The effect of combining an inhaled corticosteroid and a long-acting muscarinic antagonist on human airway epithelial cells in vitro.

BACKGROUND: Airway epithelial cells (AECs) are a major component of local airway immune responses. Direct effects of type 2 cytokines on AECs are implicated in type 2 asthma, which is driven by epithelial-derived cytokines and leads to airway obstruction. However, evidence suggests that restoring epithelial health may attenuate asthmatic features. METHODS: We investigated the effects of passive sensitisation on IL-5, NF-κB, HDAC-2, ACh, and ChAT in human bronchial epithelial cells (HBEpCs) and the effects of fluticasone furoate (FF) and umeclidinium (UME) alone and in combination on these responses. RESULTS: IL-5 and NF-κB levels were increased, and that of HDAC-2 reduced in sensitised HEBpCs. Pretreatment with FF reversed the effects of passive sensitisation by concentration-dependent reduction of IL-5, resulting in decreased NF-κB levels and restored HDAC-2 activity. Addition of UME enhanced these effects. Sensitized HEBpCs also exhibited higher ACh and ChAT levels. Pretreatment with UME significantly reduced ACh levels, and addition of FF caused a further small reduction. CONCLUSION: This study confirmed that passive sensitisation of AECs results in an inflammatory response with increased levels of IL-5 and NF-κB, reduced levels of HDAC-2, and higher levels of ACh and ChAT compared to normal cells. Combining FF and UME was found to be more effective in reducing IL-5, NF-κB, and ACh and restoring HDAC-2 compared to the individual components. This finding supports adding a LAMA to established ICS/LABA treatment in asthma and suggests the possibility of using an ICS/LAMA combination when needed.

Early pathological changes of peri-coronal tissue in the distal area of erupted or partially impacted lower third molars.

AIM: This study was performed to histologically evaluate peri-coronal tissues of partially impacted and erupted third molars that did not exhibit pathologic peri-coronal radiolucency. MATERIALS AND METHODS: Healthy patients with erupted or partially erupted (with part or all of the dental crown present in the oral cavity) mandibular third molars (classified as IA and IIA according to the Pell and Gregory classification) and vertically positioned (according to the Winter classification or erupted third molars) associated with peri coronal radiolucency of equal to or less than 2.5 mm. Associated with third molar surgery, tissue sampling from the distal area was performed, which was subjected to an anatomopathological examination to determine the histological nature. RESULTS: One hundred teeth (100 patients) were selected, and 100 specimens were analyzed. 53% of the sample were included in the non-pathological group and 47% showed pathological changes (fibrotic tissue (n 15), periodontal cyst-like (n 9), squamous epithelial metaplasia (4 cases), islands of odontogenic epithelial residues organized micro-cyst with keratocystic/ameloblastic appearance (4 cases), granulation tissue (n 8), giant cell tumour (n 4) and lobular capillary hemangioma (n 4)). Pathological changes did not have differences in incidence between the gender (p value = 0.85) and did not show any correlation with age, (p value = 0,96). CONCLUSIONS: These findings suggest that radiographic appearance may not be a reliable indicator of the absence of disease within a dental follicle. Therefore, clinicians should pay attention to or follow up on even peri-coronal radiolucency of less than 2.5 mm.

Emerging muscarinic receptor antagonists for the treatment of asthma.

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.

Pharmacokinetics and pharmacodynamics of inhaled corticosteroids for asthma treatment.

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.

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

Combining a long-acting ß2-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 M2 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.

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

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.

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

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.

Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research.

Restenosis is the pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.

Predictors of mortality in atypical antipsychotic-treated community-dwelling elderly patients with behavioural and psychological symptoms of dementia: a prospective population-based cohort study from Italy.

PURPOSE: To evaluate the effect of a broad range of covariates on the survival of a real-life long-term follow-up cohort of community-dwelling patients with behavioural and psychological symptoms of dementia who were new users of atypical antipsychotic medications (APMs). METHODS: This was a prospective cohort study of 1,618 subjects aged ≥65 years with dementia and BPSD ("behavioural and psychological symptoms of dementia") who were new users of atypical APMs and registered in a Dementia Evaluation Unit of Campania Region (Italy) from September 2006 to March 2010. The potential of baseline features to predict mortality was assessed with the Cox proportional hazards model. RESULTS: The average follow-up was 309 days. Of the 1,618 new users of atypical antipsychotics, 9.3 % experienced at least one adverse event, including death (5.1 %), drug therapeutic failure (3.0 %), extrapyramidal symptoms (0.5 %) and stroke (0.2 %). The crude all-cause mortality rate was 6.0 per 100 person-years [95 % confidence interval (CI) 4.8-7.4]; the rate was higher in patients aged >85 years (9.0 per 100 person-years, 95 % CI 6.4-12.7) and among male patients (7.5 per 100 person-years, 95% CI 5.3-10.6). In the multivariate analysis, only age was associated to all-cause mortality [hazard ratio (HR) 1.1; 95 % CI 1.0-1.1 and HR 1.4; 95 % CI: 0.9-2.2, respectively). In contrast, hallucination (HR 0.4; 95 % CI 0.2-0.6) and dosage change (HR 0.4; 95 % CI 0.2-0.78) were significantly associated with a lower risk of all-cause mortality. CONCLUSIONS: Among our patient cohort, the mortality rate of patients with BPSD receiving long-term treatment with atypical APMs was lower than that reported in other studies, and only age was found to be significant predictor factor of mortality.

The pharmacological management of asthma in adults: 2023 update.

INTRODUCTION: The pharmacotherapy of asthma is a dynamic process that changes as our knowledge of the underlying pathophysiology and treatment of this disease continues to evolve. This implies the need for continuous revision of the recommendations of asthma guidelines and strategies. AREAS COVERED: This review summarizes the latest key practical information on the pharmacological management of asthma in adults. We provide the background to the 2023 update of the GINA strategy report, focusing on changes and discussing areas of uncertainty. We review current and emerging pharmacotherapy for uncontrolled asthma, including synthetic agents and new biologics, and provide expert perspectives and opinions on the treatment of uncontrolled asthma. EXPERT OPINION: The current pharmacological treatment of asthma, based on a step-by-step, control-based approach, with ICSs, LABAs and LAMAs being the mainstay generally provides good symptom control. Biologic therapies are often effective in treating T2high severe asthma. However, there is still room for improvement, such as the discovery of new molecules that specifically target chronic inflammation and, most importantly, the ability to provide solutions to the various areas of uncertainty that still exist. Also finding solutions to improve the accessibility and affordability of rescue ICS in resource-constrained settings is critical.

The influence of propofol, remifentanil and lidocaine on the tone of human bronchial smooth muscle.

BACKGROUND: Bronchoscopy is generally a safe procedure, but the induction of anaesthesia can induce bronchospasm. Consequently we investigated the influence of propofol, remifentanil and lidocaine on the tone of the human bronchial smooth muscle. MATERIALS AND METHODS: The influence of propofol, remifentanil and lidocaine on the contractile response of human bronchial smooth muscle to electrical field stimulation (EFS) has been evaluated. The role of capsaicin-sensitive sensory nerves and of inducible nitric oxide synthase has also been assessed. Furthermore, the interaction between these three dugs has been measured by Bliss Independence (BI) theory. Statistical significance (P < 0.05) was assessed by Student's t test or ANOVA. RESULTS: Propofol (1.3 µg ml(-1)) and lidocaine (1 mg ml(-1)) reduced the baseline tone of bronchial rings (-14.45 ± 4.53% and -33.40 ± 1.07%, respectively, P < 0.05), whereas remifentanil had not such effect. Aminoguanidine prevented the relaxant effect of propofol. Propofol did not alter the bronchial contractile response to EFS following 30 min of treatment, whereas remifentanil enhanced the bronchial tension (133.83 ± 9.38%, control 101.93 ± 6.82%, P < 0.05 P < 0.05) and lidocaine completely abolished the contractility at 1 mg ml(-1) (P < 0.05). The desensitization of capsaicin-sensitive sensory nerves normalized the hyperresponsiveness induced by remifentanil (-26.77 ± 1.68%, P < 0.05). Significant BI antagonism (P < 0.001) was detected for propofol and lidocaine on the bronchial hyperresponsiveness induced by remifentanil. CONCLUSION: Propofol and remifentanil may be used safely for bronchoscopy, although remifentanil should be associated with propofol or lidocaine to prevent the potential opioid-mediated bronchospasm.

Is it preferable to administer a bronchodilator once- or twice-daily when treating COPD?

Nocturnal and early morning symptoms are common and uncomfortable in many patients with COPD, and are likely to affect their long-term outcomes. However, it is still debated whether it is better to give long-acting bronchodilators once- or twice-daily to symptomatic COPD patients. The functional link between circadian rhythms of autonomic tone and airway calibre explains why the timing of administration of bronchodilators in chronic airway diseases can induce different effects when taken at different biological (circadian) times. However, the timing also depends on the pharmacological characteristics of the bronchodilator to be used. Because the profile of bronchodilation produced by once-daily vs. twice-daily long-acting bronchodilators differs throughout 24 h, selecting long-acting bronchodilators may be customized to specific patient preferences based on the need for further bronchodilation in the evening. This is especially helpful for people who experience respiratory symptoms at night or early morning. Compared to placebo, evening bronchodilator administration is consistently linked with persistent overnight improvements in dynamic respiratory mechanics and inspiratory neural drive. The current evidence indicates that nocturnal and early morning symptoms control is best handled by a LAMA taken in the evening. In contrast, it seems preferable to use a LABA for daytime symptoms. Therefore, it can be speculated that combining a LAMA with a LABA can improve bronchodilation and control symptoms better. Both LAMA and LABA must be rapid in their onset of action. Aclidinium/formoterol, a twice-daily combination, is the most studies of the available LAMA/LABA combinations in terms of impact on daytime and nocturnal symptoms.

Pharmacokinetic considerations surrounding triple therapy for uncontrolled asthma.

INTRODUCTION: Solid pharmacological rationale and clinical evidence support the use of a combination of an inhaled corticosteroid (ICS), a long-acting ß2-agonist, and a long-acting muscarinic antagonist in severe asthma, which clinically results in increased lung function, improved symptoms, and decreased exacerbation rates. AREAS COVERED: We examined the pharmacokinetic issues associated with triple therapy for uncontrolled asthma. We considered the pharmacokinetic characteristics of the three drug classes, the role of inhalers in influencing their pharmacokinetic behavior, and the impact of severe asthma on the pharmacokinetics of inhaled drugs. EXPERT OPINION: The pharmacokinetics of ICSs and bronchodilators are not affected to a great extent by severe asthma, according to a detailed review of the currently accessible literature. Compared to healthy people, patients with severe asthma show only minor variations in a few pharmacokinetic characteristics, which are unlikely to have therapeutic significance and do not require particular attention. However, the difficulty of obtaining pharmacokinetic profiles of the three drugs included in a triple therapy suggests that the clinical response should be followed over time, which can be considered a good surrogate indicator of whether the drugs have reached sufficient concentrations in the lung to exert a valid pharmacological action.

Strategies for overcoming the biological barriers associated with the administration of inhaled monoclonal antibodies for lung diseases.

INTRODUCTION: Monoclonal antibodies (mAbs) should be administered by inhalation rather than parenterally to improve their efficiency in lung diseases. However, the pulmonary administration of mAbs in terms of aerosol technology and the formulation for inhalation is difficult. AREAS COVERED: The feasible or suitable strategies for overcoming the barriers associated with administering mAbs are described. EXPERT OPINION: Providing mAbs via inhalation to individuals with lung disorders is still difficult. However, inhalation is a desirable method for mAb delivery. Inhaled mAb production needs to be well thought out. The illness, the patient group(s), the therapeutic molecule selected, its interaction with the biological barriers in the lungs, the formulation, excipients, and administration systems must all be thoroughly investigated. Therefore, to create inhaled mAbs that are stable and efficacious, it will be essential to thoroughly examine the problems linked to instability and protein aggregation. More excipients will also need to be manufactured, expanding the range of formulation design choices. Another crucial requirement is for novel carriers for topical delivery to the lungs since carriers might significantly enhance proteins' stability and pharmacokinetic profile.

Advances in adrenergic receptors for the treatment of chronic obstructive pulmonary disease: 2023 update.

INTRODUCTION: Strong scientific evidence and large experience support the use of ß2-agonists for the symptomatic alleviation of COPD. Therefore, there is considerable effort in discovering highly potent and selective ß2-agonists. AREAS COVERED: Recent research on novel ß2-agonists for the treatment of COPD. A detailed literature search was performed in two major databases (PubMed/MEDLINE and Scopus) up to September 2023." EXPERT OPINION: Compounds that preferentially activate a Gs- or ß-arrestin-mediated signaling pathway via ß- adrenoceptors (ARs) are more innovative. Pepducins, which target the intracellular region of ß2-AR to modulate receptor signaling output, have the most interesting profile from a pharmacological point of view. They stabilize the conformation of the ß2-AR and influence its signaling by interacting with the intracellular receptor-G protein interface. New bifunctional drugs called muscarinic antagonist-ß2 agonist (MABA), which have both muscarinic receptor (mAChR) antagonism and ß2-agonist activity in the same molecule, are a new opportunity. However, all tested compounds have been shown to act predominantly as mAChR antagonists or ß2-agonists. An intriguing idea is to utilize allosteric modulators that bind to ß2-ARs at sites different than those bound by orthosteric ligands to augment or reduce the signaling transduced by the orthosteric ligand.

The long-term exercise after traumatic brain injury: Reharmonizing brain by sound body.

Traumatic brain injuries (TBI) refer to multiple acquired dysfunctions arising from damage to the brain caused by an external force, including rapid acceleration/deceleration and concussion. Among them, mild TBI (mTBI) accounts for most cases (up to 90%) of injuries. It is responsible for a variety of symptoms, including anxiety, depression, and cognitive impairments that remain difficult to be treated. It has been reported that regular physical activity, as well as, improving life quality, display a neuroprotective function, suggesting a possible role in post-traumatic rehabilitation. In this study, we investigated the effects of treadmill exercise in a mice mTBI model by behavioural, electrophysiological and neurochemical analysis. Daily exercise decreased anxiety, aggressive behavior, and depression in mTBI mice. Accordingly, electrophysiological and neurochemical maladaptive rearrangement occurring in the hippocampus of mTBI mice were prevented by the exercise.

Comparative study of the anaesthetic efficacy of 4% articaine versus 2% mepivacaine in mandibular third molar germectomy using different anaesthetic techniques: a split-mouth clinical trial.

BACKGROUND: Currently, one of the most discouraging aspects for many patients undergoing dental procedures is the administration of local anaesthesia. Therefore, there is a constant search for new techniques to avoid the invasive and painful nature of the injection. This study aimed to compare the clinical efficacy of local anaesthetics with articaine 4% or mepivacaine 2% (both with epinephrine 1:100.000), using different anaesthetic techniques to perform germectomy of lower third molars and to assess patients' feelings and pain during surgery. METHODS: Totally 50 patients (ranged 11-16 years) who required germectomy of mandibular third molars were recruited. Each patient received local anaesthesia on one side with articaine inoculated with plexus technique while on the other side with mepivacaine using inferior alveolar nerve block technique. The patients' evaluation was performed on pre and intraoperative tactile-pressure feelings and intraoperative pain with four levels on the Visual Analogue Scale (VAS). RESULTS: Surgical operations lasted less with more efficient analgesia when articaine was used. The additional intraosseous injection was required mainly in the mepivacaine group intraoperatively. A few patients had tactile-pressure feelings while intraoperative pain sensation was absent in 90% of cases with articaine. Significant differences were found in the cases who reported "absent" and "moderate" VAS values, favoring the use of articaine. CONCLUSIONS: Articaine injected with a plexus anaesthetic technique seems to be more clinically manageable than mepivacaine for the mandibular third molar germectomy. The discomfort of tactile-pressure feelings and pain experienced was lower using articaine anaesthetic technique used.

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-α.

BACKGROUND: Statins such as simvastatin are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease. In addition to their cholesterol-lowering activities, statins exert pleiotropic anti-inflammatory effects, which might contribute to their beneficial effects on lipid-unrelated inflammatory diseases. Recently it has been demonstrated that the peroxisome proliferator-activated receptor (PPAR)-α mediates anti-inflammatory effects of simvastatin in vivo models of acute inflammation. Moreover, previous results suggest that PPAR-α plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI). METHODS: With the aim to characterize the role of PPAR-α in simvastatin activity, we tested the efficacy of simvastatin (10 mg/kg dissolved in saline i.p. 1 h and 6 h after the trauma) in an experimental model of SCI induced in mice by extradural compression of the spinal cord (T6-T7 level) using an aneurysm clip with a closing force of 24 g via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-α (PPAR-α KO) with wild type (WT) mice. In order to elucidate whether the effects of simvastatin are due to activation of the PPAR-α, we also investigated the effect of a PPAR-α antagonist, GW6471 (1 mg/kg administered i.p. 30 min prior treatment with simvastatin) on the protective effects of on simvastatin. RESULTS: Results indicate that simvastatin activity is weakened in PPAR-α KO mice, as compared to WT controls. In particular, simvastatin was less effective in PPAR-α KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation, neutrophil infiltration, nitrotyrosine formation, pro-inflammmatory cytokine expression, nuclear factor (NF)-κB activation, inducible nitric-oxide synthase (iNOS) expression, and apoptosis. In addition we demonstrated that GW6471 significantly antagonized the effect of the statin and thus abolished the protective effect. CONCLUSIONS: This study indicates that PPAR-α can contribute to the anti-inflammatory activity of simvastatin in SCI.

Stem cell therapy for arterial restenosis: potential parameters contributing to the success of bone marrow-derived mesenchymal stromal cells.

PURPOSE: Restenosis is a complex and heterogeneous pathophysiological phenomenon occurring in patients submitted to revascularization procedures. Previous studies proved the antirestenotic properties of injected allogenic mesenchymal stromal cells (MSCs) in an experimental model of rat carotid (re)stenosis induced through arteriotomy. In this study we describe some of the effects subsequent to MSC treatment of rats submitted to carotid arteriotomy and possibly responsible for their antirestenotic effect. METHODS: Rat MSCs were isolated from bone marrow, expanded in vitro and characterized. Subsequently, we evaluated the effects of MSC administration via tail vein at 3 and 7 days after carotid arteriotomy both in rat serum and in injured carotids, focusing on DNA oxidative damage (8-oxo-dG detection), cell proliferation index (BrdU incorporation assay), apoptotic index (TUNEL assay), the expression of inflammation- and proliferation-related genes (RT-PCR), the release of growth factors and of inflammation-related cytokines (antibody arrays and ELISA). RESULTS: MSC administration induced a greater cell proliferation in carotids after arteriotomy, together with an increased level of VEGF in the serum and with the higher expression of VEGF mRNA in injured carotids. Serum analysis also revealed a decreased level of the pro-inflammatory cytokines CXCL1, CXCL5, L-Selectin, ICAM-1 and LIX, and of TIMP1 and SDF-1alpha in MSC-treated rats. The MSC immunomodulatory activity was confirmed by the decreased expression of TLR2 and TLR4 in injured carotids. CONCLUSIONS: MSCs play an immunomodulatory paracrine role when injected in rats submitted to carotid arteriotomy, accompanied by the release of VEGF, possibly contributing to the accelerated repair of the injured vascular wall.

Pharmacotherapy of LAMA/LABA inhaled therapy combinations for chronic obstructive pulmonary disease: a clinical overview.

INTRODUCTION: Long-acting muscarinic receptor antagonist (LAMA)/ß2-agonist (LABA) combinations represent a significant improvement in the treatment of chronic obstructive pulmonary disease (COPD) due to their remarkable ability to improve lung function, dyspnea, quality of life, and exercise capacity compared to mono-components. AREAS COVERED: This article aims to report the latest information on the clinical impact of dual bronchodilation in COPD. EXPERT OPINION: The available data supports the use of inhaled LAMA/LABA FDCs in treating COPD patients, particularly those with severe or very severe disease. These combinations provide short - and long-term benefits to COPD patients without increasing the dose of the single components, which reduces the risk of adverse events while ensuring an improvement in clinical efficacy. Unfortunately, head-to-head studies comparing all exiting LABA/LAMA combinations are relatively few. Since each available LAMA/LABA combination has a unique efficacy/safety profile that must be considered for personalized COPD therapy, further randomized controlled trials and real-world studies lasting at least one year are needed to assess what differences, if any, there are in terms of clinical outcomes when dual LAMA/LABA inhalers are compared to LAMA or LABA single inhalers, and to compare different LAMA/LABA FDCs.