Tiludronic acid: Difference between revisions

{{Short description|Chemical compound}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 376280932

| image = Tiludronic acid.svg

| alt =

<!--Clinical data-->

| tradename = Skelid

| Drugs.com = {{drugs.com|international|tiludronic-acid}}

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

| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->

| legal_CA = Rx-only

| legal_CA_comment =

| legal_UK = <!-- GSL / P / POM / CD -->

| legal_US = <!-- OTC / Rx-only -->

<!--Identifiers-->

| IUPHAR_ligand = 7604

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

| CAS_number = 89987-06-4

| ATC_prefix = M05

| ATC_suffix = BA05

| PubChem = 60937

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB01133

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = 6PNS59HP4Y

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D08599

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1350

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 54905

<!--Chemical data-->

| IUPAC_name = {[(4-Chlorophenyl)thio]methylene}bis(phosphonic acid)

| C=7 | H=9 | Cl=1 | O=6 | P=2 | S=1

| smiles = c1cc(ccc1SC(P(=O)(O)O)P(=O)(O)O)Cl

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C7H9ClO6P2S/c8-5-1-3-6(4-2-5)17-7(15(9,10)11)16(12,13)14/h1-4,7H,(H2,9,10,11)(H2,12,13,14)

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = DKJJVAGXPKPDRL-UHFFFAOYSA-N

'''Tiludronic acid''' ([[International Nonproprietary Name|INN]]; also known as tiludronate) is a [[bisphosphonate]] used for treatment of [[Paget's disease of bone]] (osteitis deformans) in human being medicine. It has the tradename '''Skelid'''. In veterinary medicine, tiludronic acid is used to treat [[navicular disease]] and [[bone spavin]] in horses. Its tradenames are '''Tildren''' and '''Equidronate'''. It is approved for treatment of navicular disease and distal, tarsal osteoarthritis in Europe,<ref>{{cite journal | vauthors = Kamm L, McIlwraith W, Kawcak C | title = A review of the Efficacy of Tiludronate in the Horse. | journal = Journal or Equine Veterinary Science | year = 2008 | volume = 28 | issue = 4 | pages = 209–214 | doi = 10.1016/j.jevs.2008.02.007 }}</ref> and was approved for treatment of navicular disease in the United States in 2014.

==Mechanism of action==

Tiludronate is a non-nitrogenous bisphosphonate that inhibits [[osteoclast]]s, the primary cell responsible for the breakdown of bone required for [[bone remodeling]]. Non-nitrogenous bisphosphonates are metabolized by osteoclasts to compounds that then replace a portion of the [[adenosine triphosphate]] (ATP) molecule, making it non-functional. These non-functional molecules then competitively inhibit ATP in the cell, reducing cell energy and leading to [[apoptosis]].<ref>{{cite journal | vauthors = Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J | title = Biochemical and molecular mechanisms of action of bisphosphonates | journal = Bone | volume = 49 | issue = 1 | pages = 34–41 | date = July 2011 | pmid = 21111853 | doi = 10.1016/j.bone.2010.11.008 }}</ref> Decreased levels of osteoclasts subsequently reduce the degree of breakdown of bone and bone turnover. Non-nitrogenous bisphosphonates are less potent than nitrogenous bisphosphonates.

{| class="wikitable"

|+Relative potency<ref>{{Cite book|title=Essentials of medical pharmacology | vauthors = Tripathi KD |isbn=9789350259375|edition= Seventh|location=New Delhi|oclc=868299888|date = 2013-09-30}}</ref>

!Bisphosphonate

!Relative potency

|-

|[[Etidronic acid|Etidronate]]

|1

|-

|Tiludronate

|10

|-

|[[Pamidronic acid|Pamidronate]]

|100

|-

|[[Alendronic acid|Aledronate]]

|100-500

|-

|[[Ibandronic acid|Ibandronate]]

|500-1000

|-

|[[Risedronic acid|Risedronate]]

|1000

|-

|[[Zoledronic acid|Zoledronate]]

|5000

|}

==Use in equine medicine==

Tiludronate has been used primarily for the treatment of diseases in horses that are associated with inappropriate osteolysis, such as [[navicular disease]]<ref>{{cite journal | vauthors = Denoix JM, Thibaud D, Riccio B | title = Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind placebo-controlled clinical trial | journal = Equine Veterinary Journal | volume = 35 | issue = 4 | pages = 407–13 | date = June 2003 | pmid = 12880010 | doi = 10.2746/042516403776014226 }}</ref> and osteoarthritis. It has specifically been shown to improve lameness in horses with osteoarthritis of the distal hock joints ([[bone spavin]])<ref>{{cite journal | vauthors = Gough MR, Thibaud D, Smith RK | title = Tiludronate infusion in the treatment of bone spavin: a double blind placebo-controlled trial | journal = Equine Veterinary Journal | volume = 42 | issue = 5 | pages = 381–7 | date = July 2010 | pmid = 20636772 | doi = 10.1111/j.2042-3306.2010.00120.x | url = http://researchonline.rvc.ac.uk/id/eprint/4274/ }}</ref> and vertebral column.<ref>{{cite journal | vauthors = Coudry V, Thibaud D, Riccio B, Audigié F, Didierlaurent D, Denoix JM | title = Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column | journal = American Journal of Veterinary Research | volume = 68 | issue = 3 | pages = 329–37 | date = March 2007 | pmid = 17331024 | doi = 10.2460/ajvr.68.3.329 }}</ref>

===Method of administration===

Tildren is administered intravenously. It is labeled for 0.1&nbsp;mg/kg dosing, once daily for 10 days by slow intravenous injection, which for a 500&nbsp;kg horse works out to be 1 vial per day. However, one study giving all 10 doses at once (1&nbsp;mg/kg IV as a single CRI) was found to have the same pharmacological effects, and is used clinically.<ref>{{cite journal | vauthors = Delguste C, Amory H, Guyonnet J, Thibaud D, Garnero P, Detilleux J, Lepage OM, Doucet M | display-authors = 6 | title = Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1 | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 31 | issue = 2 | pages = 108–16 | date = April 2008 | pmid = 18307502 | doi = 10.1111/j.1365-2885.2007.00936.x | url = http://orbi.ulg.ac.be/handle/2268/93885 }}</ref> It may be given systemically or locally, by [[limb perfusion|regional limb perfusion]]. Although RLP is thought to have certain benefits, including decreased cost and reduced risk of adverse effects, some diseases must be treated systemically, such as osteoarthritis of the vertebral column. Systemic administration is often given by adding a 1&nbsp;mg/kg dose into a 1-liter fluid bag, which is slowly given over 60–90 minutes. Its effects are reported to last 4 months or longer, with a peak effect 6–8 weeks post treatment.<ref name="AAEP">{{cite journal | vauthors = Allen KA, Johns S, Hyman SS, Sislak MD, Davis S, Amory J | title = How to Diagnose and Treat Back Pain in the Horse. | journal = AAEP Proceedings | date = December 2010 | volume = 56 | pages = 384–388 | url = http://www.pulsevet.com/wp-content/uploads/2016/04/KentAllen_Backs2010AAEP.pdf }}</ref> The effects of regional limb perfusion has come into question due to in vitro studies showing that high doses given by RLP or intraarticular injection may damage articular cartilage by chondrocyte apoptosis.<ref>{{cite journal | vauthors = Duesterdieck-Zellmer KF, Driscoll N, Ott JF | title = Concentration-dependent effects of tiludronate on equine articular cartilage explants incubated with and without interleukin-1β | journal = American Journal of Veterinary Research | volume = 73 | issue = 10 | pages = 1530–9 | date = October 2012 | pmid = 23013178 | doi = 10.2460/ajvr.73.10.1530 | doi-access = free }}</ref> Further studies are needed to evaluate the safety of Tildren administration via RLP.

===Adverse reactions and contraindications===

Tildren has been shown to have several adverse effects.<ref>{{cite web|last1=U.S. Food and Drug Administration.|title=FDA Provides Equine Veterinarians with Important Information about TILDREN and OSPHOS for Navicular Syndrome in Horses|url=http://fda.gov|access-date=3 January 2015}}</ref>

* Signs of [[horse colic|colic]], which is usually self-limiting, occurs in 30-45% of horses.

* [[Tachycardia]]

* Electrolyte disturbances: primarily calcium, magnesium, and potassium, which can last for several hours. Caution should be used in horses with disease processes that could be affected by electrolyte disturbances, such as [[hyperkalemic periodic paralysis (equine)|hyperkalemic periodic paralysis]] or cardiac disease.

* [[Nephropathy|Kidney damage]]: it is eliminated by the kidney and is not recommended for use in animals with impaired renal function.

* Less serious reactions include stiffness of the neck, decreased appetite, fever, and increased urination.

It is not recommended for animals under four years of age, due to lack of studies evaluating its safety in growing animals, nor for pregnant or lactating animals, since its effect on the fetus has not been studied.

== References ==

{{Reflist}}

== External links ==

* [http://products.sanofi-aventis.us/skelid/skelid.html Prescribing information for Skelid]

* [http://www.rxlist.com/cgi/generic2/tiludronate.htm RxList page]

* [http://www.tildren.com tildren.com]

{{Bisphosphonates}}

[[Category:Bisphosphonates]]

[[Category:Equine medications]]