Effect Of Phenobarbitone Research Articles

The effect of phenobarbitone on cognition in adult patients with new onset epilepsy: A multi-centric prospective study from India

In view of the conflicting results of cognitive and behavioral consequences of PB, the present study was planned to analyze its efficacy, serial neuropsychological functions and its impact on psychosocial functioning in adults with epilepsy while on phenobarbitone (PB). This prospective multi-centric study carried out across 4 centers in India included 75 adult patients of ≥18 years (M:F=52:23; age: 27.3 ± 8.5 years) with epilepsy who were prescribed phenobarbitone and underwent serial standardized neuropsychological assessment (NIMHANS battery for adults) at baseline, 1 month, 3 months, 6 months and 12 months. The demographic, seizure details and outcome measures were recorded. Of the 75 patients, 63 had completed clinical and neuropsychological assessment, i.e. visit 1 (baseline), visit 4 (6 months) and visit 5 (12 months). There was no deterioration rather an improvement during the follow visits in all the neuropsychological functions. The results indicate that 16 neuropsychological variables changed significantly, viz. mental speed (p<0.001), sustained attention (p<0.001), focused attention (p<0.002), planning (p<0.001), concept formation (p<0.05), set shifting (p<0.001), verbal learning (p<0.0001), verbal memory (p<0.0001), visual memory (p<0.0001) and intelligence (p<0.001). The scales measuring the outcome of psychosocial functioning significantly changed during follow up included happiness (p<0.002), Impact of Epilepsy on patient's life (p<0.02), A-B Neuropsychological Assessment (p<0.015), HADS anxiety (p<0.001) and emotional disorder (p<0.006). There was a significant reduction in seizure severity as measured by Liverpool Seizure Severity Scale (p<0.002) and seizure freedom was maintained. This study demonstrated that phenobarbitone is effective, well tolerated AED and do not have cognitive impairment over one year. There was variable but distinct improvement in cognition and psychosocial functioning, and effective seizure control could be one of the factor for it.

The in vivo and in vitro effect of diphenylhydantoin and phenobarbitone on K+ activated phosphohydrolase and (Na+, K+)-activated ATPase in particulate membrane fractions from rat brain.

Abstract The effect of diphenylhydantoin and phenobarbitone on a K+-activated phosphohydrolase, hydrolysing the artificial substrates p-nitrophenylphosphate and acetylphosphate, and (Na+, K+)-activated ATPase in particulate membrane fractions from rat brain, has been studied. Diphenylhydantoin was given orally over 20 weeks without any effect on these enzymic activities, whereas orally phenobarbitone significantly decreased the enzymic activities in the particulate membrane fractions containing synaptosomes, nerve endings and microsomes. In vitro, diphenylhydantoin inhibited the enzymic activities in the synaptosomal membrane fraction, but phenobarbitone did not. Several possibilities for the in vivo action of diphenylhydantoin are outlined; these are mainly concerned with a blocking of the passive movement of sodium into the cell. The in vivo effect of phenobarbitone is possibly a secondary pharmacological effect interfering with the utilization of ATP either directly or indirectly by a depression of some energy dependent processes such as protein synthesis.

Effect of phenobarbitone on the biliary reabsorption of [35S] sulpho-bromophthalein sodium from the rat biliary tree.

Effect of phenobarbitone on the biliary reabsorption of [35S] sulpho-bromophthalein sodium from the rat biliary tree.

Effect of phenobarbitone on the disposition of lignocaine and warfarin in the dog.

Effect of phenobarbitone on the disposition of lignocaine and warfarin in the dog.

Effect of phenobarbitone on the pharmacokinetics and tissue levels of amiodarone in the rat.

Phenobarbitone pretreatment has been shown to increase amiodarone total clearance and decrease amiodarone elimination half-life after a single intravenous amiodarone dose in the rat. Coadministration of phenobarbitone with amiodarone for 7 days resulted in decreased tissue amiodarone levels compared to controls. These results may have implications for patients undergoing therapy with amiodarone and concomitant potent enzyme inducing drugs.

Effect of Phenobarbitone Treatment Against Signal Grass (Brachiaria decumbens) Toxicity in Sheep

The effect of phenobarbitone against signal grass (Brachiaria decumbens) toxicity was studied in 26 male crossbred sheep. Grazing on signal grass significantly decreased the concentration of cytochrome P-450 and the activity of drug metabolizing enzymes, viz. aminopyrine-N-demethylase, aniline-4-hydroxylase, UDP- glucuronyltransferase and glutathione-S-transferase in liver and kidneys of affected sheep.Oral administration of phenobarbitone (30mg/kg body weight) for five consecutive days before grazing on B. decumbens pasture, and thereafter, for three consecutive days every two weeks, resulted in significant increases in hepatic and renal activities of drug-metabolizing enzymes. The induction of drug metabolizing activity in sheep grazing on signal grass group was found to be lower than in animals given phenobarbitone alone. Induction by phenobarbitone provided a degree of protection against the toxic effects of B. decumbens as indicated by the delay in the appearance of signs of toxicity. Furthermore, these were much milder compared to those in the sheep not treated with phenobarbitone. The present study suggests that phenobarbitone-type cytochrome P-450 isoenzyme-induction may increase resistance against signal grass (B. decumbens) toxicity in sheep.

Accelerated elimination of pimonidazole following microsomal enzyme induction in mice: A possible approach to reduced neurotoxicity of the pimonidazole-etanidazole combination

The pimonidazole-etanidazole combination shows promise for improved radiosensitization, although pimonidazole may increase the dose-limiting peripheral neurotoxicity of etanidazole in man. Induction of liver microsomal drug metabolizing enzymes by phenobarbitone resulted in reduced exposure to pimonidazole in plasma, brain, and tumor in mice. Peak tumor concentrations were lowered, but to a lesser extent. Phenobarbitone induction caused no change in the urinary ratio of pimonidazole to its N-oxide metabolite, and in fact, markedly reduced the circulating metabolite concentrations in plasma. There was no effect of phenobarbitone on plasma or tissue pharmacokinetics of etanidazole, which is eliminated by renal clearance. The results suggest that hepatic microsomal enzyme induction may be a possible approach to reducing the toxicity of the pimonidazole-etanidazole combination, and may also provide valuable information on the enzymology of pimonidazole metabolism.

Effect of phenobarbitone on folic acid metabolism in the rat

Anticonvulsant drugs have well-known relationships with folic acid, often leading, in epileptic patients on long term treatment to signs of folic acid deficiency and to haematological complications. The findings of this work, carried out on rats, show strong interference of phenobarbitone with folic acid metabolism, particularly with pteroylpolyglutamate synthesis in liver. This is proved by lower polyglutamate content, lower 3H folate incorporation in polyglutamate forms and in protein-bound folates, and also by lower blood radioactivity, higher urinary excretion of 3H folate metabolites and by higher 3H folate concentration in kidneys.

Dynamics of xenobiotic metabolism by isolated rat hepatocytes using a multichannel perifusion system.

The multichannel perifusion system in recirculating and non-recirculating (single-pass) mode has been used to monitor the rate of oxidative metabolism of three model substrates--7-ethoxycoumarin, dichloronitroanisole and aldrin. With control hepatocytes, the rate of de-ethylation of 7-ethoxycoumarin derived from recirculating mode was essentially similar to the rate obtained with conventional flask-incubated cell suspensions. The formation of 7-hydroxycoumarin glucuronide and sulphate by hepatocytes exposed to 7-ethoxycoumarin demonstrated the retention of conjugative ability of cells in the perifusion system. The rate of demethylation of dichloronitroanisole to dichloronitrophenol was low whilst aldrin epoxidation to dieldrin was rapid using control hepatocytes in recirculating mode. The inductive effect of phenobarbitone on hepatic mixed-function oxidases was demonstrated by a marked increase in the rate of 7-ethoxycoumarin (nine-fold) and dichloronitroanisole (64-fold) dealkylation by hepatocytes from phenobarbitone-treated animals in recirculating mode. The rate of substrate oxidation by hepatocytes perifused in the recirculating and the single-pass mode were the same. With dichloronitroanisole as substrate and a single-pass mode, the rate of dichloronitrophenol formation declined rapidly on perifusion with substrate-free medium and rapidly re-attained steady state on re-introduction of the substrate; the presence of metyrapone effectively inhibited dichloronitroanisole metabolism. The perifusion system is recommended for the study of the dynamics of xenobiotic metabolism by isolated mammalian hepatocytes.

Immuno-electron-microscopic studies on the subcellular distribution of rat liver epoxide hydrolase and the effect of phenobarbitone and 2-acetamidofluorene treatment.

The distribution of rat liver epoxide hydrolase in various subcellular fractions was investigated by immuno-electron-microscopy. Ferritin-linked monospecific anti-(epoxide hydrolase) immunoglobulins bound specifically to the cytoplasmic surfaces of total microsomal preparations and smooth and rough microsomal fractions as well as the nuclear envelope. Specific binding was not observed when the ferritin conjugates were incubated with peroxisomes, lysosomes and mitochondria. The average specific ferritin load of the individual subcellular fractions correlated well with the measured epoxide hydrolase activities. This correlation was observed with fractions prepared from control, phenobarbitone-treated and 2-acetamidofluorene-treated rats.

Phenobarbitone and kinaesthetic after-effect

The effect of phenobarbitone (phenobarbital), predominantly a central depressant, on kinaesthetic after-effect was examined. The subjects were selected after a preliminary testing with the Maudsley Personality Inventory. They were classified into two groups: extraverts and introverts. The drug was used at different dose levels. A 2 × 4 randomized block design was replicated ten times. The study supports the following conclusions: (a) the extraverted subjects show larger kinaesthetic after-effect than introverted subjects under placebo condition; (b) phenobarbitone has no effect on kinaesthetic after-effects in extraverted subjects except in small doses (30 mg) which reduce the size of the effect; (c) the drug in larger doses (60 mg and 100 rng) produces a significant increasing effect in the introverted group.

Effect of phenobarbitone on serum unconjugated oestriol levels in pregnancy: A case report

Effect of phenobarbitone on serum unconjugated oestriol levels in pregnancy: A case report

Effect of phenobarbitone on the elimination of neostigmine and its metabolites in bile

Effect of phenobarbitone on the elimination of neostigmine and its metabolites in bile

Phenobarbitone interaction with oral contraceptive steroids in the rabbit and rat.

1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls. 4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.

The effect of phenobarbitone on adult rat liver cells in primary culture

Phenobarbitone (PB) was toxic to rat liver fibroblasts within the concentration range 0.1–10 mM but was toxic to rat hepatocytes only at concentrations greater than 2 mM. This increase in cytotoxicity coincided with a decline in the PB-mediated inducibility of the microsomal monooxygenase (MMO) system. Benzanthracene (BA) was not cytotoxic to either cell type at maximal inducing concentration. Exposure of the cells to a mixture of PB + BA at maximal inducing concentrations produced synergistic toxicity to the fibroblasts, due possibly to PB-mediated induction of BA reactive metabolite formation.

Phenobarbitone-induced stimulation of protein synthesis in liver of diabetic rat

The effect of phenobarbitone on liver weight, on the rate of protein synthesis and on the sedimentation profiles of polyribosomes from livers was studied in diabetic rats. The rate of protein synthesis by isolated postmitochondrial supernatants from diabetic rats is lower than that from normal animals. The analysis of polyribosome profiles and the effect of Sephadex chromatography on protein synthesis demonstrated that the reduction was dependent in part on polyribosomal disaggregation and in part on the presence in the cytosol of low molecular weight inhibitor(s). Phenobarbitone administration had the same effect in either diabetic or normal rats in that it increased, (a) the degree of polyribosomal aggregation, (b) the rate of protein synthesis by the isolated postmitochondrial supernatants, (c) liver weight and (d) the activity of the inducible enzyme, NADPH-cytochrome c reductase. Both polyribosomal and soluble factors appear to be involved in the phenobarbitone effect. As the diabetic rats do not secrete insulin the results suggest that insulin is not involved in the control of protein synthesis by phenobarbitone. It is suggested that the intracellular redox state has a major influence on the rate of protein synthesis.

Effect of phenobarbitone and propionyl-promazine on serum enzymes in carbon-tetrachloride hepatotoxicity.

The influence of phenobarbitone givenin ten repeated doses simultaneously with small doses of CCl4 on serum enzymes was investigated in albino rats. The same experiment was repeated to investigate the influence of propionyl-promazine (phenothiazine derivative). The results proved that SGPT is a more specific and sensitive index than SGOT of hepato-cellular injury. The activity ratio between serum GOT and GPT in the normal control group was 2.44. The activity of SGPT increased nearly 6.1 fold after CCl4 administration and thus the activity ratio between GOT and GPT is sharply reduced to 0.56. The activity of serum GPT when CCl4 and phenobarbitone were administered together showed value of about 1/2 of the value when CCl4 was administered alone, while it remained high when CCl4 administration was combined with propionyl-promazine. Serum GOT and alkaline phosphatase increased significantly in all the groups. Regarding the pathological examination of the liver it was found that marked fatty necrosis could be demonstrated when high values of SGPT was found, which is not the case with serum GOT. It is concluded that in the present experimental conditions phenobarbitone protected the liver from the hepatotoxic effect of CCl4, while propionyl-promazine did not.

Microsomal enzymes inducers and serum minerals in carbon-tetrachloride hepatotoxicity.

The effect of ten repeated doses of carbon tetrachloride, phenobarbitone and propionyl promazine when administered alone or simultaneously with CCl4 on serum minerals was investigated. Carbon tetrachloride resulted in a significant increase in serum iron, copper, zinc, calcium, potassium and sodium. A portion of this rise was due to increased permeability in damaged mitochondrial membrane as a result of the action of CCl4. Propionyl promazine when administered alone or together with CCl4 has no effect on serum minerals. Phenobarbitone when administered alone increased serum minerals except sodium, but to a lesser degree than CCl4, while phenobarbitone when given repeatedly together with small doses of CCl4 led to a normalization of serum iron, calcium and potassium. Also serum zinc and copper were lower than in case of CCl4. This may be due to some protective effect of phenobarbitone on liver mitochondria. Serum magnesium was not affected in all the experimental groups.

The effect of phenobarbitone on cytoplasmic NADP-linked dehydrogenase activities in rat liver

Phenobarbitone administered in drinking water (0.5 g/l) or by daily intraperitoneal injection (100 mg/kg body weight) consistently caused an elevation of hepatic NADP-linked malic enzyme in rats maintained on a pellet diet. Three to four days appeared to be required for maximum response. The effect was also observed in animals maintained on a protein rich diet, in which the basic hepatic malic enzyme activity was low, but not in animals maintained on a sucrose rich diet, in which the basic enzyme activity was almost twice normal. Methyl cholanthrene, administered by daily intraperitoneal injection (40 mg/kg body weight), resulted in elevated levels not only of malic enzyme but also of the pentose phosphate pathway dehydrogenases. The timing of the “starve-refeed” response of the hepatic NADP-linked dehydrogenases in phenobarbitone-treated rats was similar to that in controls, and similar maximum enzyme activities were reached. The role of cytoplasmic NADP-linked dehydrogenases in the provision of reducing equivalents is discussed, particularly in relation to hepatic microsomal drug metabolism.

Effect of phenobarbitone and indoxyl sulphate on biliary excretion of foreign organic compounds during administration of carbon tetrachloride.

Effect of phenobarbitone and indoxyl sulphate on biliary excretion of foreign organic compounds during administration of carbon tetrachloride.