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Background ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer’s disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. Methods Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [ 1 ] a single ascending dose (SAD) study; [ 2 ] a 14-day multiple ascending dose (MAD) study; and [ 3 ] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. Results ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration ( C max ) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. Conclusions ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

For one century, taurine is considered as an end product of sulfur metabolism. In this review, we discuss the beneficial effect of taurine, its haloamines and taurine upregulated gene 1 (TUG1) long non-coding RNA (lncRNA) in both cancer and inflammation. We outline how taurine or its haloamines (N-Bromotaurine or N-Chlorotaurine) can induce robust and efficient responses against inflammatory diseases, providing insight into their molecular mechanisms. We also provide information about the use of taurine as a therapeutic approach to cancer. Taurine can be combined with other chemotherapeutic drugs, not only mediating durable responses in various malignancies, but also circumventing the limitations met from chemotherapeutic drugs, thus improving the therapeutic outcome. Interestingly, the lncRNA TUG1 is regarded as a promising therapeutic approach, which can overcome acquired resistance of cancer cells to selected strategies. In this regard, we can translate basic knowledge about taurine and its TUG1 lncRNA into potential therapeutic options directed against specific oncogenic signaling targets, thereby bridging the gap between bench and bedside.

Taurine (2-aminoethanesulfonic acid) contributes to homeostasis, mainly through its antioxidant and osmoregulatory properties. Taurine's influx and efflux are mainly mediated through the ubiquitous expression of the sodium/chloride-dependent taurine transporter, located on the plasma membrane. The significance of the taurine transporter has been shown in various organ malfunctions in taurine-transporter-null mice. The taurine transporter differentially responds to various cellular stimuli including ionic environment, electrochemical charge, and pH changes. The renal system has been used as a model to evaluate the factors that significantly determine the regulation of taurine transporter regulation.

The aim of the present study was to evaluate the effects of supplementation with a fixed combination of citicoline 500 mg, homotaurine 50 mg, and vitamin E 12 mg (CIT/HOMO/VITE) on contrast sensitivity and visual-related quality of life in patients with primary open-angle glaucoma (POAG) in mild stage. This was a multicenter, observational, cross-over, short-term, pilot study on POAG patients with stable controlled intraocular pressure (IOP). Patients were randomly assigned to Group 1 (current topical therapy for 4 months and then current topical therapy plus CIT/HOMO/VITE for 4 months) or Group 2 (CIT/HOMO/VITE in addition to current topical therapy for 4 months and then topical therapy alone for 4 months). Best-corrected visual acuity, IOP, visual field, and the Spaeth/Richman contrast sensitivity (SPARCS) test score were recorded at baseline and after 4 and 8 months. The Glaucoma Quality of Life-15 (GQL-15) questionnaire was administered at each check time. Forty-four patients were assigned to Group 1 and 65 to Group 2. Over the follow-up period, there were no significant changes in IOP or visual field findings, whereas SPARCS and GQL-15 findings significantly varied from baseline, both being improved in subjects treated with CIT/HOMO/VITE fixed combination. These results demonstrate that a daily intake of a fixed combination of citicoline, homotaurine, and vitamin E in addition to the topical medical treatment significantly increased the total score of the contrast sensitivity test and the quality of life in patients with POAG.

Taurine is a fundamental mediator of homeostasis that exerts multiple roles to confer protection against oxidant stress. The development of hypertension, muscle/neuro- associated disorders, hepatic cirrhosis, cardiac dysfunction and ischemia/reperfusion are examples of some injuries that are linked with oxidative stress. The present review gives a comprehensive description of all the underlying mechanisms of taurine, with the aim to explain its anti-oxidant actions. Taurine is regarded as a cytoprotective molecule due to its ability to sustain normal electron transport chain, maintain glutathione stores, upregulate anti-oxidant responses, increase membrane stability, eliminate inflammation and prevent calcium accumulation. In parallel, the synergistic effect of taurine with other potential therapeutic modalities in multiple disorders are highlighted. Apart from the results derived from research findings, the current review bridges the gap between bench and bedside, providing mechanistic insights into the biological activity of taurine that supports its potential therapeutic efficacy in clinic. In the future, further clinical studies are required to support the ameliorative effect of taurine against oxidative stress.

Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the N-acylethanolamines (NAEs) and N-acyl taurines (NATs), in central and peripheral tissues. A functional polymorphism in the human FAAH gene is linked to obesity and mice lacking FAAH show altered metabolic states, but whether these phenotypes are caused by elevations in NAEs or NATs is unknown. To overcome the problem of concurrent elevation of NAEs and NATs caused by genetic or pharmacological disruption of FAAH in vivo,we developed an engineered mouse model harboring a single-amino acid substitution in FAAH (S268D) that selectively disrupts NAT, but not NAE, hydrolytic activity. The FAAH-S268D mice accordingly show substantial elevations in NATs without alterations in NAE content, a unique metabolic profile that correlates with heightened insulin sensitivity and GLP-1 secretion. We also show that N-oleoyl taurine (C18:1 NAT), the most abundant NAT in human plasma, decreases food intake, improves glucose tolerance, and stimulates GPR119-dependent GLP-1 and glucagon secretion in mice. Together, these data suggest that NATs act as a class of lipid messengers that improve postprandial glucose regulation and may have potential as investigational metabolites to modify metabolic disease.

Background and aims Central venous catheters (CVCs) are essential for drug delivery in pediatric oncology patients but are associated with complications such as infection and thrombosis. This study aimed to compare the effects of taurolidine–citrate and unfractionated heparin lock solutions on catheter function, infection and thrombosis rates, and inflammatory markers in children with malignancies. Methods In this randomized, controlled trial, 76 pediatric oncology patients were allocated to receive either TauroLock ™ -HEP500 (containing taurolidine, 4% citrate, and 500 IU/mL heparin) or standard unfractionated heparin as the catheter lock solution. Patients were followed for 6 months. Laboratory evaluations, including complete blood count (CBC), high-sensitivity C -reactive protein (hs-CRP), and interleukin-6 (IL-6), were performed at baseline, 1 month, and 6 months, or upon clinical suspicion of infection. Results At 6 months, hs-CRP levels were significantly lower in the taurolidine–citrate group (2.1 ± 0.2 vs. 5.5 ± 2.2, p  = 0.001), as was total WBC count (3792.1 ± 325.3 vs. 4994.5 ± 462.1, p  = 0.028). IL-6 levels showed no statistically significant difference (9.2 ± 1.9 vs. 14.0 ± 3.1, p  = 0.067). The incidence of catheter-related infections (HR 3.55, 95% CI 0.68–18.4, p  = 0.460) and thrombosis (HR 4.13, 95% CI 0.43–39.91, p  = 0.221) did not differ significantly between groups. Conclusion Taurolidine–citrate exhibited a modest anti-inflammatory effect, reflected by reduced hs-CRP and WBC levels, without significant improvement in catheter-related complications or IL-6. The lack of major clinical benefit may relate to the heterogeneous and immunocompromised nature of pediatric oncology patients. Larger, adequately powered studies are warranted to clarify the long-term efficacy and safety of taurolidine–citrate in this population. Clinical Trials as IRCT20201107049296N4.

Taurine (2-aminoethanesulfonic acid) is the most abundant free amino acid in humans and plays an important role in several essential biological processes such as bile acid conjugation, maintenance of calcium homeostasis, osmoregulation and membrane stabilization. Moreover, attenuation of apoptosis and its antioxidant activity seem to be crucial for the cytoprotective effects of taurine. Although these properties are not tissue specific, taurine reaches particularly high concentrations in tissues exposed to elevated levels of oxidants (e.g., inflammatory cells). It suggests that taurine may play an important role in inflammation associated with oxidative stress. Indeed, at the site of inflammation, taurine is known to react with and detoxify hypochlorous acid generated by the neutrophil myeloperoxidase (MPO)–halide system. This reaction results in the formation of less toxic taurine chloramine (TauCl). Both haloamines, TauCl and taurine bromamine (TauBr), the product of taurine reaction with hypobromous acid (HOBr), exert antimicrobial and anti-inflammatory properties. In contrast to a well-documented regulatory role of taurine and taurine haloamines (TauCl, TauBr) in acute inflammation, their role in the pathogenesis of inflammatory diseases is not clear. This review summarizes our current knowledge concerning the role of taurine, TauCl and TauBr in the pathogenesis of inflammatory diseases initiated or propagated by MPO-derived oxidants. The aim of this paper is to show links between inflammation, neutrophils, MPO, oxidative stress and taurine. We will discuss the possible contribution of taurine and taurine haloamines to the pathogenesis of inflammatory diseases, especially in the best studied example of rheumatoid arthritis.

Golden retrievers are over-represented in cases of taurine-deficient dilated cardiomyopathy and recently a surge in cases has prompted further investigation. To describe the clinical, dietary, and echocardiographic features in golden retrievers diagnosed with taurine deficiency and dilated cardiomyopathy, and to determine specific dietary associations. A second aim was to determine the whole blood taurine concentrations in a representative sample of healthy golden retrievers. Twenty-four client-owned golden retrievers with documented taurine deficiency and dilated cardiomyopathy and 52 healthy client-owned golden retrievers. In this multicenter prospective observational study, baseline and follow-up echocardiographic data, complete diet and medical histories, and whole blood, plasma, or serum taurine concentrations were obtained. Baseline and follow-up echocardiographic data were compared. Associations were evaluated between specific diets and taurine deficiency or congestive heart failure. The prevalence of low whole blood taurine concentrations in the healthy golden retrievers was calculated. Twenty-three of 24 dogs diagnosed with taurine deficiency and dilated cardiomyopathy were fed diets that were either grain-free, legume-rich, or a combination of these factors. None of these diets were feeding trial tested using Association of American Feed Control Officials (AAFCO) procedures. Twenty-three of 24 dogs had significant improvement in their echocardiographic parameters and normalization of taurine concentrations following diet change and taurine supplementation. Nine of 11 dogs diagnosed with congestive heart failure (CHF) had resolution of their congestion at follow-up with five no longer requiring diuretic therapy and four tolerating diuretic dose reduction by >50%. Certain diets and diet characteristics were associated with the development of taurine deficiency. Taurine deficiency and dilated cardiomyopathy in golden retrievers is likely multifactorial, including a combination of dietary, metabolic, and genetic factors.

The impact of hypoxic repetitive sprint training on the overall performance of team sports remains controversial due to the specific nature of the exercise capacity required for team sports. While taurine and caffeine are widely utilized as supplements for repetitive sprint exercise in normoxic environments, their efficacy in hypoxic environments remains to be fully understood. Therefore, additional research is needed to explore the role of supplementation in hypoxic conditions. This study was to investigate the effects of caffeine (C), taurine (T), caffeine, and taurine co-ingestion (TC) or placebo (P) on repetitive sprint exercise performance and related physiological responses after exhaustion exercise in team athletes under simulated hypoxic conditions. A double-blind crossover randomized controlled experimental design was employed. 16 male participants (Age:23.69 ± 2.15 years, Body mass: 75.04 ± 7.79 kg, Height:1.78 ± 0.06 m) volunteered to receive four different supplement ingestions to complete the exercise tests: (1) placebo (5 mg/kg maltodextrin), (2) taurine (50 mg/kg), (3) caffeine (5 mg/kg), (4) taurine + caffeine (50 mg/kg + 5 mg/kg). All selected participants were university football players who had undergone rigorous training regimens (85–95% of maximum heart rate, duration of 60 min, with more than five training sessions per week). All participants completed an exhaustion test and subsequent repetitive sprint exercise in a simulated hypoxic environment (A simulation of a soccer game in sports mode). Time to exhaustion (TTE), peak power (PP), and mean power (MP) were recorded at the end of the exhaustion test and during the repetitive sprint exercise, respectively. This study designed an exercise protocol for repetitive sprinting after exhaustion exercise based on the pattern of play in football. The following variables were monitored throughout the experiments: heart rate (HR), blood lactate (B[La]), arterial oxygen saturation (SpO2), dyspnea, and rating of perceived exhaustion (RPE). The Stroop Test was administered at three separate time points: pre-test, mid-test, and post-test, throughout the exercise trial. The countermovement jump test (CMJ) was carried out at three specific time points: before the test, 3 min after the test, and 6 min after the test. The caffeine (C:618.56 + 42.50 s, p = 0.027, d = 0.996) and taurine + caffeine (TC: 613.69 + 37.74 s, p = 0.041, d = 0.902) groups significantly improved time to exhaustion compared to the placebo group. Blood lactate was significantly higher in the taurine + caffeine group than in the placebo group after repetitive sprint exercise (P: 9.87 ± 1.97, TC: 12.31 ± 2.54, p = 0.016). The caffeine group significantly reduced dyspnea, and rating of perceived exhaustion after repetitive sprint exercise (p < 0.05). The taurine (T: 43.42 ± 3.46, p = 0.005), caffeine (C: 44.11 ± 4.72, p < 0.001), and taurine + caffeine (TC: 43.04 ± 3.30, p = 0.011) groups all showed an increase in pre-exercise countermovement jump height. The caffeine group significantly reduced the consistent response time (p = 0.023) and inconsistent response time (p < 0.001) in the Stroop Test compared to the placebo group. Caffeine, along with combined taurine, significantly prolonged the duration of exhaustion exercise in a hypoxic environment; however, it did not affect subsequent repetitive sprint performance. Additionally, caffeine supplementation had a positive impact on cognitive performance during hypoxic training.