International regulatory guidelines require that new chemical entities (NCEs) be tested first on animals (preclinical studies) for safety and efficacy before the start of clinical development. Long-term nonclinical studies such as carcinogenicity testing, the subject of the present review, is conducted in tandem with on-going clinical studies. Over the last few years, a number of regulatory changes have occurred in the regulatory requirements of carcinogenicity testing and the use of such data in human risk assessment process. The efforts are to provide a better mechanistic basis in interpretation of standard lifetime and short-term rodent bioassays. The major areas of focus of this review include the basic considerations for the lifetime rodent bioassay, the recommendations of the International Conference on Harmonization (ICH), and the development and validation of new short-term or alternative models for carcinogenicity testing. The objectives of these guidelines are to avoid the unnecessary use of animals in testing and to provide consistency in world wide regulatory assessments of applications. It will ultimately improve the precision in carcinogenicity testing, minimize the time requirement for such testing, and help to conserve the resources in the process of drug discovery and development.

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Objective : To evaluate the wound healing activity of the leaf extracts and deoxyelephantopin isolated from Elephantopus scaber Linn. Materials and Methods : The effect of aqueous ethanol extracts and the isolated compound deoxyelephantopin from E. scaber Linn. (Asteraceae) was evaluated on excision, incision, and dead space wound models in rats. The wound-healing activity was assessed by the rate of wound contraction, period of epithelialization, skin-breaking strength, weight of the granulation tissue, and collagen content. Histological study of the granulation tissue was carried out to know the extent of collagen formation in the wound tissue. Results : The ethanol extract and the isolated constituent deoxyelephantopin of E. scaber promoted wound-healing activity in all the three wound models. Significant ( P <0.01) increase in the rate of wound contraction on day 16 (98.8%, P <0.01), skin-breaking strength (412 g, P <0.01), and weight of the granulation tissue on day 10 (74 mg/100 g, P <0.01) were observed with deoxyelephantopin-treated animals. In ethanol extract-treated animals, the rate of wound contraction on day 16, skin-breaking strength, and weight of the granulation tissue on day 10 ( P <0.01) were 92.4%, 380 g, and 61.67 mg/100 g, respectively. Histological studies of the granulation tissue also evidenced the healing process by the presence of a lesser number of chronic inflammatory cells, lesser edema, and increased collagenation than the control. Conclusion : The wound-healing activity was more significant in deoxyelephantopin-treated animals.

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Objective : To investigate the comparative wound-healing potency of aqueous and methanol leaf extracts of Vernonia arborea Hk. Materials and Methods : Excision, incision and dead space wound models were used to evaluate the wound-healing activity of Vernonia arborea Hk., on Swiss Wistar strain rats of either sex. In excision wound model, treatment was continued till the complete healing of the wound, in incision and dead space wound models the treatment was continued for 10 days. For topical application, 5% w/w ointment of aqueous and methanol leaf extracts was prepared in 2% sodium alginate and for oral administration suspensions containing 30 mg/ml of each of the extracts in 1% gum tragacanth were prepared. In excision and incision wound models, the control group of animals were left untreated and in dead space wound models the animals were treated with 1 ml of 1% gum tragacanth / kg, b.w. The healing of the wound was assessed by the rate of wound contraction, period of epithelialisation, skin breaking strength, granulation strength, dry granulation tissue weight, hydroxyproline estimation and histopathology of the granulation tissue. Results : Aqueous and methanol leaf extracts promoted the wound-healing activity significantly in all the wound models studied. High rate of wound contraction, decrease in the period for epithelialisation, high skin breaking strength and granulation strength, increase in dry granulation tissue weight, elevated hydroxyproline content and increased collagenation in histopathological section were observed in animals treated with methanol leaf extract and aqueous leaf extract when compared to the control group of animals. Conclusion : Methanol and aqueous leaf extracts of Vernonia arborea Hk. promote wound-healing activity. Methanol extract possesses better wound-healing property than the aqueous extract.

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Objective: To evaluate the antiplasmodial activity of leaf extract of Croton zambesicus on chloroquine-sensitive Plasmodium berghei berghei infection in mice and to confirm its traditional use as a malarial remedy in Africa. Materials and Methods : The ethanolic leaf extract of Croton zambesicus (50-200 mg/kg) was screened for blood schizontocidal activity against chloroquine-sensitive Plasmodium berghei berghei infection in mice. The schizontocidal activity during early and established infections as well as the repository activity were investigated. Results: The extract demonstrated a dose-dependent chemosuppression or schizontocidal effect during early and in established infections, and also had repository activity. The activity was lower than that of the standard drugs (chloroquine 5 mg/kg, pyrimethamine 1.2 mg/kg/day). Conclusion: The leaf extract possesses considerable antiplasmodial activity, which can be exploited in malaria therapy.

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Objective : To investigate the in vitro antioxidant activity of the hydromethanolic extract of aerial parts (leaves and stems) of Globularia alypum L. toward linoleic acid emulsion and human low-density lipoproteins (LDL) peroxidation. Materials and Methods : Lipid peroxidation was carried out in the presence of G. alypum hydromethanolic extract (10 and 100 µg of extract/ml). CuSO4 (10 µM) was used as the oxidation initiator. Conjugated dienes (CD) formation and oxygen consumption were assessed for monitoring the antioxidant properties of the plant extract. Butylated hydroxytoluene at 50 µg/ml was used as standard antioxidant. Quantification of total polyphenolic compounds was carried out according to the Folin-Ciocalteu method. Results : The hydromethanolic extract of G. alypum exhibited significant antioxidant effect. There was a significant inhibition of CD formation in copper ions-mediated linoleic acid emulsion as well as human LDL peroxidation. Analysis of the plant extract revealed a high amount of polyphenols, suggesting a possible role of these compounds in the antioxidant properties. Conclusion : The obtained results suggested that G. alypum could be a potential source of antioxidants. Further investigations are in progress to determine the active constituent(s).

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Objective: To isolate an active anticancer fraction from Emilia sonchifolia and to determine the mechanism of its anticancer activity. Materials and methods: The anticancer principle was separated using thin layer chromatography (TLC) from the most active n-hexane extract and chemically analysed. The anticancer efficacy of n-hexane extract was determined in mice using Dalton's lymphoma ascitic (DLA) cells. Cytotoxicity of the extracts and isolates to macrophages, thymocytes and DLA cells was measured using Trypan blue exclusion method, MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, DNA ladder assay and DNA synthesis in culture. Short-term toxicity evaluation of the active fraction was also carried out in mice. Results: The hexane extract was found to be most active and it showed in vitro cytotoxicity to DLA and thymocytes, but not to macrophages. In a concentration and time-dependent manner, it induced membrane blebbing, nuclear condensation, DNA ladder formation, and formation of apoptotic bodies which are characteristic to apoptotic cell death. The n-hexane fraction protected 50% of mice challenged intraperitoneally with 106 DLA cells. This fraction did not exhibit conspicuous adverse toxic symptoms in mice. An active terpene fraction was separated from the n-hexane extract by TLC. This isolate induced apoptotic cell death in DLA cells at 0.8 µg per mL level. Conclusion: An anticancer terpene fraction was isolated by TLC from Emilia sonchifolia that induced cell-specific apoptosis and appears to be a promising anticancer agent.

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Objective: To investigate the effect of azoles viz metronidazole (MTZ), tinidazole (TNZ), ketoconazole (KCZ), and fluconazole (FLZ) on resutured incision, excision, and dead space wounds in albino rats. Materials and methods: Resutured incision, excision, and dead space wounds were inflicted in albino rats of either sex under light ether anesthesia, taking aseptic precautions. Control animals received vehicle, and other groups received MTZ, TNZ, KCZ, and FLZ orally for a period of 10 days in incision and dead space wounds, whereas in excision wounds till their complete closure. On the 11th day, after estimating breaking strength of resutured incision wounds (under anesthesia), animals were sacrificed and granulation tissue removed from dead space wounds to estimate breaking strength, hydroxyproline content, quantification of granulation tissue, and histological studies in control and treated groups. In the excision wound model, wound closure rate, epithelization time, and scar features were studied from the day of wounding till the day of scab falling off with no residual raw area. Results: Except ketoconazole, rest of the azoles significantly (P<0.01, <0.05) promoted the healing process in all the three wound models studied. Conclusion: Metronidazole, tinidazole and fluconazole promote wound healing, whereas ketoconazole does not do so.

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