Diacerein: Difference between revisions

{{Short description|Chemical compound}}

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 443271804

| IUPAC_name = 4,5-diacetyloxy-9,10-dioxo-anthracene-2-<br>carboxylic&nbsp;acid

| image = Diacerein.svg

| alt = Structural formula of diacerein

| image2 = Diacerein 3D ball.png

| alt2 = Ball-and-stick model of the diacerein molecule

<!--Clinical data-->

| tradename =

| Drugs.com = {{drugs.com|international|diacerein}}

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

| pregnancy_category = Lacking information

| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->

| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| legal_status =

| routes_of_administration = Oral

<!--Pharmacokinetic data-->

| bioavailability =

| protein_bound = 99%

| metabolism = [[Liver|Hepatic]]: [[acetylation|deacetylation]] to [[Rhein (molecule)|rhein]], later [[glucuronidation]] and [[sulfate]] conjugation

| elimination_half-life = 4 to 5 hours

| excretion = [[Kidney|Renal]] (30%)

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 13739-02-1

| ATC_prefix = M01

| ATC_suffix = AX21

| PubChem = 26248

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB11994

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 4HU6J11EL5

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D07270

<!--Chemical data-->

| C=19 | H=12 | O=8

| smiles = O=C(Oc3cccc2C(=O)c1cc(cc(OC(=O)C)c1C(=O)c23)C(=O)O)C

| synonyms = <small>Diacetylrhein; Diacerhein; 2-Anthracenecarboxylic acid, 4,5-bis(acetyloxy)-9,10-dihydro-9,10-dioxo-; 2-Anthroic acid, 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-, diacetate; 9,10-Dihydro-4,5-dihydroxy-9,10-dioxo-2-anthroic acid, diacetate</small>

|drug_name=|caption=|type=|MedlinePlus=|licence_EU=|licence_US=|solubility=Practically insoluble in water 0.01}}

'''Diacerein''' ([[International Nonproprietary Name|INN]]), also known as '''diacetylrhein''', is a slow-acting medicine of the class [[anthraquinone]] used to treat joint diseases such as osteoarthritis (swelling and pain in the joints).<ref>{{cite book | first = Harry | last = Gouvas | name-list-style = vanc | title = Use of Sodium Hyaluronate in the treatment of Osteoarthritis | location = Greece | date = 2011 }}</ref> It works by inhibiting [[interleukin-1 beta]]. An updated 2014 [[Cochrane Collaboration|Cochrane]] [[systematic review|review]] found diacerein had a small beneficial effect on pain.<ref>{{cite journal | vauthors = Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moça Trevisani V | title = Diacerein for osteoarthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD005117 | date = February 2014 | pmid = 24515444 | doi = 10.1002/14651858.CD005117.pub3 | url = http://www.cochrane.org/CD005117/MUSKEL_diacerein-for-osteoarthritis | pmc = 10712695 }}</ref> Diacerein-containing medications are registered in some European Union and Asian countries{{which|date=November 2023}} and included as a treatment option on several international therapeutic guidelines.{{which|date=November 2023}}{{cn|date=November 2023}}

==Synthesis==

There are many known methods synthesis of diacerein, most of which use aloin as a starting material. It's hydroxyl groups undergo acetylation, and then the intermediates are oxidised with chromic anhydride using acetic acid as a solvent.<ref>{{Cite patent|country=|number=US8324411B2|title=Process for the preparation of DIACEREIN|status=|pubdate=2011-01-20|gdate=2012-12-04|invent1=Salvi|invent2=Nardi|invent3=Maiorana|invent4=Sada|inventor1-first=Annibale|inventor2-first=Antonio|inventor3-first=Stefano|inventor4-first=Mara|url=https://patents.google.com/patent/US8324411B2/en}}</ref>

A less common method uses [[rhein (molecule)|rhein]] as the starting compound. It involves di[[acetylation]] of the hydroxyl groups at positions C4 and C5 of rhein.<ref>{{Cite patent|number=EP0928781B1|title=Process for the preparation of rhein and its diacyl derivatives|status=|pubdate=1999-07-14|gdate=2002-03-27|invent1=Napoli|inventor1-first=Guido Di|url=https://patents.google.com/patent/EP0928781B1/en}}</ref>

==Pharmacology==

Diacerein works by blocking the actions of [[interleukin-1 beta]], a protein involved in the inflammation and destruction of [[cartilage]] that plays a role in the development of symptoms of degenerative joint diseases such as [[osteoarthritis]]. Due to its specific mode of action, which does not involve the inhibition of [[prostaglandin]] synthesis, diacerein has been shown to have anti-osteoarthritis and cartilage stimulating properties in vitro and animal models.{{Need Citation|date=February 2024|reason=No citation}}

The most common [[adverse drug reaction|side effects]] of diacerein treatment are [[gastrointestinal tract|gastrointestinal]] symptoms including soft stools and [[diarrhea]].<ref>Pavelka K, Bruyere O, Cooper C, et al. Diacerein: Benefits, Risks and Place in the Management of Osteoarthritis. An Opinion-Based Report from the ESCEO. Drugs & Aging 2016;33:75-85</ref> These are generally mild to moderate and occur more frequently in the first 2 weeks, and lessen with continued treatment. Based on review by European Medicines Agency (EMA), diacerein-containing medicines use is restricted due to severe diarrhoea and liver disorders in patients.<ref>{{cite journal | vauthors = Panova E, Jones G | s2cid = 13880003 | title = Benefit-risk assessment of diacerein in the treatment of osteoarthritis | journal = Drug Safety | volume = 38 | issue = 3 | pages = 245–52 | date = March 2015 | pmid = 25652235 | doi = 10.1007/s40264-015-0266-z }}</ref><ref>{{cite journal | vauthors = Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moça Trevisani V | title = Diacerein for osteoarthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD005117 | date = February 2014 | pmid = 24515444 | doi = 10.1002/14651858.CD005117.pub3 | pmc = 10712695 }}</ref>

An uncommon side effect is hepatic adverse events (most frequently reported as liver function test abnormalities). These have been described as mild/moderate cases of elevated liver enzymes in the blood.

Mild skin reactions (rash, pruritus and eczema) have also been reported with diacerein treatment.

Discoloration of urine (yellow or pink) is another side effect of diacerein. This effect is due to the elimination of rhein metabolites via the urine and no clinical significance has been found; it may also be dependent on general fluid intake.

==Special warning==

In 2014 the European Medicines Agency (EMA’s) Pharmacovigilance and Risk Assessment Committee (PRAC) performed a review of diacerein-containing medicines over concerns about its gastrointestinal and liver effects. As a result, the PRAC has introduced additional proposals to manage diacerein’s risks and was satisfied that with new restrictions diacerein’s benefit on pain outweighs the side effects for osteoarthritis treatment.<ref name = "Diacerein_EMA">{{cite web | url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Diacerein-containing_medicines_for_oral_administration/human_referral_prac_000010.jsp&mid=WC0b01ac05805c516f |title = Diacerein-containing medicines for oral administration|date = 2018-09-17}}</ref> The following recommendations have been made around the use of diacerein:

* Due to the potential complications that can occur as a result of [[diarrhea]] in older adults, diacerein is no longer recommended in patients aged 65 years and above.

* It is also advised that patients start treatment on half the normal dose (i.e. 50&nbsp;mg daily instead of 100&nbsp;mg daily), and should stop taking diacerein if [[diarrhea]] occurs.

* It should not be used in any patient with liver disease or a history of liver disease, and doctors should be monitoring their patients for early signs of liver problems.

* The use of diacerein is to be limited to treating symptoms of osteoarthritis affecting the hip or knee.

* Diacerein should not be administered during pregnancy and lactation.

The PRAC concluded that the benefit-risk balance of diacerein-containing medicinal products remained favourable in the symptomatic treatment osteoarthritis, subject to the agreed changes to the product information and conditions.

==Dosage and administration==

The recommended starting dose is 50&nbsp;mg once daily with evening meal for the first 2 to 4 weeks of treatment, after which the recommended daily dose is 50&nbsp;mg twice daily.<ref name = "Diacerein_EMA" />

The treatment should be taken with food, one with breakfast and the other with evening meal. The capsules must be swallowed intact, without opening them, together with a glass of water.

== See also ==

* [[Rhein (molecule)|Rhein]]

== References ==

{{Reflist}}

{{Anti-inflammatory and antirheumatic products}}

[[Category:Anti-inflammatory agents]]

[[Category:Anthraquinones]]

[[Category:Carboxylic acids]]

[[Category:Acetate esters]]