Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine)

A higher rate of congenital anomalies has been found after prenatal exposure to some combinations of antiepileptic drugs than to the separate drugs. In an earlier study a rate of 58% congenital anomalies was found among infants exposed to carbamazepine plus phenobarbitone plus valproate. In this study an attempt was made to determine whether this specific combination of drugs has teratogenic activity due to metabolic interaction. The epidemiological data were analyzed further. The high rate of congenital anomalies after prenatal exposure to this combination could not be explained by the effects of one or two of these drugs only, nor by additional exposure to phenytoin. Assuming that metabolic interaction in the arene oxide pathway resulting in accumulation of epoxide intermediates of antiepileptic drugs could be responsible for teratogenesis, the ratio of carbamazepine to carbamazepine-10, 11-epoxide concentrations in serum was determined in adult patients with epilepsy who were treated with carbamazepine only and with different combinations of phenobarbitone, valproate, and/or phenytoin. For carbamazepine monotherapy the mean ratio was 8.19. For all combinations lower ratios were found, indicating accumulation of carbamazepine-10,11-epoxide. The combination of carbamazepine, phenobarbitone, valproate, and phenytoin showed the lowest ratio (1.94), followed by carbamazepine, valproate, and phenytoin and by carbamazepine, phenobarbitone, and valproate (2.81 and 3.18, respectively). These results give rise to the question of whether the combination of carbamazepine, phenobarbitone, valproate, and/or phenytoin has teratogenic activity by accumulation of carbamazepine-10,11-epoxide or other epoxide intermediates, and stress the need to take metabolic interactions into account when investigating the teratogenic activity of antiepileptic drugs.     

The clinical pharmacology of traditional antiepileptic drugs

Despite the availability of newer agents, a number of antiepileptic drugs have continued to be employed reasonably widely, many years after their introduction to human therapeutics. These drugs comprise phenobarbitone and some of its congeners, phenytoin, ethosuximide, carbamazepine, valproate, and certain benzodiazepines. Details of their pharmacological profiles are outlined in the following account.     

Use of antiepileptic drugs in the treatment of epilepsy in people with intellectual disability

The main principles of antiepileptic drug treatment of epilepsy in patients with intellectual disability are basically the same as for other patients with epilepsy. However, some specific issues need to be taken into account These are primarily associated with the diagnostic difficulties of epilepsy in this population. In addition, a number of other relevant issues, including the degree and location of brain lesion, the nature of the underlying disease, the higher frequency of difficult-to-treat epilepsies, the additional intellectual impairment caused by inappropriate antiepileptic medication, or by frequent and prolonged seizures, the appropriate use of monotherapy versus rational polytherapy, and the use of broad-spectrum antiepileptic drugs will be discussed in the present paper. Although the goals of treatment are to keep the patient seizure-free and alert while preventing possible mental deterioration, we have to accept compromises between these primary goals in many cases. Some people with epilepsy and intellectual disability are very vulnerable to insidious neurotoxic effects; for example, sedative effects caused by phenobarbital, or cognitive and/or cerebellar dysfunction caused by long-term phenytoin, especially together with other drugs. Because of the adverse effects of phenobarbital and phenytoin, these drugs are no longer recommended as a first-choice drugs when long-term antiepileptic medication is required. In primary generalized tonic-clonic seizures, valproate, oxcarbazepine/carbamazepine and lamotrigine are recommended in this order of preference. The corresponding recommendations are: in typical absences, valproate, ethosuximide and lamotrigine; in atypical absences, valproate and lamotrigine; in juvenile myoclonic epilepsy, valproate, lamotrigine and clobazam; in infantile spasms vigabatrin, ACTH and valproate; in Lennox-Gastaut syndrome, valproate, lamotrigine and vigabatrin; in atonic seizures, valproate and lamotrigine; in simple and complex partial seizures with or without secondary generalization, oxcarbazepine/carbamazepine, valproate/ vigabatrin and lamotrigine; and in status epilepticus lorazepam, diazepam and clonazepam together with phenytoin or fosphenytoin. In cases of poor response to the monotherapy recommended above, the following combinations may be indicated: in primary generalized tonic-clonic epilepsy, valproate and oxcarbazepine/ carbamazepine, or valproate and lamotrigine; in typical absences, valproate and lamotrigine, or valproate and ethosuximide; in juvenile myolonic epilepsy, valproate and lamotrigine, or valproate and clonazepam; and in partial epilepsies, add to the monotherapy one of the following drugs, vigabatrin, lamotrigine, gabapentin, tiagabine, topiramate, zonisamide or clobazam. So far, the order of preference of these new drugs remains undetermined. More data are needed on the efficacy and adverse effects of the new drugs based on controlled studies on patients with intellectual disability and epilepsy.     

Antiepileptic drug-induced encephalopathy

The clinical features of an antiepileptic drug-induced encephalopathy (ADE) are confusion, reduction of vigilance, neurological deficits or an increase of the seizure frequency. In the electroencephalogram a general slowing or epileptic discharges are found. Characteristic are non-toxic blood levels of the antiepileptic drugs. So far an ADE was reported under phenytoin, carbamazepine or valproatic acid (valproate) therapy. More seldom, an ADE has been described after the intake of vigabatrine, lamotrigine und topiramate. Potential pathogenic mechanisms of AED are hyperammonemia, intrinsic effects on cerebral receptors, drug interactions, hepatic enzyme interactions, metabolic reasons or paradoxical proconvulsive effects of antiepileptic drugs. The medicamentous therapy consists of an immediate discontinuation of the antiepileptic drug.     

Ocular complications of neurological therapy

Treatments used for several neurological conditions may adversely affect the eye. Vigabatrin-related retinal toxicity leads to a visual field defect. Optic neuropathy may result from ethambutol and isoniazid, and from radiation therapy. Posterior subcapsular cataract is associated with systemic corticosteroids. Transient refractive error changes may follow treatment with acetazolamide or topiramate, and corneal deposits and keratitis with amandatine. Intraocular pressure can be elevated in susceptible individuals by anticholinergic drugs, including oxybutynin, tolterodine, benzhexol, propantheline, atropine and amitriptyline, and also by systemic corticosteroids and by topiramate. Nystagmus, diplopia and extraocular muscle palsies can occur with antiepileptic drugs, particularly phenytoin and carbamazepine. Ocular neuromyotonia can follow parasellar radiation. Congenital ocular malformations can result from in utero exposure to maternally prescribed sodium valproate, phenytoin and carbamazepine. Neurologists must be aware of potential ocular toxicity of these drugs, and appropriately monitor for potential adverse events.     

Cutaneous drug eruptions by current antiepileptics: case reports and alternative treatment options

Serious cutaneous drug eruptions due to antiepileptics have been defined for many drugs like carbamazepine, diphenylhydantoin, phenytoin and valproate. In recent years, adverse cutaneous reactions due to the current antiepileptic drugs have also been reported. In this paper, two cases are presented: a 48-year-old female receiving gabapentin for postherpetic neuralgia who developed leukocytoclastic vasculitis after 8 weeks and a 23-year-old male receiving lamotrigine for epileptic seizures who developed toxic epidermal necrolysis (TEN) in 15 days. Alternative therapy approaches with practical suggestions are also discussed.     

Effect of antiepileptic drugs on somatostatin release in vitro

In the present study we investigated the effect of antiepileptic drugs on high potassium (50 mM) stimulated somatostatin release in rat cortical slices in a superfusion system. The somatostatin-like immunoreactivity (SLI) in superfusate was determined by radioimmunoassay. The antiepileptic drugs studied, vigabatrin, valproate, carbamazepine, phenobarbital, primidone, clonazepam and phenytoin were tested at a concentration range of 1-1000 microM). Of the drugs used vigabatrin had the most significant inhibitory effect on SLI release (IC50 = 240 microM). Vigabatrin also caused a concomitant, dose-dependent increase in superfusate gamma-amino butyric acid (GABA) level. A 30% decrease in the release of SLI followed incubation with valproate and carbamazepine, but only at high drug concentrations (1000 microM). Phenobarbital, primidone, clonazepam and phenytoin did not affect SLI release. Addition of GABA to superfusate caused a dose-dependent decrease in the amount of SLI release (IC50 = 56 microM). In conclusion, at low concentrations the antiepileptic drugs had only minor effects on SLI release. At higher concentrations, however, vigabatrin and valproate decreased the release of SLI, which may relate to their ability to elevate tissue levels of GABA.     

Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy

Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25-hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone-specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross-linked N-telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine (p = 0.008). Insulin growth factor-I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine (p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone-specific alkaline phosphatase (p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long-term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long-term adverse effects on bone.     

Maternal valproate dosage and foetal malformations

OBJECTIVE- To study the possible dose dependence of the foetal malformation rate after exposure to sodium valproate in pregnancy METHODS- Analysis of records of all foetuses in the Australian Registry of Antiepileptic Drugs in Pregnancy exposed to valproate, to carbamazepine, lamotrigine or phenytoin in the absence of valproate, and to no antiepileptic drugs. RESULTS- The foetal malformation rate was higher (P<0.05) in the 110 foetuses exposed to valproate alone (17.1%), and in the 165 exposed to valproate, whether alone or together with the other antiepileptic drugs (15.2%), than in the 297 exposed to the other drugs without valproate (2.4%). It was also higher (P<0.10) than in the 40 not exposed to antiepileptic drugs (2.5%). Unlike the situation for the other drugs, the malformation rate in those exposed to valproate increased with increasing maternal drug dosage (P<0.05). The rate was not altered by simultaneous exposure to the other drugs. Valproate doses exceeding 1400 mg per day seemed to be associated with a more steeply increasing malformation rate than at lower doses and with a different pattern of foetal malformations. CONCLUSIONS- Foetal exposure to valproate during pregnancy is associated with particularly high, and dose-dependent risks of malformation compared with other antiepileptic drugs, and may possibly involve different teratogenetic mechanisms.     

Anticonvulsant potency and neurotoxicity of valproate alone and in combination with carbamazepine or phenobarbital

Although single drug therapy of epilepsy has been increasingly advocated, patients whose epilepsy is not controlled by monotherapy are commonly treated with more than one antiepileptic drug. In order to investigate the experimental background for antiepileptic drug combinations, the effect of the pharmacodynamic interactions between valproate and carbamazepine and between valproate and phenobarbital on the efficacy/toxicity ratio was studied in mice. All results were expressed in terms of drug concentrations in the brain in order to exclude possible pharmacokinetic interactions from the analysis. Purely additive interactions were found for the anticonvulsant effect when valproate was combined with carbamazepine as well as with phenobarbital. With regard to the neurotoxic effect, however, the interaction was additive between valproate and phenobarbital but infra-additive for valproate and carbamazepine. Thus, in this model, the combination of valproate and phenobarbital has no advantage over each drug alone, but the combination of valproate with carbamazepine has a better efficacy versus toxicity ratio than either valproate alone or carbamazepine alone. Based on these and previous results, there can be experimental evidence in favor of combining certain antiepileptic drugs, but each combination needs to be studied separately.     

Antiepileptic drugs and the immune system

Data on the effects of antiepileptic drugs on the immune system are frequently inconsistent and sometimes conflicting because the effects of drugs cannot be separated from those of seizures, first-generation drugs have been most intensively investigated, the patient's genetic background, the mechanism of action and the pharmacokinetic profile of AEDs and the concurrent use of immunosuppressant drugs may act as confounders. Valproate, carbamazepine, phenytoin, vigabatrin, levetiracetam, and diazepam have been found to modulate the immune system activity by affecting humoral and cellular immunity. AEDs are associated with pharmacokinetic interactions (most frequently occurring with carbamazepine, phenytoin, phenobarbital and valproate). Hepatic metabolism is the primary site of interaction for both AEDs and immunotherapies (ACTH, dexamethasone, hydrocortisone, methylprednisolone, cyclophosphamide, methotrexate, rituximab), which entail induction or inhibition of drug effects. However, the clinical importance of these drug interactions is still far from defined. An important adverse effect of the action of AEDs on the immune system is antiepileptic hypersensitivity syndrome (AHS), a life-threatening, idiosyncratic cutaneous reaction to aromatic AEDs resulting in end organ damage. Phenytoin, carbamazepine, phenobarbital, lamotrigine, oxcarbazepine, felbamate, and zonisamide have been implicated. The pathogenic mechanisms of AHS are incompletely understood.     

Serum hormones in male epileptic patients receiving anticonvulsant medication

Circulating sex and thyroid hormones, as well as the pituitary function, were assessed in 63 male patients with epilepsy receiving either a single medication of carbamazepine, phenytoin, or valproate or a combination of carbamazepine plus phenytoin or carbamazepine plus valproate. All therapeutic regimens, including carbamazepine and/or phenytoin were associated with low levels of circulating thyroxine (T4), free thyroxine (FT4), and dehydroepiandrosterone sulfate, and with low values for the free androgen index, and phenytoin and carbamazepine plus phenytoin were associated with high serum concentrations of sex hormone-binding globulin. These hormone parameters were unaffected by valproate monotherapy. It seems probable that accelerated hormone metabolism is responsible for the hormonal changes found in patients treated with carbamazepine and/or phenytoin. However, every drug regimen studied also had depressant and/or stimulatory effects on the function of the hypothalamic-pituitary axis. The diverse endocrine effects of different antiepileptic drug regimens should be considered when starting antiepileptic drug therapy.     

癫痫治疗中丙戊酸钠与苯妥英钠或卡马西平的相互作用

丙戊酸钠与苯妥英钠或卡马西平合用治疗各型癫痫90例,丙戊酸钠使苯妥英钠和卡马西平血浓度下降;丙戊酸钠和卡马西平是强有力的肝酶诱导剂,使丙戊酸钠血浓度降低。抗痫药之间的相互作用错综复杂,临床上选择单一用药,尽量避免联合用药。     

Children of School Age: The Influence of Antiepileptic Drugs on Behavior and Intellect

Summary: The role of antiepileptic drugs in behavior and cognitive function in children is well documented in the literature. In general, behavioral problems occur most frequently with phenobarbital and clonazepam, and appear least often with valproate and carbamazepine. Cognitive impairments occur with phenytoin, are less evident with valproate, and minimal with carbamazepine. Monotherapy, as with adults, leads to improvements in both cognitive abilities and behavior.     

Influence of N-hydroxymethyl-p-isopropoxyphenylsuccinimide on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Experimental epileptology is mainly focused on searching for some active compounds suppressing seizures that could become efficacious antiepileptic drugs. Accumulating evidence indicates that succinimide derivatives would be good candidates for novel antiepileptic drugs. Therefore, the aim of this study was to determine the effects of N-hydroxymethyl-p-isopropoxyphenyl-succinimide (HMIPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the maximal electroshock-induced seizure test in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that HMIPPS administered intraperitoneally at 100mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). HMIPPS at doses of 12.5, 25 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, HMIPPS (50mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate in the mouse maximal electroshock-induced seizure model by reducing their median effective doses (ED(50) values) from 23.25mg/kg to 16.82 mg/kg (P<0.01; for phenobarbital) and from 259.3mg/kg to 189.7 mg/kg (P<0.001; for valproate), respectively. In contrast, HMIPPS (50mg/kg) had no impact on the protective action of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. HMIPPS (25mg/kg) significantly potentiated the anticonvulsant action of valproate by reducing its ED(50) value from 259.3mg/kg to 210.6 mg/kg (P>0.05), but not that of phenobarbital, phenytoin and carbamazepine in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that HMIPPS did not alter total brain concentrations of phenobarbital or valproate in mice. Moreover, none of the examined combinations of HMIPPS (50mg/kg) with carbamazepine, phenobarbital, phenytoin and valproate (at their ED(50) values from the maximal electroshock-induced seizure test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no possible acute adverse effects in animals. In conclusion, the enhanced anticonvulsant action of phenobarbital and valproate by HMIPPS in the mouse maximal electroshock-induced seizure model, lack of pharmacokinetic interactions and no potential acute adverse effects make the combinations of HMIPPS with phenobarbital and valproate worthy of consideration for further experimental and clinical studies. The combinations of HMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.     

Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial.

Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs, utilised as monotherapy in newly diagnosed epileptic patients. Between 1981 and 1987 243 adult patients aged 16 years or over, newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission. The overall outcome with all of the four drugs was good with 27% remaining seizure free and 75% entering one year of remission by three years of follow up. No significant differences between the four drugs were found for either measure of efficacy at one, two, or three years of follow up. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomised drug, was 10%. For the individual drugs phenobarbitone (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures, the choice of drug will be more influenced by considerations of toxicity and costs.     

苯妥因钠,丙戊酸钠,卡马西平对癫痫患者智力的影响

抗癫痫药物造成认知功能的损害及损害程度至今仍无明确结果。为此，我们对４６例全身性强直一阵挛发作的癫痫患儿进行了服药前后的智力测验，并以１６例健康同龄人对照，以检测苯妥历钠，丙戊酸钠，卡马西平对智力的影响。     

Seizure-inducing effects of antiepileptic drugs: a review

Seizure-inducing effects can be observed in the treatment of epileptic patients with antiepileptic drugs (AED). This may be a paradoxical reaction (for example the increase of complex focal seizures due to carbamazepine, vigabatrin or phenytoin treatment) or a result of AED-induced encephalopathy (commonly induced by valproate in patients with complex focal seizures). A seizure increase during intoxication with AEDs is a rare phenomenon, thus, it is not directly related to this condition. An incorrect choice of drugs in the treatment of an epileptic syndrome or seizure type may provoke seizures (as for example the provocation of absences due to carbamazepine or phenytoin). The possible seizure-inducing effect of AEDs has to be differentiated from seizure occurrence due to the natural course of epilepsy. This may be especially difficult in patients suffering from West syndrome or Lennox-Gastaut syndrome, in whom seizure frequency may vary even without medication. However, especially in these patients, drug-induced worsening of seizure manifestation is often observed. In general, a seizure-inducing effect of antiepileptic drugs has to be considered when a seizure increase is observed soon after the initiation of therapy, when a stepwise increase of the dosage is followed by a further increase of seizures, a decrease of seizures is seen with tapering of the dosage and a renewed increase of seizures can be observed after this therapy has been reestablished. Finally, one knows that the clinical condition of encephalopathy due to valproate or carbamazepine is accompanied by seizure increase. In spite of these clinical aspects, the underlying mechanisms of seizure increase mostly remain unclear. From animal experiments it is obvious that especially carbamazepine and phenytoin may provoke generalized seizures as absences or myoclonic seizures. A seizure increase during vigabatrin therapy has been attributed to the increase of the cerebral amount of gamma-amino-butyric acid, which is known to possibly exhibit inhibitory or excitatory neuronal effects. The occurrence of tonic seizures in patients with Lennox-Gastaut syndrome has been attributed to the sedative effect of the drugs; however, this conclusion is controversial. From a clinical point of view, one should consider young age of the patient, mental retardation, antiepileptic polytherapy, high frequency of seizures or prominent epileptic activity in the electroencephalogram previous to medication as risk factors for a possible seizure-inducing effect of antiepileptic drugs.     

Mechanisms of Idiosyncratic Hypersensitivity Reactions to Antiepileptic Drugs

Summary: Hypersensitivity reactions to the aromatic antiepileptic drugs (AEDs) phenytoin (PHT) and carbamazepine (CBZ) appear to have an immune etiology. Current models of drug hypersensitivity center around the concept of drug bioactivation to reactive metabolites that irreversibly modify cellular proteins. These modified proteins are believed to initiate (or serve as targets of) an autoimmune-like attack on specific drug-modified proteins in target organs (e.g., liver, skin) of susceptible individuals. Consistent with this model, antibodies to drug-modified and native proteins have been identified in the sera of patients experiencing several drug hypersensitivity reactions. New models must incorporate an understanding of the mechanisms by which drug-modified proteins are processed and presented to the immune system in the appropriate context to culminate in the clinical manifestations of "hypersensitivity." Idiosyncratic toxicities associated with new AEDs, such as lamotrigine and felbamate, appear mechanistically distinct from PHT and CBZ hypersensitivity but may involve similar processes: bioactivation, detoxification, covalent adduct formation, processing and presentation of antigen to the immune system, and consequent formation of antibody and T-cell immune effectors. The goal of research is to develop a "susceptibility profile" for identifying individuals at risk for these forms of drug toxicity.