Antioxidant and hepatoprotective effects of Eucalyptus maculata.

BACKGROUND: Since phenolic compounds have been reported as effective antioxidants, this study was designed to assess the hepatoprotective and antioxidant activities of the chloroformic extract of the resinous exudate and its phenolic constituents obtained from the stems of Eucalyptus maculata. MATERIAL/METHODS: The chloroformic extract and pure phenolic isolates were evaluated for their antioxidant and hepatoprotective properties in mice and rats based on biochemical changes in serum and tissues as well as pathological changes in the liver and spleen. RESULTS: Acetaminophen (ACP) at a dose of 1 g/kg body weight produced 100% mortality in mice, while pretreatment of animals with the chloroformic extract (125 and 250 mg/kg) protected against the moralities by 66%. Pretreatment of rats with either the chloroformic extract (250 mg/kg) or any of the pure isolates (20 mg/kg) significantly reduced the increase in serum level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) produced by ACP (640 mg/kg). Pretreatment of animals with the chloroformic extract or its isolates also protected against ascorbic acid depletion in serum and kidney tissues induced by oral administration of paraquat (PQ) without modifying the serum level of glutathione (GSH) and glycogen content in liver tissue. CONCLUSIONS: The phenolic content of the chloroformic extract and the pure isolates produced an antioxidant activity which may be due to the formation of stable phenoxyl radical in addition to its effect through vitamin C.

Pretreatment with Ginkgo biloba extract weakens the hypnosis action of phenobarbital and its plasma concentration in rats.

In a previous study, we found that orally administered Ginkgo biloba extract (GBE) induced hepatic cytochrome P450 (CYP) in rats, especially the CYP2B type. This fact suggested that GBE influenced the availability and safety of drugs that were metabolized via CYP2B type enzymes. To confirm this possibility, in this study we examined the effect of feeding a 0.1, 0.5 and 1.0% GBE diet for 2 weeks on the pharmacokinetics and pharmacological action of phenobarbital, which is known to be metabolized by CYP2B in Wistar rats. The feeding of GBE markedly shortened the sleeping time in rats. Furthermore, the maximal phenobarbital plasma concentration (Cmax) and the 24-h area under the curve (AUC0-24) were decreased in rats fed GBE. These findings indicate that GBE reduces the therapeutic potency of phenobarbital via enhancement of cytochrome P450 expression, and raises the possibility that GBE and drug interactions may occur clinically.

Clinical pharmacokinetics of thalidomide

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions in being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1-2mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUCoo) of 18mg - h/L, apparent elimination half-life of 6 hours and apparent systemic clearence of 10 L/H. Thalidomide pharmacokinetics are best described by a one-comportment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacolinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than in absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accululation, with Css of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide Cmax is less than proportional to dose, and tmax is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokonetics are not expected to change in patients with impaired liver...

Chemoprevention of DMBA-induced UV-B promoted, NOR-1-induced TPA promoted skin carcinogenesis, and DEN-induced phenobarbital promoted liver tumors in mice by extract of beetroot.

Our previous studies identified the extract of Beta vulgaris (beetroot), commercially also known as betanin, as a potent cancer chemopreventive agent in both in vitro Epstein-Barr early antigen activation assay and in an in vivo two-stage mouse lung and skin carcinogenesis. To explore this issue further, we have now investigated its cancer chemopreventive potentials in three different chemical carcinogen initiation-promotion experimental tumor models in mice. Following tumor initiation with 390 nmol of 7,12-dimethylbenz(a)anthracene (DMBA) in 100 microl of acetone, the mouse skin tumor promotion with 3430 J/m(2) of ultraviolet light-B (UV-B) as well as splenomegaly was significantly inhibited by oral administration of 0.0025% betanin. At the same dose, betanin also afforded significant protection in the mouse skin cancer model following the topical application of 390 nmol of (+/-)-(E)-4-methyl-2-[(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) in 100 microl of acetone and promoted by topical administration of 1.7 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA). In the two-stage model of hepatocarcinogenesis in mice with N-nitrosodiethylamine (DEN, 30 mg/kg) as the initiator and phenobarbital as the promoter, oral administration of 0.0025% betanin also showed a very significant inhibition of both the incidence and multiplicity of the liver tumors. These findings along with our initial reports suggest that betanin which is a regularly consumed natural product colorant is an effective cancer chemopreventive agent in mice. The most interesting observation is that the cancer chemopreventive effect was exhibited at a very low dose used in the study and thus indicating that beetroot warrants more attention for possible human applications in the control of malignancy.

Niguldipine impairs the protective activity of carbamazepine and phenobarbital in amygdala-kindled seizures in rats.

There is evidence that some calcium (Ca(2+)) channel inhibitors enhance the protective activity of antiepileptic drugs. Since clinical trials have not provided consistent data on this issue, the objective of this study was to evaluate the interaction of a dihydropyridine, niguldipine, with conventional antiepileptics in amygdala-kindled rats. Niguldipine (at 7.5 but not at 5 mg/kg) displayed a significant anticonvulsant effect, as regards seizure and afterdischarge durations in amygdala-kindled convulsions in rats, a model of complex partial seizures. No protective effect was observed when niguldipine (5 mg/kg) was combined with antiepileptics at subeffective doses, i.e. valproate (75 mg/kg), diphenylhydantoin (40 mg/kg), or clonazepam (0.003 mg/kg). Unexpectedly, the combined treatment of niguldipine (5 mg/kg) with carbamazepine (20 mg/kg) or phenobarbital (20 mg/kg) resulted in a proconvulsive action. BAY k-8644 (an L-type Ca(2+) channel activator) did not modify the protective activity of niguldipine (7.5 mg/kg) or the opposite action of this dihydropyridine (5 mg/kg) in combinations with carbamazepine or phenobarbital. A pharmacokinetic interaction is not probable since niguldipine did not affect the free plasma levels of the antiepileptics. These data indicate that the opposite actions of niguldipine alone or combined with carbamazepine (or phenobarbital) were not associated with Ca(2+) channel blockade. The present results may argue against the use of niguldipine as an adjuvant antiepileptic or for cardiovascular reasons in patients with complex partial seizures.

Effect of alpha-hederin and sapindoside B on hepatic microsomal cytochrome P-450 in mice.

AIM: To study the relation between the effect of alpha-hederin (Hed) and sapindoside B (Sap B) on cytochrome P-450 and their hepatoprotection. METHODS: Mice were given sc Hed, Sap B, as well as a mixture of Hed + Sap B (1:1.5), and hepatic microsomal cytochrome P-450 was examined. RESULTS: Hed 20 mg.kg-1, Sap B 20 mg.kg-1 and Hed + Sap B 20 mg.kg-1 sc, reduced hepatic P-450 content by 40%, 55% and 50%, respectively. The effect of the saponins on P-450 was reversible, as P-450 level returned to normal after 3 d. Phenobarbital (Phe) 50 mg.kg-1 ip increased P-450 2.5-fold, the Phe-induced P-450 was inhibited 50% by Hed + Sap B. No inhibitory effect was seen when liver microsomes were incubated with Hed + Sap B in vitro. CONCLUSION: The hepatoprotective effects of Hed and Sap B were at least in part, due to its suppressive effect on liver cytochrome P-450.

[Inhibition effect of epicatechin on phenobarbitol-induced proliferation precancerous liver cells].

Epicatechin complex was given to diethylnitrosamine-initiated male Wistar rats concomitantly with the administration of phenobarbitol during hepatocarcinogenesis. The epicatechin complex was extracted from Longjing green tea and its concentration of whole epicatechin was 87.5%. The results denoted that epicatechin efficiently inhibited the promotive effect of phenobarbitol. High performance liquid chromatography analysis proved that the chemical properties of phenobarbitol and epicatechin were still well preserved when these two substances were dissolved together in distilled water. It was noted that there was no direct chemical reaction between these two substances. The inhibition mechanism and need of further studies concerning the effect of epicatechin on cell metabolism are discussed.

Inhibition of phenobarbital and dietary choline deficiency promoted preneoplastic lesions in rat liver by environmental contaminant di(2-ethylhexyl)phthalate.

The effect of di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer and environmental contaminant, on the emergence of gamma-glutamyltranspeptidase positive (GGT+) preneoplastic foci in the liver of rats fed promoting diets was studied. GGT+ foci were initiated in the liver of Sprague--Dawley male rats with a single dose of diethylnitrosamine (DEN) following partial hepatectomy. One series of control rats received saline vehicle alone. Promotion of foci was commenced by feeding: (1) a choline-deficient diet (CD); (2) a choline-supplemented diet (CS) containing 0.06% phenobarbital (CS + PHB); or (3) a CD diet containing 0.06% phenobarbital (CD + PHB). In the absence of initiation by DEN, dietary treatments did not increase the number of GGT+ foci. In rats receiving DEN, each promoting regimen effectively increased the number of GGT+ foci above levels in control rats fed only the choline-supplemented diet. Inclusion of the plasticizer at a level of 2% in each of the dietary promotion treatments, however, effectively inhibited the appearance of the foci.

Drug alterations of punished responding after chlordiazepoxide: possible screen for agents useful in minimal brain dysfunction.

In the present study, the effect of various stimulant drugs on the action of chlordiazepoxide to increase punished responding was studied. Drugs such as d-amphetamine, methylphenidate and imipramine that are effective in attentional deficit disorder (MBD) were found to reverse this benzodiazepine-induced increase in responding. Phenobarbital which worsens this condition enhanced the benzodiazepine effect. Since the impairment caused by chlordiazepoxide may be analogous to the lack of impulse control noted in MBD, the bupropion antagonism of this action of chlordiazepoxide suggests that bupropion may be useful in MBD.