Effect of tauroursodeoxycholic acid on survival and safety in amyotrophic lateral sclerosis: a retrospective population-based cohort study.

Background: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only. Methods: This propensity score-matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients. Findings: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000 mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7-93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7-41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA (HR 0.56; 95% CI 0.38-0.83; p = 0.0042) compared to both the control group and those with lower TUDCA dosages (defined as < 1000 mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae. Interpretation: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug. Funding: Emilia-Romagna Region.

Melatonin versus Sleep Deprivation for Sleep Induction in Nap Electroencephalography: Protocol for a Prospective Randomized Crossover Trial in Children and Young Adults with Epilepsy.

Electroencephalography (EEG) continues to be a pivotal investigation in children with epilepsy, providing diagnostic evidence and supporting syndromic classification. In the pediatric population, electroencephalographic recordings are frequently performed during sleep, since this procedure reduces the number of artifacts and activates epileptiform abnormalities. To date, no shared guidelines are available for sleep induction in EEG. Among the interventions used in the clinical setting, melatonin and sleep deprivation represent the most used methods. The main purpose of this study is to test the non-inferiority of 3-5 mg melatonin versus sleep deprivation in achieving sleep in nap electroencephalography in children and young adult patients with epilepsy. To test non-inferiority, a randomized crossover trial is proposed where 30 patients will be randomized to receive 3-5 mg melatonin or sleep deprivation. Each enrolled subject will perform EEG recordings during sleep in the early afternoon for a total of 60 EEGs. In the melatonin group, the study drug will be administered a single oral dose 30 min prior to the EEG recording. In the sleep deprivation group, parents will be required to subject the child to sleep deprivation the night before registration. Urinary and salivary concentrations of melatonin and of its main metabolite 6-hydroxymelatonin will be determined by using a validated LC-MS method. The present protocol aims to offer a standardized protocol for sleep induction to be applied to EEG recordings in those of pediatric age. In addition, melatonin metabolism and elimination will be characterized and its potential interference in interictal abnormalities will be assessed.

Efficacy of the Sentinox Spray in Reducing Viral Load in Mild COVID-19 and Its Virucidal Activity against Other Respiratory Viruses: Results of a Randomized Controlled Trial and an In Vitro Study.

Sentinox (STX) is an acid-oxidizing solution containing hypochlorous acid in spray whose virucidal activity against SARS-CoV-2 has been demonstrated. In this paper, results of a randomized controlled trial (RCT) on the efficacy of STX in reducing viral load in mild COVID-19 patients (NCT04909996) and a complementary in vitro study on its activity against different respiratory viruses are reported. In the RCT, 57 patients were randomized (1:1:1) to receive STX three (STX-3) or five (STX-5) times/day plus standard therapy or standard therapy only (controls). Compared with controls, the log10 load reduction in groups STX-3 and STX-5 was 1.02 (p = 0.14) and 0.18 (p = 0.80), respectively. These results were likely driven by outliers with extreme baseline viral loads. When considering subjects with baseline cycle threshold values of 20-30, STX-3 showed a significant (p = 0.016) 2.01 log10 reduction. The proportion of subjects that turned negative by the end of treatment (day 5) was significantly higher in the STX-3 group than in controls, suggesting a shorter virus clearance time. STX was safe and well-tolerated. In the in vitro study, ≥99.9% reduction in titers against common respiratory viruses was observed. STX is a safe device with large virucidal spectrum and may reduce viral loads in mild COVID-19 patients.

Does screening for adverse effects improve health outcomes in epilepsy? A randomized trial.

OBJECTIVE: To determine whether systematic screening for adverse effects of antiepileptic drugs (AEDs) reduces toxicity burden and improves health-related quality of life in patients with epilepsy. METHODS: Consecutive patients with uncontrolled seizures aged ≥16 years and a high Adverse Event Profile (AEP) score were randomized to 2 groups and followed up for 18 months at 11 referral centers. AEP scores were made available to treating physicians at all visits in the intervention group, but not in the control group. Co-primary endpoints were changes in AEP scores and Quality of Life Inventory for Epilepsy-31 (QOLIE-31) scores. RESULTS: Of 809 enrolled patients able to complete the AEP questionnaire, 222 had AEP scores ≥45 and were randomized to the intervention (n = 111) or control group (n = 111). A total of 206 patients completed the 18-month follow-up. Compared with baseline, AEP scores decreased on average by 7.2% at 6 months, 12.1% at 12 months, and 13.8% at 18 months in the intervention group (p < 0.0001), and by 7.7% at 6 months, 9.2% at 12 months, and 12.0% at 18 months in controls (p < 0.0001). QOLIE-31 scores also improved from baseline to final visit, with a mean 20.7% increase in the intervention group and a mean 24.9% increase in the control group (p < 0.0001). However, there were no statistically significant differences in outcomes between groups for the 2 co-primary variables. CONCLUSIONS: Contrary to findings from a previous study, systematic screening for adverse effects of AEDs using AEP scores did not lead to a reduced burden of toxicity over usual physician treatment. ITALIAN MEDICINES AGENCY AIFA IDENTIFIER: FARM52K2WM_003. CLINICALTRIALSGOV IDENTIFIER: NCT03939507 (registered retrospectively in 2019; the study was conducted during the 2006-2009 period and registration of clinical trials was not a widely established practice when this study was initiated). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the additional collection of formal questionnaires regarding adverse effects of AEDs does not reduce toxicity burden over usual physician treatment.

Design of in vitro skin permeation studies according to the EMA guideline on quality of transdermal patches.

Transdermal patches and medicated plasters are designed to sustain efficacious systemic or loco-regional drug concentrations, respectively. In both cases, drug skin permeation is a critical attribute from the early stage of the pharmaceutical development. In 2014, the EMA introduced the "Guideline on the quality of transdermal patches", in which the importance of equivalence of drug fluxes in in vitro skin permeation study was particularly emphasized to generic or abridged applications for the marketing authorization or manage dossier variations during the product cycle life. Moving from experimental data, this work provides information on the set-up of such studies and the statistical evaluation of obtained fluxes. In particular, the impact of the inter-sample variability on the equivalence assessment was deeply investigated by using formulation pairs containing propranolol, diclofenac or nitroglycerine. The main outputs of the work were attributable to the definition of the acceptability interval and number of replicates to be performed. As an example, the equivalence of two propranolol patches (flux variability lower than 25%) can be assessed using six replicas and a confidence limit within the 0.8-1.25 range (α = 0.05; power 90%). In contrast, the equivalence of diclofenac plasters, which exhibit a variability near the 50%, can be demonstrated increasing the number of replicas (i.e., 20 skin samples) for each formulation and widening the acceptance range according to the statistical approach proposed in the work.

Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice.

Polymorphonuclear leukocyte infiltration and activation into colonic mucosa are believed to play a pivotal role in mediating tissue damage in human ulcerative colitis (UC). Ligands of human CXC chemokine receptor 1 and 2 (CXCR1/R2) are chemoattractants of PMN, and high levels were found in the mucosa of UC patients. To investigate the pathophysiological role played by CXCR2 in experimental UC, we induced chronic experimental colitis in WT and CXCR2(-/-) mice by two consecutive cycles of 4% dextran sulfate sodium administration in drinking water. In wild-type (WT) mice, the chronic relapsing of DSS-induced colitis was characterized by clinical signs and histopathological findings that closely resemble human disease. CXCR2(-/-) mice failed to show PMN infiltration into the mucosa and, consistently with a key role of PMN in mediating tissue damage in UC, showed limited signs of mucosal damage and reduced clinical symptoms. Our data demonstrate that CXCR2 plays a key pathophysiological role in experimental UC, suggesting that CXCR2 activation may represent a relevant pharmacological target for the design of novel pharmacological treatments in human UC.

Analgesic efficacy and tolerability of ketoprofen lysine salt vs paracetamol in common paediatric surgery. A randomized, single-blind, parallel, multicentre trial.

BACKGROUND: In this study, we compared the analgesic efficacy of ketoprofen lysine salt (OKi) suppositories) vs paracetamol, in children undergoing minor surgery. We also studied the side-effects of the treatment. METHODS: Eighty-five children of both sexes, aged 6-14 years, were enrolled in a multicentre, randomized, single-blind, parallel-group study design. In all patients postsurgical pain was evaluated by visual analogue scale (VAS) and degree of distress (night-time awakening, crying, behaviour and defence posture). RESULTS: Ketoprofen lysine was more effective than paracetamol in reducing postoperative pain (P = 0.008) with earlier onset and longer duration (8 h) of the antinociceptive effect. Evaluation of area under the curve, an aggregated measure of VAS, and of distress, confirm the time profile of pain reduction. No adverse effects related to the treatment were observed. CONCLUSIONS: Ketoprofen lysine salt can be considered a potent therapeutic approach to control postsurgery pain in children, and an alternative to other established drug regimens.