- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, Journal: Acute Tetrahydrobiopterin Improves Endothelial Function in Patients with COPD. (Pubmed Central) - Sep 26, 2019
P=N/A
The improvement in endothelial function was accompanied by an increase in NOS3 phosphorylation. BH may represent a potential novel therapy to improve endothelial function and reduce CVD risk in patients with COPD.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Peptidylglycine monooxygenase activity of monomeric species of growth hormone. (Pubmed Central) - Sep 19, 2019
These findings clarify the role of GH in peptidylglycine monooxygenation and provide an explanation for earlier observations that peptide amidation is not totally obliterated in the absence of ascorbate, in cultured pituitary cells or in vivo. The evolution of bifunctional GH is also discussed, as are some of the significances of the peptidylglycine monooxygenase activity of human GH in relation to peptides such as oxytocin, glucagon-like peptide-1 and peptide PYY.
- |||||||||| Kuvan (sapropterin) / BioMarin, Daiichi Sankyo
Enrollment open: L-arginine Study for Persistent Symptoms of Schizophrenia (clinicaltrials.gov) - Sep 12, 2019
P2, N=5, Recruiting,
The evolution of bifunctional GH is also discussed, as are some of the significances of the peptidylglycine monooxygenase activity of human GH in relation to peptides such as oxytocin, glucagon-like peptide-1 and peptide PYY. Not yet recruiting --> Recruiting
- |||||||||| sapropterin / Generic mfg.
Trial completion, Enrollment change: Impact of KUVAN (clinicaltrials.gov) - Sep 10, 2019
P=N/A, N=9, Completed,
Not yet recruiting --> Recruiting Recruiting --> Completed | N=20 --> 9
- |||||||||| Kuvan (sapropterin) / BioMarin, Daiichi Sankyo
Trial completion, Trial primary completion date: TNSPKU: Nutritional Status in Phenylketonuria (clinicaltrials.gov) - Sep 9, 2019
P=N/A, N=94, Completed,
Recruiting --> Completed | N=20 --> 9 Not yet recruiting --> Completed | Trial primary completion date: Mar 2019 --> Sep 2019
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Biomarker, Review, Journal: Pterins as Diagnostic Markers of Mechanical and Impact-Induced Trauma: A Systematic Review. (Pubmed Central) - Sep 6, 2019
Pterin concentration changes in response to surgery were variable with patients undergoing cardiac surgery having immediate and sustained pterin increases, while hysterectomy, liver resection or hysterectomy showed no change. This review provides systematic evidence that pterins, in particular neopterin and total neopterin, increase in response to multiple forms of mechanical or impact-induced trauma.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells. (Pubmed Central) - Aug 30, 2019
Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Biomarker, Journal: Co-ingestion of whole eggs or egg whites with glucose protects against postprandial hyperglycaemia-induced oxidative stress and dysregulated arginine metabolism in association with improved vascular endothelial function in prediabetic men. (Pubmed Central) - Aug 23, 2019
...At 30 min intervals for 3 h, we assessed plasma NO∙ metabolites, the lipid peroxidation biomarker malondialdehyde, antioxidants, arginine and its methylated metabolites (asymmetric dimethylarginine and symmetric dimethylarginine), tetrahydrobiopterin redox status, vasoconstrictors and inflammatory markers...Thus, while each egg-based meal improved arginine metabolism, only EGG and WHITE limited lipid peroxidation. This suggests that vasoprotection mediated by EGG and WHITE likely occurs in an NO∙-dependent manner by improving arginine metabolism and attenuating oxidative stress that otherwise limit NO∙ biosynthesis and bioavailability to the vascular endothelium.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Tetrahydrobiopterin is a Novel CamKK2 Activator Which Rescues Late-stage Diabetic Cardiomyopathy in Rodent Model (Zone 2, Science and Technology Hall) - Aug 21, 2019 - Abstract #AHA2019AHA_2683;
Our results demonstrate CaMKK2 is the novel target of BH4 for the therapeutic effect on the recovery of mitochondria and cardiac dysfunction in DCM. BH4 deficiency may be a risk factor for heart failure, and the maintenance of optimal BH4 levels has therapeutic potential for the treatment of DCM with mitochondrial dysfunction.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: An Overview of Traditional and Novel Therapeutic Options for the Management of Phenylketonuria. (Pubmed Central) - Aug 3, 2019
Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase enzyme that catalyzes the conversion of L-phenylalanine to L-tyrosine using tetrahydrobiopterin (BH4) as a cofactor...Treatment with BH4 therapy is safe and effective but only in BH4-responsive PKU patients. Therefore, research efforts should be focused on the development of more targeted pharmacological and genetic therapies especially PAH gene therapy, which can reduce the burden or deleterious effects of this disease in affected patients.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Huotan Jiedu Tongluo decoction alleviates early atherosclerosis of rabbits by inhibiting eNOS uncoupling pathway (Pubmed Central) - Aug 1, 2019
...Twenty-four Japanese white rabbits were randomly divided into sham operation group, model group, HTJDTL decoction group and atorvastatin group...According to the results, it was found that HTJDTL decoction couldsignificantly prevent and improve the vascular remodeling of rabbits model with early atherosclerosis. The mechanism of decoction may largely be related to the inhibition of BH4/eNOS uncoupling and the reduction of oxidative stress.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Metabolic Pathway Engineering for High-level Production of 5-Hydroxytryptophan in Escherichia coli. (Pubmed Central) - Jul 24, 2019
...For endogenous supply of the cofactor tetrahydrobiopterin (BH4), human BH4 biosynthesis and regeneration pathway was reconstituted...The whole biosynthetic pathway was divided into three functional modules, L-tryptophan module, the hydroxylation module, and the BH4 module. By reducing the copy number of L-tryptophan module, replacing TPH1 with a more stable mutant form, and promoter regulation of the BH4 module, 5-HTP was produced at a final titer of 1.3g/L in the shake flask and 5.1g/L in a fed-batch fermenter with glycerol as the carbon source, both of which were the highest ever reported for microbial production of 5-HTP.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure. (Pubmed Central) - Jul 24, 2019
Pressure-dependent NOS activation leads to acute endothelial hyperpermeability and rapid PE by an increase in NO and ROS in a model of AHF...These results suggest a clinically relevant role of endothelial mechanotransduction in the pathogenesis of AHF and further highlights the concept of active barrier failure in AHF. Therapies targeting the prevention or reversal of endothelial hyperpermeability may be a novel therapeutic strategy in AHF.
- |||||||||| Climara (estradiol) / Bausch Health, Bayer, Cetrotide (cetrorelix) / EMD Serono
Trial completion: SHAPE2: Sex Hormones and Atherosclerosis Prevention in Perimenopausal Women (clinicaltrials.gov) - Jul 11, 2019
P1, N=100, Completed,
APV and GPV are powerful tools to investigate genotype-phenotype associations, and can be used for genetic counselling of PKU families. Active, not recruiting --> Completed
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: C-phenylalanine breath test and serum biopterin in schizophrenia, bipolar disorder and major depressive disorder. (Pubmed Central) - Jul 1, 2019
...The rate-limiting step for phenylalanine metabolism is catalyzed by phenylalanine hydroxylase (PAH) and its cofactor tetrahydrobiopterin...PAH polymorphisms were not associated with schizophrenia orC-PBT indices.C-PBT revealed reduced phenylalanine metabolism in schizophrenia, though we obtained no evidence of involvement of PAH polymorphism. Serum biopterin levels were lower in schizophrenia and MDD, warranting further investigation.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, Journal: Genotype-phenotype correlations and BH estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil. (Pubmed Central) - Jun 28, 2019
The high discordance rate between genotype-predicted and observed metabolic phenotypes in this study seems to be due partially to the high frequency of the so-called "moderate" common mutations, p.R261Q, p.V388M, and p.I65T, which are reported to be associated to erratic or more severe than expected metabolic phenotypes. Although our results of BH estimated responsiveness must be regarded as tentative, it should be emphasized that genotyping and genotype-phenotype association studies are important in selecting patients to be offered a BH overload test, especially in low-resource settings like Brazil.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Biomarker, Clinical, Journal: Functional Biomarkers of Vitamin B12 Status, Diet, and Metabolic Control in Women with Phenylketonuria (P24-005-19). (Pubmed Central) - Jun 23, 2019
...Of the 31 participants, 13 (41.9%) were on a phenylalanine-lowering medication (Kuvan)...Monitoring MMA and tHcy, regardless of B12 levels, may still have utility in this population for the detection of early deficiency. National Center for Advancing Translational Sciences of the NIH, private donations.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Pharmacological inhibition of guanosine triphosphate cyclohydrolase1 elevates tyrosine phosphorylation of caveolin1 and cellular senescence. (Pubmed Central) - Jun 7, 2019
...Oxidative stress (OS) indices such as myocardial biopterin concentrations (tetrahydrobiopterin-BH and dihydrobiopterin-BH) and plasma total nitrite and nitrate (NOx) were determined...In the independent treatment groups or the combination treatment, typical senescence indicators including myocardial telomerase-activity, NAD+-content and TAC were significantly reduced, while there was a marked elevation in the concentrations of pY14 as compared to the respective controls, reinforcing the occurrence of senescence in PBMNCs and the myocardium. We postulate that DAHP promotes early onset of cellular-senescence, potentially through OS-mediated cellular events in diabetic or non-diabetic models.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, Journal: A Compound Heterozygote for GCH1 Mutation Represents a Case of Atypical Dopa-Responsive Dystonia. (Pubmed Central) - Jun 6, 2019
...DRD is usually caused by mutation in GCH1 gene coding for GTP cyclohydrolase 1 (GTPCH1) enzyme, which is involved in biosynthesis of tetrahydrobiopterin (BH4) and dopamine...Our study confirms the variability of DRD phenotype and the reduced penetrance of GCH1 mutations. It also emphasizes the need of molecular diagnostic test and L-dopa trial especially for those with atypical DRD phenotype.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Role of protein structure in variant annotation: structural insight of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency. (Pubmed Central) - May 30, 2019
...PTPS catalyses the second step of tetrahydrobiopterin (BH) cofactor biosynthesis, and its deficiency represents the most common form of BH deficiency...Our findings illustrate the important utility of 3D protein structure in interpretation of variants and also current limitations of in silico prediction algorithms. However, software to analyse mutation in the perspective of 3D protein structure is far less readily available than other in silico prediction tools.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Research progress on phenotype and genotype of hyperphenylalaninemia (Pubmed Central) - May 26, 2019
The accumulation of the clinical database and genetic information will enhance the development of novel personalized medicine and to provide more accurate and timely diagnostic and therapeutic approaches for HPA. This paper summarizes the correlations between HPA metabolism and PAH, BH4, pathogenic genes and their distributions in HPA, as well as the phenotypes and genotypes of HPA, so as to provide reference for personalized medicine for HPA.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, Journal: Outcome of Patients With Inherited Neurotransmitter Disorders. (Pubmed Central) - May 22, 2019
Six patients (with 6-pyruvoyltetrahydropterin synthase, dihydropteridine reductase and tyrosine hydroxylase deficiencies) had normal neurodevelopmental outcome on treatment. Tetrahydrobiopterin loading test in newborns with positive newborn screening for phenylketonuria will identify patients with 6-pyruvoyltetrahydropterin synthase and dihydropteridine reductase deficiencies resulting in abnormal neurotransmitter synthesis in the central nervous system in the neonatal period to initiate disease-specific treatment to improve neurodevelopmental outcome.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. (Pubmed Central) - May 22, 2019
...The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain...Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: KLF2 regulates eNOS uncoupling via Nrf2/HO-1 in endothelial cells under hypoxia and reoxygenation. (Pubmed Central) - May 13, 2019
...Tetrahydrobiopterin (BH) and S-glutathionylation of eNOS play essential roles in eNOS uncoupling and activation...However, when combined with the Nrf2 inhibitor or HO-1 siRNA, the regulatory effect of KLF2 on eNOS uncoupling was strongly reduced. These results suggest that KLF2 could improve eNOS uncoupling via Nrf2/HO-1 in H/R-induced endothelial injury.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Review, Journal: New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease. (Pubmed Central) - May 2, 2019
With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo, s-nitrosoglutathione (N30-201) / Alpine
Biomarker, Journal: Reversible S-glutathionylation of human 6-pyruvoyl tetrahydropterin synthase protects its enzymatic activity. (Pubmed Central) - Apr 30, 2019
We also found that PTS expressed in HeLa and THP-1 cells is reversibly modified under oxidative stress conditions. Our findings suggest that PTS activity and S-glutathionylation is regulated by the cellular redox environment and that reversible S-glutathionylation protects PTS against oxidative stress.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Tetrahydrobiopterin improves hippocampal nitric oxide-linked long-term memory. (Pubmed Central) - Apr 28, 2019
It was also demonstrated that BH2 can be converted into BH4 by activating the BH4 salvage pathway under physiological conditions in the hippocampus. This is the first evidence showing that BH4 enhances aversive memory and that the BH4 salvage pathway is active in the hippocampus.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, Journal, HEOR: The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study. (Pubmed Central) - Apr 28, 2019
Together, these results show that, particularly for adult PKU-patients, HRQoL-problems are evident and that many of these problems are related to (history of) metabolic control. Beneficial effects of BH4-use appear to be limited to those associated with relief from the practical burdens related to the strict dietary treatment regimen, i.e. general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, Journal: UK patients who tested Kuvan for phenylketonuria will get supplies after trials end, says company. (Pubmed Central) - Apr 27, 2019
Beneficial effects of BH4-use appear to be limited to those associated with relief from the practical burdens related to the strict dietary treatment regimen, i.e. general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning. No abstract available
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Effect of (-)-epicatechin on the modulation of progression markers of chronic renal damage in a 5/6 nephrectomy experimental model. (Pubmed Central) - Apr 27, 2019
...The concentration of tetrahydrobiopterin (BH4), used as subrogate of endothelial dysfunction, decreased in nephrectomyzed animals, Epi treatment increased BH4 levels almost reaching normal values...Findings of this study indicate that Epi is able to counteract the deleterious effects of subtotal nephrectomy and the structural and functional changes in the remnant kidney tissue, decreasing the progression of CKD. These results warrant the possibility of implement clinical trials to limit the progression of CKD in humans.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Review, Journal: Nano-medicine and Vascular Endothelial Dysfunction: Options and Delivery Strategies. (Pubmed Central) - Apr 24, 2019
The new era with advances in nanotechnology and its ability to target a specific disease, nano-medicine explored an innovative gateway for advanced therapy for VED. The present commentary reveals the various available, pipeline nano-medicine, their interaction with endothelium and in other associated pathological conditions and their delivery strategies for target-specific treatment of VED.
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