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Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease. We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study–Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11). Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31−7·34]: 75 mg LMTM twice a day [n=257] −0·02, −1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] −0·43, −2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [−8·22, 95% CI −9·63 to −6·82]: 75 mg LMTM twice a day −0·93, −3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day −0·34, −2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants. The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon. TauRx Therapeutics.

In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinson's disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinson's disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4×1011 vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinson's disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference −0·31 [SE 2·63], 95% CI −5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. Ceregene and Michael J Fox Foundation for Parkinson's Research.

ClinicalTrials.gov Identifier: NCT05821153, Registered April 20 2023, Retrospectively registered, https://classic.TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT05821153, Registered April 20 2023, Retrospectively registered, https://classic.gov/ct2/show/NCT05821153.CLINICALTRIALSgov/ct2/show/NCT05821153.

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self‐administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. Plain Language Summary Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year.

Background We previously documented that regulatory T cells (Tregs) immunomodulatory mechanisms are compromised in Alzheimer’s disease (AD), shifting the immune system toward a pro-inflammatory response. However, Tregs are a potentially restorable therapeutic target in AD. In this study, we evaluated the safety and efficacy of two dosing frequencies of low-dose Interleukin-2 (IL-2) in expanding Tregs to modify disease progression in AD individuals. Methods In this phase 2a, randomized, double-blind, placebo-controlled study, 38 participants were assigned to receive subcutaneous IL-2 (10^6 IU/day) for five days, administered either every 4 weeks (IL-2 q4wks) or every 2 weeks (IL-2 q2wks), versus placebo, for 21 weeks, followed by 9 weeks of observation. The primary endpoints were the incidence and severity of adverse events. For the secondary endpoints, changes in Treg numbers and suppressive functions were evaluated. Exploratory endpoints included changes in plasma inflammatory mediators, CSF AD-related biomarkers, and clinical scales. Results Of the 38 participants, 9 received IL-2 q4wks, 10 received IL-2 q2wks, and 19 received placebo. All participants completed the trial with no serious adverse events or deaths. Both IL-2 dosing regimens increased Treg numbers and suppressive function, but IL-2 q4wks treatment exhibited superiority in enhancing Treg percentage and Foxp3 mean fluorescent intensity. In longitudinal analysis of 45 inflammatory mediators, IL-2 q4wks administration demonstrated greater efficacy in alleviating the plasma inflammatory mediators CCL2, CCL11, and IL-15, while enhancing IL-4 and CCL13 levels. A significant improvement in CSF Aβ42 levels ( p  = 0.045 vs. placebo) on Day 148 was observed following IL-2 q4wks administration, compared to placebo. While CSF NfL increased by 217 pg/ml in placebo recipients, it remained stable in the IL-2 q4wks group ( p  = 0.060, IL-2 q4wks vs. placebo). The adjusted mean change from baseline in the ADAS-cog score at week 22 indicated a trend toward slower clinical progression in IL-2 q4wks recipients compared to placebo ( p  = 0.061). Conclusions The IL-2 immunotherapeutic strategy was safe and well-tolerated. IL-2 q4wks effectively expanded Treg populations, leading to modification in inflammatory mediators and CSF Aβ42 levels, while also showing promising trends on clinical scales. These findings provide a foundation for further investigation of low-dose IL-2 as a potential treatment for Alzheimer’s Disease. Trial registration ClinicalTrials.gov Identifier: NCT06096090, Registration Date: 10-17-2023.

Background Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI). Methods Participants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C). Results The study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, −7.7 [6.1]; P  < .001, 95 % CI: −8.4, −7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, −8.2 [−9.4, −7.0]) and numerically exceeds the improvement seen with placebo in that study (−5.7 [−6.8, −4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline ( P  < .001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were “much” or ”very much” improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related. Conclusions DM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q. Trial registration Clinicaltrials.gov, NCT01799941, registered on 25 February 2013

Dextromethorphan (DM)/quinidine (Q) is an approved treatment for pseudobulbar affect (PBA) based on trials in amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness and tolerability for PBA secondary to dementia, stroke, or traumatic brain injury; dementia cohort results are reported. This was an open-label, multicenter, 90 day trial; patients received DM/Q 20/10 mg twice daily. Primary outcome was change in Center for Neurologic Study-Lability Scale (CNS-LS) score. Secondary outcomes included PBA episode count and Clinical and Patient/Caregiver Global Impression of Change scores with respect to PBA (CGI-C/PGI-C). 134 patients were treated. CNS-LS improved by a mean (SD) of 7.2 (6.0) points at Day 90/Endpoint (P<.001) vs. baseline. PBA episodes were reduced 67.7% (P<.001) vs. baseline; global measures showed 77.5% CGI-C and 76.5% PGI-C \"much\"/\"very much\" improved. Adverse events included headache (7.5%), urinary tract infection (4.5%), and diarrhea (3.7%); few patients dropped out for adverse events (10.4%). DM/Q significantly reduced PBA symptoms in patients with dementia; reported adverse events were consistent with the known safety profile of DM/Q. Trial Registration clinicaltrials.gov identifier: NCT01799941.

After publication of the original article [1], the authors noticed that there were errors in the caption of Fig. 3, and the y-axis of Fig. 6 itself. https://static-content.springer.com/image/art%3A10.1186%2Fs12883-016-0679-z/MediaObjects/12883_2016_679_Fig1_HTML.gif Fig. 6 Mean CNS-LS Scores Across DM/Q Studies for PBA Secondary to Diverse Neurologic Conditions. *DM/Q 30/30 mg twice daily; [dagger]DM/Q 20/10 mg twice daily. [double dagger]Improvement from baseline in mean CNS-LS (SE). 99-AVR-102 (4 week study comparing DM/Q to DM or Q monotherapy): End of study is the mean of the CNS-LS scores for Days 15 and 29; P = 0.001 vs. dextromethorphan comparator and P < 0.001 vs quinidine comparator. 02-AVR-106 (12 week DBPC study): End of study is the mean of the CNS-LS scores on Days 15, 29, 57, and 85; P < 0.0001 vs. placebo. 07-AVR-123 (12 week DBPC study): End of study is at Week 12 intent to treat; P < 0.05 vs. placebo. PRISM II: End of study is at Day 90/Final Visit; P < 0.001 vs. baseline in all 3 cohorts. ALS = amyotrophic lateral sclerosis; CNS-LS = Center for Neurologic Study-Lability Scale; DM/Q = dextromethorphan/quinidine; MS = multiple sclerosis; PBA = pseudobulbar affect; TBI = traumatic brain injury; SE = standard error The following statement should not have been included in the caption of Fig. 3: \"CNS-LS scores were not normalized.\" The CNS-LS is a rank-order scale, and is not normalized. This statement was included erroneously and the authors intended on removing it prior to resubmission, but this was unfortunately overlooked. Similarly, the y-axis within Fig. 6 was mislabelled. The CNS-LS scale ranges from 7 to 35, so the y-axis for Fig. 6 should start at a base score of 7 and not zero. The correct and updated version of Fig. 6, in which the data presented remain accurate and are unchanged, is published in this erratum.

Robbins, M. E. C., O'Malley, Y., Zhao, W., Davis, C. S. and Bonsib, S. M. The Role of the Tubulointerstitium in Radiation-Induced Renal Fibrosis. The functional and morphological response of the remaining hypertrophied kidney in unilaterally nephrectomized rats to single doses of 0–20 Gy X rays was investigated. Functional and histological end points were assessed serially 4–24 weeks postirradiation. Renal irradiation led to time- and dose-dependent reductions in renal function, seen in terms of a decreased glomerular filtration rate, increased blood urea nitrogen, and reduced hematocrit. These changes were accompanied by morphological changes in the glomerular, tubular and interstitial portions of the kidney. However, dose-dependent changes were observed only in terms of tubulointerstitial lesions. Significant increases in the degree of interstitial staining for collagen type III and fibronectin were observed 24 weeks postirradiation. These increases in extracellular matrix components were accompanied by a significant increase in interstitial α smooth muscle actin, suggesting activation of interstitial fibroblasts into myofibroblasts. There was no evidence of glomerular Tgfb after renal irradiation. A significant increase in tubular Tgfb staining was only seen 8 weeks postirradiation. In contrast, there was a shift of staining to the interstitium such that by 24 weeks postirradiation interstitial Tgfb staining was significantly greater than that seen in controls. These findings suggest that the tubule epithelial cell and the interstitial fibroblast are both active participants in the development and/or progression of radiation-induced renal fibrosis.