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The lung is a key target of the cytokine storm that can be triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the widespread clinical syndrome known as coronavirus disease 2019 (COVID-19). Indeed, in some patients, SARS-CoV-2 promotes a dysfunctional immune response that dysregulates the cytokine secretory pattern. Hypercytokinemia underlies the hyperinflammatory state leading to injury of alveolar epithelial cells and vascular endothelial cells, as well as to lung infiltration sustained by neutrophils and macrophages. Within such a pathogenic context, interleukin-6 (IL-6) and other cytokines/chemokines play a pivotal pro-inflammatory role. Therefore, cytokines and their receptors, as well as cytokine-dependent intracellular signalling pathways can be targeted by potential therapies aimed to relieve the heavy burden of cytokine storm. In particular, the anti-IL-6-receptor monoclonal antibody tocilizumab is emerging as one of the most promising pharmacologic treatments. The reviews of this paper are available via the supplemental material section.

Despite of the European League Against Rheumatism (EULAR) provided different sets of recommendations for the management of cardiovascular risk in inflammatory arthritis patients, it must be pointed out that cardiometabolic comorbidity, such as type 2 diabetes (T2D), remains still underdiagnosed and undertreated in patients affected by rheumatoid arthritis (RA). In this work, we designed a single centre, prospective study in order to better investigate the occurrence of T2D during the course of 1 year of follow-up. Furthermore, we evaluated the role of both traditional cardiovascular and RA-specific related risk factors to predict the occurrence of new T2D. In this study, we evaluated 439 consecutive RA patients and we observed that 7.1% of our patients (31/439) developed T2D, after 12 month of prospective follow-up. The regression analysis showed that the presence of high blood pressure, the impaired fasting glucose (IFG) at the first observation and the poor EULAR-DAS28 response, after 12 months of follow-up, were significantly associated with an increased likelihood of being classified as T2D. Similarly, we observed that 7.7% of our patients (34/439) showed IFG after 12 months of prospective follow-up. The regression analysis showed that the presence of high blood pressure and the poor EULAR-DAS28 response after 12 months of follow-up, were significantly associated with an increased likelihood of showing IFG. Our study supports the hypothesis of a significant short-term risk of T2D in RA patients and of a close associations between uncontrolled disease activity and glucose metabolism derangement. Further multicentre, randomised-controlled studies are surely needed in order to elucidate these findings and to better ascertain the possible contribution of different therapeutic regimens to reduce this risk.

Increased expression of interleukin-6 (IL-6) both in cerebrospinal fluid (CSF) and plasma is closely associated with convulsive epilepsy and symptom severity of depression. By comparison, at present, little is known about the role of this cytokine in childhood (non-convulsive) absence epilepsy. The aim of this work was to investigate the potential effects of acute and chronic treatment with tocilizumab (TCZ, 10 and 30 mg/kg/day), on absence seizures, their development, and related psychiatric comorbidity in WAG/Rij rats. It is known that lipopolysaccharide (LPS)-induced changes in inflammatory processes increase absence epileptic activity. In order to study the central effects of TCZ, we investigated whether administration of this anti-IL-6R antibody could modulate the lipopolysaccharide (LPS) or IL-6-evoked changes in absence epileptic activity in WAG/Rij rats. Our results demonstrate that TCZ, at both doses, significantly reduced the development of absence seizures in adult WAG/Rij rats at 6 months of age (1 month after treatment suspension) compared with untreated controls, thus showing disease-modifying effects. Decreased absence seizure development at 6 months of age was also accompanied by reduced comorbid depressive-like behavior, whereas no effects were observed on anxiety-related behavior. Acute treatment with TCZ, at 30 mg/kg, had anti-absence properties lasting ~25 h. The co-administration TCZ with i.c.v. LPS or IL-6 showed that TCZ inhibited the worsening of absence seizures induced by both proinflammatory agents in the WAG/Rij rats, supporting a central anti-inflammatory-like protective action. These results suggest the possible role of IL-6 and consequent neuroinflammation in the epileptogenic process underlying the development and maintenance of absence seizures in WAG/Rij rats. Accordingly, IL-6 signaling could be a promising pharmacological target in absence epilepsy and depressive-like comorbidity.

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.

Background: The treatment of psoriasis has made considerable progress with biologicals, including tumor necrosis factor inhibitors, and recently, monoclonal antibodies inhibiting directly interleukin (IL) 17, IL-23, or both IL-12/23. Newer biologicals are directed to the interleukin pathway and appear to improve complete or near-complete clearance. The newer biologicals have also been shown to have an excellent safety profile. However, despite experience with patients having confirmed the results obtained in clinical trials, there are still few data on using the newer biologicals. Methods: The present active study aimed to prospectively evaluate safety profiles and persistence of some biologicals in a multicenter pharmacovigilance study, that enrolled 733 patients treated with a biologic drug in five Calabrian hospital units. Informative and treatment persistence evaluations with predictors for suspension and occurrence of adverse events (AEs) were executed. In particular, reasons for treatment discontinuation in our program take account of primary/secondary failure or development of an AE. Results: AEs occurred in 187/733 patients and serious AEs (SAEs) were identified in 5/733 patients. An number of 182/733 patients showed a primary/secondary inefficacy. The AEs and SAEs were described with adalimumab, infliximab, and etanercept but not with abatacept, brodalumab, tildrakizumab, golinumab, ixekizumab, guselkumab, risankizumab, secukinumab, and ustekinumab. Conclusions: Our analysis, although limited by a small sample size and a short-term follow-up period, offers suitable data on commonly used biological agents and their safety, interruption rate, and the attendance of SAEs. Real-world studies should be carried out to evaluate other safety interests.

To evaluate the correlation between inflammatory measures and whole-body insulin sensitivity in psoriatic arthritis (PsA) patients. For the present study, 40 nondiabetic PsA patients were recruited. A standard oral glucose tolerance test (OGTT) was performed. The insulin sensitivity index (ISI), insulinogenic index (IGI) and oral disposition index (ODI) were calculated from dynamic values of glucose and insulin obtained during OGTT. In our study population, mean ISI was 3.5 ± 2.5, median IGI was 1.2 (0.7-1.8), mean ODI 4.5 ± 4.5. In univariate correlation analysis, ISI correlated inversely with systolic blood pressure (sBP) (R = -0.52, p = 0.001), diastolic blood pressure (dBP) (R = -0.45, p = 0.004) and complement C3 (R = -0.43, p = 0.006) and ODI correlated inversely with sBP (R = -0.38, p = 0.02), dBP (R = -0.35, p = 0.03) and complement C3 (R = -0.37, p = 0.02). No significant correlations were found between analyzed variables and IGI. In a stepwise multiple regression, only complement C3 entered in the regression equation and accounted for approximately 50% of the variance of ISI. Using a receiver operating characteristic (ROC) curve we identified the best cut-off for complement C3 of 1.32 g/L that yielded a sensitivity of 56% and a specificity of 96% for classification of insulin resistant patients. In conclusion, our data suggest that serum complement C3 could represent a useful marker of whole-body insulin sensitivity in PsA patients.

Metformin ( ) is a synthetic derivative of guanidine, isolated from the extracts of , a plant with a prominent antidiabetic effect. Since its discovery more than 50 years ago, metformin represents a worldwide milestone in treatment of patients with type 2 diabetes (T2D). Recent evidence in humans indicates novel pleiotropic actions of metformin which span from its consolidated role in T2D management up to various regulatory properties, including cardio- and nephro-protection, as well as antiproliferative, antifibrotic, and antioxidant effects. These findings, together with ground-breaking studies demonstrating its ability to prolong healthspan and lifespan in mice, provided the basis for defining metformin as a potential molecule. Moreover, emerging and evidence support the novel hypothesis that metformin can exhibit immune-modulatory features. Studies suggest that metformin interferes with key immunopathological mechanisms involved in systemic autoimmune diseases, such as the T helper 17/regulatory T cell balance, germinal centers formation, autoantibodies production, macrophage polarization, cytokine synthesis, neutrophil extracellular traps release, and bone or extracellular matrix remodeling. These effects may represent a powerful contributor to antiaging and anticancer properties exerted by metformin and, from another standpoint, may open the way to assess whether metformin can be a candidate molecule for clinical trials involving patients with immune-mediated diseases. In this article, we will review the available preclinical and clinical evidence regarding the effect of metformin on individual cells of the immune system, with emphasis on immunological mechanisms related to the development and maintenance of autoimmunity and its potential relevance in treatment of autoimmune diseases.

Vertigo in children is a challenging topic. The lack of dedicated trials, guidelines and papers causes inhomogeneity in the treatment of vertigo in children. Meniere’s disease, migraine equivalents, vestibular neuritis, paroxysmal positional benign vertigo (BPPV), persistent postural-perceptual dizziness (PPPD) and motion sickness may affect children with various degrees of incidence and clinical severity compared to adults. Several drugs are proposed for the management of these conditions, even if their use is subordinated to the child’s age. In this review, we summarize the existing evidence related to the use of drugs for this clinical condition in children as a start point for new trials, stating the urgent need for international guidelines.

Psoriasis is an inflammatory and chronic skin disorder associated with physical and psychological burden impairing patients' quality of life. In the last decade, biologic drugs have widely changed treatment of moderate-severe psoriasis and their number is increasing overtime. To early identify expected/unexpected adverse events (AEs) with biologic treatments, pharmacovigilance programs are needed. We designed a post-marketing active pharmacovigilance program to monitor and analyse AEs and/or serious adverse events (SAEs) reports. All consecutive patients treated with one biologic drug during a two-years period and satisfying inclusion criteria have been enrolled in five Dermatology tertiary units. Demographic and clinical features of patients, type of treatment used, therapy discontinuation, failures, switch/swap to another biologic, and possible onset of AEs were collected. Overall, 512 patients with a diagnosis of psoriasis (286; 55.9%) or arthropathic psoriasis (226; 44.1%) have been enrolled. Eighty-two (16%) patients with AEs and 5 (1%) with SAEs have been identified. Further, 59 (11.5%) had a primary/secondary failure (mainly on infliximab and etanercept). The adverse events and SAEs were reported with golimumab (4/12), adalimumab (32/167), infliximab (9/48), etanercept (31/175) and ustekinumab (11/73), no adverse events have occurred with secukinumab (0/37). Infliximab and etanercept were significantly associated with primary/secondary failures, whereas no differences have been highlighted for AEs insurgence. On the other hand, ustekinumab seems to be associated with a low rate of AEs (p = 0.01) and no adverse events or failures have been reported with secukinumab (p = 0.04 and 0.03, respectively). Our study, even though limited by a small sample size and a brief follow-up period, provide useful data on widely used biologic drugs and their tolerability, discontinuation rate and the incurrence of severe adverse events. Further studies are necessary to include the recently approved biologic drugs and to increase the sample size for more detailed analysis.

Objectives Evaluate the role of platelet-rich fibrin (PRF) as a natural carrier for antibiotics delivery through the analysis of drug release and antimicrobial activity. Materials and methods PRF was prepared according to the L-PRF ( leukocyte- and platelet-rich fibrin ) protocol. One tube was used as control (without drug), while an increasing amount of gentamicin (0.25 mg, G1; 0.5 mg, G2; 0.75 mg, G3; 1 mg, G4), linezolid (0.5 mg, L1; 1 mg, L2; 1.5 mg, L3; 2 mg, L4), vancomycin (1.25 mg, V1; 2.5 mg, V2; 3.75 mg, V3; 5 mg, V4) was added to the other tubes. At different times the supernatant was collected and analyzed. Strains of E. coli, P. aeruginosa, S. mitis, H. influenzae, S. pneumoniae, S. aureus were used to assess the antimicrobial effect of PRF membranes prepared with the same antibiotics and compared to control PRF. Results Vancomycin interfered with PRF formation. Gentamicin and linezolid did not change the physical properties of PRF and were released from membranes in the time intervals examined. The inhibition area analysis showed that control PRF had slight antibacterial activity against all tested microorganisms. Gentamicin-PRF had a massive antibacterial activity against all tested microorganisms. Results were similar for linezolid-PRF, except for its antibacterial activity against E. coli and P. aeruginosa that was comparable to control PRF. Conclusions PRF loaded with antibiotics allowed the release of antimicrobial drugs in an effective concentration. Using PRF loaded with antibiotics after oral surgery may reduce the risk of post-operative infection, replace or enhance systemic antibiotic therapy while preserving the healing properties of PRF. Further studies are needed to prove that PRF loaded with antibiotics represents a topical antibiotic delivery tool for oral surgical procedures.