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Bronchodilators are the most important drugs used for the treatment of chronic obstructive pulmonary disease (COPD). In particular, these therapeutic agents are mostly long-acting compounds utilized via inhalation, and include LAMA (long-acting muscarinic receptor antagonists) and LABA (long-acting β2-adrenoceptor agonists). Because LAMA and LABA induce bronchodilation by distinct mechanisms of action, LABA/LAMA combinations provide a reciprocal potentiation of the pharmacological effects caused by each component. Hence, many COPD patients who do not achieve a satisfactory control of their symptoms using a single, either LAMA or LABA bronchodilator, can experience relevant benefits with the use of LAMA/LABA fixed combinations. Many different LAMA/LABA combinations have been recently developed and evaluated in randomized clinical trials. In this context, our review focuses on the pharmacological mechanisms underpinning the bronchodilation elicited by the LAMA tiotropium bromide and the LABA olodaterol. We also discuss the results of the most important clinical studies carried out in COPD patients to assess the efficacy and safety of tiotropium/olodaterol combinations.

Background: Acute ischemic lesions on diffusion-weighted magnetic resonance imaging (DWI-MRI) are reliable predictors of recurrent stroke at 90 days. However, to date, limited information on transient ischemic attack (TIA) patients with positive DWI lesions for stroke risk from 1 to 5 years is available. In this study, we evaluated the role of positive DWI lesions and vascular risk factors on stroke, cardiovascular death, and mortality at 90 days (T0), 1 year (T1), and 5 years (T2). Moreover, we also evaluated the association between stroke risk and the presence of DWI lesions., Methods: We performed an observational study on consecutive patients admitted to the emergency department of San Camillo-Forlanini Hospital, Rome, Italy, from January 2007 to November 2012. Over the study period, 4300 patients with TIA or ischemic stroke were examined by stroke specialists in an emergency room setting within 1 hour from admittance., Results: In 510 of 4300 patients (11.86%), a TIA was diagnosed, and 445 patients satisfy the study inclusion criteria. For all 445 patients, the mean ABCD2 score was 4.35 ± 1.30. Using DWI-MRI, we identified acute ischemic lesions in 185 patients (41.57%). We did not observe any correlation between duration of symptoms, ABCD2 score, and positive or negative DWI lesions. Positivity for DWI was not associated with the presence of diabetes mellitus, hypertension, smoking habit, or age; however, an association with weakness was observed. We documented a time-dependent increase in the absolute risk of stroke: T0: 1.35% (95% confidence interval [CI], .81-2.8); T1: 4.78% (95% CI, 2.88-7.47); T2: 9.02% (95% CI, 4.66-5.70). We did not record any difference in stroke risk in patients with positive DWI lesions: T0: hazard ratio [HR], 1.43; 95% CI, .35-5.88; log-rank P = .60; T1: HR, 1.04; 95%CI, .42-2.61; log-rank P = .91; T2: HR, .83; 95% CI, .25-2.67; log-rank P = .86., Conclusions: This long-term follow-up study in TIA patients documents that both positive and negative DWI patients treated with fast-track had similar long-term risks of stroke., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Pressure ulcers (PUs) are a common problem in critically ill patients admitted to the intensive care units (ICUs) and they account for more than 70% of patients with low serum albumin at admission. The aim of this study was to test the efficacy of intravenous administration of albumin in patients with low serum albumin < 3·3 g/dl. In a 1-year period, a total of 73 patients were admitted to the ICU (males 45, 61·64% and females 28, 38·36%); of these, 21 patients were admitted with hypoalbuminaemia (serum albumin < 3·3 g/dl) and randomised into two groups: 11 patients were treated with 25 g intravenous albumin for the first 3 days within the first week of ICU stay (group A) and 10 patients did not receive albumin (group B). Three patients (27·27%) showed the onset of PUs in group A, whereas seven patients (70%) showed the onset of PUs within the first 7 days of stay in group B. Moreover, ulcers of group B were more severe than those of group A. This study shows that intravenous administration of albumin reduces the onset of PUs in patients admitted to the ICU and in some cases it also reduces the risk of progression to advanced stages of PUs., (© 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: In patients with carotid stenosis, the risk of plaque rupture is related to the composition of the atherosclerotic plaque rather than to its magnitude. In this regard, we evaluated the effects of a supplement, Aterofisiol,(®) containing omega-3 (EPA [eicosapen acid] DHA [docosahexaenoic acid]), vitamin K2, vitamin B6, vitamin B12, oligomeric proanthocyanidins (OPC) and resveratrol on the composition of atherosclerotic plaque and on neurological symptoms in patients with carotid stenosis undergoing carotid endarterectomy., Methods: The study was randomized, prospective, and double-blinded. Eligible patients were of both sexes, with carotid stenosis >70% who underwent endarterectomy. Enrolled patients were randomly allocated to receive either one tablet of acetylsalicylic acid 100 mg (Cardioaspirin(®)) + one tablet of Aterofisiol every 24 hours or one tablet of Cardioaspirin + one tablet of placebo every 24 hours. Each treatment was started 30 days before the surgery and was stopped 5 days before the surgery. The plaques were removed "en bloc" using standard surgical technique., Results: During the study period, 214 patients (135 men and 79 women) were enrolled for intent-to-treat and randomized in two groups: Group A: 107 patients (68 men and 39 women) were treated with Cardioaspirin + Aterofisiol. Group B: 107 patients (67 men and 40 women) were treated with Cardioaspirin + placebo. At the end of the study, 202 patients participated fully (103 patients in Group A and 99 patients in Group B), making up the protocol evaluation population (94.4%). The mean lipid content of removed plaques was significantly lower (P<0.05) in Group A. We recorded a significantly lower incidence of neurological symptoms in Group A in comparison with Group B (P<0.05)., Conclusion: In the study, Aterofisiol showed to be effective in reducing the amounts of cholesterol and lipids in the plaques and in reducing adverse neurological events in the study group with respect to controls.

We describe a case of a 61-year-old man with chronic hepatitis B, hepatitis B e antibody (HBeAb) positive, treated with tenofovir disoproxil fumarate (TDF), who developed virological and biochemical viremic reactivation with an increase in transaminase plasma levels. The patient's history revealed that he had discontinued TDF about 5 days before admission and, from December 2013, had been taking venlafaxine, paroxetine and zolpidem for some episodes of depression. Clinical evaluation and laboratory findings excluded the presence of systemic diseases that might have been able to explain the drug inefficacy, while pharmacological evaluation suggested a possible drug-drug interaction. In order to assess the possible occurrence of resistance, mutational analysis of hepatitis B virus (HBV) was performed and excluded the presence of resistance for TDF. TDF was prescribed, and venlafaxine, paroxetine and zolpidem were discontinued. The follow-up at 3, 6 and 12 months documented a good response to TDF with a time-related decrease of HBV-DNA and alanine aminotransferase., (2015 BMJ Publishing Group Ltd.)

Diabetic patients are at high risk of foot ulcerations that may lead to limb amputations with important socio-economic impact. Peripheral vascular disease may be frequently associated in diabetes mellitus type II with its main symptom, intermittent claudication. Many studies reported the known efficacy of cilostazol in treating vascular claudication. Metalloproteinase-9 (MMP-9) seems to be a biochemical marker implicated in chronic wounds and in particular in diabetic foot ulcers. Cilostazol appears to have a lowering effect on MMP-9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients. In our study, two groups of diabetic patients with peripheral vascular disease were divided into two groups according to the presence of claudication in order to receive cilostazol. Group A (31 patients without claudication) were not eligible to receive cilostazol whereas Group B (47 patients with claudication) received cilostazol administration for 24 weeks (100 mg orally twice daily). Median follow up was of 16 months. During the follow up, 4·25% of patients of Group B and 35·48% of patients of Group A (P < 0·01) showed onset of foot ulceration. Although further randomised and controlled studies are required cilostazol seems to show beneficial effects for primary prevention of diabetic foot ulcers., (© 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Chronic leg ulcers affect 1-2% of the general population and are related to increased morbidity and health costs. Staphylococcus aureus and Pseudomonas aeruginosa are the most common bacteria isolated from chronic wounds. They can express virulence factors and surface proteins affecting wound healing. The co-infection of S. aureus and P. aeruginosa is more virulent than single infection. In particular, S. aureus and P. aeruginosa have both intrinsic and acquired antibiotic resistance, making clinical management of infection a real challenge, particularly in patients with comorbidity. Therefore, a correct and prompt diagnosis of chronic wound infection requires a detailed knowledge of skin bacterial flora. This is a necessary prerequisite for tailored pharmacological treatment, improving symptoms, and reducing side effects and antibiotic resistance.

Venous ulcers are common, with an overall prevalence of up to 2% in the general population of western countries, and have significant socioeconomic impact. Matrix metalloproteinases (MMPs) are involved in the alteration of extracellular matrix that could lead to venous ulceration. Sixty-four patients with venous ulcers were recruited in a 22-month period. All patients were subjected to the most appropriate treatment considering also the patient's wishes (compression therapy followed or not by vein surgery). Patients were randomised into two groups of 32 persons in each (groups A and B). Patients of group A in addition to the basic treatment, described above, received the administration of oral low doses of doxycycline 20 mg b.i.d. for 3 months, whereas patients of group B received basic treatment only. Healing was assessed by means of direct ulcer tracing with computerised planimetry. Group A showed a higher healing rate compared with group B. In group B, the lower healing rate was related to higher levels of MMP-9; neutrophil gelatinase-associated lipocalin and vascular endothelial growth factor, documented in plasma; wound fluid and biopsies executed and compared between both groups. Pharmacological treatments, as doxycycline administration, which by means of its immunomodulatory and anti-inflammatory actions, through the inhibition of MMP, could improve extracellular matrix functioning and represent a possible solution to support wound healing., (© 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Chronic venous ulceration (CVU) is the major cause of chronic wounds of lower extremities, and is a part of the complex of chronic venous disease. Previous studies have hypothesised that several thrombophilic factors, such as hyperhomocysteinaemia (HHcy), may be associated with chronic venous ulcers. In this study, we evaluated the prevalence of HHcy in patients with venous leg ulcers and the effect of folic acid therapy on wound healing. Eighty-seven patients with venous leg ulcers were enrolled in this study to calculate the prevalence of HHcy in this population. All patients underwent basic treatment for venous ulcer (compression therapy ± surgical procedures). Patients with HHcy (group A) received basic treatment and administered folic acid (1·2 mg/day for 12 months) and patients without HHcy (group B) received only basic treatment. Healing was assessed by means of computerised planimetry analysis. The prevalence of HHcy among patients with chronic venous ulcer enrolled in this study was 62·06%. Healing rate was significantly higher (P < 0·05) in group A patients (78·75%) compared with group B patients (63·33%). This study suggests a close association, statistically significant, between HHcy and CVU. Homocysteine-lowering therapy with folic acid seems to expedite wound healing. Despite these aspects, the exact molecular mechanisms between homocysteine and CVU have not been clearly defined and further studies are needed., (© 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Objective: During menopause, lower levels of estrogen may induce bone resorption as well as anxiety and depression. Bisphosphonates represent the first choice in the treatment of osteoporosis and no data are available concerning their effects on comorbid behavior alterations. Therefore, in this study, we evaluated the effects of chronic alendronate (1 mg/kg/day) on depression and anxiety in an experimental animal model of menopause., Methods: Female Wistar rats were ovariectomized or sham operated at 6-7 months of age. Two weeks after surgery, rats were randomized into four treatment (24 consecutive weeks) groups: (1) vehicle-treated SHAM group, (2) alendronate-treated SHAM group, (3) vehicle-treated ovariectomized group, and (4) alendronate-treated ovariectomized group. After treatment, we evaluated both depressive- and anxiety-like behavior through forced swimming test (FST) and open-field test (OF). Finally, the inverted screen test was used to assess the incapacitating effects of ovariectomy in rats., Results: We documented a significant and time-related increase in immobility times and in anxiety-like behavior in rats with ovariectomy in comparison to control sham group. Alendronate at 3 months, but not at 6 months, significantly decreased both immobility time and anxiety levels, but it significantly increased motor performance. Using the Pearson's test, we documented a significant correlation between behavior and motor performance., Conclusion: Despite the apparent effects of alendronate on animal behavior, in our experiments, such effects seem to be mediated by an increase in motor performance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments.

The humanized monoclonal anti-IgE antibody omalizumab is currently the only biologic drug approved for asthma treatment. Omalizumab inhibits allergic responses by binding to serum immunoglobulins E (IgE), thus preventing their interactions with cellular IgE receptors. Omalizumab is also capable of down-regulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both peripheral blood and induced sputum. The clinical effects of omalizumab include relevant improvements in respiratory symptoms and quality of life, paralleled by a marked reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Moreover, some recent studies suggest potential benefits of omalizumab also in non allergic phenotypes of severe asthma. Very interesting are also further recent reports referring to the potential inhibitory effect of omalizumab with regard to bronchial structural changes, especially occurring in severe asthma and globally defined as airway remodeling. Omalizumab is relatively well tolerated, and only very rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent asthma, inadequately controlled by high doses of standard inhaled treatments.

Background: Pulmonary arteriovenous malformation (PAVM) is an abnormal communication between pulmonary arteries and veins responsible for right-to-left shunting that could induce the development of embolic stroke., Summary: We describe an 82-year-old woman without history of respiratory or neurological diseases, who presented at our observation unit with acute onset of cerebral ischemia. Clinical, laboratory and radiological findings diagnosed a PAVM., Key Messages: Usually, endovascular procedures based on embolization or, alternatively, surgery represent the recommended treatment. However, both hormonal therapy and thrombolytic therapy can be used. In our patient, treatment with warfarin induced a remission of symptoms. This strategy should be tested in larger studies.

Cocaine abuse remains a devastating medical problem for our society. Current concepts suggest that both hemorrhagic and ischemic stroke, particularly in young people, can result as a consequence of cocaine exposure. We provide an analysis of mechanisms of injury and a discussion of the pharmacological management of stroke following cocaine use. Preclinical research suggests that the cause of cocaine-mediated stroke is multifactorial and involves vasospasm, changes in cerebral vasculature, and platelet aggregation. We suggest that drugs able to induce vasospastic, thrombogenic, or neurotoxic effects of cocaine could be suitable as therapeutic agents. In contrast caution should be exerted when using anti-platelet and thrombolytic agents in cocaine users with stroke.

Topiramate (TPM) is an antiepileptic drug able to play a role in both neurological and psychiatric disorders. TPM facilitates gamma-aminobutyric acid (GABA) transmission and inhibits glutamatergic transmission (i.e. AMPA/kainate receptors). Several studies reported that the modulation of GABAergic and glutamatergic synaptic transmission may reduce cocaine reinforcement. Therefore, TPM could be used in the management of cocaine dependence.

Introduction: An association between arterial aneurysms and matrix metalloproteinases (MMPs) has been described previously. MMPs regulate extracellular structural proteins and tissue remodeling. Neutrophil gelatinase-associated lipocalin (NGAL) is involved in the regulation of MMP activity. The aim of this work was to study the relationship between the levels of MMPs and NGAL and arterial aneurysms., Methods: In a multicenter, open-label, parallel groups, prospective study, patients with aneurysmal disease were divided into 2 groups: Group I (with ruptured aneurysm) and group II (with nonruptured aneurysm). Healthy volunteer patients were also enrolled and represented the control group (group III)., Results: We enrolled 307 patients (107 in group I and 200 in group II) with arterial aneurysm: 49 popliteal, 31 common femoral, 2 superficial femoral, 29 common iliac artery, 3 common carotid, and 193 abdominal aorta. Finally, 11 healthy volunteer patients (9 males and 2 females; age range, 40-70 years; median 56) were enrolled in group III. Enzyme-linked immunosorbent assay and Western blot analysis revealed greater levels of immunoreactive MMP-9 and NGAL in all patients with ruptured aneurysms, both central and peripheral aneurysms, and in the aneurismal vessels., Conclusion: These results provide potentially important insights to the understanding of the natural history of arterial aneurysms. MMPs and NGAL play a role in development of arterial aneurysms and may represent molecular markers for the prevention of aneurysmal rupture., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disorder, usually characterized by progressive and poorly reversible airflow limitation. Inhaled long-acting bronchodilators, namely LABA (long-acting β2-adrenergic agonists) and LAMA (long-acting muscarinic receptor antagonists) are the mainstay of COPD treatment. Because the symptoms of many patients with COPD do not satisfactorily improve by using a single, either LABA or LAMA bronchodilator, the synergism of action resulting from the combination of the different bronchodilating mechanisms activated by LABA and LAMA, respectively, can significantly contribute to a better disease control. Based on these clinical and pharmacological considerations, several LABA/LAMA fixed-dose combinations have been developed and experimentally evaluated. Within such a context, the drug co-formulation containing indacaterol and glycopyrronium is probably the LABA/LAMA association which has been most extensively studied during the last few years.

Background and Objectives: Sudden unexplained/unexpected death (SUDEP) is related to high mortality in patients with epilepsy. The prolongation of QT interval, involved in cardiac arrhythmia-related SUDEP, may be precipitated by antiepileptic drugs (AEDs). In this study, we evaluated the effects of phenobarbital and levetiracetam on PR-QTc intervals in patients with post-stroke seizures., Methods: We performed an open-label, parallel group, prospective, multicenter study between June 2009 and December 2013 in patients older than 18 years of age with a clinical diagnosis of post-stroke seizure and treated with phenobarbital or levetiracetam. In order to exclude a role of cerebral post-stroke injury on modulation of PR and QTc intervals, patients with cerebral post-stroke injury and without seizures were also enrolled as controls., Results: Interictal electrocardiography analysis revealed no significant difference in PR interval between patients treated with an AED (n = 49) and control patients (n = 50) (181.25 ± 12.05 vs. 182.4 ± 10.3 ms; p > 0.05). In contrast, a significantly longer QTc interval was recorded in patients treated with an AED compared with control patients (441.2 ± 56.6 vs. 396.8 ± 49.3 ms; p < 0.01). Patients treated with phenobarbital showed a significantly longer QTc interval than patients treated with levetiracetam (460.0 ± 57.2 vs. 421.5 ± 50.1 ms; p < 0.05)., Conclusions: The study reported that in patients with late post-stroke seizures, phenobarbital prolonged QTc interval more so than levetiracetam.

Trabectedin (Yondelis(®)) is a potent marine-derived antineoplastic drug with high activity against various soft tissue sarcoma (STS) subtypes as monotherapy, and in combination with pegylated liposomal doxorubicin (PLD) for the treatment of patients with relapsed platinum-sensitive ovarian cancer. This article reviews the safety and pharmacokinetic profiles of trabectedin. Records were identified using predefined search criteria using electronic databases (e.g. PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published between 1 January 2006 and 1 April 2014 were included. The current safety and tolerability profile of trabectedin, based on the evaluation in clinical trials of patients treated with the recommended treatment regimens for STS and recurrent ovarian cancer, was reviewed. Trabectedin as monotherapy or in combination with PLD, was not associated with cumulative and/or irreversible toxicities, such as cardiac, pulmonary, renal, or oto-toxicities, often observed with other common chemotherapeutic agents. The most common adverse drug reactions (ADRs) were myelosuppression and transient hepatic transaminase increases that were usually not clinically relevant. However, trabectedin administration should be avoided in patients with severe hepatic impairment. Serious and fatal ADRs were likely to be related to pre-existing conditions. Doxorubicin or PLD, carboplatin, gemcitabine, or paclitaxel when administered before trabectedin, did not seem to influence its pharmacokinetics. Cytochrome P450 (CYP) 3A4 has an important role in the metabolism of trabectedin, suggesting a risk of drug-drug interactions with trabectedin used in combination with other CYP3A4 substrates. Trabectedin has a favorable risk/efficacy profile, even during extended treatment in pretreated patients.

Lung cancer is characterized by a high mortality rate probably attributable to early metastasis. Oxidative stress is involved in development and progression of lung cancer, through cellular and molecular mechanisms which at least in part overlap with proinflammatory pathways. Simvastatin is a statin with pleiotropic effects that can also act as an anti-oxidant agent, and these pharmacologic properties may contribute to its potential anti-cancer activity. Therefore, the aim of this study was to evaluate, in the human lung adenocarcinoma cell line GLC-82, the effects of a 24-hour treatment with simvastatin on hydrogen peroxide (H2O2)-induced changes in cell viability, ERK phosphorylation, matrix metalloproteinase (MMP) expression, innate immunity signaling, NF-κB activation and IL-8 secretion. Cell counting was performed after trypan blue staining, cell proliferation was assessed using MTT assay, and apoptosis was evaluated through caspase-3 activation and Tunel assay. Western blotting was used to analyze protein extracts, and IL-8 release into cell culture supernatants was assessed by ELISA. Our results show that simvastatin (30 μM) significantly (P <0.01) inhibited the proliferative effect of H2O2 (0.5 mM) and its stimulatory actions on ERK1/2 phosphorylation, NF-κB activation and IL-8 production. Furthermore, simvastatin decreased H2O2-mediated induction of the cellular expression of MMP-2 and MMP-9, as well as of several components of the signaling complex activated by innate immune responses, including MyD88, TRAF2, TRAF6 and TRADD. In conclusion, these findings suggest that simvastatin could play a role in prevention and treatment of lung cancer via modulation of important proinflammatory and tumorigenic events promoted by oxidative stress.

Background: The carotid body tumors (CBTs) are relatively rare neoplasms and may present into benign or life threatening malignant forms. Matrix metalloproteinases (MMPs) are often involved in vascular and cancer diseases. Objective of this study is to study the relationship between CBTs and MMPs., Methods: We performed a multicenter study on 14 patients with CBTs. All tumors were resected. For each patient, we evaluated the MMPs' levels in both plasma (enzyme-linked immunosorbent assay [ELISA] test) and tissue samples (Western blot analysis). These MMPs' plasma levels were compared with the MMPs' plasma levels of healthy patients., Results: Eleven patients had benign CBTs, whereas 3 patients had malignant CBTs. ELISA findings revealed significant higher levels (P < 0.01) of MMP-1, -2, -3, -8, and -9 in patients with paraganglioma with respect to healthy patients. Patients with malignant CBTs showed significantly higher levels (P < 0.01) of MMP-1, -2, and -3 compared with patients with benign CBTs., Conclusions: Because this is an exploratory study, the experience on this casuistry showed that MMPs' evaluation may help clinicians and surgeons to formulate a more rapid and clear diagnosis on CBTs' behavior. However, other studies on a large group of patients may be useful to validate these observations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) exert cholesterol-independent pleiotropic effects that include antithrombotic, antiinflammatory, and antioxidative properties. Moreover, both in vitro and in vivo studies have shown neuroprotective, antiseizure, and antiexcitotoxic effects of statins, suggesting their potential role in the treatment of neurologic diseases. Only a few studies have investigated whether statins modulate absence seizure activity and epileptogenesis., Methods: We investigated the effects of atorvastatin (5 and 10 mg/kg/day), simvastatin (10 mg/kg/day), and pravastatin (10 and 30 mg/kg/day), given orally for 17 consecutive weeks (starting at 45 days of age), on the development of absence seizures (electroencephalography [EEG] recordings), depressive-like behavior (forced swimming test [FST]), and anxiety levels (open field test [OF]) in Wistar Albino Glaxo/Rijswijk rats (WAG/Rij) rats at the age of 6 months (1 month after suspension). WAG/Rij rats are a genetic animal model of absence epilepsy, epileptogenesis, and mild-depression comorbidity. The effects of statins were also studied after acute intraperitoneal injection for 4 h after administration of various doses in 6-months-old rats. Plasma cholesterol levels were measured throughout drug treatment., Results: We found that early long-term statin treatment possesses antiepileptogenic properties, reduced immobility time in the FST, and reduced anxiety in the OF, whereas they were not effective against established absence seizures when acutely administered. The observed effects were not related to changes in plasma cholesterol levels, which remained unchanged during drug treatment., Significance: Our results suggest that statins administration might be a possible intervention and promising strategy for preventing the epileptogenesis and/or behavioral comorbidity., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Objective: To explore the effect of sequential treatment with glucocorticoid and tumor necrosis factor-alpha inhibitors in patients with Takayasu arteritis (TA)., Materials and Methods: In five patients with TA, the effects of the sequential treatment with prednisone for 5-7 months and then with adalimumab (ADA) + methotrexate (MTX) or infliximab + MTX, or with ADA only, for 12 months on both clinical and laboratory findings were evaluated., Results: All treatments improved both symptoms and laboratory parameters without the development of side-effects., Conclusions: It was hypothesized that MMP-9 and neutrophil gelatinase-associated lipocalin could be markers of the response to the treatments.

Background: Mixed venous and arterial ulcers account for approximately 15%-30% of all venous leg ulcerations. Several studies have shown that matrix metalloproteinases (MMPs) and neutrophil gelatinase-associated lipocalin (NGAL) play a central role in the pathophysiology of venous and arterial diseases. Some studies have shown the efficacy of glycosaminoglycans, such as sulodexide (SDX), in treating patients with leg ulcers. The aim of this study was to evaluate clinical effects of SDX and its correlation with MMPs and NGAL expression in patients with mixed arterial and venous leg ulcers., Methods: Patients eligible for this study were of both sexes, older than 20 years, and with a clinical and instrumental diagnosis of mixed ulcer., Results: Fifty-three patients of both sexes were enrolled and divided into two groups by means of randomization tables. Group A (treated group) comprised 18 females and ten males (median age: 68.7 years) treated with standard treatment (compression therapy and surgery) + SDX (600 lipoprotein lipase-releasing units/day intramuscularly) for 15 days followed by SDX 250 lipase-releasing units every 12 hours day orally for 6 months as adjunctive treatment. Group B (control group) comprised 17 females and eight males (median age: 64.2 years) treated with standard treatment only (compression therapy and surgery). The type of surgery was chosen according to anatomical level of vein incompetence: superficial venous open surgery and/or subfascial endoscopic perforating surgery. In all enrolled patients, blood samples were collected in order to evaluate the plasma levels of MMPs and NGAL through enzyme-linked immunosorbent assay. These results were compared to another control group (Group C) of healthy individuals. Moreover, biopsies of ulcers were taken to evaluate the tissue expression of MMPs and NGAL through Western blot analysis. Our results revealed that SDX treatment is able to reduce both plasma levels and tissue expression of MMPs improving the clinical conditions in patients with mixed ulcers., Conclusion: Inhibition of MMPs could represent a possible therapeutic intervention to limit the progression of leg ulceration. In particular, our findings demonstrate the efficacy of SDX in patients with mixed arterial and venous chronic ulcers of the lower limbs.

Background. Cerebral aneurysms are relatively common in adults, with a prevalence ranging between 1% and 5%. Subarachnoid hemorrhage, following aneurismal rupture, is a major cause of death and disability in these patients. Matrix Metalloproteinases (MMPs) and Neutrophil Gelatinase-Associated Lipocalin (NGAL) seem to be involved in the pathogenesis and in the clinical course of aneurysms. In this study, we evaluated the relationship between tissue and plasma levels of MMP-9 and NGAL in patient with ruptured and unruptured middle cerebral artery aneurysms. Methods. An open label study was conducted on 7 patients with middle cerebral aneurysms. Three patients had ruptured aneurysms (Group I) and four patients had unruptured aneurysms (Group II). All patients underwent aneurysm clipping. Plasma levels of MMP-9 and NGAL were evaluated through ELISA Test. During the surgery, biopsies of the aneurysmatic arteries were taken and frozen (- 80°C) for Western blot evaluation of MMPs and NGAL expression. Four healthy volunteers (Group III) represented the control group for ELISA testing. Results. Both plasma MMP-9 and NGAL levels were significantly high in aneurysmatic patients respect to those of control patients, and these levels were higher (P < 0.01) in patients with ruptured aneurysms respect to patients with unruptured aneurysms (P < 0.01). The latest findings were similarly evident in tissue evaluation of MMP-9 and NGAL between ruptured and unruptured aneurysms. Conclusion. This study suggests that MMP-9 and NGAL plasma levels may be useful to predict the clinical course of a cerebral aneurysms in order to evaluate the progression of the disease and the tendency of an aneurysm to rupture.

Stroke represents the most frequent cause of permanent disability in adults worldwide. Cerebral ischemia triggers the pathological pathways of the ischemic cascade and causes irreversible neuronal injury in the ischemic core within minutes of the onset. Elements of the immune system are involved in all stages of ischemic cascade from acute intravascular events triggered by the interruption of blood supply, to the parenchymal processes leading to brain damage and to the ensuing tissue repair. In this review, we will provide a brief overview of current understanding of the role of cytokines and brain inflammation during acute ischemic stroke.

Background: Since the skin represents a common site of adverse drug reactions, few data are reported at this time regarding the development of skin rash during the treatment with antidiabetic drugs., Case Presentation: We report a 29-year old woman that developed a facial skin rash during the treatment with metformin. Clinical and laboratory findings excluded the presence of systemic diseases, but several diagnosis and many drugs were administered without clinical improvement. The self-dismission of metformin induced an improvement of symptoms, while the re-challenge documented an impairments of skin rash. The Naranjo probability scale suggested a probable association between metformin and skin rash and metformin was definitively dismissed., Conclusion: We report for the first time a non vasculitis facial skin manifestation related to metformin in a young woman. However, this case may emphasizes the need to consider the ADRs as a differential diagnosis in order to reduce medical errors and the related medical costs.

Aim: The purpose of this study was to evaluate both the effects of ibuprofen and/or acetaminophen for the acute treatment of primary migraine in children in or out prophylactic treatment with magnesium., Methods: Children ranging from the ages of 5 to 16 years with at least 4 attack/month of primary migraine were eligible for participation the study. A visual analog scale was used to evaluate pain intensity at the moment of admission to the study (start of the study) and every month up to 18 months later (end of the study)., Results: One hundred sixty children of both sexes aged 5-16 years were enrolled and assigned in 4 groups to receive a treatment with acetaminophen or ibuprofen without or with magnesium. Migraine pain endurance and monthly frequency were similar in the 4 groups. Both acetaminophen and ibuprofen induced a significant decrease in pain intensity (P < .01), without a time-dependent correlation, but did not modify its frequency. Magnesium pretreatment induced a significant decrease in pain intensity (P < .01) without a time-dependent correlation in both acetaminophen- and ibuprofen-treated children and also significantly reduced (P < .01) the pain relief timing during acetaminophen but not during ibuprofen treatment (P < .01). In both acetaminophen and ibuprofen groups, magnesium pretreatment significantly reduced the pain frequency (P < .01)., Conclusions: Magnesium increased the efficacy of ibuprofen and acetaminophen with not age-related effects., (© 2013 American Headache Society.)

Soft tissue sarcomas (STS) are rare tumors with mesenchymal origin, accounting for 1% of all human cancer. Local control of STS can be obtained through the use of surgery and radiotherapy. In about 40% of these patients, disease will recur at distant sites, and of these more than 90% will die because of this aggressive malignancy. In advanced and/or metastatic STS patients treated with anthracycline-based regimen the median overall survival is about 12 months, and it has remained unchanged during the last 20 years. Clearly, this strongly suggests the need for discover more active compounds in STS, such as imatinib in GIST or dermatofibrosarcoma patients. In this paper we describe the crucial role of angiogenesis mechanisms in sarcomas development and progression. Consequentially, we focus on pazopanib, a novel multitargeted tyrosine kinase inhibitor with anti-angiogenic activity, mainly due to VEGFR2 pathway interference. We also analyze principal completed trials leading pazopanib approval in sarcomas pretreated patients., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Gambling Disorder (GD) is characterized by "the failure to resist gambling impulses despite severe personal, family or occupational consequences". In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), GD replaces the DSM-IV diagnosis of Pathological Gambling (PG). GD estimated prevalence ranges between 0.4% and 3.4% within the adult population and it seems to be more common in patients with Parkinson's disease (PD). In this population, GD recently has become more widely recognized as a possible complication of dopamine agonist (DA) therapy. This association has aroused great interest for the dramatic impact GD has on patients' quality of life. Management of PG in patients with PD could be demanding. It is based on patient and caregiver education, modification of dopamine replacement therapy, and in some cases psychoactive drug administration. In this review article, the authors provide an overview of GD pathogenesis during DA therapy as well as a summary of available treatment options.

Introduction: Carotid Body Tumors (CBTs) are Paragangliomas (PGLs) located in the head and neck region which usually do not cause overt neuroendocrine symptoms and hypertension. Matrix Metalloproteinases (MMPs) have shown a strong correlation between CBTs and their clinical behavior. Aim of this study is to analyze the relationship between changes in arterial blood pressure and metalloproteinases levels after surgical resection of CBTs., Methods: We performed a multicenter clinical study on 17 patients with benign and malignant CBTs (5 males; 12 females). Tumors were completely resected and biopsies, obtained at the time of surgery, were lysed for Western blot analysis to determine MMPs levels in tissues. An enzyme-linked immune sorbent assay (ELISA) kit was used to determine the concentration of MMPs in plasma fluid. Blood pressure values were measured at admission and at 10 days after surgery., Results: At the time of the admission, blood pressure values were higher in patients with CBTs respect to control patients; moreover in patients with malignant CBTs blood pressure values were higher (P < 0.01) respect to patients with benign CBTs. 10 days after the surgery, we documented a significant decrease (P < 0.01) in blood pressure values and in MMPs levels in all patients with CBTs., Conclusion: These results suggest that, despite the CTBs are considered non-functional tumors, an "underestimated" neuroendocrine activity on arterial blood pressure may be detected., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

With the advances in antiretroviral (ARV) therapy, patients with Human Immunodeficiency Virus (HIV) infection are living longer, however, some patients encounter co- morbidities which sometimes require treatment. Therefore, during the treatment with ARV drugs these patients could take several recreational drugs (e.g. amphetamines, hallucinogenes, opiates, or alcohol) with a possible development of drug-drug interactions (DDIs). In particular, Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) are mainly excreted through the kidney and are not substrates of the cytochrome P450 or P-glycoprotein, therefore the DDIs during this treatment are minimal. In contrast, the other ARV drugs (i.e. non-nucleoside reversetranscriptase inhibitors, Protease inhibitors, Integrase inhibitors, chemokine receptor 5 antagonists and HIV-fusion inhibitors) are an important class of antiretroviral medications that are frequent components of HAART regimens but show several DDIs related to interaction with the cytochrome P450 or P-glycoprotein. In this paper we will review data concerning the possibility of DDI in HIV patients treated with ARV and taking recreational drugs.

Chronic obstructive pulmonary disease (COPD) is a complex disorder involving both airways and lung parenchyma, usually associated with progressive and poorly reversible airflow limitation. In order to better characterize the phenotypic heterogeneity and the prognosis of patients with COPD, there is currently an urgent need for discovery and validation of reliable disease biomarkers. Within this context, proteomic and peptidomic techniques are emerging as very valuable tools that can be applied to both systemic and pulmonary samples, including peripheral blood, induced sputum, exhaled breath condensate, bronchoalveolar lavage fluid, and lung tissues. Identification of COPD biomarkers by means of proteomic and peptidomic approaches can thus also lead to discovery of new molecular targets potentially useful to improve and personalize the therapeutic management of this widespread respiratory disease.

Introduction: Pharmacovigilance (PV) is designed to monitor drugs continuously after their commercialization, assessing and improving their safety profile. The main objective is to increase the spontaneous reporting of adverse drug reactions (ADRs), in order to have a wide variety of information. The Italian Drug Agency (Agenzia Italiana del Farmaco [AIFA]) is financing several projects to increase reporting. In Calabria, a PV information center has been created in 2010., Materials and Methods: We obtained data using the database of the National Health Information System AIFA relatively to Italy and Calabria in the year 2012. Descriptive statistics were performed to analyze the ADRs., Results: A total number of 461 ADRs have been reported in the year 2012 with an increase of 234% compared with 2011 (138 reports). Hospital doctors are the main source of this reporting (51.62%). Sorafenib (Nexavar(®)), the combination of amoxicillin/clavulanic acid and ketoprofen represent the drugs most frequently reported causing adverse reactions. Adverse events in female patients (61.83%) were more frequently reported, whereas the age groups "41-65" (39.07%) and "over 65" (27.9%) were the most affected., Conclusions: Calabria has had a positive increase in the number of ADRs reported, although it has not yet reached the gold standard set by World Health Organization (about 600 reports), the data have shown that PV culture is making inroads in this region and that PV projects stimulating and increasing PV knowledge are needed.

Off-label use is very common among pediatricians, and the main cause is attributable to the lack of drugs specifically designed and marketed for children in different age groups. In this study, we evaluated, through a questionnaire, the knowledge of off-label drugs in pediatrics. Furthermore, we made a directory of 28 off-label drugs most commonly used by pediatricians in agreement with data obtained from Italian Agency for drugs (AIFA) referred to the law no. 648/1996; 180 pediatricians referred to the Italian Society of Pediatrics Calabrian section were asked to complete an online anonymous questionnaire. Eighty five (47.3%) of these completed the anonymous questionnaire, 40% revealed that they used off-label drugs "sometimes"; generally, drugs were used off-label for age and to treat respiratory diseases. For 75 pediatricians (88%) the information about the risk/benefit of off-label drugs is inadequate and 63 pediatricians (74%) did not have a good knowledge about this practice. In conclusion, the knowledge of off-label drugs is very low in pediatricians; more information about off-label drugs could be useful in order to improve the appropriateness of drugs' prescription and to reduce the development of side effects and improving drug safety.

Vaccines are administered to large population of healthy individuals, particularly to millions of infants every year, through national immunization programs. Although vaccines represent a good defense against some infectious diseases, their administration may be related with the development of adverse vaccine events (AVEs); therefore their use is continually monitored to detect these side effects. In the presents work, we reported the suspected AVEs recorded in 2012 in Calabria, Italy. We performed a retrospective study on report forms of patients that developed AVEs in Calabria from January 1, 2012 to December 31, 2012. Naranjo score was used to evaluate the association between AVEs and vaccines and only suspected AVEs definable as certain, probable, or possible were included in this analysis. During the study period, we evaluated 461 records of adverse drug reactions (ADRs) and 18 (3.9%) were probably induced by vaccination. AVEs were common in females (almost 77.7%) and in children aged 0-3 years. The largest number of non-serious AVEs involved "skin and subcutaneous tissue disorders" and "general disorders and administration site conditions." In conclusion, we documented that in Calabria the total number of AVEs is very low and it may be useful to increase the pharmacovigilance culture in order to evaluate the safety of these products in large populations.

The use of cardiovascular drugs is related to the development of adverse drug reactions (ADRs) in about 24% of the patients in the Cardiovascular Care Unit. Here, we evaluated the ADRs in patients treated with antihypertensive drugs. The study was conducted in two phases: In the first phase, we performed a retrospective study on clinical records of Clinical Divisions (i.e., Internal Medicine Operative Unit and Geriatric Operative Unit) from January 1, 2012 to December 31, 2012. Moreover from January 1, 2013 to March 30, 2013 we performed a prospective study on the outpatients attending the Emergency Department (ED) of the Pugliese-Ciaccio Hospital of Catanzaro, by conducting patient interviews after their informed consent was obtained. The association between a drug and ADR was evaluated using the Naranjo scale. We recorded 72 ADRs in the Clinical Divisions and six in the ED, and these were more frequent in women. Using the Naranjo score, we showed a probable association in 92% of these reactions and a possible association in 8%. The most vulnerable age group involved in ADRs was that of the elderly patients. In conclusion, our results indicate that antihypertensive drugs may be able to induce the development of ADRs, particularly in elderly women receiving multiple drug treatment. Therefore, it is important to motivate the healthcare providers to understand their role and responsibility in the detection, management, documentation, and reporting of ADRs, as also all the essential activities for optimizing patient safety.

Matrix metalloproteinase-9 (MMP-9) is involved in the remodeling process by degrading extracellular matrix, which is fundamental in maintaining structural integrity and favorable mechanical properties of the artery vascular wall. Neutrophil gelatinase-associated lipocalin (NGAL) seems to enhance MMP-9 activity. ELISA test was used to evaluate plasma MMP-9 and NGAL values. Moreover, Western blot analysis and RT-PCR were used to evaluate expression of MMP-9 and NGAL in aneurysmatic tissue with respect to healthy endothelial tissue of the same patient. In this rare case of abdominal aortic aneurysm associated with multiple peripheral aneurysms, both plasma and tissue levels of MMP-9 and NGAL seemed to correlate with disease progression. More studies and clinical trials are necessary to confirm our findings., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Fatigue represents a common side effect of several drugs, however, the underlying mechanisms have not been well identified. A depression of the central nervous system (CNS) and/or changes in peripheral processes have been associated with the development of fatigue. Antiepileptic drugs (AEDs), generally decreasing CNS excitability, are used in the treatment of seizures as well as other neurological and psychiatric diseases. Fatigue is certainly a common AEDs' side effect, although a high degree of variability exists depending on both patients' characteristics and the drug used. Here, we delineate the pathophysiological central and peripheral mechanisms by which AEDs may cause fatigue also reviewing the available clinical data in order to assess a possible AEDs rank and highlight each AEDs related risk. It appears that drugs acting on the GABAergic system have the highest incidence (with tiagabine exception) of fatigue followed by Gabapentin and Levetiracetam whereas drugs mainly inhibiting sodium channels (Carbamazepine, Eslicarbazepine, Lamotrigine, Phenytoin and Valproate) have the lowest. However, the dose used, AEDs related side effects and patients' characteristics might influence the degree of fatigue observed., (© 2013 Elsevier B.V. All rights reserved.)

The use of telemedicine, especially as it is relates to telestroke, has significantly expanded over the past one or two decades. The fact that stroke therapy is a time-critical disease process, coupled with the relative paucity of stroke-trained practitioners, makes telestroke an attractive technique of care. The authors' objective was to summarize the evidence that support the reliability of telemedicine for diagnosis and efficacy in acute stroke treatment in collaboration between hospitals in two different countries.

Objective: We investigated the effects of celecoxib, diclofenac, and ibuprofen on the disease-specific quality of life, synovial fluid cytokines and signal transduction pathways in symptomatic knee osteoarthritis (OA)., Design: Ninety patients scheduled for a total knee arthroplasty (TKA) were randomized to six groups that were treated with low and high dosages of celecoxib, diclofenac or ibuprofen. At the time of the first admission (T0) and at surgery (T1 = 14 days after beginning of the nonsteroidal anti-inflammatory drugs (NSAIDs)), samples of knee synovial fluid were obtained from each patient for analysis. During the surgery the synovial tissue was harvested from the knee of patients. The Western Ontario and McMaster universities (WOMAC) score was used to evaluate the patient disease-specific quality of life at T0 and T1. Microarray tests performed at T0 and T1 were used to evaluate the effects of NSAIDs on Tumor necrosis factor (TNF)-alpha, Interleukin-6 (IL-6), IL8 and Vascular endothelial growth factor (VEGF) concentration in the synovial fluid. Western blot assays evaluated the effects of NSAIDs on MAP kinase (MAPK) signal transduction pathway in the synovial membrane., Results: NSAID treatment induced a statistically significant improvement in the WOMAC score and a statistically significant decrease in the IL-6, VEGF and TNF-alpha concentration in the synovial fluid. Higher dosages of NSAIDs provided a greater improvement in the disease-specific quality of life of patients and lower concentrations of pro-inflammatory cytokines in the synovial fluid. Inhibition of MAPKs was noted after NSAID treatment., Conclusion: Short-term NSAID treatment improves the patient disease-specific quality of life with a parallel decrease in pro-inflammatory synovial fluid cytokine levels in knee OA. Signal transduction pathways may be involved in regulating the anti-inflammatory effects of NSAIDs. ClinicalTrial.gov: NCT01860833., (© 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Drug-drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications.

We report for the first time the lack of therapeutic effects after the switch from a brand formulation of allopurinol to a generic one. A 56-year-old man, with a 5 years history of well-treated gout arthropathy with allopurinol (Zyloric(®) 300 mg/die), developed acute gout arthropathy after the switch from the brand formulation of allopurinol to a generic one. Clinical evaluation and laboratory findings confirmed the diagnosis of acute gout arthropathy. Generic formulation of the drug was dismissed and Zyloric(®) was administered with an improvement of both clinical symptoms and laboratory findings. In conclusion, even if generic formulations are considered to have the same effects in comparison to the brand one, more data are necessaries in order to well define their effectiveness and rationale use., (Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)