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)

Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6-10 h. The apparent volume of distribution (V(d)/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of -13.7% in female children comedicated with vigabatrin to a maximum of -46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related.
 ...
PMID:Rufinamide: clinical pharmacokinetics and concentration-response relationships in patients with epilepsy. 1850 64

The influence of smoking on lamotrigine (LTG) serum levels in 44 patients with epilepsy treated with LTG in monotherapy was examined. Fifteen patients were smokers (range: three cigarettes per month -- three packages per day) and 29 were non-smokers. Analyzing 204 samples, smokers had a significantly lower serum level-to-dose ratio than non-smokers (0.0657mmolmg/l (smokers) vs. 0.0785mmolmg/l (non-smokers)) (p=0.0014). Analyzing only male patients, the same relationship with an almost equally high level of significance could be demonstrated (p=0.008). Our data indicate that the demonstrated effect of smoking on LTG metabolism is likely to be mediated via UDPGT2B7, as LTG is not a substrate of cytochrome P450 isoenzymes and UDPGT1A4 activity may not be affected by nicotine, but the exact mechanism underlying the demonstrated effect remains uncertain. These findings are likely to be independent from hormonal changes, as they could also be reproduced in the group of male patients. Therefore, the effect of smoking on blood levels of LTG has to be taken into account in the evaluation of treatment with this drug.
Seizure 2008 Oct
PMID:Smoking reduces serum levels of lamotrigine. 1858 61

Seizures are not uncommon in patients with human immunodeficiency virus (HIV) infection, and with the upsurge in HIV infection this may be an important cause for acute symptomatic seizures. Seizures may rarely be the presenting manifestation of HIV infection. Opportunistic infections such as toxoplasmosis, tuberculosis, progressive multifocal leucoencephalopathy (PML), cryptococcal meningitis and polymicrobial infections, metabolic and electrolyte disturbances, and drugs are common causes of new-onset seizures in HIV-seropositive individuals. In the absence of any cause, primary HIV infection may be considered responsible for seizures. Because seizures tend to recur in and because they are a poor prognostic indicator in HIV infection, treatment with antiepileptic drugs (AEDs) is the norm. The treatment of HIV-infected individuals with seizures comprises of the administration of AEDs, specific treatment of the underlying conditions, and antiretroviral drugs. Clinicians must consider both therapy-compromising drug-drug and drug-disease interactions while choosing appropriate AEDs. The ideal AED in this setting is one that does not affect viral replication, have limited protein binding, and have no effects on the hepatic cytochrome P450 enzyme system. The risks for AED-induced allergic skin rash appears to be high in HIV-seropositive individuals.
 ...
PMID:Seizures in HIV-seropositive individuals: NIMHANS experience and review. 1875 59

Children with brain tumors and other cancers can suffer from seizures. Unfortunately, most antiepileptic therapies are metabolized by the hepatic cytochrome P450 (CYP) system. Levetiracetam, a newer anticonvulsant, does not undergo CYP metabolism and does not alter the pharmacokinetics of chemotherapy, antiemetics, and corticosteroids, which are metabolized by the liver. We studied 23 patients with cancer and seizures treated with levetiracetam. Over 95% of patients had fewer seizures, with 65.2% becoming seizure free; only one patient experienced an adverse reaction. Levetiracetam is effective and well tolerated in children with brain tumors and other cancers, who are often on multiple enzyme-inducing drugs.
 ...
PMID:Levetiracetam for seizures in children with brain tumors and other cancers. 1883 Oct 33

Contraceptive counseling is a critical component of the management of the female patient with epilepsy because of the increased risk of pregnancy associated with epilepsy and the multitude of interactions between antiepileptic drugs (AEDs) and hormonal contraception. Steroid hormones and many of the AEDs are substrates for the cytochrome P450 enzyme system, in particular, the 3A4 isoenzyme. As a result, concomitant use of hormonal contraceptives and AEDs may pose a risk for unexpected pregnancy, seizures, and drug-related adverse effects. The risk of combined oral contraceptive (COC) failure is slightly increased in the presence of cytochrome P450 3A4 enzyme-inducing AEDs. Several AEDs induce the production of sex hormone binding globulin (SHBG) to which the progestins are tightly bound, resulting in lower concentrations of free progestin that may also lead to COC failure. There is no increase in the risk of COC failure in women taking nonenzyme-inducing AEDs. Oral contraceptives significantly increase the metabolism of lamotrigine, posing a risk of seizures when hormonal agents are initiated and/or toxicity during pill-free weeks. There is no evidence that COCs increase seizures in women with epilepsy. While higher dose COCs are one contraceptive option for women on enzyme-inducing AEDs, a variety of other options are available. Injectable contraception (depot medroxyprogesterone acetate) appears effective with AED use, but the potential for bone mineral density loss is a concern. Intrauterine devices (IUDs) and barrier methods do not rely on hormonal components for contraceptive efficacy, and are therefore appropriate to recommend for use in women using enzyme-inducing medications. This chapter reviews the evidence regarding the pharmacokinetic interaction between AEDs and oral contraceptive hormones, the known or potential interactions with alternative contraceptive methods, and provides practical advice for management of contraceptive needs in reproductive-age women.
 ...
PMID:Contraception in women with epilepsy: pharmacokinetic interactions, contraceptive options, and management. 1892 78

Bone disease is recognized as an important pathologic process to identify and treat in women. Women are at greater risk than men secondary to multiple factors including estrogen loss in menopause. The most important consequence of bone disease is fracture. Fracture rates are higher in persons with epilepsy treated with antiepileptic drugs (AEDs). Increased bone turnover secondary to AED exposure, higher rates of osteoporosis, adverse effects on bone quality, seizures, and impaired coordination may all contribute. There is a differential effect of AEDs on bone. Although results are mixed for some AEDs, phenytoin use is consistently associated with lower bone mineral density (BMD). As most evidence associates cytochrome P450 enzyme-inducing AEDs with abnormalities in bone, the induction of these enzymes has been proposed as the main mechanism to describe this effect. However, data suggest that this theory does not explain all findings. Many therapies are available for the treatment of bone disease, but there is limited study in persons with epilepsy. All patients should receive at least the recommended daily allowance of calcium and vitamin D and obtain vitamin D status screening. For prolonged AED exposure, BMD screening is available, particularly if the patient has other risk factors.
 ...
PMID:Bone health in women with epilepsy: clinical features and potential mechanisms. 1892 90

Rufinamide, a triazole derivative that is structurally distinct from currently marketed antiepileptic drugs (AEDs), is in development for the adjunctive treatment of Lennox-Gastaut syndrome (LGS) in children and adults. Rufinamide is well absorbed after oral administration, demonstrates low protein binding, and is metabolized by enzymatic hydrolysis without involvement of cytochrome P450 enzymes, conferring a low drug interaction potential. In a randomized, double-blind trial involving 138 adult and pediatric patients with LGS, compared with placebo, rufinamide 45 mg/kg/day resulted in significantly superior reductions in drop attacks (median change -42.5% vs +1.4% with placebo) and total seizures (-32.1% vs -11.7% with placebo), accompanied by significantly higher responder rates. These results are comparable with findings reported for other AEDs in randomized, controlled clinical trials in patients with LGS. Rufinamide produced statistically significant seizure reduction which was maintained during long-term therapy and accompanied by good tolerability. The most frequently reported adverse events from a pooled safety database evaluating short- and long-term therapy were headache (22.9% and 29.5%), dizziness (15.5% and 22.5%) and fatigue (13.6% and 17.7%). Rufinamide therefore presents a favorable efficacy and tolerability profile and is a promising candidate for the adjunctive therapy of LGS.
 ...
PMID:Role of rufinamide in the management of Lennox-Gastaut syndrome (childhood epileptic encephalopathy). 1930 May 35

Zonisamide is a modern antiepileptic drug (AED) that is distinguished from other AEDs by its unique structure and broad mechanistic profile. Preclinical studies have reported a range of potential mechanisms of action for zonisamide, such as blocking voltage-gated sodium channels, reduction of T-type calcium channel currents, and enhancement of gamma-aminobutyric acid (GABA)-mediated inhibition, which are indicative of its broad antiseizure effects. Zonisamide has a favorable linear pharmacokinetic profile, a long half-life, and a low incidence of protein-binding interactions with other AEDs. Hepatically metabolized through the cytochrome P450 pathway, zonisamide does not induce its own metabolism or liver enzymes. For more than 2 decades, zonisamide has been extensively used as monotherapy and adjunctive therapy for the treatment of partial and generalized seizures in pediatric and adult patients in Japan. Zonisamide was approved in the USA in 2000 as adjunctive therapy for partial seizures in adults. With over 2 million patient-years of exposure internationally, zonisamide has demonstrated safety and efficacy against a multitude of epilepsy and seizure types, including both partial and generalized seizures. This review focuses on the experience and use of zonisamide in partial seizures, as well as possible new uses for zonisamide.
 ...
PMID:Zonisamide - a review of experience and use in partial seizures. 1941 74

Epileptic seizures are a common clinical problem in children with brain tumors. The conventional antiepileptic drugs (AEDs) permit a good seizure control in most of these children. An emerging problem is the possible interactions between AEDs and chemotherapeutic drugs, because many of these drugs are metabolized by the cytochrome P450. The aim of this article is to propose a novel therapeutic approach for new-onset epilepsy in children with brain tumors. Among the new AEDs not metabolized by the P450 system, levetiracetam seems to be a promising AED owing to its pharmacokinetic features, efficacy, and safety.
 ...
PMID:Interactions between antiepileptic and chemotherapeutic drugs in children with brain tumors: is it time to change treatment? 1973 34

Levetiracetam is a second-generation antiepileptic drug (AED) with a unique chemical structure and mechanism of action. The extended release formulation of levetiracetam (Keppra XR(); UCB Pharma) was recently approved by the Food and Drug Administration for adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. This approval is based on a double-blind, randomized, placebo-controlled, multicenter, multinational trial. Levetiracetam XR allows for once-daily dosing, which may increase compliance and, given the relatively constant plasma concentrations, may minimize concentration-related adverse effects. Levetiracetam's mode of action is not fully elucidated, but it has been found to target high-voltage, N-type calcium channels as well as the synaptic vesicle protein 2A (SV2A). Levetiracetam has nearly ideal pharmacokinetics. It is rapidly and almost completely absorbed after oral ingestion, is <10% protein-bound, demonstrates linear kinetics, is minimally metabolized through a pathway independent of the cytochrome P450 system, has no significant drug-drug interactions, and has a wide therapeutic index. The most common reported adverse events with levetiracetam XR were somnolence, irritability, dizziness, nausea, influenza, and nasopharyngitis. Levetiracetam XR provides an efficacious and well-tolerated treatment option for adjunctive therapy in the treatment of partial-onset seizures.
 ...
PMID:Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures. 1977 68


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