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| Pronunciation | /taɪˈæɡəbiːn/ |
| Trade names | Gabitril |
| Other names | TGB; A-70569; A70569; ABT-569; ABT569; Abbott 70569; CEP-6671; CEP6671; N 05-0328; NNC 05-0328; 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][2][5] |
| Protein binding | 96%[1][5][2] |
| Metabolism | CYP3A4, possibly otherCYP450enzymes,glucuronidation[1][5][7][2] |
| Metabolites | 5-Oxotiagabine, others[1][3] |
| Onset of action | 1–1.5 hours (45 min fasted, 2.5 hours with high-fat meal) (peak)[1][3][2] |
| Eliminationhalf-life | 4.5–9.0 hours[3][6][1][2] Enzyme-induced patients: 2–3 hours[2] |
| Excretion | Feces: 63%[1][3] Urine: 25% (<3% unchanged)[1][3] |
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| Formula | C20H25NO2S2 |
| Molar mass | 375.55 g·mol−1 |
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Tiagabine, sold under the brand nameGabitril, is ananticonvulsantmedication which is used in the treatment ofepilepsy.[1][2][3][8] It is also usedoff-label in the treatment ofinsomnia[9][10][11] andanxiety disorders.[12] However, off-label use is discouraged as the drug has been associated with new-onsetseizures in people without epilepsy.[13][14][1] Tiagabine is takenorally.[3][2]
Side effects of tiagabine includedizziness,asthenia, non-specificnervousness,muscle tremors,diarrhea,depression, andemotional lability.[3][1] The drug acts as aselectiveGABA transporter 1 (GAT-1)blocker orGABA reuptake inhibitor, and hence acts as an indirectGABA receptoragonist, increasingGABAergicsignaling in thebrain.[3][15][16][17][6][18] It may increase activation of bothGABAA andGABAB receptors.[17][19][20] The effects of tiagabine onsleep resemble those ofGABAA receptor agonists likegaboxadol andmuscimol, primarily enhancingslow wave sleep, and differ from those ofGABAA receptor positive allosteric modulators likebenzodiazepines andZ drugs.[21][18][9][22][17] The drug'selimination half-life is 4.5 to 9 hours, but can be shorter in people takingenzyme-inducing anticonvulsants.[3][6][1][2]
Tiagabine was discovered in 1988[23] and was introduced for medical use in 1997.[24][8]Generic formulations have become available.[25] The drug is not acontrolled substance in theUnited States.[26]
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.[27]
Tiagabine is used in the treatment ofinsomnia.[9][28][10][11] Lower doses than those used inepilepsy, in the range of 2 to 16 mg, are used to treat insomnia.[29][30]
The drug has been found to enhanceslow wave sleep (SWS) in the context of insomnia.[9][28][31][32][33][34] Its effects on SWS aredose dependent, with a 2- to 4-fold increase in SWS at doses of 8 to 16 mg but mixed findings for a dose of 4 mg.[9][32][34][31][33] Findings are mixed in terms of the influence of tiagabine onsleep onset,sleep duration,nighttime awakenings, self-reported sleep ratings, and ratings ofrestorative or refreshing sleep.[9][31][32][33][34] Tiagabine has been found to decrease thecognitive impairment andhigh cortisol levels caused bysleep restriction, with this being related to the drug's SWS improvement.[9][35][28][36] On the other hand, despite increasing SWS, tiagabine did not improvememory consolidation.[37]
The effects of tiagabine on sleep, for instance primarily increasing SWS, resemble those ofgaboxadol andmuscimol but are very different from those of conventionalGABAA receptor positive allosteric modulators likebenzodiazepines andZ drugs.[21][18][9][22][14][17][38]
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]
Tiagabine may be prescribedoff-label to treat certainanxiety disorders, such aspanic disorder andsocial anxiety disorder.[39][40][41] Tiagabine may be used alongsideselective serotonin reuptake inhibitors (SSRIs),serotonin–norepinephrine reuptake inhibitors (SNRIs), orbenzodiazepines foranxiety.[39] The drug was ineffective forgeneralized anxiety disorder.[42][43][44]
Tiagabine can be used in the treatment ofneuropathic pain.[45][46][39] It can be used alongsideantidepressants,gabapentin, other anticonvulsants, oropioids for neuropathic pain.[39]
Tiagabine is available in the form of 2, 4, 5, 10, 12, 15, and 16 mgoraltablets.[2][1] The drug is taken 1 to 4 times per day due to its shortelimination half-life.[3] Asustained-release formulation would be advantageous but has not been developed or marketed.[2][6]
Contraindications of tiagabine includehypersensitivity (drug allergy) to tiagabine or its ingredients and severehepatic impairment.[1][3] The drug should be avoided inpregnant andnursing women.[1][3]
Side effects of tiagabine aredose-related.[27] The most common side effect of tiagabine isdizziness.[47] 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][47][48] 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).[47] Tiagabine has been associated with new-onsetseizures andstatus epilepticus in people withoutepilepsy inpost-marketing surveillance.[1][39] This may bedose-related, although it has been reported at doses of as low as 4 mg/day, and may also be related to concomitant use of othermedications that lower theseizure threshold.[1][39] Some of these seizures occurred around the time of dose increases.[1] There may be an increased risk ofpsychosis with tiagabine treatment, although data is mixed and inconclusive.[5][49] Tiagabine can also reportedly interfere with visualcolor perception.[5] It has not been found to causepsychomotor,cognitive, ormemory impairment.[3][2] Unlike certain otherGABAergic drugs likemuscimol,gaboxadol, andCI-966, tiagabine has not been associated withhallucinogenic effects.[50][51]
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.[1][52] Overdose may be fatal especially if the victim presents with severe respiratory depression or unresponsiveness.[52]
Combination of tiagabine withenzyme-inducinganticonvulsants likecarbamazepine,phenytoin,primidone, andphenobarbital can decrease theelimination half-life of tiagabine to as low as 2 to 3 hours.[3][2][1] Conversely, tiagabine does not significantly affect thehepaticmetabolism of other anticonvulsants such as carbamazepine, phenytoin, andvalproic acid.[3][1] Otherinteractions have also been reviewed.[3][1]
Tiagabine acts aselectiveGABA transporter 1 (GAT-1)blocker and hence as aGABA reuptake inhibitor (GRI).[2][3][15][1] The GAT-1 is one of at least four distinctGABA transporters (GATs), with the GAT-1 being the predominant subtype in the brain, accounting for 85% of GATs in this part of the body, and thought to be responsible for mostγ-aminobutyric acid (GABA)reuptake insynapses.[3][15][53] The drug has more than 1,000-fold selectivity for the GAT-1 over theGABA transporter 2 (GAT-2),GABA transporter 3 (GAT-3), andbetaine/GABA transporter (BGT-1; GAT-4).[15][16][54] It also shows no significantaffinity forGABA receptors or numerous othertargets.[6] In addition, it does not affect keycardiacion channels.[55] Through GAT-1 blockade, tiagabine increases levels of GABA, the majorinhibitoryneurotransmitter in thecentral nervous system, and consequently increases GABA receptoractivation andGABAergicsignaling, including of bothGABAA andGABAB receptors.[17][19][20][6][56] The drug has been found to increase GABAergic signaling in thehippocampus,globus pallidus,ventral pallidum, andsubstantia nigra in animals.[1] It producesanticonvulsant,neuroprotective,hypnotic,analgesic, andanxiolytic-like effects in animals.[3][15][1]
In rodentdrug discrimination tests, tiagabine partially substituted formuscimol anddiazepam but did not substitute forgaboxadol,phenobarbitol, orzolpidem.[53][57][58][59][60] When tiagabine was used as the training drug however, gaboxadol near-fully substituted for tiagabine.[53] Similarly,indiplon partially substituted for tiagabine.[53] On the other hand,zolpidem,eszopiclone,baclofen, andgabapentin all did not substitute for tiagabine.[53] TheGABAA receptorantagonist(+)-bicuculline at non-convulsant doses partially antagonized tiagabine'sinteroceptive effects, whereas higher doses that might more fully antagonize its cue were not assessed due to risk ofconvulsions.[53] These findings suggest involvement of the GABAA receptor in the subjective effects of tiagabine, at least in rodents.[53] Conversely, the GABAB receptor does not appear to be involved.[53]
Tiagabine increasesbenzodiazepines' affinity to cortical and limbicGABAA receptors and influenceselectroencephalography (EEG) measurements by increasing frontal activity and reducing posterior activity in the brain.[61][62]
With regard topharmacophore, the most stable binding mode of tiagabine in the GAT-1 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.[63] This interaction is mediated through GAT-1's sodium ion mimicry, hydrogen bonding and hydrophobic interactions.[63]
_induced_by_tiagabine_(15_mg)_in_14_healthy_volunteers..png)
Tiagabine enhances the power ofcorticaldelta (< 4 Hz) oscillations up to 1,000% relative to placebo, which may result in anEEG orMEG signature resemblingnon-rapid eye movement (NREM)sleep even while the person who has taken tiagabine is awake and conscious.[64] 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.[64]
Tiagabine is nearly completelyabsorbed (>95%) and has anoralbioavailability of 90%.[1][3] Thetime to peak levels is approximately 1 hour, with a range of 0.8 to 1.5 hours.[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, indicating that it delays absorption but does not reduce the extent of absorption.[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 and there is noaccumulation with repeated administration.[1][3] There have been found to be secondary peaks in circulating tiagabine levels which is suggestive ofenterohepatic recycling.[3][65][66]
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 knownpathways.[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][24] In addition, the half-life of tiagabine is extended to 11.7 to 15.9 hours inhepatic dysfunction.[3][24] These settings as such may require dose adjustment.[1][3][24]
Tiagabine, also known as (–)-(R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid, is aGABA analogue and aderivative ofnipecotic acid.[3][1] Being a nipecotic acid derivative, introduction of 4,4-diphenylbut-3-enyl and 4,4-bis(3-methylthiophene-1-yl)but-3-enylside chain increasedlipophilicity compared to the parent compound, allowingblood–brain barrierpermeability andGABA transporter 1 (GAT-1)selectivity.[2][3][67] The experimentallog P of tiagabine is 2.6.[68][69]Analogues of tiagabine includeCI-966,NNC-711, andSKF-89976A, among others.[15][54]
Tiagabine was discovered atNovo Nordisk inDenmark in 1988 by a team ofmedicinal chemists andpharmacologists under the general direction of Claus Bræstrup.[23] 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 ofepilepsy in theUnited States in September 1997.[24] In 2005, a bolded warning was added to the labeling of tiagabine by the United StatesFood and Drug Administration cautioning about association of new-onsetseizures in people without epilepsy and discouragingoff-label use.[13][14] Tiagabine was previously subject toRisk Evaluation and Mitigation Strategies (REMS) in the United States, which was instituted in 2010.[8][70] However, this requirement was eliminated in 2012.[71] United Statespatents on tiagabine listed in theOrange Book expired in April 2016.[72]
Tiagabine is available in countries throughout the world includingAustria,Denmark,France,Germany,Spain,Switzerland, theUnited Kingdom, and theUnited States.[73]
Tiagabine is aprescription-onlymedication but not an otherwisecontrolled substance in theUnited States.[26]
In addition toepilepsy, tiagabine was under formalclinical development for the treatment ofanxiety disorders,insomnia, andneuropathic pain.[8] However, development for all of these indications was discontinued.[8] There have also beencase reports andcase series of tiagabine for treatment ofbipolar disorder, though noclinical trials have been conducted.[74][75][76][77] The drug has been studied for treatment ofpost-traumatic stress disorder (PTSD).[78][79][80][81][82][83] It has been studied for treatment ofaggression.[84][85][86][87]
In 2005, the FDA announced that a bolded warning would be added to the labelling for tiagabine, to inform prescribers of the risk of seizures in those without epilepsy who were being treated with the medication; therefore, off-label use of tiagabine was discouraged.
5.1 Tiagabine and gaboxadol Two agents recently developed which have very distinct mechanisms of action are tiagabine (Gabitril, Cephalon [60]), which blocks synaptic GABA re-uptake, and gaboxadol, a selective extrasynaptic GABAA receptor agonist. [...] However, it should be mentioned that in 2005, the FDA issued a warning for de novo occurrence of seizures in patients without epilepsy, discouraging off-label use of this drug.
Another compound, tiagabine, has been recently investigated for its potential as a hypnotic. Tiagabine is a GABA uptake inhibitor launched initially as an anticonvulsant in the treatment of epilepsy. It specifically inhibits the GABA transporter GAT-1 (Fig. 1). Such pharmacological manipulation may sustain synaptically-released GABA levels in the synaptic cleft, thereby increasing GABAA-mediated inhibition as well as activation of GABAB receptors. The effects of tiagabine on sleep are similar to those evoked by selective GABAA agonists. Indeed, tiagabine elevates EEG power density in frequencies < 10 Hz during NREM sleep, including the SWA range (Mathias et al., 2001b), and increases sleep continuity and time spent in NREM sleep stage 3–4 (Mathias et al., 2001b; Walsh et al., 2005, 2006a,b; Roth et al., 2006). [...] High-amplitude EEG spike-waves seem to be a common feature of drugs enhancing GABAA-mediated tonic conductance (Fig. 3). Muscimol, another selective GABAA agonist showing very high affinity for δ-containing receptors (Quirk et al., 1995; Huh et al., 1996; Mihalek et al., 1999), induced such EEG patterns in several species (Pedley et al., 1979; Fariello et al., 1981; Peeters et al., 1989; Lancel et al., 1996, 1997; Vyazovskiy et al., 2007). Tiagabine has been reported to elicit similar alterations of the EEG (Walton et al., 1994; Coenen et al., 1995; Lancel et al., 1998).
Other compounds enhancing GABAergic transmission could be valuable hypnotic drugs, some of which are currently in development.The drugs in question are another α1-containing GABAA-enhancing drug (indiplon), GABA analogues such as gabapentin, a GABA reuptake inhibitor (tiagabine), and a GABAA agonist (gaboxadol).96 These agents, except gaboxadol, nonspecifically enhance GABAergic transmission through GABAA, GABAB, and GABAC receptors. It should be stressed that the hypnotic effects of GABAB and GABAC ligands are not qualitatively similar to those obtained with GABAA ligands.97
Pharmacological manipulation of GABAergic neurotransmission has diverse and complex effects on SWA. GABA agonists, such as muscimol and THIP (Gaboxadol) and the GABA uptake inhibitor tiagabine, increase SWA and SWS sleep time (Lancel and others 1998; Lancel 1999; Walsh and others 2006). Conversely, compounds that influence GABA receptor open-time (barbiturates, benzodiazepines, and to a lesser extent nonbenzodiazepines) reduce SWA and increase TC spindling (Lancel 1999). [...] It is also not entirely clear why benzodiazepines reduce SWA, while compounds like THIP and tiagabine increase SWA. [...] In particular, benzodiazepines act as allosteric positive modulators of GABAA receptors to enhance GABAA receptor-mediated chloride conductance. This conductance will shunt currents that mediate burst pause activity at a cellular level, thus reducing the tendency to generate SWA. Both THIP and tiagabine will increase extracellular GABA that will affect not only GABAA receptors but GABAB receptors as well. [...] Interestingly, pharmacological intensification of SWA leads to a dissociation between the restorative features of sleep and indices of sleep homeostasis. For example, tiagabine treatment increases SWS time (SWA was not reported) and relieves cognitive impairments normally observed during a sleep restriction protocol. However, placebo and tiagabine groups were equally sleepy, as measured by subjective ratings, the multiple-sleep-latency test, and changes in recovery sleep (Walsh and others 2006). Conversely, gaboxodol treatment (under the same protocol) increases SWS time to a similar degree (and intensifies SWA), but has seemingly opposite effects on daytime function and sleep pressure. In this case, gaboxodol reduces subjective and objective ratings of sleepiness without improving daytime cognitive performance (relative to placebo; Walsh and others 2008).
The effects of the GABA-uptake inhibitor tiagabine on sleep EEG resemble those of GABAA agonists. [...] Since the effects of tiagabine on sleep EEG are very similar to those after GABA agonists it appears likely that their influence on sleep may be due to tonic stimulation of GABAA receptors. The hypnotic properties of gaboxadol and tiagabine differ considerably from those of the agonistic modulators, benzodiazepines, zolpidem and zopiclone. In contrast to the latter substances these drugs mimic the sleep-promoting effect of sleep deprivation. These substances appear to represent a new class of hypnotics.
It is well established that benzodiazepines and to a lesser extent the Z-drugs, like zolpidem and zopiclone, suppress SWA and low-frequency EEG activity in the EEG during nonREM sleep and enhance high-frequency activity, in particular in the frequency range of sleep spindles (Lancel 1999). However, several compounds have been shown to ncrease SWS including, GAT-1 inhibitors, such as tiagabine (Mathias et al. 2001), GABA-A agonists such as gaboxadol, which bind to the extrasynaptic GABA-A receptor (Walsh et al. 2007; Dijk et al. 2009b), GABA-B modulators, such as GHB (Pardi and Black 2006) and 5HT 2A antagonists such as seganserin and eplivanserin (Dijk et al. 1989a; Landolt et al. 1999). [...] Tiagabine, a GAT-1 inhibitor, increases SWS in a dose-dependent manner, with a corresponding signifi cant reduction in stage 1 sleep, in both adults (Walsh et al. 2006) and elderly patients (Roth et al. 2006) with primary insomnia. Despite this increase in SWS, traditional efficacy measures such as sleep latency or number of awakenings were unaffected in both studies (Roth et al. 2006; Walsh et al. 2006).
Tiagabine, an adjuvant anticonvulsant, inhibits GABA transporter GAT1 and increases the inhibitory actions of GABA (Buysse 2011). Doses of 4–16 mg have been utilized to treat insomnia. [...]
2.10. Anticonvulsants The anticonvulsant tiagabine acts through selective inhibition of the GABA transporter (GAT-1), increasing extracellular GABA concentrations [45]. It has been investigated in five RCTs of GAD, but without evidence to support efficacy over placebo [18].
[...] tiagabine (GABA uptake inhibitor), valproate, gabapentin and progabide all increase CNS levels of GABA and yet are not associated with hallucinogenic side effects [28].
GABA-enhancing drugs, such as muscimol and Cl-966, produce mental states that differ in various ways from those of other hallucinogens. [...] Finally, we have a new group of hallucinogens, which act either as GABA uptake inhibitors or GABA, agonists. Muscimol is one of the materials derived from Amanita muscuria, along with muscarine. [...]
Tiagabine potently blocks reuptake at the GAT-1 GABA transporter, which is the predominant (85% belong to this type) GABA transporter in the brain (Borden et al. 1994).
