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

Tiagabine is a novel antiepileptic drug which has clinical efficacy against complex refractory and myoclonic seizures. The anticonvulsant mechanism of action of tiagabine results from its blockade of neuronal and glial GABA-uptake, thereby increasing GABA levels in the synaptic cleft. Here we present a comparison of the preclinical anticonvulsant profile of tiagabine with that of lamotrigine, gabapentin and vigabatrin in the following tests (all antiepileptic drugs were administered i.p.): seizures induced by pentylentetrazol (PTZ), 6,7-dimethoxy-4-ethyl-b-carboline-3-carboxylate (DMCM) and maximal electroshock (MES); sound induced seizures in DBA/2 mice and finally acute amygdala kindled seizures. Tiagabine was the most potent drug in antagonizing tonic convulsions induced by PTZ, DMCM and sound induced seizures in DBA/2 mice with ED50 values of 2, 2 and 1 mumol/kg, respectively, followed by lamotrigine with ED50 values of 9, 43 and 6 mumol/kg, respectively. Gabapentin and vigabatrin had ED50 values in the same tests of 185, 452, 66 mumol/kg and 2322, > 7740, 3883 mumol/kg, respectively. Tiagabine was the only drug capable of blocking PTZ-induced clonic convulsions (ED50 = 5 mumol/kg), an effect seen at low but not high doses of tiagabine. Lamotrigine was the only drug which antagonized tonic convulsions in the MES test (ED50 = 36 mumol/kg). Therapeutic index (TI) of antiepileptic drugs in NMRI- and DBA/2-mice ranked with decreasing TI lamotrigine > gabapentin > vigabatrin > tiagabine. All drugs reduced the generalized seizures in amygdala kindled rats, but tiagabine and gabapentin furthermore attenuated afterdischarge duration of amygdala kindled seizures. However, an ED50 value against amygdala kindled focal seizures was only obtained for tiagabine (36 mumol/kg). The data here presented show that tiagabine, lamotrigine, gabapentin and vigabatrin possess different preclinical anticonvulsant profiles which is of relevance to the clinical anticonvulsant profiles of the drugs.
 ...
PMID:Comparison of the preclinical anticonvulsant profiles of tiagabine, lamotrigine, gabapentin and vigabatrin. 925

The introduction on the French market of vigabatrin, gabapentin and lamotrigine has considerably diversified our conventional therapeutical schemes in epilepsies, as will be as amplified by the arrivals of topiramate, tiagabine and oxcarbazepine. Compared to the conventional drugs, these new products present more favorable pharmacokinetics, no or very weak interactions and a better tolerability, specially regarding the cognitive field. They should be used according to their spectrum of activity, function of their modes of action. In add-on trials on partial epilepsy patients all these new products have shown efficacy on partial and secondarily generalized seizures. Seizure frequency is reduced by at least 50 p. 100 in 30 to 50 p. 100 of the patients. A substantial number of patients can be rendered seizure-free with vigabatrin. Lamotrigine has a broader spectrum, as it is also efficacious on the different seizure types of generalized, symptomatic or idiopathic epilepsies. Main adverse events are non-specific central nervous system disturbances such as dizziness, drowsiness, ataxia, tremor or diplopia. More specifically, vigabatrin may induce weight gain and requires closer supervision in case of psychiatric history; lamotrigine which has also probable antidepressant properties, may induce skin rashs, rarely severe. Further data are needed for gabapentin which is now used at daily dosages which are two to three times those used in the initial studies. Gabamimetic agents may be worsening in some cases of generalized epilepsies, more specially on absence and myoclonic seizures. The most obvious benefits, some patients becoming seizure-free, are obtained in cases of intermediate severity, with a bitherapy including one of these new drugs. Developments in children are often delayed. Nevertheless the prognosis, including cognitive outcome, is considerably improved in infantile spasms with vigabatrin and in Lennox-Gastaut syndrome with lamotrigine and felbamate, the latter being highly toxic. For the moment in France, authorities have limited the use of all these new antiepileptic drugs to adjunctive therapy in epilepsies resisting to conventional drugs. But recent monotherapy data show similar efficacy with better tolerability. Once the pivotal, controlled studies have enabled to obtain regulatory approval, all these compounds must undergo a large-scale evaluation phase in order to better define dosages, long-term tolerability, indications and eventual contra-indications in the various epileptic syndromes, including children.
 ...
PMID:[Therapeutic options provided by new antiepileptic drugs]. 929 53

We report the results of an open trial with lamotrigine (LTG) as add-on drug in children and adolescents with refractory epilepsy and mental delay. Thirty-seven outpatients received LTG for a median period of 7 months at a daily dose of 5 and 15 mg/kg in valproate and non-valproate patients, respectively. The total number of seizures decreased by 100% in eight patients (21.6%) and by >50% in five patients (13.5%). However, the number of seizures remained unchanged in 20 patients (54.1%) and increased in four (10.8%). Lamotrigine was more effective in patients with typical and atypical absences, and in patients affected by atonic seizures. Six children (16.2%) developed generally mild adverse side-effects suggesting that LTG is well tolerated.
 ...
PMID:Lamotrigine as add-on drug in children and adolescents with refractory epilepsy and mental delay: an open trial. 933 67

In the last few years a number of new anticonvulsants have been introduced into clinical practice mainly as add-on therapy in patients who do not become seizure-free while receiving established anticonvulsants. Up to now, no single drug has been shown to be more effective at controlling seizures of a particular type than another, so other factors such as mechanism of action, pharmacokinetics, dosage regimens or the spectrum of adverse drug reactions and interactions are used when making a choice between one agent and another. The mechanism of action of tiagabine and vigabatrin is very specific; both agents increase gamma-aminobutyric acid (GABA) levels through inhibition of reuptake and catabolism respectively. However, the mechanism of action of gabapentin is unknown and those of felbamate, lamotrigine and topiramate are not sufficiently clarified as yet, and may be multiple. Great advances have been made in improving the pharmacokinetic characteristics of these newer anticonvulsants. Gabapentin and vigabatrin exhibit relatively ideal pharmacokinetic properties as they are not bound to proteins, are excreted mostly unchanged in the urine and show linear pharmacokinetics. Lamotrigine possesses a highly variable elimination half-life depending on the co-medication. Tiagabine is highly protein bound and zonisamide shows nonlinear pharmacokinetics; both these drugs are extensively metabolised. Problematic drug interactions between newer anticonvulsants and other drugs in general occur rarely when these agents are given concomitantly. However, in common with most new drugs, there are very few data on the use of the newer anticonvulsants in women of childbearing age. Studies done so far on interactions with oral contraceptives used low anticonvulsant dosages for a very short time. The newer anticonvulsants elicit adverse reactions that, while not being unique, are particularly associated with that drug. For example, felbamate may cause aplastic anaemia and fulminant liver failure, lamotrigine is prone to cause skin rash, and oxcarbazepine may cause symptomatic hyponatraemia. Topiramate and zonisamide cause kidney stones, and vigabatrin may induce psychiatric syndromes. Although highly diverse in structure and activity, these newer drugs offer new possibilities for treating refractory epilepsy. However, since no single factor can dictate the choice of drug nor predict the success of treatment, prescribing of these rather expensive drugs has to depend upon careful consideration of the aims of treatment, the characteristics of the drug and the needs of the individual patient.
 ...
PMID:Newer anticonvulsant drugs: role of pharmacology, drug interactions and adverse reactions in drug choice. 935 59

CBZ (mean 1219 mg, DS +/- 94.6) + LTG (mean 55.8 mg, DS +/- 80) were administered in 31 subjects with refractory partial complex and/or partial secondary generalized seizures. The age ranged from 18 to 62 years (mean/yr 37.1, DS +/- 12.5). This first trial is concluded after a period of 8-12 months (mean 11.4, DS +/- 11.2). A follow trial with LTG at lower dose monotherapy ranged from 125-250 mg (mean 190.32, DS +/- 40.6) was conducted in same patients. There was a 82.2% (DS +/- 15.3) reduction in total seizure frequency with LTG monotherapy compared to LTG + CBZ = 53.5 (DS +/- 29.3). The difference remained highly significant (p < 0.0001) in favor of LTG monotherapy. The LTG leads major improvement if submitted like a single drug in therapy resistant epilepsy.
 ...
PMID:[Lamotrigine: monotherapy in refractory epilepsy]. 937 49

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.
 ...
PMID:New drugs for persons with epilepsy. 940 64

Lamotrigine (LTG), an anticonvulsive drug, was tested for its effects on striatal content of DA and its metabolites, DOPAC and HVA, in audiogenic seizure-resistant (ER) and audiogenic seizure-prone (EP) lines of Balb/c mice. A single dose of LTG (20 mg/kg) prevented audiogenic seizures in seizure-prone mice, while reducing substantially the striatal content of the DA metabolite, DOPAC (to less than 50% of saline-injected controls) in both seizure-resistant and seizure-prone mice. LTG administration also resulted in significant reduction of striatal content of HVA. The in situ activity of tyrosine hydroxylase (TH) in extracts of striatum was significantly reduced by LTG administration in both ER and EP mice. These data show that DA synthesis in the striatum of mice is substantially reduced by LTG administration.
 ...
PMID:Lamotrigine inhibits the in situ activity of tyrosine hydroxylase in striatum of audiogenic seizure-prone and audiogenic seizure-resistant Balb/c mice. 941 65

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.
 ...
PMID:Antiepileptic drug cellular mechanisms of action: where does lamotrigine fit in? 942 23

Lamotrigine is a phenyltriazine derivative with anticonvulsant properties that initially was tested in adults with partial seizures. Pharmacokinetics in adults includes a volume of distribution of 1.0 to 1.3 L/kg. Plasma protein binding is 55% and none of the metabolites are active as anticonvulsants. The placebo-controlled studies evaluated the responder rate as the percent of patients with 50% or greater seizure reduction when compared to baseline assessment. The responder rate for 300 mg per day was 20% and 36% for 500 mg per day dosages. Adverse events were infrequent but the occurrence of rash appeared to correlate with rapid ascension dosing and comedication with valproic acid. Slow titration is required when initiating treatment with lamotrigine. Accumulating experience in adults suggests that lamotrigine has a broad spectrum of effect; data from further controlled trials should suggest other clinically important forms of epilepsy that respond to lamotrigine.
 ...
PMID:Adult experience with lamotrigine. 942 25

Lennox-Gastaut syndrome a combination of various generalized seizures including atypical absences and tonic seizures with generalized slow spike waves and mental deterioration, is often difficult to distinguish from a subgroup of myoclonic-astatic epilepsy, other generalized epilepsy syndromes, and various symptomatic generalized epilepsies. Conventional antiepileptic medication is poorly effective in this condition, particularly because various types of seizures respond differently to each given drug. Lamotrigine is effective in the various types of generalized seizures and efficacy has been demonstrated in Lennox-Gastaut syndrome. Given the potential of major mental deterioration within a matter of months in this condition, and the need of slow dose escalation in order to prevent skin rash, lamotrigine should be administered as soon as the diagnosis of Lennox-Gastaut syndrome is suspected. In addition, there is growing evidence that lamotrigine is also most useful in the subgroup of myoclonic-astatic epilepsy beginning in childhood, and that these patients should benefit from the drug like those affected by Lennox-Gastaut syndrome, as soon as the diagnosis is suspected. However, this drug may worsen other cases of myoclonic-astatic epilepsy beginning in infancy. These clinical observations add to the evidence for the need of clear diagnostic work-up before appropriate drug therapy is decided in pediatric epilepsy.
 ...
PMID:Use of lamotrigine in Lennox-Gastaut and related epilepsy syndromes. 942 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>