Preclinical evidences of safety of a new synthetic adjuvant to formulate with the influenza human vaccine: absence of subchronic toxicity and mutagenicity.

Context: Influenza is a severe, life-threatening viral disease that can be prevented by vaccination. However, the anti-influenza human vaccine failed to show the required efficacy both in infants under 5 years old and in the elder population, who are among those with the highest risk of developing severe complications after influenza infection. Therefore, it is of high importance to improve the vaccine efficacy and ensure its safety in these susceptible populations. GK-1, a novel 18-aa peptide adjuvant, has been proved to increase the immunogenicity of the human influenza vaccine in both young and aged mice. Objective: A preclinical study of the toxicity profile of GK-1 following the World Health Organization guidelines to support its use was herein conducted. Material and methods: GK-1 was synthetically produced following Good Manufacturing Practices. The toxicological evaluation of GK-1 peptide was performed in rats after repeated dose-ranging trials by the subcutaneous route. The mutagenic potential of GK-1 was assessed by the micronucleus, chromosomal aberration, and Ames tests, in accordance with OECD Guidelines. Results: GK-1 did not show toxic effects at doses up to 12.5mg/kg, corresponding to 25 times the dose intended for human use. No indications of mutagenic potential were observed. GK-1 after dermal administration was well tolerated locally. Conclusion: The efficacy of GK-1 to improve influenza vaccine protection, along with the absence of toxicity and mutagenicity, as reported herein, support the evaluation of this peptide in a clinical trial as a novel adjuvant for human use.

Mutagenic and antimutagenic effects of Heterotheca inuloides.

The antioxidant and hepatoprotective effects of Heterotheca inuloides have been reported before, nevertheless its use as a possible chemopreventive agent has not been documented. The aim of this study was to evaluate the mutagenic and antimutagenic activities of H. inuloides extracts using the Ames test. Both, the methanolic and acetonic extracts, were mutagenic in the TA98 but not in TA100 or TA102 strains. On the other hand, the methanolic extract reduced the mutagenicity of norfloxacin, benzo[a]pyrene and 2-aminoanthracene. Quercetin, one of the main components in the methanolic extract, also presented a mutagenic/antimutagenic dual effect and is an inhibitor of Cytochrome P450 (CYP) 1A. The antigenotoxic properties of H. inuloides could be due to the antioxidant properties previously reported and to its CYP inhibitory effect mediated by quercetin. Further studies with in vivo systems will afford information about H. inuloides beneficial and detrimental properties.

[In vitro evaluation of the chemopreventive potential of saffron]. / Evaluación in vitro del potencial quimiopreventivo del azafrán.

UNLABELLED: Cancer is a very important national health problem in Mexico, while a significant increase in the total and childhood cancer mortality has been recorded during the last decades. Chemoprevention, defined as the use of natural or synthetic agents to prevent or to block the development of cancer in human beings, is a new and promising strategy in the battle against cancer. Saffron, obtained from the dried red-dark stigmas of Crocus sativus L., an important spice rich in carotenoids, is commonly consumed in different parts of the world and used as a medical drug to treat numerous diseases. OBJECTIVE: To test the toxicity of saffron extract in vivo; to separate different ingredients in saffron extracts; to examine the cytotoxic effect of saffron and its main components on the growth of different human malignant cells in vitro; to evaluate the mutagenic and antimutagenic activities of saffron extract. METHODS: HPLC with photodiode-array detection was used for semi-preparative separation of different ingredients of saffron crude extract. Colony formation assay was used to determinate the cytotoxic activity of saffron extract and its components on human tumor cells in vitro. Mutagenicity and antimutagenicity assays were performed by the Ames method. RESULTS: Saffron is not toxic, non-mutagenic, non-antimutagenic and non-comutagenic. Twelve components were isolated: crocin-1, crocin-2, crocin-3, picrocroein, acid form of picrocrocin, HTCC-diglycosil-kaempferol trans-crocin-4, trans-crocin-2, trans-crocin-3, safranal, crocetin and cis-crocin-3. Saffron extract itself and some of its ingredients displayed a dose-dependent inhibitory activity against different types of human malignant cells in vitro. HeLa cells were more susceptible to saffron than other tested cells. CONCLUSIONS: Taken together, our results and literature data indicate that saffron could be used as a potential cancer chemopreventive agent in clinical trials.