PROSPECTS FOR CREATION OF RADIOPROTECTIVE MEANS BASED ON NATURAL POLYPHENOLS AND POLYSACCHARIDES. / PERSPEKTYVY STVORENNIa ZASOBIV RADIOZAKhYSNOÏ DIÏ NA OSNOVI KOMPOZYTsII PRYRODNYKh POLIFENOL'NYKh SPOLUK I POLISAKhARYDIV.

The high level of nuclear radiation threats in the modern world determines the need to find new means of pharmacological protection of the health of military personnel and civilians from the effects of ionizing radiation. Of particular scientific interest in this aspect are natural polyphenols as a promising basis for the development of newdrugs, radiomodifiers. OBJECTIVE: Justification of the prospects of creating radioprotective agents based on compositions of plantpolyphenolic substances (PPS) and polysaccharides. MATERIAL AND METHODS: The experiments were performed on 130 laboratory white rats-male of Wistar line sexually mature weighting 180-240 g. Animals once received a total X-ray dose equivalent to 4.25 Gy. The effects ofquercetin and patulaten to the processes of reparative regeneration under conditions of X-ray irradiation andagainst the background of butadione suppression were investigated. Indicators in the study groups were compared using the Student's t-test for independent samples; the differences were considered statistically significantat p < 0.05. RESULTS: The various biological properties of quercetin, in particular, the ability to bind hydroxyl radicals, is thepotential for developing radioprotective agents based on it. At the first stage of the study, the effect of PPS andtheir compositions with polysaccharides on reparative regeneration was studied against the background of its suppression in intact and irradiated animals. With the oral administration of PPS and their compositions with pectin towhite rats, 30 minutes before the administration of butadion, an increase in the processes of reparative regeneration in the cells of the covering epitheliumof the esophagus was observed. At the same time, quercetin granulescaused the most expressive effect, which increased the statistically significant value of the mitotic index by 78.5 %in relation to the group of animals injected with butadion. At the second stage of the study, the effect of polyphenolic substances and their compositions with pectin on the processes of reparative regeneration in intact and irradiated white rats was studied on a model of linear skin wounds. The prophylactic administration of quercetin granules and the treatment of wounds with 20 % sterile quercetin gel significantly accelerated the healing process.Experimental data indicate that quercetin granules have the ability to stimulate the processes of reparative regeneration, quercetin showed the greatest efficiency with simultaneous use inside and topically. CONCLUSIONS: The research results indicate the promise of developing radioprotective drugs that can stimulatereparative regeneration processes based on compositions of plant polyphenolic substances and polysaccharides invarious qualitative and quantitative ratios.

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance.

At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control.

[Analgesic activity of the aqueous extract from Ximenia Americana]. / Activité analgésique de l'extrait aqueux de Ximenia americana (Linné) (Olacaceae).

Pharmacological studies were conducted with the aqueous extract of the bark of the stem of Ximenia americana Linne (Olacaceae) on experimental animals, evaluating the analgesic activities. In the analgesic test, the aqueous extract elicited an inhibitory intensity on the acetic acid-induced writhing response and on the late phase of the formalin test, but possessed only a weak effect on the tail-flick response and on the early phase of the formalin test.

Evaluation of anti-inflammatory activity of Calotropis gigantea (AKANDA) in various biological system.

To evaluate the effect of Calotropis G in various experimental animal models. The anti-inflammatory activity was evaluated using carrageenin-induced kaolin -induced rat paw oedema for acute and cotton-pellet granuloma, adjuvant-induced arthritis model for chronic inflammation. Antipyretic activity was carried out using yeast induced pyresis method. Phenylquinone--induced writhing method in mice was used for analgesic activity. Test compounds exhibited variable anti-inflammatory activity and peak activity of the test compounds were reached at 2 h. Alkaloid fraction possesses comparatively high initial anti-inflammatory activity. The residual anti-inflammatory activity of alkaloid fraction of Calotropis G suggest either a greater protein binding nature of the compound there by providing a slow released pool of active drug molecule in the system or non available of possible bioactive metabolites to retain the activity profile relation.

Effects of the Geiji-Bokryung-Hwan on carrageenan-induced inflammation in mice and cyclooxygenase-2 in hepatoma cells of HepG2 and Hep3B.

We investigated the effects of a Korean traditional prescription, Geiji-Bokryung-Hwan (GBH) consisting of five herbs of Cinnamomi Ramulus (Korean name Geiji), Poria cocos (Bokryung), Moutan Cortex Radicis (Modanpi). Paeoniae Radix (Jakyak) and Persicae Semen (Doin) on tumor growth-inhibitory activity and cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Effects of the GBH extracts on carrageenan-induced edema inflammation using female (C57BL/6XC3H) F1 (B6C3F1) mice and tumorigenesis were examined. Finally, cyclooxygenase metabolites were determined after extracts treatment. These data suggest that GBH extracts merits investigation as a potential cancer chemopreventive agent in humans.

Effect of 14-deoxyandrographolide on calcium-mediated rat uterine smooth muscle contractility.

In this study, the effect of 14-deoxyandrographolide (14-DAP) on calcium channel-dependent rat uterine smooth muscle contraction was evaluated. Using a tissue bath preparation, 14-DAP was able to reduce the contractile response to 0.3 and 3.0 mm of CaCl(2), with an IC(50) of 1.24 +/- 0.23 x 10(-5) m and 5.94 +/- 0.29 x 10(-5) m, respectively. 14-DAP shifted the CaCl(2) cumulative dose response curve to the right, increasing the EC(50) from 2.08 +/- 0.20 x 10(-4) m to 4.22 +/- 0.22 x 10(-4) m (5 micrometer 14-DAP) and 2.5 +/- 1.0 x 10(-3) m (50 micrometer 14-DAP). In order to determine if 14-DAP had any effect on intracellular calcium, the relaxant response to 14-DAP following contraction by oxytocin, PGF(2alpha) and vanadate in Ca(+2)-free solution was compared with that of isoproterenol and phenylbutazone. While isoproterenol and phenylbutazone relaxed the smooth muscle in a dose-dependent manner, 14-DAP did not have any effect on either the oxytocin, PGF(2alpha) or vanadate-induced smooth muscle contraction. Based on these data, it appears that 14-DAP is an uterine smooth muscle relaxant which produces a selective blockade of voltage operated calcium channels.

Antiinflammatory and antiulcer activities of Bambusa arundinacea.

The extracts of Bambusa arundinacea have been used in Indian folk medicine to treat various inflammatory conditions. The plant has got antiulcer activity also. It is thought that these two properties in the same extract are very much useful in the treatment of inflammatory conditions. It is well known fact that the most of the available antiinflammatory drugs are ulcerogenic. The antiinflammatory effect of the methanol extract of the leaves of Bambusa arundinacea against carrageenin-induced as well as immunologically induced paw oedema and also its antiulcer activity in albino rats have been studied and found to be significant when compared to the standard drugs. The combination of methanol extract and phenylbutazone (Non-Steroidal Antiinflammatory Agent, NSAIA) has been studied and found to be the most potent antiinflammatory activity experimentally with least toxic (no ulcerogenic) activity. Thus, the combination of herbal product (methanol extract of Bambusa arundinacea) with modern medicine (NSAIAs) will produce the best antiinflammatory drug and will be useful for long-term treatment of chronic inflammatory conditions like rheumatoid arthritis with peptic ulcer, which are common.

The analgesic, antipyretic and anti-inflammatory activity of Diospyros variegata Kruz.

Pharmacological studies were conducted with the hexane extract of the dry stem of Diospyros variegata Kruz. (Ebenaceae) on experimental animals for evaluating the analgesic, antipyretic and anti-inflammatory activities. In the analgesic test, the hexane extract elicited inhibitory intensity on acetic acid-induced writhing response and on the late phase of formalin test but possessed only a weak effect on the tail-flick response and on the early phase of formalin test. The hexane extract also elicited antipyretic action when tested in yeast-induced hyperthermia in rats. In addition, the hexane extract showed an anti-inflammatory effect when tested in ethyl phenylpropiolate (EPP)- and arachidonic acid (AA)-induced rat ear edema.

Anti-inflammatory evaluation of Ficus racemosa Linn. leaf extract.

The anti-inflammatory activity of Ficus racemosa extract was evaluated on carrageenin, serotonin, histamine and dextran-induced rat hind paw oedema models. The extract at doses of 200 and 400 mg/kg has been found to possess significant anti-inflammatory activity on the tested experimental models. The extract (400 mg/kg) exhibited maximum anti-inflammatory effect, that is 30.4, 32.2, 33.9 and 32.0% at the end of 3 h with carrageenin, serotonin, histamine, dextran-induced rat paw oedema, respectively. In a chronic test the extract (400 mg/kg) showed 41.5% reduction in granuloma weight. The effect produced by the extract was comparable to that of phenylbutazone, a prototype of a non-steroidal anti-inflammatory agent.

Anti-inflammatory activity of Pothomorphe peltata leaf methanol extract.

The methanol extract of Pothomorphe peltata leaves, orally administered at the dose of 20 mg/kg (equivalent to 2.50 g dry plant/kg) body weight, exhibited a significant anti-inflammatory activity, comparable with phenylbutazone (80 mg/kg, p.o.), against adjuvant-carrageenan-induced edema in rats.

A reporter gene assay to assess the molecular mechanisms of xenobiotic-dependent induction of the human CYP3A4 gene in vitro.

1. A plasmid containing 1 kb of the CYP3A4 regulatory (promoter) region coupled to a reporter gene for secretary placental alkaline phosphatase (SPAP) was transfected into HepG2 cells. Transfected cells were dosed with several known inducers of CYP3A4 and the levels of SPAP were measured. The effect of co-transfecting a plasmid encoding the human glucocorticoid receptor on reporter gene activity was also examined. 2. Dexamethasone induced CYP3A4-dependent reporter gene expression in a concentration-dependent manner and induction was approximately doubled in the presence of the glucocorticoid receptor. Dexamethasone-dependent induction was blocked by RU-486 (a glucocorticoid receptor antagonist), in the presence of the co-transfected glucocorticoid receptor. 3. Induction of CYP3A4-dependent reporter gene expression and enhancement of the induction by the glucocorticoid receptor was also observed with pregnenolone-16alpha-carbonitrile (PCN), rifampicin, phenytoin, carbamazepine, phenylbutazone and phenobarbitone, all known in vivo inducers of CYP3A4 in man. 4. Metyrapone and sulfinpyrazone induced CYP3A4-dependent reporter gene expression, but induction was not enhanced by the glucocorticoid receptor. 5. Clotrimazole, erythromycin and triacetyloleandomycin (TAO) did not induce CYP3A4-dependent reporter gene expression, consistent with the observation that these inducers act through post-transcriptional mechanisms. 6. These results highlight differences in the molecular mechanisms of induction of CYP3A4 by the xenobiotics studied and indicate that the glucocorticoid receptor is involved in the induction of the CYP3A4 gene by some, but not all, CYP3A4 inducers. 7. We propose that the approach described here provides a useful in vitro approach for the identification of transcriptional regulators of the CYP3A4 gene.

Anti-inflammatory activity of the bark of Hippocratea excelsa.

The ethanol extract of the plant Hippocratea excelsa was examined for its anti-inflammatory effects using several animal models. It produced significant inhibition of carrageenan-induced paw edema and reduced the weight of cotton pellet-induced granuloma at doses of 25-100 mg/kg. The extract was found to exert a protective effect on heat-induced erythrocyte lysis at concentrations of 25, 50 and 100 micrograms/ml. In chronic models of formaldehyde and adjuvant arthritis, its anti-arthritic activity was found to be less than that of phenylbutazone (PNB). It may be inferred that the ethanol extract is effective against both exudative-proliferative and chronic phases of inflammation.

Pharmacology of the potent new non-steroidal anti-inflammatory agent aceclofenac.

Aceclofenac (2-[(2,6-dichlorophenyl) amine]phenylacetoxyacetic acid; CAS 89796-99-6) is a new orally effective non-steroidal anti-inflammatory agent of the phenylacetic acid group which showed remarkable anti-inflammatory, analgesic, and antipyretic properties. Hence, aceclofenac possesses a potent inhibitory activity in several models of acute and chronic inflammation in rodents, and resembles indometacin and diclofenac in its pharmacodynamic profile, being superior to naproxen and phenylbutazone. In addition, aceclofenac was found to be highly active against sodium urate-induced synovitis in dogs and adjuvant-induced polyarthritis in rats, both prophylactically and therapeutically. The analgesic effect of aceclofenac on the pain elicited by chemical and mechanical stimuli was nearly equal to or slightly better than that of indometacin and diclofenac. Fever induced by brewer's yeast injection in rats was also markedly suppressed by aceclofenac. In contrast, the acute gastric ulcerogenic activity of aceclofenac was about 2, 4 and 7-fold lesser than that of naproxen, diclofenac, or indometacin, respectively. As a consequence of its high anti-inflammatory activity and lower potential for gastric damage aceclofenac exhibited the most favourable therapeutic ratio in comparison with indometacin, diclofenac, naproxen, and phenylbutazone. These data indicate that aceclofenac could be a potent anti-inflammatory and analgesic agent with a wide margin of safety in clinical practice.

Antiinflammatory evaluation of a Pluchea indica root extract.

A methanolic fraction of a chloroform extract of defatted Pluchea indica roots was investigated for its antiinflammatory potential against several models of inflammation. The extract showed significant inhibitory activity against carrageenin-, histamine-, serotonin-, hyaluronidase- and sodium urate-induced pedal inflammation. The extract inhibited protein exudation and leucocyte migration. The extract also inhibited carrageenin- and cotton pellet-induced granuloma formation as well as turpentine-induced joint oedema and adjuvant-induced polyarthritis. The present observations establish the efficacy of the extract in the exudative, proliferative and chronic stages of inflammation.

Anti-inflammatory activity of some copper(II) complexes.

Anti-inflammatory activity of some copper(II) neutral complexes and complexated salts on different animal models of inflammation has been investigated. In a preliminary screening 5 complexes were selected for a more extensive study based on their capacity inhibiting the rat hind paw edema induced by carrageenin. These selected complexes showed inhibitory action on acute and subacute inflammation with an activity degree higher than that of indometacin. They were also effective inhibitors of primary and secondary lesions in the adjuvant-induced arthritis, with an activity similar to phenylbutazone. These complexes had no topical anti-inflammatory effect.

Anti-inflammatory activity of Echinops echinatus.

Anti-inflammatory studies were conducted on an ethanol extract of Echinops echinatus whole plant. The extract effectively inhibited the acute inflammation induced in rats by carrageenan, formaldehyde and adjuvant and the chronic arthritis induced by formaldehyde and adjuvant. The extract was more effective parenterally than orally. The toxicity studies showed reasonable safety warranting further studies.

Effect of Withania somnifera on glycosaminoglycan synthesis in carrageenin-induced air pouch granuloma.

The effect of W. somnifera on glycosaminoglycan synthesis in the granulation tissue of carrageenin-induced air pouch granuloma was studied. W. somnifera was shown to exert significant inhibitory effect on incorporation of 35S into the granulation tissue. The uncoupling effect on oxidative phosphorylation (ADP/O ratio reduction) was also observed in the mitochondria of granulation tissue. Further, Mg2+ dependent ATPase activity was found to be influenced by W. somnifera. W. somnifera also reduced the succinate dehydrogenase enzyme activity in the mitochondria of granulation tissue.

Biochemical modes of action of Cassia occidentalis and Cardiospermum halicacabum in inflammation.

The anti-inflammatory activity of Cassia occidentalis leaf powder and an ethanol extract of Cardiospermum halicacabum aerial parts were assayed in male albino rats using carrageenan-induced rat paw edema. C. occidentalis was maximally active at a dose of 2000 mg/kg, while the C. halicacabum extract was maximally effective at a dose of 500 mg/kg. In the cotton pellet granuloma assay, these drugs were able to suppress the transudative, exudative and proliferative components of chronic inflammation. Further, these drugs were able to lower the lipid peroxide content and gamma-glutamyl transpeptidase and phospholipase A2 activity in the exudate of cotton pellet granuloma. The increased alkaline phosphatase activity and decreased A/G ratio of plasma in cotton pellet granulomatous rats were normalized after treatment with these drugs. C. occidentalis powder and C. halicacabum extract were able to stabilize the human erythrocyte membrane against hypotonicity-induced lysis. It is likely that these drugs may exert their anti-inflammatory activity by inhibition of phospholipase A2, resulting in the reduced availability of arachidonic acid, a precursor of prostaglandin biosynthesis, and/or by stabilization of the lysosomal membrane system.

Analgesic, antipyretic and ulcerogenic activity of Nyctanthes arbor tristis leaf extract.

The leaves of Nyctanthes arbor tristis, besides being used in the treatment of sciatica and arthritis, are advocated for various kinds of fevers and painful conditions by the Ayurvedic physicians. In the present study, the water-soluble portion of an ethanol extract of the leaves was screened for analgesic, antipyretic and ulcerogenic activities. The extract exhibited significant aspirin-like antinociceptive activity but failed to produce morphine-like analgesia. It was also found to possess antipyretic activity against brewer's yeast-induced pyrexia in rats. The extract also produced gastric ulcers following oral administration for six consecutive days in rats. Results of the present study tend to substantiate the use of this plant in fevers and painful conditions by Ayurvedic physicians.