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PubMedDate not supplied

Evaluation of the mechanisms of antiepileptic drug-related chronic leukopenia.

Antiepileptic drug (AED)-related chronic leukopenia [white blood cell (WBC) count < 4,000/microliters] is a dilemma, especially when the AED is effective in controlling seizures. We evaluated the possible mechanisms of leukopenia in 7 patients. Mean WBC count was 3,000/microliters with a mean of 42% polymorphonuclear leukocytes (PMN). The AEDs were carbamazepine (CBZ) alone in 1 patient or CBZ combined with phenytoin (PHT), primidone (PRM), phenobarbital (PB) and/or valproate (VPA) in 5 patients; one patient was receiving PHT only. Bone marrow (BM) aspirates and PMN antibody studies using chemiluminescence were normal. Two liver-spleen scans showed mild relative splenomegaly. After exercise, WBC count (n = 7) increased by 54% (SEM 12%), while the WBC counts in controls (n = 5) increased by 52 +/- 16%. Antinuclear antibodies (Hep-2) were absent in 6 patients and positive (1:160) in 1. PMN adhesion to nylon wool was decreased (54 +/- 10% in patients vs. 80 +/- 5% in controls: n = 13, p < 0.005). Our data, particularly the appropriate WBC response to the stress of exercise, and normal BM examinations suggest that continuation of AED therapy when leukopenia is stable and the percentage of PMN is normal is probably safe. Caution should be used if the absolute PMN count is consistently < 1,000/microliters. BM examinations need not be performed routinely for every patient with neutropenia due to AEDs, especially if the leukopenia fluctuates in the range of 2,000-4,000 cells/microliters.

Adult↗
PubMed1998

Rapid switchover to carbamazepine using pharmacokinetic parameters.

PURPOSE: The standard practice of switching patients to carbamazepine (CBZ) involves initiating a low dose and raising it by small increments until the desired dose is reached, to avoid intolerable adverse effects (AE). In a pilot study, a protocol using single-dose kinetic studies was developed to switch patients to CBZ through rapid-dose increments and to manage concurrent rapid taper of the previous antiepileptic drugs (AEDs) without causing AE. The purpose of this prospective study was (a) to reassess whether a rapid switchover to CBZ could be done with minimal or no AE and without causing an increase in seizures; (b) to determine whether the maintenance dose of CBZ predicted at the time of the single-dose kinetic study can yield the desired concentration at steady state (Css); and (c) to determine the degree to which the calculated maintenance dose of CBZ will need to be adjusted after the previous AED has been discontinued for a four-week period. METHODS: Twenty-five patients taking phenytoin (PHT) and/ or phenobarbital (PB) and/or primidone (PRM) underwent a rapid switchover to CBZ following a 10 mg/kg single-dose kinetic study (day 1) which allowed calculation of a maintenance dose necessary to yield a mean Css of 10.2 (+/-2.2) mg/l. On day 2, patients received a CBZ dose equivalent to 10 mg/kg + 200 mg; thereafter, they underwent daily dose increments of 200 mg until the calculated maintenance dose was reached. Dose increments were modified in the case of AE. Concurrent tapering of the previous AED was started as of day 1: PHT by 100 mg/day, while PB and PRM were stopped on day 1; PB was restarted before patients were to be discharged from the hospital if a PB serum concentration above 10 mg/l was identified at that time. Pharmacokinetic data and occurrence of AE were compared between the two groups at the time of the single-dose kinetic study, at the completion of the switchover to CBZ, and 4 weeks after discontinuation of the previous AED. RESULTS: All patients completed the switchover to CBZ within a mean time period of 6 days (+/-2), reaching a mean maintenance dose of 1,639 mg/day (+/-370) which yielded a mean Css of 11.3 (+/-3.2) mg/l. The maintenance dose had to be lowered by 20.4% (+/-8.3) in 59% of patients within the four-week period following discontinuation of at least one of the previous AEDs. None of the patients experienced an increase in seizure frequency relative to baseline. Fifteen (60%) patients had no AE; five (20%) experienced AE of mild severity. AE rated as moderately severe (n = 4) or severe (n = 1) occurred in patients with a static encephalopathy (p = 0.02, Fisher's exact test) and among patients > or =55 years (p = 0.017, Fisher's exact test). CONCLUSIONS: A rapid switch-over to CBZ from PHT, PB, or PRM can be carried out safely with no, or minimal, AE in young adults, unless they suffer from static encephalopathy.

Adult↗
PubMed1998

Antiepileptic drug hypersensitivity syndrome.

The antiepileptic drug hypersensitivity syndrome (AHS) is an adverse drug reaction associated with the aromatic antiepileptic drugs (AEDs) phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), and primidone. The syndrome is defined by the triad of fever, skin rash, and internal organ involvement. It can also be caused by other drugs, such as sulfonamides, dapsone, minocycline, terbinafine, azathioprine, and allopurinol. Diagnosis of AHS may be difficult because of the variety of clinical and laboratory abnormalities and manifestations and because the syndrome may mimic infectious, neoplastic, or collagen vascular disorders. The incidence is approximately 1 in 3,000 exposures. AHS starts with fever, rash, and lymphadenopathy, within the first 2-8 weeks after initiation of therapy. Internal manifestations include, among others, agranulocytosis, hepatitis, nephritis, and myostitis. AHS is associated with a relative excess of reactive oxidative metabolites of the AED. Insufficient detoxification may lead to cell death or contribute to the formation of antigen that triggers an immune reaction. Crossreactivity among PHT, CBZ, and PB is as high as 70-80%.

Anticonvulsants↗
PubMed1999

Long-term neuropsychological consequences of maternal epilepsy and anticonvulsant treatment during pregnancy for school-age children and adolescents.

PURPOSE: Antiepileptic drugs (AEDs) are potential teratogenic agents. The purpose of this study was to examine the long-term effects of intrauterine AED exposure on neurologic and psychological functioning. METHODS: Of a prospective study, "Epilepsy, pregnancy, and child development," children could be retraced at school age and adolescence. Sixty-seven were born to mothers with epilepsy [no drugs during pregnancy (n = 13), monotherapy (n = 31), polytherapy (n = 23)]; 49 were nonafflicted control children. Assessments included an intelligence test (Wechsler), a neurologic examination (Touwen), and an EEG. Data analyses were performed, controlling for parental social status, type of maternal drug therapy and drug dosage, type of epilepsy, frequency of seizures during pregnancy, the original subgroups, and specific drug effects. RESULTS: Type of maternal epilepsy and type and kind of AED therapy, but not maternal seizures during pregnancy correlated with an increase in abnormal EEG patterns. Minor neurologic dysfunction was diagnosed, with increased frequency from the control to the risk/no drug or monotherapy to the polytherapy group. The compromised intelligence score of the polytherapy group was primarily due to those children who had been exposed to primidone (PRM). Level of IQ was negatively associated with PRM dosage. CONCLUSIONS: Maternal epilepsy and AED therapy during pregnancy appear to have long-term effects on the offspring well into adolescence, as evinced in EEG patterns, minor neurologic dysfunction, and intellectual performance. Severity of effects increased from control group to epilepsy/no-drug group to monotherapy group and was most marked in the polytherapy group. These group differences are assumed to reflect differential neural vulnerability to social and family factors.

Adolescent↗
PubMed1983

Serum concentration of clonazepam and the therapeutic effect of the drug.

The effect of other anticonvulsants (phenytoin, phenobarbitone and primidone) on serum clonazepam concentrations has been studied. Serum clonazepam concentrations were measured in 47 epileptic patients in whom a dose of clonazepam (3 mg or 6 mg) was added to existing therapy. 44 patients were receiving other anticonvulsants; 3 were not receiving any other medication. Patients on low doses of other anticonvulsants showed high clonazepam concentrations. Patients on multiple therapy with high doses of other anticonvulsants showed excessive side-effects on clonazepam and low serum clonazepam concentrations. We conclude that other anticonvulsants may reduce serum clonazepam concentrations and therefore that clonazepam is best given alone.

Adolescent↗
PubMed1970

Disturbance of calcium metabolism by anticonvulsant drugs.

A survey of calcium metabolism in epileptic patients in a residential centre showed a subnormal serum calcium level in 22.5% of patients and a raised alkaline phosphatase in 29%. Hypocalcaemia was related to high dosage of anticonvulsant drugs, to multiple drug therapy, and to the use of individual anticonvulsant drugs in the following order, with decreasing order of importance: pheneturide, primidone, phenytoin, phenobarbitone. Subnormal serum calcium levels occurred more commonly in patients with a raised liver alkaline phosphatase isoenzyme than in those whose phosphatase was mainly of bone origin.Preliminary results of treatment with calciferol suggested that the disturbance of calcium metabolism was the result of vitamin D deficiency. It is possible that anticonvulsant drugs accelerate the breakdown of vitamin D by liver enzyme induction.

Adolescent↗
PubMed1973

Incidence of anticonvulsant osteomalacia and effect of vitamin D: controlled therapeutic trial.

The bone mineral content (B.M.C.) in both forearms (related to total body calcium) was measured by photon absorptiometry for a controlled therapeutic trial in a representative sample of epileptic outpatients, comprising 226 patients treated with one or two major anticonvulsant drugs (phenytoin, phenobarbitone, primidone).Initially the mean B.M.C. value for all epileptic patients was 87% of normal. During treatment with 2,000 international units of vitamin D(2) daily for three months an average B.M.C. increase of 4% was found, whereas the B.M.C. values remained unchanged in the placebo group and in the control groups. The incidence of hypocalcaemia and raised serum alkaline phosphatase was 12% and 43% respectively. The biochemical indices of osteomalacia were related to B.M.C. These results indicate that epileptic patients should be closely supervised for the occurrence of anticonvulsant osteomalacia, and, possibly, receive prophylactic treatment with vitamin D.

Adult↗
PubMed1976

Anticonvulsant-induced dyskinesias: a comparison with dyskinesias induced by neuroleptics.

Anticonvulsants cause dyskinesias more commonly than has been appreciated. Diphenylhydantoin (DPH), carbamazepine, primidone, and phenobarbitone may cause asterixis. DPH, but not other anticonvulsants, may cause orofacial dyskinesias, limb chorea, and dystonia in intoxicated patients. These dyskinesias are similar to those caused by neuroleptic drugs and may be related to dopamine antagonistic properties possessed by DPH.

Adolescent↗
PubMed1988

Effectiveness of a therapeutic drug monitoring service as an aid to the control of canine seizures.

The results presented were derived from an anticonvulsant monitoring service, provided for two years to practising veterinary surgeons, in which samples of serum were taken from dogs treated with either primidone or phenobarbitone. Of the 19 patients assessed, 13 were controlled after the recommended changes in dose had been made. Of the six patients not completely controlled after changes in dose, four had a much lower incidence of seizures but two did not respond to treatment in spite of having high serum phenobarbitone levels. There were large variations between the doses of anticonvulsant drugs required to reach therapeutic serum levels; these variations underlined the value of routine monitoring for improving the control of canine seizures.

Animals↗
PubMed1976

The necessity of drug level monitoring in anticonvulsant drug therapy.

A survey of 'steady-state' serum levels of anticonvulsant drugs from 221 epileptic patients at a university hospital was conducted. Serum concentrations of phenobarbital, primidone, and diphenylhydantoin were determined by a gas chromatographic method. Sixty-five percent (130) of the patients receiving diphenylhydantoin had levels below the therapeutic range of 10-20mug/ml. Subtherapeutic levels appear to be due to inadequate dosage adjustment. Only 25% (33) of the patients receiving phenobarbital had levels below the therapeutic range. Serum levels of diphenylhydantoin or phenobarbital could not be predicted from dosage. Most patients received two or more drugs. Over 10% of the patients had potentially toxic levels of anticonvulsant drugs. High levels of diphenylhydantoin were easily recognized clinically but high levels of phenobarbital were not.

Body Weight↗
PubMed1980

Antiepileptic drug levels and side effects in man.

It was found in 22 hospitalized epileptic patients taking DPH, primidone, and phenobarbital as a combined therapy that the number of side effects per patient could be correlated only with the serum levels of DPH. In the case of clinial manifestation of side effects it might be concluded that the dosage of DPH should be reduced. One of our patients was treated in this manner resulting in a reduction of the side effects, whereas the frequency of seizures increased. But we succeeded in reducing this frequency by phenobarbital and side effects completely disappeared. If there are any side effects, then, according to our results, it seems to be better to add phenobarbital in order to decrease the DPH serum level instead of reducing DPH dosage. It is, however, known that by phenobarbital the DPH level in patients need not necessarily decrease.

Anticonvulsants↗
PubMed1979

Accuracy of serum anticonvulsant measurements. A comparison of enzyme multiplied immunoassay technique and gas-liquid chromatography.

An enzyme multiplied immunoassay technique is compared with a gas-liquid chromatographic technique for the measurement in blood serum of the anticonvulsants phenytoin, carbamazepine, phenobarbitone, primidone, and ethosuximide. The correlation between results obtained by each method was excellent, and both systematic and random errors were well within acceptable limits.

Anticonvulsants↗
PubMed1987

Factors that affect the induction of gamma glutamyltransferase in epileptic patients receiving anti-convulsant drugs.

Serum samples from 335 epileptic patients receiving one or more anticonvulsant drugs, phenobarbitone, primidone and phenytoin, have been analysed for biochemical liver profile (BLP) and serum drug concentration. The results show that the induction of serum gamma glutamyltransferase (GGT) is affected by the sex and age of the patient, type of anti-convulsant drug prescribed and duration of treatment. It is less affected by serum drug concentration. It is suggested that these factors must be considered when interpreting results involving serum GGT activity as the index of microsomal enzyme induction.

Adolescent↗
PubMed2000

Childhood head tremor.

We report here four children (three girls, one boy) with head tremor followed longitudinally, ages 15 months to 11 years, with follow-up over 1 to 8 years. Each demonstrated onset of head tremor between the ages of 5 and 10 months. In each case head tremor was characterized by a predominant "yes-yes" or "no-no" movement of the head. In two of the children the movement was slightly skewed with chin movement toward the shoulder. Oscillations were at a frequency of about 1 to 2 Hz. They were accentuated when sitting upright without head support, increased at times of movement, and dissipated while lying flat or sleeping. The children were unable to voluntarily suppress the action and did not experience any sensation of movement. Three of the children had shuddering spells prior to onset of head tremor. Two children have developed mild dystonic posturing of the legs when intently concentrating. Their general and neurologic examinations were normal. Normal investigations included brain magnetic resonance imaging and computed tomography, urine amino acids and organic acids screening, serum lactate, erythrocyte sedimentation rate, antinuclear antibodies, and ceruloplasmin and copper levels. A family history of tremor was present in two children, maternal epilepsy in one child, and infantile shuddering occurred in the father of one child. Therapy included trials of selective and nonselective beta-adrenergic blockers, alpha-adrenergic agonists, anticholinergics, anticonvulsants, and amantadine. One child responded well to both timolol and trihexyphenidyl. A second child responded moderately to primidone. Two have not been treated. Two have had head tremor spontaneously remit. We conclude from this small series of children with head tremor that it can evolve from a prior history of shuddering spells, occurs in the context of a positive family history of tremor, and can be accompanied by the development of a mild dystonia. Therapeutic response is variable to multiple agents. Spontaneous remission occurs, suggesting a benign course.

Child↗
PubMed2000

Prediction of adsorption from multicomponent solutions by activated carbon using single-solute parameters.

The adsorption of 3 barbiturates--phenobarbital, mephobarbital, and primidone--from simulated intestinal fluid (SIF), without pancreatin, by activated carbon was studied using the rotating bottle method. The concentrations of each drug remaining in solution at equilibrium were determined with the aid of a high-performance liquid chromatography (HPLC) system employing a reversed-phase column. The competitive Langmuir-like model, the modified competitive Langmuir-like model, and the LeVan-Vermeulen model were each fit to the data. Excellent agreement was obtained between the experimental and predicted data using the modified competitive Langmuir-like model and the LeVan-Vermeulen model. The agreement obtained from the original competitive Langmuir-like model was less satisfactory. These observations are not surprising because the competitive Langmuir-like model assumes that the capacities of the adsorbates are equal, while the other 2 models take into account the differences in the capacities of the components. The results of these studies indicate that the adsorbates employed are competing for the same binding sites on the activated carbon surface. The results also demonstrate that it is possible to accurately predict multicomponent adsorption isotherms using only single-solute isotherm parameters. Such prediction is likely to be useful for improving in vivo/in vitro correlations.

Adsorption↗
PubMed2002

Prediction of adsorption from multicomponent solutions by activated carbon using single-solute parameters. Part II--Proposed equation.

Prediction of multicomponent adsorption is still one of the most challenging problems in the adsorption field. Many models have been proposed and employed to obtain multicomponent isotherms from single-component equilibrium data. However, most of these models were based on either unrealistic assumptions or on empirical equations with no apparent definition. The purpose of this investigation was to develop a multicomponent adsorption model based on a thermodynamically consistent equation, and to validate that model using experimental data. Three barbiturates--phenobarbital, mephobarbital, and primidone--were combined to form a ternary system. The adsorption of these barbiturates from simulated intestinal fluid (without pancreatin) by activated carbon was studied using the rotating bottle method. The concentrations, both before and after the attainment of equilibrium, were determined with a high-performance liquid chromatography system employing a reversed-phase column. The proposed equation and the competitive Langmuir-like equation were both fit to the data. A very good correlation was obtained between the experimental data and the calculated data using the proposed equation. The results obtained from the original competitive Langmuir-like model were less satisfactory. These results suggest that the proposed equation can successfully predict the trisolute isotherms of the barbituric acid derivatives employed in this study.

Adsorption↗
PubMed1975

Cognitive and motor-sensory performances in toxic and nontoxic epileptic subjects.

Psychometric, adaptive ability, motor proficiency, and sensory discrimination measures were administered to adult seizure patients within 36 hours of blood serum determinations of diphenylhydantoin, phenobarbital, and primidone. Thirty-five subjects in whom at least one of the three drug levels fell within stated mug per milliliter toxicity ranges were compared with 28 subjects of comparable age and IQ who were identified by the same procedure to be nontoxic. The toxic group consistently obtained poorer mean test scores, and significant intergroup differences were found on several measures of attention and concentration and on tests of motor coordination and static tremor.

Adult↗