Tiagabine

Tiagabine
Systematic (IUPAC) name
(−)-(3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid
Clinical data
Pronunciation /taɪˈæɡəbiːn/
Trade names Gabitril
AHFS/Drugs.com monograph
MedlinePlus a698014
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral (tablets)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 90–95%[1]
Protein binding 96%[1]
Metabolism Hepatic (CYP450 system,[1] primarily CYP3A)[2]
Onset of action Tmax = 45 min[2]
Biological half-life 5–8 hours[3]
Excretion Fecal (63%) and renal (25%)[2]
Identifiers
CAS Number 115103-54-3 YesY
ATC code N03AG06 (WHO)
PubChem CID 60648
IUPHAR/BPS 4685
DrugBank DB00906 YesY
ChemSpider 54661 YesY
UNII Z80I64HMNP YesY
KEGG D08588 YesY
ChEBI CHEBI:9586
ChEMBL CHEMBL1027 YesY
Chemical data
Formula C20H25NO2S2
Molar mass 375.55 g/mol
  (verify)

Tiagabine (trade name Gabitril) is an anticonvulsant medication used in the treatment of epilepsy that is produced by Cephalon. 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.[4]

Side effects

The most common side effect of tiagabine is dizziness.[5] 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.[5][6] 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).[5] Tiagabine may induce seizures in those without epilepsy, particularly if they are taking another drug which lowers the seizure threshold.[4] There may be an increased risk of psychosis with tiagabine treatment, although data is mixed and inconclusive.[1][7] Tiagabine can also reportedly interfere with visual color perception.[1]

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.[8] Overdose may be fatal especially if the victim presents with severe respiratory depression and/or unresponsiveness.[8]

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).[3][9]

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.[10] 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.

Abbott did initially embrace the drug enthusiastically after its U.S. 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.

U.S. patents on tiagabine listed in the Orange Book expire in April 2016.[11]

See also

References

  1. 1 2 3 4 5 Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 562–. ISBN 978-1-60913-345-0.
  2. 1 2 3 "Gabitril (tiagabine hydrochloride) Tablets. U.S. Full Prescribing Information" (PDF). Cephalon, Inc. Retrieved 8 April 2016.
  3. 1 2 Brodie, Martin J. (1995). "Tiagabine Pharmacology in Profile". Epilepsia 36 (s6): S7–S9. doi:10.1111/j.1528-1157.1995.tb06015.x. ISSN 0013-9580.
  4. 1 2 Stahl, S. Stahl's Essential Psychopharmacology: Prescriber's Guide. Cambridge University Press: New York, NY. 2009. pp. 523-526
  5. 1 2 3 Leppik, Ilo E. (1995). "Tiagabine: The Safety Landscape". Epilepsia 36 (s6): S10–S13. doi:10.1111/j.1528-1157.1995.tb06009.x. ISSN 0013-9580.
  6. ↑ M.J. Eadie; F. Vajda (6 December 2012). Antiepileptic Drugs: Pharmacology and Therapeutics. Springer Science & Business Media. pp. 459–. ISBN 978-3-642-60072-2.
  7. ↑ J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 652–. ISBN 978-0-444-53266-4.
  8. 1 2 Spiller, Henry A.; Winter, Mark L.; Ryan, Mark; Krenzelok, Edward P.; Anderson, Debra L.; Thompson, Michael; Kumar, Suparna (2009). "Retrospective Evaluation of Tiagabine Overdose". Clinical Toxicology 43 (7): 855–859. doi:10.1080/15563650500357529. ISSN 1556-3650.
  9. ↑ 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): 1401–8. doi:10.4088/JCP.v66n1109. PMID 16420077.
  10. ↑ Andersen KE, Braestrup C, Grønwald FC, Jørgensen AS, Nielsen EB, Sonnewald U, Sørensen PO, Suzdak PD, Knutsen LJ (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". J. Med. Chem. 36 (12): 1716–25. doi:10.1021/jm00064a005. PMID 8510100.
  11. ↑ Orange Book index page. Accessed March 22, 2016

External links

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