Discovery of novel 6-p-tolyl-3-(3,4,5-trimethoxybenzyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivative as a potent tubulin inhibitor with promising in vivo antitumor activity.

Building on our prior research, a novel series of trimethoxyphenoxymethyl- and trimethoxybenzyl-substituted triazolothiadiazine compounds has been designed and achieved successfully via a direct ring-closing strategy. Initial biological evaluation illustrated that the most active derivative B5 exhibited significant cell growth inhibitory activity toward HeLa, HT-29, and A549 giving the IC50 values of 0.046, 0.57, and 0.96 µM, respectively, which are greater or similar with CA-4. The mechanism study revealed that B5 caused the G2/M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, B5 exerted significant antivascular activity in the wound-healing and tube formation assays. Most importantly, B5 remarkably inhibited tumor growth without obvious signs of toxicity in A549-xenograft mice model. These observations indicate that 6-p-tolyl-3-(3,4,5-trimethoxybenzyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine might be considered as the potential lead compound to develop highly efficient anticancer agents with potent selectivity over normal human cells.

Progression from Prodromal Alzheimer's Disease to Mild Alzheimer's Disease Dementia in the Verubecestat APECS Study: Adjudicating Diagnostic Transitions.

BACKGROUND: Delay of progression from prodromal Alzheimer's disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized. OBJECTIVE: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR). METHODS: We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participant's CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression. RESULTS: 581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria. CONCLUSION: A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.

The efficacy of taurolidine containing lock solutions for the prevention of central-venous-catheter-related bloodstream infections: a systematic review and meta-analysis.

The incidence of central venous catheter (CVC)-related bloodstream infections is high in patients requiring a long-term CVC. Therefore, infection prevention is of the utmost importance. The aim of this study was to provide an updated overview of randomized controlled trials (RCTs) comparing the efficacy of taurolidine containing lock solutions (TL) to other lock solutions for the prevention of CVC-related bloodstream infections in all patient populations. On 15th February 2021, PubMed, Embase and The Cochrane Library were searched for RCTs comparing the efficacy of TLs for the prevention of CVC-related bloodstream infections with other lock solutions. Exclusion criteria were non-RCTs, studies describing <10 patients and studies using TLs as treatment. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. A random effects model was used to pool individual study incidence rate ratios (IRRs). Subgroup analyses were performed based on the following factors: CVC indication, comparator lock and bacterial isolates cultured. A total of 14 articles were included in the qualitative synthesis describing 1219 haemodialysis, total parenteral nutrition and oncology patients. The pooled IRR estimated for all patient groups together (nine studies; 918 patients) was 0.30 (95% confidence interval 0.19-0.46), favouring the TLs. Adverse events (10 studies; 867 patients) were mild and scarce. The quality of the evidence was limited due to a high risk of bias and indirectness of evidence. The use of TLs might be promising for the prevention of CVC-related bloodstream infections. Large-scale RCTs are needed to draw firm conclusions on the efficacy of TLs.

Neuropathology of a patient with Alzheimer disease treated with low doses of verubecestat.

We report the neuropathological examination of a patient with Alzheimer's disease (AD) treated for 38 months with low doses of the BACE-1 inhibitor verubecestat. Brain examination showed small plaque size, reduced dystrophic neurites around plaques and reduced synaptic-associated Aß compared with a group of age-matched untreated sporadic AD (SAD) cases. Our findings suggest that BACE-1 inhibition has an impact on synaptic soluble Aß accumulation and neuritic derangement in AD.

A 2% taurolidine catheter lock solution prevents catheter-related bloodstream infection (CRBSI) and catheter dysfunction in hemodialysis patients.

HIGHLIGHTS: 2% taurolidine catheter lock solution without additives is safe and efficient. CRBSI and dysfunction rates compare favorably against other studies in hemodialysis. BACKGROUND: In hemodialysis patients, catheter-related bloodstream infection (CRBSI) and catheter dysfunction are common and cause significant morbidity, mortality, and costs. Catheter lock solutions reduce CRBSI and catheter dysfunction rates, but solutions containing heparin, citrate, or antibiotics are associated with adverse effects. Due to its antimicrobial and antithrombotic properties and benign safety profile, taurolidine is suitable for use in catheter lock solutions. In this study the effectiveness and safety of a catheter lock solution containing 2% taurolidine without citrate or heparin (TauroSept®, Geistlich Pharma AG, Wolhusen, Switzerland) in hemodialysis patients were investigated for the first time. METHODS: Data from 21 patients receiving chronic hemodialysis via tunneled central venous catheters with 2% taurolidine solution as a catheter lock were analyzed in a single-center retrospective study and compared with the existing literature in a review. The primary endpoint was CRBSI rate. Secondary endpoints included catheter dysfunction, treatment, and costs; catheter technical problems, resolution, and costs; and adverse events. Data were compared to outcomes with standard lock solutions in the literature. RESULTS: No CRBSIs occurred during the observation period of 5,639 catheter days. The catheter dysfunction rate was 0.71 per 1,000 catheter days, and the catheter dysfunction treatment costs were CHF (Swiss Franc) 543 per patient. No technical problems or adverse events related to the use of 2% taurolidine-containing catheter lock solution were observed. These results compare favorably with other catheter lock solutions. CONCLUSIONS: A solution containing 2% taurolidine seems suitable as a hemodialysis catheter lock. In a Swiss cohort, it prevented CRBSI, limited catheter dysfunction, and was cost-efficient.

Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease.

Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.

[Taurolidine for the prevention of catheter-related infections in children with intestinal insufficiency: preliminary experience in a Chilean tertiary hospital]. / Taurolidina para prevenir infecciones asociadas a catéter venoso central en niños con insuficiencia intestinal: experiencia preliminar en un hospital terciario chileno.

BACKGROUND: Taurolidine is a molecule with anti-endotoxic, anti-microbial and anti-inflammatory properties that inhibits bacterial adhesion, allowing for its use as lock therapy for the prevention of catheter-related bloodstream infections (CRBSI) in long-term central venous catheters (CVC). AIM: To report a preliminary experience, the first one in Chile, using lock therapy with taurolidine for the prevention of CRBSI and to report its efficacy. METHOD: A taurolidine-based solution was instilled in the CVC of three children with intestinal insufficiency dependent on parenteral nutrition, attended in a Chilean tertiary hospital, and the rate of CRBSI before and after its use was compared in retrospect. RESULTS: In the two patients who started lock therapy immediately after the installation of their CVC, the rate of CRBSI was brought to zero, whereas in the third patient, who had a 9 months-old CVC with a recurrent CRBSI history, an intercurrent CRBSI forced discontinuation of the prophylaxis. CONCLUSIONS: Lock therapy with a taurolidine-based solution prevented CRBSIs when it was begun immediately after installing the CVC, in contrast with an old CVC with a history of recurrent CRBSIs.

Taurolidina para prevenir infecciones asociadas a catéter venoso central en niños con insuficiencia intestinal: experiencia preliminar en un hospital terciario chileno / Taurolidine for the prevention of catheter-related infections in children with intestinal insufficiency: preliminary experience in a Chilean tertiary hospital

INTRODUCCIÓN: Taurolidina es una molécula con propiedades anti-endotóxicas, antimicrobianas y anti-inflamatorias, que inhibe la adhesión bacteriana, lo que ha permitido usarla como terapia de sellado en catéter venoso central de larga duración (CVC) para prevenir infecciones del torrente sanguíneo asociadas a CVC (ITS-CVC). OBJETIVO: Dar a conocer una experiencia preliminar, la primera en Chile, con taurolidina como terapia de sellado para prevenir ITS-CVC y reportar su eficacia. MÉTODO: Se instiló una solución en base a taurolidina en el CVC de tres niños con insuficiencia intestinal, dependientes de alimentación parenteral, atendidos en un hospital terciario de la Región de Valparaíso, y se comparó la tasa de ITS-CVC antes y después de su uso mediante un análisis retrospectivo. RESULTADOS: en los dos pacientes que iniciaron terapia de sellado inmediatamente después de instalado el CVC, la tasa de ITS-CVC se logró llevar a cero, mientras que, en el tercero, portador de un CVC instalado 9 meses antes, con ITS-CVC recurrentes, un nuevo episodio de ITS-CVC obligó a suspender la profilaxis. CONCLUSIONES: La terapia de sellado con solución en base a taurolidina previno las ITS-CVC cuando ésta se inició al momento de instalarse el CVC, no así en un CVC antiguo con ITS-CVC recurrentes.

BACKGROUND: Taurolidine is a molecule with anti-endotoxic, anti-microbial and anti-inflammatory properties that inhibits bacterial adhesion, allowing for its use as lock therapy for the prevention of catheter-related bloodstream infections (CRBSI) in long-term central venous catheters (CVC). AIM: To report a preliminary experience, the first one in Chile, using lock therapy with taurolidine for the prevention of CRBSI and to report its efficacy. METHOD: A taurolidine-based solution was instilled in the CVC of three children with intestinal insufficiency dependent on parenteral nutrition, attended in a Chilean tertiary hospital, and the rate of CRBSI before and after its use was compared in retrospect. RESULTS: In the two patients who started lock therapy immediately after the installation of their CVC, the rate of CRBSI was brought to zero, whereas in the third patient, who had a 9 months-old CVC with a recurrent CRBSI history, an intercurrent CRBSI forced discontinuation of the prophylaxis. CONCLUSIONS: Lock therapy with a taurolidine-based solution prevented CRBSIs when it was begun immediately after installing the CVC, in contrast with an old CVC with a history of recurrent CRBSIs.

Relapsing peritonitis and taurolidine peritoneal catheter lock: One center experience.

BACKGROUND: Relapsing peritonitis due to the development of a biofilm in the catheter's lumen remains an important complication of peritoneal dialysis therapy that endangers technique continuity. Taurolidine catheter lock has proven efficient reducing infection rates in permanent hemodialysis catheters based on its biocidal activity and biofilm detachment effect. Efficacy evidence on its use in peritoneal dialysis catheters is lacking. METHODS: We retrospectively analyzed all relapsing peritonitis episodes from June 2018 until October 2019 in our center. Patients were identified and data were collected from our electronic renal registry and patient's records. RESULTS: Six patients were identified during the study period. Most patients (66.6%) were on automated peritoneal dialysis and the median duration of peritoneal dialysis before the episode of taurolidine was started was 43.66 ± 29.64 months. Mean taurolidine doses were 10 (range: 9-11) and 83.3% (five patients, with peritonitis caused by Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Corynebacterium propinquum) had a favorable response and microbial eradication without relapses after taurolidine treatment. Only one patient relapsed by the same organism (Corynebacterium amycolatum) due to non-adherence to the antibiotic treatment prescribed. None of the patients experienced any relevant adverse events, with only two out of six presenting mild transient abdominal discomfort. CONCLUSION: We believe that peritoneal catheter taurolidine lock could be considered in cases of relapsing or refractory peritonitis, as it could prevent catheter removal and permanent switch to hemodialysis in selected cases, although literature is scarce and further studies are needed.

Retinal Optical Coherence Tomography Metrics Are Unchanged in Verubecestat Alzheimer's Disease Clinical Trial but Correlate with Baseline Regional Brain Atrophy.

BACKGROUND: We performed exploratory analyses of retinal thickness data from a clinical trial of the AßPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer's disease (AD). OBJECTIVE: To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy. METHODS: Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo. RESULTS: Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson's r values≤0.23, p-values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant. CONCLUSION: BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline. TRIAL REGISTRATION: Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348).

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.

Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease.

INTRODUCTION: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. METHODS: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. RESULTS: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. DISCUSSION: In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement.

Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study.

Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 µM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.

Anti-Aß agents for mild to moderate Alzheimer's disease: systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of Aß-targeting agents for mild to moderate Alzheimer's disease. METHODS: The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform search portal were searched from their inception to April 2020. We generated pooled estimates using random effects meta-analyses. RESULTS: Nineteen randomised controlled trials, of which 17 had a low risk of bias, included 12 903 participants. The meta-analysis showed no difference in the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog) between anti-Aß drugs and placebo (mean difference (MD): 0.20, 95% CI -0.40 to 0.81; I 2=99.8%; minimal important difference 3.1-3.8 points, moderate-certainty evidence). For ADAS-Cog, results suggested that one drug that increases Aß clearance may differ in effect (MD: -0.96, 95% CI -0.99 to -0.92) from drugs that reduce Aß production (MD: 0.78, 95% CI 0.25 to 1.32) (interaction p<0.000001); this difference also existed in the outcome of MMSE and CDR-SOB. Compared with placebo, anti-Aß drug-related adverse events were as follows: anxiety, depression, diarrhoea, fatigue, rash, syncope and vomit. DISCUSSION: From current evidence, anti-Aß interventions are unlikely to have an important impact on slowing cognitive or functional decline. Although the subgroup analysis suggested possible benefits from Aß clearance drugs, the analysis has limited credibility, and a benefit from drugs that increase clearance, if real, is very small. TRIAL REGISTRATION NUMBER: PROSPERO registration number CRD42019126272.

A Novel Selective 11ß-HSD1 Inhibitor, (E)-4-(2-(6-(2,6-Dichloro-4-(Trifluoromethyl)Phenyl)-4-Methyl-1,1-Dioxido-1,2,6-Thiadiazinan-2-yl)Acetamido)Adamantan-1-Carboxamide (KR-67607), Prevents BAC-Induced Dry Eye Syndrome.

Dry eye syndrome is the most common eye disease and it is caused by various reasons. As the balance of the tear film that protects the eyes is broken due to various causes, it becomes impossible to properly protect the eyes. In this study, the protective effects and underlying mechanisms of topical (E)-4-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)adamantan-1-carboxamide (KR-67607), a novel selective 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) inhibitor, were investigated in benzalkonium chloride (BAC)-induced dry eye syndrome. BAC-treated rat eyes induced significant increases in ocular surface damage, decreased corneal thickness, corneal basement membrane destruction in the conjunctival epithelium, and expression of pro-inflammatory cytokines tumor necrosis factor-α and 11ß-HSD1. These effects of BAC were reversed by topical KR-67607 treatment. Furthermore, KR-67607 decreased 4-hydroxynonenal expression and increased antioxidant and mucus secretion in BAC-treated rat eyes. Taken together, a novel selective 11ß-HSD1 inhibitor can prevent BAC-induced dry eye syndrome by inhibiting pro-inflammatory cytokine and reactive oxygen species expression via the inhibition of both 11ß-HSD1 activity and expression.

Minocycline-EDTA-Ethanol Antimicrobial Catheter Lock Solution Is Highly Effective In Vitro for Eradication of Candida auris Biofilms.

Candida auris is an emerging pathogen that can cause virulent central-line-associated bloodstream infections. Catheter salvage through the eradication of biofilms is a desirable therapeutic option. We compared taurolidine and minocycline-EDTA-ethanol (MEE) catheter lock solutions in vitro for the eradication of biofilms of 10 C. auris strains. MEE fully eradicated all C. auris biofilms, while taurolidine lock partially eradicated all of the C. auris biofilms. The superiority was significant for all C. auris strains tested (P = 0.002).

Taurolidine as adjuvant treatment of relapsing peritonitis in peritoneal dialysis patients. / Taurolidina como tratamiento adyuvante en casos de peritonitis recidivante en pacientes en diálisis peritoneal.

Relapsing peritonitis in peritoneal dialysis patients is one of the complications that jeopardizes the continuity of the technique. It is often associated with the formation of biofilm in the lumen of the catheter. To date, its removal remains the only recommended attitude. Due to its antimicrobial and antifungal properties, taurolidine has been previously used for the sealing of central line catheters and hemodialysis. Despite the good results obtained, there is no evidence available regarding its utility in peritoneal dialysis. This case report describes the use of taurolidine (TauroLock™HEP500) in 5 patients with relapsing peritonitis after antibiotic treatment completion. Mean follow-up for the detection of recurrences was 13.4 months. In 4 patients with infections caused by Staphylococcus epidermidis, eradication was achieved. In the remaining case, caused by Staphylococcus aureus, the taurolidine seal was ineffective and the removal of the catheter was required.

Protective effect of a novel selective 11ß-HSD1 inhibitor on eye ischemia-reperfusion induced glaucoma.

Glaucoma is one of the leading causes of preventable blindness, affecting > 2 million people in the United States. Recently, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors were found to exert preventive effects against glaucoma. However, there is no evidence for the role of 11ß-HSD1 inhibitors against glaucoma. Here, we developed a novel 11ß-HSD1 inhibitor, (1R,2S,3S,5R,6S,7S)-6-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)-adamantane-2-carboxamide (KR-67607) and showed its protective effects against ischemia-reperfusion-induced eye injury. We demonstrate that KR-67607 effectively reduced cortisol levels in mouse eyes and maintained the trabecular meshwork (TM) structure in the presence of transient ischemic stress. Furthermore, KR-67607 reversed the elevation of intra-ocular pressure (IOP), suggesting that the TM structure maintained by KR-67607 prevented the excessive rise in IOP that exacerbates glaucoma. KR-67607 was shown to have a higher specificity for 11ß-HSD1 than carbenoxolone (CBX) in vitro. Moreover, KR-67607 reduced apoptosis and the structural disruption of TM cells. Antioxidation was the major protective pathway of KR-67607 against chemically-induced ischemia-reperfusion in TM cells and the glucocorticoid receptor (GR) was closely associated with this pathway. When TM cells undergo ischemic stress, GR is activated and then translocates to the cell nucleus where it interferes with Nrf-2-mediated antioxidant gene expression. However, when KR-67607 inhibited GR translocation, Nrf-2 was able to induce antioxidant gene transcription, which consequently, enhanced the antioxidant capacity of the cells. In conclusion, our current work describes a novel selective 11ß-HSD1 inhibitor for glaucoma treatment and provides evidence of its physiological role in anti-oxidative pathways in the TM.

Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer's disease.

BACKGROUND: Verubecestat, a BACE1 inhibitor that reduces Aß levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH. METHODS: EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed. RESULTS: Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time. CONCLUSIONS: Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov NCT01739348 , registered on 29 November 2012.