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

Efficacy and safety of pharmacological treatments for patent ductus arteriosus closure: A systematic review and network meta-analysis of clinical trials and observational studies

Efficacy and safety profiles of different pharmacological interventions used to treat patent ductus arteriosus (PDA) are relatively unexplored. Integrating the findings of randomized clinical trials (RCTs) with those from observational studies may provide key evidence on this important issue. We aimed at estimating the relative likelihood of failure to close the PDA, need for surgical closure, and occurrence of adverse events among preterm and full-term infants treated with indomethacin, ibuprofen, or acetaminophen, placebo, or no treatment including both RCTs and observational studies. We searched PubMed, Embase, and the Register of Controlled Trials from inception to October 30, 2018. We first estimated proportions of subjects with failure to close the PDA, subjects in whom surgical closure was performed after pharmacological treatment, death, and subjects with selected adverse events (AEs). These estimates were obtained using frequentist random-effect meta-analysis of arm-specific proportions. We then compared active drugs with each other and with control (either placebo or no treatment) by summarizing results at the end of treatment reported in the papers, regardless of number of administration(s), dose, route and type of administration, and study design and quality. We also summarized primary outcome results separately at first, second and third cycles of treatment. These estimates were obtained using Bayesian random-effects network meta-analysis for mixed comparisons, and frequentist random-effect pairwise meta-analysis for direct comparisons. We included 64 RCTs and 24 observational studies including 14,568 subjects (5339 in RCTs and 9229 in observational studies, 8292 subjects received indomethacin, 4761 ibuprofen, 574 acetaminophen, and 941 control (including placebo or no intervention).The proportion of subjects with failure to close the PDA was 0.24 (95% Confidence Interval, CI: 0.20, 0.29) for indomethacin, 0.18 (0.14, 0.22) for ibuprofen, 0.19 (0.09, 0.30) for acetaminophen, and 0.59 (0.48, 0.69) for control. At end of treatment, compared to control, we found inverse associations between all active drugs and failure to close PDA (for indomethacin Odds Ratio, OR, was 0.17 [95% Credible Interval, CrI: 0.11-0.24], ibuprofen 0.19 [0.12-0.28], and acetaminophen 0.15 [0.09-0.26]), without differences among active drugs. We showed inverse associations between effective drugs and need for surgical closure, as compared to control (for indomethacin OR was 0.28 [0.15-0.50], ibuprofen 0.30 [0.16-0.54], and acetaminophen 0.19 [0.07-0.46]), without differences among drugs. Indomethacin was directly associated with intraventricular hemorrhage (IVH) (1.27; 1.00, 1.62) compared to ibuprofen, and to oliguria as compared to ibuprofen (3.92; 1.69, 9.82) or acetaminophen (10.8; 1.86, 93.1). In conclusion, active pharmacological treatment, with indomethacin, ibuprofen, or acetaminophen, is inversely associated with failure to close the PDA compared to non-treatment. Ibuprofen should be preferred to indomethacin to avoid occurrence of IVH or oliguria, acetaminophen should be preferred to indomethacin to avoid oliguria

Beneficial effect of prolonged heme oxygenase 1 activation in a rat model of chronic heart failure.

SUMMARY We and others have previously demonstrated that heme oxygenase 1 (HO-1) induction by acute hemin administration exerts cardioprotective effects. Here, we developed a rat model of heart failure to investigate whether a long-term induction of HO-1 by chronic hemin administration exerted protective effects. Sprague Dawley rats that underwent permanent ligation of the left coronary artery were closely monitored for survival rate analysis and sacrificed on day 28 post-operation. Administration of hemin (4 mg/kg body weight) every other day for 4 weeks induced a massive increase in HO-1 expression and activity, as shown by the increased levels of the two main metabolic products of heme degradation, bilirubin and carbon monoxide (CO). These effects were associated with significant improvement in survival and reduced the extension of myocardial damage. The ischemic hearts of the hemin-treated animals displayed reduced oxidative stress and apoptosis in comparison with the non-treated rats, as shown by the decreased levels of lipid peroxidation, free-radical-induced DNA damage, caspase-3 activity and Bax expression. Besides, chronic HO-1 activation suppressed the elevated levels of myeloperoxidase (MPO) activity, interleukin 1β (IL-1β) production and tumor necrosis factor-α (TNFα) production that were evoked by the ischemic injury, and increased the plasma level of the anti-inflammatory cytokine IL-10. Interestingly, HO-1 inhibitor zinc protoporphyrin IX (ZnPP-IX; 1 mg/kg) lowered bilirubin and CO concentrations to control values, thus abolishing all the cardioprotective effects of hemin. In conclusion, the results demonstrate that chronic HO-1 activation by prolonged administration of hemin improves survival and exerts protective effects in a rat model of myocardial ischemia by exerting a potent antioxidant activity and disrupting multiple levels of the apoptotic and inflammatory cascade

Hydrochlorothiazide Use and Risk of Nonmelanoma Skin Cancers: A Biological Plausibility Study

Recent studies reported the association between increased risk of nonmelanoma skin cancers (NMSCs) and the use of hydrochlorothiazide (HCTZ), one of the most commonly prescribed diuretic, antihypertensive drug, over the world. Although HCTZ is known to be photosensitizing, the mechanisms involved in its potential prophotocarcinogenic effects remain unclear. Under acute exposure, therapeutically relevant concentrations of HCTZ (70, 140, and 370 ng/mL) amplified UVA-induced double-strand breaks, oxidative DNA, and protein damage in HaCaT human keratinocytes, and this effect was associated to a defective activity of the DNA repair enzyme, OGG1. Oxidative damage to DNA, but not that to proteins, was reversible within few hours. After chronic, combined exposure to HCTZ (70 ng/mL) and UVA (10 J/cm(2)), for 9 weeks, keratinocytes acquired a dysplastic-like phenotype characterized by a multilayered morphology and alterations in cell size, shape, and contacts. At the ultrastructural level, several atypical and enlarged nuclei and evident nucleoli were also observed. These transformed keratinocytes were apoptosis resistant, exhibited enhanced clonogenicity capacity, increased DNA damage and inflammation, defective DNA repair ability, and increased expression of the oncogene ΔNp63α and intranuclear β-catenin accumulation (a hallmark of Wnt pathway activation), compared to those treated with UVA alone. None of these molecular, morphological, or functional effects were observed in cells treated with HCTZ alone. All these features resemble in part those of preneoplastic lesions and NMSCs and provide evidence of a biological plausibility for the association among exposure to UVA, use of HCTZ, and increased risk of NMSCs. These results are of translational relevance since we used environmentally relevant UVA doses and tested HCTZ at concentrations that reflect the plasma levels of doses used in clinical practice. This study also highlights that drug safety data should be followed by experimental evaluations to clarify the mechanistic aspects of adverse events

The impact of previous pregnancy loss on lactating behaviors and use of herbal medicines during breastfeeding: A Post Hoc analysis of the herbal supplements in breastfeeding InvesTigation (HaBIT)

Introduction. Complementary and alternative medicines (CAMs) are commonly used among lactating women, despite the poor knowledge of these products and of their safety. Perception of pregnancy- and breastfeeding-related difficulties and consequent use of CAMs may differ in bereaved women, by force of the distress related to previous loss, although no literature evidence is available. This Herbal supplements in Breastfeeding InvesTigation (HaBIT) post hoc analysis explored the impact of previous pregnancy loss on lactating behaviors and on use of CAMs during breastfeeding. Methods. A web-based survey was conducted among lactating women with no previous alive child, resident in Tuscany (Italy). Data on lactating behavior and on CAMs use were collected and evaluated among women with previous pregnancy loss as compared to control women. Results. Out of 476 women answering the questionnaire, 233 lactating women with one child were considered. Of them, 80 had history of pregnancy loss. Cesarean birth was significantly more frequent among women with history of pregnancy loss as compared to controls (41% versus 22%; p=0.004). Proportion, length of exclusive breastfeeding, and occurrence of breastfeeding-related complications were comparable among the two cohorts. More than half of women used CAMs during breastfeeding. Use of CAMs was more frequent among women with previous pregnancy loss (54% versus 68%; p=0.050), specifically considering herbal preparations (16% versus 30%; p=0.018). Major advisors for CAMs use were midwives. 18% and 23% of women without and with history of pregnancy loss declared no clear perception on CAMs efficacy and safety. Conclusion. Overcoming the social taboo of pregnancy loss and training healthcare professionals for an adequate management of the perinatal period are essential for an effective and safe care. Despite the common use and advice on CAMs use during breastfeeding, it is important to acknowledge that limited evidence supports their safety and efficacy during such critical period

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

Angiotensin-II drives human satellite cells toward hypertrophy and myofibroblast trans-differentiation by two independent pathways

Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis