- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. (Pubmed Central) - Jan 29, 2020
The GCH1-BH-phospholipid axis acts as a master regulator of ferroptosis resistance, controlling endogenous production of the antioxidant BH, abundance of CoQ, and peroxidation of unusual phospholipids with two polyunsaturated fatty acyl tails. This demonstrates a unique mechanism of ferroptosis protection that is independent of the GPX4/glutathione system.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo, peroxynitrite (INO-4885) / Rocket Pharma, napabucasin (BBI608) / Sumitomo Dainippon, Boston Pharma
Review, Journal: Chemical Pathology of Homocysteine VII. Cholesterol, Thioretinaco Ozonide, Mitochondrial Dysfunction, and Prevention of Mortality. (Pubmed Central) - Jan 24, 2020
Suppression of innate immunity is caused by the depletion of adenosyl methionine because of increased polyamine biosynthesis, resulting in inhibition of nitric oxide and peroxynitrite biosynthesis...Cholesterol inhibits the opening of the mPTP by preventing integration of the pro-apoptotic Bcl-2-associated X protein (BAX) in the outer mitochondrial membrane. This inhibition explains how elevated LDL reduces mitochondrial dysfunction by preventing loss of the active site of oxidative phosphorylation from mitochondria.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Biomarker, Clinical, Journal: Prevalence of sleep disorders in early-treated phenylketonuric children and adolescents. Correlation with dopamine and serotonin status. (Pubmed Central) - Jan 15, 2020
19 PKU patients were under dietary treatment and 13 on tetrahydrobiopterin therapy...In PKU patients, no correlations were found with peripheral biomarkers of neurotransmitter synthesis nor different Phe parameters, 43.3% had low melatonin excretion and 43.8% low platelet serotonin concentrations. Despite melatonin and serotonin deficits in early-treated PKU patients, the prevalence of sleep disorders is similar to that of the general population.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: QDPR homologues in Danio rerio regulate melanin synthesis, early gliogenesis, and glutamine homeostasis. (Pubmed Central) - Jan 10, 2020
Dihydropteridine reductase (QDPR) catalyzes the recycling of tetrahydrobiopterin (BH4), a cofactor in dopamine, serotonin, and phenylalanine metabolism...Glutamine accumulation biochemically accompanies the developmental changes. Our findings provide novel insights into the neuropathogenesis of QDPR deficiency.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment. (Pubmed Central) - Jan 1, 2020
The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH)...However, the difficult task of integrating clinical symptoms and laboratory values still leads to a critical delay in diagnosis and therapy for patients. This review aims at enhancing the understanding of neurotransmitter disorders and should help practicing clinicians to choose useful diagnostic steps on the way to a valid diagnosis.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo, succinyl norcocaine & cholera toxin B (TA-CD) / Celtic
Journal: Enhanced Nanoencapsulation of Sepiapterin within PEG-PCL Nanoparticles by Complexation with Triacetyl-Beta Cyclodextrin. (Pubmed Central) - Jan 1, 2020
In this work, we aimed to improve the encapsulation efficiency of sepiapterin (SP), the natural precursor of the essential cofactor tetrahydrobiopterin (BH4) that displays mild water-solubility and a short biological half-life, within methoxy-poly(ethylene-glycol)-poly(epsilon-caprolactone)(mPEG-PCL) nanoparticles (NPs) by means of its complexation and hydrophobization with 2,3,6-triacetyl-β-cyclodextrin (TAβCD)...Moreover, the NPs sustained the SP release with relatively low burst effect of 20%. Overall, our results confirmed that spray-drying of SP/TAβCD solutions at the appropriate molar ratio leads to the hydrophobization of the relatively hydrophilic SP molecule, enabling its encapsulation within mPEG-PCL NPs and paves the way for the use of this strategy in the development of novel drug delivery systems of this vital biological precursor.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo, fosinopril / Generic mfg.
Preclinical, Journal: Xin-Ji-Er-Kang Alleviates Myocardial Infarction-Induced Cardiovascular Remodeling in Rats by Inhibiting Endothelial Dysfunction. (Pubmed Central) - Dec 26, 2019
136 Sprague-Dawley rats were randomized into 13 groups: control group for 0wk (n = 8); sham groups for 2, 4, and 6 weeks (wk); MI groups for 2, 4, and 6 wk; MI+XJEK groups for 2, 4, and 6w k; MI+Fosinopril groups for 2, 4, and 6 wk (n = 8~10)...Colorimetric analysis was employed to detect nitric oxide (NO), and enzyme-linked immunosorbent assay (ELISA) was applied to determine N-terminal probrain natriuretic peptide (NT-ProBNP), endothelin-1 (ET-1), angiotensin II (Ang II), asymmetric dimethylarginine (ADMA), tetrahydrobiopterin (BH), and endothelial NO synthase (eNOS) content...XJEK downregulated ET-1, Ang II, and ADMA content obviously compared to sham group. In conclusion, XJEK may exert the protective effects on MI rats and could continuously ameliorate ED and reverse CR with the progression of MI over time.
- |||||||||| Azulfidine (sulfasalazine) / Generic mfg.
Journal: Anti-tumor effect of sulfasalazine in neuroblastoma. (Pubmed Central) - Dec 23, 2019
Importantly, oral/intraperitoneal (i.p.) SSZ co-administration resulted in measureable anti-tumor effects in vivo. The FDA-approved drug SSZ, a well-tolerated drug in clinical use, could be repositioned to inhibit tumor growth in NB.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo, Bystolic (nebivolol) / Allergan, Menarini
Journal: Effects of tetrahydrobiopterin combined with nebivolol on cardiac diastolic function in SHRs. (Pubmed Central) - Dec 23, 2019
Notably, combined use of BH4 and nebivolol had better cardioprotective effects than monotherapies. BH4 or nebivolol has a protective effect on diastolic dysfunction in SHRs, and BH4 combined with nebivolol may exert a synergistically cardioprotective effect through activation of β-adrenoceptor and the NO/cGMP/PKG signaling pathway.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Retrospective data, Journal: Retrospective Study of Patients with Hyperphenylalaninemia- Experience from a Tertiary Care Center in Pakistan. (Pubmed Central) - Dec 23, 2019
BH4 or nebivolol has a protective effect on diastolic dysfunction in SHRs, and BH4 combined with nebivolol may exert a synergistically cardioprotective effect through activation of β-adrenoceptor and the NO/cGMP/PKG signaling pathway. Most hyperphenylalaninemia cases were diagnosed late when intellectual disability had already developed.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Nicotine induces endothelial dysfunction and promotes atherosclerosis via GTPCH1. (Pubmed Central) - Dec 21, 2019
The objective of this study is to characterize the role of GTP cyclohydrolase 1 (GTPCH1), the rate-limiting enzyme for de novo tetrahydrobiopterin (BH4) synthesis, in the smoking-accelerated atherosclerosis and the mechanism involved...In vivo, nicotine induced endothelial dysfunction and promoted atherosclerosis in ApoE mice, which were attenuated by GTPCH1 overexpression or BH4 supplement. Our findings may provide a novel and promising approach to atherosclerosis treatment.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Preclinical, Journal: Exercise training augments neuronal nitric oxide synthase dimerization in the paraventricular nucleus of rats with chronic heart failure. (Pubmed Central) - Dec 6, 2019
Dimerization of nNOS also requires (6R)-5,6,7,8-tetrahydrobiopterin (BH4) for stability and activity...Interestingly, CHF induced decrease in GCH1 expression was increased with ExT. Our findings revealed that ExT rectified decreased PIN and GCH1 expression and increased dimer/monomer ratio of nNOS in the PVN, which may lead to increase NO• bioavailability resulting in amelioration of activated sympathetic drive during CHF.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Review, Journal: Bench to bedside review: therapeutic modulation of nitric oxide in sepsis-an update. (Pubmed Central) - Dec 5, 2019
In sepsis, nitric oxide synthesis is dysregulated with exaggerated production leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity whilst at the same time impaired microvascular function may be driven in part by reduced nitric oxide synthesis by the endothelium. This bench to bedside review summarises our current understanding of the ways in which nitric oxide production is regulated on a tissue and cellular level before discussing progress in translating these observations into novel therapeutic strategies for patients with sepsis.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Genetic study in a family with dopa-responsive dystonia revealed a novel mutation in sepiapterin reductase gene. (Pubmed Central) - Dec 1, 2019
Dopa-responsive dystonia due to sepiapterin reductase deficiency (OMIM#612716) is caused by recessive mutations in the gene encoding sepiapterin reductase (SPR), which plays an important role in the biosynthesis of tetrahydrobiopterin (BH4)...The case in this study illustrates the difficulties of diagnosing sepiapterin reductase deficiency based on clinical symptoms only and thus renders the possibilities of early management. Also, this study reinforces the importance of running WES to undiagnosed neurodevelopmental cases.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Review, Journal: Roles of eNOS in atherosclerosis treatment. (Pubmed Central) - Nov 27, 2019
eNOS can be an important target for prevention and treatment of AS, and eNOS drugs may be another potent class of effective therapeutic treatment for AS following traditional lipid-lowering, anti-platelet, vasodilator drugs. But applying these experimental results to clinic treatment still requires further studies and development of biotechnology.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Novel Treatment of Hypertension by Specifically Targeting E2F for Restoration of Endothelial Dihydrofolate Reductase and eNOS Function Under Oxidative Stress. (Pubmed Central) - Nov 19, 2019
We have shown that hydrogen peroxide (HO) downregulates tetrahydrobiopterin salvage enzyme DHFR (dihydrofolate reductase) to result in eNOS (endothelial NO synthase) uncoupling and elevated blood pressure...Bioinformatic analyses confirmed a positive correlation between E2F1 and DHFR in human endothelial cells and arteries, and downregulation of both by oxidized phospholipids. In summary, endothelial DHFR is downregulated by HO transcriptionally via an E2F-dependent mechanism, and that specifically targeting E2F1/2/3a to restore DHFR and eNOS function may serve as a novel therapeutic option for the treatment of hypertension.
- |||||||||| quercetin (LY294002) / Eli Lilly, Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo, U0126 / Promega
Journal: Nitric oxide: Is it the culprit for the continued expansion of keloids? (Pubmed Central) - Nov 14, 2019
In this study, we investigated the effect of NO on KDFs proliferation by Sodium Nitroprusside (SNP), an NO donor...U0126 and LY294002, inhibitors of Erk and Akt respectively, block SNP-enhanced KDFs proliferation effectively...Moreover, it decreased the expression of p, a cell cycle inhibitor. Our results reveal that SNP induced KDFs proliferation and loss contact inhibition led to pile up growth via activation of the Erk and Akt pathways, as well as a decreased expression of p. Thus, we speculate that the pathological feature of continuous expansion in keloids is caused by NO-induced KDFs sustained growth.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, Retrospective data, Journal: Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders. (Pubmed Central) - Nov 11, 2019
Decreased BH4 in HUVECs, due to hyperoxia or lack of ascorbic acid, does not imply corresponding decreases in NO generation. Although our data on 16 pregnancies in seven patients did not present any association of standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or paediatric outcome, an intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BHdeficiency is essential since available data on pregnancies in patients with BHdeficiencies is limited.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, P1 data, Journal: Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers. (Pubmed Central) - Nov 10, 2019
CNSA-001 was well tolerated, with no clear dose-relationship for adverse events (AE), no serious AE and no study discontinuations for AE. These data indicate that CNSA-001 is rapidly and efficiently converted to BH in humans supporting further clinical evaluation of CNSA-001 for the management of PKU, primary BH deficiencies and other diseases associated with deficient BH metabolism.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: HPAanalyze: an R package that facilitates the retrieval and analysis of the Human Protein Atlas data. (Pubmed Central) - Nov 10, 2019
These data indicate that CNSA-001 is rapidly and efficiently converted to BH in humans supporting further clinical evaluation of CNSA-001 for the management of PKU, primary BH deficiencies and other diseases associated with deficient BH metabolism. HPAanalyze integrates into the R workflow with the tidyverse framework, and it can be used in combination with Bioconductor packages for easy analysis of HPA data.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Preclinical, Journal: Tetrahydrobiopterin treatment reduces brain L-Phe but only partially improves serotonin in hyperphenylalaninemic ENU1/2 mice. (Pubmed Central) - Nov 6, 2019
Furthermore, indirect evidence indicated that the GTP cyclohydrolase I (GTPCH) feedback regulatory protein (GFRP) complex may be a sensor for brain L-Phe elevation to ameliorate the toxic effects of HPA. We conclude that BHtreatment of HPA toward systemic L-Phe lowering reverses elevated brain L-Phe content but the recovery of TPH2 protein and activity as well as serotonin levels is suboptimal, indicating that patients with mild HPA and mood problems (depression or anxiety) treated with the current diet may benefit from supplementation with BHand 5-OH-tryptophan.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: Tetrahydrobiopterin modulates ubiquitin conjugation to UBC13/UBE2N and proteasome activity by S-nitrosation. (Pubmed Central) - Oct 31, 2019
Our results highlight the widespread impact of BH4 on downstream cellular signalling as evidenced by the effect of a perturbed BH4-dependent NO-Redox balance on critical processes within the ubiquitin-proteasome system (UPS). These studies thereby uncover a novel aspect of NO associated modulation of cellular homeostasis.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: The financial and time burden associated with phenylketonuria treatment in the United States. (Pubmed Central) - Oct 30, 2019
Treatment for PKU incurs a substantial time and cost burden on persons with PKU and their families. Estimated medical expenditures using claims data varied by age group, but sapropterin represented the largest cost for PKU treatment from a payer perspective across age groups.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Journal: A Kinetic Study of Ligand Binding and Conformational Changes in Inducible Nitric Oxide Synthase. (Pubmed Central) - Oct 24, 2019
CO rebinding to the P450 form strongly depends on the presence of the substrate l-Arg, the intermediate N-hydroxy-l-arginine, and the cofactor tetrahydrobiopterin...This process can be described as a relaxation from a fast rebinding, metastable species to a slowly rebinding, thermodynamically stable species, which we associate with the enzymatically active form. Our results allow us to determine kinetic parameters of L-Arg binding to ferrous deoxy iNOS protein for the first time, and also provide clues regarding the nature of structural differences between the two interconverting species.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Clinical, Review, Journal: Late-diagnosed phenylketonuria mimicking x-linked adrenoleukodystrophy with heterozygous mutations of the PAH Gene: A case report and literature review. (Pubmed Central) - Oct 18, 2019
Phenylketonuria (PKU) is a prevalent inherited metabolic disorder caused by a phenylalanine hydroxylase (PAH) or tetrahydrobiopterin (BH4) deficiency, which leads to the accumulation of phenylalanine (PHE)...Our patient is the first case of late-diagnosed PKU with definite heterozygous PAH gene mutations reported in China albeit he had milder symptoms than the previous reported cases around world. Although late-diagnosed PKU is rare, this diagnosis should be considered for patients presenting with leukoencephalopathy accompanied by common neurological signs.
- |||||||||| doxorubicin hydrochloride / generics
Journal: Sepiapterin Enhances Tumor Radio- and Chemosensitivities by Promoting Vascular Normalization. (Pubmed Central) - Oct 16, 2019
HPLC analysis of tumor doxorubicin levels showed a greater than 50% increase in doxorubicin uptake and a synergistic effect on tumor cell apoptosis. This study highlights for the first time the importance of NOS uncoupling and endothelial dysfunction in the development of tumor vasculature and presents a new approach for improving the tumoricidal efficacies of chemotherapy and radiotherapy.
- |||||||||| sapropterin / Generic mfg.
Trial completion, Phase classification: Kuvan Therapy in Phenylketonuria (PKU): The Effect of Blood Phenylalanine Concentration on Kuvan Response (clinicaltrials.gov) - Oct 8, 2019
P2, N=21, Completed,
This study highlights for the first time the importance of NOS uncoupling and endothelial dysfunction in the development of tumor vasculature and presents a new approach for improving the tumoricidal efficacies of chemotherapy and radiotherapy. Recruiting --> Completed | Phase classification: PN/A --> P2
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Review, Journal: Say NO to ROS: Their Roles in Embryonic Heart Development and Pathogenesis of Congenital Heart Defects in Maternal Diabetes. (Pubmed Central) - Oct 5, 2019
Maternal treatment with sapropterin, a cofactor of eNOS, and antioxidants such as N-acetylcysteine, vitamin E, and glutathione as well as maternal exercise have been shown to improve eNOS function, reduce oxidative stress, and lower the incidence CHDs in the offspring of mice with pregestational diabetes. This review summarizes recent data on pregestational diabetes-induced CHDs, and offers insights into the important roles of NO and ROS in embryonic heart development and pathogenesis of CHDs in maternal diabetes.
- |||||||||| Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Biomarker, Clinical, Journal: Alterations in the reduced pteridine contents in the cerebrospinal fluids of LRRK2 mutation carriers and patients with Parkinson's disease. (Pubmed Central) - Oct 2, 2019
Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase that is essential for the biosynthesis of dopamine...The total neopterin levels in the CSF of the LRRK2-PD were significantly higher than those in the sPD and non-PD individuals, which indicated greater inflammatory responses in the brains of LRRK2-PD patients. The present results suggest that detailed analyses of pteridine levels in the CSF might be useful for understanding the pathophysiology of familial PD and for monitoring PD progression.
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