Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Between 30% and 60% of patients with epilepsy have not achieved adequate control with current medications, and side effects are a significant problem. In the past 2 years, three drugs for epilepsy have been approved. At least six more drugs are in the final stages of development, and there is an active "pipeline." None of the new drugs are panceas, but many have special advantages and meet important specific needs. Felbamate, despite a high incidence of aplastic anemia and hepatic failure, remains useful because of its lack of sedative effects and high efficacy. Gabapentin is remarkable for its favorable side effect profile, lack of interactions, and straightforward kinetics. Lamotrigine is also nonsedating and may be especially useful in generalized epilepsies. Topiramate and vigabatrin are both highly effective, although each is associated with a variety of cognitive or psychiatric side effects that may limit utility. Oxcarbazepine shares the efficacy of carbamazepine, with fewer side effects or drug interactions. Zonisamide seems to be effective and cause mild side effects, although the risk for renal stones indicates a need for cautious use. Tiagabine, like gabapentin, is a mild drug with a favorable side effect profile. New forms of old drugs will make for easier administration; fosphenytoin will increase the safety of parenchymal phenytoin use. The best of the new drugs help, at most, 10% of previously uncontrolled patients to become seizure-free. The development of new drugs remains an important need.
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PMID:New drugs for persons with epilepsy. 940 64

Current frontline antiepileptic drugs tend to fall into several cellular mechanistic categories, and these categories often correlate with the clinical spectrum of action of the various antiepileptic drugs. Many antiepileptic drugs effective in control of partial and generalized tonic-clonic seizures are use- and voltage-dependent blockers of sodium channels. This mechanism selectively dampens pathologic activation of sodium channels, without interacting with normal sodium channel function. Examples include phenytoin, carbamazepine, valproic acid, and lamotrigine. Many antiepileptic drugs effective in control of generalized absence seizures block low threshold calcium currents. Low threshold calcium channels are present in high densities in thalamic neurons, and these channels trigger regenerative bursts that drive normal and pathologic thalamocortical rhythms, including the spike wave discharges of absence seizures. Examples include ethosuximide, trimethadione, and methsuximide. Several antiepileptic drugs that have varying clinical actions interact with the gamma-amino-butyric acid (GABA)ergic system. Diazepam and clonazepam selectively augment function of a subset of GABAA receptors, and these drugs are broad-spectrum antiepileptic drugs. In contrast, barbiturates augment function of all types of GABAA receptors, and are ineffective in control of generalized absence seizures, but effective in control of many other seizure types. Tiagabine and vigabatrin enhance cerebrospinal levels of GABA by interfering with reuptake and degradation of GABA, respectively. These antiepileptic drugs are effective in partial seizures. Lamotrigine is effective against both partial and generalized seizures, including generalized absence seizures. Its sole documented cellular mechanism of action is sodium channel block, a mechanism shared by phenytoin and carbamazepine. These drugs are ineffective against absence seizures. Consequently, unless there are unique aspects to the sodium channel block by lamotrigine, it seems unlikely that this mechanism alone could explain its broad clinical efficacy. Therefore, lamotrigine may have as yet uncharacterized cellular actions, which could combine with its sodium channel blocking actions, to account for its broad clinical efficacy.
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PMID:Antiepileptic drug cellular mechanisms of action: where does lamotrigine fit in? 942 23

Tiagabine x HCl is being developed as an anti-convulsant/anti-epileptic agent for seizure disorders. The pharmacological activity of the R-(-)-enantiomer is higher than that of the S-(+)-enantiomer. Therefore, the drug is synthesized in the pure R-(-)-enantiomeric form. The enantiomers of tiagabine x HCl were separated on a modified cellulose stationary phase (Chiralcel-OD) with a mobile phase of hexane-isopropanol-ethanol (80:14:06, v/v/v). Approximately 5 ml of trifluoroacetic acid was added for each liter of the mobile phase mixture. The method is capable of separating the two enantiomers with a selectivity factor of 1.55 and a resolution factor of 3.4. The samples of tiagabine x HCl were monitored by a UV detector at 260 nm. The method was validated by conducting standard addition and recovery of the S-(+)-enantiomer in tiagabine x HCl. The R.S.D. of the method is 3.2%. The limit of quantification (LOQ) of the S-(+)-enantiomer present in tiagabine x HCl is about 0.03%.
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PMID:Separation and quantitation of the S-(+)-enantiomer in the bulk drug tiagabine x HCl by chiral high-performance-liquid chromatography using a Chiralcel-OD column. 949 77

Tiagabine is a gamma-aminobutyric acid (GABA) uptake inhibitor which is structurally related to nipecotic acid but has an improved ability to cross the blood-brain barrier. Clinical trials have shown that tiagabine is effective as add-on therapy in the management of patients with refractory partial epilepsy. In short term studies of this indication, tiagabine < or = 64 mg/day for 7 to 12 weeks reduced the complex partial and simple partial seizure frequency by > or = 50% in 8 to 31 and 28.2 to 37% of patients, respectively. Tiagabine appeared to produce a sustained reduction in seizure frequency in studies of up to 12 months' duration. Data from preliminary studies are currently insufficient to confirm the usefulness of tiagabine when used as monotherapy or in the treatment of children with epilepsy. Further studies are, therefore, necessary to more fully elucidate the efficacy of the drug in these settings. Adverse events associated with tiagabine are primarily CNS-related and include dizziness, asthenia, nonspecific nervousness and tremor. Skin rash or psychosis occurred with similar frequencies among tiagabine- and placebo-treated patients. With long term administration (> or = 1 year for many patients), the profile and incidence of adverse events was similar to that for short term therapy. Tiagabine does not appear to affect the hepatic metabolism of other drugs such as carbamazepine and phenytoin. Possible disadvantages of tiagabine include its short plasma elimination half-life, necessitating 2 to 4 times daily administration, and its inducible hepatic metabolism. Thus, tiagabine is a new antiepileptic agent with a novel mechanism of action, which has demonstrated efficacy in the adjunctive treatment of patients with refractory partial epilepsy. Further investigation of the efficacy of tiagabine is expected to provide a clearer definition of its place in the treatment of epilepsy and its relative merits in relation to other antiepileptic drugs.
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PMID:Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy. 953 May 48

In a multicentre, double-blind, parallel-group, placebo-controlled trial, a three-times daily regimen of tiagabine was evaluated as add-on therapy in 154 adult patients with refractory partial seizures. A total of 77 patients were randomised to treatment in each arm. Tiagabine HCl was titrated from an initial dose of 12-30 mg/day over 4 weeks. During the 12-week fixed-dose period, there was a significant reduction in the median 4-weekly seizure rate for all partial seizures and simple partial seizures (P < 0.05 in each case). Furthermore, the proportion of patients with a reduction of 50% or more in all partial seizures was higher in the tiagabine group than in the placebo group (14 versus 6%), though the difference did not achieve statistical significance. The difference with respect to simple partial seizures was significant (21 versus 6%, P < 0.01). The percentage of patients achieving an increase of at least 50% in the proportion of days free of all partial seizures was significantly greater in the tiagabine group compared to placebo (14 versus 4%, P<0.01). Tiagabine did not appear to influence the plasma concentrations of other concomitant antiepileptic drugs and was generally well tolerated, with most drug-related adverse events being mild or moderate in severity. The most common adverse events were dizziness, asthenia, headache and somnolence. Adverse event incidence was similar between tiagabine and placebo groups, except for dizziness which was more common with tiagabine (29 versus 10%, P < 0.01). Tiagabine had no significant effects on laboratory tests or vital signs. The present study shows that tiagabine, at a dose of 10 mg administered three-times daily, which is at the lower end of the usual recommended dose range (30-50 mg/day, tiagabine base), is generally well tolerated and demonstrates efficacy for the treatment of refractory partial seizures.
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PMID:A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group. 955 42

Tiagabine exerts its antiepileptic drug (AED) activity by selectively inhibiting the uptake of gamma-aminobutyric acid (GABA) onto the transporter molecules, and thus, increasing extracellular concentrations of GABA in the brain. The absorption and elimination of tiagabine follow linear pharmacokinetics. Tiagabine is metabolized by hepatic cytochrome P450 enzymes and enzyme-inducing AEDs increase tiagabine clearance by 50-65%. Tiagabine has shown no clinically important interactions with other drugs, including oral contraceptives. In the perforant pathway stimulation model of status epilepticus, tiagabine reduced the seizure number and severity, and also prevented the loss of pyramidal cells in the hippocampus as well as alleviated impairment of the spatial memory impairment associated with hippocampal damage. Tiagabine has both antiepileptogenic and anticonvulsant effects in the kindling model of epilepsy. Based on the data from the short- and long-term add-on studies, tiagabine is effective adjunctive therapy for all partial seizure types in adolescents and adults. Conversion to tiagabine monotherapy has been also possible in substantial amount of patients with partial seizures in three trials. Tiagabine is generally well-tolerated. The most common adverse events in controlled studies involve the central nervous system; for example, dizziness, asthenia, nervousness, tremor, depressed mood and emotional lability. Special safety analyses with formal neuropsychological testing suggest that tiagabine does not adversely affect cognition or mood. Tiagabine represents an important new therapeutic option for patients with treatment-refractory partial seizures. The role of tiagabine in the management of partial epilepsy of patients with intellectual disability is especially emphasized since tiagabine has a low side-effect profile in the cognitive area.
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PMID:Tiagabine: a new therapeutic option for people with intellectual disability and partial epilepsy. 1003 Apr 35

(1) Tiagabine combination therapy has been assessed in quality clinical trials. (2) In patients with partial epilepsy placebo-controlled trials have shown that, in combination with an antiepileptic treatment considered ineffective, tiagabine reduces the frequency of seizures by at least 50% in approximately a quarter of patients. (3) Its efficacy does not appear to be superior to that of viga batrin, gabapentin, lamotrigine or progabide, but there have been no direct comparisons between tiagabine and these other antiepileptic drugs. (4) The main adverse effects of tiagabine are neuropsychological. No serious adverse effects have been described. (5) Tiagabine is not an enzyme inducer but efficacy can be reduced if it is combined with enzyme-inducing antiepileptics. (6) Tiagabine therapy cannot be monitored using plasma drug levels.
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PMID:Tiagabine: new preparation. Refractory partial epilepsy: another alternative. 1034 43

Several medications such as baclofen, amitriptyline and even antiepileptic drugs such as carbamazepine or vigabatrin are known to induce absence status epilepticus in patients with generalized epilepsies. Tiagabine (TGB) is effective in patients with focal epilepsies. However, TGB has also been reported to induce non-convulsive status epilepticus in several patients with focal epilepsies and in one patient with juvenile myoclonic epilepsy. In animal models of generalized epilepsy, TGB induces absence status with 3-5 Hz spike-wave complexes. We describe a 32-year-old patient with absence epilepsy and primary generalized tonic-clonic seizures since 11 years of age, who developed her first absence status epilepticus while treated with 45 mg of TGB daily. Administration of lorazepam and immediate reduction in TGB dosage was followed by complete clinical and electroencephalographic remission. This case demonstrates that TGB can induce typical absence status epilepticus in a patient with primary generalized epilepsy.
Seizure 1999 Aug
PMID:Tiagabine-induced absence status in idiopathic generalized epilepsy. 1048 98

Tiagabine (TGB) is a recently approved antiepileptic drug (AED) that inhibits y-aminobutyric acid (GABA) reuptake into neurons and glia, a mechanism of action that is specific and unique among the AEDs. TGB is potent and has linear and predictable pharmacokinetics. It has no clinically relevant effects on hepatic metabolism or serum concentrations of other AEDs, effects on laboratory values, or interactions with common non-AEDs. TGB is effective as add-on therapy for partial seizures in patients with medically refractory epilepsy in doses ranging from 30 to 56 mg daily. Conversion to TGB monotherapy can be achieved in patients with medically refractory epilepsy, although additional controlled studies are needed to confirm the efficacy of TGB as monotherapy and to establish the effective dosage range. In controlled studies, the most common adverse events of TGB are dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea, and nervousness. These are usually mild to moderate in severity and almost always resolve without medical intervention.
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PMID:Tiagabine. 1053 Jun 90

Preliminary pharmacologic evidence suggests that tiagabine, a new presynaptic gamma-aminobutyric acid-uptake inhibitor developed as an antiepileptic drug, may also relieve spasticity. This pilot study assessed the drug's efficacy in 14 children with congenital or acquired spastic quadriplegia and concomitant intractable epilepsy refractory to treatment with multiple antiepileptic drugs. The primary outcome variable was change in motor function; the secondary outcome was change in seizure frequency. Tiagabine was initiated at 0.1-0.2 mg/kg/day and then gradually titrated upward until seizures ceased, adverse effects supervened, or the maximum dose of 1.1 mg/kg/day was reached. When a modified Ashworth scale was used to assess motor function, a mean improvement of approximately 50% was observed. Common findings included improved tone, strength, coordination, range of motion, and relaxation of extremities, with less ataxia and wobbling. Mean reduction in seizure frequency was 50-74%. Randomized, double-blind controlled studies are needed to confirm the suggested efficacy of tiagabine in relieving chronic spasticity in children with neurodevelopmental disorders.
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PMID:The effect of tiagabine on spasticity in children with intractable epilepsy: a pilot study. 1058 Aug 85


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