nitisinone

Nitisinone is used to treat hereditary tyrosinemia type 1{{Cite journal | vauthors = Das AM | title = Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1) | journal = The Application of Clinical Genetics | volume = 10 | pages = 43–48 | date = 2017 | pmid = 28769581 | pmc = 5533484 | doi = 10.2147/TACG.S113310 | doi-access = free | issn = 1178-704X }} (HT-1) and alkaptonuria{{Cite journal | vauthors = Ranganath LR, Psarelli EE, Arnoux JB, Braconi D, Briggs M, Bröijersén A, Loftus N, Bygott H, Cox TF, Davison AS, Dillon JP, Fisher M, FitzGerald R, Genovese F, Glasova H | title = Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial | journal = The Lancet. Diabetes & Endocrinology | volume = 8 | issue = 9 | pages = 762–772 | date = 2020-09-01 | pmid = 32822600 | doi = 10.1016/S2213-8587(20)30228-X | url = https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30228-X/abstract | language = English | issn = 2213-8587 | hdl = 11365/1115671 }} (AKU) in patients from all ages, in combination with dietary restriction of tyrosine and phenylalanine.

Since its first use {{cite book | vauthors = Lock EA | chapter = From Weed Killer to Wonder Drug | title = Hereditary Tyrosinemia: Pathogenesis, Screening and Management | series = Advances in Experimental Medicine and Biology | pages = 175–185 | date = 2017 | volume = 959 | pmid = 28755195 | doi = 10.1007/978-3-319-55780-9_16 | chapter-url = https://link.springer.com/chapter/10.1007/978-3-319-55780-9_16 | access-date = 2025-05-21 | place = Cham | publisher = Springer International Publishing | language = en | isbn = 978-3-319-55780-9 | veditors = Tanguay RM }}for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this ultra rare condition.{{cite journal | vauthors = McKiernan PJ | title = Nitisinone in the treatment of hereditary tyrosinaemia type 1 | journal = Drugs | volume = 66 | issue = 6 | pages = 743–750 | year = 2006 | pmid = 16706549 | doi = 10.2165/00003495-200666060-00002 | s2cid = 24239547 }}

It has been shown that this drug is toxic to kissing bugs,{{Cite journal | vauthors = Perdomo HD, Guizzo MG, Barletta AB, Nunes RD, Dias FA, Sorgine MH, Oliveira PL, Sterkel M | title = Tyrosine Detoxification Is an Essential Trait in the Life History of Blood-Feeding Arthropods | journal = Current Biology | volume = 26 | issue = 16 | pages = 2188–2193 | date = 2016-08-22 | pmid = 27476595 | doi = 10.1016/j.cub.2016.06.025 | bibcode = 2016CBio...26.2188S | url = https://www.sciencedirect.com/science/article/pii/S0960982216306649 | issn = 0960-9822 }} tsetse,{{Cite journal | vauthors = Haines LR, Casas-Sánchez A, Adung'a VO, Vionette-Amaral RJ, Quek S, Rose C, Santos MS, Escude NG, Ismail HM, Paine MI, Barribeau SM, Wagstaff S, MacRae JI, Masiga D, Sterkel M | title = Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis | journal = PLOS Biology | volume = 19 | issue = 1 | pages = e3000796 | date = 2021-01-26 | pmid = 33497373 | pmc = 7837477 | doi = 10.1371/journal.pbio.3000796 | doi-access = free | language = en | issn = 1545-7885 }} ticks{{Cite journal | vauthors = Matias J, Tang X, Cibichakravarthy B, DePonte K, Wu MJ, Fikrig E, Cui Y | title = Metabolomic changes associated with acquired resistance to Ixodes scapularis | journal = Ticks and Tick-borne Diseases | volume = 15 | issue = 1 | pages = 102279 | date = 2024-01-01 | pmid = 37972499 | doi = 10.1016/j.ttbdis.2023.102279 | url = https://www.sciencedirect.com/science/article/pii/S1877959X23001607 | issn = 1877-959X }}{{Cite journal | vauthors = Duke SO, Burgess ER, Swale DR, McComic SE | title = Defining the toxicological profile of 4-hydroxyphenylpyruvate dioxygenase-directed herbicides to Aedes aegypti and Amblyomma americanum | journal = Pesticide Biochemistry and Physiology | volume = 194 | pages = 105532 | date = 2023-08-01 | pmid = 37532340 | doi = 10.1016/j.pestbp.2023.105532 | bibcode = 2023PBioP.19405532M | url = https://www.sciencedirect.com/science/article/abs/pii/S0048357523001979 | issn = 0048-3575 }} and mosquitoes.{{cite journal | vauthors = Haines LR, Trett A, Rose C, García N, Sterkel M, McGuinness D, Regnault C, Barrett MP, Leroy D, Burrows JN, Biagini G, Ranganath LR, Aljayyoussi G, Acosta-Serrano Á | title = Anopheles mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone | journal = Science Translational Medicine | volume = 17 | issue = 791 | pages = eadr4827 | date = March 2025 | pmid = 40138457 | doi = 10.1126/scitranslmed.adr4827 }}{{Cite journal | vauthors = Sterkel M, Martins AJ, BP Lima J, L Oliveira P, Vergaray Ramirez MA | title = On the use of inhibitors of 4-hydroxyphenylpyruvate dioxygenase as a vector-selective insecticide in the control of mosquitoes | journal = Pest Management Science | volume = 78 | issue = 2 | pages = 692–702 | date = 2022 | pmid = 34647418 | doi = 10.1002/ps.6679 | url = https://scijournals.onlinelibrary.wiley.com/doi/10.1002/ps.6679 | language = en | issn = 1526-4998 }} It is under consideration as an agent for mosquito control.

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. Nitisinone 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.{{Cite journal | vauthors = Rodenburg IL, Harding CO, Hollak CE, Heiner-Fokkema MR, van Spronsen FJ, van Ginkel WG | title = Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1 | journal = Paediatric Drugs | volume = 21 | issue = 6 | pages = 413–426 | date = December 2019 | pmid = 31667718 | pmc = 6885500 | doi = 10.1007/s40272-019-00364-4 | issn = 1179-2019 }}

The mechanism of action of nitisinone involves inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD).{{cite journal | vauthors = Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, Smith LL, Prisbylla MP, Mutter LC, Lee DL | title = From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug | journal = Journal of Inherited Metabolic Disease | volume = 21 | issue = 5 | pages = 498–506 | date = August 1998 | pmid = 9728330 | doi = 10.1023/A:1005458703363 | s2cid = 6717818 }}{{cite journal | vauthors = Kavana M, Moran GR | title = Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione | journal = Biochemistry | volume = 42 | issue = 34 | pages = 10238–10245 | date = September 2003 | pmid = 12939152 | doi = 10.1021/bi034658b }} 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 [https://rarediseases.org/rare-diseases/tyrosinemia-type-1/ symptoms of Tyrosinemia type 1] experienced by untreated patients.{{medcn|date=September 2018}}

Alkaptonuria is caused when an enzyme called homogentisic dioxygenase (HGD) is faulty, leading to a buildup of homogentisate (HGA). 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{{Cite web |date=2023-10-26 |title=Alkaptonuria and ochronosis |url=https://dermnetnz.org/topics/alkaptonuria-and-ochronosis#:~:text=Firstly%20patients%20suffer%20low%20back%20pain%20with,spinal%20injuries%20such%20as%20prolapsed%20intervertebral%20discs. |access-date=2025-05-22 |website=DermNet® |language=en}}

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).{{cite journal | vauthors = Mitchell G, Bartlett DW, Fraser TE, Hawkes TR, Holt DC, Townson JK, Wichert RA | title = Mesotrione: a new selective herbicide for use in maize | journal = Pest Management Science | volume = 57 | issue = 2 | pages = 120–128 | date = February 2001 | pmid = 11455642 | doi = 10.1002/1526-4998(200102)57:2<120::AID-PS254>3.0.CO;2-E }} HPPD is essential in plants and animals for catabolism, or breaking apart, of tyrosine.{{cite journal | vauthors = Moran GR | title = 4-Hydroxyphenylpyruvate dioxygenase | journal = Archives of Biochemistry and Biophysics | volume = 433 | issue = 1 | pages = 117–128 | date = January 2005 | pmid = 15581571 | doi = 10.1016/j.abb.2004.08.015 }} In plants, preventing this process leads to destruction of chlorophyll and the death of the plant. In toxicology studies of the herbicide, it was discovered that it had activity against HPPD in rats{{cite journal | vauthors = Ellis MK, Whitfield AC, Gowans LA, Auton TR, Provan WM, Lock EA, Smith LL | title = Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione | journal = Toxicology and Applied Pharmacology | volume = 133 | issue = 1 | pages = 12–19 | date = July 1995 | pmid = 7597701 | doi = 10.1006/taap.1995.1121 | bibcode = 1995ToxAP.133...12E }} and humans.{{cite book | vauthors = Lindstedt S, Odelhög B | veditors = Kaufman S | chapter = 4-Hydroxyphenylpyruvate dioxygenase from human liver | title = Metabolism of Aromatic Amino Acids and Amines | volume = 142 | pages = 139–142 | year = 1987 | pmid = 3037254 | doi = 10.1016/S0076-6879(87)42021-1 | series = Methods in Enzymology | isbn = 978-0-12-182042-8 }}

In Type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine, fumarylacetoacetate hydrolase is either absent or mutated and doesn't work, leading to very harmful products building up in the body.{{cite web | vauthors = Tanguay RM | title = Physician's Guide to Tyrosinemia Type 1 | publisher = National Organization for Rare Disorders | url = https://www.rarediseases.org/docs/Tyrosinemia2_3_11.pdf | archive-url = https://web.archive.org/web/20140211203002/http://www.rarediseases.org/docs/Tyrosinemia2_3_11.pdf | archive-date = 2014-02-11 }} Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists like Edward A. Lock, 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 by Swedish Orphan International, which was later acquired by Swedish Orphan Biovitrum (Sobi).{{cn|date=September 2018}}

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