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| Pronunciation | /taɪˈæɡəbiːn/ |
| Trade names | Gabitril |
| Other names | A-70569; A70569; CEP-6671; CEP6671; NO-050328; NO050328; NO-328; NO328 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a698014 |
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| Routes of administration | Oral[1][2][3] |
| Drug class | GABA reuptake inhibitor;GABA transporter 1 (GAT-1)inhibitor;Anticonvulsant;Hypnotic;Anxiolytic |
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| Pharmacokinetic data | |
| Bioavailability | 90%[1][3][5] |
| Protein binding | 96%[1][5] |
| Metabolism | CYP3A4, possibly otherCYP450enzymes,glucuronidation[1][5][7] |
| Metabolites | 5-Oxotiagabine, others[1][3] |
| Onset of action | ~1 hour (peak)[1] |
| Eliminationhalf-life | 4.5–9.0 hours[3][6][1] |
| Excretion | Feces: 63%[1] Urine: 25%[1] |
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| Chemical and physical data | |
| Formula | C20H25NO2S2 |
| Molar mass | 375.55 g·mol−1 |
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Tiagabine, sold under the brand nameGabitril, is ananticonvulsantmedication produced byCephalon that is used in the treatment ofepilepsy.[2][3] It is also usedoff-label in the treatment ofanxiety disorders includingpanic disorder[8] and to treatinsomnia.[9][10][11] The drug is takenorally.[2][3]
Tiagabine is approved by theUnited StatesFood and Drug Administration (FDA) as anadjunctive treatment forpartial seizures inepilepsy in individuals of age 12 and up. It is effective asmonotherapy andcombination therapy with otheranticonvulsant drugs in the treatment ofpartial seizure.[12]
It may also be prescribedoff-label by physicians to treatanxiety disorders, such aspanic disorder andsocial anxiety disorder.[13][14][15] Tiagabine may be used alongsideselective serotonin reuptake inhibitors (SSRIs),serotonin–norepinephrine reuptake inhibitors (SNRIs), orbenzodiazepines foranxiety.[13]
Tiagabine can be used in the treatment ofneuropathic pain.[16][17][13] It can be used alongsideantidepressants,gabapentin, other anticonvulsants, oropioids for neuropathic pain.[13]
Tiagabine has been used in the treatment ofinsomnia and has been found to enhanceslow wave sleep (SWS) in this context.[9][10][11] However, theAmerican Academy of Sleep Medicine's 2017clinical practice guidelines recommended against the use of tiagabine in the treatment of insomnia due to limited effectiveness and very lowquality of evidence.[10]
Side effects of tiagabine are dose-related.[12] The most common side effect of tiagabine isdizziness.[18] Other side effects that have been observed with a rate of statistical significance relative toplacebo includeasthenia,somnolence, nervousness,memory impairment,tremor,headache,diarrhea, anddepression.[3][18][19] Adverse effects such asconfusion,aphasia,stuttering, andparesthesia (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).[18] Tiagabine may induceseizures in those withoutepilepsy, particularly if they are taking another drug which lowers theseizure threshold.[13] There may be an increased risk ofpsychosis with tiagabine treatment, although data is mixed and inconclusive.[5][20] Tiagabine can also reportedly interfere with visualcolor perception.[5]
Tiagabineoverdose can produce neurological symptoms such aslethargy, single or multipleseizures,status epilepticus,coma,confusion,agitation,tremors,dizziness,dystonias,abnormal posturing, andhallucinations, as well asrespiratory depression,tachycardia, andhypertension orhypotension.[21] Overdose may be fatal especially if the victim presents with severe respiratory depression or unresponsiveness.[21]
Tiagabine increases the level ofγ-aminobutyric acid (GABA), the major inhibitoryneurotransmitter in thecentral nervous system, by blocking theGABA transporter 1 (GAT-1), and hence is classified as aGABA reuptake inhibitor (GRI).[6][22]
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 γ-aminobutyric acid (GABA), the central nervous system's major inhibitory neurotransmitter. Tiagabine is thought to block GABA reuptake into presynaptic neurons through inhibition ofGAT-1 and, as a result of this action, allowing more GABA to be available for receptor binding on the surfaces of post-synaptic cells.[23][24] In rat studies, tiagabine prolonged GABA-mediated inhibitory post-synaptic potentials in the hippocampus, as well as increased GABA concentration in the extracellular space of the globus pallidus, ventral palladum and substantia nigra.[1] However, tiagabine does not decrease neuronal GABA levels and induces compensatory GABA synthesis from glucose or glial glutamine precursors.[25]
Being a nipecotic acid derivative, introduction of 4,4-diphenylbut-3-enyl and 4,4-bis(3-methylthiophene-1-yl)but-3-enyl sidechain increasedlipophilicity compared to the parent compound, allowingblood-brain barrier crossing and GAT-1 selectivity.[24]
Tiagabine also increasesbenzodiazepine-type anticonvulstants' affinity to cortical and limbicGABAA receptors and influencesEEG measurements by increasing frontal activity and reducing posterior activity in the brain.[26][27]
Tiagabine does not affect keycardiacion channels.[28]
With regard topharmacophore, the most stable binding mode of tiagabine in the GAT-1 transporter is that where thenipecotic acid fragment is located in the main ligand binding site, and aromatic thiophene rings are arranged within the allosteric site, which yields GAT-1 in an outward-open state. This interaction is mediated through GAT-1's sodium ion mimicry, hydrogen bonding and hydrophobic interactions.[29]
Tiagabine is nearly completelyabsorbed (>95%) and has anoralbioavailability of 90%.[1][3] Thetime to peak levels is approximately 1 hour.[3] Peak levels occur after 45 minutes in a fasted state and after 2.5 hours when taken with a high fat meal.[1][3] A high fat meal decreasespeak levels by 40% but does not affectarea-under-the-curve levels.[1][3] Tiagabine was administered with food in clinical trials and it is recommended that it be taken with food.[1][3] Thepharmacokinetics of tiagabine are linear over a dose range of 2 to 24 mg.[1][3]Steady-state levels are achieved after 2 days of continuous dosing.[1]
Tiagabine is widelydistributed through the body.[3] Itsvolume of distribution is approximately 1 L/kg.[3] The drug readily crosses theblood–brain barrier.[3] Theplasma protein binding of tiagabine is 96%, mainly toalbumin andα1-acid glycoprotein.[1]
Themetabolism of tiagabine has not been fully characterized.[1] In any case, it is metabolized by at least two known pathways.[1] One isthiopheneringoxidation resulting in 5-oxotiagabine and the other isglucuronidation.[1] 5-Oxotiagabine is said not to contribute to thepharmacodynamics of tiagabine.[1]In-vitro studies suggest that tiagabine is metabolized primarily by thecytochrome P450enzymeCYP3A4, although involvement of other enzymes likeCYP1A2,CYP2D6, orCYP2C19 has not been excluded.[1] Two othermetabolites of tiagabine have yet to be identified.[3]
Tiagabine isexcreted about 2% unchanged.[1][3] About 25% is excreted inurine and 63% is excreted infeces.[1][3] Theelimination half-life of tiagabine is 4.5 to 9.0 hours.[1][3] The half-life of tiagabine was found to be decreased by 50 to 65% to 3.8 to 4.9 hours (range 2–5 hours) in patients whosehepatic enzymes had been induced with otheranticonvulsants includingcarbamazepine,phenytoin,primidone, andphenobarbital.[1][3][30] In addition, the half-life of tiagabine is extended to 11.7 to 15.9 hours inhepatic dysfunction.[3][30] These settings as such may require dose adjustment.[1][3][30]
Tiagabine is aGABA analogue and aderivative ofnipecotic acid.[3]
Tiagabine was discovered atNovo Nordisk in Denmark in 1988 by a team ofmedicinal chemists andpharmacologists under the general direction of Claus Bræstrup.[31] The drug was co-developed withAbbott Laboratories, in a 40/60 cost sharing deal, with Abbott paying a premium for licensing the IP from the Danish company.[citation needed] It was approved for treatment of epilepsy in theUnited States in September 1997.[30]
US patents on tiagabine listed in theOrange Book expired in April 2016.[32]
Tiagabine was previously subject toRisk Evaluation and Mitigation Strategies (REMS) in the United States, which was instituted in 2010.[33][34] However, this requirement was eliminated in 2012.[35]
In addition to epilepsy, tiagabine was under formal development for the treatment ofanxiety disorders,insomnia, andneuropathic pain.[33] However, development for all of these indications was discontinued.[33]
There have beencase reports andcase series of tiagabine for treatment ofbipolar disorder.[36] However, noclinical trials have been conducted.[36]
_induced_by_tiagabine_(15_mg)_in_14_healthy_volunteers..png)
Tiagabine enhances the power of corticaldelta (< 4 Hz) oscillations up to 1,000% relative to placebo, which may result in anEEG orMEG signature resemblingnon-rapid eye movement sleep even while the person who has taken tiagabine is awake and conscious.[37] 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.
