Removal Of Phenytoin Research Articles

A model-based analysis of phenytoin and carbamazepine toxicity treatment using binding-competition during hemodialysis

Hemodialysis (HD) has limited efficacy towards treatment of drug toxicity due to strong drug-protein binding. In this work, we propose to infuse a competitor drug into the extracorporeal circuit that increases the free fraction of a toxic drug and thereby increases its dialytic removal. We used a mechanistic model to assess the removal of phenytoin and carbamazepine during HD with or without binding-competition. We simulated dialytic removal of (1) phenytoin, initial concentration 70 mg/L, using 2000 mg aspirin, (2) carbamazepine, initial concentration 35 mg/L, using 800 mg ibuprofen, in a 70 kg patient. The competitor drug was infused at constant rate. For phenytoin (~ 13% free at t = 0), HD brings the patient to therapeutic concentration in 460 min while aspirin infusion reduces that time to 330 min. For carbamazepine (~ 27% free at t = 0), the ibuprofen infusion reduces the HD time to reach therapeutic concentration from 265 to 220 min. Competitor drugs with longer half-life further reduce the HD time. Binding-competition during HD is a potential treatment for drug toxicities for which current recommendations exclude HD due to strong drug-protein binding. We show clinically meaningful reductions in the treatment time necessary to achieve non-toxic concentrations in patients poisoned with these two prescription drugs.

Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup

The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence-based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence= C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning.

Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation.

Phenytoin is a widely used antiepileptic drug that induces cell proliferation in several tissues, such as heart, bone, skin, oral mucosa and neural precursors. Some of these effects are mediated via fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR). These receptors are strongly expressed in the adult ventricular-subventricular zone (V-SVZ), the main neurogenic niche in the adult brain. The aim of this study was to determine the cell lineage and cell fate of V-SVZ neural progenitors expanded by phenytoin, as well as the effects of this drug on EGFR/FGFR phosphorylation. Male BALB/C mice received 10 mg/kg phenytoin by oral cannula for 30 days. We analysed the proliferation of V-SVZ neural progenitors by immunohistochemistry and western blot. Our findings indicate that phenytoin enhanced twofold the phosphorylation of EGFR and FGFR in the V-SVZ, increased the number of bromodeoxyuridine (BrdU)+/Sox2+ and BrdU+/doublecortin+ cells in the V-SVZ, and expanded the population of Olig2-expressing cells around the lateral ventricles. After phenytoin removal, a large number of BrdU+/Receptor interacting protein (RIP)+ cells were observed in the olfactory bulb. In conclusion, phenytoin enhanced the phosphorylation of FGFR and EGFR, and promoted the expression of neural precursor markers in the V-SVZ. In parallel, the number of oligodendrocytes increased significantly after phenytoin removal.

Phenytoin Removal by Continuous Venovenous Hemofiltration

To describe 2 cases of clinically significant phenytoin removal during continuous venovenous hemofiltration (CVVH) and review the relevant literature regarding phenytoin removal by renal replacement modalities. A 64-year-old female with chronic kidney disease and cirrhosis was admitted to the intensive care unit (ICU) with a traumatic subdural hematoma and seizures. The patient received a loading dose of intravenous phenytoin 1000 mg, followed by maintenance intravenous administration of phenytoin 100 mg and levetiracetam 250 mg every 12 hours. CVVH was initiated for acidosis. A 63-year-old male was admitted to the ICU after cardiac surgery complicated by hypotension. CVVH was initiated for fluid overload, and phenytoin was initiated 3 days later for seizures. A loading dose of intravenous phenytoin 2700 mg was administered, followed by maintenance dosing of intravenous phenytoin 150 mg every 8 hours. Concentrations of unbound phenytoin in serum and CVVH effluent samples were measured during concomitant treatment in each patient. In both patients, serum and effluent concentrations of unbound phenytoin fell steadily while they were on CVVH. Clearance of phenytoin by CVVH was calculated, as was the daily removal of phenytoin, as a percentage of total daily phenytoin dosage during each sampling period. Phenytoin clearance by CVVH ranged from 11 to 13 mL/min in these patients. The clearance of phenytoin with CVVH in these 2 patients was much higher than the renal clearance of phenytoin reported in healthy volunteers with normal renal function. Previous case reports have demonstrated that only small, clinically insignificant amounts of phenytoin are removed by hemodialysis, and the only published report of phenytoin removal by continuous renal replacement therapy used hemofiltration rates much lower than those used in the 2 cases described here. These cases demonstrate that a substantial amount-approximately 30%-of total daily phenytoin dose may be removed by CVVH, and patients may require higher than expected empiric doses. Phenytoin concentrations should be closely monitored in critically ill patients receiving CVVH.

Faster phenytoin removal from serum by electrodialysis: a potential use in hemodialysis?

Protein binding of drug is responsible of ineffectiveness of conventional hemodialysis. The aim of the present study was to investigate the potential of electrodialysis, i.e. the transport of charged solutes through a membrane under the influence of an external electric potential, to increase the clearance of phenytoin, i.e. a model albumin-bound drug from human serum in vitro. Electrodialysis was performed through cellulose triacetate membrane mounted onto electrodialyser built in-house which separated: (a) saline solution, (b) 4% albumin saline solution or (c) human serum and dialysate compartments. The electric current density between both electrodes placed into donor (cathode) and dialysate (anode) compartments was settled to 0.79 mA/cm 2 for 3 h at 37 °C. Recovery of phenytoin in dialysate from either (a) saline solution or (b) 4% albumin saline solution was significantly higher than that obtained by classical dialysis ((a): 42% versus 24%; (b): 30% versus 6%). In human serum, the effectiveness of electrodialysis was appreciated by the unbound phenytoin clearance, which was about twice higher than in dialysis (0.22 ml/h versus 0.12 ml/h). However, the removed fraction of 10% in the human serum could just reflect the usual unbound phenytoin. Consequently, the impact of electrodialysis on the protein binding was not affirmed, but the ability of this technique to eliminate shortly free drug was clearly demonstrated. Electrodialysis would be a promising improvement of hemodialysis for the elimination of ionized drugs from human blood.

Effects of Long-Term Video-electroencephalographic Monitoring on Mood in Epilepsy Patients

This study examines changes in mood of 79 epilepsy patients who completed the Profile of Mood States during long-term video-electroencephalographic monitoring (LTM). Statistical linear models included the effects of age, gender, increased seizure frequency, sleep deprivation, and taper of antiepileptic drugs (AEDs) on mood. Sleep deprivation increased fatigue and decreased vigor from baseline to Day 3, but not from baseline to Day 8 or the final day of the protocol. Taper of AEDs did not adversely affect mood, with removal of phenytoin improving mood. Subjects who had seizures during LTM also improved in mood, becoming less depressed and less fatigued than those who did not have seizures. Overall, our data indicate that LTM does not adversely affect mood. However, in the first few days of LTM, sleep deprivation may produce fatigue and lack of vigor, and should be used only as needed to provoke seizures.

Significant removal of phenytoin during high flux dialysis with cellulose triacetate dialyzer

Significant removal of phenytoin during high flux dialysis with cellulose triacetate dialyzer

Effect of Continuous Hemofiltration on Phenytoin Elimination

Phenytoin is frequently used to treat seizure episodes in critically ill patients. Some of these patients have acute renal failure, requiring continuous hemofiltration to help maintain fluid and solute balance. We evaluated the removal of phenytoin in patients who received the drug while undergoing continuous hemofiltration treatment. Arterial and ultrafiltrate sample pairs were collected for phenytoin concentration determination. The ultrafiltrate drug concentrations were almost identical to the free serum phenytoin concentrations. Thus the ultrafiltrate/arterial drug concentration ratios resembled the percentages of serum free drug. Between 0.32 and 0.78 mg of phenytoin/h was removed by hemofiltration. The magnitude of hemofiltration phenytoin removal was related to the free drug concentration, total serum drug concentration, and ultrafiltration flow rate. When the ultrafiltration flow rate was low, the amount of phenytoin removed by hemofiltration was small relative to the usual daily dose. However, in patients with renal failure in whom serum phenytoin protein binding is substantially reduced, continuous hemofiltration at a high ultrafiltration rate may remove a clinically significant amount of the drug. Higher daily doses of phenytoin may be needed to maintain the therapeutic effect. Serum drug concentration monitoring will be necessary to determine the optimal dosage regimen.

Effects of Removal of Phenytoin, Carbamazepine, and Valproate on Cognitive Function

Changes in cognitive function were noted in a double-blind, prospective, placebo-controlled study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 58 patients with active epilepsy, receiving multiple antiepileptic drugs (AEDs). A control group of 25 patients continued with existing therapy. A simple test battery, which would be directly applicable to a clinical setting, with measures of mental speed, attention, performance of a learned skill, short-term memory, concentration, and simple coordinated hand movements was used. Cognitive assessments were made before and at the end of discontinuation of a drug and 4 weeks later. Simple motor skills became faster on discontinuation of PHT, CBZ, and VPA (p less than 0.0005), with a further improvement in the subsequent 4 weeks (p = 0.03) and no significant difference between the AEDs. Performance on a measure of attention and concentration improved on discontinuation of PHT (p = 0.005) and did not alter with removal of CBZ or VPA; the improvement in the PHT discontinuation group was significantly different from that in the control group (p = 0.001). These results suggest that all three AEDs studied may adversely affect motor function and that PHT may be more deleterious to function in higher cognitive tasks than in CBZ or VPA.

Effects of the Removal of Phenytoin, Carbamazepine, and Valproate on the Electroencephalogram

We report the EEG changes that occurred on discontinuance of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in patients with active epilepsy. Discontinuation of CBZ was associated with an increase in mean frequency of dominant rhythm and reduction in amount of slow activity. Patients who had a marked increase in seizures on discontinuation of an antiepileptic drug had a slower mean dominant rhythm at baseline than did patients who did not have an increase in seizures. Subsequent EEGs, during and at the end of drug reduction, showed an increase in bursts of interictal epileptiform activity (IEA) and in slow activity in patients who had a marked increase in seizures. The amount of slow activity and IEA did not alter in patients who did not have an increase in seizures. No patients developed photosensitivity.

Carbamazepine replacement of phenytoin, phenobarbital and primidone in a rehabilitation setting: effects on seizure control

Most patients who receive anticonvulsants after traumatic brain injury are treated with the sedative anticonvulsants phenytoin and/or phenobarbital, or perhaps primidone. However, there is considerable evidence demonstrating that these medications have a deleterious effect on cognitive function. Thus, in a rehabilitation setting, alternatives should be sought. Carbamazepine has been found to be relatively free of such effects, and would be an optimum alternative if seizure control were comparable. We have studied the effects of withdrawing phenytoin, phenobarbital and primidone, and using carbamazepine as the primary anticonvulsant in 27 patients at the Greenery Rehabilitation and Skilled Nursing Center for whom ongoing anticonvulsant treatment was considered to be necessary due to previous seizures or a high risk of the occurrence of seizure. We compared a 3 month baseline period (just prior to carbamazepine introduction or sedative anticonvulsant tapering), to a 3 month post-withdrawal period immediately following sedative anticonvulsant withdrawal, when carbamazepine was the sole anticonvulsant. In 20 out of 21 patients in whom carbamazepine replaced sedative anticonvulsants seizure control was essentially similar or somewhat improved. In only one patient did the substitution with carbamazepine result in a loss of seizure control. Six patients were initially receiving carbamazepine in combination with phenytoin and/or phenobarbital. The removal of phenytoin and phenobarbital, leaving carbamazepine as sole therapy, resulted in improved seizure control in three patients and no change in the other three. In the light of carbamazepine's reportedly less detrimental effects on cognitive function and behaviour in other patient populations, it should perhaps be considered as a first line anticonvulsant, especially for patients in rehabilitation settings.

Effect of the removal of individual antiepileptic drugs on antipyrine kinetics, in patients taking polytherapy.

1. Antipyrine (AP) clearance, half-life and volume of distribution were determined in 52 patients, taking one or more antiepileptic drug (AED), before and 4 weeks after the complete removal of phenytoin (PHT, n = 20), carbamazepine (CBZ, n = 15) and sodium valproate (VPA, n = 17). 2. PHT removal was associated with a mean 13% fall in AP clearance and a mean 16% increase in AP half-life, in patients who were also taking CBZ with or without barbiturates. There was no significant difference between patients who did, and did not, take barbiturates, in addition to CBZ. 3. CBZ removal was associated with a mean 45% fall in AP clearance and a mean 69% increase in AP half-life, if there was no inducing AED comedication, but had no effect on AP clearance and half-life if PHT and/or barbiturates were also being taken. 4. Removal of VPA had no effect on AP clearance or half-life. 5. The removal of PHT, CBZ and VPA had no significant effect on AP volume of distribution. 6. PHT appears to be a more powerful inducer of hepatic enzyme activity, as measured by the AP test, than is CBZ.

Phenytoin pharmacokinetics in therapeutic plasmapheresis.

Total and free serum phenytoin concentrations and net phenytoin removal were examined in two stable patients (henceforth referred to as patient D.K. and patient C.L.) receiving therapeutic plasmapheresis for myasthenia gravis at Mercy Hospital. Similar serum determinations were obtained on the days prior to and after plasmapheresis in order to determine if a single patient plasma volume exchange replaced isovolumetrically with a 4.0 g% albumin solution would significantly alter serum concentrations of phenytoin.

Removal of Phenytoin by Hemodialysis in Uremic Patients

The removal of phenytoin by hemodialysis was determined in seven uremic patients. Four patients were receiving phenytoin sodium for therapeutic purposes; three received one dose each intravenously to quantitate its disposition in uremia. The drug was measured in whole blood, plasma, saliva, and dialysate. Only 2% to 4% of the intravenous dose was recovered in the dialysate. Phenytoin clearance by dialysis was 7 to 14 ml/min; plasma clearance was 53 to 133 ml/min. Since hemodialysis contributes little toward shortening to 11-to-18-hour half-life of phenytoin in the uremic patients, no supplemental dose is necessary for uremic patients undergoing hemodialysis.

Removal of phenytoin by hemodialysis in uremic patients

Removal of phenytoin by hemodialysis in uremic patients

Hemodialysis of phenytoin in a uremic patient.

Removal of phenytoin by hemodialysis was determined in a uremic patient. The rate of appearance of the drug in dialysate, the plasma concentration with time, and the plasma clearance by dialysis were measured. Plasma protein binding of phenytoin was also determined. In spite of greatly reduced plasma protein binding in the uremic patient, removal rate was observed to be less than 10% of the rate of presentation of the dialyzer. During the 6-hr period of dialysis, the plasma concentration showed little change. The amount collected in the dialyase, 43.6 mg, was only a small fraction of drug in the body. These results indicate that replacement of phenytoin based on the amount of drug removed by dialysis is unnecessary in chronically dialyzed uremic patients. In addition, the utility of hemodialysis in phenytoin overdose is questioned.