Therapy For Seizures In Patients Research Articles

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam.

Clobazam (CLB) is a 1,5‐benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox‐Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single‐ and multiple‐dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N‐desmethylclobazam. The half‐life of CLB after a single oral dose ranges from 36 to 42 hours; the half‐life of N‐desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox‐Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike.

Optimizing therapy of seizures in patients with brain tumors

The mechanism of epilepsy in brain tumor patients is probably multifactorial, and its incidence depends on tumor type and location. Refractory epilepsy is common in patients with structural brain lesions, and a role for multidrug-resistance proteins has been suggested. The medical treatment of epilepsy in brain tumor patients has mainly been studied retrospectively, and the optimal management of seizures with antiepileptic drugs (AEDs) is unclear. Enzyme-inducing anticonvulsants are generally not recommended because they can lead to insufficient serum levels of concomitantly administered chemotherapeutic drugs. Although valproic acid is an enzyme inhibitor and may therefore lead to toxic levels of simultaneously administered chemotherapeutic agents, this does not appear to be a major problem in patients with brain tumors. Preliminary observations of add-on treatment with the AEDs levetiracetam or gabapentin suggest that these non-enzyme-inducing AEDs can be useful for control of seizures in patients with brain tumors. Conversely, prophylactic use of AEDs in brain tumor patients is generally not recommended.

Optimizing therapy of seizures in patients with HIV and cysticercosis

Worldwide, about 40 million people are living with HIV and 50 million people have neurocysticercosis (NCC). About 5% of patients with HIV and the majority of patients with NCC develop recurrent seizures. Mechanisms of seizure production in HIV include mass lesions, meningitis, encephalitis, and ischemia. Seizures in NCC may occur at all stages of cyst development, from the vesicular and colloidal to the calcified stages. Seizures in HIV present special problems with regard to choice of antiepileptic drug (AED) and the potential for drug-drug interactions with antiretroviral (ARV) treatments. Newer AEDs with simpler pharmacokinetic profiles may be the preferred agents, particularly when protease inhibitors form part of ARV regimens. Seizures in NCC are easily controlled with the older AEDs. Although there has been some debate about the value of antiparasitic drugs in NCC, accumulating data suggest that the use of these agents in active disease decreases the risk for development of chronic epilepsy.

Optimizing therapy of seizures in patients with endocrine disorders

Endocrinologic disorders, such as thyroid dysfunction or diabetes, may be comorbidities in patients with epilepsy. The choice of medication should address such comorbidities wherever possible. Enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine, phenytoin, barbiturates, and oxcarbazepine among the new AEDs, may reduce the levels of free and total thyroxin. However, clinically relevant thyroid dysfunction owing to AED treatment is rare. Nevertheless, there are now better alternative AEDs with similar efficacy to the classic first-line drugs but without their enzyme-inducing properties. Such drugs should be considered in cases of thyroid dysfunction to reduce the likelihood of iatrogenic adverse effects. Sufficient data on some of the new AEDs to support this hypothesis are, however, still lacking and urgently needed. Several reports have pointed out the possible negative impact of valproate on glucose and insulin metabolism and particularly on body weight. The increased risk for development of polycystic ovarian syndrome remains a matter of debate but is certainly another argument for the development of alternative agents. The group of new AEDs offers some potential candidates. Topiramate is the AED that is most likely to lead to weight loss; this may be perceived as a positive side effect in some patients. This review summarizes the data on the possible impact of AEDs in endocrinological disorders, concentrating on thyroid dysfunction, insulin/glucose metabolism, and body weight.

Optimizing therapy of seizures in patients with renal or hepatic dysfunction

Patients with epilepsy may suffer from renal or hepatic diseases that interfere with their antiepileptic drug (AED) treatment. Furthermore, such diseases may themselves cause seizures. Reduced renal function and hypoalbuminemia lead to accumulation of renally excreted AEDs, such as gabapentin, vigabatrin, topiramate, levetiracetam, and phenytoin. Valproate, lamotrigine, and benzodiazepines are less affected. Low protein-bound AEDs are extensively removed by hemodialysis and supplemental doses are required for dialysis patients. Uremia and related conditions, including intracranial hemorrhage, glucose and electrolyte imbalances, and concomitant drug use, can cause seizures, as can dialysis encephalopathy, primary cerebral lymphoma, fungal infections, and immunosuppressant toxicity in renal transplant recipients. Hepatic dysfunction reduces enzymatic metabolism of AEDs and causes hypoalbuminemia. Gabapentin, topiramate, and levetiracetam are preferred in these conditions, whereas conversely valproate and felbamate are potentially hepatotoxic and should be avoided. Seizures related to hepatic encephalopathy are controlled by oral lactulose or neomycin. Porphyria sufferers may benefit from gabapentin, oxcarbazepine, or levetiracetam. Seizures in Wilson's disease may derive from d-penicillamine-induced pyridoxine deficiency. Effective treatment of seizures in renal and hepatic diseases requires attention to changes in AED pharmacokinetics and adequate care of the underlying illnesses. Monitoring of free drug concentrations is a valuable aid to therapy.

Efficacy and tolerability of gabapentin in clinical practice

The efficacy and tolerability of gabapentin therapy for seizures in patients in clinical practice were retrospectively evaluated. Demographics, seizure type and history, prior anticonvulsant therapy, concomitant anticonvulsant medications, gabapentin dosing, side effects, seizure response, and tolerability data were obtained from 100 consecutive clinical practice patients (47 men and 53 women) treated with gabapentin. All patients had been previously treated with a mean of 2.9 anticonvulsant drugs and were currently taking a mean of 1.75 anticonvulsant drugs. Seventy-two patients experienced a greater than 50% reduction in seizures, and 23 of these patients experienced a greater than 75% reduction; 57 patients continued gabapentin treatment, 5 of whom remain seizure free and side effect free with gabapentin monotherapy. Of the 42 patients discontinuing treatment, 17 had no seizure reduction, 17 had side effects, and 8 had both. One additional patient died. The mean daily dosage for all 100 patients was 2107 mg, and the mean daily dosage for patients who continued gabapentin treatment was 2270 mg. No linear relationship was found between dosage and patient weight. Fifty-two patients had the dosage of at least 1 concomitant anticonvulsant medication reduced, 31 had at least 1 concomitant anticonvulsant medication removed from the regimen, and 9 required a dosage increase of at least 1 anticonvulsant medication. Twenty patients experienced fatigue, which was usually transient after treatment initiation; in 13 patients fatigue was associated with carbamazepine therapy. In addition, 7 patients experienced ataxia (6 of whom were taking concomitant carbamazepine), and 2 experienced weight gain. Patients experiencing side effects resulting in discontinuation were taking a mean daily dose of gabapentin of 1182 mg. The maximum effective and tolerable daily dosage under clinical practice conditions appears to exceed dosages established in clinical trials. The results of our study suggest broader treatment parameters for gabapentin than initially determined in the more restrictive clinical trials conducted during the drug's development.