Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics.

Phenobarbital is an effective and safe anticonvulsant drug introduced in clinical use in 1904. Its mechanism of action is the synaptic inhibition through an action on GABAA. The loading dose of phenobarbital is 20 mg/kg intravenously and the maintenance dose is 3 to 4 mg/kg by mouth. The serum concentration of phenobarbital is up to 40 µg/ml. Nonresponders should receive additional doses of 5 to 10 mg/kg until seizures stop. Infants with refractory seizures may have a serum concentration of phenobarbital of 100 µg/ml. Phenobarbital is metabolized in the liver by CYP2C9 with minor metabolism by CYP2C19 and CYP2E1. A quarter of the dose of phenobarbital is excreted unchanged in the urine. In adults, the half-life of phenobarbital is 100 hours and in term and preterm infants is 103 and 141 hours, respectively. The half-life of phenobarbital decreases 4.6 hours per day and it is 67 hours in infants 4 week old.

Phenobarbitone concentrations in the hair, saliva and plasma of eight epileptic dogs.

Samples of plasma, saliva and hair were collected from eight dogs receiving phenobarbitone for idiopathic epilepsy. The concentrations of phenobarbitone in hair and plasma were correlated with the daily dose rate, and the concentrations in hair were also correlated with the concentration in plasma, the dose rate of the drug over the preceding six months and the ratio of the six-month dose to body surface area. The concentration of phenobarbitone in saliva was not correlated with either the concentration in plasma or the dose rate of the drug.

[Sorption properties of Polish sorbents of the 2nd generation in relation to phenobarbital]. / Wlasciwosci sorpcyjne Polskich sorbentów polimerowych II generacji wobec fenobarbitalu.

Two polymers sorbents of the 2nd generation Vinylsorb SS and Vinylsorb S (modified) were compared with commercial sorbent Amberlite XAD-4 to present their abilities to bond phenobarbital (Luminalum-Polfa). In the tests on perfusion of whole blood it was noticed that all three sorbents have similar ability to eliminate phenobarbital from the blood. About 80% of phenobarbital was adsorbated from the blood after 90 minutes of tests. Sorption properties of the sorbents were kept until 240 minutes of the experiment.

Microencapsulation using poly(DL-lactic acid). IV: Effect of storage on the microcapsule characteristics.

Poly (DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone were prepared using a W/O emulsion method. Microcapsules of nominal C : P ratio, 1 : 2 and 1 : 3 using three different molecular weight polymers, 20,500, 13,300 and 5,200 were investigated to study the effect of storage conditions on the microcapsule properties. All microcapsules were stored under desiccated condition at temperatures of 4 degrees, 20 degrees and 37 degrees C for six months. Storage temperatures of 4 degrees and 20 degrees C did not cause appreciable changes in the release rate after storage. Microcapsules stored at 37 degrees C showed an annealing effect, causing shrinkage of microcapsules, and lowering of the release rate after storage for six months. The microcapsules prepared from low molecular weight DL-PLA fused completely whilst stored at 37 degrees C and the other two high molecular DL-PLA also showed some aggregation. There were insignificant variations in the mean microcapsule diameter during storage. The phenobarbitone content of the microcapsules was also unchanged.

Microencapsulation using poly(DL-lactic acid). III: Effect of polymer molecular weight on the release kinetics.

Poly(DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone (PB) were prepared using a w/o emulsion-evaporation method. DL-PLA of three different molecular weights, 20,200, 13,300 and 5,200 were used to prepare microcapsules of nominal core: polymer (C:P) ratios of 1 : 2, 1 : 2.5, 1 : 3 and 1 : 4. The release of PB was investigated in aqueous buffer of pH 2, pH 7 and pH 9 at 37 degrees C and found to follow a square root of time dependent release mechanism. The first order and zero order release mechanisms were disproved by the lower correlation coefficient of the release data as compared to that of the t1/2 mechanism. These microcapsules showed an initial burst phase release followed by a lag phase, during which time little PB was released. This lag time was affected by the polymer molecular weight and pH of the buffer. The polymer matrix was hydrated during the lag phase and a steady state release occurred. The steady state release rate per unit specific surface area (Kh2/SSA) was found to increase exponentially with the increase in core loading of the microcapsules. However the extent of normalized release rate reduced linearly with the increase in polymer molecular weight at any particular core loading (e.g. 20 per cent or 30 per cent). Increases in the normalized steady state release rate with an increase in buffer pH could be correlated to PB solubility in the dissolution medium. PB release from these microcapsules was diffusion controlled. However, swelling and erosion also contributed to the release process.

The effect of surfactants on the microencapsulation and release of phenobarbitone from gelatin-acacia complex coacervate microcapsules.

The effects of sodium lauryl sulphate (SLS), cetrimide and polysorbate 20 surfactants at concentrations below, at and above their critical micelle concentration (CMC) on the microencapsulation and release of phenobarbitone have been described. Bimodal particle size distributions were produced both in the absence and presence of each of the three surfactants. The presence of surfactant had little or no effect on the particle size distribution at any given stirring speed. A large variation was noted in the amount of phenobarbitone microencapsulated dependent upon the type of surfactant and its concentration. The amount of phenobarbitone encapsulated decreased with increasing concentration of polysorbate 20 and with SLS. Cetrimide (0.025 per cent w/v) enhanced encapsulation with 2 per cent w/w colloids but higher concentrations at the CMC and above decreased encapsulation. The results are explained in terms of decreased interfacial tension by the surfactant and by steric and electrostatic effects caused by surfactant adsorption onto the coacervate droplets and phenobarbitone particles.

[In vitro studies of the adsorption behavior of Wofatit Y 88 in relation to various drugs]. / In-vitro-Untersuchungen zum Adsorptionsverhalten von Wofatit Y 88 gegenüber verschiedenen Arzneimitteln.

The adsorber Wofatit Y 88 (VEB Chemiekombinat Bitterfeld) was tested regarding its adsorption properties in comparison with Hämoresin (B. Braun, Melsungen, FRG) Hemosorbent SKN-2K (USSR) and the own product Wofatit UH 91. As adsorptives the hypnotics Metaqualon, Pyrithyldion, Crotylbarbital and Phenobarbital were used. The investigation have been performed in a single-pass system in a relation of 1:25 to the clinical practice conditions. The concentration measurements to the estimation of adsorbed amounts were made by UV-VIS spectrometry. It was found that Wofatit Y 88 is superior to Hämoresin with regard to adsorbed amounts and adsorption speed. For all drugs Wofatit Y 88 was superior to UH 91.

Formulation factors affecting drug release from poly(lactic acid) (PLA) microcapsule tablets.

A sustained-release (SR) formulation of phenobarbital (PB) microcapsule tablet was prepared using low molecular weight (MW) DL- and high MW L-poly(lactic acid) (PLA) polymer. Microencapsulation of PB showed a unimodal size distribution (375 to 550 microns) of the microcapsules with high loading capacity (> 84%). Drug release from the microcapsule was influenced by the polymer ratios and increased with an increase in L-PLA amount. Microcapsules and physical mixtures of PB and the PLA were directly compressed independently to form microcapsule and matrix tablets, respectively. Drug release from the microcapsule tablets was significantly lowered (p < .001) compared to matrix tablets or free microcapsule (free microcapsule > matrices > microcapsule tablets). We also investigated the effect of tablet adjuvants, compression pressures, and microcapsule loading on the tablet performance in terms of friability, hardness, porosity, tensile strength, and the release kinetics of PB. The drug release rate increased with increasing compression pressure in the case of Emcompress or lactose, but not Avicel. The drug release rate was three- to fivefold increased with sodium starch glycolate compared to tablets without a disintegrant. With an increase in microcapsule loading, a decrease in the drug release rate was observed; however, the tablet performance remained satisfactory. The morphology of the microcapsules was monitored microscopically after the dissolution and the disintegration of tablets. The drug release accelerated with compression pressures and microcapsule loading from the tablets due to mechanical destruction of the microcapsule wall, which was more clearly seen after disintegration and dissolution of the tablets. Our data suggest that the PLA microcapsule can be tableted to make a SR product without significantly affecting its release kinetics.

[Saliva phenobarbital concentration in epileptics].

The concentrations of phenobarbital were measured in saliva-serum pairs obtained simultaneously from 33 epileptics by RIA. The mean concentration of phenobarbital in saliva was 3.2 +/- 1.78 micrograms/ml, in serum was 11.75 +/- 7.4 micrograms/ml, the mean saliva-to-serum ratio for phenobarbital was 0.27 +/- 0.08. The results suggested that saliva concentration of phenobarbital was found to be correlated closely with the total serum level (R = 0.7922, P less than 0.01). The high correlation between saliva and serum concentrations supports the use of saliva measurement in epileptics. The simplicity and convenience of saliva collection and its noninvasiveness make it represent serum concentration of phenobarbital as an efficient monitoring method.

Prevention of gastrointestinal absorption of phenobarbital by activated carbon beads as an oral adsorbent.

The in vitro adsorption characteristics of activated carbon beads suitable for oral administration and the original fine powder were examined, using phenobarbital as the test drug. The extent and rate of drug adsorption on carbon in the beads were almost equal to those on the powder. In three healthy volunteers, 10 g of activated carbon beads administered orally 20 min after 120 mg of phenobarbital, reduced the total bioavailability by 57% (p less than 0.005), based on the salivary AUC-value during 96 h and the achieved peak concentration of the drug in salvia by 51%. These results demonstrated the potency of activated carbon beads as a gastrointestinal adsorbent in acute intoxications from phenobarbital.

A computer model for the measurement of compliance using a dual tracer technique.

AIMS: We aimed to determine whether simultaneous use of two tracer compounds with long and differing elimination half-lives may permit more precise recognition of percent compliance and discrimination among remote, intermediate, and recent patterns of daily dosing. METHODS: We have derived, through computer modelling, the potential utility of digitoxin and phenobarbitone as simultaneous tracers. From kinetic data on these reliably measured compounds with long half-lives we defined the percentage error below which this pair of tracers can be expected to discern the precise, and the approximate, pattern and number of daily doses taken over a mouth. RESULTS: The longer the half-lives of the tracers the greater the sensitivity of our model to percentage compliance. At extremely long half-lives, relative to the period of dosing being monitored, sensitivity approaches 100% if measurement error is in the 1-2% range. The ratio of the half-lives between the two tracers that is optimal for detection of percentage compliance is 0.2 to 0.8. The detection of pattern does not depend importantly either on the tracer half-lives or on their ratio to each other. The greater the percentage compliance, the more accurately our two-tracer model determines the pattern of dosing. CONCLUSIONS: Precise characterization of compliance using tracers must probably await the development of compounds with half-lives measured in weeks or months. The probability of compliance of a given degree can be derived from our two-tracer technique with best-fit analysis such as we describe.

Daily salivary anticonvulsant monitoring in patients with intractable epilepsy.

Daily salivary anticonvulsant monitoring in epileptic patients with frequent seizures appears a promising, practicable and inexpensive approach which may assist in the management of drug therapy. It offers the possibility of predicting the optimal drug concentration likely to minimise seizure activity in a given patient, and sometimes allows the inference that different anticonvulsant drugs should be tried forthwith. The use of the method is described in one patient who collected daily saliva specimens and recorded any seizure activity over periods of several weeks. Whilst taking carbamazepine monotherapy, her seizures tended to occur on days where the salivary carbamazepine level was lower than on seizure-free days. As the predicted level of carbamazepine to allow full seizure control (obtained from linear regression analysis of seizures against drug concentration) could not be tolerated by the patient, methylphenobarbitone was added to her therapy. Saliva was again collected daily over another 3 months. Analysis of the data on this occasion suggested that carbamazepine, in the presence of methylphenobarbitone, may have played little role in seizure prevention, and also predicted the salivary level of phenobarbitone likely to minimise seizures. Unfortunately the patient again could not tolerate the drug doses necessary to attain this phenobarbitone concentration.

Cloud-point extraction for the determination of the free fraction of antiepileptic drugs in blood plasma and saliva.

A method for the determination of the free fraction of antiepileptic drugs in plasma and saliva was developed. The separation of free and protein-bound fractions was obtained by cloud-point extraction under optimum conditions of pH, surfactant type, and concentration. It is shown that the free fraction of carbamazepine and of phenobarbital in plasma coincides with the drug concentration in saliva. The dependence of the free fraction in plasma on the administered dose was studied. The influence of the simultaneous administration of the two drugs on their free concentrations was revealed: In the presence of carbamazepine the free fraction of phenobarbital is decreased markedly whereas phenobarbital does not influence the behavior of carbamazepine.

In vitro removal of therapeutic drugs with a novel adsorbent system.

BACKGROUND/AIMS: Substances in the middle molecular weight range have been shown to play a significant pathogenetic role in as diverse disorders as end-stage renal disease and multiple organ failure. To overcome the limitations in the amount removed by hemofilters, new sorbents with a high biocompatibility are actively being developed. Furthermore, biocompatible sorbents by their nonspecific adsorptive behavior could have great impact on detoxification treatment in exogenous intoxications. We performed an in vitro evaluation of a newly developed highly biocompatible sorbent cartridge (Betasorb((R))), examining its adsorptive capacity concerning therapeutic drugs. METHODS: Uremic blood spiked with a range of therapeutic drugs was recirculated for 2 h in an in vitro hemoperfusion circuit containing a Betasorb device for hemoperfusion. The drug concentrations before and after the passage of the cartridge were measured, and the total amount removed was calculated. RESULTS: The sorbent showed effective removal of glycopeptide antibiotics, digoxin, theophylline, phenobarbital, phenytoin, carbamazepine, and valproic acid. Moderate removal could be demonstrated for tacrolimus and cyclosporine A; aminoglycosides were removed to a small extent only. CONCLUSION: Betasorb hemoperfusion shows a potent adsorptive capacity concerning therapeutic drugs (except aminoglycosides) and could be of major value in the treatment of intoxications. On the other hand, drug monitoring and possible adjustments are necessary during Betasorb hemoperfusion to maintain the therapeutic ranges of the drugs in blood.