Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin). Medical use
Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride (BH4*2HCL). It was approved for use in the United States as a tablet in December 2007 and as a powder in December 2013. It was approved for use in the European Union in December 2008, Canada in April 2010, and Japan in July 2008. It is sold under the brand names Kuvan and Biopten. The typical cost of treating a patient with Kuvan is US$100,000 per year. BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020.Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency. Also, BH4*2HCL is FDA approved for use in phenylketonuria (PKU), along with dietary measures. However, most people with PKU have little or no benefit from BH4*2HCL. Adverse effects
The most common adverse effects, observed in more than 10% of people, include headache and a running or obstructed nose.
Folic acid and its metabolites seem to be particularly important in the recycling of BH4 and NOS coupling. Research
Other than PKU studies, tetrahydrobiopterin has participated in clinical trials studying other approaches to solving conditions resultant from a deficiency of tetrahydrobiopterin. These include autism, depression, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease. Experimental studies suggest that tetrahydrobiopterin regulates deficient production of nitric oxide in cardiovascular disease states, and contributes to the response to inflammation and injury, for example in pain due to nerve injury. A 2015 BioMarin-funded study of PKU patients found that those who responded to tetrahydrobiopterin also showed a reduction of ADHD symptoms. Depression
In psychiatry, tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression, although evidence is inconclusive to date. Autism
In 1997, a small pilot study was published on the efficacy of tetrahydrobiopterin (BH4) on relieving the symptoms of autism, which concluded that it "might be useful for a subgroup of children with autism" and that double-blind trials are needed, as are trials which measure outcomes over a longer period of time. In 2010, Frye et al. published a paper which concluded that it was safe, and also noted that "several clinical trials have suggested that treatment with BH4 improves ASD symptomatology in some individuals." Cardiovascular disease
Since nitric oxide production is important in regulation of blood pressure and blood flow, thereby playing a significant role in cardiovascular diseases, tetrahydrobiopterin is a potential therapeutic target. In the endothelial cell lining of blood vessels, endothelial nitric oxide synthase is dependent on tetrahydrobiopterin availability.