Evaluation of teratogenicity and genotoxicity induced by kramecyne (KACY).

Kramecyne (KACY), a polymer isolated from Krameria cytisoides Cav, has anti-inflammatory, anti-nociceptive, anti-arthritic and anti-ulcerogenic properties. As a part of standard preclinical safety tests, the present study sought to determine potential developmental toxicity (in female rats) and genotoxicity (in male mice) of KACY. Pregnant female rats were divided into six groups: the negative control (vehicle), the positive control (250 mg/kg of acetylsalicylic acid (ASA)), and four experimental groups (50, 250, 500 and 1000 mg/kg of KACY). To evaluate genotoxicity by in vivo micronuclei (MN) and sister chromatid exchange (SCE) tests, male mice were divided into five groups: the negative control (vehicle), the positive control (1.5 and 2.5 mg/kg of doxorubicin for MN and SCE, respectively), and three experimental groups (50, 500 and 1000 mg/kg of KACY). All treatments were administered by oral gavage. A slight maternal toxicity was evidenced by lower weight gain for rats receiving 500 and 1000 mg/kg of KACY, but no fetal malformations were found. However, there were less live fetuses/litter and greater post-implantation loss/litter at these two doses. Manifestations of developmental toxicity were limited to a higher rate of skeletal alterations. The MN tests did not evidence genotoxicity or cytotoxicity. KACY caused a slightly but significantly increased frequency of SCE. Although KACY-treated rats had skeletal alterations, these apparently were not caused by a mechanism of genotoxicity. Furthermore, the same administration in adult male mice did not produce genotoxicity. Hence, KACY herein proved to be safe for rats during the period of organogenesis.

Investigation of the antifungal potential of linalool against clinical isolates of fluconazole resistant Trichophyton rubrum.

The aim of this study was to investigate the activity of the monoterpene linalool against clinical isolates of Trichophyton rubrum. Initially, a sensitivity assay for commercial antifungals with solid disks in diffusion medium was performed. Minimum inhibitory concentration (MIC) of linalool and ketoconazole (positive control) were determined by microdilution in RPMI 1640 medium (CLSI M38-A2). We then evaluated the action of linalool and ketoconazole at different concentrations (1/2MIC, MIC and 2×MIC) on mycelial growth (radial mycelial growth), conidia production and conidia germination using a hemacytometer. The effects on cell membrane (release of intracellular material) were also investigated. Finally, changes in fungal morphology as induced by the test drugs were analyzed. Based on the sensitivity tests, the fungal strains showed resistance to 5-fluorocytosine and fluconazole. The linalool MIC values ranged from 256µg/mL to 512µg/mL, whereas ketoconazole showed values of 4µg/mL to 8µg/mL. For the LM 305 strain, the test drugs showed the following MIC values: linalool 256µg/mL and ketoconazole 8µg/mL. The mycelial growth of T. rubrum LM 305 was inhibited by linalool (2×MIC) and ketoconazole (1/2MIC, MIC, 2×MIC), in 7 days of treatment (P<0.05). The test-drugs also inhibited conidial germination and conidiogenesis (P<0.05). Linalool also caused leakage of intracellular material (P<0.05). Finally, we verified the effectiveness of linalool and ketoconazole to induce micro-morphological changes, forming abnormal, wide, short and crooked hyphae. Based on these results, we conclude that linalool presents as an antifungal agent with anti-Trichophyton rubrum potential, an important dermatophytosis agent.