Nitisinone, sold under the brand name Orfadin among others, is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

used to slow the effects of hereditary tyrosinemia type 1 (HT-1).

Uses

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. Since its first use for this indication in 1991, it has replaced

liver transplantation Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, al ...

as the first-line treatment for this ultra rare condition.

Adverse effects

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.

Mechanism of action

The

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...

of nitisinone involves

inhibition Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

of 4-Hydroxyphenylpyruvate dioxygenase (HPPD). 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. This causes the symptoms of Tyrosinemia type 1 experienced by untreated patients.

Alkaptonuria 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 (it is a recessive condition), the body ac ...

is caused when an enzyme called homogentisic dioxygenase (HGD) is faulty, leading to a buildup of homogenisate.

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 Ochronosis is a syndrome caused by the accumulation of homogentisic acid in connective tissues. The condition was named after the yellowish (ocher-like) discoloration of the tissue seen on microscopic examination. Macroscopically, though, the af ...

experienced by older

alkaptonuria 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 (it is a recessive condition), the body ac ...

patients.

History

Nitisinone was discovered as part of a program to develop a class of

herbicides Herbicides (, ), also commonly known as weedkillers, are substances used to control undesired plants, also known as weeds.EPA. February 201Pesticides Industry. Sales and Usage 2006 and 2007: Market Estimates. Summary in press releasMain page fo ...

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 Leptospermone is a chemical compound (a β-triketone) produced by some members of the myrtle family ('' Myrtaceae''), such as '' Callistemon citrinus'' (Lemon Bottlebrush), a shrub native to Australia, and ''Leptospermum scoparium'' (Manuka), a Ne ...

, obtained from the Australian bottlebrush plant (''

Callistemon citrinus ''Melaleuca citrina'', the common red bottlebrush, crimson bottlebrush, or lemon bottlebrush, is a plant in the myrtle family Myrtaceae, and is endemic to eastern Australia. Some Australian state herbaria continue to use the name ''Callistemon ...

''). HPPD is essential in plants and animals for

catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...

, or breaking apart, of

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) 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 Gr ...

. In plants, preventing this process leads to destruction of

chlorophyll Chlorophyll (also chlorophyl) is any of several related green pigments found in cyanobacteria and in the chloroplasts of algae and plants. Its name is derived from the Greek words , ("pale green") and , ("leaf"). Chlorophyll allow plants to a ...

and the death of the plant. In

toxicology Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating expo ...

studies of the herbicide, it was discovered that it had activity against HPPD in rats and humans. In Type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine,

fumarylacetoacetate hydrolase 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. Function Fumarylacetoacetate hydrolase ( ...

is mutated and doesn't work, leading to very harmful products building up in the body. Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists working on making

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 An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

Swedish Orphan International, which was later acquired by Swedish Orphan Biovitrum (Sobi).

Research

Nitisinone is being studied as a treatment for

References

External links

* {{Portal bar , Medicine Herbicides Nitrobenzenes Orphan drugs Aromatic ketones Trifluoromethyl compounds