Tiagabine: Difference between revisions

Browse history interactively ← Previous editContent deleted Content addedVisual WikitextInline

Revision as of 11:43, 7 November 2011 editCheMoBot (talk \| contribs)Bots141,565 edits Updating {{drugbox}} (changes to verified fields - added verified revid - updated 'ChEBI_Ref') per Chem/Drugbox validation (report errors or bugs)← Previous edit		Latest revision as of 13:33, 8 November 2024 edit undoKaustubh 808 (talk \| contribs)10 editsm Edited distinguishing note
(88 intermediate revisions by 55 users not shown)
Line 1:		Line 1:
			{{Short description\|Anticonvulsant medication}}
			{{cs1 config\|name-list-style=vanc}}
			{{distinguish\|Tianeptine\|Tiapride}}
	{{Drugbox		{{Drugbox
		⚫	\| verifiedrevid = 470609936
	\| Verifiedfields = changed
		⚫	\| IUPAC_name = (−)-(3''R'')-1--3-piperidinecarboxylic acid
⚫	\| verifiedrevid = ~~459442232~~
			\| image = Tiagabine.svg
⚫	\| IUPAC_name = (''R'')-1- ~~piperidine~~-3-~~carboxylic~~ acid
			\| width = 250
	\| image = Tiagabin Structural Formulae.png

	<!--Clinical data-->		<!--Clinical data-->
	\| tradename = Gabitril		\| tradename = Gabitril
	\| Drugs.com = {{drugs.com\|monograph\|tiagabine-hydrochloride}}		\| Drugs.com = {{drugs.com\|monograph\|tiagabine-hydrochloride}}
			\| pronounce = {{IPAc-en\|t\|aɪ\|ˈ\|æ\|ɡ\|ə\|b\|iː\|n}}
	\| MedlinePlus = a698014		\| MedlinePlus = a698014
			\| pregnancy_AU = B3
	\| pregnancy_category = B3 <small>(])</small>, C <small>(])</small>
			\| pregnancy_US = C
	\| legal_status = ] <small>(])</small>, ℞-only <small>(U.S.)</small>
			\| legal_AU = S4
⚫	\| routes_of_administration = Oral
			\| legal_BR = C1
			\| legal_BR_comment = <ref>{{Cite web \|author=Anvisa \|author-link=Brazilian Health Regulatory Agency \|date=2023-03-31 \|title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial \|trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control\|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 \|url-status=live \|archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 \|archive-date=2023-08-03 \|access-date=2023-08-16 \|publisher=] \|language=pt-BR \|publication-date=2023-04-04}}</ref>
			\| legal_CA = Rx-only
			\| legal_UK = POM
			\| legal_US = Rx-only
		⚫	\| routes_of_administration = Oral (])

	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
			\| bioavailability = 90–95%<ref name="LemkeWilliams2012">{{cite book\| vauthors = Leduc B \| chapter = Antiseizure Drugs \| veditors = Lemke TL, Williams DA \|title=Foye's Principles of Medicinal Chemistry\| chapter-url= https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA562\|date=24 January 2012\|publisher=Lippincott Williams & Wilkins\|isbn=978-1-60913-345-0\|pages=562–}}</ref>
	\| bioavailability = 90%
	\| protein_bound = 96%		\| protein_bound = 96%<ref name="LemkeWilliams2012" />
	\| metabolism = ] (] system)		\| metabolism = ] (] system,<ref name="LemkeWilliams2012" /> primarily ])<ref name="PI">{{cite web\|title=Gabitril (tiagabine hydrochloride) Tablets. U.S. Full Prescribing Information\|url=http://www.gabitril.com/Gabitril_PI.pdf\|publisher=Cephalon, Inc.\|access-date=8 April 2016}}</ref>
			\| onset = ] = 45 min<ref name="PI" />
	\| elimination_half-life = 7-9 hours
			\| elimination_half-life = 5–8 hours<ref name="Brodie1995">{{cite journal \| vauthors = Brodie MJ \| title = Tiagabine pharmacology in profile \| journal = Epilepsia \| volume = 36 \| issue = Suppl 6 \| pages = S7–S9 \| year = 1995 \| pmid = 8595791 \| doi = 10.1111/j.1528-1157.1995.tb06015.x \| s2cid = 27336198 }}</ref>
	\| excretion = Fecal and ]		\| excretion = ] (63%) and ] (25%)<ref name="PI" />

	<!--Identifiers-->		<!--Identifiers-->
			\| IUPHAR_ligand = 4685
	\| CASNo_Ref = {{cascite\|correct\|CAS}}
	\| CAS_number_Ref = {{cascite\|correct\|??}}		\| CAS_number_Ref = {{cascite\|correct\|??}}
	\| CAS_number = 115103-54-3		\| CAS_number = 115103-54-3
Line 27:		Line 38:
	\| ATC_suffix = AG06		\| ATC_suffix = AG06
	\| PubChem = 60648		\| PubChem = 60648
	\| DrugBank_Ref = {{drugbankcite\|~~changed~~\|drugbank}}		\| DrugBank_Ref = {{drugbankcite\|correct\|drugbank}}
	\| DrugBank = ~~APRD00344~~		\| DrugBank = DB00906
	\| ChemSpiderID_Ref = {{chemspidercite\|correct\|chemspider}}		\| ChemSpiderID_Ref = {{chemspidercite\|correct\|chemspider}}
	\| ChemSpiderID = 54661		\| ChemSpiderID = 54661
Line 35:		Line 46:
	\| KEGG_Ref = {{keggcite\|correct\|kegg}}		\| KEGG_Ref = {{keggcite\|correct\|kegg}}
	\| KEGG = D08588		\| KEGG = D08588
			\| ChEBI = 9586
	\| ChEMBL_Ref = {{ebicite\|correct\|EBI}}		\| ChEMBL_Ref = {{ebicite\|correct\|EBI}}
	\| ChEMBL = 1027		\| ChEMBL = 1027

	<!--Chemical data-->		<!--Chemical data-->
	\| C=20 \| H=25 \| N=1 \| O=2 \| S=2		\| C=20 \| H=25 \| N=1 \| O=2 \| S=2
		⚫	\| SMILES = O=C(O)1CN(CCC1)CC/C=C(/c2sccc2C)c3sccc3C
	\| molecular_weight = 375.55 ]/]
⚫	\| ~~smiles~~ = O=C(O)1CN(CCC1)CC/C=C(/c2sccc2C)c3sccc3C
	\| InChI = 1/C20H25NO2S2/c1-14-7-11-24-18(14)17(19-15(2)8-12-25-19)6-4-10-21-9-3-5-16(13-21)20(22)23/h6-8,11-12,16H,3-5,9-10,13H2,1-2H3,(H,22,23)/t16-/m1/s1
	\| InChIKey = PBJUNZJWGZTSKL-MRXNPFEDBV
	\| StdInChI_Ref = {{stdinchicite\|correct\|chemspider}}		\| StdInChI_Ref = {{stdinchicite\|correct\|chemspider}}
	\| StdInChI = 1S/C20H25NO2S2/c1-14-7-11-24-18(14)17(19-15(2)8-12-25-19)6-4-10-21-9-3-5-16(13-21)20(22)23/h6-8,11-12,16H,3-5,9-10,13H2,1-2H3,(H,22,23)/t16-/m1/s1		\| StdInChI = 1S/C20H25NO2S2/c1-14-7-11-24-18(14)17(19-15(2)8-12-25-19)6-4-10-21-9-3-5-16(13-21)20(22)23/h6-8,11-12,16H,3-5,9-10,13H2,1-2H3,(H,22,23)/t16-/m1/s1
Line 50:		Line 59:
	}}		}}

	'''Tiagabine''' (~~{{IPAc-en\|icon\|t\|aɪ\|ˈ\|æ\|ɡ\|ə\|b\|iː\|n}}~~ is an ] ] produced by ] ~~and~~ ~~marketed~~ ~~under the brand name '''Gabitril'''. The drug was discovered at Novo Nordisk~~ in ~~Denmark~~ ~~in 1988 and was co-developed with Abbott. After a period~~ of ~~co-promotion, Cephalon licensed Tiagabine from Abbott/Novo and now is the exclusive producer~~. The ~~medication~~ is also used in the treatment of ], as ~~are~~ ~~a few other anticonvulsants~~.		'''Tiagabine''' (trade name '''Gabitril''') is an ] ] produced by ] that is used in the treatment of ]. The drug is also used ] in the treatment of ]s and ].

	==~~Indications~~==		==Medical uses==
	Tiagabine is approved by U.S. ] (FDA) as an adjunctive treatment for partial ] in ~~ages~~ 12 and up. It may also be prescribed to treat ] and ] (including ]). For anxiety and neuropathic pain, tiagabine is used primarily to augment other treatments. Tiagabine may be used alongside ], ] or ] for anxiety, or ], ], ] or ] for neuropathic pain. <ref name="Stahl">Stahl, S. Stahl's ~~Essential~~ ~~Psychopharmacology~~: ~~Prescriber~~'s ~~Guide.~~ Cambridge University Press: New York, NY. ~~2009~~. pp. ~~523~~-~~526~~</ref>		Tiagabine is approved by U.S. ] (FDA) as an adjunctive treatment for partial ] in individuals of age 12 and up. It may also be prescribed off-label by physicians to treat anxiety disorders and panic disorder as well as ] (including ]). For anxiety and neuropathic pain, tiagabine is used primarily to augment other treatments. Tiagabine may be used alongside ]s, ]s, or ]s for anxiety, or ]s, ], other anticonvulsants, or ]s for neuropathic pain.<ref name="Stahl">{{cite book \| vauthors = Stahl SM \|title=Stahl's essential psychopharmacology: the prescriber's guide; antipsychotics and mood stabilizers \|date=2009 \|publisher=Cambridge University Press \|location=New York, NY \|isbn=978-0-521-75900-7 \|edition=3rd \| pages = 523–526 }}</ref> It is effective as monotherapy and combination therapy with other antiepileptic drugs in the treatment of partial seizure.<ref name=":0">{{Citation\| title=Tiagabine \|date=2012 \|url=http://www.ncbi.nlm.nih.gov/books/NBK548376/\|work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury\|place=Bethesda (MD)\|publisher=National Institute of Diabetes and Digestive and Kidney Diseases\|pmid=31643697\|access-date=2021-12-24}}</ref>

			The ]'s 2017 ]s recommended against the use of tiagabine in the treatment of insomnia due to poor effectiveness and very low ].<ref name="pmid27998379">{{cite journal \| vauthors = Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL \| title = Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline \| journal = Journal of Clinical Sleep Medicine \| volume = 13 \| issue = 2 \| pages = 307–349 \| date = February 2017 \| pmid = 27998379 \| pmc = 5263087 \| doi = 10.5664/jcsm.6470 }}</ref>

			==Side effects==
			Side effects of tiagabine are dose related.<ref name=":0" /> The most common ] of tiagabine is ].<ref name="Leppik1995">{{cite journal \| vauthors = Leppik IE \| title = Tiagabine: the safety landscape \| journal = Epilepsia \| volume = 36 \| issue = Suppl 6 \| pages = S10–S13 \| year = 1995 \| pmid = 8595787 \| doi = 10.1111/j.1528-1157.1995.tb06009.x \| s2cid = 24203401 }}</ref> Other side effects that have been observed with a rate of statistical significance relative to ] include ], ], nervousness, ], ], ], ], and ].<ref name="Leppik1995" /><ref name="EadieVajda2012">{{cite book\| vauthors = Eadie MJ, Vajda F \|title=Antiepileptic Drugs: Pharmacology and Therapeutics\|url=https://books.google.com/books?id=8iv6CAAAQBAJ&pg=PA459\|date=6 December 2012\|publisher=Springer Science & Business Media\|isbn=978-3-642-60072-2\|pages=459–}}</ref> Adverse effects such as ], ] (difficulty speaking clearly)/], and ] (a tingling sensation in the body's extremities, particularly the hands and fingers) may occur at higher dosages of the drug (e.g., over 8 mg/day).<ref name="Leppik1995" /> Tiagabine may induce ] in those without ], particularly if they are taking another drug which lowers the ].<ref name="Stahl" /> There may be an increased risk of ] with tiagabine treatment, although data is mixed and inconclusive.<ref name="LemkeWilliams2012" /><ref name="Aronson2009">{{cite book \| chapter = Antihistamines \| veditors = Aronson JK \|title=Meyler's Side Effects of Psychiatric Drugs\| chapter-url = https://books.google.com/books?id=AmYFTSO8jCkC&pg=PA652 \|year=2009 \|publisher=Elsevier \|isbn=978-0-444-53266-4\|pages=652–}}</ref> Tiagabine can also reportedly interfere with visual ].<ref name="LemkeWilliams2012" />

			== Warning ==

			* CNS depression
			* Dermatologic reactions
			* Generalized weakness
			* Ophthalmic effects
			* Suicidal ideation<ref>{{cite journal \| vauthors = Pellock JM \| title = Tiagabine (gabitril) experience in children \| journal = Epilepsia \| volume = 42 \| issue = Suppl 3 \| pages = 49–51 \| date = 2001-12-20 \| pmid = 11520324 \| doi = 10.1046/j.1528-1157.2001.042suppl.3049.x \| s2cid = 23614412 \| doi-access = free }}</ref>

			==Overdose==
			Tiagabine ] can produce neurological symptoms such as ], single or multiple ]s, ], ], ], ], ]s, ], ]s/], and ]s, as well as ], ], ], and ].<ref name="SpillerWinter2009">{{cite journal \| vauthors = Spiller HA, Winter ML, Ryan M, Krenzelok EP, Anderson DL, Thompson M, Kumar S \| title = Retrospective evaluation of tiagabine overdose \| journal = Clinical Toxicology \| volume = 43 \| issue = 7 \| pages = 855–859 \| year = 2009 \| pmid = 16440513 \| doi = 10.1080/15563650500357529 \| s2cid = 25469390 }}</ref> Overdose may be fatal especially if the victim presents with severe respiratory depression and/or unresponsiveness.<ref name="SpillerWinter2009" />

	==Pharmacology==		==Pharmacology==
	It ~~is believed that the pharmacology is related to its ability, documented in in vitro experiments, to enhance~~ the ~~activity~~ of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system~~. These experiments have shown that tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that~~, by ~~this~~ ~~action, tiagabine blocks~~ GABA ~~uptake~~ ~~into~~ ~~presynaptic neurons~~, ~~permitting~~ ~~more GABA to be available for receptor binding on the surfaces of post-synaptic cells. Evidence~~ is ~~available that it operates~~ as a ~~selective~~ ].<ref name="pmid16420077">{{cite journal \|~~author~~=Pollack MH, Roy-Byrne PP, Van Ameringen M, ~~''et~~ ~~al.''~~ \|title=The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study \|journal=The Journal of ~~clinical~~ ~~psychiatry~~ \|volume=66 \|issue=11 \|pages=~~1401–8~~ \|~~year~~=2005 \|~~month=November~~ \|pmid=16420077 \|doi= 10.4088/JCP.v66n1109~~\|url=http://article.psychiatrist.com/?ContentType=START&ID=10001907~~}}</ref>		Tiagabine increases the level of ] (GABA), the major inhibitory ] in the ], by blocking the ] (GAT-1), and hence is classified as a ] (GRI).<ref name="Brodie1995" /><ref name="pmid16420077">{{cite journal \| vauthors = Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, Rickels K \| title = The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study \| journal = The Journal of Clinical Psychiatry \| volume = 66 \| issue = 11 \| pages = 1401–1408 \| date = November 2005 \| pmid = 16420077 \| doi = 10.4088/JCP.v66n1109 }}</ref>

	== ~~Side effects~~ ==		== Pharmacodynamics ==
			Tiagabine is primarily used as an anticonvulsant in the treatment of epilepsy as a supplement. Although the exact mechanism by which Tiagabine exerts its antiseizure effect is unknown, it is thought to be related to its ability to increase the activity of gamma aminobutyric acid (GABA), the central nervous system's major inhibitory neurotransmitter. Tiagabine attaches to the GABA uptake carrier's recognition sites. Tiagabine is thought to block GABA uptake into presynaptic neurons as a result of this action, allowing more GABA to be available for receptor binding on the surfaces of post-synaptic cells.<ref>{{Cite web\|title=Gabitril (tiagabine) dosing, indications, interactions, adverse effects, and more\|url=https://reference.medscape.com/drug/gabitril-tiagabine-343022#91\|access-date=2021-12-24\|website=reference.medscape.com}}</ref>
	Tiagabine's most common side effects include confusion, difficulty speaking clearly/stuttering, mild sedation, and in doses over 8 mg, a tingling sensation (]) in the body's extremities, particularly the hands and fingers. Tiagabine may induce ] in those without ], especially if they are taking another drug which lowers the seizure threshold.<ref name="Stahl" />

			== Effects on cortical delta oscillations ==
	With overdoses in the range of 20-40 mg or more it will cause extreme sedation, temporary retardation, muscle tremors and spasms, uncontrollable bodily tremors, retrograde and anterograde amnesia, thrashing, screaming, flailing and extreme hostility, unconsciousness with seizures or seizure-like symptoms. Upon consciousness: extreme confusion with an inability to form coherent sentences, express ideas, or do the most basic activities for several hours. {{Or\|date=May 2009}} Unlike the ] Tiagabine (Gabitril) has been shown to have no recreation value and any euphoria is most likely a placebo effect or because of consumption with alcohol.
			Tiagabine enhances the power of cortical ] (< 4 Hz) oscillations up to 1000% relative to placebo, which may result in an ] or ] signature resembling ] even while the person who has taken tiagabine is awake and conscious.<ref>{{cite journal \| vauthors = Frohlich J, Mediano PA, Bavato F, Gharabaghi A \| title = Paradoxical pharmacological dissociations result from drugs that enhance delta oscillations but preserve consciousness \| journal = Communications Biology \| volume = 6 \| issue = 1 \| pages = 654 \| date = June 2023 \| pmid = 37340024 \| doi = 10.1038/s42003-023-04988-8 \| pmc = 10282051 }}</ref> This demonstrates that cortical delta activity and wakeful consciousness are not mutually exclusive, i.e., high amplitude delta oscillations are not always a reliable indicator of unconsciousness.
			] ] power in healthy volunteers.]]

			== Monitoring Parameters ==
	==Synthesis==
			Seizure frequency, liver function tests, suicidality<ref>{{cite journal \| vauthors = Adkins JC, Noble S \| title = Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy \| journal = Drugs \| volume = 55 \| issue = 3 \| pages = 437–460 \| date = March 1998 \| pmid = 9530548 \| doi = 10.2165/00003495-199855030-00013 \| s2cid = 70426629 }}</ref>
	]

			== History ==
	{{Cite journal\|doi=10.1021/jm00064a005\|title=The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1--3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate\|pmid=8510100\|year=1993\|last1=Andersen\|first1=Knud Erik\|last2=Braestrup\|first2=Claus\|last3=Groenwald\|first3=Frederik C.\|last4=Joergensen\|first4=Anker S.\|last5=Nielsen\|first5=Erik B.\|last6=Sonnewald\|first6=Ursula\|last7=Soerensen\|first7=Per O.\|last8=Suzdak\|first8=Peter D.\|last9=Knutsen\|first9=Lars J. S.\|journal=Journal of Medicinal Chemistry\|volume=36\|issue=12\|pages=1716}}
			Tiagabine was discovered at ] in Denmark in 1988 by a team of ] and ] under the general direction of Claus Bræstrup.<ref name="Andersen_1993">{{cite journal \| vauthors = Andersen KE, Braestrup C, Grønwald FC, Jørgensen AS, Nielsen EB, Sonnewald U, Sørensen PO, Suzdak PD, Knutsen LJ \| display-authors = 6 \| title = The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1--3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate \| journal = Journal of Medicinal Chemistry \| volume = 36 \| issue = 12 \| pages = 1716–1725 \| date = June 1993 \| pmid = 8510100 \| doi = 10.1021/jm00064a005 }}</ref> The drug was co-developed with ], in a 40/60 cost sharing deal, with Abbott paying a premium for licensing the IP from the Danish company.{{citation needed\|date=October 2014}}

			U.S. patents on tiagabine listed in the ] expired in April 2016.<ref>{{cite web \| title = Search Results for Tiagabine \| work = Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations \| publisher = U.S. Food and Drug Administration \| url = http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020646&TABLE1=OB_Rx \| archive-url = https://web.archive.org/web/20160422163656/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020646&TABLE1=OB_Rxx \| archive-date = 22 April 2016 \| access-date = 22 March 2016 }}</ref>
⚫	==References==
	{{reflist}}

	== ~~External~~ ~~links~~ ==		== See also ==
			* ]
⚫	* (manufacturer's website)
			* ]
	*
			* ]
			* ]

		⚫	== References ==
			{{Reflist}}

			== External links ==
		⚫	* (manufacturer's website)

	{{Anticonvulsants}}		{{Anticonvulsants}}
	{{Anxiolytics}}		{{Anxiolytics}}
			{{GABA metabolism and transport modulators}}
	{{Mood stabilizers}}
	{{Bipolar disorder}}
	{{GABAergics}}

			]
	]		]
		⚫	]
			]
	]		]
⚫	]
	]		]
	]		]

	]
	]

Latest revision as of 13:33, 8 November 2024

Anticonvulsant medication

Not to be confused with Tianeptine or Tiapride. Pharmaceutical compound

Tiagabine
Clinical data

Pronunciation	/taɪˈæɡəbiːn/
Trade names	Gabitril
AHFS/Drugs.com	Monograph
MedlinePlus	a698014
Pregnancy category	AU: B3
Routes of administration	Oral (tablets)
ATC code	N03AG06 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	90–95%
Protein binding	96%
Metabolism	Hepatic (CYP450 system, primarily CYP3A)
Onset of action	Tmax = 45 min
Elimination half-life	5–8 hours
Excretion	Fecal (63%) and renal (25%)
Identifiers
IUPAC name (−)-(3R)-1--3-piperidinecarboxylic acid
CAS Number	115103-54-3
PubChem CID	60648
IUPHAR/BPS	4685
DrugBank	DB00906
ChemSpider	54661
UNII	Z80I64HMNP
KEGG	D08588
ChEBI	CHEBI:9586
ChEMBL	ChEMBL1027
CompTox Dashboard (EPA)	DTXSID5023663
Chemical and physical data
Formula	C₂₀H₂₅NO₂S₂
Molar mass	375.55 g·mol
3D model (JSmol)	Interactive image
SMILES O=C(O)1CN(CCC1)CC/C=C(/c2sccc2C)c3sccc3C
InChI InChI=1S/C20H25NO2S2/c1-14-7-11-24-18(14)17(19-15(2)8-12-25-19)6-4-10-21-9-3-5-16(13-21)20(22)23/h6-8,11-12,16H,3-5,9-10,13H2,1-2H3,(H,22,23)/t16-/m1/s1 Key:PBJUNZJWGZTSKL-MRXNPFEDSA-N
(verify)

Tiagabine (trade name Gabitril) is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. The drug is also used off-label in the treatment of anxiety disorders and panic disorder.

Medical uses

Tiagabine is approved by U.S. Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures in individuals of age 12 and up. It may also be prescribed off-label by physicians to treat anxiety disorders and panic disorder as well as neuropathic pain (including fibromyalgia). For anxiety and neuropathic pain, tiagabine is used primarily to augment other treatments. Tiagabine may be used alongside selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or benzodiazepines for anxiety, or antidepressants, gabapentin, other anticonvulsants, or opioids for neuropathic pain. It is effective as monotherapy and combination therapy with other antiepileptic drugs in the treatment of partial seizure.

The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of tiagabine in the treatment of insomnia due to poor effectiveness and very low quality of evidence.

Side effects

Side effects of tiagabine are dose related. The most common side effect of tiagabine is dizziness. Other side effects that have been observed with a rate of statistical significance relative to placebo include asthenia, somnolence, nervousness, memory impairment, tremor, headache, diarrhea, and depression. Adverse effects such as confusion, aphasia (difficulty speaking clearly)/stuttering, and paresthesia (a tingling sensation in the body's extremities, particularly the hands and fingers) may occur at higher dosages of the drug (e.g., over 8 mg/day). Tiagabine may induce seizures in those without epilepsy, particularly if they are taking another drug which lowers the seizure threshold. There may be an increased risk of psychosis with tiagabine treatment, although data is mixed and inconclusive. Tiagabine can also reportedly interfere with visual color perception.

Warning

CNS depression
Dermatologic reactions
Generalized weakness
Ophthalmic effects
Suicidal ideation

Overdose

Tiagabine overdose can produce neurological symptoms such as lethargy, single or multiple seizures, status epilepticus, coma, confusion, agitation, tremors, dizziness, dystonias/abnormal posturing, and hallucinations, as well as respiratory depression, tachycardia, hypertension, and hypotension. Overdose may be fatal especially if the victim presents with severe respiratory depression and/or unresponsiveness.

Pharmacology

Tiagabine increases the level of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, by blocking the GABA transporter 1 (GAT-1), and hence is classified as a GABA reuptake inhibitor (GRI).

Pharmacodynamics

Tiagabine is primarily used as an anticonvulsant in the treatment of epilepsy as a supplement. Although the exact mechanism by which Tiagabine exerts its antiseizure effect is unknown, it is thought to be related to its ability to increase the activity of gamma aminobutyric acid (GABA), the central nervous system's major inhibitory neurotransmitter. Tiagabine attaches to the GABA uptake carrier's recognition sites. Tiagabine is thought to block GABA uptake into presynaptic neurons as a result of this action, allowing more GABA to be available for receptor binding on the surfaces of post-synaptic cells.

Effects on cortical delta oscillations

Tiagabine enhances the power of cortical delta (< 4 Hz) oscillations up to 1000% relative to placebo, which may result in an EEG or MEG signature resembling non-rapid eye movement sleep even while the person who has taken tiagabine is awake and conscious. This demonstrates that cortical delta activity and wakeful consciousness are not mutually exclusive, i.e., high amplitude delta oscillations are not always a reliable indicator of unconsciousness.

Monitoring Parameters

Seizure frequency, liver function tests, suicidality

History

Tiagabine was discovered at Novo Nordisk in Denmark in 1988 by a team of medicinal chemists and pharmacologists under the general direction of Claus Bræstrup. The drug was co-developed with Abbott Laboratories, in a 40/60 cost sharing deal, with Abbott paying a premium for licensing the IP from the Danish company.

U.S. patents on tiagabine listed in the Orange Book expired in April 2016.

References

Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
^ Leduc B (24 January 2012). "Antiseizure Drugs". In Lemke TL, Williams DA (eds.). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 562–. ISBN 978-1-60913-345-0.
^ "Gabitril (tiagabine hydrochloride) Tablets. U.S. Full Prescribing Information" (PDF). Cephalon, Inc. Retrieved 8 April 2016.
^ Brodie MJ (1995). "Tiagabine pharmacology in profile". Epilepsia. 36 (Suppl 6): S7 – S9. doi:10.1111/j.1528-1157.1995.tb06015.x. PMID 8595791. S2CID 27336198.
^ Stahl SM (2009). Stahl's essential psychopharmacology: the prescriber's guide; antipsychotics and mood stabilizers (3rd ed.). New York, NY: Cambridge University Press. pp. 523–526. ISBN 978-0-521-75900-7.
^ "Tiagabine", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID 31643697, retrieved 2021-12-24
Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL (February 2017). "Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline". Journal of Clinical Sleep Medicine. 13 (2): 307–349. doi:10.5664/jcsm.6470. PMC 5263087. PMID 27998379.
^ Leppik IE (1995). "Tiagabine: the safety landscape". Epilepsia. 36 (Suppl 6): S10 – S13. doi:10.1111/j.1528-1157.1995.tb06009.x. PMID 8595787. S2CID 24203401.
Eadie MJ, Vajda F (6 December 2012). Antiepileptic Drugs: Pharmacology and Therapeutics. Springer Science & Business Media. pp. 459–. ISBN 978-3-642-60072-2.
Aronson JK, ed. (2009). "Antihistamines". Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 652–. ISBN 978-0-444-53266-4.
Pellock JM (2001-12-20). "Tiagabine (gabitril) experience in children". Epilepsia. 42 (Suppl 3): 49–51. doi:10.1046/j.1528-1157.2001.042suppl.3049.x. PMID 11520324. S2CID 23614412.
^ Spiller HA, Winter ML, Ryan M, Krenzelok EP, Anderson DL, Thompson M, Kumar S (2009). "Retrospective evaluation of tiagabine overdose". Clinical Toxicology. 43 (7): 855–859. doi:10.1080/15563650500357529. PMID 16440513. S2CID 25469390.
Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, Rickels K (November 2005). "The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study". The Journal of Clinical Psychiatry. 66 (11): 1401–1408. doi:10.4088/JCP.v66n1109. PMID 16420077.
"Gabitril (tiagabine) dosing, indications, interactions, adverse effects, and more". reference.medscape.com. Retrieved 2021-12-24.
Frohlich J, Mediano PA, Bavato F, Gharabaghi A (June 2023). "Paradoxical pharmacological dissociations result from drugs that enhance delta oscillations but preserve consciousness". Communications Biology. 6 (1): 654. doi:10.1038/s42003-023-04988-8. PMC 10282051. PMID 37340024.
Adkins JC, Noble S (March 1998). "Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy". Drugs. 55 (3): 437–460. doi:10.2165/00003495-199855030-00013. PMID 9530548. S2CID 70426629.
Andersen KE, Braestrup C, Grønwald FC, Jørgensen AS, Nielsen EB, Sonnewald U, et al. (June 1993). "The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1--3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate". Journal of Medicinal Chemistry. 36 (12): 1716–1725. doi:10.1021/jm00064a005. PMID 8510100.
"Search Results for Tiagabine". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration. Archived from the original on 22 April 2016. Retrieved 22 March 2016.

External links

Gabitril(manufacturer's website)

Anticonvulsants (N03)

GABAergics

GABA_AR PAMs	Barbiturates: Barbexaclone Metharbital Methylphenobarbital Pentobarbital Phenobarbital Primidone; Carbamates: Cenobamate Felbamate; Benzodiazepines: Clobazam Clonazepam Clorazepate Diazepam Lorazepam Midazolam Nimetazepam Nitrazepam Temazepam; Others: Bromide (potassium bromide, sodium bromide) Imepitoin Paraldehyde Stiripentol
GABA-T inhibitors	Fatty acids (and related): Valproate Valpromide Valproate pivoxil Vigabatrin
Others	GABAR agonists: Progabide; GAT-1 inhibitors: Tiagabine

Channel
modulators

Sodium blockers	Hydantoins: Ethotoin Fosphenytoin Mephenytoin Phenytoin; Ureides: Acetylpheneturide Chlorphenacemide Phenacemide Pheneturide; Fatty acids: Valproate Valpromide Valproate pivoxil; Carboxamides: Carbamazepine Eslicarbazepine acetate Oxcarbazepine; Others: Lacosamide Lamotrigine Rufinamide Topiramate Zonisamide
Calcium blockers	Oxazolidinediones: Ethadione Paramethadione Trimethadione; Succinimides: Ethosuximide Mesuximide Phensuximide; Gabapentinoids: Gabapentin Pregabalin; Others: Imepitoin Lamotrigine Topiramate Zonisamide
Potassium openers	Retigabine

Others

CA inhibitors	Sulfonamides: Acetazolamide Ethoxzolamide Sultiame Topiramate Zonisamide
Others	Albutoin Beclamide Brivaracetam Cannabidiol Carisbamate Etiracetam Fenfluramine Ganaxolone Levetiracetam Perampanel

WHO-EM
Withdrawn from market
Clinical trials:
- Phase III
- Never to phase III

v t e Anxiolytics (N05B)
5-HT_1ARTooltip 5-HT1A receptor agonists	Buspirone Gepirone Tandospirone
GABA_ARTooltip GABAA receptor PAMsTooltip positive allosteric modulators	Benzodiazepines: Adinazolam Alprazolam Bromazepam Camazepam Chlordiazepoxide Clobazam Clonazepam Clorazepate Clotiazepam Cloxazolam Diazepam Ethyl loflazepate Etizolam Fludiazepam Halazepam Ketazolam Lorazepam Medazepam Nordazepam Oxazepam Pinazepam Prazepam; Others: Alpidem Barbiturates (e.g., phenobarbital) Carbamates (e.g., meprobamate) Carisoprodol Chlormezanone Ethanol (alcohol) Etifoxine
Hypnotics	Zopiclone
Gabapentinoids (α₂δ VDCC blockers)	Gabapentin Gabapentin enacarbil Phenibut Pregabalin
Antidepressants	SSRIsTooltip Selective serotonin reuptake inhibitors (e.g., escitalopram) SNRIsTooltip Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine) SARIsTooltip Serotonin antagonist and reuptake inhibitors (e.g., trazodone) TCAsTooltip Tricyclic antidepressants (e.g., clomipramine) TeCAsTooltip Tetracyclic antidepressants (e.g., mirtazapine) MAOIsTooltip Monoamine oxidase inhibitors (e.g., phenelzine); Others: Agomelatine Bupropion Tianeptine Vilazodone Vortioxetine
Antipsychotics	Quetiapine Flupentixol
Sympatholytics (Antiadrenergics)	Alpha-1 blockers (e.g., prazosin) Alpha-2 agonists (e.g., clonidine, dexmedetomidine, guanfacine) Beta blockers (e.g., propranolol)
Others	Benzoctamine Cycloserine Fabomotizole Hydroxyzine Lorpiprazole Mebicar Mepiprazole Nicotine Opipramol Oxaflozane Phenaglycodol Phenibut Picamilon Selank Tiagabine Tofisopam Validolum
WHO-EM Withdrawn from market Clinical trials: Phase III Never to phase III

GABATooltip γ-Aminobutyric acid metabolism and transport modulators

Transporter

GATTooltip GABA transporter	Inhibitors: 4-Aminovaleric acid β-Alanine Arecaidine CI-966 DABA Deramciclane (EGIS-3886, EGYT-3886) EF-1502 Gabaculine Guvacine Ibotenic acid Muscimol Nipecotic acid NNC 05-2090 NO-711 Riluzole SKF-89976A SNAP-5114 TACA Tiagabine
VIAATTooltip Vesicular inhibitory amino acid transporter	Inhibitors: β-Alanine Bafilomycin A1 Chicago sky blue 6B Evans blue GABA Glycine N-Butyric acid Nigericin Nipecotic acid Valinomycin Vigabatrin