Publications by authors named "Barbara Rinaldi"

57 Publications

An in vitro study to assess the effect of hyaluronan-based gels on muscle-derived cells: Highlighting a new perspective in regenerative medicine.

PLoS One 2020 6;15(8):e0236164. Epub 2020 Aug 6.

Department of Experimental Medicine, School of Medicine, University of Campania "Luigi Vanvitelli," Via L. De Crecchio, Naples, Italy.

Hyaluronan (HA) is a nonsulfated glycosaminoglycan that has been widely used for biomedical applications. Here, we have analyzed the effect of HA on the rescue of primary cells under stress as well as its potential to recover muscle atrophy and validated the developed model in vitro using primary muscle cells derived from rats. The potentials of different HAs were elucidated through comparative analyses using pharmaceutical grade a) high (HHA) and b) low molecular weight (LHA) hyaluronans, c) hybrid cooperative complexes (HCC) of HA in three experimental set-ups. The cells were characterized based on the expression of myogenin, a muscle-specific biomarker, and the proliferation was analyzed using Time-Lapse Video Microscopy (TLVM). Cell viability in response to H2O2 challenge was evaluated by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and the expression of the superoxide dismutase enzyme (SOD-2) was assessed by western blotting. Additionally, in order to establish an in vitro model of atrophy, muscle cells were treated with tumor necrosis factor-alpha (TNF-α), along with hyaluronans. The expression of Atrogin, MuRF-1, nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB), and Forkhead-box-(Fox)-O-3 (FoxO3a) was evaluated by western blotting to elucidate the molecular mechanism of atrophy. The results showed that HCC and HHA increased cell proliferation by 1.15 and 2.3 folds in comparison to un-treated cells (control), respectively. Moreover, both pre- and post-treatments of HAs restored the cell viability, and the SOD-2 expression was found to be reduced by 1.5 fold in HA-treated cells as compared to the stressed condition. Specifically in atrophic stressed cells, HCC revealed a noteworthy beneficial effect on the myogenic biomarkers indicating that it could be used as a promising platform for tissue regeneration with specific attention to muscle cell protection against stressful agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236164PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410276PMC
October 2020

New perspectives on the role of muscarinic antagonists in asthma therapy.

Expert Rev Respir Med 2020 08 26;14(8):817-824. Epub 2020 Apr 26.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata" , Rome, Italy.

Introduction: There is increasing evidence that tiotropium, a long-acting muscarinic agent (LAMA), is useful in the presence of severe-uncontrolled asthma despite the optimization of therapy with inhaled corticosteroids (ICSs) and long-acting β agonists (LABAs) as recommended by the current guidelines. Furthermore, in recent years there have been several  preclinical and clinical studies on the pharmacological and therapeutic impact of other LAMAs in asthma.

Areas Covered: We have conducted an extensive search on muscarinic antagonists in asthma therapy throughout several sources and discuss what has emerged in the last 3 years (January 2017-March 2020).

Expert Opinion: New evidence indicates that the effectiveness of adding a LAMA, at least tiotropium, is independent of the degree of the type 2 inflammation and age of patient. Therefore, tiotropium can be administered without the need for patient phenotyping. Umeclidinium and glycopyrronium also appear effective in asthma. Initial treatment with LAMA+ICS for those with mild asthma may be an equally effective therapeutic option as LABA+ICS but this hypothesis should be confirmed by statistically powered trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17476348.2020.1758069DOI Listing
August 2020

Emerging muscarinic receptor antagonists for the treatment of asthma.

Expert Opin Emerg Drugs 2020 06 17;25(2):123-130. Epub 2020 Jun 17.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata" , Rome, Italy.

Introduction: The increased acetylcholine signaling in asthma pathophysiology offers the rationale for the use of LAMAs in the treatment of asthmatic patients. Tiotropium is still the only LAMA approved for use in asthma but there is a real interest in developing novel LAMAs for the treatment of asthma, or at least to extend this indication to other LAMAs already on the market.

Areas Covered: We examined and discussed trials and research that have studied or are evaluating the role of LAMAs already on the market in asthma and possible novel muscarinic acetylcholine receptor antagonists.

Expert Opinion: Glycopyrronium and umeclidinium will soon be included in the GINA strategy with the same current indications of tiotropium. It is likely that the choice of the LAMA will be influenced not so much by its pharmacological profile as by the type of triple therapy chosen. It is extremely difficult to identify a new LAMA that is more effective than tiotropium, but is it plausible that new technologies that will allow delivering the drug in a more targeted way and with a lower risk of adverse effects may represent the real progress in the use of LAMAs in asthma in the coming years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14728214.2020.1758059DOI Listing
June 2020

A review of the pharmacokinetics of M muscarinic receptor antagonists used for the treatment of asthma.

Expert Opin Drug Metab Toxicol 2020 Feb 30;16(2):143-148. Epub 2020 Jan 30.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

: There is solid evidence that in patients with poorly controlled severe asthma despite the use of ICS and LABA, the addition of LAMAs, such as tiotropium, significantly increases the time to the first severe exacerbation and provides a modest but sustained bronchodilation. However, only a very limited number of pharmacokinetic studies with these agents have been performed in asthmatic patients.: The pharmacokinetic profile of inhaled tiotropium, umeclidinium and glycopyrronium in healthy volunteers and that of inhaled tiotropium and umeclidinium in asthmatic patients have been reviewed.: In asthmatic patients, LAMAs are rapidly absorbed into the systemic compartment and demonstrate bi-exponential elimination (rapidly declining plasma concentrations followed by slow apparent terminal elimination). Apparently, the severity of asthma does not change the pharmacokinetics of LAMAs. The limited information available is focused on the plasma pharmacokinetic profile of these drugs and, consequently, although suitable for establishing a systemic safety profile, it does not tell us much about possible therapeutic efficacy of LAMAs in asthmatics because quantification of systemic plasma values is neither at the airways, which are their site of action nor representative of their transport to this site.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2020.1716730DOI Listing
February 2020

Protective effect of piceatannol and bioactive stilbene derivatives against hypoxia-induced toxicity in H9c2 cardiomyocytes and structural elucidation as 5-LOX inhibitors.

Eur J Med Chem 2019 Oct 10;180:637-647. Epub 2019 Jul 10.

Consorzio Sannio Tech-AMP Biotec, Appia Str. 7, Apollosa, BN, 82030, Italy; Institute of Food Sciences, National Research Council, Roma Str. 64, Avellino, 83100, Italy. Electronic address:

Stilbenes with well-known antioxidant and antiradical properties are beneficial in different pathologies including cardiovascular diseases. The present research was performed to investigate the potential protective effect of resveratrol (1) and piceatannol (2), against hypoxia-induced oxidative stress in the H9c2 cardiomyoblast cell line, and the underlying mechanisms. Compounds 1 and 2 significantly inhibited the release of peroxynitrite and thiobarbituric acid levels at na no- or submicromolar concentrations, and this effect was more evident in piceatannol-treated cells, that significantly increased MnSOD protein level in a concentration dependent manner. Furthermore, since piceatannol, which is far less abundant in natural sources, displayed a higher bioactivity than the parent compound, we hereby report on a very fast synthesis and detailed structure-based design of a focused stilbene library. Finally, taking into account that hypoxia-induced ROS accumulation also increases expression and activity of 5-lipoxygenase (5-LOX) with production of leukotrienes, we have disclosed structural key factors crucial for 5-LOX activity. Among the synthesized analogues ( 3-7), compound 7 was the most effective in improving cardiomyocytes viability and in 5-LOX inhibition. In conclusion, modeling and experimental studies provided the basis for further optimization of stilbene analogues as multi-target inhibitors of the inflammatory and oxidative pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2019.07.033DOI Listing
October 2019

Pharmacokinetics and pharmacodynamics of inhaled corticosteroids for asthma treatment.

Pulm Pharmacol Ther 2019 10 23;58:101828. Epub 2019 Jul 23.

University of Rome "Tor Vergata", Department of Experimental Medicine, Rome, Italy. Electronic address:

The differences in the pharmacokinetic (PK) characteristics of inhaled corticosteroids (ICSs) critically influence the profile of each of them, but also the significant differences in glucocorticoid receptor selectivity, potency, and physicochemical properties are critical in defining the pharmacodynamic (PD) profile of an ICS. The PK and PD properties of ICSs used in asthma and the importance of their interrelationship have been reviewed. The differences among the ICSs in PK and PD must be considered when an ICS should be prescribed to an asthmatic patient because a better understanding of the PK/PD interrelationship of ICSs could be important to better fit with the between-patient variability and within-patient repeatability in the response to ICSs that often complicate the therapeutic approach to the asthmatic patient. The role of the device in influencing the PK profile of an ICS must be always considered because it is crucial. Also patient-related factors and disease severity affect pulmonary deposition of ICS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pupt.2019.101828DOI Listing
October 2019

Addition of the Aldose Reductase Inhibitor Benzofuroxane Derivative BF-5m to Prolonged and Moderate Exercise Training Enhanced Protection of the Rat Heart From Type-1 Diabetes.

Front Pharmacol 2019 16;10:392. Epub 2019 Apr 16.

Department of Experimental Medicine, Pharmacology Division, University of Campania "L. Vanvitelli", Naples, Italy.

Moderate exercise training may not be sufficient to exert beneficial effects on the cardiovascular system because of the long-term multifactorial etiology of diabetic complications. The addition of a proper pharmacological tool to the physical exercise should improve the outcomes of the diabetic damage. Here it is shown that 8 weeks exercise training of type 1 diabetic Sprague-Dawley (SD) rats resulted in a significantly increased heart rate, a 14% increase in the left ventricular ejection fraction (LVEF) increased plasma insulin levels and a 13% decrease in plasma glucose with respect to sedentary animals. The training also resulted in a 22% reduction in cardiac QT interval from a diabetic sedentary value of 185 ± 19 ms. Treatment of trained rats with the new antioxidant and NO-releasing aldose reductase 2 inhibitor 5(6)-(benzo[]thiazol-2-ylmethoxy) benzofuroxane BF-5m, 20 mg/kg/day, added a further and significant ( < 0.01 vs. sedentary) increase of the LVEF up to 38% at 8 week time point. The long QT interval recorded in trained rats was reduced to further 12% by addition to the training of pharmacological treatment with 20 mg/kg/day BF-5m. At this time, the association of the two treatments improved the expression into the cardiac tissue of sarcoplasmic reticulum Ca ATPase 2 (SERCA2) and manganese superoxide dismutase (MnSOD), and reduced the fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.00392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476970PMC
April 2019

Pharmacological characterization of the interaction between tiotropium bromide and olodaterol on human bronchi and small airways.

Pulm Pharmacol Ther 2019 06 12;56:39-50. Epub 2019 Mar 12.

Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Combining a long-acting β-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the LAMA tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pupt.2019.03.004DOI Listing
June 2019

Cardioprotective effect of a moderate and prolonged exercise training involves sirtuin pathway.

Life Sci 2019 Apr 5;222:140-147. Epub 2019 Mar 5.

Department of Experimental Medicine, Pharmacology Division, University of Campania "L. Vanvitelli", 80138, Naples, Italy. Electronic address:

Aim: To investigate the cardioprotective effects of prolonged and moderate exercise training on cellular and molecular events early after myocardial infarction.

Materials And Methods: Male Wistar rats were divided in sedentary or exercised group; both groups underwent to a myocardial infarction. All the molecular and immunohistochemical analyses on hearts of sedentary and exercised rats were performed 48 h after surgical procedure. SIRT1 and SIRT3 expression were measured and two of the pathways activated by sirtuins, p53-induced apoptosis and Forkhead boxO (FOXO)3a-induced oxidative stress, were investigated. All the experiments were performed also in presence of the SIRT inhibitor, EX527.

Key Findings: Fourty-eight hours post myocardial infarction, exercise training induced the activation of SIRT1 and SIRT3 pathway reducing cardiomyocytes apoptosis and oxidative damage. Molecular data were confirmed by immunohistochemical evaluations. These effects are more evident in border infarcted zone than in the remote myocardium.

Significance: Exercise training is a non-pharmacological prevention strategy in cardiovascular diseases and the sirtuins family seems to be as novel and attractive target in cardioprotection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2019.03.001DOI Listing
April 2019

AT1-receptor blockade: Protective effects of irbesartan in cardiomyocytes under hypoxic stress.

PLoS One 2018 24;13(10):e0202297. Epub 2018 Oct 24.

Department of Experimental Medicine, Section of Pharmacology, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.

Hypoxia induces myocardial injury through the activation of inflammatory and oxidative processes. The pivotal role of the renin angiotensin system (RAS) in the pathogenesis of cardiovascular diseases has been firmly established in clinical trials and practice; in fact many experimental and clinical data have highlighted that its inhibition has a cardioprotective role. Activated RAS also stimulates inflammation directly inducing proinflammatory and oxidative gene expression. This study aimed to investigate the protective role of a pre-treatment (10 and 100 μM) with irbesartan on injury induced by 24 h of hypoxia in HL-1 cardiomyocytes; in particular, we have analyzed the natriuretic peptide (BNP) expression, a biomarker able to modulate inflammatory reaction to cardiac injury and some markers involved in oxidative stress and inflammation. Our results demonstrated that a pre-treatment with 100 μM irbesartan significantly increased SOD activity and catalase expression of 15 and 25%, respectively, compared to hypoxic cells (P<0.05). On the other hand, it was able to reduce the release of peroxynitrite and iNOS protein expression of 20 and 50% respectively (P<0.05). In addition irbesartan exerts an anti-inflammatory activity reducing Toll-like receptors (TLRs)-2 and -4 mRNA expression, TNF-alpha expression and activity (20%) and increasing the expression of the cytokine IL-17 (40%) (P<0.05 vs hypoxia). Our findings also showed that BNP induced by ischemia was significantly and in a concentration-dependent manner reduced by irbesartan. The findings of our study demonstrated that the AT1 receptor antagonist irbesartan exerts a protective role in an in vitro hypoxic condition reducing oxidative stress and inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202297PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200178PMC
March 2019

Pharmacokinetic considerations concerning the use of bronchodilators in the treatment of chronic obstructive pulmonary disease.

Expert Opin Drug Metab Toxicol 2018 Oct 9;14(10):1101-1111. Epub 2018 Oct 9.

c Department of Experimental Medicine and Surgery , University of Rome Tor Vergata , Rome , Italy.

Introduction: Bronchodilators are central to the symptomatic treatment of chronic obstructive pulmonary disease (COPD). Their pharmacodynamic aspects have been extensively described, but the pharmacokinetic profile of these drugs is much less well known. There are very few studies that describe the levels of drugs in the lung compartment following inhalation, and still very little is known about the relationships between drug levels in the lung and biological activity of bronchodilators. Areas covered: We review the existing evidence on the pharmacokinetics of bronchodilators, especially when administered to patients with COPD. Expert opinion: COPD does not substantially influence the pharmacokinetics of bronchodilators, although a modest signal, perhaps, exists for theophylline. We must highlight that plasma pharmacokinetics is suitable for establishing a systemic safety profile of inhaled bronchodilators but not their pulmonary efficacy profile because measurement of systemic blood values is neither at the site of action nor representative of transport to the site of action (the airways). However, there are large amounts of information from research in this field and recent advances with microdialysis and matrix-assisted laser desorption-ionization time-of-flight mass spectrometry to measure drugs in lung tissues that hopefully will lead to a better understanding of the pharmacokinetic/pharmacodynamic relationships for inhaled medicines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2018.1530215DOI Listing
October 2018

Role of statins and mevalonate pathway on impaired HDAC2 activity induced by oxidative stress in human airway epithelial cells.

Eur J Pharmacol 2018 Aug 18;832:114-119. Epub 2018 May 18.

Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.

In patients with chronic obstructive pulmonary disease (COPD) the inflammatory response is often steroid-resistant, likely since oxidative stress and cigarette smoking impair histone deacetylase 2 (HDAC2) activity. Since it has been demonstrated that statins may restore the HDAC2 activity in cultured human endothelial cells, the aim of this study was to investigate the effects of statins in reversing the steroid-resistance induced by oxidative stress. We evaluated the effects of simvastatin and dexamethasone on HDAC2 expression and activity, and the role of mevalonate and Rho/ROCK pathways in A549 cells, a human lung type II epithelial cell line stressed with HO. Our results documented that HO significantly reduced the HDAC2 expression and activity. In HO treated cells dexamethasone was unable to restore the activity of HDAC2, whereas simvastatin restored both the expression and the activity of this enzyme. Our data also showed that mevalonate reduced the activity of HDAC2 whereas Y27632, a Rho/ROCK inhibitor, had no effect on HDAC2 activity when co-administered with simvastatin. Our data suggest that statins could have the potential to restore corticosteroid sensitivity in A549 cells. The evidences of this study suggest that, although both mevalonate and Rho/ROCK pathways are involved in the detrimental effect elicited by oxidative stress, statins may restore the function and expression of depleted HDAC2 via modulating the mevalonate cascade, at least in A549 cells. In conclusion, the modulation of histone acetyltransferase/deacetylase activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2018.05.023DOI Listing
August 2018

β2-Adrenoceptor signalling bias in asthma and COPD and the potential impact on the comorbidities associated with these diseases.

Curr Opin Pharmacol 2018 06 12;40:142-146. Epub 2018 May 12.

Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy. Electronic address:

Inhaled selective β2-agonists are the most widely used treatment for obstructive airway diseases. The classical mechanism of action of these drugs is considered as their ability to activate β2-adrenergic receptors (β2-AR) on airway smooth muscle leading to G-protein activation and subsequent generation of c-AMP causing bronchodilation. However, there is now growing evidence to suggest that binding of β2-agonists to β2-AR is pleotropically coupled to many intracellular pathways whereby depending on the state of the β2-AR when activated, a subset of different intracellular responses can be triggered. This is called biased agonism (or functional selectivity) and this type of activity has now been observed with different types of G protein-coupled receptor (GPCR), not just β2-AR. Accordingly, drug efficacy for many agonists binding to GPCRs can no longer be solely described in terms of a single relationship between binding of a ligand to a receptor and the subsequent magnitude of the cellular response, but is often far more complex reflecting a specific complement of signals following binding of a ligand to its receptor. These differences in responses depending on what state the receptor is in when the ligand binds to it can subsequently influence the intracellular signalling that in turn can influence the efficacy of β2-AR ligands. Such findings suggest that in the future it may be possible to develop new synthetic β2-agonists that could preferentially confine their activity in stabilizing/activating the receptor to a certain conformation which could lead to improved drugs either to reduce adverse responses or to avoid drugs that activate certain conformations of the receptors that may lead to tolerance or desensitization following repeated activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.coph.2018.04.012DOI Listing
June 2018

N-Acetylcysteine protects human bronchi by modulating the release of neurokinin A in an ex vivo model of COPD exacerbation.

Biomed Pharmacother 2018 Jul 24;103:1-8. Epub 2018 Apr 24.

Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, Italy. Electronic address:

Aims: N-Acetylcysteine (NAC) reduces the risk of exacerbation of chronic obstructive pulmonary disease (COPD). Although NAC also has anti-inflammatory activity, the detailed mechanism leading to its protective role remains to be elucidated. We tested the impact of NAC against the effects of lipopolysaccharide (LPS) in an ex vivo model of COPD exacerbation, and investigated the role of neurokinin A (NKA) in this context.

Main Methods: Isolated airways from COPD patients were incubated overnight with LPS (100 ng/ml). NAC was tested at concentrations resembling the plasma levels elicited by oral administration of NAC at 200 mg/day (very low dose), 600 mg/day (low dose) and 1.200 mg/day (high dose).

Key Findings: NAC at high concentrations normalized the peroxidase activity, HO, malondialdehyde (MDA), nitric oxide, glutathione (GSH), total antioxidant capacity (TAC), and interleukin 6 (IL-6) (overall change 34.32% ± 4.22%, P < 0.05 vs. LPS-treated). NAC at low concentrations modulated peroxidase activity, HO, MDA, GSH, TAC, and IL-6 (overall change 34.88% ± 7.39%, P < 0.05 vs. LPS-treated). NAC at very-low concentrations was effective on peroxidase activity, HO, GSH, and IL-6 (overall change 35.05 ± 7.71%, P < 0.05 vs. LPS-treated). Binary logistic regression analysis indicated that the modulatory effect of NAC on NKA levels was associated with a reduction of pro-oxidant factors and IL-6, and selectively blocking the NK receptor abolished such an association.

Significance: This study demonstrates that, along with its well-known antioxidant activity, the protective effect of NAC against the detrimental effect of LPS is due to the modulation of NKA and IL-6 levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2018.04.011DOI Listing
July 2018

Pharmacogenetic and pharmacogenomic considerations of asthma treatment.

Expert Opin Drug Metab Toxicol 2017 Nov 23;13(11):1159-1167. Epub 2017 Oct 23.

b Department of Systems Medicine , University of Rome Tor Vergata , Rome , Italy.

Introduction: Pharmacogenetic and pharmacogenomic approaches are already utilized in some areas, such as oncology and cardiovascular disease, for selecting appropriate patients and/or establishing treatment and dosing guidelines. This is not true in asthma although many patients have different responses to drug treatment due to genetic factors. Areas covered: Several genetic factors that affect the pharmacotherapeutic responses to asthma medications, such as β-AR agonists, corticosteroids, and leukotriene modifiers and could contribute to significant between-person variability in response are described. Expert opinion: An expanding number of genetic loci have been associated with therapeutic responses to asthma drugs but the individual effect of one single-nucleotide polymorphism is partial. In fact, epigenetic changes can modify genetic effects in time-, environment-, and tissue-specific manners, genes interact together in networks, and nongenetic components such as environmental exposures, gender, nutrients, and lifestyle can significantly interact with genetics to determine the response to therapy. Therefore, well-designed randomized controlled trials or observational studies are now mandatory to define if response to asthma medications in individual patients can be improved by using pharmacogenetic predictors of treatment response. Meanwhile, routine implementation of pharmacogenetics and pharmacogenomics into clinical practice remains a futuristic, far-off challenge for many clinical practices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2017.1391215DOI Listing
November 2017

Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury.

Biosci Rep 2017 Oct 27;37(5). Epub 2017 Sep 27.

Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy.

Inflammatory cells play key roles in restenosis upon vascular surgical procedures such as bypass grafts, angioplasty and stent deployment but the molecular mechanisms by which these cells affect restenosis remain unclear. The p110δ isoform of phosphoinositide 3-kinase (PI3K) is mainly expressed in white blood cells. Here, we have investigated whether p110δ PI3K is involved in the pathogenesis of restenosis in a mouse model of carotid injury, which mimics the damage following arterial grafts. We used mice in which p110δ kinase activity has been disabled by a knockin (KI) point mutation in its ATP-binding site (p110δ PI3K mice). Wild-type (WT) and p110δ mice were subjected to longitudinal carotid injury. At 14 and 30 days after carotid injury, mice with inactive p110δ showed strongly decreased infiltration of inflammatory cells (including T lymphocytes and macrophages) and vascular smooth muscle cells (VSMCs), compared with WT mice. Likewise, PI-3065, a p110δ-selective PI3K inhibitor, almost completely prevented restenosis after artery injury. Our data showed that p110δ PI3K plays a main role in promoting neointimal thickening and inflammatory processes during vascular stenosis, with its inhibition providing significant reduction in restenosis following carotid injury. p110δ-selective inhibitors, recently approved for the treatment of human B-cell malignancies, therefore, present a new therapeutic opportunity to prevent the restenosis upon artery injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BSR20171112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617917PMC
October 2017

Pharmacokinetic/pharmacodynamic drug evaluation of benralizumab for the treatment of asthma.

Expert Opin Drug Metab Toxicol 2017 Sep 24;13(9):1007-1013. Epub 2017 Jul 24.

b Department of Systems Medicine , University of Rome Tor Vergata , Rome , Italy.

Introduction: In many severe asthmatics, eosinophils cause inflammation and airways hyperresponsiveness, resulting in frequent exacerbations, impaired lung function, and reduced quality of life. Interleukin-5 (IL-5) is a key cytokine for eosinophil growth, differentiation, recruitment, activation, and survival. Anti-IL-5-based therapies (mepolizumab and reslizumab are humanized monoclonal antibodies (hmAbs) that recognize free IL-5, benralizumab is a hmAb directed at the α subunit of the IL-5R) target the IL-5-signaling in eosinophilic asthma. Areas covered: The pharmacodynamic/pharmacokinetic profile of benralizumab and how it provided indications that permitted optimization of the design and timelines of the pivotal trials are described. Expert opinion: Benralizumab has the advantage over other anti-IL-5 therapies to target the IL-5Rα itself. Afucosylation enhances its interaction with its binding site and facilitates its pharmacological activity. Other benefits of benralizumab are fast (within 24 h) depletion of peripheral blood eosinophils, potent suppressive activity of bone marrow eosinophils and eosinophil precursors, tissue eosinophil apoptosis regardless of the presence of eosinophil survival factors and even at low IL-5R densities. The fact that benralizumab is dosed subcutaneously and is equally effective when given every eight weeks instead than every four weeks provides patients with convenience of self-administration and make it appealing for patients who dislike injections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2017.1359253DOI Listing
September 2017

Management of Chronic Obstructive Pulmonary Disease in Patients with Cardiovascular Diseases.

Drugs 2017 May;77(7):721-732

Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.

Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases often coexist. The mechanistic links between these two diseases are complex, multifactorial and not entirely understood, but they can influence the therapeutic approach. Therapy can be primarily directed towards treating the respiratory symptoms and reducing lung inflammation. Smoking cessation, bronchodilators and inhaled corticosteroids are central to this therapeutic approach. The underlying pathophysiological mechanisms that are responsible for the increased cardiovascular risk in COPD remain unclear, but might include arterial stiffness, inflammation and endothelial dysfunction as a consequence of systemic exposure to chemicals in cigarette smoke or airborne pollution. Therefore, it is plausible that treatment of cardiovascular co-morbidities might reduce morbidity and mortality in patients with COPD and, consequently, therapy of COPD should be shifted to the treatment of cardiovascular diseases and systemic inflammation. In support of this approach, early data suggest that patients with COPD treated with angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, statins, anti-platelet drugs or β-adrenoceptor blockers may have improved survival and reduced hospitalisation from acute exacerbations of COPD. In this review, the potential impact of traditional therapies for COPD that are centred on treating the lungs and newer strategies potentially able to affect and mitigate cardiovascular risks in patients with COPD are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40265-017-0731-3DOI Listing
May 2017

Assessing the viability of long-acting β-agonists in paediatric asthma patients: a pharmacokinetic/pharmacodynamic perspective.

Expert Opin Drug Metab Toxicol 2017 Feb 14;13(2):129-136. Epub 2016 Sep 14.

b Department of Systems Medicine , University of Rome Tor Vergata , Rome , Italy.

Introduction: Long-acting β-agonists (LABAs) combined with inhaled corticosteroids (ICSs) are still commonly prescribed to asthmatic children. Unfortunately, pediatric LABA use is based primarily on data from adults, despite the fact that children are not simply small adults and the magnitude of changes in dose exposure and/or exposure response may not be solely reflected by differences in body weight. Areas covered: The differences in pharmacokinetics (PK) and pharmacodynamics (PD) of LABAs are described and discussed with reference children and adults. Expert opinion: Data on the PK behavior of LABAs is very limited and there is almost no data on once-daily LABAs available in the pediatric population. We do not believe that this is due to a fundamental lack of information because therapeutic response and adverse effects are more useful for the optimization of β-agonist treatment than measurement of plasma drug concentrations per se. Nevertheless, population PK-PD studies in children are needed according to the European rules in order to define rational, patient-tailored dosing schemes. Population PK-PD modeling and simulation using non-linear mixed effect modeling should be considered as the preferred tool to develop effective and safe dosing regimens for children because they present an opportunity to analyze sparse and unbalanced datasets, thereby minimizing the burden for each child.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2017.1234604DOI Listing
February 2017

Brain natriuretic peptide: Much more than a biomarker.

Int J Cardiol 2016 Oct 9;221:1031-8. Epub 2016 Jul 9.

Department of Experimental Medicine, Second University of Naples, Naples, Italy.

Brain natriuretic peptide (BNP) modulates several biological processes by activating the natriuretic peptide receptor A (NPR-A). Atria and ventricles secrete BNP. BNP increases natriuresis, diuresis and vasodilatation, thus resulting in a decreased cardiac workload. BNP and NT-proBNP, which is the biologically inactive N-terminal portion of its pro-hormone, are fast and sensitive biomarkers for diagnosing heart failure. The plasma concentrations of both BNP and NT-proBNP also correlate with left ventricular function in patients with acute exacerbation of COPD, even without history of heart failure. Several studies have been conducted in vitro and in vivo, both in animals and in humans, in order to assess the potential role of the NPR-A activation as a novel therapeutic approach for treating obstructive pulmonary disorders. Unfortunately, these studies have yielded conflicting results. Nevertheless, further recent specific studies, performed in ex vivo models of asthma and COPD, have confirmed the bronchorelaxant effect of BNP and its protective role against bronchial hyperresponsiveness in human airways. These studies have also clarified the intimate mechanism of action of BNP, represented by an autocrine loop elicited by the activation of NPR-A, localized on bronchial epithelium, and the relaxant response of the surrounding ASM, which does not expresses NPR-A. This review explores the teleological activities and paradoxical effects of BNP with regard to chronic obstructive respiratory disorders, and provides an excursus on the main scientific findings that explain why BNP should be considered much more than a biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2016.07.109DOI Listing
October 2016

Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment of asthma.

Expert Opin Drug Metab Toxicol 2016 Jul 9;12(7):813-22. Epub 2016 Jun 9.

b Department of Experimental Medicine, Section of Pharmacology 'L. Donatelli', Centre of Excellence for Cardiovascular Diseases , Second University of Naples , Naples , Italy.

Introduction: The pharmacokinetic (PK) and pharmacodynamic (PD) effects of long-acting β2-agonists and mostly inhaled corticosteroids (ICSs) shape the efficacy and safety of these agents in the treatment of asthma. In fact, the PK and PD characteristics of the drug largely determine the degree of pulmonary targeting Areas covered. In this review, we summarize the PK and PD properties of inhaled fluticasone furoate (FF) and vilanterol trifenatate (VI) and their fixed-dose combination (FDC) for the treatment of asthma Expert opinion. It is difficult to interpret the data that we have described because the preclinical and clinical development of FF/VI FDC was not really based on solid information on quantitative PK/PD approach. Unfortunately, for both FF and VI we only know concentrations in systemic blood, a compartment that is downstream of both target and non-target respiratory tissue. This lack of information does not allow us to understand the temporal relationship between the delivered dose and the drug concentration at the sites of action within the lungs. In addition, all studies performed with FF and VI did not address the fundamental issue that asthma can significantly alter lung deposition, absorption and also clearance of inhaled medicines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2016.1192125DOI Listing
July 2016

Long-term administration of ranolazine attenuates diastolic dysfunction and adverse myocardial remodeling in a model of heart failure with preserved ejection fraction.

Int J Cardiol 2016 Aug 12;217:69-79. Epub 2016 May 12.

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.

Background: To investigate the effects of chronic administration of ranolazine (RAN) on experimental model of heart failure with preserved ejection fraction.

Methods: Seven-weeks old Dahl salt-sensitive rats were fed a high salt diet for 5weeks to induce hypertension. Afterwards, rats continued with a high salt diet and were administered either with vehicle or RAN (20mg/kg/die, ip) for the following 8weeks. Control rats were maintained on a low salt diet.

Results: While systolic parameters were not altered, diastolic parameters were changed in high salt animals. Hemodynamic analysis showed a decreased dP/dt min, increased LVEDP, longer time constant and steeper slope of the end-diastolic pressure-volume relationship. Treatment with RAN attenuated these alterations and determined a reduction in mortality. Additionally, the magnitude of myocardial hypertrophy and activation of PI3K/Akt pathway were reduced. Alteration in diastolic compliance as a consequence of elevated myocardial stiffness was confirmed by an increase of collagen deposition and activation of pro-fibrotic TGF-β/SMAD3/CTGF signaling. These effects were counteracted by RAN. High salt rats had a decrease in SERCA2 and an increase in Na(+)/Ca(2+) exchanger (NCX). Treatment with RAN reduced NCX expression and determined an increment of SERCA2. Moreover, the levels of nitrotyrosine and oxidized dyhydroethidium were higher in high salt rats. RAN induced a decrement of oxidative stress, supporting the concept that reduction in ROS may mediate beneficial effects.

Conclusions: Our findings support the possibility that diastolic dysfunction can be attenuated by RAN, indicating its ability to affect active relaxation and passive diastolic compliance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2016.04.168DOI Listing
August 2016

Olodaterol for the treatment of asthma.

Expert Opin Investig Drugs 2016 Jul 23;25(7):861-6. Epub 2016 May 23.

a Department of Systems Medicine , University of Rome Tor Vergata , Rome , Italy.

Introduction: Long-acting β-agonist (LABA)/inhaled corticosteroid (ICS) combinations are still the mainstay of asthma therapy but there is a pressing need to increase adherence to the prescribed treatment achievable in general by reducing the dose frequency. Consequently, there is considerable interest within the pharmaceutical industry in the discovery of once-daily β2-agonists (ultra-LABAs) to be used as a part of a combination therapy for treating asthma.

Areas Covered: The authors review the preclinical and clinical development of olodaterol, a new ultra-LABA characterized by an improved selectivity for β2-adrenoceptors and a rather high intrinsic efficacy profile, in asthma. The clinical results were generated by 4 Phase 2 trials, which have enrolled 731 asthmatic patients.

Expert Opinion: The available results indicate that olodaterol is able to induce an effective 24-h bronchodilation and is safe. However, one cannot formulate a solid conclusion on the best dose and/or dose frequency to be used in asthma because trials were not powered to assess the differences between doses and dose frequencies. Apparently, there is no Phase 3 trial planned or ongoing for olodaterol monotherapy in patients with asthma and also no attempt to combine olodaterol with an ICS, which is surprising.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13543784.2016.1188078DOI Listing
July 2016

Propofol protects against opioid-induced hyperresponsiveness of airway smooth muscle in a horse model of target-controlled infusion anaesthesia.

Eur J Pharmacol 2015 Oct 11;765:463-71. Epub 2015 Sep 11.

Department of Experimental Medicine, Second University of Naples, Naples, Italy.

General anaesthesia in horses is associated with elevated mortality rate in subjects suffering of heaves. Target-controlled infusion (TCI) of sedative-hypnotic medications and opioids represents a total intravenous anaesthesia (TIVA) method validated in veterinary medicine. Since there are no data concerning the impact of these classes of drugs in inducing bronchial hyperresponsiveness (BHR) in horses, the aim of this study was to investigate the effect propofol and remifentanil on the contractile response of equine airway smooth muscle. The influence of propofol and remifentanil on the contractile response of equine isolated bronchi to electrical field stimulation (EFS) was assessed. The role of capsaicin-sensitive sensory nerves, inducible nitric oxide synthase (iNOS) and neurokinin 2 (NK2) receptor was also assessed. The interaction analysis was performed by Bliss Independence theory. Experiments were repeated in desensitized and passively sensitized airways. Remifentanil induced BHR in both non-sensitized and passively sensitized bronchi, (+56.33±8.01% and +99.10±14.52%, respectively; P<0.01 vs. control) and propofol significantly prevented this effect (P>0.05 vs. remifentanil). The inactivation of capsaicin-sensitive sensory nerves via desensitization and blocking NK2 receptor inhibited the BHR remifentanil-induced (P>0.05 vs. controls). The inhibition of iNOS reverted the protective effect of propofol on the BHR induced by remifentanil (non-sensitized: +47.11±7.70%; passively sensitized: +70.51±11.39%; P<0.05 vs. control). Propofol synergistically interacted (overall ≈40%) in preventing the remifentanil-induced BHR. Remifentanil induces BHR via stimulating capsaicin-sensitive sensory nerves that facilitate the cholinergic neurotransmission through the activation of NK2 receptor. The propofol/remifentanil combination may be safely administered in course of TCI-TIVA procedures also in heaves affected horses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2015.09.007DOI Listing
October 2015

Effect of Prolonged Moderate Exercise on the Changes of Nonneuronal Cells in Early Myocardial Infarction.

Neural Plast 2015 22;2015:265967. Epub 2015 Jul 22.

Department of Experimental Medicine, Division of Pharmacology, The Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.

Myocardial infarction (MI) is one of the leading causes of death in developed countries and it is characterized by several associated symptomatologies and poor quality of life. Recent data showed a possible interaction between infarction and brain inflammation and activity. Previous studies have demonstrated the beneficial effect of exercise training on deterioration in cardiac function after MI. In this study we analyzed in sedentary and trained rats the microglia and astrocytes 48 hours after MI in PVN, thalamus, prefrontal cortex, and hippocampus through immunofluorescence approach. We found significant changes in specific microglia phenotypes in the brain areas analyzed together with astrocytes activation. Prolonged exercise normalized these morphological changes of microglia and astrocytes in the prefrontal cortex, hippocampus, and thalamus but not in the PVN. Our data suggest that there is an early brain reaction to myocardial infarction induction, involving nonneuronal cells, that is attenuated by the prolonged exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/265967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526216PMC
April 2016

G-CSF contributes at the healing of tunica media of arteriotomy-injured rat carotids by promoting differentiation of vascular smooth muscle cells.

J Cell Physiol 2016 01;231(1):215-23

Department of Experimental Medicine, Biotechnology, and Molecular Biology Section, Second University of Naples, Naples, Italy.

Restenosis is a complex pathophysiological disease whose causative mechanisms are not fully understood. Previous studies allowed us to demonstrate the efficacy of bone marrow mesenchymal stromal cells (MSCs) transplantation in limiting the pathophysiological remodeling in a model of arteriotomy-induced (re) stenosis. In the current research we studied the effectiveness of G-CSF treatment on male rate rats that were subjected carotid arteriotomy in order to evaluate a potentially effective non-invasive strategy that recapitulates the MSC-mediated recovery of injured vessels. WKY male rats were subjected carotid arteriotomy and given a nine day treatment (3 days pre- to 6 days post-arteriotomy) with G-CSF or saline. Carotids were harvested 7 and 30 days following arteriotomy (early- and late-phase, respectively). Although morphometrical analysis did not reveal differences in lumen narrowing between G-CSF- and PBS-carotids 30 days following arteriotomy, we detected a noticeable conservative effect of G-CSF treatment on vascular wall morphology. Histological and molecular analysis revealed an increase in cellularity within the tunica media with a concomitant increase of the VSMCs differentiation markers both at early- and late-phases of (re) stenotic response in G-CSF-treated carotids (Sm22-alpha, Myocd, and Smtn). These findings were accompanied by the downregulation of oxidative stress-related genes in G-CSF-injured rats. The effect exerted by G-CSF in our model of arteriotomy-induced (re) stenosis seemed support the recovery of the architecture of the tunica media of injured vessels by: (i) inducing VSMCs differentiation; and (ii) limiting the oxidative-stress response induced by arteriotomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.25074DOI Listing
January 2016

AXL is an oncotarget in human colorectal cancer.

Oncotarget 2015 Sep;6(27):23281-96

Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi ", Seconda Università degli Studi di Napoli, Napoli, Italia.

AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples. Taken together, AXL inhibition could represent a novel therapeutic approach in CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.3962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695118PMC
September 2015

Contribution of sensory nerves to LPS-induced hyperresponsiveness of human isolated bronchi.

Life Sci 2015 Jun 24;131:44-50. Epub 2015 Apr 24.

Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy.

Aims: Bacterial lipopolysaccharide (LPS) can induce bronchial hyperresponsiveness (BHR), but the underlying mechanisms remain to be determined. Here, the possible contribution of sensory nerves to LPS-induced BHR was examined in human isolated bronchi to pharmacologically identify the mechanisms underlying this phenomenon.

Main Methods: Human isolated bronchial tone was induced by electrical field stimulation (EFS). The responses of airways to LPS, with or without capsaicin desensitization or thiorphan treatment were studied and the transient receptor potential vanilloid type 1 (TRPV1) expression was assessed. We performed similar experiments in the presence of a TRPV1 or a neurokinin (NK) 2 receptor antagonist using SB366791 and GR159897, respectively.

Key Findings: LPS increased (≃2.3-fold, P<0.001) the contraction induced by EFS, compared to control tissues. Acute administration of capsaicin enhanced (≃2.3-fold, P<0.001) the EFS-mediated contraction, but did not potentiate the effect of LPS. Thiorphan increased (≃1.3-fold, P<0.05) the contractile response of LPS treated tissues and, at lower frequencies, it enhanced (≃1.7-fold, P<0.001) the capsaicin-induced contraction. In capsaicin-desensitized bronchi, LPS did not modify (P>0.05) the EFS contractile response, nor after treatment with thiorphan. Capsaicin desensitization reduced (≃0.4-fold, P<0.001) the LPS-induced BHR. SB366791 and GR159897 prevented the LPS-induced BHR and the release of NKA. LPS increased (+85.3±9.5%, P<0.01) the surface membrane expression of TRPV1 in parasympathetic ganglia.

Significance: Our results demonstrate the involvement of capsaicin-sensitive sensory nerves and neutral endopeptidases in LPS-induced BHR of the human bronchi, associated with an upregulation of TRPV1 and release of NKA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2015.03.023DOI Listing
June 2015

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab.

Clin Cancer Res 2015 Jul 2;21(13):2975-83. Epub 2015 Apr 2.

Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.

Purpose: In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance.

Experimental Design: We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).

Results: Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.

Conclusions: The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-15-0020DOI Listing
July 2015

Effects of chronic treatment with the new ultra-long-acting β2 -adrenoceptor agonist indacaterol alone or in combination with the β1 -adrenoceptor blocker metoprolol on cardiac remodelling.

Br J Pharmacol 2015 Jul 12;172(14):3627-37. Epub 2015 May 12.

Centre of Excellence for Cardiovascular Diseases, Second University of Naples, Naples, Italy.

Background And Purpose: The ability of a chronic treatment with indacaterol, a new ultra-long-acting β2 -adrenoceptor agonist, to reverse cardiac remodelling and its effects in combination with metoprolol, a selective β1 -adrenoceptor antagonist, were investigated on myocardial infarction in a rat model of heart failure (HF).

Experimental Approach: We investigated the effects of indacaterol and metoprolol, administered alone or in combination, on myocardial histology, β-adrenoceptor-mediated pathways, markers of remodelling and haemodynamic parameters in a rat model of HF. Five groups of rats were assessed: sham-operated rats; HF rats; HF + indacaterol 0.3 mg·kg(-1) ·day(-1) ; HF + metoprolol 100 mg·kg(-1) ·day(-1) ; HF + metoprolol + indacaterol. All pharmacological treatments continued for 15 weeks.

Key Results: Treatment with either indacaterol or metoprolol significantly reduced the infarct size in HF rats. However, the combination of indacaterol and metoprolol reduced the infarct size even further, reduced both BP and heart rate, reversed the decrease in ejection fraction, normalized left ventricular systolic and diastolic internal diameters, normalized the decreased β1 adrenoceptor mRNA expression as well as cardiac cAMP levels and reduced cardiac GPCR kinase 2 expression, compared with the untreated HF group.

Conclusion And Implications: The results of our study demonstrated an additive interaction between indacaterol and metoprolol in normalizing and reversing cardiac remodelling in our experimental model of HF. The translation of these findings to clinical practice might be of interest, as this combination of drugs could be safer and more effective in patients suffering from HF and COPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.13148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507164PMC
July 2015