Drug Res (Stuttg) 2021; 71(02): 73-82
DOI: 10.1055/a-1286-5358
Original Article

Assessment of the Genotoxic Potential of Cizolirtine a Substance-P and Calcitonin Gene-Related Peptide Release Modulator

1   Department of Toxicology, ESTEVE Pharamaceuticals, Barcelona and Department of Toxicology, WELAB, Barcelona, Spain
,
Ana-Paz Marín
1   Department of Toxicology, ESTEVE Pharamaceuticals, Barcelona and Department of Toxicology, WELAB, Barcelona, Spain
,
Araceli Tortajada
1   Department of Toxicology, ESTEVE Pharamaceuticals, Barcelona and Department of Toxicology, WELAB, Barcelona, Spain
,
Cristina Vila
1   Department of Toxicology, ESTEVE Pharamaceuticals, Barcelona and Department of Toxicology, WELAB, Barcelona, Spain
,
Antonio Guzmán
1   Department of Toxicology, ESTEVE Pharamaceuticals, Barcelona and Department of Toxicology, WELAB, Barcelona, Spain
› Author Affiliations

Abstract

The analysis of the genotoxic potential of cizolirtine, a compound being developed as a drug for analgesia and for urinary incontinence, was carried out using a battery of in vitro and in vivo assays as recommended in the guidelines for medicinal products. Negative results were obtained in an Ames test (up to 5000 µg/plate), in a Mouse Lymphoma assay (up to 2000 µg/ml) and in a single dose mouse bone marrow micronucleus assay (up to 300 mg/kg). In a human lymphocyte chromosome aberration assay, a slight statistical increase in the frequency of cells with chromosome aberrations including gaps was reported for the concentrations of 200 and 1600 μg/ml at the 24-h sampling time. This minor increase in chromosome aberrations was considered of questionable biological relevance since it was moderate, was within the laboratory historical control values, did no show a dose-dependent effect and was not observed at similar concentrations in a repeat assay. Taking into considerations the results obtained in the different in vitro and in vivo assays and a weight-of-evidence analysis, it suggests that cizolirtine would not pose a genotoxic risk when administered to humans.



Publication History

Received: 02 July 2020

Accepted: 05 October 2020

Article published online:
04 November 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Alvarez I, Andreu F, Buxens J. et al. Pharmacology of cizolirtine: A new analgesic agent. Methods Find. Exp Clin Pharmacol 2000; 22: 211-221 DOI: 10.1358/mf.2000.22.4.584453.
  • 2 Aubel B, Kayser V, Farré A. et al. Evidence for adenosine- and serotonin-mediated antihyperalgesic effects of cizolirtine in rats suffering from diabetic neuropathy. Neuropharmacology 2007; 52: 487-496. DOI: 10.1016/j.neuropharm.2006.08.017.
  • 3 Farre AJ, Frigola J. Cizolirtine Citrate. Drugs Future 2002; 27: 721-732. doi:10.1358/dof.2002.027.08.692100
  • 4 Matthew IR, Ogden GR, Frame JW. et al. Dose response and safety of cizolirtine citrate (E-4018) in patients with pain following extraction of third molars. Curr Med Res Opin 2000; 16: 107-114
  • 5 Kayser V, Farré A, Hamon M. et al. Effects of the novel analgesic, cizolirtine, in a rat model of neuropathic pain. Pain 2003; 104: 169-177. DOI: 10.1016/s0304-3959(02)00497-9.
  • 6 Aubel B, Kayser V, Mauborgne A. et al. Antihyperalgesic effects of cizolirtine in diabetic rats: behavioral and biochemical studies. Pain 2004; 110. DOI: 10.1016/j.pain.2004.03.001.
  • 7 Shembalkar P, Täubel J, Abadias M. et al. Cizolirtine citrate (E-4018) in the treatment of chronic neuropathic pain. Curr Med Res Opin 2001; 17: 262-266
  • 8 Ballet S, Aubel B, Mauborgne A. et al. The novel analgesic, cizolirtine, inhibits the spinal release of substance P and CGRP in rats. Neuropharmacology 2001; 40: 578-589. DOI: 10.1016/s0028-3908(00)00186-6.
  • 9 Montier F, Carruette A, Moussaoui S. et al. Antagonism of substance P and related peptides by RP 67580 and CP-96,345, at tachykinin NK1 receptor sites, in the rat urinary bladder. Eur J Pharmacol 1994; 251. DOI: 10.1016/0014-2999(94)90436-7.
  • 10 Irwin DE, Mungapen L, Milsom I. et al. The economic impact of overactive bladder syndrome in six Western countries. BJU Int 2009; 103: 202-209 DOI: 10.1111/j.1464-410X.2008.08036.x.
  • 11 Irwin DE, Milsom I, Hunskaar S. et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: Results of the EPIC study. Eur Urol 2006; 50: 1306-1314 DOI: 10.1016/j.eururo.2006.09.019.
  • 12 Novara G, Galfano A, Secco S. et al. A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Eur Urol 2008; 54: 740-763 DOI: 10.1016/j.eururo.2008.06.080.
  • 13 Martínez-García R, Abadías M, Arañó P. et al. Cizolirtine citrate, an effective treatment for symptomatic patients with urinary incontinence secondary to overactive bladder: a pilot dose-finding study. Eur Urol 2009; 56: 184-190. DOI: 10.1016/j.eururo.2008.04.027.
  • 14 Zát’ura F, Vsetica J, Abadías M. et al. Cizolirtine citrate is safe and effective for treating urinary incontinence secondary to overactive bladder: a phase 2 proof-of-concept study. Eur Urol 2010; 57: 145-152 DOI: 10.1016/j.eururo.2009.04.045.
  • 15 Parliament E, Council E. Directive 2010/63/EU on the protection of animals used for scientific purposes. EU Off J 2010; L276
  • 16 Maron DM, Ames BN. Revised methods for the Salmonella mutagenicity test. Mutat Res 1983; 113 doi:10.1016/0165-1161(83)90010-9
  • 17 OECD. (1997) Test No. 471: Bacterial Reverse Mutation Test
  • 18 Dunnett CW. A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 1955; 50: 1096-1121 Accessed 2 April 2020
  • 19 Dean BJ, Danford N. Assays for the detection of chemically-induced chromosome damage in cultured mammalian cells. In: Venitt, S, Parry, JM, editors. Mutagenicity Testing: A practical approach. Oxford: IRL Press; 1984: 187-232
  • 20 OECD. (1983) Test No. 473: In Vitro Mammalian Chromosomal Aberration Test
  • 21 Richardson C, Williams JA, Allen JA. et al. Analysis of data from in vitro cytogenetic assays. Kirkland DJ. Statistical evaluation of mutagenicity test data. UKEMS Guidelines Subcommittee Report, Part III. Cambridge University Press; 1989: 141-154
  • 22 Cole J, Mc Gregor DB, Fox M. et al. Gene mutation assay in cultured mammalian cells. Kirkland DJ. Basic mutagenicity tests UKEMS Recommended Procedures. Cambridge University Press; 1990: 87-114
  • 23 OECD. (2016) Test No. 476: In Vitro Mammalian Cell Gene Mutation Tests using the Hprt and xprt genes
  • 24 Robinson WD, Green MHL, Cole J. et al. Statistical evaluation of bacteria/mammalian fluctuation test. Kirkland DJ. Statistical Evaluation of Mutagenicity Test Data. Cambridge University Press; 1990: 102-140
  • 25 Moore MM, Honma M, Clements J. et al. Mouse lymphoma thymidine kinase gene mutation assay: follow-up meeting of the International Workshop on Genotoxicity Testing–Aberdeen, Scotland, 2003–Assay acceptance criteria, positive controls, and data evaluation. Environ Mol Mutagen 2006; 47. DOI: 10.1002/em.20159.
  • 26 Schmid W. The micronucleus test. Mutat Res 1975; 31. doi:10.1016/0165-1161(75)90058-8
  • 27 OECD. (2016) Test No. 474: Mammalian Erythrocyte Micronucleus Test
  • 28 Scott D, Galloway SM, Marshall RR. et al. International Commission for Protection Against Environmental Mutagens and Carcinogens. Genotoxicity under extreme culture conditions. A report from ICPEMC Task Group 9. Mutat Res 1991; 257 DOI: 10.1016/0165-1110(91)90024-p.
  • 29 ICH S2. (2012) Genotoxicity testing and data interpretation for pharaceuticals intended for human use
  • 30 Topaktaş M, Rencüzoğullar E. Chromosomal aberrations in cultured human lymphocytes treated with Marshal and its effective ingredient Carbosulfan. Mutat Res 1993; 319: 103-111. doi:10.1016/0165-1218(93)90068-o
  • 31 NTP Toxicology and Carcinogenesis Studies of Diphenhydramine Hydrochloride (CAS No. (1989). Natl Toxicol Program Tech Rep Ser, 355
  • 32 Snyder RD. A review and investigation into the mechanistic basis of the genotoxicity of antihistamines. Mutat Res 1998; 411: 235-248 doi:10.1016/s1383-5742(98)00016-7