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Abstract Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). Alveolar macrophage (AM)-derived PD-L1 binds to its receptor, PD-1, on surveilling lymphocytes, leading to lymphocyte exhaustion. Increased PD-L1 expression is associated with cigarette smoke (CS)-exposure. However, the PD-L1 role in CS-associated lung diseases associated with NSCLC, such as chronic obstructive pulmonary disease (COPD), is still unclear. In two different cohorts of ever smokers with COPD or NSCLC, and ever and never smoker controls, we evaluated PD-L1 expression: (1) via cutting-edge digital spatial proteomic and transcriptomic profiling (Geomx) of formalin-fixed paraffin-embedded (FFPE) lung tissue sections (n = 19); and (2) via triple immunofluorescence staining of bronchoalveolar lavage (BAL) AMs (n = 83). PD-L1 mRNA expression was also quantified in BAL AMs exposed to CS extract. PD-L1 expression was increased in the bronchiolar wall, parenchyma, and vascular wall from mild-moderate (GOLD 1–2) COPD patients compared to severe-very severe (GOLD 3–4) COPD patients and controls. Within all the COPD patients, PD-L1 protein expression was associated with upregulation of genes involved in tumor progression and downregulation of oncosuppressive genes, and strongly directly correlated with the FEV1% predicted, indicating higher PD-L1 expression in the milder vs. more severe COPD stages. In bronchioles, PD-L1 levels were strongly directly correlated with the number of functionally active AMs. In BAL, we confirmed that AMs from patients with both GOLD 1–2 COPD and NSCLC had the highest and similar, PD-L1 expression levels versus all the other groups, independently from active cigarette smoking. Intriguingly, AMs from patients with more severe COPD had reduced AM PD-L1 expression compared to patients with mild COPD. Acute CS extract stimulation increased PD-L1 mRNA expression only in never-and not in ever-smoker AMs. Lungs from patients with mild COPD and NSCLC are characterized by a similar strong PD-L1 expression signature in bronchioles and functionally active AMs compared to patients with severe COPD and controls. Active smoking does not affect PD-L1 levels. These observations represent a new resource in understanding the innate immune mechanisms underlying the link between COPD and lung cancer onset and progression and pave the way to future studies focused on the mechanisms by which CS promotes tumorigenesis and COPD.

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.

Introduction: Neuropathic pain is defined as pain induced by a lesion or disease of the somatosensory nervous system. Pharmacological and non-pharmacological treatments are frequently employed. In the current clinical investigation, we assessed the effects of sex on the safety and effectiveness of medications used to treat neuropathic pain. Methods: We conducted a prospective analysis between 1 February 2021 and 20 April 2024, involving patients with neuropathic pain referred to the Ambulatory of Pain Medicine of "Renato Dulbecco" University Hospital in Catanzaro (Calabria, Italy). Patients over 18 years old with signs of neuropathic pain (Douleur Neuropathique en 4 questionnaire ≥ 4) were included. Exclusion criteria comprised patients with Alzheimer's disease; patients with nociplastic or nociceptive pain; and patients with neoplasms. Patients with fewer than two accesses to ambulatory care were excluded, as were those who did not sign the informed consent. Clinical data were collected from each enrolled patient and subsequently analyzed, considering clinical outcomes. Sex and gender differences in efficacy were estimated using multivariate linear modeling and propensity-score matching. Results: During the study, 531 patients were screened, and 174 were enrolled (33.5%, mean age 61.5 ± 13.1; 64 males and 110 females, mean age 60.6 ± 13.4 and 61.96 ± 13.0) in accordance with the inclusion and exclusion criteria. Only minor differences in treatment prescription were observed based on age, body mass index, and comorbidities. Smoking, sex, educational level, and body mass index did not induce a significant change in pain perception. Males required slightly higher, though not significantly, doses of drugs for pain control than females. The treatment was not significantly more effective for females than for males. Females did not exhibit a significantly lower number of adverse drug reactions compared to males. Conclusions: The current study found that there are no appreciable differences between the sexes when it comes to the treatment of neuropathic pain.

Escin, extracted from horse chestnut ( Aesculus hippocastanum ) has anti-edema and anti-inflammatory effects. It is used to treat several clinical conditions, including venous insufficiency, pain, inflammation, and edema. Considering escin's pharmacodynamic, the inhibition of the bradykinin pathway represents a particular effect, decreasing the local edema and conferring an advantage in comparison to other compounds. In this narrative review, we described the effects of escin considering its effects on bradykinin pathway.

Background: Even if Meares-Stamey 4-glass (M&S) test is regarded a decisive tool for diagnosing prostatitis its use is only rarely performed in everyday clinical practice. Here, we analyze if the diagnostic yield of the M&S test could be improved by a pre-test categorization of patients due to undergo a M&S test., Methods: All clinical and microbiological data of patients who underwent M&S test in two urological centers from January 2004 to December 2021 were analyzed in this retrospective cohort study. One center has a dedicated staff member for the study of prostatitis (Cohort I), while the other center is a general urological unit (Cohort II). All patients were divided into 3 groups on the basis of the assembled data: patients with symptoms related to prostatitis only (Group I), patients with symptoms related to both prostatitis and BPH (Group II), patients with symptoms related to BPH only (Group III). The rates of positive microbiological results in each group were compared., Results: In the whole period, 9347 patients were analyzed and categorized as follows: Group I, 1884; Group II, 5151; Group III, 2312. Three-thousand and eight-hundred twenty-three patients showed positive culture results (40.9%). The most common isolated species was Escherichia coli (49.7%), followed by Enteroccus spp. (31.8%). The rates of positive M&S tests in the different symptom groups were: Group I, 1532 (81.4%); Group II, 1494 (29.0%); Group III, 797 (34.4%). The overall rate of positive M&S tests in each urology center showed that the center with a staff member who is dedicated to prostatitis studies (Cohort I) had a significantly higher rate of positive M&S tests than the general urological department (Cohort II) (64.3% vs 31.4%; p < 0.001)., Conclusions: Symptom-based patient selection and dedicated staff members will increase the diagnostic yield of the M&S test and reduce the number of unnecessary tests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is commonly considered to be a potent driver of non-small cell lung cancer (NSCLC) development and related mortality. A growing body of evidence supports a role of the immune system, mainly played by alveolar macrophages (AMs), in key axes regulating the development of COPD or NSCLC phenotypes in response to harmful agents. MicroRNAs (miRNAs) are small non-coding RNAs that influence most biological processes and interfere with several regulatory pathways. The purpose of this study was to assess miRNA expression patterns in patients with COPD, NSCLC, and ever- or never-smoker controls to explore their involvement in smoking-related diseases. Bronchoalveolar lavage (BAL) specimens were collected from a prospective cohort of 43 sex-matched subjects to determine the expressions of hsa-miR-223-5p, 16-5p, 20a-5p, -17-5p, 34a-5p and 106a-5p by RT-PCR. In addition, a bioinformatic analysis of miRNA target genes linked to cancer was performed. Distinct and common miRNA expression levels were identified in each pathological group, suggesting their possible role as an index of NSCLC or COPD microenvironment. Moreover, we identified miRNA targets linked to carcinogenesis using in silico analysis. In conclusion, this study identified miRNA signatures in AMs, allowing us to understand the molecular mechanisms underlying smoking-related conditions and potentially providing new insights for diagnosis or pharmacological treatment.

Background : The management of erectile dysfunction (ED) shows several grey zones and new treatments are required to reduce the percentage of patients discontinuing treatment. Here, we aim to evaluate the role of a natural mixture named Icarifil® (L-Citrulline, L-Carnitine, Eruca vesicaria , Panax ginseng , Tribulus terrestris , Turnera diffusa , Taurine, Vitamin E, Zinc) in the management of patients with ED. Methods : From September 2022 to March 2023, all patients attending 3 urological institutions due to ED were randomized to receive the following for 3 months: Icarifil® 1 sachet every 24 h (Group 1) or Icarifil® 1 sachet + tadalafil 5 mg 1 tablet every 24 h (Group 2) or tadalafil 5 mg 1 tablet daily (Group 3). All patients underwent urologic visits and dedicated questionnaires (IIEF-5, SEP-2, SEP-3) at enrollment and at the follow-up evaluation (3 months). Patient-Reported Outcomes (PROs) at the follow-up evaluation were used. The primary endpoint was the difference in the questionnaires at the follow-up visit compared to the one at enrollment among the study groups. Results : In the per-protocol analysis, 52 patients in Group 1, 55 in Group 2 and 57 in Group 3 were analyzed. At the follow-up evaluation, IIEF-5 scores improved in all the 3 groups between enrollment and the follow-up evaluation, but a statistically significant difference was reported between Group 2 (+7.4) and Group 1 (+4.1) or Group 3 (+5.1), ( p < 0.001; p < 0.001). Moreover, 47 patients (94.0%) in Group 2 showed an improvement in the SEP questionnaires, when compared with the baseline, while 29 in Group 1 (56.9%) and 42 in Group 3 (82.3%) showed a statistically significant difference ( p = 0.004; p = 0.003) among the groups. The PRO analysis reported better efficacy and patient satisfaction in Group 2 when compared with Group 1 or Group 3. Conclusions : In conclusion, Icarifil ® is able to improve penile erectile function in mild-moderate ED and significantly improve the clinical efficacy of daily used tadalafil 5 mg. Icarifil ® could represent an interesting alternative treatment in patients experiencing adverse effects or with contraindications for chronic treatment with PDE5-is., Competing Interests: The authors declare no conflicts of interest.

Temporal lobe epilepsy (TLE) represents the most common form of refractory focal epilepsy. The identification of innovative clinical biomarkers capable of categorizing patients with TLE, allowing for improved treatment and outcomes, still represents an unmet need. Circulating microRNAs (c-miRNAs) are short non-coding RNAs detectable in body fluids, which play crucial roles in the regulation of gene expression. Their characteristics, including extracellular stability, detectability through non-invasive methods, and responsiveness to pathological changes and/or therapeutic interventions, make them promising candidate biomarkers in various disease settings. Recent research has investigated c-miRNAs in various bodily fluids, including serum, plasma, and cerebrospinal fluid, of TLE patients. Despite some discrepancies in methodologies, cohort composition, and normalization strategies, a common dysregulated signature of c-miRNAs has emerged across different studies, providing the basis for using c-miRNAs as novel biomarkers for TLE patient management.

Disease-modifying therapies (DMTs) can affect vaccine responses in individuals with multiple sclerosis (MS). We assessed the humoral and T-cell responses following SARS-CoV-2 mRNA vaccination in MS patients receiving various DMTs. We prospectively enrolled 243 participants, including 113 healthy control subjects and 130 MS patients. Blood samples for detecting SARS-CoV-2 antibodies were collected at three time points: T0, before the first vaccine dose; T1, before the second dose; and T2, one month after the second dose. In a subgroup of 51 patients and 20 controls, samples were collected at T0 and T2 to assess the T-cell immune response to the Spike antigen of SARS-CoV-2 using ELISPOT-IFNγ. The IgG levels in patients treated with fingolimod and ocrelizumab (159.1 AU/ml and 467.1 AU/ml, respectively) were significantly lower than those in healthy controls and patients on other DMTs (P ​< ​0.0001). The mean Ig titers were higher in patients with an absolute lymphocyte count ≥1000 ​cells/mm3 compared to those with a count between 500 and 1000 and with a count <500 (mean ​± ​SD:7205.6 ​± ​7339.2, 2413.1 ​± ​4515.4 and 165.9 ​± ​152.2, respectively; p ​= ​0.008). We found correlations between antibody levels and age (r ​= ​0.233, p ​= ​0.008). A positive Spike-specific T-cell response was detectable in 100 ​% of vaccinated healthy controls and patients treated with teriflunomide, dimethyl-fumarate, and natalizumab, in 90.5 ​% of fingolimod patients, and in 63.8 ​% of ocrelizumab patients. There is a correlation between IgG-specific titer after SARS-CoV-2 vaccination and clinical variables (age, lymphocyte count). Notably, a T-cell-specific response to SARS-CoV-2 developed in patients treated with fingolimod and ocrelizumab, even with lower rates of humoral response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Polypharmacy is an important issue in older patients affected by dementia because they are very vulnerable to the side effects of drugs'. Between October 2021 and September 2022, we randomly assessed 205 old-aged outpatients. The study was carried out in a Center for Dementia in collaboration with a university center. The primary outcomes were: (1) deprescribing inappropriate drugs through the Beers and STOPP&START criteria; (2) assessing duplicate drugs and the risk of iatrogenic damage due to drug-drug and drug-disease interactions. Overall, 69 men and 136 women (mean age 82.7 ± 7.4 years) were assessed. Of these, 91 patients were home care patients and 114 were outpatient. The average number of the drugs used in the sample was 9.4 drugs per patient; after the first visit and the consequent deprescribing process, the average dropped to 8.7 drugs per patient ( p = 0.04). Overall, 74 potentially inappropriate drugs were used (36.1%). Of these, long half-life benzodiazepines (8.8%), non-steroidal anti-inflammatory drugs (3.4%), tricyclic antidepressants (3.4%), first-generation antihistamines (1.4%), anticholinergics (11.7%), antiplatelet drugs (i.e., ticlopidine) (1.4%), prokinetics in chronic use (1.4%), digoxin (>0.125 mg/day) (1.4%), antiarrhythmics (i.e., amiodarone) (0.97%), and α-blockers (1.9%) were included. The so-called "duplicate" drugs were overall 26 (12.7%). In total, ten potentially dangerous prescriptions were found for possible interactions (4.8%). We underline the importance of checking all the drugs taken periodically and discontinuing drugs with the lowest benefit-to-harm ratio and the lowest probability of adverse reactions due to withdrawal. Computer tools and adequately trained teams (doctors, nurses, and pharmacists) could identify, treat, and prevent possible drug interactions.

Background: Dietary nitrate (NO 3 - ) has been shown to be useful as an ergogenic aid with potential applications in health and disease (e.g., blood pressure control). However, there is no consensus about the effects of dietary NO 3 - or beetroot (BR) juice supplementation on cognitive function., Objective: The aim of this study was to evaluate the effects of a single dose of a chewable BR-based supplement on cognitive performance., Methods: A double-blind randomized placebo-controlled two-period crossover clinical trial was carried out based on the extension of the CONSORT guidelines for randomized crossover trials. A total of 44 participants (24 F; 20 M; 32.7 [12.5] years; 66.3 [9.0] kg; 170 [9.2] cm; 22.8 [1.4] kg/m 2 ) were randomly allocated to receive first either four BR-based chewable tablets (BR-CT) containing 3 g of a Beta vulgaris extract (RedNite ® ) or four tablets of a placebo (maltodextrin). A 4-day washout period was used before crossover. Ninety minutes after ingestion of the treatments, a neuropsychological testing battery was administered in each period. The trial was registered at clinicaltrials.gov NCT05509075., Results: Significant improvements with moderate effect size were found on memory consolidation at the short and long term only after BR-CT supplementation via the Rey Auditory Verbal Learning Test immediate (+ 20.69%) and delayed (+ 12.34%) recalls. Likewise, enhancement on both frontal lobe functions (+ 2.57%) and cognitive flexibility (+ 11.16%) were detected after BR-CT. There was no significant change (p < 0.05) on verbal memory of short-term digits, working memory and information processing speed. Mixed results were found on mood and anxiety through the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI-Y1 and STAI-Y2); however, sequence and period effects were seen on STAI-Y2., Conclusions: The acute administration of a chewable BR-based supplement improves certain aspects of cognitive function in healthy females and males, particularly memory capacity and frontal skills., (© 2023. The Author(s).)

Background: We aimed to evaluate the impact of two different phytotherapeutic agents on decision making regarding prostate biopsy for patients with higher-than-normal prostate-specific antigen (PSA) levels., Methods: From June 2022 to May 2023, all patients attending two urological institutions due to higher-than-normal PSA levels were randomized to receive either oral capsules of Curcuma Longa, Boswellia, Pinus pinaster and Urtica dioica (Group A) or Serenoa Repens 320 mg (Group B) for 3 months. At the follow-up visit after 3 months, all patients underwent PSA tests and multiparametric magnetic resonance imaging (mpMRI)., Results: In the per-protocol analysis, data from 66 patients in Group A and 76 in Group B were analyzed. Fifty patients in Group A (75.7%) showed a significant reduction in total PSA compared to forty-nine in Group B (64.4%) ( p < 0.001). Twenty-eight patients had PI-RADS III or higher in mpMRI: twelve in Group A and fourteen in Group B. Twenty-three patients (34.8%) in Group A and fifty-nine (77.6%) in Group B ( p < 0.001) underwent prostate biopsy based on the mpMRI findings and PSA values. Three patients in Group A showed a significant reduction in total PSA values while having positive mpMRI findings (6%) compared with nine in Group B (19.5%) ( p < 0.001). On the contrary, 7 patients in Group A did not show significant reduction in total PSA values and had negative mpMRI findings (43%) compared to 22 in Group B (81.4%) ( p < 0.001)., Conclusions: In conclusion, a three-month course of a combination of Curcuma Longa, Boswellia, Pinus pinaster and Urtica dioica seems to be an interesting tool to avoid unnecessary prostate biopsies among men with higher-than-normal PSA levels.

Clinical studies documented that cenobamate (CNB) has a marked efficacy compared to other antiseizure medications (ASMs) in reducing focal seizures. To date, different aspects of CNB need to be clarified, including its efficacy against generalized seizures. Similarly, the pattern of drug-drug interactions between CNB and other ASMs also compels further investigation. This study aimed to detect the role of CNB on generalized seizures using the DBA/2 mouse model. We have also studied the effects of an adjunctive CNB treatment on the antiseizure properties of some ASMs against reflex seizures. The effects of this adjunctive treatment on motor performance, body temperature, and brain levels of ASMs were also evaluated. CNB was able to antagonize seizures in DBA/2 mice. CNB, at 5 mg/kg, enhanced the antiseizure activity of ASMs, such as diazepam, clobazam, levetiracetam, perampanel, phenobarbital, topiramate, and valproate. No synergistic effects were observed when CNB was co-administered with some Na + channel blockers. The increase in antiseizure activity was associated with a comparable intensification in motor impairment; however, the therapeutic index of combined treatment of ASMs with CNB was more favorable than the combination with vehicle except for carbamazepine, phenytoin, and oxcarbazepine. Since CNB did not significantly influence the brain levels of the ASMs studied, we suggest that pharmacokinetic interactions seem not probable. Overall, this study shows the ability of CNB to counteract generalized reflex seizures in mice. Moreover, our data documented an evident synergistic antiseizure effect for the combination of CNB with ASMs including phenobarbital, benzodiazepines, valproate, perampanel, topiramate, and levetiracetam., Competing Interests: Declaration of competing interest Every author declare that no financial support or compensation has been received from any individual or corporate entity for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Ethical guidelines were followed for animal experimentation. The contents of the manuscript have not been previously published elsewhere neither are under submission., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Drug-drug interactions (DDIs) represent an important clinical problem, particularly in older patients, due to polytherapy, comorbidity, and physiological changes in pharmacodynamic and pharmacokinetic pathways. In this study, we investigated the association between drugs prescribed after discharge from the hospital or clinic and the risk of DDIs with drugs used daily by each patient., Methods: We performed an observational, retrospective, multicenter study on the medical records of outpatients referred to general practitioners. DDIs were measured using the drug interaction probability scale. Potential drug interactions were evaluated by clinical pharmacologists (physicians) and neurologists. Collected data were analyzed using the Statistical Package for the Social Sciences., Results: During the study, we evaluated 1772 medical records. We recorded the development of DDIs in 10.3% of patients; 11.6% of these patients required hospitalization. Logistic regression showed an association among DDIs, sex, and the number of drugs used ( p = 0.023)., Conclusions: This observational real-life study shows that the risk of DDIs is common in older patients. Physicians must pay more attention after hospital discharge, evaluating the treatment to reduce the risk of DDIs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the management of fever, pain, and inflammation. However, they have always been considered to have a double-faced role, according to their capacity to manage inflammation but also their possible reduction of immune system response and diagnosis delay. This last point could favor a dramatic increase of viral infection diffusion, possibly leading to a more severe outcome. The advent of severe acute respiratory syndrome coronavirus 2 excluded the use of NSAIDs, particularly ibuprofen, and then indicated this drug as the better NSAID to manage infected outpatients and prevent complications. Several authors described the role of NSAIDs and ibuprofen in preventing cytokine storm and modulating the immune system. However, the development of both adverse drug reactions (i.e., gastrointestinal, renal, hepatic, and cardiovascular) and drug interaction recalled the necessity of prescribing the better NSAID for each patient. In this narrative review, we describe the role of NSAIDs, particularly of ibuprofen, in the management of viral symptoms, suggesting that the NSAID may be chosen considering the characteristics of the patient, the comorbidity, and the polytherapy., (© 2023, The American College of Clinical Pharmacology.)

Epilepsy is a chronic neurological disease characterized by abnormal brain activity, which results in repeated spontaneous seizures. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related premature death, particularly in drug-resistant epilepsy patients. The etiology of SUDEP is a structural injury to the brain that is not fully understood, but it is frequently associated with poorly controlled and repeated generalized tonic-clonic seizures (GTCSs) that cause cardiorespiratory and autonomic dysfunctions, indicating the involvement of the brainstem. Both respiratory and cardiac abnormalities have been observed in SUDEP, but not much progress has been made in their prevention. Owing to the complexity of SUDEP, experimental animal models have been used to investigate cardiac and/or respiratory dysregulation due to or associated with epileptic seizures that may contribute to death in humans. Numerous rodent models, especially mouse models, have been developed to better understand epilepsy and SUDEP physiopathology. This review synthesizes the current knowledge about dilute brown agouti coat color (DBA/2) mice as a possible SUDEP model because respiratory arrest (RA) and sudden death induced by audiogenic generalized seizures (AGSs) have been observed in these animals. Respiratory/cardiac dysfunction, brainstem arousal system dysfunction, and alteration of the neurotransmitter systems, which are observed in human SUDEP, have also been observed in these mice. In particular, serotonin (5-HT) alteration and adenosine neurotransmission appear to contribute to not only the pathophysiological mechanisms of medication but also seizure-related respiratory dysfunctions in this animal model. These neurotransmitter systems could be the relevant targets for medication development for chronic epilepsy and SUDEP prevention. We reviewed data on AGSs in DBA/2 mice and the relevance of this model of generalized tonic-clonic epilepsy to human SUDEP. Furthermore, the advantages of using this strain prone to AGSs for the identification of possible new therapeutic targets and treatment options have also been assessed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bosco, Guarnieri, Leo, Tallarico, Gallelli, Rania, Citraro and De Sarro.)

Background: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels., Methods: In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague-Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ., Results: In Sprague-Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats., Conclusions: these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors.

A eutectic mixture of prilocaine/lidocaine spray (Fortacin™, Recordati, Milan, Italy) has been approved for the management of patients affected by life-long premature ejaculation (PE), but to date, there is a lack of dose- or time-finding studies in the literature that indicate the best method of intake to optimize treatment outcomes. In this multicentre, randomized, two-phase study, we aimed to compare, in terms of treatment effectiveness (primary objective) and safety (secondary objective), different treatment regimens (various doses and times of drug delivery) of Fortacin™ in 91 patients affected with lifelong PE who were recruited at four different centres and randomized (1:1:1 ratio) into three different groups. The study included two phases: during the first phase (focused on time-finding), the same drug dose (three sprays) was taken at different intervals before intercourse (5, 15, 30 min). In the second phase (focused on dose finding), different drug doses (1, 3, 5 sprays) were taken at the same interval before intercourse (5 min). The main outcome measure instruments were self-measured intravaginal ejaculation latency time (sm-IELT), the premature ejaculation diagnostic tool (PEDT), and the International Index of Erectile Function-5 (IIEF-5). Furthermore, patients were asked to report any side effects that appeared during the study period. Our main study findings showed that the treatment regimen with three sprays of Fortacin™ administered 5 min before sexual intercourse showed the best results in terms of ejaculation time and control (Phase I, IELT 221 ± 3.4, PEDT 7.7 ± 0.3; Phase II, IELT 213 ± 4.9, PEDT 7.8 ± 0.4) with a safety profile that was identical to other treatment regimens. Based on these data, patients who are prescribed Fortacin™ should stick to this regimen to optimize treatment results., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Asthma and nasal polyposis often coexist and are frequently intertwined by tight pathogenic links, mainly consisting of the cellular and molecular pathways underpinning type 2 airway inflammation. The latter is characterized by a structural and functional impairment of the epithelial barrier, associated with the eosinophilic infiltration of both the lower and upper airways, which can be driven by either allergic or non-allergic mechanisms. Type 2 inflammatory changes are predominantly due to the biological actions exerted by interleukins 4 (IL-4), 13 (IL-13), and 5 (IL-5), produced by T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2). In addition to the above cytokines, other proinflammatory mediators involved in the pathobiology of asthma and nasal polyposis include prostaglandin D 2 and cysteinyl leukotrienes. Within this context of 'united airway diseases', nasal polyposis encompasses several nosological entities such as chronic rhinosinusitis with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD). Because of the common pathogenic origins of asthma and nasal polyposis, it is not surprising that the more severe forms of both these disorders can be successfully treated by the same biologic drugs, targeting many molecular components (IgE, IL-5 and its receptor, IL-4/IL-13 receptors) of the type 2 inflammatory trait.

Biological drugs are used to treat severe asthma with an improvement of clinical symptoms. Data on sex difference of these drugs in patients with severe asthma are sparse. This study aimed to assess the effects of sex-related differences on biological drugs in patients with severe asthma. In this observational, open-label, prospective, noncontrolled, single-center cohort pilot study, we enrolled adult patients aged >18 years diagnosed with severe asthma and not previously treated with biological drugs. The first clinical end point was the statistical difference (P < .05) in the efficacy of biological drugs evaluated using the asthma control test and spirometry between sexes. The first safety end point was the statistical difference (P < .05) in developing adverse drug reactions between sexes. We enrolled 74 patients with severe asthma (48 women and 26 men) with a mean age of 59.4 (standard deviation, 11.8) years. The mean forced expiratory volume in 1 second was 6.9 (standard deviation, 13.9) for women and 9.4 (standard deviation, 10.7) for men and improved significantly after the treatment (P < .01), with no significant differences in sex (P = .8). Similarly, the asthma control test improved 12 months after the beginning of the treatment without significant differences between men and women (P = .5). The most common drug used was omalizumab (45.9% of the patients; P < .01) without significant differences between sex (P > .05). We did not observe the development of adverse drug reactions during the study. In conclusion, in asthmatic patients, sex does not have a role in either the effectiveness or safety of biological drugs., (© 2022, The American College of Clinical Pharmacology.)

Atopy is an exaggerated IgE-mediated immune response to foreign antigens in which metabolic abnormalities of the leukotrienes (LTs) pathway play a crucial role. Recent studies have described sex as a key variable in LT biosynthesis, partly explaining why treatment with anti-LT drugs in atopic subjects leads to better control of symptoms in women. In addition, variability in LT production is often associated with single nucleotide polymorphisms (SNPs) in the arachidonate 5-lipoxygenase ( ALOX5 ) gene, which encodes the leukotriene-synthesizing enzyme machinery, 5-lipoxygenase ( 5-LO ). This study aimed to investigate whether two SNPs of ALOX5 are implicated in sex differences in allergic diseases in a prospective cohort of 150 age- and sex-matched atopic and healthy subjects. Rs2029253 and rs2115819 were genotyped using allele-specific RT-PCR, and serum levels of 5-LO and LTB4 were measured by ELISA. Both polymorphisms are significantly more common in women than in men, and their influences on LT production vary as a function of sex, leading to a decrease in men's and an increase in women's serum levels of 5-LO and LTB4 . These data represent a new resource for understanding sex-related differences in lung inflammatory diseases, partly explaining why women are more likely to develop allergic disorders than men.

In agreement with the International Association for the Study of Pain, chronic pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. To date, there are several types of pain: nociceptive, neuropathic, and nociplastic. In the present narrative review, we evaluated the characteristics of the drugs used for each type of pain, according to guidelines, and their effects in people with comorbidity to reduce the development of severe adverse events.

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., (© 2023. The Author(s).)

Current cardiovascular disease prevention strategies are based on the management of cardiovascular risk as a continuum, redefining the therapeutic goals for each individual based on the estimated global risk profile. Given the frequent clustering of the principal cardiovascular risk factors, such as hypertension, diabetes and dyslipidaemia, in the same individual, patients are required to take multiple drugs to achieve therapeutic targets. The adoption of single pill fixed dose combinations may contribute to achieve better control of blood pressure and cholesterol compared to the separate administration of the individual drugs, mostly due to better adherence related to therapeutic simplicities. This paper reports the outcomes of an Expert multidisciplinary Roundtable. In particular, the rational and potential clinical use of the single pill fixed dose combination "Rosuvastatin-Amlodipine" for the management of concomitant hypertension/hypercholesterolemia in different clinical fields are discussed. This Expert Opinion also illustrates the importance of an early and effective management of total cardiovascular risk, highlights the substantial benefits of combining blood pressure and lipid-lowering treatments in a single-pill fixed dose combination and attempts to identify and overcome the barriers to the implementation in clinical practice of the fixed dose combinations with dual targets. This Expert Panel identifies and proposes the categories of patients who may benefit the most from this fixed dose combination., (© 2023. The Author(s).)

Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide and represents an impending burden on the healthcare system. Despite increasing attention, the mechanisms underlying tumorigenesis in cancer-related diseases such as COPD remain unclear, making novel biomarkers necessary to improve lung cancer early diagnosis. MicroRNAs (miRNAs) are short non-coding RNA that interfere with several pathways and can act as oncogenes or tumor suppressors. This study aimed to compare miRNA lung expression between subjects with NSCLC and COPD and healthy controls to obtain the miRNA expression profile by analyzing shared pathways. Lung specimens were collected from a prospective cohort of 21 sex-matched subjects to determine the tissue miRNA expression of hsa-miR-34a-5p, 33a-5p, 149-3p, 197-3p, 199-5p, and 320a-3p by RT-PCR. In addition, an in silico prediction of miRNA target genes linked to cancer was performed. We found a specific trend for has-miR-149-3p, 197-3p, and 34a-5p in NSCLC, suggesting their possible role as an index of the tumor microenvironment. Moreover, we identified novel miRNA targets, such as the Cyclin-Dependent Kinase (CDK) family, linked to carcinogenesis by in silico analysis. In conclusion. this study identified lung miRNA signatures related to the tumorigenic microenvironment, suggesting their possible role in improving the evaluation of lung cancer onset.

Background: A correct approach to recurrent urinary tract infections (rUTIs) is an important pillar of antimicrobial stewardship. We aim to define an Artificial Neural Network (ANN) for predicting the clinical efficacy of the empiric antimicrobial treatment in women with rUTIs., Methods: We extracted clinical and microbiological data from 1043 women. We trained an ANN on 725 patients and validated it on 318., Results: The ANN showed a sensitivity of 87.8% and specificity of 97.3% in predicting the clinical efficacy of empirical therapy. The previous use of fluoroquinolones (HR = 4.23; p = 0.008) and cephalosporins (HR = 2.81; p = 0.003) as well as the presence of Escherichia coli with resistance against cotrimoxazole (HR = 3.54; p = 0.001) have been identified as the most important variables affecting the ANN output decision predicting the fluoroquinolones-based therapy failure. A previous isolation of Escherichia coli with resistance against fosfomycin (HR = 2.67; p = 0.001) and amoxicillin-clavulanic acid (HR = 1.94; p = 0.001) seems to be the most influential variable affecting the output decision predicting the cephalosporins- and cotrimoxazole-based therapy failure. The previously mentioned Escherichia coli with resistance against cotrimoxazole (HR = 2.35; p < 0.001) and amoxicillin-clavulanic acid (HR = 3.41; p = 0.007) seems to be the most influential variable affecting the output decision predicting the fosfomycin-based therapy failure., Conclusions: ANNs seem to be an interesting tool to guide the antimicrobial choice in the management of rUTIs at the point of care.

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs to provide updates on therapy evolution regarding a proportion of CF non-responder patients to current treatment, and we summarize the role of MMPs in pathogenesis and as future therapeutic targets of CF.

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a role in the modulation of neuropathic and nociceptive pain. The heterogeneity of clinical and pre-clinical data is an important issue in this experimental context. Despite the presence of a good number of studies on MMP inhibitors, these drugs showed scarce efficacy and relevant side effects. In the present manuscript, we reviewed studies in the literature that define a possible role of MMPs in pain and the effects of their modulation.

Nesfatin-1 is a new anorexigenic neuropeptide involved in the regulation of hunger/satiety, eating, and affective disorders. We aimed to investigate nesfatin-1 secretion in vitro, in murine adipose cells, and in human adipose fat samples, as well as to assess the link between circulating nesfatin-1 levels, NUCB2 and Fat Mass and Obesity Gene ( FTO ) polymorphisms, BMI, Eating Disorders (EDs), and pathological behaviors. Nesfatin-1 secretion was evaluated both in normoxic fully differentiated 3T3-L1 mouse adipocytes and after incubation under hypoxic conditions for 24 h. Omental Visceral Adipose tissue (VAT) specimens of 11 obese subjects, and nesfatin-1 serum levels' evaluation, eating behaviors, NUCB2 rs757081, and FTO rs9939609 polymorphisms of 71 outpatients seeking treatment for EDs with different Body Mass Index (BMI) were studied. Significantly higher levels of nesfatin-1 were detected in hypoxic 3T3-L1 cultured adipocytes compared to normoxic ones. Nesfatin-1 was highly detectable in the VAT of obese compared to normal-weight subjects. Nesfatin-1 serum levels did not vary according to BMI, sex, and EDs diagnosis, but correlations with grazing; emotional, sweet, and binge eating; hyperphagia; social eating; childhood obesity were evident. Obese subjects with CG genotype NUCB2 rs757081 and AT genotype FTO rs9939609 polymorphisms had higher nesfatin-1 levels. It could represent a new biomarker of EDs comorbidity among obese patients.

This prospective, open-label clinical study was carried out to evaluate both the efficacy and safety of intramuscular paravertebral injections of an oxygen−ozone (O2−O3) mixture in patients with cervicobrachial pain. We enrolled 540 subjects affected by cervicobrachial pain referred to the Ozone Therapy Ambulatory at the Mater Domini Hospital of Catanzaro (Italy) and to the Center of Pain in Taurianova (Reggio Calabria, Italy). All the subjects (n = 540) completed the treatment and the follow-up visits. The subjects received a mean of 11 cervical intramuscular treatments with an O2−O3 mixture (5 mL) with an O3 concentration of 10 μg/mL bis a week. The improvement of pain was measured by a change in the mean of the Visual Analog Scale (VAS) score from baseline to the end of treatment and during follow-ups. Patient satisfaction was assessed at the end of treatment using the SF-36 Questionnaire. The development of adverse drug reactions was recorded. The mean (±standard deviation) VAS pain score at baseline, at the end of treatment, and during follow-ups showed a significant reduction in pain over time (p < 0.001). All the patients who were enrolled (n: 540) were pain-free after one year. According to the pain distribution, all subjects showed a significant reduction in pain over time in each group (p < 0.05). No significant differences were observed with respect to sex or age. No adverse events were observed during the study. In conclusion, we documented that the intramuscular injection of an O2−O3 mixture is an effective and safe treatment option for patients with cervicobrachial pain.