ICH-Harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact

Müller, Lutz; Kikuchi, Yasumoto; Probst, Gregory S.; Schechtman, Leonard M.; Shimada, Hiroyasu; Sofuni, Toshio; Tweats, David

doi:10.1016/s1383-5742(99)00004-6

Cited by 154 publications

(62 citation statements)

References 33 publications

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“…Therefore, the determination of the potential mutagenic effect of any drug under development is mandatory [55]. The Ames assay, which is recommended for testing the mutagenicity of chemical compounds with potential pharmacological application [56] was used in the present study.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Safety of Three Phenolic Compounds from <i>Dipteryx alata</i> Vogel with Antiophidian Potential

Yoshida¹,

Ferraz²,

Tribuiani³

et al. 2015

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Phenolic compounds from Dipteryx alata Vogel were assayed against the in vitro neurotoxic effect induced by Bothrops jararacussu (Bjssu) venom. Mutagenicity was assessed by the Ames test using Salmonella typhimurium strains TA98, TA97a, TA100, and TA102, in experiments with and without metabolic activation. Anti-bothropic activity was obtained by using mouse phrenic nerve-diaphragm (PND) preparation and myographic technique. Control experiments with physiological Tyrode solution were used for keeping the PND preparations alive (n = 4). Concentrations of phenolic compounds were as follow: protocatechuic and vanillic acids (200 µg/mL, n = 4), vanillin (50 µg/mL, n = 4). These compounds were used alone or pre-incubated with the venom (40 µg/mL), 30 min prior the addition to the organ bath (n = 4). Phenolic compounds significantly inhibited the neuromuscular blockade of Bjssu in the following order of potency: vanillic acid > protocatechuic = vanillin. Vanillic acid added 10 min after the Bjssu venom was also able to avoid the venomblockade evolution. The mutagenicity assay indicated that all phytochemicals were unable to increase the number of revertants, demonstrating the absence of mutagenic activity. This study * Corresponding author. E. H. Yoshida et al.2 demonstrated both the safety and therapeutical potential of the three phenolic compounds as novel complementary anti-bothropic agents.

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Section: Resultsmentioning

confidence: 99%

Evaluation of the Safety of Three Phenolic Compounds from <i>Dipteryx alata</i> Vogel with Antiophidian Potential

Yoshida¹,

Ferraz²,

Tribuiani³

et al. 2015

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“…However, it should be considered that efforts to develop and refine methods for genotoxicity and carcinogenicity testing of pharmaceuticals started approximately 20 years ago, and current guidelines were published in 1996-97 [1][2][3][4][5].…”

Section: Discussionmentioning

confidence: 99%

“…According to Tata et al [16], there is some evidence of a modest increase in congenital malformations in children born to women with asthma, but this was not explained by gestational exposure to asthma drugs. No data are available [14] to evaluate the carcinogenicity to human Drugs with at least one result in tests for gene mutation in mammalian cells (3,5,8,9,10,11,14,17,18,19,20) 11 (23.9%) Drugs with at least one result in in vitro tests for SCE, chromosomal aberrations, aneuploidy or micronucleus in animal or human cells (1,3,4,5,7,8,10,11,13,14,15,17,18,19,20,21) 16 (34.8%)…”

Section: Epidemiological Studiesmentioning

confidence: 99%

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Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Brambilla

Mattioli

Robbiano

et al. 2013

Basic Clin Pharma Tox

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This survey is a compendium of genotoxicity and carcinogenicity information of bronchodilators and antiasthma drugs. Data from 46 marketed drugs were collected. Of these 46 drugs, 25 (54.3%) did not have retrievable genotoxicity or carcinogenicity data. The remaining 21 (45.7%) had at least one genotoxicity or carcinogenicity test result. Of these 21 drugs, 10 had at least one positive finding: three tested positive in at least one genotoxicity assay, eight in at least one carcinogenicity assay, and one of them gave positive results in both genotoxicity assay and carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the result(s) of long-term carcinogenesis assays, 15 drugs had both genotoxicity and carcinogenicity data: seven of them (46.6%) were neither genotoxic nor carcinogenic, 6 (40.0%) were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, 1 (6.7%) tested positive in genotoxicity assay but was non-carcinogenic, and 1 (6.7%) gave positive responses in both genotoxicity and carcinogenicity assay. Only 11 (23.9%) of the 46 drugs considered had all data required by current guidelines for testing of pharmaceuticals, but a large fraction of them were developed and marketed prior to the present regulatory climate.Bronchodilators and antiasthma drugs are continuously or frequently used in the treatment for chronic airways diseases. Among the various adverse reactions of concern that these pharmaceuticals might cause, genotoxic and carcinogenic effects cannot be excluded. Therefore, we deemed useful to verify to what extent the drugs of this family have been tested for their potential genotoxic and carcinogenic risk to human beings.The regulatory authorities of USA, Europe and Japan recommend th at genotoxicity and carcinogenicity assays are performed before application for marketing approval of pharmaceuticals. Present guidelines for genotoxicity testing of pharmaceuticals [1-3] indicate a standard test battery that consists of (i) a test for gene mutation in bacteria; (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mammalian cells gene mutation assay and (iii) an in vivo test for chromosomal damage performed with rodent hematopoietic cells. Guidelines for carcinogenicity testing of pharmaceuticals [4,5] indicate that long-term carcinogenicity studies in rodents should be performed for all pharmaceuticals whose expected clinical use is continuous for at least 6 months as well as for pharmaceuticals used frequently in an intermittent manner in the treatment for chronic recurrent conditions. In long-term carcinogenicity assays, the highest dose should be at least 25 times higher, on a mg/m 2 basis, than the maximum recommended human daily dose or represent a 25-fold ratio of rodent to human AUC. In the chapter bronchodilators and antiasthma drugs of the 2007 edition of Martindale: The Complete Drug Reference [6] are included 46 drugs still on the market, the majority of wh...

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“…1 Due to the complexity and high cost of long-term animal studies, early judgments about a compound's genotoxicity are made on the basis of results from a battery of regulatory tests. 2 Currently, 3 tests are required, which include a Salmonella bacterial reversion assay (Ames), an in vitro assessment of chromosomal damage in mammalian cells (metaphase chromosome aberration test or in vitro micronucleus test) or an in vitro mouse lymphoma L5178Y thymidine kinase mutation assay (MLA), and an in vivo assessment of chromosome damage using rodent hematopoietic cells (International Conference on Harmonisation [ICH] guideline S2(B)). An additional in vivo assessment is required when there are positive in vitro data.…”

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confidence: 99%

Development and Validation of a Higher Throughput Screening Approach to Genotoxicity Testing Using the GADD45a-GFP GreenScreen HC Assay

2008

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There is a pressing need to develop rapid yet accurate screening assays for the identification of genotoxic liability and for early hazard assessment in drug discovery. The GADD45a-GFP human cell-based genotoxicity assay (GreenScreen HC) has been reformatted to test 12 compounds per 96-well microplate in a higher throughput, automated screening mode and the protocol applied to the analysis of 1266 diverse, pharmacologically active compounds. Testing from a fixed starting concentration of 100 μM and over 3 serial dilutions, the hit rates for genotoxicity (7.3%) and cytotoxicity (33%) endpoints of the assay have been determined in a much wider chemical space than previously reported. The degree of interference from color, autofluorescence, and low solubility has also been assessed. The assay results have been compared to an in silico approach to genotoxicity assessment using Derek for Windows software. Where carcinogenicity data were available, GreenScreen HC demonstrated a higher specificity than in silico methods while identifying genotoxic species that were not highlighted for genotoxic liability in structure-activity relationship software. Higher throughput screening from a fixed, low concentration reduces sensitivity to less potent genotoxins, but the maintenance of the previously reported high specificity is essential in early hazard assessment where misclassification can lead to the needless rejection of potentially useful compounds in drug development. (Journal of Biomolecular Screening 2009:16-30)

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ICH-Harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact

Cited by 154 publications

References 33 publications

Evaluation of the Safety of Three Phenolic Compounds from <i>Dipteryx alata</i> Vogel with Antiophidian Potential

Evaluation of the Safety of Three Phenolic Compounds from <i>Dipteryx alata</i> Vogel with Antiophidian Potential

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Development and Validation of a Higher Throughput Screening Approach to Genotoxicity Testing Using the GADD45a-GFP GreenScreen HC Assay

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ICH-Harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact

Cited by 154 publications

References 33 publications

Evaluation of the Safety of Three Phenolic Compounds from &lt;i&gt;Dipteryx alata&lt;/i&gt; Vogel with Antiophidian Potential

Evaluation of the Safety of Three Phenolic Compounds from &lt;i&gt;Dipteryx alata&lt;/i&gt; Vogel with Antiophidian Potential

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Development and Validation of a Higher Throughput Screening Approach to Genotoxicity Testing Using the GADD45a-GFP GreenScreen HC Assay

Contact Info

Product

Resources

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Evaluation of the Safety of Three Phenolic Compounds from <i>Dipteryx alata</i> Vogel with Antiophidian Potential

Evaluation of the Safety of Three Phenolic Compounds from <i>Dipteryx alata</i> Vogel with Antiophidian Potential