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Trade names | Nityr, Orfadin |
Other names | NTBC |
AHFS/Drugs.com | Professional Drug Facts |
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Routes of administration | By mouth |
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Elimination half-life | Approximately 54 h |
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ECHA InfoCard | 100.218.521 |
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Formula | C14H10F3NO5 |
Molar mass | 329.231 g·mol−1 |
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Nitisinone, sold under the brand name Orfadin among others, is a medication used to slow the effects of hereditary tyrosinemia type 1 (HT-1).
It is available as a generic medication. [1] [2]
Nitisinone is used to treat hereditary tyrosinemia type 1 (HT-1) in patients from all ages, in combination with dietary restriction of tyrosine and phenylalanine.[ medical citation needed ]
Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this ultra rare condition. [3]
The most common adverse reactions (>1%) for nitisinone are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash and alopecia.has several negative side effects; these include but are not limited to: bloated abdomen, dark urine, abdominal pain, feeling of tiredness or weakness, headache, light-colored stools, loss of appetite, weight loss, vomiting, and yellow-colored eyes or skin.[ medical citation needed ]
The mechanism of action of nitisinone involves inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD). [4] [5] This is a treatment for patients with Tyrosinemia type 1 as it prevents the formation of 4-Maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys. [3] This causes the symptoms of Tyrosinemia type 1 experienced by untreated patients.[ medical citation needed ]
Alkaptonuria is caused when an enzyme called homogentisic dioxygenase (HGD) is faulty, leading to a buildup of homogenisate. Alkaptonuria patients treated with nitisinone produce far less HGA than those not treated (95% less in the urine), because nitisinone inhibits HPPD, resulting in less homogenisate accumulation. Clinical trials are ongoing to test whether nitisinone can prevent ochronosis experienced by older alkaptonuria patients.[ medical citation needed ]
Nitisinone was discovered as part of a program to develop a class of herbicides called HPPD inhibitors. It is a member of the benzoylcyclohexane-1,3-dione family of herbicides, which are chemically derived from a natural phytotoxin, leptospermone, obtained from the Australian bottlebrush plant ( Callistemon citrinus ). [6] HPPD is essential in plants and animals for catabolism, or breaking apart, of tyrosine. [7] In plants, preventing this process leads to destruction of chlorophyll and the death of the plant. [7] In toxicology studies of the herbicide, it was discovered that it had activity against HPPD in rats [8] and humans. [9]
In Type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine, fumarylacetoacetate hydrolase is mutated and doesn't work, leading to very harmful products building up in the body. [10] Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists working on making herbicides in the class of HPPD inhibitors hypothesized that inhibiting HPPD and controlling tyrosine in the diet could treat this disease. A series of small clinical trials attempted with one of their compounds, nitisinone, were conducted and were successful, leading to nitisinone being brought to market as an orphan drug Swedish Orphan International, [4] which was later acquired by Swedish Orphan Biovitrum (Sobi).[ citation needed ]
L-Tyrosine or tyrosine or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Greek tyrós, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional group or side chain. While tyrosine is generally classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine. It is encoded by the codons UAC and UAU in messenger RNA.
Herbicides, also commonly known as weed killers, are substances used to control undesired plants, also known as weeds. Selective herbicides control specific weed species while leaving the desired crop relatively unharmed, while non-selective herbicides can be used to clear waste ground, industrial and construction sites, railways and railway embankments as they kill all plant material with which they come into contact. Apart from selective/non-selective, other important distinctions include persistence, means of uptake, and mechanism of action. Historically, products such as common salt and other metal salts were used as herbicides, however, these have gradually fallen out of favor, and in some countries, a number of these are banned due to their persistence in soil, and toxicity and groundwater contamination concerns. Herbicides have also been used in warfare and conflict.
Alkaptonuria is a rare inherited genetic disease which is caused by a mutation in the HGD gene for the enzyme homogentisate 1,2-dioxygenase ; if a person inherits an abnormal copy from both parents, the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form alkapton are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage and heart valves, as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth.
Tyrosinemia or tyrosinaemia is an error of metabolism, usually inborn, in which the body cannot effectively break down the amino acid tyrosine. Symptoms of untreated tyrosinemia include liver and kidney disturbances. Without treatment, tyrosinemia leads to liver failure. Today, tyrosinemia is increasingly detected on newborn screening tests before any symptoms appear. With early and lifelong management involving a low-protein diet, special protein formula, and sometimes medication, people with tyrosinemia develop normally, are healthy, and live normal lives.
HPPD may refer to:
Homogentisic acid is a phenolic acid usually found in Arbutus unedo (strawberry-tree) honey. It is also present in the bacterial plant pathogen Xanthomonas campestris pv. phaseoli as well as in the yeast Yarrowia lipolytica where it is associated with the production of brown pigments. It is oxidatively dimerised to form hipposudoric acid, one of the main constituents of the 'blood sweat' of hippopotamuses.
4-Hydroxyphenylpyruvate dioxygenase (HPPD), also known as α-ketoisocaproate dioxygenase, is an Fe(II)-containing non-heme oxygenase that catalyzes the second reaction in the catabolism of tyrosine - the conversion of 4-hydroxyphenylpyruvate into homogentisate. HPPD also catalyzes the conversion of phenylpyruvate to 2-hydroxyphenylacetate and the conversion of α-ketoisocaproate to β-hydroxy β-methylbutyrate. HPPD is an enzyme that is found in nearly all aerobic forms of life.
Hawkinsinuria is an autosomal dominant metabolic disorder affecting the metabolism of tyrosine.
Homogentisate 1,2-dioxygenase (homogentisic acid oxidase, homogentisate oxidase, homogentisicase) is an enzyme which catalyzes the conversion of homogentisate to 4-maleylacetoacetate. Homogentisate 1,2-dioxygenase or HGD is involved in the catabolism of aromatic rings, more specifically in the breakdown of the amino acids tyrosine and phenylalanine. HGD appears in the metabolic pathway of tyrosine and phenylalanine degradation once the molecule homogentisate is produced. Homogentisate reacts with HGD to produce maleylacetoacetate, which then is further used in the metabolic pathway. HGD requires the use of Fe2+ and O2 in order to cleave the aromatic ring of homogentisate.
Tyrosine aminotransferase is an enzyme present in the liver and catalyzes the conversion of tyrosine to 4-hydroxyphenylpyruvate.
Fumarylacetoacetase is an enzyme that in humans is encoded by the FAH gene located on chromosome 15. The FAH gene is thought to be involved in the catabolism of the amino acid phenylalanine in humans.
In enzymology, a cyclohexane-1,3-dione hydrolase (EC 3.7.1.10) is an enzyme that catalyzes the chemical reaction
Tyrosinemia type III is a rare disorder caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase, encoded by the gene HPD. This enzyme is abundant in the liver, and smaller amounts are found in the kidneys. It is one of a series of enzymes needed to break down tyrosine. Specifically, 4-hydroxyphenylpyruvate dioxygenase converts a tyrosine byproduct called 4-hydroxyphenylpyruvate to homogentisic acid. Characteristic features of type III tyrosinemia include mild mental retardation, seizures, and periodic loss of balance and coordination. Type III tyrosinemia is very rare; only a few cases have been reported.
Leptospermone is a chemical compound produced by some members of the myrtle family (Myrtaceae), such as Callistemon citrinus, a shrub native to Australia, and Leptospermum scoparium (Manuka), a New Zealand tree from which it gets its name. Modification of this allelopathic chemical to produce mesotrione led to the commercialization of derivative compounds as HPPD inhibitor herbicides.
Mesotrione is the ISO common name for an organic compound that is used as a selective herbicide, especially in maize. A synthetic inspired by the natural substance leptospermone, it inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) and is sold under brand names including Callisto and Tenacity. It was first marketed by Syngenta in 2001.
4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are a class of herbicides that prevent growth in plants by blocking 4-Hydroxyphenylpyruvate dioxygenase, an enzyme in plants that breaks down the amino acid tyrosine into molecules that are then used by plants to create other molecules that plants need. This process of breakdown, or catabolism, and making new molecules from the results, or biosynthesis, is something all living things do. HPPD inhibitors were first brought to market in 1980, although their mechanism of action was not understood until the late 1990s. They were originally used primarily in Japan in rice production, but since the late 1990s have been used in Europe and North America for corn, soybeans, and cereals, and since the 2000s have become more important as weeds have become resistant to glyphosate and other herbicides. Genetically modified crops are under development that include resistance to HPPD inhibitors. There is a pharmaceutical drug on the market, nitisinone, that was originally under development as an herbicide as a member of this class, and is used to treat an orphan disease, type I tyrosinemia.
Succinylacetone is a chemical compound that is formed by the oxidation of glycine and is a precursor of methylglyoxal. It is a pathognomonic compound found in the urine of patients with tyrosinemia type 1, which is due to congenital deficiency of an enzyme, fumarylacetoacetate hydrolase. This enzyme is involved in the catabolism of tyrosine, and if deficient, leads to accumulation of fumarylacetoacetate which is subsequently converted to succinylacetone which can be detected in the urine by GCMS. Succinylacetone also inhibits ALA dehydratase which increases ALA and precipitates acute neuropathic symptoms, similar to porphyria.
1,3-Cyclohexanedione is an organic compound with the formula (CH2)4(CO)2. It is one of three isomeric cyclohexanediones. It is a colorless compound that occurs naturally. It is the substrate for cyclohexanedione hydrolase. The compound exists mainly as the enol tautomer.
Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe. If diagnosed through newborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.
Clethodim is an organic compound. A member of the cyclohexanedione family of herbicides, it is used to control grasses, especially Lolium rigidum. Although impure samples appear yellowish, the compound is colorless.