Serum Phenytoin Research Articles

The Safety and Feasibility of Continuous Intravenous Magnesium Sulfate for Prevention of CerebralVasospasm in Aneurysmal Subarachnoid Hemorrhage

Cerebral vasospasm in aneurysmal subarachnoid hemorrhage (SAH) is associated with poor outcome. The safety and feasibility of continuous high-dose intravenous magnesium sulfate (MgSO4) for the prevention of cerebral vasospasm and ischemic cerebral injury has not been well studied. Patients presenting to our center within 72 hours of aneurysmalSAH (confirmed by computed tomography [CT] scanning and cerebral angiography) between June 2001 and October 2002 were enrolled in a prospective pilot study in which they received MgSO4 as an adjunct to standard SAH management. Study patients received an intravenous infusion of 12 g of MgSO4 in a 500-mL solution of 0.9% NaCl administered at a rate of 4.06 mM (or 0.5 g) every hour over a 24-hour period for 10 days to achieve a target predetermined serum Mg range of more than 1.5 to less than 4.0 mM/L. The effect of MgSO4 on clinical examination, heart rate, and blood pressure was measured every 2 hours; serum glucose and phenytoin levels were monitored daily. Outcome measures included evidence of vasospasm on clinical examination, transcranial Doppler study ((TCD); velocity >or=100 cm/s), or repeat cerebral angiogram obtained within 10 days of SAH; and Glasgow Outcome Scale (GOS) score assessment and CT scan evidence of ischemic infarction at 30 days. Nineteen patients (mean age: 55 years; range: 39-84 years; 11 males, 8 females) were enrolled in the study. Presenting Hunt Hess grade was II or higher; mean Fisher grade was 3. Vasospasm was observed in nine patients (by clinical examination in two, TCD in five, and angiogram in nine). The mean serum Mg level was 2.7 mM/L (standard deviation: +/- 0.37) and was maintained during the infusion period. No clinical adverse effects, hemodynamic changes, or fluctuations in serum glucose or phenytoin levels were observed. None of the patients died; no CT evidence of ischemic infarction was present; and most had good outcomes (GOS 5 in 10 patients; GOS 4 in 8 patients). Our study confirmed the safety and feasibility of a continuous infusion of high-dose intravenous MgSO4 in patients with aneurysmal SAH. Randomized controlled trials are required to confirm the promising results.

Acute Phenytoin Intoxication: Causes, Symptoms, Misdiagnoses, and Outcomes

Phenytoin is a commonly prescribed antiepileptic drug. Due to its saturation (zero-order) pharmacokinetics, phenytoin carries a special risk of dose-related toxicity that is an important issue in emergency medicine. The purpose of this cross-sectional case-series study was to investigate the causes, symptoms, misdiagnoses, and outcomes of acute phenytoin intoxication. It was based on a retrospective chart review of 30 inpatients (mean age, 41.6 +/- 22.8 years) with 36 episodes of acute phenytoin intoxication at our university hospital in the past 13 years. The average initial serum phenytoin level was 47.3 +/- 9.7 microg/mL (range, 27.9-70.4 microg/mL). Excessive self-medication, misunderstanding of the prescription order, and probable drug interaction were the three leading causes of acute phenytoin intoxication. Unsteady gait, dizziness/vertigo, nausea/vomiting, general weakness, and drowsiness were the most common presenting symptoms. The tentative diagnostic accuracy was 67%. The most common initial misdiagnosis was brainstem or cerebellum stroke (14%). The clinical course in all patients was uneventful under temporary withdrawal of phenytoin and supportive care. We concluded that acute phenytoin intoxication was relatively under-diagnosed in the emergency service. Although acute phenytoin intoxication causes no mortality and has a good outcome, the unsteady gait increases the risk of injuries caused by falls. The management of acute phenytoin intoxication includes temporary withdrawal of phenytoin and supportive care.

Serum albumin-adjusted phenytoin levels: an approach for predicting drug efficacy in patients with epilepsy, suitable for developing countries

The antiepileptic drug phenytoin has a high degree of plasma protein binding. Therefore, total phenytoin levels in plasma are misleading indicators of clinical efficacy. This study was designed to investigate whether serum albumin-adjusted phenytoin levels in Indian patients with epilepsy predict clinical outcome better than total phenytoin levels. Fifty patients with epilepsy were included in the study and were followed-up for a period of 6 months. Serum albumin levels were estimated spectrophotometrically using the bromocresol green dye method, and serum phenytoin levels were estimated using high pressure liquid chromatography. Values were expressed as mean +/- SEM. Corrected phenytoin levels were calculated using the Sheiner-Tozer equation. Corrected phenytoin levels = Measured total phenytoin(micromol/l) [(albumin g/1 x 0.9)+ 0.1] 40. At Visit 1, mean serum albumin levels were 44.1 +/- 1.1 micromol/l and mean serum phenytoin levels were 33.9 +/- 2.8 g/l. After correction of the total phenytoin levels using the Sheiner-Tozer equation, 30% of the patients shifted to a different category. The follow-up visits showed similar results. Throughout the study, the corrected phenytoin levels were better indicators of clinical outcome than the total levels. In 23% of patients there was a significant difference between total and corrected phenytoin levels. In patients with serum albumin levels in the hyper- and hypoalbuminemic range, corrected phenytoin levels were better indicators of clinical outcome. In developing countries like India, where estimation of free drug levels is expensive and suitable equipment is not available in most centers, serum albumin-adjusted levels can be used by pharmacologists to predict response and thus assist in clinical decision-making.

Simultaneous spectrophotometric determination of carbamazepine and phenytoin in serum by PLS regression and comparison with HPLC

Carbamazepine (CBZ) and phenytoin (PHT) are two antiepileptic drugs which are used simultaneously. In this paper a partial least-squares (PLS) calibration method is described for the simultaneous spectrophotometric determination of CBZ and PHT in plasma. Standard binary mixtures of CBZ and PHT have been resolved by application of PLS-1 to their UV spectra. Then, the binary standard solutions, spiked to plasma, were prepared and after the extraction of the drugs, their corresponding UV spectrum were analyzed by PLS regression to calculate the concentration of drugs in unknown plasma. A leave one out cross-validation procedure was employed to find the optimum numbers of latent variables using PRESS. A HPLC method was also applied for simultaneous determination of two drugs in the plasma and in methanol. The mean recoveries obtained by PLS were 98.4 and 98.2 for CBZ and PHT and those obtained by HPLC were 100.1 and 101.7, respectively. Although, the HPLC method showed better performance than PLS, it was found that the results obtained by PLS were comparable with those obtained by HPLC method.

Simple and rapid micellar electrokinetic capillary chromatographic method for simultaneous determination of four antiepileptics in human serum.

A very rapid and simple MEKC method was developed for the simultaneous determination of four antiepileptic drugs, ethosuximide (Etho), primidone (Pri), phenytoin (Pht) and carbamazepine (Cbz) in human serum. Sample analysis required only 100 microL of human serum which only needed to be centrifuged, decanted and combined with the running buffer [5.3 mM Na(2)HPO(4)/3.2 mM borax buffer (pH 9.5) containing 55 mM SDS and 3.5% (v/v) acetone]. The analysis was performed in only 10 min into fused-silica capillaries (57 cm total length with 50 microm i.d. and 50 cm to the detector) using the MEKC methodology with diode-array detection at 220 nm. The calibration graphs were established for ethoximide, primidone, phenytoin and carbamazepine between 0 and 20 mg/L. Recoveries were between 85 and 87%. The simplicity of the proposed methodology makes it suitable for routine clinical use, especially for epileptic patients on polytherapy.

Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data

The influence of aging on the pharmacokinetics of phenytoin at steady-state was evaluated retrospectically by comparing apparent oral clearance values (CL/ F) in 75 patients aged 65–90 years (mean, 71.7 ± 5.3 years) receiving phenytoin alone ( n = 58) or in combination with phenobarbital ( n = 17) and in an equal number of control patients aged 20–50 years (mean, 36.7 ± 8.5 years) matched for gender, body weight, and comedication. All data were derived from the database of the therapeutic drug monitoring service (TDMS) of an academic neurological hospital. On average, elderly patients were found to exhibit slightly higher CL/ F values compared with controls (14.6 ± 4.7 ml h −1 kg −1 versus 13.1 ± 4.2 ml h −1 kg −1, P < 0.05), the difference being probably related to the dose-dependent nature of phenytoin metabolism and the fact that elderly patients received lower dosages (4.4 ± 1.1 mg kg −1 day −1 versus 5.3 ± 1.1 mg kg −1 day −1, P < 0.001) and had lower serum phenytoin concentrations (14.1 ± 5.7 μg ml −1 versus 18.6 ± 6.8 μg ml −1, P < 0.0001). Gender and phenobarbital comedication were not found to exert any statistically significant influence on phenytoin CL/ F. By contrast, in the elderly group, CL/ F values were negatively correlated with age. On average, CL/ F values decreased by about one-third between 65 and 85 years of age, but interindividual variability was considerable and age explained only 7.8% of the variation in CL/ F in the elderly group. Overall, these findings indicate that aging is associated with a progressive decline in phenytoin clearance, presumably as a result of decreased drug metabolizing capacity. Because assessment was based on total serum phenytoin concentrations and the unbound fraction of phenytoin is known to decrease in old age, the influence of aging as quantified in this study may underestimate the magnitude of changes in the clearance of unbound, pharmacologically active drug. Based on these data, it is prudent to utilize initially smaller phenytoin dosages in old patients, and to make subsequent dose adjustments based on clinical response and serum drug level measurements. Interpretation of the latter, however, should take into account the possibility of an increase in the fraction of unbound drug.

Phenytoin use in elderly nursing home residents

Background: Phenytoin (PHT) dosing regimens are often determined based on experience in those aged < 65 years rather than in those aged ≥65 years. Objective: The goal of this study was to determine the impact of sex, age, receipt of concomitant inhibitors or inducers of PHT metabolism, and albumin levels on doses and total serum concentrations of PHT in elderly nursing home residents. Methods: Consulting pharmacists to nursing homes located throughout the United States collected data from June 1998 to December 2000. The mean daily dose per person and mean total serum PHT concentration were tested for statistical differences by sex, age group (6–74, 75–84, and ≥85 years), coadministration of PHT inhibitors or inducers, and albumin levels. Results: Data were collected from 387 residents (259 women, 128 men) of 112 nursing homes in 19 states who received PHT and for whom PHT concentrations were available. The mean (SD) age of the study population was 79.4 (7.8) years; women constituted 67.0% of the study population. The mean (SD) total daily dose and total PHT concentration were 4.9 (1.8) mg/kg and 11.7 (6.4) mg/L, respectively. In general, women received higher mean (SD) daily doses of PHT compared with men (5.1 [1.8] vs 4.6 [1.6] mg/kg, respectively; P = 0.017) to achieve similar total serum concentrations (11.6 [6.4] and 12.0 [6.6] mg/L). PHT doses and serum concentrations were similar between age groups. There were no differences in daily doses (mg/kg or mg/d) or total serum concentrations of PHT based on concomitant use of inhibitors or inducers of PHT metabolism or on albumin levels, Conclusions: In this study in elderly nursing home residents, women received higher doses of PHT than men to achieve similar total serum PHT concentrations. There were no differences in doses or total serum PHT concentrations by age group, use of concomitant inducers or inhibitors of PHT metabolism, or albumin levels.

CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects

Previous studies suggested that the onset of phenytoin-induced gingival overgrowth depended on serum phenytoin concentration. Cytochrome P450 2C (CYP2C) plays an important role in phenytoin metabolism. Recently, single nucleotide polymorphisms in the coding region of CYP 2C influencing phenytoin metabolism were identified. The purpose of the present study was to see if CYP 2C polymorphisms might relate to the onset and severity of phenytoin-induced gingival overgrowth. Twenty-eight epileptic patients taking phenytoin aged 15 to 75 (mean age: 42.2 years old, 20 males and 8 females) and 56 unrelated healthy subjects aged 30 to 48 (mean age: 36.8 years old, 48 males and 8 females) were examined for CYP 2C polymorphisms. All epileptic subjects were examined for the degree of gingival overgrowth, daily phenytoin dose and serum phenytoin concentration. The results indicated about 7% of the subjects including epileptic and healthy subjects examined were positive for CYP 2C9*3. However, the degree of gingival overgrowth did not directly correlate with CYP 2C polymorphisms. Nevertheless, the subjects with severer gingival overgrowth exhibited significantly higher serum phenytoin concentration, indicating that phenytoin metabolism is an important determinant for the severity of the disease. Additionally, CYP 2C9*3 carriers exhibited significantly higher serum drug concentration to drug dose. Therefore, we concluded although the gene analysis is not directly related to diagnose the disease itself, it can be utilized in estimating serum phenytoin concentration from drug dose, which in turn serves to predict the future development and clinical course of the disease.

Variability of Phenytoin Levels in Elders

Serum phenytoin levels sometimes fluctuate markedly for no apparent reason. In this study, researchers examined variability in phenytoin levels among

Significación clínica de la corrección del nivel sérico de fenitoína en función de la albuminemia en pacientes hospitalizados y ambulatorios

It has recently been reported that in developing countries, which have a high prevalence rate of hypoalbuminaemia, the total concentration of phenytoin in serum would often provide incorrect clinical information. The serum levels of phenytoin and albumin were determined in 400 adult patients of both sexes (231 hospitalized and 169 outpatients) attended in our hospital, and the concentrations of the drug were corrected using the Sheiner Tozer equation (STE). A clinically significant difference between the corrected and experimental concentrations of phenytoin (< 1.2 mg/L) was found in 74.4% of the hospitalized patients and in 21.3% of the outpatients. According to these findings and given the fact that determining the concentration of free phenytoin (i.e. not linked to albumin) is not routinely carried out, we recommend the systematic correction of phenytoin levels in our community in order to better adjust dosages. The possible limitations of the use of STE for standardizing phenytoin concentrations are also discussed.

Primary Standardization of Assays for Anticonvulsant Drugs: Comparison of Accuracy and Precision

The accuracy and precision of methods for the measurement of the anticonvulsants phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, and valproate in human serum were assessed in 297 laboratories that were participants in the United Kingdom National External Quality Assessment Scheme (UKNEQAS). We distributed lyophilized, serum-based materials containing low, medium, and high weighed-in concentrations of the drugs. The 297 participating laboratories received the materials on two occasions, 7 months apart. Expected concentrations were determined by gas chromatography or HPLC methods in five laboratories using serum-based NIST reference materials as calibrators. In general, bias was consistent across concentrations for a method but often differed in magnitude for different drugs. Bias ranged from -1.9% to 8.6% for phenytoin, -2.7% to 3.1% for phenobarbital, -2.7% to 0.5% for primidone, -8.6% to 0.3% for carbamazepine, -5.6% to 2.0% for ethosuximide, and -7.2% to 0.1% for valproate. Intralaboratory sources of imprecision significantly exceeded interlaboratory sources for many drug/method combinations. The mean CVs for intra- and interlaboratory errors for the different drugs were 6.3-7.8% and 3.3-4.2%, respectively. For these long-established and relatively high-concentration analytes, the closed analytical platforms generally performed no better than open systems or chromatography, where use of calibrators prepared in house predominated. To improve the accuracy of measurements, work is required principally by the manufacturers of immunoassays to ensure minimal calibration error and to eliminate batch-to-batch variability of reagents. Individual laboratories should concentrate on minimizing dispensing errors.

Randomized Controlled Trial of Prophylactic Phenytoin After Neurosurgery for Brain Tumor

Add-on Phenytoin Fails to Prevent Early Seizures after Surgery for Supratentorial Brain Tumors: A Randomized Controlled StudyDe Santis A, Villani R, Sinisi M, Stocchetti N, Perucca EEpilepsia 2002;43:175–182PurposeTo determine the potential effectiveness of phenytoin (PHT) in preventing early postoperative seizures in patients undergoing craniotomy for supratentorial brain tumors. Two hundred patients requiring elective craniotomy for supratentorial brain tumors were randomized to two groups of equal size, with a prospective, open-label, controlled design. One group received PHT (18 mg/kg as an intravenous intraoperative load, followed by additional daily doses aimed at maintaining serum PHT concentrations within the 10- to 20-age/ml range) for 7 consecutive days. In the other group, PHT was not administered. More than 90% of patients in both groups continued to take preexisting anticonvulsant medication (AEDs) with carbamazepine or phenobarbital throughout the study. The primary efficacy end point was th...

Randomized Controlled Trial of Prophylactic Phenytoin After Neurosurgery for Brain Tumor.

Add-on Phenytoin Fails to Prevent Early Seizures after Surgery for Supratentorial Brain Tumors: A Randomized Controlled Study De Santis A, Villani R, Sinisi M, Stocchetti N, Perucca E Epilepsia 2002;43:175–182 Purpose To determine the potential effectiveness of phenytoin (PHT) in preventing early postoperative seizures in patients undergoing craniotomy for supratentorial brain tumors. Two hundred patients requiring elective craniotomy for supratentorial brain tumors were randomized to two groups of equal size, with a prospective, open-label, controlled design. One group received PHT (18 mg/kg as an intravenous intraoperative load, followed by additional daily doses aimed at maintaining serum PHT concentrations within the 10- to 20-age/ml range) for 7 consecutive days. In the other group, PHT was not administered. More than 90% of patients in both groups continued to take preexisting anticonvulsant medication (AEDs) with carbamazepine or phenobarbital throughout the study. The primary efficacy end point was the number of patients remaining free from seizures during the 7-day period after the operation. Of 100 patients allocated to PHT, 13 experienced seizures during the 7-day observation period, compared with 11 of 100 patients in the placebo group (p &gt; 0.05). Most seizures occurred in the first day after surgery in both groups. There were no differences between groups in the proportion of patients experiencing more than one seizure, but there was a trend for generalized seizures to be more common in PHT-treated patients than in controls (11 vs. five patients, respectively). Status epilepticus occurred in one patient in the PHT group and in two patients in the control group. Of the 13 PHT-treated seizure patients, 11 had serum PHT concentrations within the target range, and only two had concentrations below range on the days their seizures occurred. PHT, given at dosages producing serum concentrations within the target range, failed to prevent early postoperative seizures in patients treated with concomitant AEDs. Prophylactic administration of PHT cannot be recommended in these patients.

Simple and rapid HPLC method for simultaneous determination of multiple antiepileptic drugs in human serum

A very rapid, sensitive and reproducible HPLC method was developed for simultaneous determination of eight anti-epileptic drugs (AEDs): lamotrigine, primidone, ethosuximide, sulthiame, felbamate, phenobarbital, carbamazepine, phenytoin and oxcarbazepine-metabolite (10-hydroxy-carbazepine) in human serum. Sample purification requires only protein precipitation with an appropriate reagent. Separation was by reversed-phase HPLC, using a C18 column, 20% acetonitrile and 40 mM phosphoric acid buffer as mobile phase. Column temperature was set at 50°C, and measurement was by UV detection at 205 nm. The inter and intra-assay coefficients of variation (CV) ranged 1.13–7.10% and 1.14–8.49%, respectively. The absolute (measured) and relative (analytic) recoveries of the drugs ranged 96.7%–104.4% and 97.3%–106.1%, respectively. No interference with other common antiepileptic drugs and analgesics were observed. The method requires only 100 μl serum or less. It is very fast (sample preparation and analysis time approx. 23 min for all 9 AEDs), and suitable for routine clinical use, especially for epileptic patients on polytherapy.

Are serum anticonvulsant levels in people with epilepsy appropriately monitored?

The medical care of people with epilepsy has often been described as being poor, although objective markers for the quality of epilepsy care are lacking. This paper describes the results of using a simple quality marker, appropriate measuring of serum anticonvulsant levels, in assessing the quality of epilepsy care. The checking of serum phenytoin levels in certain clinical circumstances is advocated, whereas the checking of serum sodium valproate levels is not generally supported. A total of 1254 people with epilepsy in the community had their medical records examined for evidence of checking of anticonvulsant levels and 1204 of these individuals completed questionnaires about their epilepsy and its treatment. Of those on phenytoin, only 26% to 47% had phenytoin levels checked appropriately; 23% of patients on sodium valproate were inappropriately having their serum levels checked. The only clinical or organizational factor that predicted whether checking of serum phenytoin levels was performed was whether or not patients reported three common phenytoin side-effects but this still showed a small effect size (odds ratio 2.4).

Topical Phenytoin Treatment of Stage II Decubitus Ulcers in the Elderly

To compare the healing of stage II decubitus ulcers with topically applied phenytoin sodium with two other standard topical treatment procedures in a long-term care setting; and to assess the extent of systemic absorption after topical application in the phenytoin group. Forty-seven nursing home patients with stage II decubitus ulcers were chosen for this study. The patients were matched for age, gender, and size and severity of wounds, and randomly assigned to each treatment group. Clinical assessment of decubitus ulcers was performed at the beginning of treatment and at each dressing change. Ulcers were examined for the presence of healthy granulation tissue, reduction in surface dimensions, and time to healing. Two phenytoin sodium plasma concentrations were to be obtained on all patients in the phenytoin group. Topical phenytoin therapy resulted in a shorter time to complete healing and formation of granulation tissue when compared with DuoDerm dressings or triple antibiotic ointment applications (p < or = 0.05). The mean +/- SD time to healing in the phenytoin group was 35.3 +/- 14.3 days compared with 51.8 +/- 19.6 and 53.8 +/- 8.5 days for the DuoDerm and triple antibiotic ointment groups, respectively. Healthy granulation tissue in the phenytoin group appeared within two to seven days in all subjects. Patients in the standard treatment groups required six to 21 days to produce new granulation tissue. Serum phenytoin sodium concentrations were nondetectable. No patient withdrew from the study secondary to adverse treatment effects. Both the phenytoin and standard treatment groups showed progress over the study period. However, the phenytoin group demonstrated more rapid results in all aspects of ulcer healing.

Anticonvulsant Blood Levels: Historical Review With a Pediatric Focus

Epilepsy is heterogeneous and its treatment is often complicated by variable drug responses. Buchtal et al reported a close correlation between serum phenytoin levels, electroencephalographic findings, and clinical status in 1960. They suggested that physicians adjust dosage to attain a "therapeutic level." The concept was enthusiastically received. "Therapeutic serum levels" were proposed for most anticonvulsant drugs, and by 1975, most authorities believed that pharmacokinetic factors explained individual differences in drug response. However, Froscher found that measuring levels did not improve patient outcome. More recently, Schumacher's double-blind study found no correlation between phenytoin levels and seizure control or adverse effects. Pharmacodynamic variables (differences in drug responsiveness) are more important than pharmacokinetic factors for many drugs, especially receptor-active drugs. Pharmacokinetic variables were studied first, and led to a simplistic model. They are less significant than pharmacodynamic factors in the case of warfarin anticoagulation. Anticonvulsant levels can reveal noncompliance and pharmacokinetic differences. They say nothing about pharmacodynamics. Reports of "subtherapeutic levels" imply a need to increase dosage, but this is not supported by outcome data. We still lack evidence that specific drug levels are a valid intermediate target 40 years after Buchtal's paper. Responses to some anticonvulsants could depend primarily on pharmacokinetic factors, while pharmacodynamic factors could be supreme for others.

In Vivo Binding Characteristics of Phenytoin to Serum Proteins in Monotherapy for Adults With Epilepsy

The aim of the present study was to determine the binding characteristics of phenytoin (PHT) to serum proteins in the adults. Binding parameters of PHT to serum proteins in our study were compared with in vivo or in vitro binding parameters of PHT to serum proteins reported by other investigators. Serum samples in the study were obtained from 36 adult patients (17 men, 19 women) receiving PHT monotherapy. A total of 43 steady-state concentrations were analyzed in the study. Patients' age ranged from 16 to 73 years (mean [SD], 42.9 [14.7] years). The in vivo population binding parameters of PHT to serum proteins and theoretical minimal unbound serum PHT fraction (fu) were determined using an equation derived from the Scatchard equation. The association constant (K) was 0.014 L x micromol(-1), whereas the total concentration of binding sites (n(Pt)) was 754 micromol x L(-1). The number of binding sites per albumin molecule (n) was 1.16, whereas binding ability (n.K) was 0.016 L x micromol(-1). The fu was 0.087. The n.K is approximately 1.2 times higher in PHT monotherapy patients of Pospísil and Perlík (ie, 0.0191 L x micromol(-1)) than in all our patients. The association constant is approximately 1.3 times higher in the in vitro study of Monks et al (ie, 0.0186 L x micromol(-1)) than in our study, whereas n is similar between the two studies. The fu in our patients is similar to the unbound serum PHT fraction in patients receiving PHT therapy reported by Richens (ie, 0.1). Our results suggest that there may be small differences in the binding affinity of PHT to serum proteins between in vivo and in vitro studies. The unbound serum fraction of PHT in epileptic patients can be assumed to be relatively constant in the therapeutic concentration range of PHT.

Carbamazepine Diminishing the Effects of Warfarin and Leading to Mesenteric Embolism in a Patient with Atrial Fibrillation

LEARNING OBJECTIVE: 1). To know drugs that decrease warfarin levels CASE: A 66 year old woman, nursing home resident, with history of chronic atrial fibrillation, hemiplegia secondary to a stroke, congestive heart failure, hypertension and seizure disorder, presented to the hospital with worsening nausea and vomiting persisting for 3 weeks. Her medications included digoxin, warfarin and enalapril. The physical exam showed hemiplegia. Standard admission work up revealed an INR of 2.3 and a high serum phenytoin level of 42 mg/dl. The patient had phenytoin toxicity, so phenytoin was stopped and the patient observed. Two days later the patient developed generalized clonic-tonic seizures. At that time the phenytoin level was 22 mg/dl. It was decided to give the patient loading doses of carbamazepine oral suspension in order to prevent further seizures. The following evening the patient suddenly developed acute abdomen. The INR was 1.4. The patient developed mesenteric infarction secondary to embolism, as revealed by urgent exploratory laparotomy. The patient expired the next day. DISCUSSION: The event was brought on by inadequate anticoagulation secondary to a drug-drug interaction between warfarin and carbamazepine that resulted in a drop in INR. This, in our patient with atrial fibrillation, allowed for cardiac thrombi formation and their embolisation to the mesenteric circulation. Drug-drug interactions with warfarin are among the most common interactions seen in clinical practice. The following drugs decrease warfarin level and predispose to thrombosis (remember the acronym DECREASE): Diuretics: spironolactone Estrogen containing oral contraceptives Carbamazepine, Corticosteroides, Rifampin Ethchlorvynol Alcoholism, Aminogluthethimide Sucralfate Etc: barbiturates, griseofulvin, and vitamin K (broccoli and bananas).

Changes in Serum Phenytoin Concentrations in Epileptic Patients Produced by Changing Phenytoin Preparation from Granular Form to a Novel 10% Powder.

Purpose: It is well known that there is a significant difference in the bioavailability of different preparations of phenytoin (PHT). A novel 10 % powder formulation of PHT (Aleviatino‐10 % powder), which was believed to have equivalent bioavailability to the tablet and granular formulations, was developed by Dainippon Pharmaceutical Co., LTD. in 1997. This lead us to switch 12 outpatients with epilepsy from the granular preparation of PHT (Aleviatino‐granules) to the novel 10 96 powder. Here, we report that changing the PHT formulation from the granular to the novel powder form produced a significant change in hioavailability. Methods: Subjects consisted of 8 men and 4 women with epilepsy; mean age, 32.7 years; range, 21–58 years; 2 generalized epilepsies and 10 localization‐related epilepsies recruited from the outpatient clinics. The dose of the granular form of PHT was 90‐390 mg/day (mean, 258.3 mg/day). Four patients received only PHT and the remaining patients received PHT and at least 1 other AED. The serum PHT concentrations were determined prior to and more than 2 weeks after changing the formulations. We used the same dose for each preparation, and the dose of any other anticonvulsant drug taken by the patients was not changed during the study. Results: The mean serum PHT level was significantly elevated from 9.66 to 19.51 pg/ml after switching the patients to the 10% powder formulation (p &lt; 0.01). The mean ratio of serum PHT concentrations (S, pg/ml) to dose (D, mgikgiday), i.e. S/D ratio, was also increased significantly from 2.1 to 4.3 after switching preparations (p &lt; 0.01). A decrease in the dose (mean, 85 %) was required in 6 patients. There was a significant positive correlation between extent of the elevation of serum PHT concentration after switching to the 10 % powder and serum PHT concentration before the switch (r = 0.86, p c 0.0003). Furthermore, the elevation of serum PHT levels in the patients receiving only PHT was significantly greater than that in the patients receiving 1 or more other anticonvulsants (p &lt; 0.05). Cuncbsion: These results suggest that the 10% powder formulation of PHT (Aleviatino‐10% powder) has a significantly greater bioavailability than the granular form (Aleviatino‐granules). Therefore, one must be vigilant when switching patients from one formulation of PHT to another, particularly in patients receiving only PHT. In addition, upon switching, one should consider adjusting the dose to decrease the likelihood of adverse effects and interactions between PHT and other anticonvulsants.