Epilepsy trials

In the early 1960s, there was a near-simultaneous introduction of carbamazepine and valproic acid and its derivatives, as new treatments for epilepsy. Although in 1882 Beverly S. Burton, an American working in Europe, had prepared valproic acid, its antiepileptic utility was not appreciated until this was serendipitously discovered 65 years later by Meunier in France. Carbamazepine was first synthesized in 1960, in the United States by Schindler — who, a decade earlier, had patented the stmcturally closely related imipramine and it was found to have antiepileptic properties. When concurrent remedial effects on mood and behaviour were noted with both carbamazepine and valproic acid in the very early epilepsy trials, both drags were soon appropriated by psychiatrists, first by Lambert in France (1966), using the amide derivative of valproic acid. 

Gupta, M., Aneja, S. Kohli, K. (2005). Add-on melatonin improves sleep behavior in children with epilepsy randomized, double-blind, placebo-controlled trial. 

Richens, A., Chadwick, D. W., Duncan, J. S., et al. (1995) Adjunctive treatment of partial seizures with tiagabine a placebo-controlled trial. Epilepsy Res. 21, 37 42. 

Ben-Menachem, E., Soderfelt, B., Hamberger, A., Hedner, T., and Persson, L. I. (1995) Seizure frequency and CSF parameters in a double-blind placebo controlled trial of gabapentin in patients with intractable complex partial seizures. Epilepsy Res. 21,231-236. 

In addition to epilepsy, neuronal death due to the toxic effects of glutamate has also been implicated in cerebral ischaemia associated with multi-infarct dementia and possibly Alzheimer s disease. With the plethora of selective excitatory amino acid receptor antagonists currently undergoing development, some of which are already in clinical trials, one may expect definite advances in the drug treatment of neurodegenerative disorders in the near future. 

Somnolence - In controlled trials of patients with epilepsy, 14.8% of levetiracetam-treated patients reported somnolence compared with 8.4% of placebo patients. 

Elderly No overall differences in safety were observed between subjects 65 years of age or older and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the efficacy of levetiracetam in these patients. Because elderly patients are more likely to have decreased renal function, take care in dose selection it may be useful to monitor renal function. 

Seizures An increased incidence of seizures has been reported in patients with a history of epilepsy who received the related drug amantadine. In clinical trials, the occurrence of seizure-like activity was observed in a small number of patients with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine. If seizures develop, discontinue the drug. 

The use of estimates of treatment effect based on indirect comparisons when there is a common comparator has recently been shown on many occasions to agree with the results of head-to-head clinical trials (Song et al. 2003). Clearly a more challenging situation exists where there is not a common parameter, for example, in a recent study of the relative cost effectiveness of newer drugs for treatment of epilepsy (Wilby et al. 2003). In this study, Bayesian Markov chain Monte Carlo models for multiparameter synthesis were used (Ades 2003). Here, complex models were used to analyze a set of clinical studies involving a series of clinical alternatives, including the two alternatives of interest. 

Bassel W, Abou-Khalil MD. Comparative monotherapy trials and the clinical treatment of epilepsy. Epilepsy Cnrr 2007 7(5) 127-9. 

An other Cochrane review of nine trials representing 1049 randomized patients concludes Top-iramate has efficacy as an add-on treatment in patients with drug resistant partial epilepsy. However, trials reviewed were of relatively short duration, and provide no evidence for the long term efficacy of top-iramate. Results cannot be extrapolated to monotherapy or patients with other epilepsy types . 

Felbamate (Felbatol) was introduced with the expectation that it would become a major drug in the treatment of epilepsy. Felbamate exhibited few manifestations of serious toxicity in early clinical trials. Soon after its introduction, however, it became apparent that its use was associated with a high incidence of aplastic anemia. Consequently, felbamate is indicated only for patients whose epilepsy is so severe that the risk of aplastic anemia is considered acceptable. 

Brodie MJ and Whitehead J (2006) Active control comparisons the ideal trial design Epilepsy Research, 68, 70-73... 

High plasma levels of DVP (80-150 pg/mL 555-1,040 pmol/L) are expected to produce significantly more frequent tremors, thrombocytopenia, alopecia, asthenia, diarrhea, vomiting, and anorexia, compared to low serum levels (25-50 j,m/mL 175-345 pmol/L), as shown in a multicenter trial of DVP monotherapy in patients with poorly controlled partial epilepsy (Beydoun et al., 1997). 

Beydoun, A., Sackellares, J.C., and Shu, V. (1997) Safety and efficacy of divalproex sodium monotherapy in partial epilepsy a doubleblind, concentration-response design clinical trial. Depakote Monotherapy for Partial Seizures Study Group. Neurology 48 182-188. 

Elood JE, Earr SA, Uezo K, et al The pharmacology of post-trial memory processing in septum. Eur. J Pharmacol 350 31-38, 1998 Elor-Henry P Psychosis and temporal lobe epilepsy a controlled investigation. Epilepsia 10 363-395, 1969... 

Kramer MS, Cutler NR, Ballenger JC, et al A placebo-controUed trial of L-365,260, a CCKB antagonist, in panic disorder. Biol Psychiatry 37 462-466, 1995 Krauss GL, Fisher RS Cerebellar and thalamic stimulation for epilepsy, in Electrical and Magnetic Stimulation of the Brain and Spinal Cord. Edited by Devinsky O, Beric A. New York, Raven, 1993, pp 231-245 Krell RD, Goldberg AM Effect of acute and chronic administration of lithium on steady-state levels of mouse brain choline and acetylcholine. Biochem Pharmacol 22 3289-3291, 1973... 

Since the dawn of humankind, efforts have been made to discover remedies for the ailments of life. Although there are numerous examples of the trials and tribulations associated with these efforts, the story of epilepsy affords many instructive anecdotes. 

Table 5-27 and Table 5-28 summarize the clinically relevant pharmacokinetic and pharmacodynamic properties of other novel antipsychotics ( 326). Drug interactions with these agents were not systematically evaluated because controlled clinical trials usually prohibit concurrent medications. There are also many special circumstances (e.g., patients with comorbid medical diseases, substance abuse, epilepsy, or atypical indications such as agitation associated with mental retardation or dementia) that are not usually addressed in clinical research trials. Thus, much remains to be learned about significant drug interactions in these patient groups. To our knowledge, however, no consistent, serious, clinically relevant interactions have been reported. 

This herb has been part of folk medicine since pre-Christian times (247). It has been primarily used as a sedative and for the treatment of epilepsy. Consistent with this use, this herb reportedly can increase synaptic concentrations of GABA (248). GABA has also been isolated from Valeria and extracts of Valeria have been reported to bind to GABA receptors in rat brain. Although Valeria has been reported to be active in rodent models of depression, there have been no efficacy trials in humans. The potential adverse effects of Valeria include the sensation of strangeness ( 247) and several cases of liver damage (e.g., central lobular necrosis) (249). Mutagenicity in bacteria has been reported and attributed to unstable, water-insoluble valepotriates ( 238). As a result of these reports, many, but not all, commercial preparations of Valeria use water-soluble extracts standardized for their content of valeric acid. 

Gabapentin has been approved in the United States since 1993 for adjunctive use in the management of treatment-refractory partial epilepsy. Early evidence in open-label trials indicated possible mood-stabilizing properties ( 227, 234). Recent data from a placebo-controlled crossover trial, however, found no difference between gabapentin and placebo for manic or depressed episodes (235). 

Because of the heterogeneity of epilepsy, complete discontinuance of antiseizure drug administration is an especially difficult problem. If a patient is seizure-free for 3 or 4 years, a trial of gradual discontinuance is often warranted. 

Safinamide is a mixed Na+ and Ca2+ channel blocker with anticonvulsant, neuroprotective and anti-parkinsonian properties and is currently in phase II clincical trials for the indications epilepsy and Morbus parkinson (for review see Chazot, 2001). Additionally, analgesic activity has been shown in acute pain models (hot plate, tail flick) and more pronounced in a chronic, persistent pain model (formalin test) in mice in a dose range of 7.5 to 120 mg/kg p.o. (Salvati et al., 1999). 

Retigabine which is in phase II clinical trials for epilepsy, is a derivative of the analgesic flupirtine which also has anticonvulsant activity. The anticonvulsant action of retigabine is greater than that of flupirtine, however retigabine is not effective in models of acute pain. 

Talampanel, phase II clinical trials for epilepsy and Parkinson s disease (Eli Lilly)... 

AMP-397A, phase I clinical Irampanel, phase II clinical trials for trials for epilepsy (Novartis) cerebral ischemia, combined AMPA... 

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