Serum Phenobarbital Concentrations Research Articles

Rapid switchover to carbamazepine using pharmacokinetic parameters.

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

PHENOBARBITAL IN SERA OF EPILEPTIC MOTHERS AND THEIR INFANTS

The phenobarbital (PB) transition from epiletpic mothers to their breast milks and offspring in cases of PB monopharmacy with other antiepileptic drugs was investigated in 26 epileptic mothers and 24 offspring who were taking the breast milk from epileptic mothers. The mother's serum PB concentration in monopharmacy was almost the same in various stages (stage I, with 5 days after the delivery; stage II, 6--10 days after; stage III, 1--2 mothers after; stage IV, 3--5 months after). However, the PB concentrations in polypharmacy were markedly higher than those in monopharmacy. Concerning the PB concentration in breast milk, a significant increase was found in polypharmacy in comparison with monopharmacy only in stage I. On the other hand, the offspring's PB concentration in polypharmacy was markedly higher than that in monopharmacy, particularly in stage I. In another stages, PB concentration in monopharmacy gradually decreased according to the increase of stages. These results indicate that pharmacokinetics of antiepileptic drugs in the perinatal may be considerably different in PB monopharmacy and polypharmacy.

Effects of short- and long-term administration of phenobarbital on endogenous ACTH concentration and results of ACTH stimulation tests in dogs

Summary The effects of short-term phenobarbital administration were evaluated in 6 adult mixed-breed dogs that received phenobarbital (5 mg/kg of body weight, PO, q 12 h) for 8 consecutive weeks. Six additional dogs served as untreated controls. At 2-week intervals, endogenous adrenocorticotropic hormone (ACTH) concentration and cortisol concentration before and 2 hours after administration of porcine aqueous ACTH (2.2 IU/kg, M) were measured. By means of oneway ANOVA, we were not able to detect a significant (P ≥ 0.05) difference in endogenous ACTH concentration and cortisol concentration before and after exogenous ACTH administration within groups over time or between groups at any time. To evaluate effects of long-term phenobarbital administration, sera and plasma were collected from 5 epileptic dogs that had received phenobarbital for > 2 years and had serum phenobarbital concentrations > 20 μg/dl. Endogenous ACTH concentration and cortisol concentration, before and after administration of ACTH, were within established reference ranges for all 5 dogs. Together, these results suggest that phenobarbital administration alone does not affect endogenous ACTH concentration or response to exogenous ACTH administration in dogs, and that these may be valid screening tests for hyperadrenocorticism in most dogs receiving phenobarbital.

Hepatotoxicity of phenobarbital in dogs: 18 cases (1985-1989)

Summary The medical records of 18 dogs that had hepatic disease and received phenobarbital as an anticonvulsant for 5 to 82 months were reviewed. Clinical signs included sedation and ataxia in all dogs, 5 dogs were also anorectic, 2 had coagulopathy, 3 were icteric, and 5 had ascites. Serum biochemical analysis revealed serum albumin concentration ≤ 2.2 g/dl in 12 dogs, serum alkaline phosphatase activity ≥ 169 U/L in 18 dogs, serum alanine transaminase activity ≥ 57 U/L in 15 dogs, and total bilirubin concentration ≥ 1 mg/dl (in the absence of lipemia) in 7 dogs. Serum phenobarbital concentration was ≥ 40 μg/ml in 12 of 17 dogs. Sulfobromophthalein excretion was prolonged in 8 of 10 dogs. Preprandial serum bile acid concentrations were high in 8 of 10 dogs, and 2-hour postprandial serum bile acid concentrations were high in 9 of 10 dogs. Two of 4 dogs tested had resting plasma ammonia concentrations > 200 mg/dl. An ammonia tolerance test was performed on 2 other dogs; both had ammonia concentration ≥ 200 mg/dl in the plasma 30 minutes after receiving 100 mg of ammonium chloride/kg of body weight, po. Nine dogs died, 1 was euthanatized, and necropsies were performed on these 10 dogs. Biopsies and necropsies of 6 dogs revealed chronic hepatic fibrosis with nodular regeneration (cirrhosis). One dog had hepatocellular carcinoma and mild cirrhosis. In 1 dog, after phenobarbital had been withheld, necropsy revealed complete recovery of the previously observed lesions.

Intraindividual Variability of Carbamazepine, Phenobarbital, and Phenytoin Concentrations in Saliva

The intraindividual variability of salivary carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations was studied in six healthy male volunteers. During three consecutive 1-week phases, subjects took one of the antiepileptic drugs (AED) for 5 days. Nine saliva and nine blood samples were collected simultaneously over the last 4 days of each phase. Salivary, unbound serum, and total serum CBZ, PB, and PHT concentrations were determined by fluorescence polarization immunoassay. Individual mean saliva (Cs)/total serum (Ct), unbound serum (Cu)/Ct, and Cs/Cu concentration ratios for CBZ, PB, and PHT were similar to those reported previously. The intraindividual mean (+/- SD) coefficients of variation (%) of the Cs/Ct, Cu/Ct, and Cs/Cu ratios for CBZ were 4.8 +/- 2.2%, 4.4 +/- 1.8%, and 5.0 +/- 1.9%, respectively; for PB they were 5.1 +/- 0.8%, 3.6 +/- 0.9%, and 6.4 +/- 1.0%, respectively; and for PHT they were 7.4 +/- 3.1%, 5.5 +/- 1.2%, and 8.3 +/- 3.2%, respectively. The mean Cs/Ct and Cu/Ct ratios for CBZ and PHT were not significantly different, but they were different for PB (p = 0.01). However, the range of individual coefficients of variation of the Cs/Ct ratio for PB was 4.0-6.2%, which is acceptable for clinical monitoring. We conclude that the intraindividual variability of CBZ, PB, and PHT concentrations in saliva, based upon the saliva/serum concentration ratios of each AED, is not a factor that should dissuade clinicians from using saliva for the therapeutic monitoring of these agents.

Use Of Activated Charcoal To Reduce Elevated Serum Phenobarbital Concentration In A Neonate

The course of a neonate administered activated charcoal orally for elevated phenobarbital concentration is described. The neonate required a serum concentration of phenobarbital eventually exceeding 80 micrograms/mL for seizure control. However, due to the severe CNS injury as a result of the asphyxia at birth, a diagnosis of cerebral death by electroencephalogram and apnea test was pursued. This required the phenobarbital concentration to be less than 30 micrograms/mL. Serial phenobarbital concentrations during this time indicated a 250 hour half-life, which would require two weeks for the phenobarbital to drop below 30 micrograms/mL. With the administration of six doses of activated charcoal at 0.7 g/kg/dose, the phenobarbital serum concentration decreased to 22 micrograms/mL, giving an estimated phenobarbital half-life of 22 hours. This, and two other subsequent cases, indicates repeated doses of activated charcoal are effective in augmenting the clearance of certain drugs in the neonatal age group.

新生児・未熟児におけるフェノバルビタール静注時の薬物動態

Phenobarbital (PB) pharmacokinetics were studied in order to find the optimal intravenous dose for neonatal convulsion. The subjects consisted of twenty-nine neonates (17males and 12 females) with seizure or intraventricular hemorrhage or asphyxia at birth.The mean gestational age and birth weight of the subjects were 37 weeks and 2.61 kg. The subjects over1, 000 g received 10 to 20 mg/kg of PB, and blood samples for assay of PB serum concentration were collected several times for one week after the intravenous administration. Pharmacokinetic parameters of one-compartment model for i. v. were calculated in each subject and compared with the results of laboratory examination.Twenty-one (95%) in twenty-two subjects who received single intravenous injection of 20mg/ kg PB showed serum concentration over 15, ug/ml within 6 hours after the administration.The i.v.dose of 20mgfkg was considered to be enough to protect neonatal convulsion. Calculated volume of disribution index (Vd) and elimination constant (Ke) were 0.924 +/0.247 (mean +/-SD) 1/kg and0.00512+/-0.00297 1/hr, respectively. There were positive correlation between total volume of distribution and body weight and negative one between Ke and serum creatinine concentration or blood urea nitrogen.

Evaluation of Ames Seralyzer for the Therapeutic Drug Monitoring of Phenobarbital and Phenytoin

Comparison of a reflective photometry assay (Ames Seralyzer) and a fluorescence polarization immunoassay (Abbott TDx) for measuring phenobarbital and phenytoin serum concentration was performed. Routine phenobarbital and phenytoin plasma levels drawn from patients in the pediatric neurology clinic and pediatric intensive care unit were determined in duplicate by the Abbott TDx and Ames Seralyzer systems. A total of 40 samples were assayed. The interday and intraday variability of the Ames system was determined using calibrators of known concentrations (5-25 micrograms/ml). There was significant correlation between the serum phenobarbital or phenytoin concentrations when determined by the Seralyzer and TDx systems. The intraday variability for the measurement of phenytoin when determined by the Seralyzer had coefficients of variation ranging from 2.2 to 8.9%. The interday variability for phenytoin when measured by both the TDx and the Seralyzer correlated well with known calibrators. The utility of the Ames Seralyzer for acute-care facilities, physician offices, and pharmacy satellites is apparent. Based on statistical analysis, the Seralyzer provides accurate phenobarbital and phenytoin serum measurements for clinical use in therapeutic drug monitoring.

The Efficacy of Generic Primidone-Reply

In Reply. — We presented the events of our case honestly and completely, just as they occurred, and our report passed a critical peer review before publication. Most important, the Food and Drug Administration investigation provided no new evidence to alter the reported critical facts in the case. The key issues in our report were that our patient had been taking Mysoline (Ayerst Laboratories, New York, NY) for 13 days before the October 1985 hospital admission, that serum primidone and phenobarbital concentrations were adequate at the time of that admission, and that serum drug concentrations dropped dramatically during hospitalization, with no other plausible cause than the switch to generic medication. These facts remained firm after the Food and Drug Administration investigation and are dated clearly in the medical record just as they were reported in our article. No relevant or important information was excluded from our published report. Eventually, after

Rapid Sequential Phenobarbital Treatment of Neonatal Seizures

The optimal serum concentration of phenobarbital in newborns and its safety at high doses are not well established. The dose response relationship of rapid sequential phenobarbital loading in the newborn was examined and the efficacy of high-dose monotherapy was compared with the addition of a second anticonvulsant for persistent seizure activity. A single loading dose of phenobarbital 15 to 20 mg/kg was initially administered to 120 newborns. Nonresponders received sequential bolus doses of 5 to 10 mg/kg until seizures ceased or a serum concentration of 40 micrograms/mL was obtained. Infants with refractory seizures received additional phenobarbital to a maximum serum concentration of 100 micrograms/mL. The seizures of 48 babies (40%) were controlled after initial loading and 37 of the remaining 72 subjects (51%) responded at serum concentrations of as great as 40 micrograms/mL. The seizures of only seven subjects were controlled at greater concentrations. A second anticonvulsant controlled seizures in 13 of the 28 subjects (46%) whose seizures were refractory to phenobarbital. A gestational age of less than 32 weeks was associated with a significantly better response to phenobarbital. Serum phenobarbital concentrations greater than 50 micrograms/mL produced only occasional feeding difficulty and sedation. It was concluded that sequentially administered IV phenobarbital controls seizures in both term and preterm newborns (77%). This therapeutic effect is dose dependent but plateaus at a serum concentration of 40 micrograms/mL. At greater serum concentrations, unresponsive patients should receive a second antiepileptic agent.

Accelerated elimination of phenobarbital by oral activated charcoal suspensions with alkaline diuresis in an overdose patient.

A patient with phenobarbital overdose was treated with gastric administration of multiple doses of activated charcoal suspensions with alkaline diuresis. The decline of serum phenobarbital concentrations was sharper during the therapy than a control period. Elimination half-lives of phenobarbital of 15. 5 and 39. 1 h were obtained for the period of charcoal treatment with and without alkaline diuresis, respectively. As a normal elimination half-life of the patient was 82. 2 h, combined use of oral activated charcoal with alkaline diuresis proved to be an effective, safe, and inexpensive therapeutic measure in a case of phenobarbital overdose.

小児におけるフェノバルビタール血中濃度 Ｓ／Ｄ比と年齢の関係及び併用薬の影響

The effects of age and concurrent administration of antiepileptic drugs on phenobarbital serum concentration/dosage ratio in children were studied. The ratio of serum concentration/dosage for phenobarbital both without and with the concurrent administration of antiepileptic drugs was significantly correlated with the age of patients, and the ratio increased with the increase in the age of children. The ratio of patients who had taken valproate sodium and/or more than two kinds of anti-epileptics with phenobarbital washigher than that of patients had taken phenobarbital alone.Therefore, the patients who are taking valproate sodium and/or more than two kinds of anti-epileptics with phenobarbital is needed careful monitoring of phenobarbital serum concentrations because of their drug interaction.

Serum phenobarbital concentration predictions by a personal computer software system.

The ability of a personal computer software system to predict actual serum phenobarbital concentrations (SPC) in outpatients taking phenobarbital chronically was assessed by comparing actual with predicted SPC for accuracy, bias, and precision. Data for a four-year period were collected on patients at an outpatient clinic's pharmacokinetic consultation service. The study group included 50 adults and children with at least one SPC taken at a known time after dose administration. Input variables were weight, sex, height, age, concomitant drugs and diseases, phenobarbital dosage regimen, and the time and reported value of all SPC. Initially, SIMKIN (SIMulated KINetics) simulated dosing regimens on the basis of literature estimates of pharmacokinetic parameters; SPC were then estimated for these regimens and compared with actual values. One or two additional SPC were added to the input data and analyzed, and the predicted SPC compared with actual values. Although SIMKIN's accuracy and bias as measured by regression analysis and mean prediction error, respectively, were within clinically acceptable limits, the precision was not. However, these results are limited by the population studied. Patient compliance, concomitant phenytoin therapy, changes in phenobarbital pharmacokinetic parameters with chronic dosing, and disease interactions may significantly affect predictive ability. The clinical effects of these factors need to be evaluated to further improve predictions.

DEVELOPMENTAL ASPECTS OF PHENOBARBITAL DOSAGE REQUIREMENTS IN NEWBORN INFANTS FOR SEIZURE CONTROL

Phenobarbital (PB) is the most widely used drug to control seizures but specific dosage guidelines are not available in infants of varying gestational ages (GA). The primary objective of this study was to develop the dosage guidelines in newborn infants relative to age to control seizures. Fifty-one patients (27 premature infants: GA 27-38 weeks; 24 term infants) receiving PB, 3-6 mg/kg/d were studied during the first month after birth. Multiple serum concentrations were determined in each patient during extended therapy. Trough serum concentration of PB ranged from 12.5-50.2 μg/ml. PB serum concentrations were within therapeutic range (15-40 μg/ml) in 99 of 114 cases at the maintenance dose of 3.5-4.5 mg/kg/d. The remaining 15 cases were above 35 weeks of GA and required PB doses of 5 mg/kg/d to control seizures. These data suggest that the maintenance dose of PB during the first month after birth should be 3.5-4.5 mg/kg/d in infants < 35 weeks and 4.0-5.0 mg/kg/d in those > 35 weeks GA. Term infants with asphyxia had higher trough serum concentration than those with asphyxia. In six infants, trough serum concentration decreased by 30-50 percent at the same dose during a three weeks period. This suggests that PB serum concentration should be monitored frequently during the developmental period.

抗てんかん薬服用患者における錠剤・散剤投与後の血中濃度変動とその要因の検討

Serum concentrations of phenytoin and phenobarbital which were administered as the tablet or the powder in epileptic patients were determined by the fluorescence polarization immunoassay method. The serum concentrations of phenytoin administered as the tablet (Hydantol®) were higher than those as the powder (Aleviatin ® fine granules). To investigate the differences in serum levels following administration of each preparation, compliance, dissolution characteristics of the preparations and losses of the powder after operating the dividing and packing machines were investigated. Since phenytoin dissolved from the Hydantol ® tablet more slowly than from the Aleviatin ® fine granules, the differences in dissolution rates of both preparations do not seem to be the cause of higher serum concentrations in patients taking the Hydantol ® tablet.The amount of the powder after operating three types of dividing and packing machines was decreased about 2-8% of the original amount of the powder by adhesion to various dividing sites of the machine. Accordingly, the lower serum concentrations of phenytoin after the administration of the powder may be due to losses of the powder by the adhesion to dividing and packing machine and due to non-compliance.Although there was no significant difference in the serum concentrations of phenobarbital between the tablet (Phenobal ®) and the powder (JP X phenobarbital powder), large variations in the serum concentrations were observed following administration of the powder. In view of the result of questionnaire and bitterness of the drug, a possibility of non-compliance of the powder was considered. Thus, it may be suggested that these factors should be concerned invariations of the serum concentrations.

血清中抗てんかん薬濃度測定へのセラライザーシステムの適用 フェニトイン，フェノバルビタール

Apoenzyme reactivation immunoassay system with Seralyzer reflectance photometer for the determination of serum phenytoin (PHT) and phenobarbital (PB) concentration (Seralyzer method) was evaluated. Each coefficient of variation of within-run and between-run precision for 3 concentrations of PHT or PB in serum was less than 4.0%. The serum PHT (33 samples) or PB (31 samples) concentrations were determined by Seralyzer method and compared with those determined by high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA method). There were good agreements between HPLC and Seralyzer method results and FPIA method and Seralyzer method results, where all correlation coefficients were more than 0.992. The cross-reactivities of p-hydroxyphenylphenylhydantoin in PHT reagent strips, and p-hydroxyphenobarbital and several barbiturates in PB reagent strips were found. However, these cross-reactivities are not serious problems in clinical condition. Therefore, the Seralyzer method may be useful for serum drug-level monitoring of patients under PHT or PB therapy.

Correlation between the saliva and free serum concentration of phenobarbital in epileptic children.

Twenty epileptic children taking phenobarbital (PB) were evaluated for the concentration of PB in their saliva (Sa), total serum concentration (TS), free serum concentration (FS), and also the pH of the saliva samples. The Sa/TS ratio was 43.0 +/- 5.2% (mean +/- SD), and showed a close relationship between the two (r = 0.98). The free serum concentrations for PB were also observed to be closely correlated to the saliva concentration (r = 0.99), as well as to the total serum concentration, with the FS/TS ratio being 45.0 +/- 5.6%. However, no obvious relationship between the salivary pH and the Sa/TS ratio for PB was observed. This suggested the usefulness of monitoring the PB saliva concentrations in clinical management of epilepsy.

Long-term behavioral effects of phenobarbital in suckling rats

Long-term effects of phenobarbital on behavior and learning, persisting after drug withdrawal, have not been defined. To look for such effects on the developing nervous system, we treated albino rat pups with phenobarbital for 30 days and then tested them at intervals starting 10 days after the cessation of drug therapy. Beginning at age 6 days, 12 pups were given Ph subcutaneously, gradually increasing the dose to 30 mg/kg/dose b.i.d. by 11 days and continued until 36 days. Twelve control pups were injected with saline. Serum phenobarbital concentrations at 16 days were 54 to 32 μg/ml and at 31 days 36 to 4 μg/ml. From 46 to 55 days, all animals were tested in a water T maze. The experimental animals completed the four daily runs faster than controls ( P = 0.003), made fewer errors ( P = 0.003), and spent less time on error-free runs ( P = 0.04). When the same animals were retested in the maze at 129 to 136 days, the trend toward faster times was not significant. There were no differences in brain weights of experimental and control rats at 157 days. Twelve pups treated similarly with phenobarbital at 20 mg/kg/dose b.i.d. spent less time on error-free runs than 12 controls when tested at 48 to 57 days of age ( P = 0.05) but no differences were found when 12 similarly treated pups were tested at 79 to 85 days. There were no differences in brain weights of the treated and control rats at 78 days of age. Thus it was shown that phenobarbital administration in suckling rats had an effect on behavior that was present 10 to 20 days after the drug was cleared from their serum.

Use of serum drug concentrations in outpatient clinics

A four-month retrospective study was conducted to analyze the use of serum drug concentrations (SDCs) in the outpatient clinics of a teaching hospital. The general internal medicine, asthma and allergy, cardiology, and neurology clinics were selected as frequent users of SDCs. Serum theophylline, digoxin, quinidine, procainamide, carbamazepine, phenytoin, and phenobarbital concentrations obtained during patient clinic visits were audited by trained pharmacy students using medical records and computer-generated laboratory data. The SDCs were evaluated for (1) the appropriateness of how they were obtained, (2) the appropriateness of the actions taken on the results, (3) the reasons they were ordered, and (4) the patient charges secondary to obtaining SDCs incorrectly or taking inappropriate actions on the results. Overall, the SDCs from all the clinics combined were obtained appropriately 251 (61.4%) of 409 times. Appropriate actions were taken on the SDC results 82.4% of the time. A change in therapy was made after an SDC was ordered 24.4% of the time. A total of $4975 of patient charges was associated with incorrectly obtained SDCs or inappropriate actions taken on SDC results. The asthma and allergy clinic, which was staffed by a clinical pharmacist, used SDCs more appropriately than the other clinics. Pharmacists or other professionals should be used to obtain accurate SDC information and to follow-up on SDC results to maximize drug therapy and reduce costs.

Studies with stable isotopes II: Phenobarbital pharmacokinetics during monotherapy.

Six healthy adults receiving no other medications were given tracer doses of 90 mg of stable isotope-labeled phenobarbital (PB) intravenously before, and four weeks after, and 12 weeks after beginning therapy. Serum samples were collected for 96 hours after each injection, and the concentration of stable isotope-labeled PB in each sample was determined by gas chromatographic mass spectrometry. The volume of distribution, elimination half-life, and total clearance of PB did not differ significantly on any of the three occasions measured. Phenobarbital clearance did not correlate significantly with total PB serum concentration. Clearances determined from single-dose studies before beginning PB therapy accurately predicted steady-state PB serum concentrations. Therefore, it is not necessary to adjust PB dosage for time-dependent or dose-dependent changes in clearance during monotherapy. In addition, clearance or serum concentration determined at one dosing rate directly predicts serum concentration at another dosing rate.