Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Flucytosine: Difference between pages

{{Short description|Chemical compound}}

| verifiedrevid =

| image = .svg

| image2 = Flucytosine-3D-balls.png

| tradename = Ancobon

| routes_of_administration = Oral, [[intravenous therapy|intravenous]]

| bioavailability = 75 to 90% ()

| metabolism = , in the [[Gastrointestinal tract|GI tract]]

| excretion = [[]] (90%)

| = {{cascite|correct|}}

| C=4 | H=4 | F=1 | N=3 | O=1

| smiles = (=O)

| melting_point = 295

| melting_high = 297

| melting_notes = (dec.)

<!-- Definition and medical uses -->

'''Flucytosine''', also known as '''5-fluorocytosine''' ('''5-FC'''), is an [[antifungal medication]].<ref name=AHFS2016/> It is specifically used, together with [[amphotericin B]], for serious [[Candida infection|''Candida'' infection]]s and [[cryptococcosis]].<ref name=AHFS2016/> It may be used by itself or with other antifungals for [[chromomycosis]].<ref name=AHFS2016/> Flucytosine is used [[Oral administration|by mouth]] and by [[intravenous|injection into a vein]].<ref name=AHFS2016>{{cite web|title=Flucytosine|url=https://www.drugs.com/monograph/flucytosine.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220231247/https://www.drugs.com/monograph/flucytosine.html|archive-date=20 December 2016}}</ref><ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free |page=147 }}</ref>

<!-- Side effects and mechanism -->

Common side effects include [[bone marrow suppression]], loss of appetite, [[diarrhea]], vomiting, and [[psychosis]].<ref name=AHFS2016/> [[Anaphylaxis]] and other [[allergic reactions]] occasionally occur.<ref name=AHFS2016/> It is unclear if use in [[pregnancy]] is safe for the baby.<ref>{{cite web|title=Flucytosine (Ancobon) Use During Pregnancy|url=https://www.drugs.com/pregnancy/flucytosine.html|website=www.drugs.com|access-date=11 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220231425/https://www.drugs.com/pregnancy/flucytosine.html|archive-date=20 December 2016}}</ref> Flucytosine is in the fluorinated [[pyrimidine analogue]] family of medications.<ref name=AHFS2016/> It works by being converted into [[fluorouracil]] inside the fungus, which impairs its ability to [[Protein biosynthesis|make]] [[protein]].<ref name=AHFS2016/>

<!-- Society and culture -->

Flucytosine was first made in 1957.<ref>{{cite book | author = Northern Neonatal Network |title=Neonatal Formulary: Drug Use in Pregnancy and the First Year of Life|date=2008|publisher=John Wiley & Sons|isbn=9780470750353|page=108|edition=5th | chapter = Drug Monographs: Flucytosine | chapter-url=https://books.google.com/books?id=aumIBqHmChwC&pg=PA108|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220092419/https://books.google.ca/books?id=aumIBqHmChwC&pg=PA108|archive-date=2016-12-20}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> As of 2016, in the United States the medication cost about US$2,000 per day while in the United Kingdom it is about US$22 per day.<ref name=Mer2016>{{cite journal | vauthors = Merry M, Boulware DR | title = Cryptococcal Meningitis Treatment Strategies Affected by the Explosive Cost of Flucytosine in the United States: A Cost-effectiveness Analysis | journal = Clinical Infectious Diseases | volume = 62 | issue = 12 | pages = 1564–1568 | date = June 2016 | pmid = 27009249 | pmc = 4885648 | doi = 10.1093/cid/ciw151 }}</ref> It is not available in much of the [[developing world]].<ref>{{cite book| vauthors = Brew BJ, Laffan A | chapter = Opportunistic infections in HIV-positive subjects and AIDS patients | veditors = Lisak RP, Truong DD, Carroll WM, Bhidayasiri R |title=International Neurology|date=2016|publisher=John Wiley & Sons|isbn=9781118777350|page=343|edition=2nd | chapter-url=https://books.google.com/books?id=xHb4CwAAQBAJ&pg=PA343|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220092339/https://books.google.ca/books?id=xHb4CwAAQBAJ&pg=PA343|archive-date=2016-12-20}}</ref>

==Medical uses==

Flucytosine by mouth is used for the treatment of serious infections caused by susceptible strains of ''[[Candida (fungus)|Candida]]'' or ''[[Cryptococcus neoformans]]''. It can also be used for the treatment of [[chromomycosis]] (chromoblastomycosis), if susceptible strains cause the infection. Flucytosine must not be used as a sole agent in life-threatening fungal infections due to relatively weak antifungal effects and fast development of resistance, but rather in combination with amphotericin B and/or [[azole]] antifungals such as [[fluconazole]] or [[itraconazole]]. Minor infections such as candidal [[cystitis]] may be treated with flucytosine alone. In some countries, treatment with slow [[intravenous infusion]]s for no more than a week is also a therapeutic option, particular if the disease is life-threatening.{{cn|date=December 2022}}

Serious fungal infections may occur in those who are immunocompromised. These people benefit from combination therapy including flucytosine, but the incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher.{{cn|date=December 2022}}

===Pregnancy and breastfeeding===

In animal models (rats), flucytosine has been found to be [[teratogenic]]. Sufficient human data does not exist. [[Pregnant]] women should be given flucytosine only if the potential benefits exceed the potential harm to the fetus.{{cn|date=December 2022}}

It is not known if flucytosine is distributed in human breast milk. Given the potential risk to the child, the patient should not [[breastfeeding|breastfeed]] during treatment with flucytosine.{{cn|date=December 2022}}

===Children===

The efficacy and safety in patients under 18 years of age has not been determined.{{cn|date=December 2022}}

==Side effects==

* Patients treated with drugs compromising bone marrow function (e.g. [[cytostatic]]s) should be treated carefully. [[Blood cell count]]s should be taken very frequently.

* Patients with renal disease should receive flucytosine cautiously and in reduced doses. Guidelines for proper dosing exist. Serum level determinations are mandatory for these patients.

* All patients receiving flucytosine should be under strict medical supervision.

* [[Hematological]], [[renal]] and liver function studies should be done frequently during therapy (initially daily, twice a week for the rest of treatment).

* Patients with preexisting bone marrow depression and liver impairment should be treated with caution.

* Antiproliferative actions on bone marrow and GI tissue: Due to the drug's preference for rapidly proliferating tissues, bone marrow depression ([[anemia]], [[leukopenia]], [[pancytopenia]], or even rarely [[agranulocytosis]]) may occur. [[Aplastic anemia]] has also been seen. Bone marrow toxicity can be irreversible and may cause death, particularly in immunocompromised patients. GI toxicity may be severe or rarely fatal and consists of anorexia, abdominal bloating, [[abdominal pain]], [[diarrhea]], dry mouth, [[duodenal ulcer]], GI hemorrhage, nausea, vomiting, and [[ulcerative colitis]].

* Liver function: Elevations of [[liver enzymes]] and [[bilirubin]], hepatic dysfunction, [[jaundice]] and, in one patient, liver necrosis have all been seen. Some fatal cases have been reported; however, the majority of cases was reversible.

* Renal function: Increased [[Blood urea nitrogen|BUN]] and serum [[creatinine]] have been noted. [[Crystalluria]] (formation of crystals and excretion in the urine) and [[acute kidney injury]] have also been seen.

* Adverse [[central nervous system]] effects are frequent and include confusion, [[hallucination]]s, [[psychosis]], [[ataxia]], [[hearing loss]], headache, [[paresthesia]], [[parkinsonism]], [[peripheral neuropathy]], vertigo and sedation.

* Skin reactions: Rash, pruritus, and [[photosensitivity]] have all been noticed. Toxic epidermal necrolysis ([[Lyell's syndrome]]) may also be encountered and may be life-threatening.

* [[Anaphylaxis]]: Sometimes cases of anaphylaxis consisting of diffuse erythema, pruritus, conjunctival injection, fever, abdominal pain, edema, hypotension and bronchospastic reactions are observed.

It is not known if flucytosine is a human [[carcinogen]]. The issue has been raised because traces of [[5-fluorouracil]], which is a known carcinogen, are found in the colon resulting from the metabolization of flucytosine.

== Interactions ==

Flucytosine may increase the toxicity of [[amphotericin B]] and vice versa, although the combination may be life-saving and should be used whenever indicated (e.g., [[Cryptococcus neoformans|cryptococcal]] meningitis). The cytostatic [[cytarabine]] inhibits the antimycotic activity of flucytosine.{{cn|date=December 2022}}

==Overdose==

Symptoms and their severities are unknown, because flucytosine is used under close medical supervision, but expected to be an excess of the usually encountered [[adverse drug reaction|side effects]] on the [[bone marrow]], gastrointestinal tract, [[liver]] and [[kidney]] function. Vigorous hydration and [[hemodialysis]] may be helpful in removing the drug from the body. Hemodialysis is particular useful in patients with impaired renal function.{{cn|date=December 2022}}

==Pharmacology==

===Mechanisms of action===

Two major mechanisms of action have been elucidated:

* Flucytosine is intrafungally converted into the cytostatic fluorouracil<ref name="pmid10933638">{{cite journal | vauthors = Vermes A, Guchelaar HJ, Dankert J | title = Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions | journal = The Journal of Antimicrobial Chemotherapy | volume = 46 | issue = 2 | pages = 171–179 | date = August 2000 | pmid = 10933638 | doi = 10.1093/jac/46.2.171 | doi-access = free }}</ref> which undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis thus disturbing the building of certain essential proteins.

* Flucytosine also undergoes conversion into 5-fluorodeoxyuridinemonophosphate which inhibits fungal DNA synthesis.

=== Spectrum of susceptible fungi and resistance ===

Flucytosine is active ''in vitro'' as well as ''in vivo'' against some strains of ''[[Candida (genus)|Candida]]'' and ''[[Cryptococcus (fungus)|Cryptococcus]]''. Limited studies demonstrate that flucytosine may be of value against infections with ''[[Sporothrix]]'', ''[[Aspergillus]]'', ''[[Cladosporium]]'', ''[[Exophiala]]'', and ''[[Phialophora]]''.

Resistance is quite commonly seen as well in treatment-naive patients and under current treatment with flucytosine. In different strains of ''Candida'' resistance has been noted to occur in 1 to 50% of all specimens obtained from patients.{{cn|date=December 2022}}

=== Pharmacokinetic data ===

Flucytosine is well absorbed (75 to 90%) from the [[gastrointestinal tract]]. Intake with meals slows the absorption, but does not decrease the amount absorbed. Following an oral dose of 2&nbsp;grams peak serum levels are reached after approximately 6 hours. The time to peak level decreases with continued therapy. After 4 days peak levels are measured after 2 hours. The drug is eliminated renally. In normal patients flucytosine has reportedly a half-life of 2.5 to 6 hours. In patients with impaired renal function higher serum levels are seen and the drug tends to accumulate. The drug is mainly excreted unchanged in the urine (90% of an oral dose) and only traces are metabolized and excreted in the feces. Therapeutic serum levels range from 25 to 100&nbsp;μg/ml. Serum levels in excess of 100&nbsp;μg are associated with a higher incidence of side effects. Periodic measurements of serum levels are recommended for all patients and are a must in patients with renal damage.{{cn|date=December 2022}}

==Economics==

Although a generic, off patent medication in the U.S., as of January 2016, there was only one FDA-approved pharmaceutical supplier, [[Valeant Pharmaceuticals]]. Due to this monopoly, the cost per 250&nbsp;mg tablet was $70.46 per tablet for a daily treatment cost of ~$2110/day for a 75&nbsp;kg adult (165 pounds) adult and $29,591 for a two-week treatment course as of December 2015.<ref name=Mer2016/> This cost of flucytosine is more than 100-fold higher in the U.S. than in the United Kingdom and Europe via [[Meda AB]] Pharmaceuticals.

==Other animals==

In some countries, such as [[Switzerland]], flucytosine has been licensed to treat cats, dogs and birds (in most cases together with amphotericin B) for the same indications as in humans.{{cn|date=December 2022}}

== References ==

{{Reflist}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/flucytosine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Flucytosine }}

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