Systematic Data Monitoring and Analysis of Cardiovascular Off-label Prescriptions in Pediatrics: Focus on Angiotensin-Converting Enzyme Inhibitors (ACE-I) and Beta Blockers.

INTRODUCTION: Many efforts have been made to stimulate clinical trials (CTs) in pediatrics but most of the drugs are still authorized only in adults and used off-label in the pediatric population. AIM: To assess how widespread is the off-label prescription in Italy and to identify areas of unmet medical need by applying a model for the systematic collection and analysis of data. METHODS: A study was performed using 2015 data from the Italian Medicines Utilization Monitoring Centre Health Database (OsMed). A study sample of 3,726,583 pediatric patients, was considered. Cardiovascular drugs were selected for this study. Assessment of the off-label use, the analysis of the pharmacovigilance signals, a bibliographic research and the analysis of ongoing CTs were carried out. RESULTS: In 2015, 8,544 pediatric patients received treatment with a cardiovascular drug. Angiotensin converting enzyme inhibitors (ACE-I) followed by beta blockers agents are the most prescribed molecules. Eight molecules were selected and an in-depth analysis conducted. The PhV network showed only one record of adverse reaction as off-label in 2015. The results show several therapeutic areas of use in pediatrics. CONCLUSION: Off-label in pediatrics is largely widespread in Europe and US and our results show it is also present in Italy. Molecules selected are used off-label for therapeutic areas such as oncologic, hematological and rare diseases. Results of pharmacovigilance suggests underreporting. The analysis carried out in this study could be an open track for a systematic monitoring activity and of interest for prescribers, pediatricians and other healthcare professionals during the clinical practice.

Lercanidipine and T-type calcium current.

OBJECTIVE: Lercanidipine is a calcium antagonist with no cardiodepressant activity, long lasting antihypertensive action and reno-protective effect. Our previous data demonstrated that lercanidipine blocks L-type calcium channels (CaL). However, no data are available concerning its effects on T-type calcium channels (CaT). The aim of this study was to evaluate the effect on both CaL and CaT and the selectivity ratio of R-lercanidipine, S-lercanidipine and RS-lercanidipine. A comparison with other dihydropyridines (amlodipine and lacidipine) and the CaT blocker mibefradil was also performed. MATERIALS AND METHODS: In patch-clamped guinea-pig ventricular myocytes, a voltage protocol was applied mimicking a normal action potential: HP of -90 mV, 200 ms depolarizing steps to -50/+50 mV. Lercanidipine was tested at concentrations (1-10 µM) able to block ≈ 50% CaL evoked from a HP in the range of -50 to -30 mV. Cells were superfused with a Na+ and K+ free solution pre-warmed to 35°C to abolish overlapping currents. RESULTS: Using the described voltage protocol, all dihydropyridines at 1 µM blocked less than 20% CaL, with the exception of lacidipine, that reduced CaL >60% of control. All calcium channel blockers (CCBs) blocked a significant amount of CaT, varying from 28% (mibefradil) to 4.3% (amlodipine). Based on the ratio between CaT and CaL blockade in each cell (T/L), mibefradil, as expected, showed the highest T affinity (T/L=1.3). Lercanidipine, either racemate or enantiomers, showed a noticeable T selectivity, T/L varying from 1.05 (S-lercanidipine) to 1.15 (R-lercanidipine). CONCLUSIONS: All CCBs examined in this study showed both T- and L-channel blocking activities and can be differentiated based on their relative affinity. Among tested dihydropyridines, lercanidipine showed the highest T/L selectivity.

Antidepressants and the risk of arrhythmia in elderly affected by a previous cardiovascular disease: a real-life investigation from Italy.

PURPOSE: The study aimed to fill existing knowledge gaps on the safety of antidepressant drugs (ADs) by estimating the risk of hospitalization for arrhythmia associated with use of selective serotonin reuptake inhibitors (SSRIs) and newer atypical ADs (NAAs) among elderly with previous cardiovascular (CV) events. METHODS: The cohort was composed by 199,569 individuals aged ≥ 65 years from five Italian healthcare territorial units who were discharged for cardiovascular outcomes in the years 2008-2010. The 17,277 patients who experienced hospital admission for arrhythmia during follow-up were included as cases. Odds of current ADs use among cases (i.e., 14 days before hospital admission) was compared with (i) odds of current use of 1:5 matched controls (between-patients case-control) and with (ii) odds of previous use during 1:5 matched control periods (within-patient case-crossover). The risk of arrhythmia associated with ADs current use was modelled fitting a conditional logistic regression. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS: Current users of SSRIs and NAAs were at increased risk of arrhythmia with case-control odds ratios (OR) of 1.37 (95% confidence interval, CI 1.18 to 1.58) and 1.41 (1.16 to 1.71) and case-crossover OR of 1.48 (1.20 to 1.81) and 1.72 (1.31 to 2.27). An increased risk of arrhythmia was associated with current use of trazodone (NAA) consistently in case-control and case-crossover designs. CONCLUSIONS: Evidence that current use of SSRIs and NAAs is associated to an increased risk of arrhythmia among elderly with CV disease was consistently supplied by two observational approaches.

Polypill, hypertension and medication adherence: The solution strategy?

INTRODUCTION: Hypertension is an important global health challenge and a leading preventable risk factor for premature death and disability worldwide. In current cardiology practice, the main obstacles in the management of patients affected by hypertension are comorbidities and poor adherence to pharmacological treatments. The World Health Organization has recently highlighted increased adherence as a key development need for reducing cardiovascular disease. METHODS: Principal observational and clinical trial data regarding adherence, reductions in cardiovascular risk and safety of the polypill approach are summarized and reviewed. CONCLUSIONS: The polypill approach has been conclusively shown to increase adherence relative to usual care in all cardiovascular patients, furthermore, concomitant risk factor reductions have also been suggested. To date, the use of polypill could represent a solution strategy in patients affected by hypertension, comorbidities and non-adherence even though further studies, especially in the real-world settings, are needed in order to better understand its role in clinical practice.

First Evidence of Cardiac Stem Cells From the Left Ventricular Apical Tip in Patients With Left Ventricular Assist Device Implantation.

BACKGROUND: Recent studies have challenged the dogma that the adult heart is a postmitotic organ and raise the possibility of the existence of resident cardiac stem cells (CSCs). Our study aimed to explore if these CSCs are present in the "ventricular tip" obtained during left ventricular assist device (LVAD) implantation from patients with end-stage heart failure (HF) and the relationship with LV dysfunctional area extent. METHODS: Four consecutive patients with ischemic cardiomyopathy and end-stage HF submitted to LVAD implantation were studied. The explanted "ventricular tip" was used as a sample of apical myocardial tissue for the pathological examination. Patients underwent clinical and echocardiographic examination, both standard transthoracic echocardiography (TTE) and speckle tracking echocardiography (STE), before LVAD implantation. RESULTS: All patients presented severe apical dysfunction, with apical akinesis/diskinesis and very low levels of apical longitudinal strain (-3.5 ± 2.9%). Despite this, the presence of CSCs was demonstrated in pathological myocardial samples of "ventricular tip" in all 4 of the patients. It was found to be a mean of 6 c-kit cells in 10 fields magnification 40×. CONCLUSIONS: Cardiac stem cells can be identified in the LV apical segment of patients who have undergone LVAD implantation despite LV apical fibrosis.

The prevention of analgesic opioids abuse: expert opinion.

Opioids are drugs of reference for the treatment of moderate to severe pain. Their proper use and a periodic assessment of the patient are crucial to prevent misuse. A multidisciplinary group suggests strategies for all stakeholders involved in the management of pain and suggests the importance of the doctor-patient relationship.

Can estragole in fennel seed decoctions really be considered a danger for human health? A fennel safety update.

Fennel (Foeniculum vulgare Mill.) mature fruit (commonly known as seeds) and essential oil of fennel are widely used as flavoring agents in food products such as liqueurs, bread, cheese, and an ingredient of cosmetics and pharmaceutical products. Moreover fennel infusions are the classical decoction for nursing babies to prevent flatulence and colic spasm. Traditionally in Europe and Mediterranean areas fennel is used as antispasmodic, diuretic, anti-inflammatory, analgesic, secretomotor, secretolytic, galactagogue, eye lotion, and antioxidant remedy and integrator. Topically, fennel powder is used as a poultice for snake bites. In Asian cultures fennel was ingested to speed the elimination of poisons. As one of the ancient Saxon people's nine sacred herbs, fennel was credited with the power to cure. Fennel was also valued as a magic herb: in the Middle Ages it was draped over doorways on Midsummer's Eve to protect the household from evil spirits. Recently because of estragole carcinogenicity, fennel has been charged to be dangerous for humans especially if used as decoction for babies. But this allegation do not consider the remedy is prepared as a matrix of substances, and recent researches confirm that pure estragole is inactivated by many substance contained in the decoction.

Anaphylaxis during the first course of high-dose methotrexate: a case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Methotrexate (MTX) is widely used in the management of paediatric cancer with a generally favourable benefit/risk profile. We report an unusual adverse drug reaction with the first course of high-dose MTX in a paediatric patient and review the literature for similar cases. CASE SUMMARY: An 11-year-old boy with small-cell osteoblastic osteosarcoma in the lower limb experienced a case of life-threatening anaphylaxis during the first course of high-dose MTX. The adverse event occurred during the first course, likely due to an immune-mediated mechanism. We postulate that prior antineoplastic treatment might have contributed to the immune response to MTX. WHAT IS NEW AND CONCLUSION: Given that this reaction has rarely been reported, we discuss the present case with a review of other similar cases. Further studies are needed to substantiate this 'signal alarm' for serious MTX-related hypersensitivity reactions.

Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression.

BACKGROUND AND PURPOSE: Recent clinical data suggest beneficial effects of ivabradine, a specific heart rate (HR)-lowering drug, in heart failure patients. However, the mechanisms responsible for these effects have not been completely clarified. Thus, we investigated functional/molecular changes in I(f), the specific target of ivabradine, in the failing atrial and ventricular myocytes where this current is up-regulated as a consequence of maladaptive remodelling. EXPERIMENTAL APPROACH: We investigated the effects of ivabradine (IVA; 10 mg·kg(-1) ·day(-1) for 90 days) on electrophysiological remodelling in left atrial (LA), left ventricular (LV) and right ventricular (RV) myocytes from post-mycardial infarcted (MI) rats, with sham-operated (sham or sham + IVA) rats as controls. I(f) current was measured by patch-clamp; hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms and microRNA (miRNA-1 and miR-133) expression were evaluated by reverse transcription quantitative PCR. KEY RESULTS: Maximal specific conductance of I(f) was increased in MI, versus sham, in LV (P < 0.01) and LA myocytes (P < 0.05). Ivabradine reduced HR in both MI and sham rats (P < 0.05). In MI + IVA, I(f) overexpression was attenuated and HCN4 transcription reduced by 66% and 54% in LV and RV tissue, respectively, versus MI rats (all P < 0.05). miR-1 and miR-133, which modulate post-transcriptional expression of HCN2 and HCN4 genes, were significantly increased in myocytes from MI + IVA. CONCLUSION AND IMPLICATION: The beneficial effects of ivabradine may be due to the reversal of electrophysiological cardiac remodelling in post-MI rats by reduction of functional overexpression of HCN channels. This is attributable to transcriptional and post-transcriptional mechanisms.

Is suboptimal prescribing a risk factor for poor health outcomes in community-dwelling elders? The ICARe Dicomano study.

PURPOSE: Mostly because of comorbidity and drugs consumption, older persons are often exposed to an increased risk of sub-optimal prescribing (SP). At present, few studies investigated the association between SP and long-term health outcomes. We examined the relation between SP and the risk of mortality and hospitalization in Italian older community-dwellers. METHODS: Older (65+ years) community-dwelling residents of a small town in Tuscany were enrolled in a longitudinal study. SP was defined as polypharmacy (use of 5+ drugs), prescription of inappropriate drugs (ID) according to Beers' criteria, and of potentially interacting drugs (PID), evaluated in 1995 and 1999. These three forms of SP were entered as time-dependent exposures into multivariable Cox regression analysis models, whose outcomes were mortality and hospitalizations through 2003. RESULTS: Of 1022 participants (mean age 73.0 +/- 6.8, 57% women), 220 were evaluated in 1995, 234 in 1999 and 568 in both waves. In univariate analysis, mortality was two-fold higher in participants with polypharmacy (73.4/1000 person/years, 95% CI 58.2-92.4 vs. 34.1, 95% CI 29.7-39.2; p < 0.001) or PID (72.7/1000 person/years, 95% CI 46.3-113.9 vs. 38.0, 95% CI 33.5-43.1; p < 0.001), whereas it was unrelated to the presence of ID. Hospitalization rates were independent of any form of SP. In multivariable models, polypharmacy, ID, and PID were no longer associated with an increased risk of death, and ID predicted a slightly increased risk of hospitalizations (HR 1.03, 95% CI 1.0-1.06, p = 0.048). CONCLUSIONS: In this cohort, SP was not associated with an excess risk of poor health outcomes.

Potential drug-drug interactions and radiodiagnostic procedures: an in-hospital survey.

OBJECTIVES: To evaluate the type, frequency, severity and predictors of potential Drug-Drug Interactions (DDIs) in a cohort of patients undergoing radiodiagnostic procedures. SETTING: Eight Radiology wards located in Tuscany (Italy). METHODS: All participants exposed to at least two medications were included in the analysis. DDIs were grouped according to their severity as 'minor', 'moderate' or 'major'. A logistic model was used to estimate Odds Ratios and 95% Confidence Intervals for all predictors of potential DDI. MAIN OUTCOME MEASURES: Type and predictors of potential DDI in a cohort of patients undergoing radiodiagnostic procedures. RESULTS: One-thousand-and-two subjects (57.6% females; mean age: 67.3 +/- 12.2) entered the analysis, and 46.1% of them incurred in a potential DDI (78.9% 'moderate' in severity). The combination of allopurinol and ACE-inhibitors was the most frequent (21/153) among major potential DDIs, while steroids were involved in all cases of potential DDI due to premedication. Co-morbidity, number of co-medications, advanced age and premedication use increased the risk of potential DDI; a protective role was found for positive history of allergy. When the analysis was restricted to subjects with premedication (n = 93), only 12.9% of them reported a potential DDI directly attributable to premedication drugs. CONCLUSIONS: Among patients undergoing radiological examination, types and predictors of potential DDIs appeared in agreement with other kind of in-hospital populations. Premedication revealed to be a proxy predictor for potential DDIs. Considering the poor capability of the prescriber in recognizing interactions, their systematic evaluation (using an informatics tool) in patients undergoing radiological examination might be helpful in preventing the occurrence of clinically relevant DDIs.

Increased levels of CA 125 and CA 19.9 serum tumour markers following cyclic combined hormone replacement therapy.

We report a case of increase in serum tumour markers CA 125 and CA 19.9 induced by cyclic combined hormone replacement therapy (HRT). A 52-year-old Caucasian post-menopausal woman presented with a slight enlargement of the right ovary and uterine fibromyomatosis. She was taking HRT for 4 years in a cyclic combined regimen of 2 mg oestradiol with 1 mg cyproterone acetate. The serum tumour markers occasionally measured were in normal range except CA 19.9 (997 U/mL; normal values 0.0-37) and CA 125 (85 U/mL; normal values 0.0-35). However, on one occasion, the CA 19.9 and CA 125 were high and then showed persistently high values (1005 and 81.3 U/mL, respectively). Radiodiagnostic investigations excluded any malignancies and a hysteroscopy showed endometrial thickening. After discontinuation of HRT, CA 125 levels returned to normal after 1 month, whereas CA 19.9 took 6 months to do so. Four months after the beginning subsequent therapy with over-the-counter phyto-oestrogens a new serum test showed an increase in CA 19.9 but CA 125 remained within the normal range. Phyto-oestrogen therapy was then interrupted and 1 month later CA 19.9 returned to normal. In this case, cyclic HRT was the probable cause of CA 19.9 and CA 125 increase. Positive dechallenge and subsequent CA 19.9 increase after phyto-oestrogen intake seem to confirm the role of oestrogens as the cause of the endometrial thickening through hormonal imbalance. Increased CA 19.9 and CA 125 levels in benign gynaecological conditions may be a source of misdiagnosis of malignant disease.

Functional coupling of angiotensin II type 1 receptor with insulin resistance of energy substrate uptakes in immortalized cardiomyocytes (HL-1 cells).

BACKGROUND AND PURPOSE: Increased angiotensin II levels and insulin resistance coexist at the early stages of cardiomyopathies. To determine whether angiotensin II increases insulin resistance in cardiomyocytes, we studied the effect of angiotensin II on basal and insulin-stimulated transport rate of energy substrates in immortalized cardiomyocytes (HL-1 cells). EXPERIMENTAL APPROACH: Glucose and palmitic acid uptakes were measured using [(3)H]2-deoxy-D-glucose and [(14)C]palmitic acid, respectively, in cells exposed or not exposed to angiotensin II (100 nM), angiotensin II plus irbesartan or PD123319, type 1 and 2 receptor antagonists, or PD98059, an inhibitor of ERK1/2 activation. Cell viability, DNA, protein synthesis and surface area were evaluated by the MTT test, [(3)H]thymydine, [(3)H]leucine and morphometric analysis, respectively. Type 1 receptor levels were measured by western blot analysis. KEY RESULTS: Basal uptakes of glucose and palmitic acid by HL-1 cells (0.37+/-0.07 and 7.31+/-0.22 pmol per 10(4)cells per min, respectively) were both stimulated by 100 nM insulin (+91 and +64%, respectively). Cells exposed to angiotensin II remained viable and did not show signs of hypertrophy. In these conditions, the basal palmitic acid uptake of the cells increased (11.41+/-0.46 pmol per 10(4) cells per min) and insulin failed to stimulate the uptake of glucose and fatty acids. Changes in the rate of uptake of energy substrates were prevented or significantly reduced by irbesartan or PD98059. CONCLUSIONS AND IMPLICATIONS: Angiotensin II is a candidate for increasing insulin resistance in cardiomyocytes. Our results suggest a further mechanism for the cardiovascular protection offered by the angiotensin II type 1 receptor blockers.

The properties of the pacemaker current I(F)in human ventricular myocytes are modulated by cardiac disease.

The pacemaker current I(f)is present in ventricular myocytes from the human failing heart where it may contribute to arrhythmogenesis. The role of cardiac disease in the modulation of I(f)expression is still uncertain. We studied the functional expression and properties of I(f)in human ventricular myocytes isolated from control donor hearts or from explanted failing hearts of patients with ischemic and dilated cardiomyopathy. In patch-clamped cells, I(f)was elicited by hyperpolarization. Membrane capacitance (C(m)) was significantly higher in dilated cardiomyopathy than in control or ischemic cardiomyopathy. I(f)was present in all ischemic and dilated cardiomyopathy tested cells and in 76% of control cells. In ischemic and dilated cardiomyopathy, I(f)amplitude measured at -120 mV was significantly greater than in control. However, I(f)density (i.e. current normalized to C(m)) was significantly higher in ischemic cardiomyopathy (2.0+/-0.2 pA/pF) than in dilated cardiomyopathy (1.2+/-0.1 pA/pF) or control (1.0+/-0.1 pA/pF). In diseased hearts, the activation curve was significantly shifted to more positive values compared to control. The slope of the fully-activated I-V relations was greater in ischemic cardiomyopathy than in dilated cardiomyopathy or control (P<0.05) while the intercept with the x -axis (V(rev)) was similar. In conclusion, I(f)is overexpressed in human ventricular myocytes from failing hearts; its functional expression seems related to the etiology of the disease, being higher in ischemic than in dilated cardiomyopathy, and not to the degree of cell hypertrophy.

Myocardial remodeling and arrhythmogenesis in moderate cardiac hypertrophy in rats.

In 47 male adult Wistar rats with 4-wk aortic coarctation (AC) and 39 age-matched sham-operated rats (SO) chronically instrumented for telemetry electrocardiogram recording, we investigated the mechanisms of arrhythmogenesis in moderate cardiac hypertrophy, with an approach from "in vivo" toward the cellular level, analyzing 1) stress-induced cardiac arrhythmias in all rats and 2) myocardial fibrosis in 35 animals and action potential duration and density of hyperpolarization-activated current in 19 others at the ventricular level. Aortic banding increased arterial blood pressure, cardiac weight, and ventricular myocyte volume by 11, 25, and 14%, respectively (P < 0.001-0.05). Ventricular arrhythmias occurred at similar rates in AC and SO rats throughout the stress procedure. Action potential duration and hyperpolarization-activated current were about twice as great and myocardial fibrosis about four times greater in AC animals (P < 0.005-0.05). Electrocardiogram data also revealed more supraventricular arrhythmias in AC rats during the baseline period and after stress and fewer atrioventricular block episodes after stress (P < 0.05). Thus stress-induced supraventricular and atrioventricular nodal, but not ventricular, arrhythmias were affected in moderate cardiac hypertrophy when ventricular morphofunctional alterations were evident.

Electrophysiologic effects of lercanidipine on repolarizing potassium currents.

Blockade of cardiac repolarizing potassium channels by drugs may result in QT-interval prolongation, eventually degenerating into "torsades de pointes," a life-threatening arrhythmia. Lercanidipine (LER) is a recently introduced lipophilic calcium antagonist with no cardiodepressant activity and long-lasting antihypertensive action. Its chemical structure is characterized by the presence of a diphenylpropylaminoalkyl group, which is present in some of the drugs that have been reported to cause QT-interval prolongation. Our previous data demonstrated that LER blocks L-type calcium channels without affecting sodium current; however, no data are available concerning its effects on cardiac potassium channels. Transient outward (I(to)), delayed rectifier (I(K)), background currents, and action potential (AP) profile were measured from patch-clamped ventricular myocytes isolated from rat, guinea pig, or human hearts using enzymatic dissociation procedures. LER did not affect I(K) (and I(Kr)) density and activation curve in guinea pig myocytes; the reversal potential of the background current (I(K1)) and its slope were not changed by the drug. Maximal diastolic potential (MDP) and duration of the AP measured at -60 mV (APD(-60)) were not significantly changed. I(to) density and activation curves measured in rat myocytes were similar in the absence and presence of 1 or 10 microM LER. Finally, the effect of LER was tested in human ventricular myocytes: superfusion with 1 microM LER did not affect MDP and APD(-60). I(to) density and the midpoint of activation and inactivation curves were similar in the absence and presence of LER. In conclusion, our data demonstrate that LER does not affect repolarizing potassium currents and action potential profile recorded from guinea pig, rat, and human ventricular myocytes. It is unlikely that LER could cause QT prolongation in vivo.