115103-54-3 Usage
Description
Tiagabine, also known as Gabitril, is a second-generation antiepileptic drug (AED) that functions as a potent and selective inhibitor of GABA uptake. It is structurally related to nipecotic acid and has an improved ability to cross the blood-brain barrier. Tiagabine is a white to off-white crystalline solid and is marketed as the single R(-)-enantiomer. It is well absorbed and readily metabolized by CYP3A4 to an inactive metabolite, 5-oxo-tiagabine, or eliminated as a glucuronide of the parent molecule.
Uses
Used in Pharmaceutical Industry:
Tiagabine is used as an antiepileptic drug for the treatment of epilepsy. It acts as a GABA uptake inhibitor, specifically targeting the GAT-1 GABA transporter in neurons and glia, thereby enhancing inhibitory GABAergic transmission. Its selectivity for the GAT-1 transporter and ability to cross the blood-brain barrier make it a potent GABA uptake inhibitor with a reduced potential for neurological side-effects.
Used in Epilepsy Treatment:
Tiagabine is used as an add-on therapy for patients with epilepsy who are refractory to other epilepsy treatments. It increases extracellular GABA concentration in the hippocampus, striatum, and cortex, prolonging the inhibitory action of GABA released synaptically. This helps in controlling partial seizures and provides an alternative treatment option for patients who do not respond well to other antiepileptic medications.
Generic formulation
MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):
It is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/ dosing error.
Indications
Epilepsy: adjunctive therapy for focal seizures with or without secondary generalization that are not satisfactorily controlled by other AEDs.
Recommendations summarized from NICE (2012)
Seizure types: on referral to tertiary care (focal seizures), contraindicated (generalized tonic- clonic seizures, tonic/ atonic seizures, absence seizures, myoclonic seizures).
Epilepsy types: on referral to tertiary care (benign epilepsy with centrotemporal spikes, panayiotopoulos syndrome, late- onset childhood occipital epilepsy), contraindicated (absence syndromes, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, Dravet syndrome, Lennox– Gastaut syndrome).
Dose titration
Epilepsy— adjunctive therapy (with enzyme- inducing AEDs): 5–10 mg daily divided into 1 or 2 doses for 7 days, then increased by 5–10 mg daily every 7 days; usual maintenance 30– 45 mg daily divided into 2 or 3 doses.
Epilepsy— adjunctive therapy (without enzyme- inducing AEDs): 5–10 mg daily divided into 1 or 2 doses for 7 days, then increased by 5–10 mg daily every 7 days; usual maintenance 30– 45 mg daily divided into 2–3 doses.
Plasma levels monitoring
The inter- individual variation in liver metabolism makes Tiagabine a strong candidate for therapeutic drug monitoring. A broad reference range of 20– 200 ng/ mL has been proposed, however, the relatively short half- life of Tiagabine under most conditions means that care must be taken in drawing blood for therapeutic drug monitoring. The high binding to serum proteins further suggests that measurement of free drug concentrations may be useful. However, there has been little investigation of the relationship between serum/ plasma concentrations and therapeutic efficacy.
Cautions
Patients with acute porphyrias.
Patients with absence, myoclonic, tonic and atonic seizures (risk of exacerbation).
Adverse effects
Tiagabine can be associated with adverse effects at the level the nervous system and other systems.
Interactions
With AEDs
AEDs that induce hepatic enzymes (such as carbamazepine, phenytoin, phenobarbital, and primidone) enhance the metabolism of tiagabine: the plasma concentration of tiagabine may be reduced by a factor .5– 3 by concomitant use of these AEDs.
Tiagabine reduces the plasma concentration of valproate by about 0% (this is not considered clinically important and does not warrant a dose modification).
With other drugs
Cimetidine increases the bioavailability of tiagabine by about 5% (this is not considered clinically important and does not warrant a dose modification).
The combination of tiagabine with St John Wort (Hypericum perforatum) may lead to lower exposure and loss of efficacy of tiagabine, due to the potent induction of CYP3A4 by St John Wort, resulting in increased tiagabine metabolism. Therefore, the combination of tiagabine with St John’s Wort is contraindicated.
With alcohol/food
There are no known specific interactions between alcohol and tiagabine and there are no specific foods that must be excluded from diet when taking tiagabine. Administration with food results in a decreased rate and not extent of absorption
Special populations
Hepatic impairment
Reduce dose, prolong the dose interval, or both, in mild to moderate impairment.
Avoid in severe impairment.
Renal impairment
Renal insufficiency does not affect the pharmacokinetics of Tiagabine, therefore its dosage does not need to be modified.
Pregnancy
Clinical experience of the use of tiagabine in pregnant women is limited and no information on tiagabine during breastfeeding is available. Therefore, as a precautionary measure, it is preferable not to use tiagabine during pregnancy or breast- feeding unless the potential benefits of treatment outweigh the potential risks.
In case of tiagabine treatment during pregnancy, the dose should be monitored carefully and adjustments made on a clinical basis.
Behavioural and cognitive effects in patients with epilepsy
Treatment with tiagabine has often been associated with depression and irritability.
Results from randomized double- blind, controlled trials with tiagabine
as adjunctive treatment have confirmed the incidence of psychiatric problems,
which can be mild- to- moderate in severity and can be reported more frequently
by patients with a personal history of affective disorders, or in case of rapid initial
titration. Tiagabine is characterized by a good profile in terms of cognitive adverse
effects, with mild effects on concentration and memory, which can be minimized
by slow initial titration.
Psychiatric use
Tiagabine has no approved indications in psychiatry and there is no conclusive evidence for its efficacy in the treatment of any behavioural problems.
Originator
Novo Nordisk (Denmark)
Manufacturing Process
A solution of 34 ml of n-butyl lithium in 30 ml of anhydrous ether was cooled
to -65°C under nitrogen and 5.3 ml of 3-methyl-2-bromothiophene in 10 ml
anhydrous ether was added dropwise over a period of 10 min. The reaction
mixture was stirred at -65°C for 1 h and 2.7 ml of ethyl 4-bromo-butyrate in
10 ml of anhydrous ether was added slowly. The reaction was stirred for 4 h
while the temperature raised to -20°C, 20 ml water was added, and the
mixture was stirred for 5 min after which the aqueous layer was removed. The
ether layer was washed with 20 ml of water, and the combined aqueous
phases were extracted with 50 ml of ether. The combined organic phases were
dried over anhydrous sodium sulfate, which after evaporation yielded 9 g of 1-
bromo-4,4-bis(3-methylthien-2-yl)but-3-ene as an oil.
This compound was without further purification used for coupling with ethyl
nipecotate.
A suspension of 5.0 g of 1-bromo-4,4-bis(3-methylthien-2-yl)but-3-ene, 3.4 g
of nipecotic acid ethyl ester and 3.3 g of potassium carbonate in 150 ml of dry
acetone was kept under reflux for 15 h. The reaction mixture was evaporated
and, after addition of 30 ml of water, the resulting solution was extracted
twice with 50 ml of ethyl acetate. The ethyl acetate extracts were dried and
evaporated leaving 7.3 g of an oil. By column chromatography on silica gel
using methanol as eluent, N-(4,4-bis(3-methylthien-2-yl)but-3-enyl)nipecotic
acid ethyl ester was isolated.
5.3 g of N-(4,4-bis(3-methylthien-2-yl)but-3-enyl)nipecotic acid ethyl ester
was dissolved in 100 ml of ethanol and 200 ml of an 8 N sodium hydroxide
solution was added. The mixture was heated at reflux for 1 h, cooled and
acidified by adding 10% hydrochloric acid. The resulting solution was
evaporated and 100 ml of water was added to the residue. The resulting acid
solution was extracted with ethyl acetate and the dried extract was
evaporated to give (R)-N-(4,4-bis(3-methylthien-2-yl)but-3-enyl)nipecotic acid
hydrochloride, melting point 187°-189°C.
Therapeutic Function
Antiepileptic
Biological Functions
Tiagabine (Gabitril) blocks the reuptake of GABA into
neurons and glia, thereby resulting in higher levels of
GABA in the synaptic cleft. The ability to increase
GABA concentrations is presumed to be involved in
the effectiveness of tiagabine in the treatment of seizure
disorders. It is primarily used in the treatment of partial
complex seizures.Adverse effects of tiagabine administration
include dizziness, somnolence, nervousness, nausea,
and confusion.
Mechanism of action
Tiagabine is a nipecotic acid derivative with an improved ability to cross the blood-brain barrier. It was rationally designed to
be a GABA uptake inhibitor based on the fact that nipecotic acid (piperidine-3-carboxylic acid) inhibits GABA uptake by glial cells. Tiagabine binds to the GABA transporter GAT1, blocking the uptake of GABA into both neurons and glia, thus enhancing
GABA-mediated inhibition. Tiagabine is presently approved for adjunct use in patients with epilepsy who are
older than 12 years and have partial seizures not controlled by first-line drugs.
Pharmacokinetics
Tiagabine is well absorbed, with an oral bioavailability of 90 to 95%. It displays linear pharmacokinetics, with a plasma half-life
of 5 to 8 hours, necessitating a multiple daily dosing regimen. It also is highly protein bound (96%). The major pathway of
metabolism for tiagabine is oxidation by CYP3A4, followed by glucuronidation. Its pharmacokinetics are altered by the coadministration of enzyme-inducing AEDs, even though tiagabine does not appear to induce or inhibit hepatic microsomal
metabolizing enzymes.
Clinical Use
Antiepileptic
Side effects
Side effects are more common with tiagabine than with other adjunct drugs and most often involve the CNS. They include
somnolence, headache, dizziness, tremor, abnormal thinking, depression, and psychosis. Furthermore, recent reports have
implicated tiagabine in the development of nonconvulsive status epilepticus. There is an increased risk of seizure in
patients being treated for off-label psychiatric indications. Tiagabine may interfere with visual color perception.
Tiagabine does not affect the hepatic metabolism of other AEDs, but its half-life is decreased by enzyme-inducing AEDs, such
as CBZ, phenytoin, and barbiturates. Other CYP3A4-inducing drugs may act similarly. Valproate decreases the protein binding
of tiagabine. increasing its plasma concentration in these patients.
Hepatic disease causes decreased clearance of tiagabine, and a dose reduction may be required. Renal disease does not
affect elimination.
Drug interactions
Potentially hazardous interactions with other drugs Antidepressants: antagonism of anticonvulsant effect with SSRIs, tricyclics and MAOIs (convulsive threshold lowered); avoid with St John’s wort. Antiepileptics: concentration reduced by phenytoin, carbamazepine and phenobarbital. Antimalarials: mefloquine antagonises anticonvulsant. Antipsychotics: anticonvulsant effect antagonised. Orlistat: possibly increased risk of convulsions.
Metabolism
Tiagabine has negligible renal clearance. Hepatic metabolism is the principle route for elimination of tiagabine. Less than 2% of the dose is excreted unchanged in urine and faeces. No active metabolites have been identified.
Check Digit Verification of cas no
The CAS Registry Mumber 115103-54-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,5,1,0 and 3 respectively; the second part has 2 digits, 5 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 115103-54:
(8*1)+(7*1)+(6*5)+(5*1)+(4*0)+(3*3)+(2*5)+(1*4)=73
73 % 10 = 3
So 115103-54-3 is a valid CAS Registry Number.
InChI:InChI=1/C20H25NO2S2/c1-14-7-11-24-18(14)17(19-15(2)8-12-25-19)6-4-10-21-9-3-5-16(13-21)20(22)23/h6-8,11-12,16H,3-5,9-10,13H2,1-2H3,(H,22,23)/t16-/m1/s1
115103-54-3Relevant articles and documents
Iridium-catalyzed enantioselective hydrogenation of unsaturated heterocyclic acids
Song, Song,Zhu, Shou-Fei,Pu, Liu-Yang,Zhou, Qi-Lin
, p. 6072 - 6075 (2013/07/05)
Spiral binding: A highly enantioselective hydrogenation of unsaturated heterocyclic acids has been developed by using chiral iridium/spirophosphino oxazoline catalysts (see scheme; BArF-=tetrakis[3,5- bis(trifluoromethyl)phenyl]borate, Boc=tert-butoxycarbonyl). This reaction provided an efficient method for the preparation of optically active heterocyclic acids with excellent enantioselectivities. Copyright
MODIFIED FORM OF THE R(-)-N-(4,4-DI(3-METHYLTHIEN-2-YL)BUT-3-ENYL)-NIPECOTIC ACID HYDROCHLORIDE
-
, (2008/06/13)
-
The Synthesis of Novel GABA Uptake Inhibitors. 1. Elucidation of the Structure-Activity Studies Leading to the Choice of (R)-1--3-piperidinecarboxylic Acid (Tiagabine) as an Anticonvulsant Drug Candidate
Andersen, Knud Erik,Braestrup, Claus,Groenwald, Frederik C.,Joergensen, Anker S.,Nielsen, Erik B.,et al.
, p. 1716 - 1725 (2007/10/02)
A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties.The in vitro value for inhibition of 3H>-GABA uptake in rat synaptosomes was determined for each compound.It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroatomic groups.The majority of the compounds described are structurally related to tiagabine, (R)-1--3-piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.