Blood Levels Of Phenytoin Research Articles

Intranasal fosphenytoin: The promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs.

Intranasal administration could increase both safety and efficacy of drugs acting on the central nervous system, but low solubility severely limits administration through this route. Phenytoin's prodrug, fosphenytoin, is hydrophilic and freely soluble in water, but less permeable since it is dianionic. We aimed to assess whether this phosphoester prodrug could be a suitable alternative to phenytoin in intranasal delivery. Secondly, we aimed to compare simple formulation strategies in fosphenytoin delivery. Fosphenytoin formulations containing thermosensitive and/or mucoadhesive (hydroxypropyl methylcellulose, HPMC) polymers were developed, guided by viscosity, gelling temperatures, osmolality, and in vitro drug release tests. Then, a pharmacokinetic study was performed, comparing an intravenous fosphenytoin solution, an intranasal fosphenytoin solution, and intranasal fosphenytoin mucoadhesive formulations with or without albumin. Formulations containing HPMC allowed high drug strengths, and had a relatively fast release profile, which was not changed by albumin. Intranasal administration of a formulation with HPMC and albumin prolonged drug concentration over time and led to complete or even increased absolute bioavailability. Moreover, phenytoin's blood levels did not reach the high peak obtained with intravenous administration. In conclusion, the use of phosphate ester prodrugs could be an efficient and safe strategy to increase the intranasal bioavailability of poorly soluble drugs.

Association of CYP2C9*3 with phenytoin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: A systematic review and meta-analysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that can be induced by phenytoin (PHT). CYP2C9*3 is the key enzyme in PHT metabolism. The aim of this meta-analysis was to evaluate the association between CYP2C9*3 and PHT-induced SJS/TEN. An extensive search was performed in multiple databases, including the Cochrane Library, EMBASE, PubMed, OVID and EBSCO. Studies exploring the relationship between CYP2C9*3 and PHT-induced SJS and TEN were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were calculated for dichotomous data. Data analysis was performed using Review Manager (version 5.3). Four studies, with 117 PHT-induced SJS/TEN cases and 338 matched controls (PHT-tolerant patients) or 4231 population controls (general population), were identified. SJS and TEN were found to be significantly associated with the CYP2C9*3 allele, comparing both matched controls (OR, 8.93; 95% CI, 2.63-30.36; P=.0005) with substantial heterogeneity (I2 =46%) and population controls (OR, 8.88; 95% CI, 5.01-15.74; P<.00001). A significant association between CYP2C9*3 and PHT-induced SJS/TEN was identified, especially in a Thai population. CYP2C9*3 is thus a credible predictive genetic marker of PHT-induced SJS/TEN. Further multicenter studies and large prospective observational studies are, however, still required to determine the influence of CYP2C*3 on blood levels of PHT and its metabolites, and their association with SJS/TEN.

Inhibition of phenytoin hydroxylation in human liver microsomes by several selective serotonin re-uptake inhibitors

Several case reports have indicated that the selective serotonin re-uptake inhibitor (SSRI) fluoxetine increases phenytoin blood levels when given concurrently. The mechanism of this drug–drug interaction has been attributed to inhibition of CYP2C9-catalyzed hydroxylation of phenytoin to its major oxidative metabolite in humans, para-hydroxyphenyl phenyl hydantoin (HPPH). With a bank of human liver microsomes (HLM), four SSRIs (fluoxetine, norfluoxetine, sertraline, and paroxetine) were tested for inhibition of HPPH formation. Initially, the K m and V max values of phenytoin hydroxylation to HPPH were determined in the individual HLM samples. The average K m ( n=8) was 9.7±2.9 μM. The V max varied fivefold, with an average value of 113±53 pmol HPPH/min/nmol CYP450. All of the SSRIs inhibited HPPH formation; resulting Ki values were 31.1±10.1 μM (fluoxetine) ( n=5), 51.1±9.4 μM (norfluoxetine) ( n=3), 52.2±21.5 μM (sertraline) ( n=3), and 80.0±7.2 μM (paroxetine) ( n=3). Sulfaphenazole (10 μM), utilized as a positive control for inhibition of HPPH formation, inhibited phenytoin hydroxylation (>95%) in all HLM samples. Diclofenac hydroxylation to 4′-OH diclofenac, a specific marker for CYP2C9 activity, was determined in HLM1–HLM6 and was highly correlated with HPPH formation in HLM1–HLM6, indicating that phenytoin hydroxylation in human liver microsomes is largely due to CYP2C9. This work presents direct evidence that the effect of fluoxetine on phenytoin blood levels may be explained by inhibition of CYP2C9-catalyzed phenytoin hydroxylation. In light of typical SSRI blood levels observed in patients, this study also suggests that the risk of a SSRI–phenytoin interaction is highest with fluoxetine and norfluoxetine, and less likely with sertraline and paroxetine.

Intoxication aiguë à la phénytoïne par erreur d’administration de la fosphénytoïne (Prodilantin®)

Following surgery for a chronic subdural haematoma, a 74-year-old patient received fosphenytoin as prophylaxis for epilepsy. The patient received 10 times the prescribed dose. This error in the administration of fosphenytoine was facilitated by a confusing labeling of the product. The phenytoin blood level was 79 μg·mL –1. The main adverse effect was a coma requiring 5 days of mechanical ventilation. No adverse cardiovascular event was noted. The phenytoin blood levels returned toward the therapeutic range in 8 days. At discharge from the hospital 20 days after surgery, the patient did not have any sequela from the fosphenytoin intoxication.

Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy

Intractable seizures are the most common manifestation in severe cases of tuberous sclerosis. Multidrug resistance type 1 (MDR1) gene expression is directly linked to the resistance of tumor cells to chemotherapy as the major cause of treatment failure, but it has not been reported in tuberous sclerosis cells nor has the relationship between the MDR1 gene and antiepileptic drugs been described. A 4-month-old female is described with poorly controlled seizures secondary to tuberous sclerosis. The patient was treated with antiepileptic drugs, including phenytoin, phenobarbital, and lorazepam, without improvement of symptoms. Phenytoin blood levels were invariably subtherapeutic and ranged from 0.45 to 3.55 μg/mL, despite several consecutive intravenous loading doses. Surgical treatment with total resection of the brain lesions was performed as a last resort. Immunohistochemical analysis of the resected tissues revealed high levels of P-glycoprotein 170 expression, the product of the MDR1 gene. Both MDR1 gene expression and persistently low phenytoin levels likely share a common pathway liable to induce drug-resistant epilepsy.

Magnesium sulfate versus phenytoin for seizure prevention in amygdala-kindled rats

Objective: Magnesium sulfate is widely used for seizure prophylaxis in preeclampsia-eclampsia. However, its anticonvulsant effects in other types of seizures have not been proved. Diphenylhydantoin has been widely characterized as the “gold standard” of anticonvulsants. In this study we compared the anticonvulsant effects of therapeutic blood levels of magnesium sulfate and phenytoin in seizures generated in amygdala-kindled rats.Study Design: Eighteen male rats had a bipolar electrode stereotaxically implanted into the central nucleus of the amygdala. After recovery an electrical seizure threshold was determined for each rat. Rats were stimulated twice daily at their seizure thresholds (i.e., kindling) until three consecutive generalized tonic-clonic seizures occurred. Kindled rats randomly received one of the following intravenous injections in a volume of 1.5 ml/kg: saline solution, magnesium sulfate (30, 60, or 90 mg/kg), or phenytoin (12.5, 25, or 50 mg/kg). Fifteen minutes after injection rats were stimulated at their seizure thresholds, and electrical and behavioral seizure activity was assessed. Statistical comparisons were made by analysis of variance and post hoc comparisons where appropriate.Results: Magnesium sulfate had no effect on any of the seizure parameters assessed. Phenytoin significantly reduced seizure duration (p < 0.01), duration of postictal depression (p < 0.01), and behavioral seizure stage (p < 0.01).Conclusion: Amygdala-kindled seizures are more potently inhibited by phenytoin than by magnesium sulfate.

Photosensitive complex partial seizures aggravated by phenytoin

A 10-year-old girl is described with pure photosensitive complex partial seizures which consisted of a frightening visual phenomenon of seeing “shadow people“, then staring blankly with lip smacking and sometimes becoming limp. The seizures were triggered by bright sunlight. With the institution of phenytoin therapy, her seizure frequency increased dramatically without any clinical evidence of toxicity and her phenytoin blood levels were within the therapeutic range. Discontinuation of phenytoin led to a return to baseline seizure frequency. The mechanism by which antiepileptic drugs may aggravate seizures is still not understood; therefore, awareness of this phenomenon is crucial for early diagnosis and appropriate treatment.

Felbamate for partial seizures

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.

The administration of folic acid to institutionalized epileptic adults with phenytoin-induced gingival hyperplasia: A double-blind, randomized, placebo-controlled, parallel study

Twenty severely retarded institutionalized epileptic adults with phenytoin-induced gingival hyperplasia were divided into two groups and received a daily 3 mg capsule of either folic acid or lactose for 16 weeks in a randomized, double-blind, parallel study. Serum folate and phenytoin levels were recorded at baseline and on completion of the study. Twelve areas of the gingiva on each patient were graded at 4-week intervals for 16 weeks with respect to the three indexes: hyperplasia, gingival health, and plaque index. There were no significant differences between treatment groups for any of the three indexes over time. The poststudy serum folate levels were three times baseline levels for the active drug group ( p < 0.001) but unchanged in the placebo group. Phenytoin blood levels that began within the therapeutic window (10 to 20 μg/ml) tended to remain within the therapeutic window for both groups, with no reported seizure activity. A single daily oral 3 mg capsule of folic acid did not show efficacy as the sole therapeutic agent in the reduction of phenytoin-induced gingival hyperplasia.

Effect of folic acid on recurrence of phenytoin‐induced gingival overgrowth following gingivectomy

This study examined the effect of folic acid supplementation on the recurrence of phenytoin-induced gingival overgrowth following gingivectomy. 8 residents of an institution for the developmentally disabled were randomly assigned to a treatment (N = 4) or control (N = 4) group. Subjects in the treatment group received an oral supplementation of 5 mg of folic acid daily during the study; those in the control group did not. A gingivectomy with an external beveled incision made to the crest of the alveolus was completed by quadrants. The following data were obtained prior to gingivectomy, 2 weeks following the last quadrant of surgery, and at 3 and 6 months post-surgery: plaque and gingival index scores, red blood cell folic acid levels, free phenytoin blood levels, photographs, and impressions. % change in overgrowth was determined from cross-sectional area measurements made on dies obtained from bucco-lingual cuts on stone models. Differences across time between and within groups were tested by a two-factor repeated measure analysis of variance. The groups did not differ in plaque and gingival index scores or free phenytoin blood levels. The treatment group had significantly higher red blood cell folic acid levels (p less than or equal to 0.0001). Reduction in gingival overgrowth as a result of surgery was similar in both groups. Although the treatment group had significantly less recurrence of gingival overgrowth (p less than or equal to 0.05), the mean differences amounted to only 6-7% at 3 and 6 months.

Developmental Retardation in Children with Refractory Epilepsy

It is controversial whether developmental retardation occurs in children with epilepsy and what causes the retardation if it occurs. The present study aims to reveal the factors associated with the retardation. The patients were 126 children who had been developmentally normal before the onset of epilepsy and had been followed for more than five years. Forty-eight of the 126 children showed mental retardation, and the remaining 78 had normal mental development at the follow-up. Developmental retardation was observed in children with onset before one year, known etiology, diffuse slow spike-wave or hypsarrhythmia on EEG, ingestion of six or more drugs and high blood levels of phenobarbital or phenytoin. Late onset of epilepsy, idiopathic or familial etiology, ingestion of five drugs or less and low blood level of phenobarbital or phenytoin were associated with normal development.

The effect of solvent composition upon the blood and lymph levels of phenytoin in rats after gastric administration

The effects of six different solvents on the blood and lymph levels of [ 14C]phenytoin after intragastric administration were studied in rats. The solvents studied were a diverse group which consisted of water, olive oil, 10% Liposyn, 10% ethanol, and aqueous solutions of 1% and 2.5% Na oleate. Chronic collection of lymphatic fluid from the unanesthetized rat was accomplished by cannulation of the major lymphatic structure in the abdominal cavity, the cisterna chyli, which is the terminal sac of the thoracic lymph duct. Blood and lymph were sampled for 24 h. The solvents which resulted in the greatest bioavailability in blood and lymph were the 10% ethanol and 1% Na oleate solutions. The 10% ethanol, olive oil and 10% Liposyn treatments resulted in total lymph volumes which were statistically larger ( P < 0.05) than the other groups. Thus, the solvent may not only affect the bioavailability of a drug in the blood and lymph, but may also affect the lymphatic flow. This may be of significance in the design of dosage forms which are concerned with both the concentration of the drug: in the blood and lymph, and with the total amount of drug delivered into the lymph.

Therapeutic blood levels of phenytoin in treatment of paroxysmal choreoathetosis.

Eight patients with paroxysmal choreoathetosis received phenytoin therapy, starting from 50 mg of oral phenytoin with a gradual increment of the dose. After successful control of the paroxysmal attacks, blood levels of phenytoin in these patients were measured by enzyme immunoassay. The mean phenytoin blood level was 5.2 +/- 3.2 micrograms/ml, with a range of 1.1-10.9 micrograms/ml. It is proposed that phenytoin can be maintained at a lower level in the treatment of paroxysmal choreoathetosis than in seizure control.

Effect of empiric dosing on blood levels of theophylline and phenytoin

To evaluate empiric dosing guidelines for aminophylline and phenytoin in the management of acute exacerbations of obstructive lung disease and seizure disorders, we utilized an emergency department (ED)-based EMIT system to measure stat plasma theophylline and phenytoin levels in patients intended to receive these drugs. Plasma drug level results were available prior to initiation of therapy. Of the patients evaluated, 45 of 163 (27.6%) aminophylline patients and 21 of 73 (28.7%) phenytoin patients were projected to have plasma concentrations below the recommended therapeutic range if empiric dosing schedules were employed. In addition, 39 of 163 (23.9%) aminophylline and 10 of 73 (13.7%) phenytoin patients, had they received these drugs empirically, would have had plasma theophylline and phenytoin levels in excess of the recommended therapeutic range using empiric dosing. We conclude that the use of empiric dosing guidelines for aminophylline and phenytoin in the ED do not reliably produce therapeutic plasma concentrations. The development of a stat drug analysis laboratory in the hospital or within the ED would improve the effectiveness and safety of these acutely used drugs with narrow therapeutic ranges.

Emergency phenytoin loading by constant intravenous infusion

We evaluated the efficacy of constant intravenous (IV) phenytoin infusion. Thirty-eight patients were evaluated prospectively for complications of continuous-infusion phenytoin loading. A total dose of 18 mg/kg was administered as a solution of 500 mg phenytoin in 50 mL normal saline using a constant infusion pump. The initial delivery rate was 40 mg/min. Cardiac rhythm was monitored by telemetry, and rhythm strips and vital signs were obtained every 15 minutes during infusion. Therapeutic phenytoin blood levels (greater than 10 micrograms/mL) were achieved in 37 patients (97%). Infusion was discontinued in one patient because of IV site irritation shortly after initiation of the infusion. Phenytoin levels in the toxic range were seen immediately postinfusion in 22 patients and in the four-hour postinfusion samples of 16 patients. Thirteen of 18 levels drawn 12 to 24 hours after infusion were therapeutic. Phenytoin levels greater than 20 micrograms/mL were tolerated without significant change in rhythm, QRS interval, or QT interval. A small statistically significant (P less than .05) decrease in systolic and mean arterial pressure was noted during the infusion. Complications included burning at the IV infusion site in four patients; the discomfort was relieved in three cases by reducing the rate of infusion to 20 mg/min. Seizures occurred in two patients during the infusion, requiring the additional use of diazepam or phenobarbital. Administration of a loading phenytoin dose by constant IV infusion is an effective means for achieving therapeutic levels quickly.

Evaluation of an ultrafiltration-fluorescence polarization immunoassay for monitoring unbound phenytoin.

To evaluate a new ultrafiltration-fluorescence polarization immunoassay (FPIA) for monitoring blood levels of unbound phenytoin, the drug, with or without a 14C label, was added to three serum pools obtained from normal, uremic, and hypoalbuminemic patients and to 10 individual patient sera that varied greatly in phenytoin binding (11-50%). Protein-unbound phenytoin fractions were obtained from the sera by ultrafiltration using the Amicon Micropartition System and by a classic equilibrium dialysis method. The percent unbound phenytoin in each serum was determined by a radioassay and an automated FPIA (TDx System). An analysis of variance revealed no significant difference in the percent unbound phenytoin obtained at 37 degrees C by the FPIA and radioassay methods (alpha = 0.05). The data indicate that the ultrafiltration system can be combined with FPIA to produce a convenient laboratory method for routine therapeutic drug monitoring that gives results comparable to the equilibrium dialysis, radioassay reference method.

Das EEG bei Phenytoin-Intoxikation

Four patients had Phenytoin intoxications, whereby 3 of them suffered from acute and one from subacute symptoms (in all of them reversible cerebellar symptoms and acute organic brain syndrome and in one of them an axonal polyneuropathy which lasted a bit longer). The clinic-neurologic symptoms, the Phenytoin blood levels and the current EEG changes were compared. Three patients had blood levels in a high toxic range, the fourth one had levels within the therapeutic range. The EEG changes of acute phase of intoxications showed in each case nonspecific mostly diffused slowing of the traces with theta- and delta-activity over the convexity (Tab. 1a, 2c, d). Although the EEG changes were reversible, they lasted longer than the clinical intoxication phase. These EEG changes were already manifest several days before the clinical symptoms. We feel therefore that the EEG examination is indicated especially in doubtful cases because it is easier to execute than the blood level estimation, - even though the changes are nonspecific. One case (Nr. 1), which was more closely explores, did not develop any epileptic fits, instead the fits were retrospectively seen as stemming from a psychogenic origin, which was treated with Phenytoin. The EEG of this patient showed generalised irregular SW-paroxyms (Tab. 1b) as the medication blood level was receding (120 muMol/l). This would be a manifestation of an independent Phenytoin effect in the high toxic dosage respectively in withdrawal.

Acute effects of phenytoin on peripheral nerve function in the rat.

The acute effect of intraperitoneal injection of phenytoin on rat peripheral nerve was studied. Conduction velocities in the ventral caudal nerve were measured hourly and phenytoin blood levels were obtained 4 to 5 hours after injection. Conduction velocity decreased by 23% in the 25 phenytoin-treated animals from a control value of 30.0 plus or minus 1.3m/sec (mean plus or minus SEM) to a 4-hour value of 23.0 plus or minus 1.3 m/sec (P less than 0.001). The phenytoin blood level 4 hours after injection was 45.0 plus or minus 1.3 micrograms/ml. Amplitudes of evoked muscle action potentials in the treated group decreased by 37% from control values. High levels of phenytoin induce prompt slowing of nerve conduction velocity within hours, which may be mediated by mechanisms similar to those responsible for toxic central effects.

Phenytoin Toxicity and Blood Levels after a Large Oral Dose

The pharmacokinetics and side effects of a single oral 900-mg dose of phenytoin sodium were studied in six healthy men. Nine 100-mg phenytoin sodium capsules were administered with water to six fasting healthy men. Phenytoin plasma levels were measured by gas chromatography for up to 48 hours after dosing. Patients were observed and tested for gastrointestinal, cardiovascular, and neurologic side effects. Peak total (bound and free) plasma phenytoin levels were within the therapeutic range (10--20 microgram/ml) for two subjects and close (not less than 8.39 microgram/ml) for the remaining four. Peak free drug levels were 1.01--1.60 microgram/ml. Time to reach total and free peak plasma levels was long and variable (6--14 hours and 2--10 hours, respectively). Phenytoin protein binding (11.9--13.6%) was relatively stable among patients and at various plasma levels. A few mild transient side effects were noted; most occurred within two to four hours after dosing. Sinus bradycardia and a shortened PR interval were noted in two patients but did not correlate with peak plasma phenytoin levels. It appears that an oral loading dose of phenytoin sodium may be useful in ambulatory patients but further study of its side effects is recommended.

A Comparison of Plasma Phenytoin Level Determinations by EMIT and Gas-Liquid Chromatography in Patients with Renal Insufficiency

Monitoring the blood levels of antiepileptic drugs (AED) has proven to be of value in the clinical management of epileptic patients. We have compared the plasma concentrations of AED determined by enzyme multiplied immunoassays (EMIT) and gas-liquid chromatography (GLC) assays and identified a group of patients (n = 22) in whom the EMIT values for phenytoin were up to three times higher than those obtained by GLC. All these patients were oliguric with various degrees of azotemia, most of them undergoing weekly hemodialysis. The ratio of EMIT over GLC was 2.0 in 14 patients, 2.5 in 5 patients, and near 3.0 in 3 patients. These ratios remained relatively constant during repeated determinations over several months. The magnitude of difference between EMIT and GLC values (microgram/ml) was not related to the degree of azotemia. The discrepancy remained unchanged when various modifications of EMIT and GLC techniques were used. When phenytoin was added in vitro to plasma from nonepileptic oliguric azotemic patients, the measured phenytoin values were close to and not higher than the target values by either methodology. We feel that, when monitoring phenytoin blood levels in epileptic patients with renal insufficiency, one should be aware of a discrepancy between phenytoin values assayed by GLC and EMIT.