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Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT00104247. 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9·7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) μmol/L in patients assigned to receive sapropterin, and 888 (323) μmol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) μmol/L, compared with a 3 (240) μmol/L increase in the placebo group (p<0·0001). After 6 weeks, 18/41 (44%) patients (95% CI 28–60) in the sapropterin group and 4/47 (9%) controls (95% CI 2–20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 μmol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0·0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0·80). Upper respiratory tract infections were the most common disorder. In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.

Background During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH 4 ), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0–4 years with BH 4 -responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin. Results All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only (‘sapropterin extension’ group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period (‘sapropterin continuous’ group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the ‘sapropterin continuous’ group (95% CI 28.9, 48.6; p  < 0.0001). In the ‘sapropterin extension’ group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI − 2.8, 13.8; p  = 0.1929). Patients in both groups had normal neuromotor development and growth parameters. Conclusions Long-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH 4 -responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH 4 -responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908 .

Phenylketonuria is an inherited metabolic disorder that leads to neurobehavioral dysfunction. The main treatment is a low-phenylalanine diet and/or the cofactor tetrahydrobiopterin. Regular outpatient follow-up care and measurement of the phenylalanine levels in the blood are required. We aimed to analyze the economic burden of phenylketonuria on families and the state. The patients with phenylketonuria were divided into three groups according to their treatment: a low-phenylalanine diet group (n = 50), a tetrahydrobiopterin group (n = 44), and a group taking tetrahydrobiopterin together with the diet (n = 25). A comparative cost analysis was carried out. The annual economic burden to the state was calculated to average EUR 18,801 ± 15,345 and was lowest in the diet group, then in the tetrahydrobiopterin group, and highest in the tetrahydrobiopterin + diet group (p < 0.001). Out-of-pocket costs amounted to EUR 1531 ± 1173 per year, and indirect losses averaged EUR 2125 ± 1930 per year for all families. The economic loss was significantly lower in the families taking tetrahydrobiopterin than in the other groups (p = 0.001). The combined use of medical nutrition and BH4 treatments has been shown to increase the economic burden on the state. Reimbursing low-protein products and increasing the number of patients eligible for financial allowances may reduce the economic burden on families.

Background This study investigated the effects of phototherapy on serum BH4 levels, evoked potentials, and cognitive impairment in post-stroke depression patients. Methods We conducted a prospective study with 160 post-stroke depression patients, randomly assigned to an experimental group receiving daily 40 min of phototherapy alongside routine treatment, and a control group receiving only routine treatment. Serum tetrahydrobiopterin (BH4) levels were measured via ELISA. Evoked potentials were assessed using an ERP recorder, depressive symptoms were evaluated with the Hamilton Depression Scale (HAM-D), and cognitive function was analyzed using the Montreal Cognitive Assessment (MoCA). Inflammatory factor expression was detected via RT-PCR. Results Both groups exhibited increased BH4 levels, but the phototherapy group had significantly higher levels ( P  < 0.05). The phototherapy group also demonstrated improved ERP parameters, with higher MMN latency, P300 latency, and amplitudes compared to controls ( P  < 0.05). HAM-D scores decreased more in the phototherapy group ( P  < 0.05), while MoCA scores increased significantly ( P  < 0.05). Additionally, inflammatory markers IL-6, TNF-α, and IL-1β were lower in the phototherapy group ( P  < 0.05). Conclusions Phototherapy positively influenced BH4 levels, improved evoked potentials, alleviated depressive symptoms, enhanced cognitive function, and reduced inflammation in post-stroke depression patients.

The aim of this study was to investigate the overall effects of phototherapy on biopterin (BH4), neopterin (BH2), tryptophan (Trp), and behavioral neuroinflammatory reaction in patients with post-stroke depression. There involved a total of 100 hospitalized patients with post-stroke depression at our hospital from February 2021 to December 2022. The participants enrolled were randomly assigned to either the control group or the experimental group. The control group received routine treatment, including medication and psychological support, while the experimental group received 30 min of phototherapy daily for 8 weeks. All participantsvoluntarily participated in the study and provided informed consent. Baseline characteristics of the patients were statistically analyzed. The severity of depressive symptoms was evaluated using the hamilton depression scale (HAMD) and the beck depression inventory (BDI). Levels of amino acid neurotransmitters, including gamma-aminobutyric acid (GABA), aspartic acid (Asp), and glutamic acid (Glu), were measured using radioimmunoassay. Plasma levels of neuroinflammatory factors, such as TNF-α, IL-6, and IL-1β were, determined using ELISA. Plasma levels of BH4, BH2, and Trp were detected by HPLC. Levels of SOD, GPx, CAT, and MDA in plasma were measured using corresponding kits and colorimetry. Quality of life was assessed using the SF-36 scale. There were no differences in baseline characteristic between the two groups (P > 0.05). The HAMD and BDI scores in the experimental group were lower than those in the control group (P < 0.05), indicating phototherapy could reduce the severity of post-stroke depression. The levels of GABA, Glu, and Asp in both groups significantly increased after treatment compared to their respective levels before treatment (P < 0.01).The levels of GABA in the experimental group were higher than those in the control group (P < 0.01),while the levels of Glu, and Asp were lower than those in the control group (P < 0.01). The plasma levels of TNF-α, IL-6, and IL-1β in the experimental group were evidently lower than those in the control group (P < 0.05). Moreover, the levels of BH4 and Trp in experimental group were significantly higher than those in the control group (P < 0.05), while the levelsof BH2 in the experimental group were significantly lower than the control group (P < 0.05). Additionally, the levels of SOD, GPx, and CAT in the experimental group were evidently higher than those in the control group (P < 0.05), whereas the levels of MDA in the experimental group were significantly lower than control group (P < 0.05). The experimental group showed higher scores in physical function, mental health, social function, and overall health compared to the control group (P < 0.05). Phototherapy exerted a profound impact on the metabolism of BH4, BH2, and Trp, as well as on behavioral neuroinflammatory reactions and the quality of life in patients suffering from post-stroke depression. Through its ability to optimize the secretion and synthesis of neurotransmitters, phototherapy effectively regulated neuroinflammatory reactions, improved biochemical parameters, enhancedantioxidant capacity, and alleviated depressive symptoms. As a result, phototherapy was considered a valuable adjuvant therapeutic approach for patients with post-stroke depression.

Background Sapropterin dihydrochloride, a synthetic formulation of BH 4 , the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH 4 -responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years. Results In total, 109 male or female children <4 years with confirmed BH 4 -responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7–42.3) mg/kg/day higher than in the diet-only group ( p  < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. Conclusions The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH 4 -responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH 4 -responsive phenylketonuria. Trial registration ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.

Background/Objectives: A pilot study was conducted to investigate the effect of four weeks of creatine monohydrate (CrM) on vascular endothelial function in older adults. Methods: In a double-blind, randomized crossover trial, twelve sedentary, healthy older adults were allocated to either the CrM or placebo (PL) group for four weeks, at a dose of 4 × 5 g/day for 5 days, followed by 1 × 5 g/day for 23 days. Macrovascular function (flow-mediated dilation [FMD%], normalized FMD%, brachial-ankle pulse wave velocity [baPWV], pulse wave analysis [PWA]), microvascular function (microvascular reperfusion rate [% StO2/sec]), and biomarkers of vascular function (tetrahydrobiopterin [BH4], malondialdehyde [MDA], oxidized low-density lipoprotein [oxLDL], glucose, lipids) were assessed pre- and post-supplementation with a four-week washout period. Results: CrM significantly increased FMD% (pre-CrM, 7.68 ± 2.25%; post-CrM, 8.9 ± 1.99%; p < 0.005), and normalized FMD% (pre-CrM, 2.57 × 10−4 ± 1.03 × 10−4%/AUCSR; post-CrM, 3.42 × 10−4 ± 1.69 × 10−4%/AUCSR; p < 0.05), compared to PL. Microvascular reperfusion rates increased following CrM (pre-CrM, 2.29 ± 1.42%/sec; post-CrM, 3.71 ± 1.44%/sec; p < 0.05), with no change following PL. A significant reduction in fasting glucose (pre-CrM, 103.64 ± 6.28; post-CrM, 99 ± 4.9 mg/dL; p < 0.05) and triglycerides (pre-CrM, 99.82 ± 35.35; post-CrM, 83.82 ± 37.65 mg/dL; p < 0.05) was observed following CrM. No significant differences were observed for any other outcome. Conclusions: These pilot data indicate that four weeks of CrM supplementation resulted in favorable effects on several indices of vascular function in older adults.

Sepiapterin is an exogenously synthesized new chemical entity that is structurally equivalent to endogenous sepiapterin, a biological precursor of tetrahydrobiopterin (BH 4 ), which is a cofactor for phenylalanine hydroxylase. Sepiapterin is being developed for the treatment of hyperphenylalaninemia in pediatric and adult patients with phenylketonuria (PKU). This study employed concentration-QT interval analysis to assess QT prolongation risk following sepiapterin treatment. Data from three phase 1 studies and one phase 3 study were pooled for this analysis. Pediatric and adult PKU patients ≥ 2 years received multiple doses at 60 mg/kg and adult healthy volunteers received a single or multiple doses at 20 or 60 mg/kg. Time-matched triplicate ECG measurements and plasma samples for pharmacokinetic analysis were collected. Prespecified linear mixed models relating ΔQTcF to concentrations of sepiapterin and the major active circulating metabolite BH 4 were developed for the analysis. The analysis demonstrated that there is no QTcF prolongation risk in patients with PKU following sepiapterin dosing at the highest therapeutic dose, 60 mg/kg/day. The final model showed a marginal but negligible QTcF reduction with increasing sepiapterin and BH 4 concentrations. The effect on ΔQTcF was estimated to -2.72 [-3.72, -1.71] and − 1.25 [-2.75, 0.25] ms at mean baseline adjusted BH 4 C max of 332 ng/mL (therapeutic exposure) and 675 ng/mL (supratherapeutic exposure) at dose 60 mg/kg, respectively, in PKU patients with food and in healthy volunteers with a high fat diet. Various covariates, such as clinical study ID, age, sex, food effect, race, body weight, and disease status, on QTcF interval were investigated and were found insignificant, except for food effect and age. This study concludes that there is no QTcF prolongation risk in patients with PKU following sepiapterin dosing up to 60 mg/kg/day, and BH 4 and sepiapterin concentrations minimally affect ΔQTcF after adjustment for time, sex, and meal. Graphical Abstract

Tetrahydrobiopterin (BH4), a cofactor of nitric oxide synthase, might have a role in the treatment of portal hypertension (PHT) as its administration improves endothelial nitric oxide generation and hepatic endothelial dysfunction, and reduces portal pressure in experimental models of cirrhosis. Sapropterin is an oral synthetic analogue of BH4 recently approved for the treatment of phenylketonuria. This study evaluated the safety and effects of sapropterin on hepatic and systemic hemodynamics in patients with cirrhosis and PHT. Forty patients with cirrhosis and PHT (hepatic venous pressure gradient (HVPG) ≥10 mm Hg) were randomly allocated to receive sapropterin (n=19) for 2 weeks (5 mg/kg/day increased to 10 at day 8) or placebo (n=21) in a double-blind multicenter clinical trial. Randomization was stratified according to concomitant treatment with β-adrenergic blockers. We studied at baseline and post-treatment splanchnic (HVPG and hepatic blood flow (HBF)) and systemic hemodynamics, endothelial dysfunction and oxidative stress markers (von Willebrand factor and malondialdehyde), liver function tests, and safety variables. HVPG was not modified by either sapropterin (16.0±4.4 vs. 15.8±4.7 mm Hg) or placebo (16.0±4.6 vs. 15.5±4.9 mm Hg). HBF, systemic hemodynamics, endothelial dysfunction markers, and liver function tests remained unchanged. Sapropterin was well tolerated (no patient required dose adjustment or withdrawal), and adverse events were mild and similar between groups. Sapropterin, an oral synthetic analogue of BH4, at the used dose did not reduce portal pressure in patients with cirrhosis. Sapropterin was safe and no serious adverse effects or deleterious systemic hemodynamic effects were observed.

Traumatic brain injury (TBI) is an important cause of death and disability. Safety and pharmacodynamics of 4-amino-tetrahydrobiopterin (VAS203), a nitric oxide (NO)-synthase inhibitor, were assessed in TBI in an exploratory Phase IIa study (NOSynthase Inhibition in TRAumatic brain injury=NOSTRA). The study included 32 patients with TBI in six European centers. In a first open Cohort, eight patients received three 12-h intravenous infusions of VAS203 followed by a 12-h infusion-free interval over 3 days (total dose 15 mg/kg). Patients in Cohorts 2 and 3 (24) were randomized 2:1 to receive either VAS203 or placebo as an infusion for 48 or 72 h, respectively (total dose 20 and 30 mg/kg). Effects of VAS203 on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain metabolism using microdialysis, and the therapy intensity level (TIL) were end points. In addition, exploratory analysis of the extended Glasgow Outcome Score (eGOS) after 6 months was performed. Metabolites of VAS203 were detected in cerebral microdialysates. No significant differences between treatment and placebo groups were observed for ICP, CPP, and brain metabolism. TIL on day 6 was significantly decreased (p<0.04) in the VAS203 treated patients. The eGOS after 6 months was significantly higher in treated patients compared with placebo (p<0.01). VAS203 was not associated with hepatic, hematologic, or cardiac toxic effects. At the highest dose administered, four of eight patients receiving VAS203 showed transitory acute kidney injury (stage 2–3). In conclusion, the significant improvement in clinical outcome indicates VAS203-mediated neuroprotection after TBI. At the highest dose, VAS203 is associated with a risk of acute kidney injury.