Objective Comparison of Phenobarbital and Diphenylhydantoin in Epileptic Patients

Gruber, Charles M.; Mosier, Jack M.; Grant, Phyllis; Glen, Ruby

doi:10.1212/wnl.6.9.640

Cited by 14 publications

(4 citation statements)

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“…In humans, the isobologram method cannot be used because it is impossible to titrate to exactly the same effect in all treatment groups. Gruber et al (43) used an approach somewhat similar to the isobologram method by giving patients 50 mg phenytoin, 50 mg phenobarbital, or a combination of 2.5 mg phenytoin plus 2.5 mg phenobarbital. All three regimens were found to have equal efficacy in this study, although it is surprising that 50 mg phenytoin was found to be as efficacious as 50 mg phenobarbital.…”

Section: Human Datamentioning

confidence: 99%

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

et al. 2000

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Summary:Purpose: When monothempy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which cornbinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches.Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers.Results: Thirty-nine papers were identified reporting on twodrug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. Conclusions:There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seeins less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.

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Section: Human Datamentioning

confidence: 99%

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

et al. 2000

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“…It is the purpose of this review to consider what is known about the efficacy and toxicity of commonly used, currently marketed antiepileptic drugs, as derived from information obtained from Pryse-Phillips et al, 1970Rodin et al, 1974 Carbarnazepine vs. phenytoin Rajotte et al, 1967Sirnonsen et al, 1976Troupin et al, 1977Kosteljanetz et al, 1979Ramsay et al, 1983Majerrison et al, 1968Rodin et al, 1976Mikkelsen et al, 1981 phenobarbital Cereghino et al, 1974 Carbarnazepine vs. phenytoin vs. phenobarbital vs. primidone Mattson et al, 1985 Carbarnazepine vs. phenytoin and/or phenobarbital and/or primidone Bird et al, 1966 placebo Gruber et al, 1956 primidone vs. placebo White et al, 1966 Phenytoin vs. pheneturide Gibberd et al, 1982Phenobarbital vs. clorazepate Wilensky et al, 1981 Valproic acid vs. placebo Richens andAhmad, 1975 Gram et al, 1977 Valproic acid vs. valproic acid Gram et al, 1979 Carbamazepine vs. phenobarbital (i.e., how long the drug remains sufficiently effective with sufficiently few side effects for the patient to continue using that drug rather than switching to another). -This review considers the results from the 20 controlled trials, discussed here in the context of these criteria for the evaluation of the efficacy of antiepileptic drugs.…”

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confidence: 99%

Efficacy and Safety of Antiepileptic Drugs: A Review of Controlled Trials

Treiman

1987

Epilepsia

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Twenty randomized, double-blind, controlled clinical trials of antiepileptic drugs (AEDs) in mostly adult patients with mostly partial onset and/or generalized tonic-clonic seizures have been reported, with a total of 1,336 patients. None of these studies has demonstrated significant differences in antiepileptic efficacy between available antiepileptic drugs, but the results show that there are considerable individual differences between patients' responses to the same drug. While side effects are common with all of the antiepileptic drugs currently available, these are usually mild and reversible. Although some toxic effects may occur more frequently with certain drugs, there is sufficient overlap between the effects of various antiepileptic drugs that most side effects cannot be attributed with certainty to any one drug. Since side effects are generally dose-related, they can frequently be avoided or minimized by careful dosage titration and individualization of therapy.

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“…Some of these weaknesses could be explained by poor understanding of clinical pharmacological principles, and by insufficient knowledge of the pharmacokinetics of the compounds being tested and the role of drug interactions. One illustrative example is a randomised placebo‐controlled cross‐over comparison of primidone and phenobarbital conducted in the mid fifties (Gruber et al , 1957). Twenty patients with epilepsy and focal brain damage were randomised to receive, in random order, each of as many as eight treatments, which consisted of phenobarbital at 50 mg and 100 mg, primidone at 125, 250, 500 and 1,000 mg, primidone at 125 mg plus phenobarbital at 50 mg, and placebo.…”

Section: The Days Of the Pioneers (Before 1970)mentioning

confidence: 99%

What clinical trial designs have been used to test antiepileptic drugs and do we need to change them?^*

Perucca¹

2012

Epileptic Disorders

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Designs used to evaluate the efficacy and safety of antiepileptic drugs (AEDs) have evolved considerably over the years. A major impulse to develop methodologically sound randomised controlled trials dates back to the Kefauver‐Harris Drug Amendment of 1962, through which the US congress introduced the requirement of substantial evidence for proof of efficacy in a new drug application. The mainstay for the initial approval of most new AEDs has been, and still is, the placebo‐controlled adjunctive therapy trial, which evolved over the years from the cross‐over to the parallel‐group design. In the early days, when few AEDs were available, enrolment of patients into these trials was relatively easy and prolonged placebo exposure could be justified by lack of alternative treatment options. With more than 20 drugs now available to treat epilepsy, however, exposing patients to placebo or to a potentially ineffective investigational agent faces practical and ethical concerns. Recruitment difficulties have led sponsors to markedly increase the number of trial sites, but there is evidence that this may adversely affect the ability to differentiate between effective and ineffective treatments. Methodological and practical difficulties are also encountered with monotherapy trials. Because regulatory guidelines for monotherapy approval differ between Europe and the US, sponsors need to pursue separate and costly development programs on the two sides of the Atlantic. Moreover, the scientific validity of the monotherapy trial paradigms currently used in Europe (the non‐inferiority design) and in the US (the conversion to monotherapy design with historical controls) has been questioned. This article will review these issues in some detail and discuss how trial designs and regulatory approval processes may evolve in the future to address these concerns.

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Objective Comparison of Phenobarbital and Diphenylhydantoin in Epileptic Patients

Cited by 14 publications

References 0 publications

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

Efficacy and Safety of Antiepileptic Drugs: A Review of Controlled Trials

What clinical trial designs have been used to test antiepileptic drugs and do we need to change them?^*

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Objective Comparison of Phenobarbital and Diphenylhydantoin in Epileptic Patients

Cited by 14 publications

References 0 publications

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

Efficacy and Safety of Antiepileptic Drugs: A Review of Controlled Trials

What clinical trial designs have been used to test antiepileptic drugs and do we need to change them?*

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Product

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What clinical trial designs have been used to test antiepileptic drugs and do we need to change them?^*