The effect of resveratrol on pharmacokinetics of aripiprazole in vivo and in vitro

1.?The objective of this study were to investigate the effect of orally administered resveratrol on the pharmacokinetics of aripiprazole (APZ) in rat, and the inhibitory effects of resveratrol on APZ dehydrogenation activity in liver microsomes and human cytochrome P450 3A4 and 2D6.

2.?Twenty-five healthy male Sprague–Dawley rats were randomly divided into five groups: A (control group), B (multiple dose of 200?mg/kg resveratrol), C (multiple dose of 100?mg/kg resveratrol), D (a single dose of 200?mg/kg resveratrol) and E (a single dose of 100?mg/kg resveratrol). A single dose of 3?mg/kg APZ administered orally 30?min after administration of resveratrol. In addition, CYP2D6*1, CYP3A4*1, human and rat liver microsomes were performed to determine the effect of resveratrol on the metabolism of APZ in vitro.

3.?The multiple dose of 200 or 100?mg/kg resveratrol significantly increased the AUC and C_max of APZ. The resveratrol also obviously decreased the CL, but without any significant difference on t_1/2 in vivo. On the other hand, resveratrol showed inhibitory effect on CYP3A4*1, CYP2D6*1, human and rat microsomes, the IC₅₀ of resveratrol was 6.771, 87.87, 45.11 and 35.59?μmol?l^?1, respectively.

4.?Those results indicated more attention should be paid when APZ was administrated combined with resveratrol.     

Cardioprotective effect of ascorbic acid on doxorubicin-induced myocardial toxicity in rats

Objective:

To investigate the preventive and curative role of ascorbic acid on doxorubicin (dox)-induced myocardial toxicity in rats.

Materials and Methods:

Animals were divided into five groups of six animals each. Group I served as normal control and received saline 5 ml/kg/day intraperitoneal (i.p.) for a period of 15 days. Group II animals received ascorbic acid 20 mg/kg per oral (p.o.) for 15 days as a pretreatment control (PR). Group III animals received dox 2.5 mg/kg body weight (b.w.), i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg b.w. Group IV animals received ascorbic acid 20 mg/kg p.o. for 15 days as a pretreatment followed by dox 2.5 mg/kg b.w., i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg body weight. Group V animals received dox 2.5 mg/kg b.w., i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg b.w. followed by ascorbic acid 20 mg/kg p.o for 15 days as post-treatment control (CR). The biochemical parameters such as tissue glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD), and enzyme biomarkers such as creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were monitored.

Results:

Pretreatment with ascorbic acid (20 mg/kg p.o.) significantly protected the myocardium from the toxic effect of dox (PR), by increasing the levels of antioxidant enzymes such as GSH, SOD, and CAT toward normal and decreased the levels of MDA, CPK, LDH, AST, and ALT as compared with dox-treated rats. Post-treatment with ascorbic acid to dox-treated group (CR) significantly increased the levels of tissue GSH, SOD, CAT and significantly decreased the level of MDA as compared with dox-treated group. It also reduced the severity of cellular damage of the myocardium as confirmed by histopathology. The restoration of the endogenous antioxidant system clearly depicts that ascorbic acid produced its protective effect by scavenging the reactive oxygen species.

Conclusion:

The results obtained in this study provide evidence for the usefulness of the ascorbic acid as a cardioprotective agent.     

Effect of cytochrome P450 inhibitors (diethyl dithiocarbamate, ketoconazole and grapefruit juice) on the pharmacokinetics of all-trans-retinoic acid

Diethyl dithiocarbamate (DEDTC) has been reported to be a more powerful inhibitor of all-trans-retinoic acid (ATRA) in vitro metabolism than the well-established cytochrome P450 (CYP) inhibitor ketoconazole (KC). In recent years grapefruit juice (GJ) has been shown to be able to increase the oral bioavailability of several drugs by inhibiting intestinal CYP. This study investigated the in vivo effect of these CYP inhibitors on the pharmacokinetics of ATRA. The latter was administered to rats as a constant-rate intravenous (i.v.) infusion (0.48 mg h(-1) kg(-1)) during 10 h and orally (1.6 mg kg(-1)). DEDTC (320 mg kg(-1) x 2 i.v., 6.4 and 32 mg kg(-1) per os (p.o.)) did not change the ATRA concentration-time profiles, whereas KC (320 and 32 mg kg(-1) p.o.)--with i.v. infused or orally dosed ATRA--increased the mean concentration-time curve value by 160% and 78%, respectively. A high dose of DEDTC (320 mg kg(-1) p.o.) caused a marked decrease in plasma levels of ATRA. GJ (6.4 ml kg(-1) p.o.) did not affect the plasma levels of ATRA. It is concluded that the in vivo effect of CYP inhibitors (DEDTC and KC) on the elimination rate of ATRA is qualitatively different from that expected from in vitro studies.     

Neuroprotective effect of sinapic acid in a mouse model of amyloid β1-42 protein-induced Alzheimer's disease

Sinapic acid (SA) is a phenylpropanoid compound with anti-inflammatory and neuroprotective activities. The neuroprotective effects of SA in a mouse model of amyloid β (Aβ)_1-42 protein-induced Alzheimer's disease (AD) were investigated. Mice received a bilateral injection of Aβ_1-42 protein into the hippocampus to verify the efficacy of SA. Mice were treated with SA (10 mg/kg/day, p.o.) for 7 days beginning immediately after Aβ_1-42 protein injection, and an acquisition trial of the passive avoidance task was conducted 1 h after the last administration of SA. Retention trial was conducted 24 h after the acquisition trial, and mice were sacrificed for immunohistochemistry immediately after the retention trial. SA rescued neuronal cell death in the hippocampal CA1 region and also attenuated the increase of iNOS expression, glial cell activations and nitrotyrosine expressions induced by Aβ_1-42 protein. SA significantly attenuated memory impairment in the passive avoidance task. These results suggest that SA ameliorated Aβ_1-42 protein-related pathology including neuronal cell death and cognitive dysfunction via its anti-oxidative and anti-inflammatory activities, and may be an efficacious treatment for AD.     

Effect of ambroxol, spirulina and vitamin-E in naphthalene induced cataract in female rats

Anticataract activity of Ambroxol, Spirulina and Vitamin E was examined using the naphthalene cataract model. Adult female albino rats of Wistar strain weighing between 180 and 220 grams were taken and divided into eight groups. Group I received light liquid paraffin 5 ml/kg/ day p.o. for 6 weeks. Group II received naphthalene solution 0.5 gm/kg/ day p.o. for first three days and 1 gm/kg/day p.o. thereafter for six weeks. Group III received Ambroxol suspension in 0.5% carboxy methyl cellulose (CMC) at the dose of 100 mg/kg/day p.o. alongwith naphthalene. Group IV received Spirulina in distilled water at the dose of 1500 mg/kg/ day p.o. alongwith naphthalene. Group V received Vitamin E emulsion at the dose of 50 mg/kg/day p.o. alongwith naphthalene. Group VI received Ambroxol alone at the dose of 100 mg/kg/day p.o. Group VII received Spirulina alone at the dose of 1500 mg/kg/day p.o. Group VIII received vitamin E alone at the dose of 50 mg/kg/day p.o. Lens glutathione, soluble protein and water content profiles revealed the preventive role of Ambroxol, Spirulina and Vitamin E in naphthalene-induced cataract in female rats.     

Ellagic acid mitigates sodium arsenite-induced renal and hepatic toxicity in male Wistar rats

Background

The aim of this study was to investigate the effect of ellagic acid (EA) on arsenic-induced renal and hepatic toxicity in rats.

Potential antidiabetic effect of the Semecarpus anacardium in a type 2 diabetic rat model

Semecarpus anacardium Linn. nut milk extract (SA) was evaluated for its antidiabetic role in type 2 diabetic rats. Type 2 diabetes was induced in rats by feeding high-fat diet for 2 weeks followed by single intraperitoneal injection of streptozotocin 35 mg/kg body weight. Diabetic rats were treated with SA orally at a dosage of 200 mg/kg body weight daily for 30 days. Metformin (500 mg/kg body weight, orally) was used as a reference drug. SA significantly (p < 0.05) reduced the blood glucose levels and decreased the levels of HbA1c and the glucose intolerance. SA treatment significantly (p < 0.05) decreased the increase in lipid profile. The levels of urea, uric acid and creatinine were restored to near normal levels when compared with control diabetic rats. The histopathological abnormalities were also found to be normalized after treatment with SA nut milk extract. The potential antihyperglycemic action of SA is plausibly due to its underlying antioxidant role.     

α-Chymotrypsin regulates free fatty acids and UCHL-1 to ameliorate N-methyl nitrosourea induced mammary gland carcinoma in albino wistar rats

This study was undertaken to investigate the effect of α-chymotrypsin on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized into four groups (six animals in each). Group I (sham control 0.9 % normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v.); Group III (α-chymotrypsin, 5 mg/kg, p.o.); Group IV (α-chymotrypsin, 10 mg/kg p.o.). Toxicity was induced by single i.v. injection of MNU followed by α-chymotrypsin supplementation therapy for 100 days. MNU treatment was evident with increased alveolar bud count, differentiation score, upregulated inflammatory enzymes markers (COX, LOX and NO) antioxidative stress markers (TBARs, SOD, catalase and GSH).MNU associated toxicity was also ascertained by PGP 9.5 and NF-κB expression in the mammary gland tissue followed by FAME analysis for fatty acid profiling. α-chymotrypsin afforded significant protection against the deleterious effects of MNU.     

Dose-dependent effects of intravenous alprazolam on neuroendocrine,biochemical, cardiovascular,and behavioral parameters in humans

Neuroendocrine, biochemical, cardiovascular, and behavioral parameters were assessed in seven normal volunteers for 2 h after intravenous administration of alprazolam (APZ). Three doses of APZ (0.003, 0.007, and 0.02 mg/kg) were administered to each subject in a random order with at least 4 days between infusions. Plasma growth hormone and sedation increased in a dose dependent manner after APZ, and there was a dose dependent change in the shape of the cortisol response to APZ. No dose-response relationships were evident for plasma ACTH and norepinephrine. These differences in dose-response relationships may reflect the involvement of multiple systems in controlling neuroendocrine, biochemical, and subjective responses to APZ infusion. The optimal dose of APZ needed to produce a neuroendocrine or behavioral change appears to differ depending on the parameter of interest.     

Two Formulations of Venlafaxine are Bioequivalent when Administered as Open Capsule Mixed with Applesauce to Healthy Subjects

Venlafaxine is a unique antidepressant approved for treatment of various depressive disorders. A single dose, cross-over bioequivalence study was performed with two different formulations of venlafaxine 150 mg extended-release capsules in which the contents of capsule were mixed with applesauce and administered to healthy subjects under fed condition. A total of 24 healthy adult male subjects participated in this randomized, single-dose, non-blinded, two-way crossover study conducted at a single centre and 23 subjects completed the study as per the study protocol. After an overnight fast of 10 h, a high-fat and high-calorie breakfast was served 30 min before dosing. The subjects then received a single dose of either formulation administered with apple sauce followed by 240 ml of water as per randomized schedule in each period separated by a washout period of 7 days. A series of blood samples were collected upto 72 h for estimation of venlafaxine and its active metabolite, O-desmethylvenlafaxine. The quantification of venlafaxine and O-desmethylvenlafaxine was done by LC-MS/MS method and pharmacokinetic and statistical analysis by WinNonlin^® 5.2 and SAS^® 9.1.3. The results of the study demonstrated bioequivalence of two formulations as the 90% confidence interval for the intra-individual mean ratio of log-transformed C_max, AUC_0-t and AUC_0-inf of the test to the reference formulation were found within the defined bioequivalence range of 80.00%-125.00%. Both the formulations were well tolerated. This alternative mode of administration may provide benefits to patients who have difficulty in swallowing the capsule as a whole.     

The protective effect of (4R)-hexahydro-7, 7-dimethyl-6-oxo-1, 2, 5-dithiazocine-4-carboxylic acid (SA3443), a novel cyclic disulfide, on acetaminophen-induced liver injury

Effects of (4R)-hexahydro-7, 7-dimethyl-6-oxo-1, 2, 5-dithiazocine-4-carboxylic acid (SA3443) on acetaminophen-induced liver injury were investigated in BALB/c mice. SA3443 (30-300 mg/kg, p.o.) dose-dependently suppressed the elevation of serum transaminase activities and the histological changes of liver induced by acetaminophen (150 mg/kg, p.o.). The compound at the same doses also reduced the mortality due to the lethal acute hepatic failure induced by acetaminophen (350 mg/kg, p.o.). Other hepatoprotective agents, cianidanol (500 mg/kg, p.o.), malotilate (100 mg/kg, p.o.), grycyrrhizine (10 mg/kg, i.p.) and cysteine (300 mg/kg, p.o.) similarly reduced it. SA3443 had no effect on glutathione (GSH) contents in the liver of normal mice, but it dose-dependently suppressed the decrease of GSH contents in the liver of BALB/c mice treated with acetaminophen. These results suggest that SA3443, a novel cyclic disulfide, provides considerable protection against acetaminophen-induced liver injury and that one of the modes of the hepatoprotective action of this compound is suppression of the decrease of GSH contents in the liver.     

The effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan

Losartan, a selective angiotensin receptor antagonist, is mainly metabolized by CYP2C9 to an active carboxylic acid, E3174, which is pharmacologically more potent inhibitor than the parent compound. We evaluated the effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan and E3174, which were measured by high performance liquid chromatography in human volunteers and rats. A randomized crossover design study with two phases was done in the volunteer study. In the first phase, the volunteers received losartan 25 mg alone orally (LOS group), and, in the second phase, losartan 25 mg was given after repeated oral administration of 300 mg bucolome for 7 days (LOS+BUC group). In the LOS group, the maximum concentration (C(max)) and area under the concentration curve (AUC) of losartan were significantly higher than in the LOS+BUC group. On the other hand, in the LOS+BUC group, the C(max) and AUC of E3174 were significantly lower than in the LOS group. In the rat study, male Wistar ST rats were used. In the first phase, the rats orally received losartan 10 mg/kg alone or after bucolome was given repeatedly at a dose of 20, 50, or 200 mg/kg for 7 days. In the second phase for steady state, the rats were given losartan 10 mg/kg for 14 days (group A) or losartan 10 mg/kg and bucolome 50 mg/kg for 14 days (Group B). Bucolome at doses 50 and 200 mg/kg significantly increased the AUC losartan and significantly decreased the AUC of 3174. At the steady state, there were no significant differences in AUC of losartan between Group A and B, but the C(max) and AUC of E3174 were significantly lower in Group B than Group A.     

Self-administered ethanol as a discriminative stimulus in rats.

The neurochemical and behavioral effects produced by drugs can differ based on whether self-administered or experimenter-administered. In addition, self-administered drugs, particularly those taken orally or by inhalation, have peripheral stimulus effects that are not present following experimenter administration. One drug with highly prominent peripheral stimulus effects when taken orally is ethanol. The purpose of the present experiment was to examine whether orally self-administered (SA) ethanol would serve as a discriminative stimulus and to determine if the peripheral effects of ethanol play a major role in the discriminative stimulus of orally SA ethanol. Twelve Long-Evans rats were trained to orally self-administer 750 mg/kg of 10% (w/v) ethanol and then discriminate that dose of ethanol from SA water. Six of twelve rats were successfully trained to discriminate oral SA ethanol from water. Intraperitoneal experimenter-administered and orally SA ethanol doses of 100-1320 mg/kg were tested for substitution. SA and i.p. ethanol doses of 750, 1000, and 1320 mg/kg fully substituted for the SA training dose. SA doses of 100, 320 and 560 mg/kg partially substituted for the SA ethanol training dose, whereas the 100 and 320 mg/kg i.p. ethanol doses did not substitute for SA ethanol. The ED(50) values for SA and i.p. ethanol were not significantly different from one another. The results indicate that SA ethanol can serve as a discriminative stimulus in rats and that i.p. ethanol can substitute for SA ethanol. In addition, the results also show that the discriminative stimulus effects of SA ethanol are primarily mediated by CNS drug effects.     

Stress‐induced cardiac insufficiency relating to abnormal leptin and FKBP12.6 is ameliorated by CPU0213, an endothelin receptor antagonist,which is not affected by the CYP3A suppressing effect of erythromycin

Objectives Cardiac injury induced by isoprenaline produces stress. This stress can be mediated by the activated endothelin and leptin pathway; thus, the endothelin receptor antagonist CPU0213 may reverse these changes. CPU0213 is metabolized mainly by cytochrome P450 (CYP)3A, thus, erythromycin, an inhibitor of CYP3A, could affect its effects by raising its plasma levels. Methods Forty rats were divided into five groups. Group 1 rats were normal. Group 2 rats were administered isoprenaline (1 mg/kg, s.c.) for 10 days. Groups 3, 4 and 5 were administered isoprenaline, but group 3 was given erythromycin (100 mg/kg, p.o.) alone on days six to ten, group 4 was given CPU0213 20 mg/kg (s.c.) on days six to ten, whilst group 5 received erythromycin plus CPU0213 on days six to ten. Measurements were conducted to observe changes in the haemodynamics, cardiac weight index, serum lactate dehydrogenase and creatine kinase levels, and expression of endothelin receptor A (ET_a ), leptin and its OBRb receptor. Key findings In isoprenaline‐treated rats, cardiac hypertrophy and dysfunction were found. This was associated with upregulated myocardial leptin protein and OBRb receptor mRNA. Immunohistochemical assay of ET_a was upregulated, accompanied with downregulation of FKBP12.6 (calstabin 2) in isoprenaline‐treated rats. These effects were significantly reversed by CPU0213. HPLC assay presented an increased plasma level of CPU0213 by erythromycin, but no change in its effects. Conclusions CPU0213 improved isoprenaline‐induced cardiomyopathy by modulating ET_a , leptin and FKBP12.6. However, erythromycin increased plasma levels but did not change its effects.     

Pharmacokinetic interactions of Mentat with carbamazepine and phenytoin.

In the present study, Mentat, a herbomineral psychotropic preparation, was studied for its pharmacokinetic interaction with the commonly used anti-epileptic drugs, carbamazepine and phenytoin. The interaction of carbamazepine and phenytoin with Mentat was studied in rabbits. Thirty two rabbits were divided into four groups of eight each. Animals of Group I were treated with carbamazepine (50 mg/kg b.wt. p.o.), Group II were treated with carbamazepine (50 mg/kg b.wt. p.o.) + Mentat (500 mg/kg b.wt. p.o.), Group III were treated with phenytoin (50 mg/kg b.wt. p.o.) and Group IV were treated with phenytoin (50 mg/kg b.wt. p.o.) + Mentat (500 mg/kg b.wt. p.o.) for a period of 8 days. On day 0 and day 8, plasma carbamazepine and phenytoin levels were estimated at different time intervals. A simultaneous treatment with Mentat resulted in a significant increase in plasma AUC of carbamazepine as well as phenytoin as compared to carbamazepine or phenytoin alone. Cmax and Tmax of carbamazepine and phenytoin also were evaluated. The results suggest that co-administration of Mentat could improve the effectiveness of anti-epileptic drugs due to the increased bioavailability of the latter. However, this has to be done with critical medical supervision to avoid any toxic reactions and preferably with therapeutic drug monitoring (TDM) which could also help in dose optimization.     

Thymoquinone attenuates cyclophosphamide-induced pulmonary injury in rats

Objective

Antioxidant therapy may be useful in diseases with impaired oxidant–antioxidant balance. This study was designed to examine the effects of thymoquinone (TQ), an anti-inflammatory, antioxidant agent against cyclophosphamide (CP)-induced pulmonary oxidative damage.

Materials and methods

Male Sprague-Dawley rats were categorized into four groups. Group I was control. Group II received TQ (100 mg/kg/day, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received TQ for 7 consecutive days, before and after CP injection. The parameters of study were tissue oxidant/antioxidant biomarkers and histological changes in rat lungs.

Results

A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in the content of lipid peroxides in lung were seen that paralleled the decreased levels of reduced glutathione. Cyclophosphamide increased the level of serum biomarkers: total protein, lactate dehydrogenase, and tumor necrosis factor-alpha (TNF-α). Treatment of rats with TQ 7 days before and after cyclophosphamide injection significantly attenuated the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation and restoration of antioxidants. Moreover, TQ attenuated the secretion of pro-inflammatory cytokine, TNF-α in rat serum. In addition, TQ effectively alleviated CP-induced histopathological changes in lung tissue.

Discussion and conclusion

Our results suggest that TQ produces a protective mechanism against CP-induced pulmonary damage and suggest a role of oxidative stress and inflammation in the pathogenesis.     

Antinociceptive effect of trans-resveratrol in rats: Involvement of an opioidergic mechanism

trans-Resveratrol, a polyphenolic compound with potent antioxidant activity has recently been shown to be effective against carrageenan-induced hyperalgesia. In the present study, the effect of graded doses of trans-resveratrol was studied using a hot plate analgesiometer in rats. trans-Resveratrol at graded doses of 5, 10, 20 and 40 mg/kg i.p. produced dose-dependent analgesia. Pretreatment (20 min) with naloxone (1 mg/kg i.p.) blocked the analgesic effect. When the submaximal dose of trans-resveratrol (5 mg/kg i.p.) was combined with a submaximal dose of morphine (2 mg/kg i.p.), a potentiation effect was observed. The effect of trans-resveratrol (20 mg/kg i.p.) was also studied on morphine tolerance. Rats were divided into different groups: Group 1: morphine (10 mg/kg i.p.); Group 2: trans-resveratrol (5 mg/kg i.p.) administered 10 min before morphine (2 mg/kg i.p.); Group 3: trans-resveratrol (20 mg/kg i.p.) per se. Vehicle treated groups were run parallel. The treatment continued for 7 days. The occurrence of tolerance was estimated by comparing the antinociceptive effect of morphine with trans-resveratrol on day 1 and day 8. Both morphine and trans-resveratrol produced tolerance. However, in the group that received the combination of submaximal doses of trans-resveratrol and morphine, there was insignificant tolerance. These findings suggest that trans-resveratrol analgesia is mediated via an opioidergic mechanism and produces tolerance to its analgesic effect similar to morphine.     

Tolerance of haloperidol catalepsy

Haloperidol (0.75 and 1.5 mg/kg p.o.) was administered daily for 16 days to male Wistar rats. The animals received an acute injection of haloperidol (0.5-2.0 mg/kg i.p. or 1.0-4.0 mg/kg p.o.) and catalepsy was measured. After 16 days on haloperidol, all animals became tolerant to the drug, exhibiting decreased cataleptic response to haloperidol; the intensity of catalepsy returned to normal after an additional 16 days abstinence from the drug. In addition, a group of animals treated and tested daily for catalepsy demonstrated that the time course of tolerance development to haloperidol was biphasic, with a rapid phase (T1/2 = 2.5 days) and a slower phase (T1/2 = 5.5 days).     

Characterization of anticonvulsant and antiepileptogenic potential of thymol in various experimental models

The present study was to investigate the anticonvulsant and antiepileptogenic potential of thymol. Anticonvulsant activity of thymol (5–100 mg/kg i.p.) was studied using maximal electroshock, pentylenetetrazole (PTZ), strychnine and 4-aminopyridine (4-AP) models. Thymol at the selected dose was also studied for its effect on locomotion. Antiepileptogenic property of thymol (5–25 mg/kg) was evaluated using PTZ-induced kindling model along with its effect on malondialdehyde and glutathione levels. Thymol (50 and 100 mg/kg, i.p.) showed anticonvulsant activity against maximal electroshock and pentylenetetrazole (66.66 and 83.33 % protection at 50 and 100 mg/kg, respectively) model but not against strychnine and 4-aminopyridine models. Thymol exhibited decreased locomotor activity in dose-dependent manner at the same dose range. Thymol at the dose of (25 mg/kg, i.p.) significantly decreased the seizure score, increased glutathione levels and decreased malondialdehyde levels in pentylenetetrazole-induced kindling model. Thymol exhibited significant anticonvulsant and antiepileptogenic property.     

A study on the disulfiram-like reaction of T-2588. Influence of the consecutive administration of T-2588 on hepatic alcohol dehydrogenase and aldehyde dehydrogenase activities and blood levels of ethanol and acetaldehyde

A study on disulfiram-like reaction of T-2588 was carried out using Sprague-Dawley male rats. A 500 mg/kg/day dose of T-2588 was given orally to 14 male rats once daily for 7 days. Disulfiram (200 mg/kg/day X 3 days, p.o.), cephalexin (CEX) (500 mg/kg/day X 7 days, p.o.) and cefmetazole (CMZ) (500 mg/kg/day X 7 days, i.v.) were used as the positive control and 2 comparative controls, respectively. The results obtained were summarized below. Each parameter (aldehyde dehydrogenase activity and the blood aldehyde level) in the disulfiram-like reaction was not affected by the T-2588 administration. A marked inhibition of aldehyde dehydrogenase activity (low-Km ALDH, Enzyme I) and a significant increase of the blood aldehyde level were observed in the rats receiving disulfiram. No drug-related disulfiram-like reaction was induced in the male rats receiving CEX, while alterations similar to the disulfiram action were recognized in rats receiving CMZ.