Rational Polytherapy Research Articles

Pharmacodynamic interactions between antiepileptic drugs: preclinical data based on isobolography

Background: At least 20 – 30% of epileptic patients do not sufficiently respond to monotherapy. Some of them can benefit from drug combinations; hence, animal data may provide some useful novel clues for rational polytherapy. Objective: To review combinations of antiepileptic drugs, evaluated with the help of isobolographic analysis, in terms of their efficacy and adverse effects. Methods: A literature search, on the basis of experimental studies, with no time limit was carried out. Results/conclusion: Preclinical data indicate that a synergy occurred for the combinations of valproate + phenytoin, valproate + ethosuximide, lamotrigine + valproate, gabapentin + valproate, gabapentin + carbamazepine, topiramate + carbamazepine, topiramate + valproate, topiramate + oxcarbazepine, levetiracetam + topiramate, levetiracetam + oxcarbazepine, oxcarbazepine + gabapentin, tiagabine + gabapentin and lamotrigine + topiramate. On the other hand, lamotrigine combined with carbamazepine or oxcarbazepine resulted in a clear-cut antagonism. Interestingly, a combination of oxcarbazepine + clonazepam produced variable responses, including synergy, additivity or antagonism, depending on the dose ratio of these drugs. In no case did pharmacokinetic factors contribute to the final analysis of the effects of drug combinations. Pharmacokinetic factors can contribute to the final effect of drug combinations, such as when stiripentol is added to valproate, or clobazam is added to valproate. It may be concluded that the rational treatment of drug-resistant epilepsy needs to consider the results of preclinical studies.

To the Editors:

Bergin and colleagues challenge the academic epilepsy community to move outside our box of how we do clinical studies to help address common, important clinical problems for which we lack data: go to the net. It is an awesome idea. The nemesis, the devil, lies in the detail. No one can doubt the power of the Internet: its reach, its exponential capacities, its speed, its potential to answer questions. Academic medicine must embrace it. But how? Bergin and colleagues suggest that randomized prospective research protocols could be successfully executed to study problems such as the comparative efficacy and toxicity of different two antiepileptic drug therapies as well as different therapies for specific etiologies of epilepsy. As a resident (OD), I was struck by a distinguished epileptologist, a basic scientist, who lectured on “Rational Polytherapy.” This doctor published articles in leading scientific journals and understood the burden of scientific proof, yet gave an hour lecture on the wonderful merits of some antiepileptic drug combinations and trashed others as toxic and illogical. To summarize, if the presumed mechanisms of action were different, he liked the combos. If they were the same, he disliked them. What about clinically proven breakthroughs in cancer therapy that targeted multiple sites in a specific pathway, all acted by the same general “mechanism of action.” That was 1986 – two decades later and the evidence for “rational polytherapy” remains a cacophony of experts opining in the dark. The Internet could waken us from our sleep, not only by giving us a new tool, but by allowing us to ask new questions, and by providing new partners. Not only academicians, but patients. Sites such as http://www.patientslikeme.com allow patients and families with ALS to partner in information, and look at subtypes, progression, mainstream and alternative therapies, etc. Databases and tracking devices can be mined by patients to help them make decisions. Discussions are underway to bring this to epilepsy. It is time for doctors and patients to work together to advance knowledge. For both professional and lay efforts, one challenge will be the quality of the data (who checks that it was entered correctly?, who checks that it is correct?). There are endless questions of methodology— accuracy of classification of seizures and seizure counts, inclusion of nonepileptic patients, compliance, classification of lesions, heterogeneity of lesions (cavernomas may be more grey or white matter based, may have bled minimally or moderately, occur in sensory or limbic or frontal or temporal regions, be single or multiple, occur with or without other structural problems, etc.). Large numbers may address these issues of data quality. As noted in a Wikipedia entry on signal noise, “In science… noise is fluctuations in (and the addition of external factors to) the stream of target information (signal) being received at a detector.” As the number of data points increases, the probability of discerning signals through noise increases. The opportunity to gather large numbers is a core strength of the Internet. Still, only random noise eliminates itself with numbers. Accuracy and consistency of data and classification will still matter if errors show consistent bias. Large numbers will help address small sample size and loss of power with subgroup analyses, but they will not address all problems with the accuracy and consistency of the data that is entered. And therein lies the rub, the challenge to making this work. Bergin and colleagues' suggestion should be pursued. However, a central oversight and monitoring committee that guides evolution will be critical to success in this endeavor as they have been in the success of Wikipedia itself. We must start with version 1.0 although the fruits will likely lie in subsequent versions.

Reinvestigation and Reduction of Polytherapy in Children With Chronic Seizures

From October 2001 to October 2003, the authors reviewed all patients with chronic seizures taking antiepileptic drugs for more than 2 years with follow-up at the pediatric neurological clinic. They identified 31 patients who were using 3 or more drugs. Twenty-nine patients agreed to undergo a drug reduction and readjustment. The authors spent a mean period of 14.1 months to either purely reduce the numbers of drugs or introduce a new drug (rational polytherapy) plus removal of some drugs to achieve the end goal of a maximum of 2 or 3 drugs (if necessary). Seizure control in 96.6% of patients (28 of 29 patients) did not worsen after the readjustment and reduction of the antiepileptic drugs. Instead, 65.5% (19 of 29 patients) got better, and 37.9% (11 of 29) were seizure free. The number of antiepileptic drugs before and after adjusting was 3.6 (range, 3-6) to 1.9 (4 monotherapy, 22 duotheray, and 2 triple drugs). The most common combined therapies were sodium valproate/lamotrigine (n = 10) and carbamazepine/ topiramate (n = 5). Although the results could be possibly attributed to the spontaneous remission of the seizures, it was still shown that those patients were overtreated. Serial addition to 3 or more antiepileptic drugs is less likely to lead to seizure freedom for patients with difficult-to-treat epilepsy. On the contrary, polytherapy and some antiepileptic drugs could aggravate seizures. Certain combinations of antiepileptic drugs (rational polytherapy) offer better efficacy to control seizures.

Combined Ketogenic Diet and Vagus Nerve Stimulation: Rational Polytherapy?

The concept of "rational polypharmacy" has been associated with anticonvulsant management for decades, but the term has not been applied to nonpharmacologic therapies. We conducted a multicenter, retrospective study of children who received concurrent diet (ketogenic or modified Atkins) and vagus nerve stimulation (VNS) treatment for medically intractable epilepsy. Thirty children in total from six epilepsy centers were treated over a 6-yr period. The median age at the initiation of combination therapy was 10 yr (range, 4-24 yr). Sixteen (53%) received dietary therapy followed by VNS; no differences were noted between centers. After 3 months, 21 (70%) had seizure reduced by >50% over the previous single nonpharmacologic treatment, of whom 13 (62%) had improvement within the first month. A 5-min VNS off-time correlated with >90% seizure reduction (p = 0.02). The median duration of nonpharmacologic polytherapy was 12 months (range, 0.5-96 months); 17 (57%) remain on dual therapy at this time. No side effects were noted. Most patients who discontinued combination therapy did so because of a lack of efficacy rather than restrictiveness. In this small group, the combined use of diet and VNS appeared synergistic and yielded rapid benefits. It may be more effective with longer VNS off-times. Further prospective studies of this combination in refractory pediatric epilepsy are needed to help guide optimal use.

Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin--PHT, carbamazepine--CBZ, valproate--VPA and phenobarbital--PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis. Drug-related adverse effects were ascertained by use of the chimney test (motor impairment) and the step-through passive avoidance task (learning and retrieval). It was observed that the combination of LCZ with VPA or PB, at the fixed ratio of 1:1, was supra-additive (synergistic) and the combination of LCZ with CBZ, at all fixed ratios tested (1:3, 1:1 and 3:1), was supra-additive against electroconvulsions. The remaining combinations evaluated, i.e., LCZ with PB or VPA at fixed ratios of 1:3 and 3:1, as well as all fixed-ratio combinations between LCZ and PHT, were additive in the MES test in mice. Pharmacokinetic characterization revealed that LCZ significantly increased both free plasma and brain concentrations of CBZ and PHT, but was without effect on PB. Moreover, a bi-directional pharmacokinetic interaction between LCZ and VPA was observed in that while LCZ increased free plasma, but not total brain VPA concentrations, VPA increased the total brain, but not free plasma LCZ concentrations. Adverse-effect testing revealed that for all antiepileptic drug combinations neither motor performance nor long-term memory was altered. Of the drug combinations investigated, only that of LCZ and PB at the fixed ratio of 1:1 was not associated with any pharmacokinetic interactions, and thus it may be concluded that the supra-additive (synergistic) isobolographic interaction was pharmacodynamic in nature. Furthermore, the fact that LCZ and PB have similar mechanisms of action would suggest that drugs with similar mechanisms of action may provide rational polytherapy regimens.

Interaction between lamotrigine and felbamate in the maximal electroshock-induced seizures in mice: an isobolographic analysis

Isobolographic profile of interactions between lamotrigine (LTG) and felbamate (FBM), two second-generation antiepileptic drugs, against maximal electroshock (MES)-induced seizures, and neurotoxic adverse effects in the chimney test in mice were determined. LTG combined with FBM at the fixed ratios of 1:3, 1:1, and 3:1 exerted merely additive interactions against MES-induced seizures. In the chimney test, isobolography revealed that LTG coadministered with FBM at the fixed ratio of 1:1 displayed subadditivity (antagonism), whereas the remaining combinations tested (1:3 and 3:1) exerted additivity in terms of their neurotoxic side effects. LTG (at the dose of 2.3 mg/kg) coadministered with FBM (25.7 mg/kg) at the fixed ratio of 1:1 from the MES test did not impair long-term memory of mice challenged with the passive avoidance task. Furthermore, FBM (25.7 mg/kg) altered neither the free plasma nor brain concentration of LTG, hence pharmacokinetic events, which might affect the observed interactions in the MES test, are unlikely. Considering benefit indices for the respective fixed ratio combinations, it may be concluded that the combination of LTG with FBM at the fixed ratio of 1:1 is advantageous from a preclinical point of view, offering the highest benefit index reaching the value of 1.46. Likewise, the two-drug combination of 1:3 was also beneficial and is worth recommendation with benefit index amounting to 1.36. Only the combination of 3:1 was neutral with a benefit index of 1.08. Protection offered by LTG in combination with FBM against maximal electroconvulsions and its favorable neurotoxic side effect profile might provide the patients with intractable seizures with an efficacious treatment, as the rational polytherapy however, it requires to be clinically confirmed and verified.

Impact of New-Generation Agents on Antiepileptic Drug Prescribing Patterns in a Residential ICF-MR Facility

Describe the impact of newer antiepileptic drugs (AEDs) on prescribing practices in a large, residential intermediate-care facility for the mentally retarded (ICF-MR), with onsite clinical pharmacist support services, over a 15-year period. All residents at the facility receiving AEDs for management of seizure disorder were included in this retrospective assessment. Number and type of AEDs used per individual were recorded and analyzed over the 15-year interval. Current prescribing practices were evaluated regarding rational polytherapy prescribing trends. 400-bed residential ICF-MR for the severe to profoundly mentally retarded. All individuals residing at the ICF-MR facility receiving AED therapy for a seizure disorder. Residents were primarily in the severe to profound range of developmental disability, with multiple medical comorbidities. Clinical pharmacists actively participate in all treatment teams and monthly neurology clinic to promote and encourage rational pharmacotherapy. Prescribing trends related to AED therapy were followed over a 15-year period. Comparisons were made regarding monotherapy and polytherapy at multiple-year intervals, with specific emphasis on how the newer generation AEDs have affected use of older medications. Overall trend from 1988 suggests more monotherapy and less use of barbiturates. Introduction of a new generation of AEDs has not affected the overall trend toward one- or two-drug regimens over the period in review. The relative stability of the number of AEDs per resident during the introduction of a new generation of AEDs suggests that as new drugs are added, ineffective or problem-prone drugs are discontinued.

Drug treatment of epilepsy: when does it fail and how to optimize its use?

Although modern community-based studies have shown that a majority of people with newly diagnosed epilepsy will enter long-term remission, seizures remain refractory to treatment in a substantial proportion of this population--perhaps as much as 40%. A consensus is being reached that, for operational purposes, pharmacoresistance can be suspected when two appropriately chosen, well-tolerated, first-line antiepileptic drugs (AEDs) or one monotherapy and one combination regimen have failed due to lack of efficacy. Poor prognostic factors include lack of response to the first AED, specific syndromes, symptomatic etiology, family history of epilepsy, psychiatric comorbidity, and high frequency of seizures. These observations suggest that prognosis can often be determined early in the course of the disorder. We propose a management paradigm that aims to maximize the chance of successful AED therapy, including the early use of "rational polytherapy" for patients not responding to monotherapy, and to identify efficiently patients suitable for "curative" resective surgery, in particular those with mesial temporal lobe epilepsy. An orderly approach to each epilepsy syndrome will optimize the chance of perfect seizure control and help more patients achieve a fulfilling life.

A four-ligand hypercube model to quantify allosteric interactions within the GABA A receptor complex

The aim of this study was to investigate the couplings between various binding sites on the GABA A receptor complex. We investigated combinations of three test compounds: (1) GABA (γ-aminobutyric acid), (2) Org 20549 [(2β3α5α)-21hydroxy- 3Hydroxy-2(4morpholinyl)pregnan-20one methane-sulphonate)], a neuroactive steroid and (3) retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester), a new antiepileptic drug. Receptor-binding assays were conducted using rat brain membranes. [ 3H]TBOB ([ 3H]- t-butyl-bicyclo-ortho-benzoate) was the tracer ligand. All three test compounds inhibited the binding of [ 3H]TBOB with EC 50's of 4.0, 98 and 23 μM, respectively. Isobolic analysis of the combination data showed that the three compounds act in synergy in displacing [ 3H]TBOB. These interactions could be described and quantified by a hypercube model in which each of the three test compounds and [ 3H]TBOB bind to different, allosterically coupled sites such that each of the test compounds allosterically displaces the tracer [ 3H]TBOB and allosterically enhances the affinity of any other test compound by a factor 4.4. The simultaneous binding of any two ligands enhances the affinity of the third by a factor 9. These results may contribute to the understanding of individual variability in drug responses and to the discussion about rational polytherapy.

Interaction of topiramate with conventional antiepileptic drugs in mice

Topiramate [2,3:4,5-bis- O-(1-methyl-ethylidene-)-β- d-fructopyranose sulfamate], administered intraperitoneally (i.p.) up to 5 mg/kg, did not influence the threshold for electroconvulsions. In doses of 10–30 mg/kg, topiramate significantly raised the threshold. This novel antiepileptic drug, in subprotective doses, enhanced the protective activity of i.p. given valproate, carbamazepine, dihenylhydantoin and phenobarbital against maximal electroshock-induced convulsions in mice. The potentiation induced by topiramate (2.5–5 mg/kg) was most profound for carbamazepine and phenobarbital. The anticonvulsive activity of valproate and diphenylhydantoin was potentiated by topiramate only at 5 mg/kg. Topiramate (5 mg/kg) combined with valproate, phenobarbital and diphenylhydantoin did not alter their free plasma levels but its combination with carbamazepine resulted in an increased free plasma level of this antiepileptic drug. Treatment with topiramate (5 mg/kg) alone or in combination with the studied antiepileptics (providing 50% protection against maximal electroshock) resulted in no adverse effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-term memory). In contrast, valproate administered alone at its ED 50 against maximal electroshock impaired motor coordination. It is noteworthy that valproate and carbamazepine at their respective ED 50 values of 248 and 11.2 mg/kg disturbed long-term memory. The results provide an experimental basis for rational polytherapy.

Politerapia antiepiléptica racional. Interacciones medicamentosas y elección del fármaco

Following twenty years of antiepileptic biotherapy, monotherapy superseded this when it was shown to be equally effective, have fewer problems of drug interactions and the patients were more likely to actually take their drugs. However, the development of the so-called new antiepileptic drugs gives rational biotherapy a new chance. In this article we discuss the basis of reasoned polytherapy and some of the possible interactions between antiepileptic and other drugs. When polytherapy is considered, antiepileptic drugs with different modes of action and profiles of adverse effects should be used. Some epileptic patients may attain control of their seizures with rational polytherapy. The drug reactions between the antiepileptic drugs themselves and with other drugs are frequent but not usually of clinical importance. We discuss some of the more relevant interactions. Choice of the initial antiepileptic drug is based on various factors, basically the type of seizure, age of the patient, epileptic syndrome, possibility of pregnancy, family and job considerations.

A molecular model for the synergic interaction between γ-aminobutyric acid and general anaesthetics

Within the context of the discussion about rational polytherapy, we determined the effects of four anaesthetics on the binding of [ 3 H ] t-butylbicycloorthobenzoate ([ 3 H ]TBOB) to the GABA A receptor complex in the presence of several concentrations of GABA (γ-aminobutyric acid), in order to build a molecular model that can describe and quantify the interactions between the compounds. The empirical isobole method revealed that GABA and the anaesthetics acted synergically in displacing [ 3 H ]TBOB. This synergy could be described by a simple molecular model in which both GABA and the anaesthetics displaced [ 3 H ]TBOB allosterically and in which GABA allosterically enhanced the binding of the anaesthetics. To get information about the interaction between GABA and anaesthetics, we used [ 3 H ]TBOB as a tracer ligand. The model indicated that GABA enhanced the affinity of thiopental 3.0-fold, propofol 5.0-fold, the neuroactive steroids Org 20599 3.5-fold and Org 20549 13-fold. Insight into the molecular mechanism and strength of these interactions can help clinicians to choose therapeutically optimal drug and dose combinations: a step towards rational polytherapy.

Monotherapy or polytherapy for epilepsy?

Monotherapy has been promoted as the ideal in epilepsy treatment because of reduced side effects, absence of drug interactions, better compliance, lower cost and, in many cases, improved seizure control compared to polytherapy. The question of monotherapy vs. polytherapy has assumed increasing importance with the availability of multiple new antiepileptic drugs (AEDs), initially tested as add-on agents. The new drugs clobazam, lamotrigine, vigabatrin, gabapentin and topiramate, have also been shown to be effective as monotherapy. These data bring up the possibility of using them as first-line agents. However, a high percentage of patients with resistant epilepsy are treated with polytherapy, which probably benefits only a minority of them. The availability of multiple drugs with different mechanisms of action favours the possibility of "rational polytherapy", taking advantage of possible synergism, a yet unproven concept. This article reviews the theoretical advantages of monotherapy and monotherapy with traditional and newer AEDs.

Role of vigabatrin and lamotrigine in treatment of childhood epileptic syndromes.

Vigabatrin (VGB) and lamotrigine (LTG) are two new antiepileptic drugs (AEDs) with different mechanisms of action for treatment of refractory epilepsies. Previous reports have indicated efficacy of both drugs in a number of epileptic syndromes. We compared these new AEDs drugs to determine their respective efficacy against different types of epileptic syndrome and to develop a rational approach to their use. We reviewed the charts of 105 children, with partial and generalized epilepsies. VGB was to be significantly more effective in children with partial epilepsies, and LTG was more effective in those with generalized epilepsies. VGB and LTG have different therapeutic profiles. Combination treatment with the two drugs may represent rational polytherapy for patients with epilepsy resistant to treatment with either drug alone or as add-on to other AED treatment.

Estratégias terapêuticas em epilepsia.

With the advances in the so-called classic antiepileptic drugs (AED)--carbamazepine, phenobarbital, phenytoin and valproate--monotherapy has become the most popular strategy for the treatment of epilepsies, based on their unquestionable clinical efficacy and on frequent drug interactions and teratogenesis caused by polypharmacy. The choice of an AED should be ruled by its efficacy against a given seizure type; by its toxicity, either acute, dose-related or idiosyncratic, or chronic, due to the length of therapy or AED dosage; by its capacity to interact with other drugs, either AEDs or not, mainly through pharmacokinetic interactions, leading to fluctuation in the plasma concentration of the target drug and hence decreased in their efficacy; by its potential cognitive and behavioural side effects; by its teratogenesis which is common to all AEDs; by its cost. Despite their efficacy, about 35% of the patients are inadequately treated with monotherapy, partial, symptomatic or associated to encephalopathy being the most frequent of their seizures. For this particular group, the association of two AEDs could play an important role. The increasing knowledge of the mechanisms of the new generation of AEDs, such as vigabatrin and lamotrigine, and their favourable pharmacokinetic and pharmacodynamic profiles, rise to the new concept of rational polytherapy which allows an additive or supra-additive therapeutic efficacy, a limited toxicity, a decrease in drug interactions and an increased compliance. Although monotherapy should continue to be the choice therapy for epilepsies, this concept could be a reasonable and early option in the treatment of some refractory epilepsies.

Epilepsy care: image of the future.

A number of factors have contributed to improvements in the care of epilepsy during the past decade, including the International League Against Epilepsy classifications, therapeutic antiepileptic drug (AED) monitoring and the concept of monotherapy, new AEDs with novel mechanisms of action, and new insights into etiology that suggest novel therapies. Pharmacologically "clean" AEDs acting on a single known mechanism will be an important element in the future care of patients with epilepsy. Augmentation of GABAergic inhibition is being successfully exploited by AEDs, and there remains much room for further pharmacologic innovation. The potential role of AEDs acting specifically on the GAT-1 or GAT-4 subgroup of gamma-aminobutyric acid transporters is a topic of current research. Specifically acting AEDs designed to have a single and known mode of action will permit true monotherapy, one AED with one target as opposed to one AED with several targets, and may open the way to rational polytherapy, i.e., designed use of one AED per mechanism in epilepsies with multifactorial causation. New research demonstrating a possible autoimmune basis for some forms of epilepsy illustrates the potential for novel nonpharmacologic approaches, and the role of prevention must also be emphasized. The image of the future is an optimistic one.

Antiepileptic drugs in development: prospects for the near future.

Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.