Administration Of Phenytoin Research Articles

English

The aim of the study was to evaluate the haematological alterations following the administration of carbamazepine (CBZ) and/or phenytoin (PHE). Forty apparently, healthy male adult Wistar rats weighing between 144 and 300 g were used for the experiment. They were divided into four groups of 10 animals each. Rats in group I (controls) were given distilled water at the dose of 2 ml/kg and they served as untreated controls. Rats in groups II, III and IV were given CBZ (20 mg/kg), PHE (100 mg/kg) and CBZ + PHE (20 and 100 mg/kg), respectively. All treatments were administered orally by gavage. The regimens were given once daily for a period of eight weeks. At the end of the experiment, the rats were sacrificed and blood samples were collected for the evaluation of total erythrocyte (RBC) count, packed cell volume (PCV), haemoglobin (Hb) concentration, and platelet counts. Also, total and differential leucocyte counts were evaluated using standard laboratory procedures. There was no significant (P > 0.05) change in the value of the PCV, Hb and platelets but the RBC decreased (P < 0.01) in the CBZ-treated group. There were increases in lymphocytes (P < 0.05) and neutrophils (P < 0.01) in rats treated with CBZ. In conclusion, the administration of CBZ caused alterations in haematological parameters, the changes observed in the other treatment groups which are PHE and CBZ + PHE are not statistically significant. Haematological parameters should be strictly monitored regularly in individuals administered with CBZ and/or PHE. If there are persistent alterations, the administration of the drugs should be discontinued.   Key words: Carbamazepine, phenytoin, rats, oral administration, 8 weeks, haematological parameters.

Comparison of the prevalence of convulsions associated with the use of cefepime and meropenem

The US Food and Drug Administration reported seizures associated with the use of cefepime (primarily in patients with renal impairment who did not receive appropriate dose adjustments of cefepime). The maximum dose of cefepime in the USA (6 g per day) is higher than that in Japan (4 g per day). We investigated the prevalence of convulsions associated with the use of cefepime by comparing it with that of meropenem. A retrospective study was undertaken in 183 patients treated with cefepime and 745 patients treated with meropenem over 2 years at Ehime University Hospital. Cefepime or meropenem-associated convulsions were defined according to the following criteria: (1) administration or dose escalation of diazepam, phenytoin, phenobarbital and thiamylal given via the intravenous route (2) convulsions recorded in medical records during administration of cefepime or meropenem. The prevalence of convulsions was significantly greater in the cefepime treated group than in the meropenem-treated group. Among the patients who had cefepime-associated convulsions, none had renal failure. Cefepime-associated convulsions occurred only in patients with brain disorders. Cefepime-associated convulsions should be recognized as potential complications even in patients with normal renal function. Brain disorders may increase the risk of cefepime-associated convulsions.

A randomized, placebo-controlled proof-of-concept, crossover trial of phenytoin for hydrocortisone-induced declarative memory changes

BackgroundCorticosteroid excess is associated with declarative memory impairment and hippocampal atrophy. These findings are clinically important because approximately 1% of the population receives prescription corticosteroids at any time, and major depressive disorder is associated with elevated cortisol levels and hippocampal atrophy. In animals, hippocampal changes with corticosteroids are blocked by phenytoin. The objective of the current study was to extend these preclinical findings to humans. We examined whether phenytoin attenuated the effects of hydrocortisone on declarative memory. Functional magnetic resonance imaging (fMRI) assessed task-related hippocampal activation. MethodsA randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in 17 healthy adult volunteers. Participants received hydrocortisone (2.5 days), phenytoin (3.5 days), both medications together, or placebo, with 21-day washouts between conditions. Differences between treatments were estimated using a mixed-effects repeated measures analysis. ResultsFifteen participants had data from at least two treatment conditions and were used in the analysis. Basal cortisol levels negatively correlated with fMRI BOLD activation in the para-hippocampus with a similar trend observed in the hippocampus. Decrease in declarative memory with hydrocortisone was blocked with concomitant phenytoin administration. Relative to the placebo condition, a significant decrease in hippocampal BOLD activation was observed with hydrocortisone and phenytoin alone, and the two medications in combination. Declarative memory did not show significant correlations with hippocampal activation. LimitationsThe modest sample size, which limited our statistical power, was a limitation. ConclusionsFindings from this pilot study suggest phenytoin attenuated effects of corticosteroids memory in humans, but potentiated the reduction in hippocampal activation.

A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors

Seizures are a potentially devastating complication of resection of brain tumors. Consequently, many neurosurgeons administer prophylactic antiepileptic drugs (AEDs) in the perioperative period. However, it is currently unclear whether perioperative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Therefore, the authors conducted a prospective, randomized trial examining the use of phenytoin for postoperative seizure prophylaxis in patients undergoing resection for supratentorial brain metastases or gliomas. Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection were randomized to receive either phenytoin for 7 days after tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events. Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a Type I error of 0.05 and a Type II error of 0.20, a target accrual of 142 patients (71 per arm) was planned. The trial was closed before completion of accrual because Bayesian predictive probability analyses performed by an independent data monitoring committee indicated a probability of 0.003 that at the end of the study prophylaxis would prove superior to observation and a probability of 0.997 that there would be insufficient evidence at the end of the trial to choose either arm as superior. At the time of trial closure, 123 patients (77 metastases and 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no prophylaxis (observation group). The incidence of all seizures was 18% in the observation group and 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of early seizures (< 30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more adverse events (18% vs 0%, p < 0.01). Therapeutic phenytoin levels were maintained in 80% of patients. The incidence of seizures after surgery for brain tumors is low (8% [95% CI 3%-18%]) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rate of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.

Effects of Administration of Carbamazepine and/or Phenytoin on Serum Biochemical Parameters in Wistar Rats.

This study was conducted to evaluate the serum biochemical alterations following the administration of carbamazepine (CBZ) and/or phenytoin (PHE) in Wistar rats. Forty male adult Wistar rats weighing between 144 and 300 g were used for the experiment. They were divided into four (4) groups of 10 animals each. Rats in groups II, III and IV were given CBZ (20 mg/kg), PHE (100 mg/kg) and CBZ+PHE (20 and 100 mg/kg separately), respectively. Rats in group I were given distilled water at 2 ml/kg and served as untreated control. All treatments were administered orally by gavage. The regimens were given once daily for a period of eight weeks. At the end of the experiment, the rats were sacrificed and serum samples were obtained for the analysis of total proteins, albumin, globulin, urea, Na + , K + , Cl - , and activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). There was an increase in the concentration of Na + (P < 0.0001) concentration, albumin (P < 0.01) and a decrease in urea (CBZ and PHE groups) (P < 0.05), globulin (P < 0.05) and K + (CBZ group) (P < 0.05) concentrations. The activities of ALT in the CBZ and CBZ+PHE groups and that of AST activity in the PHE group increased significantly (P < 0.05). In conclusion, administration of CBZ and/or PHE induced significant alterations in serum biochemical parameters in Wistar rats. It is recommended that serum biochemical parameters should be strictly monitored and regularly evaluated in individuals treated with CBZ and/or PHE in order to alleviate or prevent some of these changes.

Toxic Epidermal Necrolysis Associated with Antiepileptic Drugs and Cranial Radiation Therapy

Case reports on the development of toxic epidermal necrolysis (TEN) associated with concurrent administration of phenytoin with cranial radiation therapy (Ahmed (2004), Criton et al. (1997), and Rzany et al. (1996)), but reports about erythema multiforme, which can develop in patients treated with levetiracetam and cranial irradiation, are very limited. This paper presents evidence that TEN may be induced by concurrent use of radiation with both phenytoin and levetiracetam. Our case is a 42-year-old male patient, a case of gliosarcoma who developed purpuric dermatitis associated with phenytoin when combined with cranial radiation therapy; although phenytoin was discontinued and switched to levetiracetam, the patient had more severe symptoms of toxic epidermal necrolysis (TEN) on levetiracetam; the patient improved with aggressive symptom management, discontinuation of antiepileptic drugs (AEDs), and holding radiotherapy. Although TEN is a rare toxicity, physicians should pay a special attention to the monitoring of brain tumor patients on antiepileptic prophylaxis during cranial irradiation; furthermore, patients should be counselled to notify their physicians if they develop any new or unusual symptoms.

Compartment syndrome as a spectrum of purple glove syndrome following intravenous phenytoin administration in a young male: A case report and review of literature

Compartment syndrome is a rare complication of spectrum of purple glove syndrome, seen as a side effect of intravenous phenytoin. This involves rapid discolouration of the involved limb along with edema and sometimes blistering of the skin also. Treatment is usually conservative and rarely requires surgery. We present a case of compartment syndrome following intravenous phenytoin administration and review of literature related to the case.

Risk assessment of folic acid supplementation in phenytoin-treated epileptic patients: A pilot study

Background: There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the antiepileptic therapy in the prevention of antiepileptic drug-induced gingival enlargement. However, studies conducted in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin-induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy. Subjects and Methods: A total of 25 patients aged between 18 and 50 years clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was done prior to the start of and after 6 months of phenytoin therapy. The statistical analysis was done using t-test and the baseline serum folate levels and the serum folate levels obtained after 6 months of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula. Results: The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin-induced gingival enlargement justifying the judicious use of folate supplementation to prevent this inadvertent side effect of phenytoin administration. Conclusions: The results of the study suggest a higher incidence of gingival enlargement in phenytoin-treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases.

Purple Glove Syndrome after Intravenous Phenytoin Administration Presenting in the Emergency Department

Purple Glove Syndrome after Intravenous Phenytoin Administration Presenting in the Emergency Department

Dendritic, Axonal, and Spinal Pathology of the Purkinje Cells and the Neurons of the Dentate Nucleus After Long-Term Phenytoin Administration

Phenytoin is a commonly prescribed anticonvulsant drug; however, there is evidence that long-term administration is related to cerebellar ataxia, cerebellar atrophy, loss of Purkinje cells, and hyperplasia of Bergman glia cells. The aim of the present study was to detect and describe any possible alterations of the Purkinje cells, and neurons of the dentate nucleus, as those can be seen with the use of silver impregnation techniques, such as Golgi and Nauta method. The study was performed on a 7-year-old boy who was under phenytoin treatment for more than 3.5 years and had clinical manifestations of cerebellar ataxia. Golgi silver impregnation technique revealed substantial loss of dendritic spines and tertiary dendritic branches, both on the Purkinje cells and the neurons of the dentate nucleus, whereas the Nauta method demonstrated swollen and degenerated axons of Purkinje cells.

Cough and Bronchospasm After Rapid Intravenous Administration of Phenytoin

Department of Neuroanaesthesiology All India Institute of Medical Sciences New Delhi, India The authors have no funding or conflicts of interest to disclose.

Phenytoin in treatment of amiodarone-induced Torsades de pointes

Phenytoin, a class IB anti-arrhythmic agent, is considered the drug of choice for ventricular arrhythmias due to digoxin toxicity. We report successful reversion of polymorphic ventricular tachycardia secondary to amiodarone toxicity by phenytoin administration that was resistant to the conventional drugs (magnesium sulphate, lidocaine and atropine).

Gingival Enlargement in Epileptic Patients on Phenytoin Therapy-An Evidence Based Approach

Epilepsy is a common neurological disorder with recurrent seizures due to a chronic underlying process. Despite tremendous advances in the field of understanding the etio-pathogenesis of epilepsy, phenytoin still remains the drug of choice in its management. Chronic administration of phenytoin has been associated to have a number of adverse effects. Gingival enlargement is one such most often reported adverse drug sequela of long term phenytoin usage with exclusion of local factors contributing towards gingival enlargement. Hence, the study was planned to investigate the association of phenytoin and gingival enlargement seen in epileptic patients being treated with phenytoin. For this, 25 patients between the ages of 18-50 years clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of gingival status was done using the index originally described by Angelopoulos and Goaz and later modified by Miller and Damm [Go Index]. The results of the study confirmed a significant association between long term usage of phenytoin and the onset and severity of gingival enlargement in epileptic patients being treated with phenytoin. This is a baseline study; the results of the study suggest a higher incidence of gingival enlargement in phenytoin treated epileptic patients with local factors having a little role, if any, towards phenytoin induced gingival enlargement.

The Anticonvulsant Response to Valproate in Kindled Rats Is Correlated with Its Effect on Neuronal Firing in the Substantia Nigra Pars Reticulata: A New Mechanism of Pharmacoresistance

Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy treatment. However, mechanisms of resistance are only incompletely understood. We have recently shown that repeated administration of the AED phenytoin allows selecting resistant and responsive rats from the amygdala kindling model of epilepsy, providing a tool to study mechanisms of AED resistance. We now tested whether individual amygdala-kindled rats also differ in their anticonvulsant response to the major AED valproate (VPA) and which mechanism may underlie the different response to VPA. VPA has been proposed to act, at least in part, by reducing spontaneous activity in the substantia nigra pars reticulata (SNr), a main basal ganglia output structure involved in seizure propagation, seizure control, and epilepsy-induced neuroplasticity. Thus, we evaluated whether poor anticonvulsant response to VPA is correlated with low efficacy of VPA on SNr firing rate and pattern in kindled rats. We found (1) that good and poor VPA responders can be selected in kindled rats by repeatedly determining the effect of VPA on the electrographic seizure threshold, and (2) a significant correlation between the anticonvulsant response to VPA in kindled rats and its effect on SNr firing rate and pattern. The less VPA was able to raise seizure threshold, the lower was the VPA-induced reduction of SNr firing rate and the VPA-induced regularity of SNr firing. The data demonstrate for the first time an involvement of the SNr in pharmacoresistant experimental epilepsy and emphasize the relevance of the basal ganglia as target structures for new treatment options.

A Critical Look at Phenytoin Use for Early Post-Traumatic Seizure Prophylaxis

The American Academy of Neurology recommended using phenytoin or carbamazepine to prevent early post-traumatic seizures (PTS) in severe traumatic brain injuries (TBI). In this study, we examined the effects of using phenytoin prophylaxis on mild, moderate, and severe TBIs. There have been no studies looking at compliance rate and side effects of systematic use of phenytoin at a large population scale. The goal of this study is to determine 1) the proportion of TBI patients receiving phenytoin prophylaxis; 2) which parameters decided when to decide administer phenytoin; 3) prophylaxis efficacy and complication rate. We retrospectively studied all patients admitted with a TBI over a two year-period and collected the following information: age, GCS score, CT-scan Marshall grade, incidence of early PTS, incidence of phenytoin use and time delay, side effects, and incidence of over-dosage or under-dosage. 1008 patients were included. 5.4 % had early PTS, 2.3 % while on prophylaxis and 3.1% while not on prophylaxis, 1.9% before reaching the hospital and 1.2% prior to phenytoin administration while in hospital. Delay of administration was 5 hours. 64.8% received prophylaxis and physicians used positive CT scan as the primary decision-making parameter (p<.001). Compliance with guidelines was 99.7%. Adverse reactions occurred in 0.5%. Levels were drawn in 42.2% (52% therapeutic, 41% low, 7% high). Phenytoin is used according to guidelines, with CT scan being the main decision factor for its use. The frequency of early PTS rate is low and side effects are rare. However, earlier administration of phenytoin and adequate levels could further prevent early PTS.

Phenytoin, Levetiracetam, and Pregabalin in the Acute Management of Refractory Status Epilepticus in Patients with Brain Tumors

There were nearly 700,000 patients in the United States in 2010 living with brain tumor diagnoses. The incidence of seizures in this population is as high as 70% and is historically difficult to control. Approximately 30-40% of brain tumors patients who present with status epilepticus (SE) will not respond to typical therapy consisting of benzodiazepines and phenytoin (PHT), resulting in patients with refractory status epilepticus (RSE). RSE is usually treated with anesthetic doses of propofol or midazolam infusions. This therapy can have significant risk, particularly in patients with cancer. A retrospective chart review was performed on 23 patients with primary or metastatic brain tumors whose SE was treated with intravenous PHT, levetiracetam (LEV), and oral pregabalin (PGB). In all the patients under study, PHT or LEV was used as first-line therapy. PGB was typically used as third-line treatment. The median daily dose of PGB was 375 mg (usually divided BID or TID), and the median daily dose of LEV 3000 mg (usually divided BID). Cessation of SE was seen in 16/23 (70%) after administration of PHT, LEV, and PGB. SE was aborted, on average, 24 h after addition of the third antiepileptic drug. Only one patient in the responder group required intubation. Mortality rate was zero in the responder group. No adverse reactions to this medication regimen were observed. Our study suggests that the administration of PHT, LEV, and PGB in brain tumor patients with RSE is safe and highly effective.

Accidental Intraventricular Administration of Phenytoin Through an External Ventricular Drain: Case Report

A 52-year-old man with an external ventricular drain was transferred from the local neurosurgical intensive care unit to the general intensive care unit for renal replacement therapy. While the patient was in the general intensive care unit, phenytoin was accidentally administered via the external ventricular drain. Tachycardia and hypertension ensued and then seizure activity. The drain was aspirated and then washed out. Propofol was infused for 24 hours and then was stopped to allow continuing neurological assessment. The route of administration of phenytoin was changed from intravenous to oral, and care continued as before. After resolution of the renal failure, the patient was returned to the neurological intensive care unit. He recovered slowly and had no adverse effects due to the error in administration of phenytoin.

Impact of seizure activity on free extracellular phenytoin concentrations in amygdala-kindled rats

Access of antiepileptic drugs (AEDs) to the epileptic focus region is considered to be influenced by seizure-associated changes in blood–brain barrier (BBB) function and blood flow. Enhanced leakiness of the BBB has been reported as a consequence of seizure activity, and this is controversially discussed to either favor accumulation of AEDs in epileptic tissue or to limit free extracellular concentrations of AEDs due to enhanced protein extravasation. On the other hand, multidrug transporter overexpression has been described following seizure activity, which can limit brain penetration of AEDs in brain regions involved in seizure generation and spread. Aim of the present study was to determine, how these complex alterations at the BBB influence penetration of a standard AED to the site of seizure initiation. Microdialysis experiments were performed in amygdala-kindled rats and in electrode-implanted, non-kindled rats with the microdialysis probe located directly adjacent to the stimulation-recording depth electrode. Penetration of the AED phenytoin to the extracellular fluid in the focus region was investigated at different time points in relation to seizure activity elicited in kindled rats. Integrity of the BBB was determined by Evans blue. Access of phenytoin to the amygdala proved to be comparable in non-kindled, electrode-implanted control rats and in kindled rats 2 h or fourteen days following a single generalized seizure. When a single generalized seizure was elicited 10 min following phenytoin administration, average phenytoin brain dialysate levels were significantly lower (up to 45%) than those of control animals. During a self-sustained status epilepticus, phenytoin access to the site of seizure initiation tended to be lower in the early phase following drug administration, but reached control level 2 h later. The data clearly demonstrate that seizure-induced alterations in BBB integrity and function do not increase extracellular brain levels of phenytoin in affected brain regions, but rather tend to decrease the free concentration of phenytoin in the extracellular compartment.

Effect of prenatal phenytoin administration on brain tryptophan metabolism of rat offspring during the preweaning period.

Serum 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) concentrations in control rat offspring increased progressively during the preweaning period reaching adult values by day 21. It has been shown the prenatal phenytoin administration (100 mg kg-1 orally, days 7-19 of pregnancy) increased serum tryptophan and brain tryptophan, 5-HT and 5-HIAA of rat offspring at 3 days of age but not at 4, 15 or 21 days of age. The effect of prenatal phenytoin administration on the offspring at 3 days of age was not observed when these pups were cross-fostered to control mothers at 2 days of age suggesting that the alteration in rain tryptophan metabolism during the development of tryptaminergic neurons in rat offspring, as a result of prenatal phenytoin administration is mediated through changes in lactation or nursing ability of the mothers. It is important that such non-specific factors are controlled when studying the effect of prenatally administered drugs on neonatal brain transmitter concentrations.

Herb — drug interaction of noni juice and Ginkgo biloba with phenytoin

The common perception regarding the herbal medicines is that they are natural and safe. Although considered natural, most of the herbal medicine can interact with other drugs causing either potentially dangerous side effects or they can lead to loss or decreased therapeutic benefits of the drugs. Currently, there is growing concern to analyse and understand the herb — drug interactions. This study investigates effects of noni juice/Ginkgo biloba on the pharmacokinetics of phenytoin and also on the oxidative stress associated with long term administration of phenytoin. After pretreatment for 7 days with noni juice and G. biloba, on day 8 the phenytoin was co-administered orally with noni juice and G. biloba and the serum pharmacokinetics were determined at various time points (1, 2, 4,6, 8,12 and 24 h) by HPLC. The oxidative stress markers were determined after 30 days of treatment. Noni juice pretreated rats decreased the bioavailability of phenytoin by 2.81 fold, whereas G. biloba pretreated rats increased the bioavailability by 2.08 fold when compared with control. Noni juice and G. biloba treated rats provided significant protective effect against the oxidative stress induced by long term administration of phenytoin. It is observed that noni juice and G. biloba might have altered the bioavailability of phenytoin due to induction and inhibition of CYP2C9 enzymes.