S. Mansueto

Interleukin‐15, as Interferon‐gamma, Induces the Killing of Leishmania infantum in Phorbol‐Myristate‐Acetate‐Activated Macrophages Increasing Interleukin‐12

The potential leishmanicidal activity of interleukin‐15 (IL‐15) was examined while priming with the cytokine phorbol‐myristate‐acetate (PMA)‐activated macrophages and infecting them with Leishmania infantum parasites. The activation of macrophage cultures with IL‐15 determined a significant anti‐leishmanial activity, comparable with that induced by interferon‐gamma (IFN‐γ). The killing of Leishmania in macrophages primed with IL‐15, as well as with IFN‐γ, was followed by an increase in the IL‐12 synthesis. The neutralization of IL‐15 or IFN‐γ, by specific monoclonal antibodies (MoAb) caused a significant reduction in leishmanicidal activity. Furthermore, in PMA‐activated macrophages, the neutralization of IL‐12 production by a specific anti‐IL‐12 MoAb reduced leishmanicidal activity induced by IL‐15 and IFN‐γ. Data indicate that IL‐15 could have a role as an activator of leishmanicidal activity, directly or indirectly, by inducing IL‐12 production.

IL-15 in human visceral leishmaniasis caused by Leishmania infantum

Interleukin (IL)‐15 is a recently discovered cytokine with the ability to stimulate the proliferation activity of Th1 and/or Th2 lymphocytes. Here, we investigated the involvement of IL‐15 in the immune response to Leishmania infantum infection by studying patients with visceral leishmaniasis (VL). We found that IL‐15 is produced by leishmanial antigen (LAg)‐stimulated peripheral blood mononuclear cells (PBMC) from active VL patients at a significantly higher level than those produced by cells from healed VL subjects or healthy controls. A significant increase in IL‐15 serum blood levels was also observed in acute VL patients compared with healed ones. Furthermore, recombinant IL‐15 had an appreciable effect in vitro in reducing IL‐4 and increasing the production of IL‐12 in response to LAg, but it was ineffective in altering the production of interferon‐γ (IFN‐γ). The production of endogenous IL‐15 in acute VL patients appeared to be insufficient to activate both IFN‐γ and IL‐12, as attested by the absence of modification of these two cytokines by neutralization experiments in the presence of anti‐IL‐15 monoclonal antibodies (MoAB). On the contrary, the neutralization of IL‐15 increased IL‐4 production. Together, these results indicate that endogenous IL‐15 plays a role in the suppression of Th2‐type cytokines, even though it does not enhance the production of Th1 cytokines in acute VL patients. Since IL‐15, in the presence of anti‐IL‐4 MoAb, caused a further increase in IL‐12 production and led to a significant production of IFN‐γ, one of its indirect effects on Th1 cell activation could be due to the latter’s effect on Th2 cytokines such as IL‐4. Therefore, our observations indicate that there is a potential for IL‐15 to augment the T‐cell response to human intracellular pathogens.

The significance of serum soluble IL-2 receptor as a marker for active visceral leishmaniasis in Sicilian patients.

Sera from nine Sicilian patients with confirmed visceral leishmaniasis (Leishmania donovani infantum; VL), at the moment of the diagnosis, during the course of the disease and after clinical recovery, were analysed for the concentration of soluble IL‐2 receptor (sIL‐2R). The results show that sIL‐2R is a marker of disease activity, since it is in high concentration at the beginning of infection and returns to the normal range following successful chemotherapy. At the same time of serum analysis for sIL‐2R, peripheral blood mononuclear cells (PBMC) of VL patients were stimulated with phytohaemagglutinin (PHA) or antigen and supernatant tested for IL‐2 and interferon‐gamma (IFN‐γ) production. Data demonstrate that there is an inverse relation between concentration of IL‐2 and IFN‐γ in the supernatants and sIL‐2R secretion in the sera.

Linking the Price of Cancer Drug Treatments to Their Clinical Value

Background and ObjectiveAppropriate pricing of medications is one of the ultimate goals for decision makers, but reliable data on the risk/benefit ratio are often lacking when a Marketing Authorization Application is submitted. Here we propose a method to consistently evaluate price adequacy, which we applied to six anticancer medications approved in Italy in recent years.MethodsWe obtained ratios of cost per survival per day (cost/survival/day) by dividing the total costs of evaluated medications for the median survival gain in days. Each cost/survival/day corresponds to a crude score, with 0 assigned to a cost/survival/day ≥€586. The maximum price considered as adequate was €91 cost/survival/day (score 75) while a score of 100 corresponded to a cost/survival/day ≤€11, based on the thresholds set by the British National Health System (NHS) and the “willingness-to-pay” of the Italian NHS. Crude scores were then adjusted using correction factors for efficacy, safety, quality of life, and prevalence of disease.ResultsNone of the analyzed medications (abiraterone, afatinib, aflibercept, bevacizumab, dabrafenib, and ipilimumab) achieved a final score of 75, corresponding to adequate pricing. The final score for afatinib was the highest with 55 points. Prices of all the other drugs resulted in being inadequate, with negative final scores for bevacizumab, dabrafenib, and ipilimumab.ConclusionsThis method may be considered a tool for the evaluation of appropriateness of price proposed at negotiation and could represent a reliable resource for decision-making. Furthermore, this analysis suggests that most recently approved cancer drugs in Italy do not fulfill price adequacy.

Safety of Antiplatelet Agents: Analysis of 'Real-World' Data from the Italian National Pharmacovigilance Network.

IntroductionAccording to the Italian National Report on drug use, thienopyridines (ticlopidine, clopidogrel and prasugrel) and ticagrelor represent the most prescribed antiplatelet agents, beside aspirin. The aim of this study was to analyse the safety profile of these drugs using data from spontaneous reporting of suspected adverse reactions (ADRs).MethodsSuspected ADRs for ticlopidine, clopidogrel, prasugrel and ticagrelor, reported on the Italian National Pharmacovigilance Network between January 2009 and December 2016, were included in the analysis. All suspected ADRs were classified by frequency, seriousness, outcome, age and system organ class.ResultsClopidogrel showed the highest absolute number of suspected ADRs, followed by ticlopidine. However, these data need to be contextualized in view of the differences in marketing authorization dates, prescription rates and a characterization of the relative seriousness of ADRs per each drug. After the correction for prescription rate, ticagrelor showed the highest reporting trend and ticlopidine the lowest. Most ADRs occurred in the elderly, in particular for ticlopidine. Bleeding represents one of the most reported events (ticlopidine 40%, clopidogrel 26%, prasugrel 42%, ticagrelor 30%) and aspirin was the most frequently associated suspected drug. The majority of ADRs had complete recovery and were non-serious, except for ticlopidine (serious ADRs 53%). Prasugrel showed the highest percentage of ‘life-threatening’ events and ‘death’.ConclusionsBased on the analysis conducted on spontaneous ADRs reporting system in Italy, the safety profile of antiplatelet drugs seems favourable. However, the overall risk-benefit ratio of these drugs needs to be reassessed taking into account the appropriateness of use in particular populations at risk, such as the elderly. Based on this information, we believe that more attention from clinicians and/or an implementation of regulatory measures could be useful for clinical practice.

Off-Label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study

BACKGROUND Given the growing use of off-label in pediatric practice, there is a growing interest on pharmacovigilance programs monitoring the occurrence of adverse drug reactions related to off-label drug prescription in childhood. PATIENTS AND METHODS The results of a one-year program of pharmacovigilance issued in the Sicilian Region, Italy, are herein presented. The study involved 6 pediatric and neonatal centres and prospectively reviewed the prescriptions of 5,060 patients, who were stratified for age (newborn, infant, children, adolescents). RESULTS A total of 14,916 prescriptions were issued for 5,060 patients. Among them, 454 patients [8.97%] received at least one off-label drug. Among the off-label treated patients, 255 [56.2%] were newborns. Anti-infective drugs were the most frequent off-label used drugs, followed by drugs for alimentary tract and metabolism and drugs for blood or blood forming organs. Ninety adverse drug reactions were recorded [1.78% of the total patients]. They occurred after an off-label prescription in 33 out of 90 [36.7%], while those occurring after an on-label prescription were 57 [63.3%]. Patients treated with an off-label drug had a significantly higher risk of adverse drug reactions [7.3% vs. 1.2%; p <0.01]. CONCLUSION The present study indicates that children admitted to neonatal intensive care units are likely to receive an off-label medication; children who receive an off-label medication are usually more likely to be treated with more medication than the others; adverse drug reactions occur in patients admitted in neonatal intensive care and pediatrics are units are more frequently with off-label than with on-label drugs.