to 2010 in a large area in Italy on the basis of dispensing data drawn from the regional administrative database. For each calendar year those who had at least one recorded dispensation of lithium were defined as lithium users. Those who received more than 4 dispensations per year were defined as lithium-treated. RESULTS: Rates of lithium utilization did not change during the observation period, but the amount of drug prescribed increased as a result of longer treatment and higher doses. The prevalence of use showed an initial increase of 8% (2000-2002), followed by a 13% decrease (2002-2006) and a subsequent rise of 11% (2006-2010). The prevalence of treatment grew by 38% during the whole observation period. The proportion of former lithium users who received other drugs or discontinued any treatment increased from 41% in 2002 to 52% in 2006, and then fell to 40% in 2010. CONCLUSION: The initial decline (2002-2006) and the subsequent rise (2006-2010) of lithium use can be explained by a fall and rise of new prescriptions. This finding together with a similar but opposite change in prescriptions of the other mood-stabilizing agents suggests a temporary change in prescribing attitudes which was subsequently reconsidered.

Elevated risk of death and major cardiovascular events in subjects with newly diagnosed diabetes: findings from an administrative database.

AIMS: To investigate the incidence of major cardiovascular complications and mortality in the first years of follow-up in patients with newly diagnosed diabetes. METHODS AND RESULTS: We examined incidence rates of hospitalization for cardiovascular reasons and death among new patients with diabetes using the administrative health database of the nine million inhabitants of Lombardy followed from 2002 to 2007. Age and sex-adjusted rates were calculated and hazard ratios (HR) were estimated with a matched population without diabetes of the same sex, age (± 1 year) and general practitioner. There were 158,426 patients with newly diagnosed diabetes and 314,115 subjects without diabetes. Mean follow-up was 33.0 months (SD ± 17.5). 9.7% of patients with diabetes were hospitalized for cardiovascular events vs. 5.4% of subjects without diabetes; mortality rate was higher in patients with diabetes (7.7% vs. 4.4%). The estimated probability of hospitalization during the follow up was higher in patients with diabetes than in subjects without for coronary heart disease (HR 1.4, 95% CI 1.3-1.4), cerebrovascular disease (HR 1.3.95% CI 1.2-1.3), heart failure (HR 1.4, 95% CI 1.3-1.4) as was mortality (HR 1.4, 95% CI 1.4-1.4). Younger patients with diabetes had a risk of death or hospital admission for cardio-cerebrovascular events similar to subjects without diabetes ten years older. CONCLUSIONS: The elevated morbidity and mortality risks were clear since the onset of diabetes and rose over time. These data highlight the importance of prompt and comprehensive patients care in addition to anti-diabetic therapy in patients with newly diagnosed diabetes.

Validation of healthcare administrative data for the diagnosis of epilepsy.

BACKGROUND: Administrative databases have become an important tool to monitor diseases. Patients with epilepsy could be traced using disease-specific codes and prescriptions, but formal validation is required to obtain an accurate case definition. The aim of the study was to correlate administrative data on epilepsy with an independent source of patients with epilepsy in a district of Lombardy, Northern Italy, from 2000 to 2008. METHODS: Data of nearly 320 600 inhabitants in the district of Lecco collected from the Drug Administrative Database of the Lombardy Region were analysed. Among them were included patients who fulfilled the International Classification of Diseases 9 (ICD-9) codes and/or the disease-specific exemption code for epilepsy and those who had at least one EEG record and took antiepileptic drugs (AEDs) as monotherapy or in variable combinations. To ascertain epilepsy cases, 11 general practitioners (GPs) with 15 728 affiliates were contacted. Multiple versions of the diagnostic algorithm were developed using different logistic regression models and all combinations of the four independent variables. RESULTS: Among the GP affiliates, 71 (4.5/1000) had a gold standard diagnosis of epilepsy. The best and most conservative algorithm included EEG and selected treatment schedules and identified 61/71 patients with epilepsy (sensitivity 85.9%, CI 76.0% to 92.2%) and 15 623/15 657 patients without epilepsy (specificity 99.8%,CI 99.7% to 99.8%). The positive and negative predictive values were 64.2% and 99.9%. Sensitivity (86.7%) and the positive predictive value (68.4%) increased only slightly when patients with single seizures were included. CONCLUSIONS: A diagnostic algorithm including EEG and selected treatment schedules is only moderately sensitive for the detection of epilepsy and seizures. These findings apply only to the Northern Italian scenario.

Reducing the costs of paediatric antibiotic prescribing in the community by implementing guideline recommendations.

WHAT IS KNOWN AND OBJECTIVE: Italian children receive a high number of antibiotic prescriptions, and the use of second-choice antibiotics is common. A few studies in other countries have demonstrated that the implementation of international guidelines for the most common paediatric diseases may reduce the associated costs. A cost analysis of the expenditure for antibiotic prescriptions in outpatient children in the Lombardy region (Italy) and for each of the region's local health units (LHUs) was performed using a pharmacoepidemiological approach. The safety and cost impact associated with a quali-quantitative improvement in antibiotic prescribing was estimated. METHODS: The data source was the Lombardy region's prescription database (year 2008) for outpatient children <14 years old. The average total expenditure for each package, and per capita, was calculated for each active substance considered and for each LHU. An estimate of the possible cost reduction was elaborated using, as a reference, the prescription profile of a group of paediatricians that has been involved in initiatives concerning care for years. The hospital admission rates for acute respiratory infections (ARI) and their major complications were evaluated at the regional level and in the group of children followed by the reference paediatricians. RESULTS AND DISCUSSION: The cost reduction estimate reveals a possible decrease in antibiotic expenditure of about 3·6 million euros (-19·5%) in the Lombardy region. Large variability was observed between different LHUs (-33·3 to +9·2% of difference). The hospital admission rate was not different when comparing the group of children followed by the reference paediatricians to the rest of the study population, but the hospital admission rate for ARI was lower in the reference group (χ(2) = 16·4, P < 0·001). WHAT IS NEW AND CONCLUSION: This is the first Italian study to evaluate the costs related to a specific prescription profile, which already exists in the real setting, hypothesizing its application in a large outpatient child population of the same geographical area. The results show that by improving prescribing appropriateness, it is possible to reduce the expenditure associated with antibiotic prescriptions to outpatient children in the Lombardy region by about one-fifth. The lower rate of hospital admissions for ARI suggests that the adopted profile is also beneficial to children's health.

Use of antipsychotic drugs and mood stabilizers in women of childbearing age with schizophrenia and bipolar disorder: epidemiological survey.

Aims. To determine the prevalence of women of childbearing age with schizophrenia and bipolar disorder exposed to antipsychotic (AP) drugs and mood stabilizers (MS) in Lombardy, a European region of 10 million inhabitants and 1 752 285 women of childbearing age. Methods. The data concerning psychiatric care, drug treatments and pregnancy outcomes were retrieved from local administrative databases during a 12-month census period. Results. During a 12-month census period, 2893 women of childbearing age with schizophrenia (74.8% of all women of childbearing age with schizophrenia) and 918 with bipolar disorder (80.1% of all women of childbearing age with bipolar disorder) were exposed to AP drugs or MS, yielding a prevalence of exposure for women with schizophrenia of 1.65 (95% confidence interval (CI) 1.59-1.71) per 1000 female inhabitants, and for women with bipolar disorder of 0.52 (95% CI 0.49-0.55) per 1000 female inhabitants. Persistent exposure to potentially teratogenic medications accounted for one in every 1000 women of childbearing age. Of the 57 pregnancies in women with schizophrenia, normal delivery was recorded in 23 (40%) cases; of the 26 pregnancies in women with bipolar disorder, normal delivery was recorded in 10 (38%) cases. Conclusions. In women of childbearing age with severe mental disorders, exposure to psychotropic drugs is substantial, which suggests that the issue of reproductive health is epidemiologically relevant and a major public health concern.

Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian population-based study.

AIMS: To describe trends in diagnosed diabetes prevalence, incidence and mortality from 2000 to 2007 in the most heavily populated Italian region. METHODS: We examined the prevalence and incidence rates of Type 1 and Type 2 diabetes and yearly mortality rates among individuals with diabetes from 2000 to 2007 using an administrative health database of prescription, disease-specific exemption and hospitalization records of more than 9 million inhabitants of Lombardy. Age- and sex-specific rates were calculated and temporal trends for subjects aged ≥ 30 years were analysed. RESULTS: The crude point diabetes prevalence rose from 3.0% in 2000 to 4.2% in 2007, a 40% increase. The incidence remained stable during the study period with a rate of 4/1000 per year. Overall mortality declined from 43.2/1000 in 2001 to 40.3/1000 in 2007 (6.7% decrease) at a rate slightly higher than that of the general population (4.8% decrease). Our projection in subjects aged ≥ 30 years indicates that the prevalence will rise continuously over the next years, reaching 11.1% in 2030. CONCLUSIONS: The prevalence of diabetes increased substantially between 2000 and 2007, mainly because there are more patients with a new diagnosis each year than those who die. The increase observed by 2007 almost reached the World Health Organization prediction for 2030. Our analyses suggest that the increase will continue over the next few decades. These data are important for defining the burden of diabetes in the near future, to help in planning health services and ensure proper allocation of resources.

Differences in outpatient antibiotic prescription in Italy's Lombardy region.

OBJECTIVES: We assessed the antibiotic patterns of use and geographical distribution of prevalence and consumption by age in 15 Local Health Units (LHUs) of Italy's Lombardy region. METHODS: A retrospective analysis of reimbursement data for the community-dwelling population in 2005 was performed. Prescriptions reimbursed by the National Health System and consumption as defined daily doses (DDD) per 1,000 inhabitants per day (DID) were analyzed. A logistic regression was performed to evaluate the association between antibiotic drug prescription and age, gender, and LHU of residence of the population. RESULTS: During 2005, a total of 3,120,851 people (34% of the population) received at least one antibiotic drug prescription. The highest prescription prevalence was observed in the 0-17 and 80 or more years age ranges (41.6 and 41.9%, respectively). Large differences were found in the prevalence rates between different LHUs (ranging from 28.7% in Milan to 39.4% in Brescia) and in DID (ranging from 12.6 DID in Sondrio to 18.9 DID in Brescia). The age and residence of the population were the main determinants of drug exposure. In particular, patients aged <18 years (odds ratio [OR] = 1.73; 95% confidence interval [CI] 1.73, 1.74), aged 65 years or older (OR = 1.64; 95% CI 1.63, 1.65), and those that live in Brescia (OR = 1.66; 95% CI 1.65, 1.66) had a statistically significant higher risk of antibiotic drug exposure. CONCLUSIONS: The observed intra-regional differences underline the need for a careful monitoring with the aim to reduce antibiotic resistance and improve the rational use of drugs.

Potentially severe drug interactions in elderly outpatients: results of an observational study of an administrative prescription database.

PURPOSE: To estimate the prevalence of potentially severe drug-drug interactions (DDIs) and their relationship with age, sex and number of prescribed drugs. METHODS: We analysed all prescriptions dispensed from 1 January 2003 to 31 December 2003 to individuals aged 65 or more registered under the Local Health Authority of Lecco, a northern Italian province with a population of almost 330 000 persons. Elderly who received at least two co-administered prescriptions were selected to assess the presence of DDIs. RESULTS: The prevalence of potentially severe DDIs was 16%, and rose with increasing patient's age and number of drugs prescribed. At multivariate analysis, the adjusted odds ratios rose from 1.07 (95% CI 1.03-1.11) in patients aged 70-74 to 1.52 (95% CI 1.46-1.60) in those aged 85 or older. Elderly taking more than five drugs on a chronic basis had a statistically significant higher risk of sever DDIs than those receiving less than 3 or 3-5 such drugs. CONCLUSIONS: The elderly constitutes a population at high risk of DDIs. As physicians still have some difficulty in managing this problem, it is essential to highlight for them, which factors raise the risk of DDIs.

Epidemiology of first- and second-generation antipsychotic agents in Lombardy, Italy.

INTRODUCTION: This study investigated the age and gender distribution of antipsychotic prescribing in Lombardy, a region of nine million inhabitants in northern Italy. METHODS: From the Regional Administrative Database of Lombardy, all ambulatory prescriptions of antipsychotics dispensed during 2001 were extracted and prevalence data were calculated by dividing users by the total number of male and female residents in each age group. RESULTS: During the study period 86,187 subjects were dispensed antipsychotic agents, yielding a prevalence of use of 0.87 (95 % CI: 0.86, 0.88) per 100 males and 1.01 (95 % CI: 1.00, 1.02) per 100 females. The prevalence of use progressively rose with age in both sexes, with the highest rates in old and very old subjects. The prevalence of use of first-generation antipsychotics progressively increased with age and dramatically increased in old and very old subjects; in contrast, the prevalence of use of second-generation antipsychotics remained substantially stable or slightly decreased up to 65 years of age and increased thereafter. CONCLUSION: Antipsychotic agents are prescribed widely in the general population, and very high rates were observed in those aged 80 years or more.

Stat1 is induced and activated by all-trans retinoic acid in acute promyelocytic leukemia cells.

Treatment of freshly isolated acute promyelocytic leukemia (APL) cells and the myelogenous leukemia cell lines, NB4, HL-60, and U937, with all-trans retinoic acid (ATRA) results in a remarkable elevation in the amounts of Stat1 alpha and Stat2 proteins. Stat1 alpha protein levels are augmented by ATRA as a consequence of elevated amounts of the corresponding transcripts. The retinoid increases the levels of nuclear complexes that are capable of binding to interferon (IFN)-regulated consensus sequences and contain Stat1 and/or Stat2 proteins, and causes a rapid and long-lasting elevation in Stat1 alpha tyrosine phosphorylation. Transient transfection experiments show that ATRA enhances the transactivating properties of Stat1 alpha observed on an appropriate reporter gene, in the presence of the RAR alpha retinoic acid receptor, but not in the presence of the PML-RAR protein. Treatment of NB4 cells with ATRA is associated with a remarkable upregulation of the two IFN-responsive genes IFN-responsive factor 1 and 2'-5' oligoadenylate synthetase, as well as with an augmentation in the levels of IFN alpha secretion. Our data show that ATRA is capable of modulating the amounts and the state of activation of some of the components of the IFN intracellular signaling pathways. They also suggest that the retinoid can bypass IFN/IFN-receptor interactions and induce the expression of IFN-regulated genes.

Molecular mechanisms of retinoid action in acute promyelocytic leukemia (Review).

Acute promyelocytic leukemia (APL) is, at present, the first and only example of leukemia which can be induced into remission with a single cyto-differentiating agent. This is due to the fact that APL is exquisitely sensitive to the differentiating action of all-trans retinoic acid (ATRA). Thus, the APL model offers a unique opportunity to study the cyto-differentiating action of ATRA and synthetic retinoids in a clinically relevant setting. This review article summarizes the work relating to the molecular mechanisms underlying the action of retinoic acid and retinoids in APL cells, and focuses on: a) genes which are expressed and regulated by ATRA; b) synthetic retinoids as cyto-differentiating agents; c) rational combinations between retinoids and cytokines or other cyto-differentiating agents; d) cellular paradigms of retinoic acid resistance. It is our aim to give an updated, about nonexhaustive, account of some of the most recent development regarding the pharmacological action of retinoic acid and its derivatives in APL cells.

Functional impairment in protein kinase C by RACK1 (receptor for activated C kinase 1) deficiency in aged rat brain cortex.

Several laboratories have reported a lack of protein kinase C (PKC) activation in response to various stimuli in the brain of aged rats. It has been suggested that changes in lipid membrane composition could be related to this functional deficit. However, recent evidence has indicated that the translocation of PKC to the different subcellular compartments is controlled by protein-protein interactions. Recently, a class of proteins, termed receptors for activated C kinase (RACKs), have been described that bind PKC. The present study was conducted to determine whether alterations in RACK1, the best-characterized member of RACKs, were associated with changes in translocation and expression of PKC. Quantitative immunoblotting revealed that RACK1 content was decreased by approximately 50% in aged rat brain cortex, compared with that in adult and middle-aged animals. The levels of calcium-independent PKC delta and epsilon, interacting with RACK1, and related calcium-independent PKC activity were not modified by the aging process. By comparison, phorbol ester-stimulated translocation of this activity and of PKC delta and epsilon immunoreactivity was absent in cortex from aged animals, as well as the translocation of the calcium-dependent PKC beta, also known to interact with RACK1. These results indicate that a deficit in RACK1 may contribute to the functional impairment in PKC activation observed in aged rat brain.

Differential isoform-specific regulation of calcium-independent protein kinase C in rat cerebral cortex.

Regulation of the Ca(2+)-independent protein kinase C (PKC) activity and isoforms by phorbol esters was investigated in rat cerebral cortex. Loss of soluble PKC eta immunoreactivity from the soluble fraction was dramatic with only a small increase in the membrane fraction. The kinetics of PKC epsilon and -delta translocation were slower than that for PKC eta, while phorbol esters had no effect on PKC zeta translocation. Despite the translocation of PKC delta, -epsilon and -eta from the soluble to the membrane fraction, both fractions showed a loss of PKC activity. These data indicate that the rates of translocation, inactivation and/or downregulation appear to be different not only among these Ca(2+)-independent isozymes, but also from that reported for the Ca(2+)-dependent PKCs. In addition, these results emphasize the importance of measuring both Ca(2+)-independent PKC activity and immunoreactivity in evaluating activation of these isoforms.