Tiagabine

Epilepsy Tiagabine is approved by the United States Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures in epilepsy in individuals of age 12 and up. It is effective as monotherapy and combination therapy with other anticonvulsant drugs in the treatment of partial seizure. Other uses Insomnia Tiagabine is used in the treatment of insomnia. The drug has been found to enhance slow wave sleep (SWS) in the context of insomnia. Tiagabine has been found to decrease the cognitive impairment and high cortisol levels caused by sleep restriction, with this being related to the drug's SWS improvement. On the other hand, despite increasing SWS, tiagabine did not improve memory consolidation. The effects of tiagabine on sleep, for instance primarily increasing SWS, resemble those of gaboxadol and muscimol but are very different from those of conventional GABAA receptor positive allosteric modulators like benzodiazepines and Z drugs. The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of tiagabine in the treatment of insomnia due to limited effectiveness and very low quality of evidence. Anxiety disorders Tiagabine may be prescribed off-label to treat certain anxiety disorders, such as panic disorder and social anxiety disorder. Tiagabine may be used alongside selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), or benzodiazepines for anxiety. Neuropathic pain Tiagabine can be used in the treatment of neuropathic pain. Available forms Tiagabine is available in the form of 2, 4, 5, 10, 12, 15, and 16mg oral tablets. The drug is taken 1 to 4times per day due to its short elimination half-life. A sustained-release formulation would be advantageous but has not been developed or marketed. ==Contraindications==

Contraindications of tiagabine include hypersensitivity (drug allergy) to tiagabine or its ingredients and severe hepatic impairment. The drug should be avoided in pregnant and nursing women. ==Side effects==

Side effects of tiagabine are dose-related. 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, 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 can also reportedly interfere with visual color perception. ==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, and hypertension or hypotension. Overdose may be fatal especially if the victim presents with severe respiratory depression or unresponsiveness. ==Interactions==

Combination of tiagabine with enzyme-inducing anticonvulsants like carbamazepine, phenytoin, primidone, and phenobarbital can decrease the elimination half-life of tiagabine to as low as 2 to 3hours. Conversely, tiagabine does not significantly affect the hepatic metabolism of other anticonvulsants such as carbamazepine, phenytoin, and valproic acid. Other interactions have also been reviewed. ==Pharmacology==

Pharmacodynamics Tiagabine acts a selective GABA transporter 1 (GAT-1) blocker and hence as a GABA reuptake inhibitor (GRI). Through GAT-1 blockade, tiagabine increases levels of GABA, the major inhibitory neurotransmitter in the central nervous system, and consequently increases GABA receptor activation and GABAergic signaling, including of both GABAA and GABAB receptors. The drug has been found to increase GABAergic signaling in the hippocampus, globus pallidus, ventral pallidum, and substantia nigra in animals. When tiagabine was used as the training drug however, gaboxadol near-fully substituted for tiagabine. With regard to pharmacophore, the most stable binding mode of tiagabine in the GAT-1 is that where the nipecotic 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. delta power in healthy volunteers. Tiagabine enhances the power of cortical delta (1-acid glycoprotein. Metabolism The metabolism of tiagabine has not been fully characterized. In any case, it is metabolized by at least two known pathways. One is thiophene ring oxidation resulting in 5-oxotiagabine and the other is glucuronidation. 5-Oxotiagabine is said not to contribute to the pharmacodynamics of tiagabine. In-vitro studies suggest that tiagabine is metabolized primarily by the cytochrome P450 enzyme CYP3A4, although involvement of other enzymes like CYP1A2, CYP2D6, or CYP2C19 has not been excluded. Two other metabolites of tiagabine have yet to be identified. Elimination Tiagabine is excreted about 2% unchanged. About 25% is excreted in urine and 63% is excreted in feces. The elimination half-life of tiagabine is 4.5 to 9.0hours. The half-life of tiagabine was found to be decreased by 50 to 65% to 3.8 to 4.9hours (range 2–5hours) in patients whose hepatic enzymes had been induced with other anticonvulsants including carbamazepine, phenytoin, primidone, and phenobarbital. In addition, the half-life of tiagabine is extended to 11.7 to 15.9hours in hepatic dysfunction. These settings as such may require dose adjustment. ==Chemistry==

Tiagabine, also known as (–)-(R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid, is a GABA analogue and a derivative of nipecotic acid. The experimental log P of tiagabine is 2.6. Analogues of tiagabine include CI-966, NNC-711, and SKF-89976A, among others. ==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. It was approved for treatment of epilepsy in the United States in September 1997. In 2005, a bolded warning was added to the labeling of tiagabine by the United States Food and Drug Administration cautioning about association of new-onset seizures in people without epilepsy and discouraging off-label use. However, this requirement was eliminated in 2012. United States patents on tiagabine listed in the Orange Book expired in April 2016. ==Society and culture==

Availability Tiagabine is available in countries throughout the world including Austria, Denmark, France, Germany, Spain, Switzerland, the United Kingdom, and the United States. Legal status Tiagabine is a prescription-only medication but not an otherwise controlled substance in the United States. ==Research==

In addition to epilepsy, tiagabine was under formal clinical development for the treatment of anxiety disorders, insomnia, and neuropathic pain. However, development for all of these indications was discontinued. The drug has been studied for treatment of post-traumatic stress disorder (PTSD). It has been studied for treatment of aggression. ==See also==