Tiagabine

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Tiagabine
Tiagabine2DCSD.svg
Tiagabine3DanJ.gif
Systematic (IUPAC) name
(R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl] piperidine-3-carboxylic acid
Clinical data
Trade names Gabitril
AHFS/Drugs.com monograph
MedlinePlus a698014
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 90%
Protein binding 96%
Metabolism Hepatic (CYP450 system)
Half-life 7-9 hours
Excretion Fecal and renal
Identifiers
CAS number 115103-54-3 YesY
ATC code N03AG06
PubChem CID 60648
DrugBank DB00906
ChemSpider 54661 YesY
UNII Z80I64HMNP YesY
KEGG D08588 YesY
ChEMBL CHEMBL1027 YesY
Chemical data
Formula C20H25NO2S2 
Mol. mass 375.55 g/mol
 YesY (what is this?)  (verify)

Tiagabine (/tˈæɡəbn/ is an anti-convulsive medication produced by Cephalon and marketed under the brand name Gabitril. The drug was discovered at Novo Nordisk in Denmark in 1988 by a team of chemists and pharmacologists under the general direction of Dr. Claus Bræstrup. An article authored by Dr. Lars J. S. Knutsen describing the design, selection, pharmacology and synthesis of tiagabine was published in the Journal of Medicinal Chemistry in 1993, pulling together the work of the team at Novo Nordisk. The drug was co-developed with Abbott, in a 40/60 cost sharing deal, with Abbott paying a premium for licensing the IP from the Danish company.

Abbott did initially embrace the drug enthusiastically after its US launch in 1998, and provided further clinical studies with the goal of gaining FDA approval for monotherapy in epilepsy. However, the senior management at Abbott drew back after realizing that the original deal with Novo would limit the company's financial gain from a monotherapy approval. After a period of co-promotion, Cephalon licensed Tiagabine from Abbott/Novo and now is the exclusive producer. The medication is also utilized in the treatment of panic disorder, as are a few other anticonvulsants.

Indications[edit]

Tiagabine is approved by U.S. Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures in ages 12 and up. It may also be prescribed off-label by physicians knowledgeable about the field to treat anxiety disorders and neuropathic pain (including fibromyalgia). For anxiety and neuropathic pain, tiagabine is used primarily to augment other treatments. Tiagabine may be used alongside SSRIs, SNRIs or benzodiazepines for anxiety, or antidepressants, gabapentin, anticonvulsants or opiates for neuropathic pain.[1]

Pharmacology[edit]

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 GABA reuptake inhibitor.[2]

Side effects[edit]

Tiagabine's most common side effects include confusion, difficulty speaking clearly/stuttering, mild sedation, and in doses over 8 mg, a tingling sensation (paresthesia) in the body's extremities, particularly the hands and fingers. Tiagabine may induce seizures in those without epilepsy, especially if they are taking another drug which lowers the seizure threshold.[1]

Tiagabine overdose can produce neurologic symptoms such as lethargy, seizures (multiple), status epilepticus, seizure (single), coma, confusion, agitation, tremors, dizziness, dystonias/abnormal posturing, and hallucinations. Other symptoms of tiagabine overdose include respiratory depression, tachycardia, hypertension, and hypotension. Overdose may be fatal especially if the victim presents with severe respiratory depression and/or fails to respond to verbal and physical stimuli. Emergency medical services should be sought immediately for any overdose.

Synthesis[edit]

Tiagabine Rxn.png

Andersen, Knud Erik; Braestrup, Claus; Groenwald, Frederik C.; Joergensen, Anker S.; Nielsen, Erik B.; Sonnewald, Ursula; Soerensen, Per O.; Suzdak, Peter D.; Knutsen, Lars J. S. (1993). "The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate". Journal of Medicinal Chemistry 36 (12): 1716–25. doi:10.1021/jm00064a005. PMID 8510100. 

Diversion from the legitimate pharmaceutical market[edit]

The attorneys-general of Connecticut and Pennsylvania have launched investigations into its diversion from the legitimate pharmaceutical market, including Cephalon's "sales and promotional practices for Provigil, Actiq and Gabitril". Availability

References[edit]

  1. ^ a b Stahl, S. Stahl's Essential Psychopharmacology: Prescriber's Guide. Cambridge University Press: New York, NY. 2009. pp. 523-526
  2. ^ Pollack MH, Roy-Byrne PP, Van Ameringen M, et al. (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): 1401–8. doi:10.4088/JCP.v66n1109. PMID 16420077. 

External links[edit]