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Safety Assessment of OTC Drugs: Doxylamine Succinate

  • Conference paper
Book cover Toxicology in Transition

Part of the book series: Archives of Toxicology ((TOXICOLOGY,volume 17))

Abstract

Safety assessment of over-the-counter (OTC) drug products frequently involves ongoing evaluation as new data become available on the active ingredients used in these products. This is particularly true for drugs that have been in use for many years and were developed prior to the routine use of certain types of toxicological studies such as the two-year rodent bioassay for evaluation of carcinogenicity. Presented here is a case study involving doxylamine succinate (DOX). DOX is an antihistamine of the ethanolamine class which has a long history of safe and effective use in OTC allergy products, multi-symptom cold medications, and sleep aids and which has recently been the subject of two-year rodent bioassays.

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References

  • Brennan LM and Creasia DA (1982) The effects of methapyrilene hydrochloride on hepatocarcinogenicity and pentobarbital-induced sleeping time in rats and mice. Toxicol. Appl. Pharmacol. 66,252–258.

    Article  PubMed  CAS  Google Scholar 

  • Budroe JD, Shaddock JG and Casciano DA (1984) A study of the potential genotoxicity of methapyrilene and related antihistamines using the hepatocyte/DNA repair assay. Mutat. Res. 135, 131–137.

    Article  PubMed  CAS  Google Scholar 

  • Capen CC (1992) Pathophysiology of chemical injury of the thyroid gland. Toxicol. Lett. 64/65, 381–388.

    Article  PubMed  Google Scholar 

  • Casciano DA, Schol HM, Shaddock JG and Feuers RJ (1986) Failure of methapyrilene and selected analogues to induce mutations in the Chinese hamster ovary mutagenesis assay system. Environ. Mutagen. 8 (Suppl. 6), 16.

    Google Scholar 

  • Clemmesen J and Hjalgrim-Jensen S (1978) Is phenobarbital carcinogenic? A follow-up of 8078 epileptics. Ecotoxicol. Environ. Safety 1,457–470.

    Article  PubMed  CAS  Google Scholar 

  • Clemmesen J and Hjalgrim-Jensen S (1981) Does phenobarbital cause intracranial tumors? A follow-up through 35 years. Ecotoxicol. Environ. Safety 5, 255–260.

    Article  PubMed  CAS  Google Scholar 

  • Curran PG and DeGroot LJ (1991) The effect of hepatic enzyme-inducing drugs on thyroid hormones and the thyroid gland. Endocrine Rev. 12,135–150.

    Article  CAS  Google Scholar 

  • Danhof M and Teunissen WE (1984) Antipyrine as a model drug to assess oxidative drug metabolizing activity in man. Pharm. Int. 5, 11–15.

    CAS  Google Scholar 

  • Diwan BA, Palmer AE, Ohshima M and Rice JM (1985) N-nitroso-N-methylurea initiation in multiple tissues for organ-specific tumor promotion in rats by phenobarbital. J. Natl. Cancer Inst. 75, 1099–1105.

    PubMed  CAS  Google Scholar 

  • Doniach I (1970) Aetiological consideration of thyroid carcinoma. In: Tumors of the thyroid gland. Vol. 6. D Smithers (ed) E & S Livingstone, London, 55–72.

    Google Scholar 

  • Ged C, Rouillon JM, Pichard L, Combalert J, Bressot N, Bories P, Michel H, Beaune P and Maurel P (1989) The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br. J. Clin. Pharmacol. 28, 373–387.

    PubMed  CAS  Google Scholar 

  • Grasso P, Sharratt M and Cohen AJ (1991) Role of persistent, non-genotoxic tissue damage in rodent cancer and relevance to humans. Annu. Rev. Pharmacol.Toxicol. 31, 253–287.

    Article  PubMed  CAS  Google Scholar 

  • Habs, M, Shubik, P and Eisenbrand, G (1986) Carcinogenicity of methapyrilene hydrochloride, mepyramine hydrochloride, thenyldiamine hydrochloride and pyribenzamine hydrochloride in Sprague-Dawley rats J. Cancer Res. Clin., Oncol. 111,71–74.

    Article  CAS  Google Scholar 

  • Zeiger E, Anderson B, Haworth S Lawlor T, Mortelmans K and Speck W (1987) Salmonella mutagenicity tests III. Results from the testing of 255 chemicals. Environ. Mutagen. 9 (Suppl. 9), 1–110.

    Article  PubMed  CAS  Google Scholar 

  • Hartleb M (1991) Drugs and the liver. Part II. The role of the antipyrine test in drug metabolism studies. Biopharm. Drug Dispos. 12, 559–570.

    Article  PubMed  CAS  Google Scholar 

  • Haseman JK (1983) A reexamination of false-positive rates for carcinogenicity studies. Fund. Appl. Toxicol. 3, 334–339.

    Article  CAS  Google Scholar 

  • Haseman JK (1984) Statistical issues in the design, analysis and interpretation of animal carcinogenicity studies. Environ. Health Perspect. 58, 385–392.

    Article  PubMed  CAS  Google Scholar 

  • Haseman JK, Arnold J and Eustis SL (1990) Tumor incidences in F344 rats: NTP historical data. In: Pathology of the Fischer Rat — Reference and Altas. Boorman, GA, Eustis SL, Elwell, MR, Montgomery Jr. CA, and MacKenzie W (eds.) Academic Press, 555–564.

    Google Scholar 

  • Hiasa Y, Kitahori Y, Ohshima M, Fujita T, Yuasa T, Konishi N and Miyashiro A (1982) Promoting effects of phenobarbital and barbital on development of thyroid tumors in rats treated with N-bis (2-hydroxypropyl) nitrosamine. Carcinogenesis 3, 1187–1190.

    Article  PubMed  CAS  Google Scholar 

  • Hill RN, Erdreich, LS, Paynter, OE, Roberts PA, Rosenthal SL and Wilkinson CF (1989) Thyroid follicular cell carcinogenesis. Fund. Appl. Toxicol. 12, 629–697.

    Article  CAS  Google Scholar 

  • IARC Scientific Publications No. 65 (1985) Interpretation of negative epidemiological evidence for carcinogenicity. Proceedings of a symposium held in Oxford 4–6 July 1983. N.J. Wald and R. Doll (eds.), 151–160.

    Google Scholar 

  • Jackson CD (1991) Chronic study of doxylamine in Fischer 344 rats and B6C3F1 mice. NCTR Technical Report for Experiment 406 and 407. April.

    Google Scholar 

  • Jackson CD and Blackwell BN (1993) Two-year toxicity study of doxylamine succinate in the Fischer 344 rat. J. Am. Coll. Toxicol. 12, 1–11.

    CAS  Google Scholar 

  • Jackson CD and Sheldon W (1993) Two-year toxicity study of doxylamine succinate in B6C3F1 mice. J. Am. Coll. Toxicol. 12, 311–321.

    CAS  Google Scholar 

  • Lijinsky W, Reuber MD and Blackwell BN (1980) Liver tumors induced in rats by oral administration of the antihistaminic methapyrilene hydrochloride. Science 209, 817–819.

    Article  PubMed  CAS  Google Scholar 

  • Lijinsky W, Knutsen G and Reuber MD (1983) Failure of methapyrilene to induce tumors in hamsters and guinea pigs. J. Toxicol. Environ. Health 12, 653–657.

    Article  PubMed  CAS  Google Scholar 

  • Lijinsky W and Kovatch RM (1986) Carcinogenicity studies of some analogs of the carcinogen methapyrilene in F344 rats. J. Cancer Res. Clin. Oncol. 112, 57–60.

    Article  PubMed  CAS  Google Scholar 

  • Littlefield NA, Gaylor DW, Blackwell BN and Allen RR, (1989) Chronic toxicity/carcinogenicity studies of Gentian Violet in Fischer 344 rats: two-generation exposure. Fd. Chem. Toxicol. 27, 239–247.

    Article  CAS  Google Scholar 

  • Loft S (1990) Metronidazole and antipyrine as probes for the study of foreign compound metabolism. Pharmacol. Toxicol. 66 (Suppl. VI), 1–31.

    Article  PubMed  CAS  Google Scholar 

  • Loft S, Sonne J, Poulsen HE, Petersen KT, Jorgensen BG and Dossing M (1987) Inhibition and induction of metronidazole and antipyrine metabolism. Eur. J. Clin. Pharmacol. 32, 35–41.

    Article  PubMed  CAS  Google Scholar 

  • Lubet RA, Nims RW, Ward JM, Rice JM and Diwan BA (1989) Induction of cytochrome P450b and its relationship to liver tumor promotion. J. Am. Coll. Toxicol. 8, 259–268.

    CAS  Google Scholar 

  • McClain RM (1989) The significance of hepatic microsomal enzyme induction and altered thyroid function in rats: implications for thyroid gland neoplasia. Toxicol. Pathol. 17, 294–306.

    Article  PubMed  CAS  Google Scholar 

  • McClain RM (1992) Thyroid gland neoplasia: non-genotoxic mechanisms. Toxicol. Lett. 64/65, 397–408.

    Article  PubMed  Google Scholar 

  • McClain RM, Levin AA, Posch R and Downing JC (1989) The effect of phénobarbital on the metabolism and excretion of thyroxine in rats. Toxicol. Appl. Pharmacol. 99, 216–228.

    Article  PubMed  CAS  Google Scholar 

  • Muller L, Korte A and Madie S (1989) Mutagenicity testing of doxylamine succinate, an antinauseant drug. Toxicol. Lett. 49, 79–86.

    Article  PubMed  CAS  Google Scholar 

  • National Toxicology Program Results Report (1987) Results and status information on all NTP chemicals. July 7.

    Google Scholar 

  • Ohnhaus EE, Breckenridge AM and Park BK (1989) Urinary excretion of 6β– hydroxycortisol and the time course measurement of enzyme induction in man. Eur. J. Clin. Pharmacol. 36, 39–46.

    Article  PubMed  CAS  Google Scholar 

  • Olsen JH, Boice JD, Jensen JPA and Fraumeni, JF (1989) Cancer among epileptic patients exposed to anticonvulsant drugs. J. Natl. Cancer Inst. 81, 803–808.

    Article  PubMed  CAS  Google Scholar 

  • Park BK and Breckenridge AM (1981) Clinical implications of enzyme induction and enzyme inhibition. Clin. Pharmacokinet. 6, 1–24.

    Article  PubMed  CAS  Google Scholar 

  • Park BK and Kitteringham NR (1989) Relevance and means of assessing induction and inhibition of drug metabolism in man. In Progress in Drug Metabolism, Gibson GG, (ed.) Taylor & Francis, New York, 1–60.

    Google Scholar 

  • Park BK and Kitteringham NR (1990) Assessment of enzyme induction and enzyme inhibition in humans: toxicological implications. Xenobiotica 20, 1171–1185.

    Article  PubMed  CAS  Google Scholar 

  • Poulsen HE and Loft S (1988) Antipyrine as a model drug to study hepatic drug– metabolizing capacity. J. Hepatol. 6, 374–382.

    Article  PubMed  CAS  Google Scholar 

  • Saenger P (1983) 6ß-Hydroxycortisol in random urine samples as an indicator of enzyme induction. Clin Pharmacol. Ther. 34, 818–821.

    Article  PubMed  CAS  Google Scholar 

  • Shirts SB, Annegers JF, Hauser WA and Kurland LT (1986) Cancer incidence in a cohort of patients with seizure disorders. J. Natl. Cancer Inst. 77, 83–87.

    PubMed  CAS  Google Scholar 

  • St. Peter JV and Awni WM (1991) Quantifying hepatic function in the presence of liver disease with phenazone (antipyrine) and its metabolites. Clin. Pharmacokinet. 20, 50–65.

    Article  Google Scholar 

  • Tsuda H, Fukushima S, Imaida K, Kurata Y and Ito N (1983) Organ-specific promoting effect of phenobarbital and saccharin in induction of thyroid, liver, and urinary bladder tumors in rats afler initiation with N-nitrosomethylurea. Cancer Res. 43, 3292–3296.

    PubMed  CAS  Google Scholar 

  • U.S. Fed. Regist. (Jan. 28, 1994) Vol. 59, No. 19, 4216–4218.

    Google Scholar 

  • Waxman DJ, Attisano C, Guengerich FP and Lapenson DP (1988) Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6-beta-hydroxylase cytochrome P-450 enzyme. Arch. Biochem. Biophys. 263,424–436.

    Article  PubMed  CAS  Google Scholar 

  • White SJ, McLean AEM and Howland C (1979) Anticonvulsant drugs and cancer. A cohort study in patients with severe epilepsy. Lancet 2,458–461.

    Article  PubMed  CAS  Google Scholar 

  • Williams GM (1990) Epigenetic mechanisms of liver tumor promotion. In: Mouse Liver Carcinogenesis: Mechanisms and Species Comparisons. Stevenson, DE et al. (eds) Alan R. Liss, Inc., New York, 131–145.

    Google Scholar 

  • Zeiger E, Anderson B, Haworth S Lawlor T, Mortelmans K and Speck W (1987) Salmonella mutagenicity tests III. Results from the testing of 255 chemicals. Environ. Mutagen. 9 (Suppl. 9), 1–110.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. The Procter & Gamble Company, Cincinnati, OH, 45242, USA

    J. A. Skare, V. A. Murphy, R. C. Bookstaff, G. A. Thompson, M. A. Heise, Z. D. Horowitz & J. H. Powell

  2. University of Kansas Medical Center, Kansas City, KS, 66160, USA

    A. Parkinson

  3. Drug Evaluation Unit, Minneapolis, MN, 55415, USA

    J. V. St. Peter

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  1. J. A. Skare
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  2. V. A. Murphy
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  3. R. C. Bookstaff
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  4. G. A. Thompson
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  6. Z. D. Horowitz
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  7. J. H. Powell
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  8. A. Parkinson
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Editor information

Editors and Affiliations

  1. Institut für Arbeitsphysiologie an der Universität Dortmund, Ardeystr. 67, D-44139, Dortmund, Germany

    Gisela H. Degen

  2. Interkantonale Kontrollstelle für Heilmittel, Erlachstr. 8, CH-3000, Bern 9, Switzerland

    Jürg P. Seiler

  3. Ciba-Geigy Ltd., K-136.3.23, CH-4002, Basel, Switzerland

    Philip Bentley

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© 1995 Springer-Verlag Berlin Heidelberg

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Skare, J.A. et al. (1995). Safety Assessment of OTC Drugs: Doxylamine Succinate. In: Degen, G.H., Seiler, J.P., Bentley, P. (eds) Toxicology in Transition. Archives of Toxicology, vol 17. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79451-3_27

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  • DOI: https://doi.org/10.1007/978-3-642-79451-3_27

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-79453-7

  • Online ISBN: 978-3-642-79451-3

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