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Antioxidants & Redox Signaling Mar 2013The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca(2+) homeostasis, relaxation and... (Review)
Review
SIGNIFICANCE
The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca(2+) homeostasis, relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology.
RECENT ADVANCES
Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of post-translational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease.
CRITICAL ISSUES
Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress.
FUTURE DIRECTIONS
Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance.
Topics: Animals; Arginase; Autocrine Communication; Biopterins; Calcium Signaling; Cyclic GMP; Diabetes Mellitus; Disease Progression; Enzyme Activation; Enzyme Induction; Heart Diseases; Heart Failure; Humans; Hypertension; Myocardium; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase; Paracrine Communication; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein Transport; Signal Transduction; Superoxides
PubMed: 22871241
DOI: 10.1089/ars.2012.4824 -
Free Radical Biology & Medicine Oct 2009(6R)-5,6,7,8-Tetrahydrobiopterin (BH(4)) is an endogenously produced pterin that is found widely distributed in mammalian tissues. BH(4) works as a cofactor of aromatic... (Review)
Review
(6R)-5,6,7,8-Tetrahydrobiopterin (BH(4)) is an endogenously produced pterin that is found widely distributed in mammalian tissues. BH(4) works as a cofactor of aromatic amino acid hydroxylases and nitric oxide synthases. In the vasculature a deficit of BH(4) is implicated in the mechanisms of several diseases including atherosclerosis, hypertension, diabetic vascular disease, and vascular complications from cigarette smoking and environmental pollution. These ill-effects are connected to the ability of BH(4) to regulate reactive oxygen species levels in the endothelium. The possibility of using BH(4) as a therapeutical agent in cardiovascular medicine is becoming more compelling and many biochemical and physiological aspects involved in this application are currently under investigation. This review summarizes our current understanding of BH(4) reactivity and some aspects of cellular production and regulation.
Topics: Biopterins; Cardiovascular Diseases; Humans; Superoxides; Vasodilation
PubMed: 19628033
DOI: 10.1016/j.freeradbiomed.2009.07.024 -
Orphanet Journal of Rare Diseases Mar 2017Sapropterin dihydrochloride, a synthetic formulation of BH, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sapropterin dihydrochloride, a synthetic formulation of BH, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH-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-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-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-responsive phenylketonuria.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.
Topics: Algorithms; Biopterins; Child, Preschool; Diet; Female; Humans; Infant; Infant, Newborn; Male; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias
PubMed: 28274234
DOI: 10.1186/s13023-017-0600-x -
Neurotherapeutics : the Journal of the... Jul 2021Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4), in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic... (Observational Study)
Observational Study
Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4), in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice, suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 drug (sapropterin) might increase the risk of autoimmune diseases. The present study assessed the implications for multiple sclerosis (MS) as an exemplary CNS autoimmune disease. Plasma levels of biopterin were persistently low in MS patients and tended to be lower with high Expanded Disability Status Scale (EDSS). Instead, the bypass product, neopterin, was increased. The deregulation suggested that BH4 replenishment might further drive the immune response or beneficially restore the BH4 balances. To answer this question, mice were treated with sapropterin in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood. Mechanistically, sapropterin treatment was associated with increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood-brain barrier in EAE mice. Indeed, RNA data analyses revealed upregulations of genes involved in ceramide synthesis in brain endothelial cells of EAE mice (LASS6/CERS6, LASS3/CERS3, UGCG, ELOVL6, and ELOVL4). The results support the view that BH4 fortifies autoimmune CNS disease, mechanistically involving lipid deregulations that are known to contribute to the EAE pathology.
Topics: Adolescent; Adult; Aged; Animals; Biopterins; Brain; Cells, Cultured; Cross-Sectional Studies; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Multiple Sclerosis; Neopterin; Young Adult
PubMed: 33844153
DOI: 10.1007/s13311-021-01043-4 -
Molecular Genetics and Metabolism Apr 2015The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are...
The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 ± 382 μmol/L at baseline to 392 ± 239 μmol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 ± 959 mg/day (pre-sapropterin baseline) to 1539 ± 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in ≤ 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance.
Topics: Adolescent; Adult; Biopterins; Child; Child, Preschool; Diet; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Phenylalanine; Phenylketonurias; Registries; Time Factors; Tyrosine; Young Adult
PubMed: 25724073
DOI: 10.1016/j.ymgme.2015.02.003 -
British Journal of Clinical Pharmacology Jun 2010
Topics: Biopterins; Humans; Phenylalanine; Phenylketonurias
PubMed: 20565448
DOI: 10.1111/j.1365-2125.2010.03643.x -
Molecular Genetics and Metabolism Feb 2021Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce...
Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was -0.5768 with a lower limit of the 95% confidence interval (CI) of -1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of -3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120-360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.
Topics: Biopterins; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Persons with Mental Disabilities; Phenylalanine; Phenylketonurias
PubMed: 33485801
DOI: 10.1016/j.ymgme.2021.01.001 -
BMB Reports Sep 2010Tetrahydrobiopterin (BH4) is a multifunctional cofactor of aromatic amino acid hydroxylases and nitric oxide synthase (NOS) as well as an intracellular antioxidant in... (Review)
Review
Tetrahydrobiopterin (BH4) is a multifunctional cofactor of aromatic amino acid hydroxylases and nitric oxide synthase (NOS) as well as an intracellular antioxidant in animals. Through regulation of NOS activity BH4 plays a pivotal role not only in a variety of normal cellular functions but also in the pathogenesis of cardiovascular and neurodegenerative diseases, which develop under oxidative stress conditions. It appears that a balanced interplay between BH4 and NOS is crucial for cellular fate. If cellular BH4 homeostasis maintained by BH4 synthesis and regeneration fails to cope with increased oxidative stress, NOS is uncoupled to generate superoxide rather than NO and, in turn, exacerbates impaired BH4 homeostasis, thereby leading to cell death. The fundamental biochemical events involved in the BH4-NOS interplay are essentially the same, as revealed in mammalian endothelial, cardiac, and neuronal cells. This review summarizes information on the cellular BH4 homeostasis in mammals, focusing on its regulation under normal and oxidative stress conditions.
Topics: Animals; Biopterins; Humans; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Superoxides
PubMed: 20846489
DOI: 10.5483/BMBRep.2010.43.9.584 -
Nutrients Aug 2023In phenylketonuria (PKU) changes in dietary patterns and behaviors in sapropterin-responsive populations have not been widely reported. We aimed to assess changes in... (Observational Study)
Observational Study
INTRODUCTION
In phenylketonuria (PKU) changes in dietary patterns and behaviors in sapropterin-responsive populations have not been widely reported. We aimed to assess changes in food quality, mental health and burden of care in a paediatric PKU sapropterin-responsive cohort.
METHODS
In an observational, longitudinal study, patient questionnaires on food frequency, neophobia, anxiety and depression, impact on family and burden of care were applied at baseline, 3 and 6-months post successful sapropterin-responsiveness testing (defined as a 30% reduction in blood phenylalanine levels).
RESULTS
17 children (10.8 ± 4.2 years) completed 6-months follow-up. Patients body mass index (BMI) z-scores remained unchanged after sapropterin initiation. Blood phenylalanine was stable. Natural protein increased ( < 0.001) and protein substitute intake decreased ( = 0.002). There were increases in regular cow's milk ( = 0.001), meat/fish, eggs ( = 0.005), bread ( = 0.01) and pasta ( = 0.011) intakes but special low-protein foods intake decreased. Anxiety ( = 0.016) and depression ( = 0.022) decreased in caregivers. The impact-on-family, familial-social impact ( = 0.002) and personal strain ( = 0.001) lessened. After sapropterin, caregivers spent less time on PKU tasks, the majority ate meals outside the home more regularly and fewer caregivers had to deny food choices to their children.
CONCLUSION
There were significant positive changes in food patterns, behaviors and burden of care in children with PKU and their families after 6-months on sapropterin treatment.
Topics: Animals; Cattle; Female; Bread; Diet; Follow-Up Studies; Longitudinal Studies; Phenylketonurias
PubMed: 37630793
DOI: 10.3390/nu15163603 -
Molecular Genetics and Metabolism Jan 2024Phenylketonuria is characterized by intellectual disability and behavioral, psychiatric, and movement disorders resulting from phenylalanine (Phe) accumulation....
Phenylketonuria is characterized by intellectual disability and behavioral, psychiatric, and movement disorders resulting from phenylalanine (Phe) accumulation. Standard-of-care treatment involves a Phe-restricted diet plus medical nutrition therapy (MNT), with or without sapropterin dihydrochloride, to reduce blood Phe levels. Pegvaliase is an injectable enzyme substitution treatment approved for adult patients with blood Phe >600 μmol/L despite ongoing management. A previous comparative effectiveness analysis using data from the Phase 3 PRISM trials of pegvaliase (NCT01819727 and NCT01889862) and the Phenylketonuria Demographics, Outcomes and Safety Registry (PKUDOS; NCT00778206) suggested that pegvaliase was more effective at lowering mean blood Phe levels than sapropterin + MNT or MNT alone at 1 and 2 years of treatment. The current work augments and complements the previous analysis by including additional follow-up from the completed studies, robust methods reflecting careful consideration of issues with the distribution of Phe, and alternative methods for adjustment that are important for control of potential confounding in comparative effectiveness. Median blood Phe levels were lower, and median intact protein intakes were higher, in the pegvaliase group (n = 183) than in the sapropterin + MNT (n = 82) and MNT (n = 67) groups at Years 1, 2, and 3. In the pegvaliase group, median blood Phe levels decreased from baseline (1244 μmol/L) to Year 1 (535 μmol/L), Year 2 (142 μmol/L), and Year 3 (167 μmol/L). In the sapropterin + MNT group, median blood Phe levels decreased from baseline (900 μmol/L) to Year 1 (588 μmol/L) and Year 2 (592 μmol/L), and increased at Year 3 (660 μmol/L). In the MNT group, median blood Phe levels decreased slightly from baseline (984 μmol/L) to Year 1 (939 μmol/L) and Year 2 (941 μmol/L), and exceeded baseline levels at Year 3 (1157 μmol/L). The model-estimated proportions of participants achieving blood Phe ≤600 μmol/L were 41%, 100%, and 100% in the pegvaliase group at Years 1, 2, and 3, respectively, compared with 55%, 58%, and 38% in the sapropterin + MNT group and 5%, 16%, and 0% in the MNT group. The estimated proportions of participants achieving more stringent blood Phe targets of ≤360 μmol/L and ≤120 μmol/L were also higher in the pegvaliase group than in the other groups at Years 2 and 3. Overall, our results indicate that, compared with standard therapy, pegvaliase induces a substantial, progressive, and sustained decrease in blood Phe levels - to a much greater extent than sapropterin + MNT or MNT alone - which is expected to improve long-term outcomes in patients with phenylketonuria.
Topics: Adult; Humans; Phenylketonurias; Phenylalanine Ammonia-Lyase; Nutrition Therapy; Phenylalanine; Biopterins; Recombinant Proteins
PubMed: 38142628
DOI: 10.1016/j.ymgme.2023.108114