Update on genotoxicity and carcinogenicity testing of 472 marketed pharmaceuticals

Brambilla, Giovanni; Martelli, Antonietta

doi:10.1016/j.mrrev.2008.09.002

Cited by 102 publications

(66 citation statements)

References 250 publications

(36 reference statements)

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“…For the next phase, we obtained information on the carcinogenicity evaluation (CE) as reported in the text of the approved drug labels as well as a recent compilation (Brambilla and Martelli 2009). For those studies that were not reported in labeling text, we used the current regulatory criteria to determine the acceptability of the study.…”

Section: Immunologically Active Drugsmentioning

confidence: 99%

Establishing the Carcinogenic Risk of Immunomodulatory Drugs

Weaver

2011

Toxicol Pathol

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The first effective immunosuppressive drug (ISD) was azathioprine, approved in 1968. Early experience with this drug suggested that patients might have an excess risk of tumors including lymphoma and skin tumors. Comparison among various registries has shown that the cumulative risk of tumors increases over time. The risk is additionally increased by the more intense immunosuppressive regimens needed for lung or heart-lung transplants. The link between immunosuppression and tumorigenesis was further reinforced by the high concordance of tumor types between transplant and HIV patients. The role of the immune system in tumor defense includes both direct tumor surveillance and immunity against oncogenic viruses. In transplant patients, at least two-thirds of the lymphomas are Epstein-Barr virus (EBV)-positive. Existing methods of testing for carcinogenicity are not considered adequate to identify the hazard of tumorigenesis due to these drugs. Research is ongoing in Food and Drug Administration laboratories and at collaborators' laboratories to evaluate experimental systems that may have the ability to adequately identify this class of hazard. Initial work is on various model systems similar to EBV. These include the MHV-68 mouse model, lymphocryptovirus (LCV-1) in the cynomolgus monkey, and preliminary work with mice with humanized immune systems using EBV directly.

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Section: Immunologically Active Drugsmentioning

confidence: 99%

Establishing the Carcinogenic Risk of Immunomodulatory Drugs

Weaver

2011

Toxicol Pathol

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“…The ability of drugs and additives to cause genotoxic and/or carcinogenic effects was first reported in the 1970s amongst textile and hair dye applicators (Fraumeni Jr and Miller, 1972;Brambilla and Martelli, 2009). The benzidine-based dyes in use then were reported to cause an increased risk of up to 6.4 times than the expected rate of developing bladder cancer later in life (Golka et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Toxicity of food colours and additives: A review

Thomas¹,

Adegoke²

2015

Afr. J. Pharm. Pharmacol.

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Majority of consumer goods are required to be presented with good aesthetics in order to improve acceptability in terms of colours and in some instances taste. When related to food, beverages and drug products, additives are usually added to mask un-inviting colours, obscure offensive odours and increase taste. Food additives therefore include colourants, sweeteners, preservatives and anti-caking agents. Admissible daily intake limits are often recommended for these additives. Being food products, the amount consumed over time may be subject to individual preferences and thus negating the desire to regulate and control the amount consumed cumulatively. There have been several concerns about the safety of food additives and several batteries of tests, and reports are available in literature. This review attempted to give an update on reports that have surfaced in literature over recent past on the use and safety of food colours and other additives. Some safety concerns have been related to three determinations; cytotoxicity, genotoxicity and induction or potential of inducing mutagenicity. In order to accomplish these targeted evaluations, several tests have been prescribed by International conference on harmonization (ICH), organization for economic co-operation and development (OECD) and European food safety authority (EFSA). It is observed that no single test can give a full proof of safety of these food colours and additives, hence minimal tests are recommended to be carried out in order to guarantee safety of these products. Survey of literature, revealed that once some approved additives or colours become a subject of safety concerns, comprehensive evaluations are carried out by researchers and these have often led to the de-classification of some hitherto reported agents as being non-genotoxic or non-carcinogenic. The declassifications of some food colors and additives as human carcinogens are regularly done following the comprehensive evaluation of results of mutagenicity and genotoxicity tests in vitro and some in vivo tests in mammalian tissues and whole animals. However, such declassifications are often done with caution and the implication is that regular and more comprehensive tests must be carried out. In addition, the requirements of testing for chronic exposures to this and other agents must be emphasized to prevent occurrence of subtle yet terrible side effects resulting from consuming sub-toxic doses of the additives over time.

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“…Due to increased serotonergic and noradrenergic activity, sibutramine reduces food intake, which is responsible for weight loss (Luque and Rey, 2002). Although sibutramine did not show mutagenic activity in previous in vitro assays in mice (Snyder and Green, 2001), it is known that M1 and M2 metabolites have divergent effects in terms of mutagenic activity in an Ames test (Brambilla and Martelli, 2009). The genotoxic potential of sibutramine was also verified in mice in vivo (Silva et al, 2010), where low doses (5 and 7 mg/kg) of sibutramine were shown to induce DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Can Spirulina maxima reduce the mutagenic potential of sibutramine?

Araldi

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The worldwide obesity pandemic requires the use of antiobesity drugs. Sibutramine is an anti-obesity drug that has been used worldwide but is indiscriminately consumed in Brazil. Several studies have demonstrated that sibutramine promotes weight loss and weight maintenance, but several side effects have been associated with its systematic consumption. For this reason, sibutramine was withdrawn from the European and American markets, but still remains legal for use in Brazil. Studies have shown that a 5-10% reduction in body weight results in outstanding health benefits for obese patients. However, in order to promote significant weight loss, it is necessary to use sibutramine for at least 2 years. This long-term exposure has carcinogenic potential, as sibutramine causes DNA damage. Thus, this study evaluated the in vivo mutagenic potential of sibutramine alone (5, 7, 10, 15, and 20 mg/kg) and in association with Spirulina maxima (150 and 300 mg/kg), a cyanobacterium with antioxidant potential, using the polychromatic erythrocyte micronucleus test. Our results reinforced the mutagenic potential of sibutramine alone, which showed a time-dependent action. Combinatory treatments with S. maxima were not able to reduce the genotoxicity of sibutramine. These results were confirmed in vitro with the cytokinesis-blocked micronucleus test. In conclusion, our data showed that new alternative anti-obesity treatments are needed since the consumption of sibutramine can increase the risk of cancer in overweight patients.

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Update on genotoxicity and carcinogenicity testing of 472 marketed pharmaceuticals

Cited by 102 publications

References 250 publications

Establishing the Carcinogenic Risk of Immunomodulatory Drugs

Establishing the Carcinogenic Risk of Immunomodulatory Drugs

Toxicity of food colours and additives: A review

Can Spirulina maxima reduce the mutagenic potential of sibutramine?

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