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PurposeReport pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.MethodsPatients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 − 2, pre-dose and 2 h post-dose on D15 of C1 − 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously.ResultsPK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease).ConclusionOnce-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma.Clinical trial registrationNCT02989857 Registered February 20, 2017.

The authors previously confirmed the serum uric acid-lowering effects of the combination of glycine and tryptophan in subjects with mild hyperuricemia. This study examined whether combined supplementation with glycine and tryptophan suppressed the elevation in serum uric acid levels caused by purine ingestion and accelerated urinary uric acid excretion in subjects with lower urate excretion using a randomized, single-blind, placebo-controlled, crossover clinical trial design. Healthy Japanese adult males with lower urate excretion ingested water containing purines in addition to dextrin (placebo), tryptophan, glycine, or a glycine and tryptophan mixture. The combined supplementation with glycine and tryptophan significantly reduced the elevated serum uric acid levels after purine ingestion. Glycine alone and in combination with tryptophan significantly increased urinary uric acid excretion and urate clearance compared with the effects of the placebo. Urinary pH increased by the ingestion of the mixture. These results suggested that the improved water solubility of uric acid due to increased urinary pH contributed to the increase of urinary uric acid excretion.

Background Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia in dialysis-dependent chronic kidney disease (CKD) with a starting dose of 300 mg once daily (dose adjustments up to 600 mg). A recent phase 1b study evaluated the pharmacokinetics, pharmacodynamics, and safety of higher vadadustat doses (500–900 mg) in healthy volunteers. Here we report the pharmacokinetic (PK), pharmacodynamic (PD), and safety characterization of higher doses of vadadustat in patients with CKD receiving dialysis. Methods This phase 1b, randomized, open-label study evaluated the pharmacokinetics and pharmacodynamics of vadadustat (600, 750, or 900 mg) in patients with CKD-related anemia receiving hemodialysis over a 10-day treatment period. Forty-six eligible patients were randomized to vadadustat 600, 750, or 900 mg daily or an intravenous erythropoiesis-stimulating agent. For vadadustat groups, blood samples for PK and PD analyses were collected on Day 1 and Day 8. PK analyses included area under the plasma concentration time curve (AUC) from dosing to last quantifiable concentration and to infinity, and to maximum plasma concentration (C max ). PD analyses measured serum erythropoietin (EPO), hemoglobin, and red blood cells (RBCs). Safety assessments included adverse events in the safety population (patients who received ≥ 1 dose of study drug). Patients underwent a 30-day safety follow-up period after the last dose of study drug. Results In the vadadustat groups, a dose-dependent increase in plasma exposure of vadadustat (C max and AUC) with modest accumulation was observed on Day 1 and Day 8. Vadadustat increased plasma EPO concentrations, with a variable EPO response observed in each group. Relative to baseline, mean hemoglobin and RBC levels remained unchanged, with no significant changes observed in any treatment group. Vadadustat was welltolerated. Conclusions The current study characterized the PK and PD response (EPO and reticulocytes) and safety profile of vadadustat at doses of 600, 750, and 900 mg in patients with CKD receiving dialysis. Overall, vadadustat was well tolerated. These findings will contribute to the development of higher-dose regimens for further investigation in phase 3 studies. Trial Registration ClinicalTrials.gov ID NCT03992066; https://clinicaltrials.gov/study/NCT03992066 ; Retrospectively registered on June 18, 2019. Accessed January 13, 2025.

Background Chronic nonextreme sun exposure induces two mechanisms of skin pigmentation, causing immediate darkening and delayed tanning. A new molecule, 2‐mercaptonicotinoyl glycine (2‐MNG), has been shown in vitro to inhibit both immediate darkening and new melanin synthesis via covalent conjugation of the thiol group of 2‐MNG to melanin precursors. Objective To evaluate 2‐MNG in preventing both mechanisms in vivo. Methods In a randomized, intra‐individual and controlled study, 33 subjects with melanin‐rich skin were exposed to UV daylight on designated areas on the back and treated with a cosmetic formula containing 0.5% or 1% 2‐MNG alone or 0.5% 2‐MNG in association with lipohydroxy acid (LHA, 0.3%) plus Mexoryl‐SX (MSX, 1.5%). The respective vehicles were used as controls and 4‐n‐butyl‐resorcinol (4‐n‐BR, 2.5%) as a positive reference. Results 2‐MNG alone significantly reduced immediate darkening and inhibited new melanin production when compared with vehicle, with higher performance at 1% than at 0.5%. 2‐MNG at 0.5% in association with LHA and MSX showed significantly higher performance than 2‐MNG 0.5% alone. 2‐MNG at 0.5% and 1% showed significantly better performance than 4‐n‐BR. Conclusions 2‐MNG inhibited both UV‐induced skin pigmentation mechanisms in vivo. The association of 2‐MNG with LHA plus MSX showed the highest efficacy on melanin‐rich skin with pigmentation induced by UV exposure.

The objective of this study was to investigate the feasibility of using glycine nano-selenium (NS-Gly) as a feed supplement and to evaluate its influence on production performance, egg quality, serum biochemistry, oxidative status, and the intestinal morphology and absorption of laying hens. A total of 864 hens at 40 weeks were randomly assigned into six groups including the basal diet (control, 0.13 mg Se/kg); basal diet + 0.30 mg Se/kg (Na2SeO3) diet; and basal diet + 0.15, 0.30, 0.45, and 0.60 mg Se/kg (NS-Gly) diet. After 8 weeks of Se supplementation, no difference was observed among the treatments on production performance and egg quality (P > 0.05). The levels of albumin (ALB) and alanine aminotransferase (GPT) were significantly influenced by dietary Se supplementation (P < 0.05). In the serum, the level of glutathione peroxide (GSH-Px) was significantly increased in the groups with the dietary NS-Gly supplementation (P < 0.05). The superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) levels in all groups of NS-Gly supplementation had a remarkable increase (P < 0.05). In the liver, GSH-Px was significantly increased in 0.45 and 0.60 mg/kg NS-Gly groups (P < 0.05). The activities of SOD and catalase (CAT) were significantly increased in the groups of 0.30 mg/kg NS-Gly diet (P < 0.05). The results of intestinal morphology showed that the crypt depth was affected by higher dose groups of NS-Gly diets in the duodenum, and the differences (P < 0.05) were obtained in villus height, the crypt depth, and the V/C in the jejunum. In the ileum, a significant increase (P < 0.05) of villus height was observed in 0.15 and 0.3 mg/kg Se-added groups. The V/C was the highest in the SS groups (P < 0.05). The mRNA levels of solute carrier family 3 member 1 (rBAT), solute carrier family 6 member 19 (B0AT1), and solute carrier family 15 member 1 (PepT1) increased at different degrees in the duodenum, especially in 0.15 and 0.60 mg/kg NS-Gly groups (P < 0.05). In the jejunum, the expression of B0AT1 was similar to that in the duodenum, and the expression of rBAT increased significantly in the 0.30 and 0.45 mg/kg NS-Gly groups (P < 0.05). The mRNA level of PepT1 increased significantly in the 0.30 mg/kg SS group. Conclusively, dietary NS-Gly supplementation could improve the antioxidant capacity, as well as the structure of small intestine in laying hens, although have no significant effects on the production performance and egg quality.

Background and Objective Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in phase III development for the treatment of anaemia associated with chronic kidney disease. This study evaluated the effects of moderate hepatic impairment on roxadustat pharmacokinetics, pharmacodynamics and tolerability. Methods This was an open-label study in which eight subjects with moderate hepatic impairment (liver cirrhosis Child–Pugh score 7–9) and eight subjects with normal hepatic function (matched for body mass index, age and sex) received a single oral 100 mg roxadustat dose under fasted conditions. Blood samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function. Results In subjects with moderate hepatic impairment, area under the concentration–time curve (AUC) from the time of drug administration to infinity (AUC ∞ ) and observed maximum concentration ( C max ) were 23 % higher [geometric least-squares mean ratio (GMR) 123 %; 90 % CI 86.1–175] and 16 % lower (GMR 83.6 %; 90 % CI 67.5–104), respectively, than in subjects with normal hepatic function. Mean terminal half-life ( t ½ ) appeared to be longer (17.7 vs. 12.8 h) in subjects with moderate hepatic impairment, however intersubject variability on apparent total systemic clearance after single oral dosing (CL/ F ), apparent volume of distribution at equilibrium after oral administration ( V z / F ) and t ½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUC E,last ) and maximum effect ( E max ) were 31 % (GMR 68.95 %; 90 % CI 29.29–162.29) and 48 % (GMR 52.29 %; 90 % CI 28.95–94.46) lower, respectively, than in subjects with normal hepatic function. The single oral roxadustat dose was generally well tolerated. Conclusions This study demonstrated the effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat relative to subjects with normal hepatic function. These differences are not expected to be of clinical significance.

Background Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel‐oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N‐acetylcysteine [NAC]) in aged mice improves naturally‐occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance. This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition. Methods A 36‐week open‐label clinical trial was conducted in eight OAs and eight young adults (YAs). After all the participants underwent an initial (pre‐supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red‐blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait‐speed, grip‐strength, 6‐min walk test; cognitive tests; genomic‐damage; glucose‐production and muscle‐protein breakdown rates; and body‐composition. Results GlyNAC supplementation for 24 weeks in OA corrected RBC‐GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin‐resistance, genomic‐damage, cognition, strength, gait‐speed, and exercise capacity; and lowered body‐fat and waist‐circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks. Conclusions GlyNAC supplementation for 24‐weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin‐resistance and endothelial dysfunction, and genomic‐damage, and improved strength, gait‐speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation. This study found that compared to healthy young adults, older humans have severely elevated oxidative stress, glutathione deficiency, impaired mitochondrial function, increased inflammation, insulin resistance and endothelial dysfunction, and lower muscle strength and mental cognition. We tested and found that supplementing GlyNAC (combination of glycine and N‐acetylcysteine) improved all these defects, and that stopping GlyNAC resulted in a loss of benefits. The results of this trial suggests that GlyNAC supplementation could be a simple, safe and effective nutritional strategy to boost cellular defenses to protect against oxidative stress, correct mitochondrial defects to improve energy availability, increase muscle strength and cognition, and thereby promote healthy aging in humans.

•Guanidinoacetic acid (GAA) appears to be a novel energy-enhancing supplement for brain and muscle.•The combination of creatine and GAA results in more powerful elevation of tissue creatine than equimolar creatine.•Better outcomes were reported for upper body muscular strength and less weight gain in the GAA–creatine group.•The GAA–creatine mixture is an effective and safe creatine-boosting alternative to creatine alone in healthy men. Co-administration of creatine and guanidinoacetic acid (GAA) has been recently put forward as an advanced dietary strategy to optimize tissue bioenergetics. We hypothesized that creatine-GAA mixture would result in a more powerful rise in brain and skeletal muscle creatine, as compared to creatine supplementation alone. A randomized, double-blinded, crossover superiority trial has been performed at the University of Novi Sad from December 2016 to November 2017. A total of 14 healthy young men were randomized to receive GAA-creatine mixture (1 grams of GAA and 3 grams of creatine per day) or equimolar creatine (4 grams per day) by oral administration for 4 weeks. Creatine-GAA mixture was superior to creatine alone to increase mean creatine levels in skeletal muscle (16.9 ± 20.2 vs. 2.0 ± 6.0%; P = 0.02) and grey matter (5.8 ± 5.3% vs. 1.5 ± 3.2%; P = 0.02), also for bench press performance (6.0% vs. 5.1%; P < 0.01). Compared with creatine administration alone, combined GAA and creatine resulted in less weight gain (1.6 ± 0.2 kg vs. 0.7 ± 0.2 kg; P < 0.01). No inter-group differences were observed in terms of cardiorespiratory endurance, serum biomarkers, or adverse events. Creatine-GAA mixture appeared to be superior to creatine alone for up-swinging tissue creatine content and upper body strength, and tended toward a lower risk of weight gain in healthy active men. The formulation might be considered as a novel energy-boosting alternative to creatine alone in weight-sensitive setups. ClinicalTrials.govNCT03350282.

Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40–200 mg/kg) and ORG24598 (0.63–5 mg/kg), the agonists, glycine (40–800 mg/kg), and D-serine (10–160 mg/kg) and the partial agonists, S18841 (2.5 mg/kg s.c.) and D-cycloserine (2.5–40 mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20 mg/kg), and the glycine modulatory site antagonist, L701,324 (10 mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5–10 μg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10 mg/kg s.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired.

Guanidinoacetic acid (GAA) is the natural biosynthetic precursor of creatine, in a metabolic reaction that requires only a methyl group transfer. The use of GAA as a food additive for restoring creatine load in human tissues is rather unexplored and data on efficacy and safety are limited. In particular, an increase in serum homocysteine after GAA administration can be regarded as critical and should be prevented. The present study evaluated the effects of orally administered GAA with and without methyl group donors on serum and urine creatine concentrations, and the occurrence of adverse events during an intervention in healthy human subjects. A total of twenty male and female volunteers were randomised in a double-blind design to receive either GAA (2·4 g/d) or GAA with methyl donors (2·4 g/d of GAA and 1·6 g/d of betaine HCl, 5 μg/d of vitamin B12, 10 mg/d of vitamin B6 and 600 μg/d of folic acid) by oral administration for 8 weeks. Serum and urine creatine increased significantly from before to after administration in both groups (P< 0·001). The proportion of participants who reported minor adverse events was 33·3 % in the GAA group, and 10·0 % in the GAA with methyl donors group (P= 0·30). Hyperhomocysteinaemia was found in 55·6 % of participants supplemented with GAA, while no participant experienced hyperhomocysteinaemia in the group supplemented with GAA and methyl donors (P= 0·01). In summary, both interventions strongly influenced creatine metabolism, resulting in a significant increase in fasting serum creatine. The concomitant supplementation of methyl donors along with GAA largely precluded the elevation of serum homocysteine caused by GAA administration alone.