Long-lasting enhancement of CYP activity after discontinuation of repeated administration of phenobarbital in dogs

We investigated how long in vivo hepatic cytochrome P450 (CYP) activity is enhanced even after discontinuation of repeated oral administration of phenobarbital (PB) in dogs using antipyrine clearance, which reflects hepatic CYP activity. A single antipyrine (5 mg/kg) was administered intravenously before and 34 days after the repeated oral administration of PB (5 mg/kg, bid) and 2, 4, 6, and 8 weeks after the discontinuation of PB in 5 dogs. Antipyrine clearance was increased by the repeated administration of PB, and remained increased 2 and 4, but not 6 and 8 weeks after the discontinuation of PB. The result suggests that hepatic CYP activity was enhanced by the repeated administration of PB, and this enhancement may last for at least 4 weeks even after its discontinuation.     

苯巴比妥与牛血清白蛋白的相互作用

为镇静、睡眠类药物的研发提供理论依据,用紫外-可见光谱法和荧光光谱法研究了苯巴比妥(Ph)与牛血清白蛋白(BSA)之间的相互作用。结果表明:Ph对BSA有较强的荧光猝灭作用,其猝灭机理属于静态猝灭,主要靠氢键和范德华力相互作用。Ph可以被BSA运输,结合位置位于BSA的亚结构ⅡA中,结合过程中对温度比较敏感,Ph与BSA的结合位点偏向于色氨酸。Mn2+、Cu2+、Co2+对Ph与BSA结合产生竞争作用,增强药效;Ni 2+和Fe3+对Ph与BSA结合产生促进作用,延长药效时间。     

动物性食品中苯巴比妥残留检测研究进展

针对苯巴比妥(PB)在动物性食品中的残留检测方法及国内外研究进展等进行了详尽阐述。     

Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs

Phenobarbital can interfere with the thyroid axis in human beings and rats by accelerating hepatic thyroxine metabolism because of enzyme induction. In human beings, it also can interfere with the low-dose dexamethasone suppression test (LDDST) used to assess adrenal function by accelerating dexamethasone metabolism. This effect can cause a lack of suppression of pituitary ACTH and subsequent adrenal cortisol release after dexamethasone administration. The effects of phenobarbital on the thyroid axis, the adrenal axis, and adrenal function tests were prospectively investigated in 12 normal, adult dogs. Phenobarbital was administered at 5 mg per kilogram of body weight (range, 4.8–6.6 mg/kg) PO q12h for 29 weeks, resulting in therapeutic serum concentrations (20–40 μg/mL). Serum total thyroxine (TT4), free thyroxine (FT4) by equilibrium dialysis, total triiodothyronine (TT3), thyrotropin (TSH), and cholesterol were determined before and during phenobarbital treatment. LDDST, ACTH stimulation tests, and ultra-sonographic evaluation of the adrenal glands were performed before and during treatment. TT4 and FT4 decreased significantly ( P ≤ .05), TT3 had minimal fluctuation, TSH had only a delayed compensatory increase, and cholesterol increased during phenobarbital treatment. The delayed increase in TSH, despite persistent hypothyroxinemia, suggests that accelerated hepatic thyroxine elimination may not be the only effect of phenobarbital on the thyroid axis. There was no significant effect of phenobarbital on either of the adrenal function tests. With the methods employed, we did not find any effects of the drug on the hormonal equilibrium of the adrenal axis.     

Euthyroid sick syndrome in dogs with idiopathic epilepsy before treatment with anticonvulsant drugs

Euthyroid sick syndrome is a common finding in dogs and is attributable to nonthyroidal illness or treatment with any of a variety of drugs such as phenobarbital. In dogs with epilepsy, treatment with anticonvulsant drugs can lead to subnormal plasma thyroid hormone concentrations despite normal thyroid function. One-hundred thirteen dogs with seizure activity were retrospectively evaluated to determine the influence of idiopathic epilepsy (IE) on thyroid hormone concentrations. Blood samples were taken from 60 dogs with IE before initiation of anticonvulsant therapy. Control groups consisted of 34 dogs with IE and receiving anticonvulsants and 19 dogs with secondary epilepsy. Thyroid concentrations consistent with euthyroid sick syndrome were diagnosed in 38% of dogs with untreated IE without clinical signs of hypothyroidism or concomitant diseases. There was a significant correlation (r = 0.363, P = .01) between seizure frequency and plasma thyroid hormone concentrations: the longer the interval between 2 seizure events, the higher the serum total thyroxine concentration. There was no correlation between the degree of alteration of thyroid hormone concentrations and the time span between the most recent seizure event and blood collection, the type of the most recent seizure event, the duration of the complete seizure history, or the predominant seizure type. These results suggest that IE can be a reason for euthyroid sick syndrome in dogs. The effect of phenobarbital on plasma thyroid hormone concentrations must be investigated in future studies, as it might be less pronounced than expected.     

Involvement of hepatic xenobiotic related genes in bromadiolone resistance in wild Norway rats, Rattus norvegicus (Berk.)

To examine the role of xenobiotic relevant genes in bromadiolone resistance in wild Norway rats (Rattus norvegicus) we compared the constitutive liver gene expression and expression upon bromadiolone administration in bromadiolone resistant and anticoagulant susceptible female rats using a LNA microarray and quantitative PCR. Resistant rats showed significantly higher constitutive expression of the cytochrome P450 genes Cyp2c13 and Cyp3a2 and lower expression of Cyp2e1 and Gpox1 compared to the susceptible rats. The Cyp1a2, Cyp2c13, Cyp2e1, Cyp3a2 and Cyp3a3 genes were significantly higher expressed in resistant than susceptible rats upon bromadiolone exposure. To establish how bromadiolone affected xenobiotic gene expression in the two strains we compared bromadiolone expression profiles to saline profiles of both strains. Bromadiolone mediated significant up-regulation of Cyp2e1 and Cyp3a3 expression in the resistant rats whereas the rodenticide conferred down-regulation of Cyp2e1, Cyp3a3 and Gpox1 and induction of Cyp2c12 expression in susceptible rats. Cyp2c13 and Cyp3a2 expression were markedly suppressed in both strains upon treatment. This suggests that xenobiotic relevant enzymes play a role in bromadiolone resistance in the Norway rat. A high constitutive expression of Cyp2c13 and Cyp3a2 and induction of Cyp1a2, Cyp2e1 and Cyp3a3 expression during bromadiolone exposure may increase the resistance to bromadiolone presumably by facilitating increased detoxification and decreased liver injury.     

Juvenile idiopathic epilepsy in Egyptian Arabian foals: 22 cases (1985-2005)

Background:Epilepsy is relatively uncommon in horses compared with other species and limited information is available.
Hypothesis:The objectives of the study were to describe the age of onset, clinical signs, clinicopathologic data, electroencephalographic findings, treatment, and outcome, including long-term prognosis in Arabian foals with idiopathic epilepsy.
Animals:Twenty-two foals were included in the study.
Materials and Methods: Medical records from 1985 to 2005 were reviewed.
Results:The age of onset of affected foals ranged from 2 days to 6 months. Seizures were characterized by generalized tonic and clonic motor activity, staring, and loss of consciousness. The most common postictal signs were transient blindness and abnormal mental status. The interictal neurologic examination was otherwise normal. Clinicopathologic data and imaging diagnostics were normal except in 4 foals that developed complications. Electroencephalography revealed epileptiform activity in 9 of 13 foals. Foals were treated with benzodiazepines for the short-term; whereas phenobarbital was used over the long-term. Potassium bromide was added in 3 foals in which seizures were multiple, frequent, and difficult to control. The long-term prognosis was favorable with cessation of seizures by 1 year of age. The most common complication was head trauma. The most common concurrent disease was pneumonia.
Conclusions and Clinical Importance: Juvenile idiopathic epilepsy of Egyptian Arabian foals has an early clinical onset but appears to be self-limiting. Information obtained from this study strongly suggests a heritable condition that merits further investigation.     

苯巴比妥在动物生产中的非法使用及毒性作用

通过综述苯巴比妥的非法使用、毒性作用、中毒的临床症状,介绍了我国政府对苯巴比妥非法使用的综合治理。