Administration Of Phenobarbital Research Articles

A review of the current treatment methods for posthaemorrhagic hydrocephalus of infants

Posthaemorrhagic hydrocephalus (PHH) is a major problem for premature infants, generally requiring lifelong care. It results from small blood clots inducing scarring within CSF channels impeding CSF circulation. Transforming growth factor – beta is released into CSF and cytokines stimulate deposition of extracellular matrix proteins which potentially obstruct CSF pathways. Prolonged raised pressures and free radical damage incur poor neurodevelopmental outcomes. The most common treatment involves permanent ventricular shunting with all its risks and consequences.This is a review of the current evidence for the treatment and prevention of PHH and shunt dependency. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) and PubMed (from 1966 to August 2008) were searched. Trials using random or quasi-random patient allocation for any intervention were considered in infants less than 12 months old with PHH. Thirteen trials were identified although speculative interventions were also evaluated.The literature confirms that lumbar punctures, diuretic drugs and intraventricular fibrinolytic therapy can have significant adverse effects and fail to prevent shunt dependence, death or disability. There is no evidence that postnatal phenobarbital administration prevents intraventricular haemorrhage (IVH). Subcutaneous reservoirs and external drains have not been tested in randomized controlled trials, but can be useful as a temporising measure. Drainage, irrigation and fibrinolytic therapy as a way of removing blood to inhibit progressive deposition of matrix proteins, permanent hydrocephalus and shunt dependency, are invasive and experimental. Studies of ventriculo-subgaleal shunts show potential as a temporary method of CSF diversion, but have high infection rates.At present no clinical intervention has been shown to reduce shunt surgery in these infants. A ventricular shunt is not advisable in the early phase after PHH. Evidence exists that pre-delivery corticosteroid therapy reduces mortality and IVH and there may be trends towards reduced disability in the short term. There is also evidence that postnatal indomethacin reduces IVH but with no effect on mortality or disability. Overall, there is still no definitive algorithm for the treatment of PHH or prevention of shunt dependence. New therapeutic approaches in neonatal care, including those aimed at pre-empting PHH, offer the best hope of improving neurodevelopmental outcomes.

Changes in blood coagulation-related parameters in phenobarbital-treated rabbits

The effects of repeated administration of phenobarbital (PB) on blood coagulation time were examined using male Japanese white SPF rabbits, which are widely used for toxicological studies. PB was administered to the rabbits by oral gavage for 2 weeks, at dose levels of 0, 12.5, 25 and 50 mg/kg/day. Blood was collected on Days 8 and 14 after each day's dosing to perform blood coagulation examination. The liver was excised, weighed and examined histopathologically. Activated partial thromboplastin time (APTT) was prolonged at dose levels of 12.5 mg/kg/day or more and Thrombotest (TBT) was prolonged at 50 mg/kg/day on Day 8. APTT was prolonged at dose levels of 12.5 mg/kg/day or more, TBT was prolonged at 25 mg/kg/day or more and factor IX activity decreased at 50 mg/kg/day on Day 14. At pathological examination, liver weight increased at dose levels of 25 mg/kg/day or more, and a ground-glass appearance of the hepatocytes was observed in the central and middle parts of lobules at 12.5 mg/kg/day or more. However, changes in factor VII or X activity or prolongation of prothrombin time (PT) were not observed. Therefore, prolongation of blood coagulation time by PB administration in rabbits was considered to be due to PB's effect on the endogenous pathway alone. Moreover, an increase in anti-thrombin III (ATIII) concentration was noted at 50 mg/kg/day; however, no change was noted at dose levels of 25 mg/kg/day or less. This suggests that the contribution of ATIII to the PB-induced prolongation of coagulation time in rabbits was small.

JDSA JOURNAL ABSTRACTS

JDSA JOURNAL ABSTRACTS

Pharmacology Review

The incidence of neonatal seizures is 3.5/1,000 live births. (1) The clinical manifestations are very diverse and not always easy to recognize. Amplitude-integrated electroencephalography (aEEG), a method for continuous monitoring of brain function used increasingly in neonatal intensive care units, (2) may aid in recognition of neonatal seizures. Apart from being able to detect abnormal brain activity, aEEG also enables immediate and continuous evaluation of the effect of anticonvulsive treatment. aEEG often reveals electrographic discharges without clinical manifestations, especially following initiation of drug therapy for clinical seizures. (3)(4) Continuation of electrographic seizures without a clinical correlate is referred to as “uncoupling.” (3) Several studies have shown that the success rate of the most commonly used anticonvulsant drugs, phenobarbitone and phenytoin, frequently is disappointing in neonates. (5) Lidocaine is an effective drug for second- or third-line treatment of neonatal seizures not responding to traditional anticonvulsant therapy. (6)(7)(8) In this article, we review the effectiveness and safety of lidocaine and discuss the clinical value of routine measurements of drug concentrations because of the pharmacokinetic and pharmacodynamic properties of lidocaine. We hypothesize the effects of therapeutic hypothermia on lidocaine drug disposition and response. Lidocaine is used widely as a local anesthetic for pain prevention and as a type 1b antiarrhythmic agent for short-term control of ventricular arrhythmias. In 1948, the drug was synthesized as an amide derivative of the anesthetic cocaine. Lidocaine acts as a central nervous system depressant with sedative, analgesic, and anticonvulsant properties. Scandinavia has a long therapeutic tradition of using lidocaine for the treatment of severe neonatal seizures. Hellstrom-Westas and associates (7) showed in 1988 that lidocaine was effective in most patients suffering clinically suspected epileptic seizures that persisted in spite of phenobarbital and diazepam administration. In a second study, they determined the …

Influence of Antiepileptic Drugs on Amplitude-Integrated Electroencephalography

Amplitude-integrated electroencephalography monitors different aspects of cerebral function in neonatal intensive care units. To examine the influence of various antiepileptic drugs on the background patterns and voltage of amplitude-integrated electroencephalography recordings, we screened 191 tracing segments originating from 77 newborns treated with antiepileptic drugs. The influences of lorazepam, diazepam, and phenobarbital given as bolus doses, and midazolam and lidocaine given in continuous infusion, were examined. Voltages and patterns before and after drug administration were assessed. Time taken to return to previous voltage was assessed in clinically significant cases. Chi-square and Wilcoxon tests were used for statistical analyses. Significant changes were evident after lorazepam, diazepam, phenobarbital, and midazolam administration. Depending on the voltage-assessment method, a clinically significant depression of the lower voltage border occurred in 25-35% of tracings, and of the upper border in 16-32%. In 12% of tracings, change to a worse pattern was noted. The average time for recovery to predrug administration voltage was 2.5 hours (range, 15 minutes to 15 hours). Changes in amplitude-integrated electroencephalography tracings occur after antiepileptic drugs are infused. These changes include deterioration of pattern and depression of voltage that may persist for a considerable period. The potential depressing effects of these drugs should be taken into consideration when assessing amplitude-integrated electroencephalogram tracings.

Effect of early bosentan administration on the development of esophageal varices in cirrhotic rats: experimental study in Wistar rats

This study was conducted to investigate the effect of chronic bosentan administration on the development of esophageal varices in carbon tetrachloride-induced cirrhosis in rats. For the development of liver cirrhosis and esophageal varices, 60 rats underwent ligation of the left adrenal vein, followed by phenobarbital and carbon tetrachloride administration. Two weeks after the beginning of carbon tetrachloride administration, rats were separated into two groups. In group I, comprising 30 rats, bosentan was continuously administered throughout the study, whereas in group II, also 30 rats, placebo instead of bosentan was continuously administered. Hemodynamic studies and morphometric analysis of the lower esophagus were performed after complete induction of cirrhosis. The total number of veins counted in the submucosa, the number of submucosal veins/mm(2) of submucosa, the total submucosal area occupied by vessels, the mean cross-sectional vessel area, the relative submucosal area (percentage) occupied by vessels, and the area of the single most-dilated submucosal vein were studied. Bosentan induced a significant (P < 0.05) decrease in portal pressure, while morphometric analysis revealed a significant reduction (P < 0.05) of all parameters studied in bosentan-treated rats, except in the total and relative number of submucosal veins. Bosentan administration seemed to significantly attenuate dilation of submucosal veins in the lower esophagus of cirrhotic rats. This effect was mainly attributed to a decrease in the portal pressure induced by chronic bosentan administration.

Early Propranolol Administration Does Not Prevent Development of Esophageal Varices in Cirrhotic Rats

Background and Aims: Variceal bleeding is the most serious complication of portal hypertension associated with high mortality. This study was conducted to investigate any protective effect of early propranolol administration in the development and degree of esophageal varices in cirrhotic rats with portal hypertension. This topic is controversial in the literature. Methods: For the development of liver cirrhosis and esophageal varices, 60 rats underwent ligation of the left adrenal vein and complete devascularization of the left renal vein, followed by phenobarbital and carbon tetrachloride (CCl₄) administration. This operation enhances the development of cephalad collaterals, responsible for the induction of esophageal varices. After 2 weeks of CCl₄ administration, the rats were randomly separated into 2 groups. In group I, propranolol was continuously administered intragastrically throughout the study, whereas in group II normal saline (placebo) was administered instead. Cirrhosis was detected clinically by ascites development. Hemodynamic studies and morphometric analysis of the lower esophagus were performed after complete induction of cirrhosis, measuring the following parameters: portal pressure, total number of submucosal veins, total submucosal vessel area, mean cross-sectional submucosal vessel area, relative submucosal area (percentage) occupied by vessels and area of the single most dilated submucosal vein. Results: The statistical analysis revealed no statistically important difference between the 2 groups for the morphometrically studied parameters. However, portal venous pressure was lower in group I. Conclusion: Early propranolol administration did not protect rats from developing esophageal varices, despite the fact that a significant decrease in portal pressure was detected.

Effects of choline‐deprivation on paracetamol‐ or phenobarbital‐induced rat liver metabolic response

Choline is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions in both humans and rodents. Various pathophysiological states have been linked to choline deprivation (CD). The aim of the present study was to determine the effect of CD upon biochemical, histological and metabolic alterations induced by drugs that affect hepatic functional integrity and various drug metabolizing systems via distinct mechanisms. For this purpose, paracetamol (ACET) or phenobarbital (PB) were administered to male Wistar rats that were fed with standard rodent chow (normally fed, NF) or underwent dietary CD. The administration of ACET increased the serum aspartate aminotransferase levels in NF rats, while CD restricted this increase. On the other hand, ACET suppressed alkaline phosphatase levels only in CD rats. Moreover, CD prevented the PB-induced increase of the mitotic activity of hepatocytes. The administration of ACET down-regulated CYP1A2 and CYP2B1 expression in CD rats, while up-regulating them in NF rats. The administration of PB suppressed CYP1A2 apoprotein levels in CD rats, whereas the drug had no effect on NF rats. The PB-induced up-regulation of CYP2B, CYP2E1 and CYP1A1 isozymes was markedly higher in CD than in NF rats. In addition, PB increased glutathione-S-transferase activity only in CD rats. Hepatic glutathione content (GSH) was suppressed by ACET in NF rats, whereas the drug increased GSH in CD rats. Our data suggest that CD has a significant impact on the hepatic metabolic functions, and in particular on those related to drug metabolism. Thus, CD may modify drug effectiveness and toxicity, as well as drug-drug interactions, particularly those related to ACET and PB.

Brain penetration and anticonvulsant efficacy of intranasal phenobarbital in rats

The use of alternate methods for antiepileptic drug delivery has been proposed as a putative strategy to enhance efficacy and tolerability of chronic pharmacotherapy. Intranasal administration is of specific interest based on its general potential for targeted central nervous system delivery. Therefore we analyzed whether intranasal administration of phenobarbital may render a valuable therapeutic approach. Brain penetration of phenobarbital following its intranasal administration in rats was studied by microdialysis and by analysis of brain homogenates. The anticonvulsant efficacy of intranasal phenobarbital was determined in the amygdala kindling model. Phenobarbital was efficiently delivered to the rat brain following intranasal administration. A mucoadhesive preparation of phenobarbital thereby resulted in brain concentrations that were superior to those obtained with intranasal administration of an aqueous solution. In comparison with concentrations reached following intravenous administration of 5.4 mg/kg phenobarbital, intranasal administration of the same dosage resulted in 2.4-fold higher C(max) values in cortical dialysates. Ten minutes following intranasal administration, PB concentrations in the olfactory bulb exceeded that in more caudal parts of the brain, thus, indicating that phenobarbital has at least been partially targeted to the brain via local pathways. Testing in the amygdala kindling model demonstrated that effective brain concentrations were reached with intranasal phenobarbital delivery. In conclusion, intranasal administration of phenobarbital in rats is associated with efficient brain penetration rates allowing to achieve therapeutic concentrations. Based on these data, intranasal phenobarbital administration seems to render a suitable alternate delivery route for this antiepileptic drug, which should be further evaluated.

Pharmacokinetics of zonisamide and drug interaction with phenobarbital in dogs

The purposes of the present study were to elucidate the pharmacokinetics of zonisamide, determine the presence of a drug interaction with phenobarbital, and evaluate how long any interaction lasted after discontinuation of phenobarbital in dogs. Five dogs received zonisamide (5 mg/kg, p.o. and i.v.) before and during repeated oral administration of phenobarbital (5 mg/kg, bid, for 30-35 days). Zonisamide (5 mg/kg, p.o.) was also administered 8, 10, and 12 weeks after discontinuation of phenobarbital. Blood was sampled until 24 h after each zonisamide administration and serum concentrations of zonisamide were determined. Repeated phenobarbital decreased the maximum serum concentration, area under the serum concentration vs. time curve, apparent elimination half-life, and bioavailability of zonisamide. Total clearance increased. Time to maximum serum concentration and volume distribution were not changed. The maximum serum concentration and area under the serum concentration vs. time curve of zonisamide continued to be low until 10 weeks after the discontinuation of phenobarbital. They were restored to the same serum concentration as before phenobarbital administration 12 weeks after the discontinuation of phenobarbital. These data suggested that repeated administration of a clinical dose of phenobarbital enhanced the clearance of zonisamide and the enhanced clearance lasted at least 10 weeks after the discontinuation of phenobarbital. Caution may be necessary when zonisamide is given with phenobarbital and when antiepileptic therapy is changed from phenobarbital to zonisamide.

Type 1 diabetes mellitus in a child with phenobarbital hypersensitivity syndrome

To report a case of type 1 diabetes mellitus (T1DM) in a child with phenobarbital hypersensitivity syndrome with an emphasis on the clinical presentation, diagnostic modalities and treatment options. A 5-yr-old girl developed fever, rash and hepatic inflammation after receiving phenobarbital. Infection and connective tissue diseases were excluded and an adverse event following phenobarbital administration [anticonvulsant hypersensitivity syndrome (AHS)] was considered. Clinical manifestation was somewhat improved after systemic hydrocortisone and other antiallergic drugs were administrated. However, polyuria, polydipsia, dehydration, severe metabolic acidosis with increased anion gap and hyperglucosemia were found about 4 weeks after stopping phenobarbital. Increased blood ketone and glycosylated hemoglobin (HbA1c), and decreased blood insulin and C-peptide confirmed the diagnosis of T1DM. Insulin was used and gamma-immunoglobulin was administered on the 25th day after admission. Since then, clinical symptoms and signs improved significantly and the patient was discharged on the 45th day after admission. Postdischarge course was uneventful and the patient is well with sequential HbA1c of 7.3% 1 month after discharge. AHS should be suspected in patients who develop unexplained systemic manifestations following exposure to aromatic antiepileptics, including phenobarbital. The timely recognition and treatment with corticosteroids and immunoglobulin is required and useful. The potential damage of beta-cells should be considered in patients with AHS.

Blood coagulation-related parameter changes in Sprague-Dawley (SD) rats treated with phenobarbital (PB) and PB plus vitamin K

Effects of dose and duration of phenobarbital (PB) administration and those of co-administration of PB and vitamin K on blood coagulation-related parameters were examined in specific pathogen-free (SPF) rats of Sprague-Dawley strain kept on an ordinary diet. In Experiment 1, oral administration of PB (0, 25, 50, 100 or 150 mg/kg/day) for 2 weeks induced increases in hepatic cytochrome P450 content and CYP2B expression, prolongation of coagulation time (activated partial thromboplastin time (APTT) and Thrombotest (TBT)) and an increase in anti-thrombin III (AT III) concentration in a dose-dependent manner. In Experiment 2, PB administration (100 mg/kg/day) for up to 14 days produced time-dependent increases in hepatic cytochrome P450 content and CYP2B (CYP2B1 and CYP2B2) expression. APTT was prolonged from day 1 and AT III concentration was increased from day 2, whereas the coagulation time (TBT) was prolonged from day 7. In Experiment 3, APTT prolonged by PB (100 mg/kg/day) was shortened after vitamin K(2) (30 mg/kg/day) co-administration, although AT III concentration was still increased. This suggests that not AT III but PB-induced vitamin K deficiency may play an important role in PB-induced prolongation of coagulation time in SPF rats kept on an ordinary diet.

Exposure to Phenobarbital in a Foal after Nursing a Mare Treated with Phenobarbital

Exposure to Phenobarbital in a Foal after Nursing a Mare Treated with Phenobarbital

A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens

A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens

A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens

A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens

Effect of Experimentally Induced Liver Cirrhosis on Wound Healing of the Post-Extraction Tooth Socket in Rats

Background: Wound healing in liver cirrhosis is known to be impaired possibly due to liver insufficiency and subsequent malnutrition status; however, there is no study to examine healing effectiveness of the tooth socket following an extraction in such patients. Materials and Methods: Irreversible cirrhosiswas induced in 30 Wistar rats by repetitive weekly doses of CCl₄ and continuous administration of phenobarbital in a 12-week course was monitored by body weight measurement and ascites development, and was proved histologically. One week later, cirrhotic and control rats were subjected to extractions of two maxillary grinders on each side, one side by simple method, the other by surgical method. Half of the animals of each subgroup were sacrificed on the 10th post-extraction day, whereas the other half on the 30th post-extraction day, and histological sections were examined from all tooth sockets for wound-healing activity. Results: A malnutrition status was detected in cirrhotic rats with significant difference in their body weight. Several histological parameters of socket healing were not statistically different between cirrhotic and control animals. However, a significant delay on epithelialization and cancellous bone formation was detected on the 10th post-extraction day for either simple or surgical extractions in cirrhotic animals. Conclusions: Liver cirrhosis in rats provokes a significant delay on epithelialization and mature cancellous bone formation and consecutively on early socket wound healing after a tooth extraction.

Effect of phenobarbital on hepatic cell proliferation and apoptosis in mice deficient in the p50 subunit of NF-κB

Phenobarbital (PB) is a nongenotoxic tumor promoter in the liver. One mechanism by which PB may exert its tumor promoting activity is by inducing oxidative stress. We previously found that PB administration increased hepatic NF-κB DNA binding activity. In this study we examined the hypothesis that the effects of PB on cell proliferation and apoptosis are dependent on NF-κB. We used a mouse model that is deficient in the p50 subunit of NF-κB; previous studies had found that p50−/− mice were less sensitive to the induction of hepatic cell proliferation by PCBs or peroxisome proliferators. Mice (p50−/− and wild-type B6129) were fed a control diet or one containing 0.05% PB for 3, 10 or 34 days. At the end of the experiment, the mice were euthanized and livers removed and processed. PB increased cell proliferation at 3 and 10 days (but not at 34 days), but the deletion of the NF-κB p50 subunit did not inhibit these increases. p50−/− Mice had higher cell proliferation at the 3 day (only in mice fed PB) and 34-day timepoints. PB decreased hepatocyte apoptosis after 3 days, slightly decreased it after 10 days, and did not affect it after 34 days. The deletion of the NF-κB p50 subunit did not influence PB's effect on apoptosis. In p50−/− mice, apoptosis was increased after 3 or 10 days compared to wild-type mice, but no effect was seen after 34 days. The hepatic expression of the NF-κB-regulated gene TNF-α correlated more with the hepatic cell proliferation data than with hepatic apoptosis, and was not decreased by the deletion of the p50 subunit. These findings show that the p50 subunit of NF-κB is not required for the alteration of hepatocyte proliferation or apoptosis by PB up to 34 days after its administration.

Increased P-glycoprotein expression and decreased phenobarbital distribution in the brain of pentylenetetrazole-kindled rats

The purposes of this study were to investigate whether P-glycoprotein (P-GP) is overexpressed in the brain of pentylenetetrazole (PTZ)-kindled rats, and to investigate the effects of P-GP up-regulation on the distribution of phenobarbital (PB) in brain and its antiepileptic effects. Kindled rats were developed using a subconvulsive dose of PTZ (30 mg/kg, once every 2 days, i.p.) for 24 days. P-GP expression and function were measured by Western blot analysis and rhodamine 123 (Rho 123) distribution in brain. Kindled rats received 10 mg/kg of PB alone or co-administration of cyclosporine A (CsA, 5 mg/kg). At 60 min after administration of PB, concentrations of PB in brain and plasma were measured and the tissue-to-plasma concentration ratios of PB were calculated. Anticonvulsive effects of PB (13.2 mg/kg) alone or co-administration of CsA on the kindled rats were observed. The results showed that kindling resulted in 1.7-fold increase of P-GP level in brain, accompanied by significant decrease of tissue-to-plasma concentration ratios of Rho 123 and PB in hippocampus and cortex without affecting their concentrations in plasma. Co-administration of CsA reversed the decrease of PB concentration in brain without affecting PB level in plasma and significantly potentiated the anticonvulsive effects of PB. The present study demonstrated that chronic PTZ-kindling might increase P-GP expression and function in brain of rat, resulting in decrease of Rho 123 and PB levels in brain tissues. Co-administration of CsA increased PB levels in brain and enhanced anticonvulsive effects of PB by inhibiting P-GP function.

Depletion of High‐density Lipoprotein and Appearance of Triglyceride‐rich Low‐density Lipoprotein in a Japanese Patient With FIC1 Deficiency Manifesting Benign Recurrent Intrahepatic Cholestasis

Lipoprotein metabolism in FIC1 deficiency due to ATP8B1 mutations has never been studied sufficiently. This study was performed to investigate the detailed lipoprotein metabolism in benign recurrent intrahepatic cholestasis (BRIC) caused by FIC1 deficiency. Lipoprotein profile and major lipoprotein regulators such as lecithin:cholesterol acyltransferase (LCAT), hepatic triglyceride lipase (HTGL), lipoprotein lipase, and cholesteryl ester transfer protein in a Japanese patient with BRIC were serially examined during a bout of cholestasis. Liver expression of farnesoid X receptor (FXR), which suppresses high-density lipoprotein (HDL) generation, was also examined. Hypercholesterolemia and lipoprotein X accumulation were never observed throughout this study. When the cholestasis was severe, triglyceride-rich low-density lipoprotein (LDL) accounted for most of the plasma lipoproteins whereas HDL was hardly detectable. Concurrently, activities of all regulators were decreased, together with decreases of the serum parameter for liver protein synthesis. In particular, suppressions of LCAT and HTGL activities were severe and greatly contributed to the appearance of triglyceride-rich LDL. As the cholestasis improved, this LDL gradually transformed into normal LDL with the recoveries of LCAT and HTGL activities. The activities of all regulators for the last 1 to 2 months were normal but HDL remained depleted. His liver showed low FXR expression compared with control livers. The present study showed an appearance of triglyceride-rich LDL due to suppressions of LCAT and HTGL activities and a depletion of HDL that is not able to be explained by lipoprotein regulators or FXR in our patient.

A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens

Acute Care Surgery, University of Michigan, Ann Arbor, MI (Hayanga) General Surgery, Johns Hopkins Medical Institutions, Baltimore, MD (Weiss)