Hepatoprotective potential of aqueous extract of Butea monosperma against CCl(4) induced damage in rats.

Aqueous extract of flowers of Butea monosperma (Fabaceae) was evaluated at different dose levels (200, 400, 800 mg/kg, p.o.) for its protective efficacy against CCl(4) (1.5 ml/kg i.p.) induced acute liver injury to validate its use in traditional medicines. The CCl(4) administration altered various biochemical parameters, including serum transaminases, protein, albumin, hepatic lipid peroxidation, reduced glutathione and total protein levels, which were restored towards control by therapy of B. monosperma Adenosine triphosphatase and glucose-6-phosphatase activity in the liver were decreased significantly in CCl(4) treated animals. Therapy of B. monosperma showed its protective effect on biochemical and histopathological alterations at all the three doses in dose dependent manner. B. monosperma extract possess modulatory effect on drug metabolizing enzymes as it significantly decreased the hexobarbitone induced sleep time and increased excretory capacity of liver which was measured by BSP retention. Histological studies also supported the biochemical finding and maximum improvement in the histoarchitecture was seen at higher dose of BM extract.

[Repellent effect of volatile oil from whitefly (Syngonium podophyllum) on aphids and its chemical constituents].

The interference effect of volatile oil from whitefly (Syngonium podophyllum) on aptera aphid, guard aphid (Aphis gossypii), mustard aphid (Lipaphis erysimi) and red peach aphid (Myzus persicae) was studied by using four arms olfraetometes. The results showed that the volatile oil had distinct repelling effect. The staying periods of test aphids in test areas were obviously shorter than in control areas, and the selecting frequencies were less than the control, too. The volatile oil did not show repelling effect on red peach aphid at the test concentrations. The components of the volatile oil from S. podophyllum were analysed by GC-MS. 43 constituents were identified.

Safety pharmacology of CKD-602, a novel anticancer agent.

CKD-602 ((20S)-7-[2-(N-isopropylamino)-ethyl]-camptothecin.HCl, CAS 213819-48-8) is a new class of anticancer drug that belongs to the topoisomerase inhibitors. Its effect on the central nervous system (CNS), general behavior, cardiovascular-respiratory system and the other organ systems were studied. When intravenously administered, CKD-602 up to doses of 5 mg/kg caused an increase of body temperature, increase of respiration rate, decrease of gastrointestinal transport, showed analgesic action and produced antisecretory action in pylorus ligated rats. However, CKD-602 showed no effects on general behavior, motor coordination, spontaneous locomotor activity, hexobarbital sleeping time, convulsion, cardiovascular, smooth muscle and urinary tract system. These findings demonstrate that CKD-602 in doses up to 5 mg/kg has minor effects on the CNS in animals. However, CKD-602 does not exert any general pharmacological effects at the dose of 1 mg/kg except the effects on gastric secretion.

Evaluation of toxic activity of 2,4-dihydroxythiobenzanilides.

2,4-Dihydroxythiobenzanilides represent a new group of compounds with significant fungistatic and bacteriostatic properties. The results of investigations on their cytotoxicity are also very convincing. Therefore LD50 doses were determined for five compounds, they ranged from 239 to 840.5 mg/kg. The results of the tests for spontaneous locomotor activity and hexabarbiturane sleeping time indicate low toxicity of the compounds tested.

[Modulation by ultralow intensity electromagnetic fields on pharmacologic effects of psychotropic drugs]. / Moduliruiushchee vliianie élektromagnitnykh polei sverkhnizkoi intensivnosti na farmakologicheskie éffekty nekotorykh psikhotropnykh preparatov.

The ultralow-intensity electromagnetic fields (EMF, frequency of 4200, modulated by a quasistochastic signal in the range of 20-20,000 Hz, power density of 15 microW/cm2, specific body absorption rate up to 4.5 mJ/kg) potentiated the hypnogenic effect of hexenal. The exposure to the EMF shortened the time of falling asleep induced by this drug and increased sleep duration in rats. The exposure to the EMF also potentiated haloperidol catalepsy: it decreased the drug threshold dose and increased the catalepsy duration. The EMF influence on the haloperidol effects was of a prolonged character: it was manifest in a selected suppression of the emotional excitation in the open-field test within 24 hours after the exposure.

Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors.

LY354740 is a conformationally constrained analog of glutamate which is a potent agonist for group II cAMP coupled metabotropic glutamate receptors (mGluRs). The discovery of this novel pharmacological agent has allowed the exploration of the functional consequences of activating group II mGluRs in vivo. In an effort to evaluate the clinical utility of LY354740 as an anxiolytic, we examined its effects in the fear potentiated startle and elevated plus maze models of anxiety and compared the results with the clinically prescribed anxiolytic diazepam. In the fear potentiated startle and elevated plus maze models, both LY354740 and diazepam produced significant anxiolytic activity (ED50 values of 0.3 and 0.4 mg/kg p. o. for fear potentiated startle and 0.2 and 0.5 mg/kg for the elevated plus maze, respectively). The duration of pharmacological effect for LY354740 in the efficacy models was 4 to 8 hr. In contrast to diazepam, acute administration of LY354740 did not produce sedation, cause deficits in neuromuscular coordination, interact with central nervous system depressants, produce memory impairment or change convulsive thresholds at doses 100- to 1000-fold the efficacious doses in animal models of anxiety. Thus, LY354740 has anxiolytic activity in animal models that are sensitive to benzodiazepines such as diazepam. However, at anxiolytic doses in these models, LY354740 produced none of the unwanted secondary pharmacology associated with diazepam. These data indicate a functional role for group II mGluRs in fear/anxiety responses in animals and suggest that compounds in this class may be beneficial in the treatment of anxiety-related disorders in humans without the side effects seen with currently prescribed medications.

The upregulating effect of dexamethasone on tumor necrosis factor production is mediated by a nitric oxide-producing cytochrome P450.

Dexamethasone (DEX) is a well-known inhibitor of tumor necrosis factor (TNF) production when given shortly before lipopolysaccharide (LPS). However, DEX (10 mg/kg, ip) potentiates TNF production when administered 24-48 hr before LPS (16 micrograms/kg, ip). We have found that this is probably due to DEX induction of cytochrome P450 3A, which is known to produce nitric oxide (NO). The upregulating effect of DEX on TNF production is associated with increased NO production. Both the upregulation of NO and of TNF production by DEX are inhibited by co-administration of the P450 3A inhibitor troleandomycin (TAO, 40 mg/kg, ip). These data suggest that P450 3A-generated NO might be involved in TNF induction.

Synthesis and CNS activities of pyridopyrazinone and pyridodiazepinone derivatives.

New tricyclic derivatives with cyclocondensed pyrido-pyrazine 7,10 and pyrido-diazepine 20a,20b skeletons were synthetized and biologically investigated. The compounds, preliminarily tested on explorative, muscle relaxing, antinociceptive, spontaneous motor activities and influence on the narcotic effect of Evipan, revealed interesting CNS depressant and analgesic activities. The pyrido[2,3-e]pyrrolo[1,2-a]pyrazine structure of 7 appeared the most promising for analgesic and neuroleptic activities. The above compounds were assayed also for their capacity to inhibit DNA synthesis in Ehrlich ascites tumor cells; 20a appeared to be able of inducing a significant inhibition.

Role of endotoxin in alterations of hepatic drug metabolism by diphtheria and tetanus toxoids and pertussis vaccine adsorbed.

Administration of diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) or endotoxin (LPS) resulted in marked alterations in hepatic drug-metabolizing enzymes in endotoxin-responsive (R) and non-endotoxin-responsive (NR) mice. A single human dose (0.5 ml) of DTP vaccine increased hexobarbital-induced sleep times to 1.6- to 1.8-fold above those of controls in both strains of mice. This effect persisted for 7 days. In contrast, Bordetella pertussis LPS-treated mice showed an increase at 1 day (3.0-fold for R mice and 1.5-fold for NR mice), which returned to control levels by day 7. Furthermore, cytochrome P-450 levels were decreased 30 to 40% 24 h after DTP vaccine administration in both R and NR mice, while after LPS administration they were decreased 30% in R mice and less than 10% in NR mice. Both spleen and liver weights of R and NR mice were increased 7 to 14 days following DTP vaccine administration. However, LPS treatment had no apparent effect on liver weights, and spleen weights of R mice were elevated from days 3 to 7. Histopathologic tissue examination showed random, multifocal inflammation with hepatocyte necrosis after DTP vaccine administration to both R and NR mice and an absence of lesions in LPS-treated mice. Premixing LPS with polymyxin eliminated the increased sleep times, but premixing DTP vaccine with polymyxin did not affect the increased sleep times. Levels of tumor necrosis factor and interleukin-6 in plasma of R mice were markedly increased after DTP and LPS treatment, while NR mice had reduced increases. These results suggest that LPS contributes to the alterations in R and NR mice seen within the first 24 h of vaccine administration but that it is not likely to contribute to the effects observed at later time points.

Inhibition of hepatic drug biotransformation by carrageenan-induced inflammation in the rat: effect of sex hormone alterations.

Following in vivo treatment with carrageenan, sex-related differences in alteration of hepatic drug metabolism were found in the rat. In adult male rats, marked decreases were observed in hepatic 9000 x g supernatant cytochrome P-450 content and in the biotransformation of hexobarbital, aminopyrine, ethylmorphine, and meperidine. Hexobarbital hypnosis was significantly prolonged by carrageenan treatment in intact and testectomized animals as compared to their respective controls. Although carrageenan-treated intact animals slept 480% longer, carrageenan-treated testectomized rats slept only 60% longer than the respective control animals. However, testectomy or administration of 17 beta-estradiol to testectomized male rats did not inhibit the monooxygenase activities by carrageenan-treatment. Furthermore, administration of testosterone to ovariectomized female rats did not antagonize the inhibitory effects of the carrageenan-induced inflammation. The inhibitory effects produced by carrageenan-induced inflammation on the microsomal enzyme system were observed only in mature male rats and were not observed in mature female rats or in sexually immature rats of either sex. Thus, these results suggest that the inhibitory effects of carrageenan-induced inflammation on hepatic 9000 x g supernatant monooxygenases in the male rat are partially mediated through the toxic action of carrageenan-induced inflammation on androgen-dependent factors in this enzyme system.

[A comparative evaluation of the changes in the duration of "hexenal sleep" in acute radiation and combined radiation-thermal lesions]. / Sravnitel'naia otsenka izmenenii prodolzhitel'nosti "geksenalovogo sna" pri ostrykh luchevykh i kombinirovannykh radiatsionno-termicheskikkh porazheniiakh.

In experiments with Wistar rats it was found that the increase in the length of the "hexenal dream" during the first week after the effect of a mixture of radiation and heat is much more pronounced than that observed after exposure to radiation alone and independent of the severity of a radiation component (gamma radiation, 4, 6 and 7.5 Gy). The peculiarities revealed in the hypnotic effect of hexenal develop against the background of the postirradiation aggravation of hypoalbuminemia and decrease in the liver ATP.

General pharmacology of recombinant human tumor necrosis factor. 2nd communication: effects on central nervous system functions.

Effects of recombinant human Tumor Necrosis Factor (rHu-TNF, PT-050) administered s.c. and i.v. on the central nervous system were investigated behaviorally and physiologically in different animal species. With i.v. administration at doses of 10(4) U/kg and less, PT-050 produced no significant changes in most of behavioral and physiological tests, except that a transient increase in rectal temperature in dogs occurred with 0.765 x 10(4) U/kg and acetic acid-induced writhing syndrome in mice was inhibited with 10(4) U/kg. Locomotor activity in mice was inhibited after 3 x 10(4) U/kg. With 10(5) U/kg and more, in addition to the above effects, diverse effects were observed as follows: various symptoms were induced in general behavior in mice such as piloerection, catalepsy, lowering of body position, ptosis and pupil dilatation; rectal temperature was increased in rats and decreased in mice; cortical EEG was synchronized in hippocampal theta waves were disturbed in gallamine-immobilized cats. On the other hand, with s.c. administration, the effect on rectal temperature was seen at 10(4) U/kg in dogs and at 10(5) U/kg in rats. Cortical EEG in conscious rabbits was affected with 10(6) U/kg. At higher dose of 10(7) U/kg. PT-050 (s.c.) further influenced locomotor activity, rectal temperature and acetic acid-induced writhing syndrome in mice. However, even with 10(7) U/kg (s.c.), no effect was found in general behavior, rotarod performance and hexobarbital narcosis in mice. Thus, it is concluded that PT-050 has weaker effects on the central nervous system by s.c. route than by i.v. route. From the present findings and the efficacy of PT-050 as TNF, it is suggested that PT-050, when administered intratumorally, may be useful for cancer therapy without severe side effects.

Acetaminophen hepatotoxicity: is there a role for prostaglandin synthesis?

The hepatotoxicity of acetaminophen (APAP) overdose depends on metabolic activation to a toxic reactive metabolite via hepatic mixed function oxidase. In vitro studies have indicated that APAP may also be cooxidized by prostaglandin H synthetase. The present experiments were designed to assess the possible contribution of hepatic prostaglandin synthesis to APAP toxicity. Adult fed male mice were overdosed with 400 mg APAP/kg. Liver toxicity was estimated by measurement of serum transaminases. Hypertonic xylitol or sodium chloride (2250 mOsm/l), administered intragastrically to stimulate prostaglandin synthesis, increased APAP toxicity. By contrast, the cyclooxygenase inhibiting drugs aspirin (at 25 mg/kg) and indomethacin (at 10 mg/kg) protected against APAP-induced toxicity. APAP kinetics were not affected by hypertonic xylitol or indomethacin, nor were hepatic glutathione levels in overdosed mice. Imidazole, a nonspecific thromboxane synthetase inhibitor, also protected overdosed mice. This drug prolonged hexobarbital sleeping time and prevented the depletion of hepatic glutathione that followed APAP intoxication. Thus, the data support the conclusion that APAP-induced hepatoxicity may be modulated not only by inhibition of cytochrome P450 mediated oxidation, but also by controlling hepatic cyclooxygenase activity.

Isobolographic characterization of drug interactions incorporating biological variability.

Isobolograms have been widely used to characterize the nature of the interaction between combinations of drugs or chemicals. Some authors have applied this technique without accounting for the variability in the data or without adjusting for multiple comparisons to the line of additivity. This paper develops a graphical procedure which takes into account the variability of the data and which maintains favorable statistical properties. The isobolographic procedure utilized is illustrated by using three classical pharmacological drug combinations in female ICR mice. An additive relationship is illustrated with the loss of righting reflex after combinations of doses of sodium hexobarbital with itself. An antagonistic relationship is illustrated with the protection by mecamylamine of nicotine-induced lethality. A synergistic relationship is illustrated with the loss of righting reflex after combinations of ethanol and chloral hydrate. The procedure's statistical properties (level of significance and power) were determined using a simulation study. The isobolographic procedures developed here are applicable for quantal, continuous and count data. These procedures are applicable for identifying beneficial drug combinations, or conversely, identifying hazards resulting from exposure to multiple toxicants.

[The role of catecholaminergic synapses in the mechanisms of the formation of adaptation with the participation of polyphenol adaptogens]. / O roli katekholaminergicheskikh sinapsov v mekhanizme formirovaniia adaptatsii pri uchastii polifenol'nykh adaptogenov.

The analysis of the role of catecholaminergic synapses in the process of adaptation showed that the main point of the influence of polyphenolic adaptogens was a catechol-O-methyltransferase. Inhibiting the latter, the polyphenolic adaptogens exert a correcting effect on catecholaminergic (mainly dopaminergic) synapses and prevent the transmitter from reduction in them.

Influence of anaesthetics on the fibrinolytic activity in minipigs.

The activator of the fibrinolytic system measured in minipigs may be profoundly influenced by ether and halothane. Hexobarbital anaesthesia is recommended for studies where effects of fibrinolysis have to be measured. "Fibrinolytic shutdown" during anaesthesia may be prevented by prophylactic administration of a plasminogen activator releasing agent (pentosan polysulphate).

Cadmium sensitivity differences between liver microsomal drug metabolizing enzyme systems of guinea-pig and rat.

1. Male guinea-pigs (400-500 g) and rats (225-275 g) were given a single dose of cadmium chloride (CdCl2) (2 mg Cd2+/kg i.p.) and 72 hr later the liver microsomal drug metabolizing enzyme activities and Cd levels of tissues and microsomes were determined. 2. No significant differences were noted between Cd treated and control animal tissue weights of microsomal protein contents in either guinea-pigs or rats. 3. Cd treatment exhibited significant inhibition of the activities of aniline 4-hydroxylase and ethylmorphine N-demethylase and on the levels of cytochrome P-450 and cytochrome b5 of liver of both species but the degree of inhibition were not the same in the species; they were 23, 34, 16 and 10% in guinea-pigs and 58, 57, 25 and 13% in rats, respectively. 4. No activity changes were observed in liver NADPH-cytochrome c reductase of the species by Cd treatment. 5. The duration of hexobarbital sleeping time was significantly prolonged in both species. However, the prolongation was 1.6 fold in guinea-pigs but 3.4 fold in rats. 6. No significant differences were found between either tissue or microsomal Cd levels of guinea-pigs and rats.

[Interaction of the complex copper compound Cu-2 with liver monooxygenases]. / Vzaimodeistvie kompleksnogo soedineniia medi Cu-2 s monooksigenazami pecheni.

It has been shown that the antitumour drug Cu-2 (copper complex compound) inhibited the activity of liver monooxygenases in male CBA mice. The in vivo experiments have revealed a considerably increased duration of sleep in mice treated with hexenal after the administration of different Cu-2 doses. In vitro, after the incubation of intact mouse liver microsomal fractions with different concentrations of Cu-2 the level of cytochrome Y-450 was decreased and a non-active form of hemoprotein--cytochrome P-420--appeared. At the same time, after the incubation of Cu-2 with liver microsomal fractions stabilized by 20% glycerol type I spectral changes (Ks 330 microM) were registered. This shows the possible metabolism of Cu-2 by cytochrome P-450. The role of the revealed interaction of Cu-2 with liver microsomes is being discussed for the chemotherapy of cancer.