Skip to main content
SpringerLink
Log in

Toxicology of Glucosidase Inhibitors

  • Chapter
Oral Antidiabetics

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 119))

Abstract

A large number of toxicity studies have been performed on the general and reproduction toxicology, genotoxicity and carcinogenicity of acarbose. Besides the usual guideline studies required by the international authorities for registration, several special studies have also been initiated to clarify the effects that were observed in the original long-term study of acarbose in rats and which were of questionable relevance for the clinical situation. Some of these results have been published in previous articles (Schlüter1982a, 1988).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 74.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Ahr HJ, Boberg M, Krause HP, Maul W, Müller FO, Ploschke HJ, Weber H, Wünsche C (1989) Pharmacokinetics of acarbose. Part I: absorption, concentration in plasma, metabolism and excretion after single administration of [14C]acarbose to rats, dogs and man. Drug Res 39:1254–1260

    CAS  Google Scholar 

  • Atkinson JE, Daly IW, Saulog TM, Suzuki T (1991a) One-year oral gavage toxicity study of AO-128 in rats. Jpn Pharmacol Ther 19:233–260

    Google Scholar 

  • Atkinson JE, Daly IW, Saulog TM, Fukuda R, Tanakamaru Z, Nonoyama T (1991b) Oncogenicity study of AO-128 in mice. Jpn Pharmacol Ther 19:131–142

    Google Scholar 

  • Atkinson JE, Daly IW, Saulog TM, Suzuki T (1991c) One-year oral toxicity study of AO-128 in beagle dogs. Jpn Pharmacol Ther 19:261–282

    Google Scholar 

  • Bär A (1992) Significance of leydig cell neoplasia in rats fed lactitol or lactose. J Am Coll Toxicol 11:189–207

    Article  Google Scholar 

  • Balfour JA, McTavish D (1993) Acarbose. An update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 46:1025–1054

    Article  PubMed  CAS  Google Scholar 

  • Bomhard E (1992) Frequency of spontaneous tumours in wistar rats in 30-month studies. Exp Toxicol Pathol 44:381–392

    Article  PubMed  CAS  Google Scholar 

  • Bomhard E, Karbe E, Löser E (1986) Spontaneous tumours of 2000 wistar TNO/W 70 rats in two-year carcinogenicity studies. J Environ Pathol Toxicol Oncol 7:35–52

    PubMed  CAS  Google Scholar 

  • Bomhard E, Rinke M (1994) Frequency of spontaneous tumours in wistar rats in 2-year studies. Exp Toxicol Pathol 46:17–29

    Article  PubMed  CAS  Google Scholar 

  • De Groot AP (1987) Biological effects of low digestibility carbohydrates. In: Leegwater DC, Feron VJ, Hermus RJJ (eds) Low digestibility carbohydrates. Pudoc, Wageningen, pp 12–22

    Google Scholar 

  • Doherty NS, Beaver TH (1990) Comparison of the anaphylactoid response induced in rats by castanospermine and dextran. Int Arch Allergy Appl Immunol 93:19–25

    Article  PubMed  CAS  Google Scholar 

  • Fafournoux P, Rémésy C, Demigné C (1993) Control of alanine metabolism in rat liver by transport processes or cellular metabolism. Biochem J 210:645–652

    Google Scholar 

  • Gardner KD (1961) The effect of pH on the filtration, reabsorption and excretion of protein by the rat kidney. J Clin Invest 40:525–535

    Article  PubMed  CAS  Google Scholar 

  • Geddes R, Taylor JA (1985) Lysosomal glycogen storage induced by acarbose, a 1,4-alpha-glucosidase inhibitor. Biochem J 228:319–324

    PubMed  CAS  Google Scholar 

  • Gross L (1988) Inhibition of the development of tumours or leukemia in mice and rats after reduction of food intake. Cancer 62:1463–1465

    Article  PubMed  CAS  Google Scholar 

  • Haase P (1978) Parathyroid stimulation in phosphate induced nephrocalcinosis. J Anat 125:299–311

    PubMed  CAS  Google Scholar 

  • Heard CR, Frangi SM, Wright PM, Mccartney PR (1977) Biochemical characteristics of different forms of protein-energy malnutrition: an experimental model using young rats. Br J Nutr 37:1–21

    Article  PubMed  CAS  Google Scholar 

  • Kamikawa T, Yamashita S, Kobayashi N, Minaga T (1989a) Acute toxicity study of acarbose with a single oral or intravenous administration in rats (in Japanese). Clin Res 23 (12):7–10

    Google Scholar 

  • Kamikawa T, Yamashita S, Kobayashi N, Minaga T (1989b) Toxicity study in rats treated orally with acarbose for 13 weeks (in Japanese). Clin Res 23(12):11–34

    Google Scholar 

  • Keenan K, Smith P, Ballam G, Soper K, Bokelman D (1992) The effect of diet and dietary optimisation (caloric restriction) on survival in carcinogenicity studies — an industry viewpoint. In: McAuslane JAN, Lumley CE, Walker SR (eds) The carcinogenicity debate. Quay Publishing, pp 77–102

    Google Scholar 

  • Konishi Y, Hata Y, Fujimori K (1989) Formation of glycogenosomes in rat liver induced by injection of acarbose, an α-glucosidase inhibitor. Acta Histochem Cytochem 22:227–231

    Article  CAS  Google Scholar 

  • Konishi Y, Okawa Y, Hosokawa S, Fujimori K, Fuwa H (1990) Lysosomal glycogen accumulation in rat liver and its in vivo kinetics after a single intraperitoneal injection of acarbose, an α-glucosidase inhibitor. J Biochem 107:197–201

    PubMed  CAS  Google Scholar 

  • Lembcke B, Löser C, Frölsch UR, Wöhler J, Creutzfeld W (1987) Adaptive responses to pharmacological inhibition of small intestinal α-glucosidase in the rat. Gut 28:181–187

    Article  PubMed  CAS  Google Scholar 

  • Lembcke B, Lamberts R, Wöhler J, Creutzfeld W (1991) Lysosomal storage of glycogen as a sequel of a α-glucosidase inhibition by the absorbed deoxyno-jirimycin derivative emiglitate (Bay o 1248). Res Exp Med (Berl) 191:389–404

    Article  CAS  Google Scholar 

  • Lina B, Dreef-Van Der Meulen HC, De Groot AP, Suzuki T (1991) Subchronic (90-day) oral toxicity study with AO-128 in rats. Jpn Pharmacol Ther 19:181–208

    Google Scholar 

  • Lord GH, Newberne PM (1990) Renal mineralization — A ubiquitous lesion in chronic rat studies. Food Chem Toxicol 28:449–455

    Article  PubMed  CAS  Google Scholar 

  • Lüllmann-Rauch R (1981) Lysosomal storage glycogen mimicking the cytological picture of Pompe’s disease as induced in rats by injection of an α-glucosidase inhibitor. I. Alterations in liver. Virchows Arch 38:89–100

    Article  Google Scholar 

  • Lüllmann-Rauch R (1982) Lysosomal glycogen storage mimicking the cytological picture of Pompe’s disease as induced in rats by injection of an α-glucosidase inhibitor. II. Alterations in kidney, adrenal gland, spleen and soleus muscle. Virchows Arch 39:187–202

    Article  Google Scholar 

  • Macgregor JT, Caldwell K, Crawford L (1989) Biological effects of plant secondary metabolites in mammals. Fedrip Database; National Technical Information Service (NTIS). Western Regional Res Center/Toxicology & Biological Eval/Research Unit. Albany, California 94710

    Google Scholar 

  • Maeshiba Y, Kondo, Kobayashi T, Tanayama K (1991) Metabolic fate of AO-128, a new α-glucosidase inhibitor, in rats and dogs (in Japanese). Jpn Pharmacol Ther 19:247–257

    Google Scholar 

  • Morseth SL, Nakatsu T (1991a) Reproduction study in rats with AO-128. Jpn Pharmacol Ther 19:29–44

    Google Scholar 

  • Morseth SL, Nakatsu T (1991b) Teratological study in rats with AO-128. Jpn Pharmacol Ther 19:45–67

    Google Scholar 

  • Morseth SL, Nakatsu T (1991c) Perinatal and postnatal study in rats with AO-128. Jpn Pharmacol Ther 19:79–100

    Google Scholar 

  • Morseth SL, Nakatsu T (1991d) Teratological study in rabbits with AO-128. Jpn Pharmacol Ther 19:69–78

    Google Scholar 

  • Nakai Y, Doi T, Inoue S (1991) Antigenicity of AO-128 in guinea pigs and mice (in Japanese). Jpn Pharmacol Ther 19:101–105

    Google Scholar 

  • Nonoyama T, Imai R, Tensha S, Nagai H, Sakura Y, Wada T (1991) Onocogenncity study of AO-128 in rats (in Japanese). Jpn Pharmacol Ther 19:119–129

    Google Scholar 

  • Otto K (1965) Alanin-transaminase und gluconeogenese. Hoppe-Seylers Zschr Physiol Chem 341:99–104

    Article  CAS  Google Scholar 

  • Pickering RG, Pickering CE (1984) The effect of diet on the incidence of pituitary tumours in female wistar rats. Lab Anim 18:298–314

    Article  PubMed  CAS  Google Scholar 

  • Rhinehart BL, Begovic ME, Robinson KM (1991) Quantitative relationship of lysosomal glycogen accumulation to lysosomal α-glucosidase inhibition in cas-tanospermine treated rats. Biochem Pharmacol 41:223–228

    Article  PubMed  CAS  Google Scholar 

  • Roe FJC, Bär A (1985) Enzootic and epizootic adrenal medullary proliferative disease of rats: influence of dietary factors which affect calcium absorption. Hum Toxicol 4:27–52

    Article  PubMed  CAS  Google Scholar 

  • Rowsell EV, Snell K, Carnie JA, Al-Tai AH (1969) Liver L-alanine-glyoxylate and L-serine-pyruvate aminotransferase activities: an apparent association with gluconeogenesis. Biochem J 115:1071–1073

    PubMed  CAS  Google Scholar 

  • Rowsell EV, Al-Tai AH, Carnie JA (1973) Increased liver L-serine-pyruvate aminotransferase activity under gluconeogenic consitions. Biochem J 134:349–351

    PubMed  CAS  Google Scholar 

  • Sakamoto Y, Fujikawa K, Nakamura M, Hitotumachi S (1991) Mutagenicity studies of AO-128 (in Japanese). Jpn Pharmacol Ther 19:107–117

    Google Scholar 

  • Saul R, Ghidoni JJ, Molyneux RJ, Elbein AD (1985) Castanospermine inhibits α-glucosidase activities and alters glycogen distribution in animals. Proc Natl Acad Sci 82:93–97

    Article  PubMed  CAS  Google Scholar 

  • Saxton JA, Sperling GA, Barnes LL, Mccay CM (1948) The influence of nutrition upon the incidence of spontaneous tumours of the albino rat. Acta Unio Int Cancrum 6:423–431

    Google Scholar 

  • Schlüter G (1982) Toxicology of acarbose. In: Creutzfeld W (ed) Proceedings of 1. international symposium of acarbose. Excerpta Medica Amsterdam 1982, International Congress Series 594, pp 49–54

    Google Scholar 

  • Schlüter G (1988) Toxicology of acarbose, with special reference to long-term carcinogenicity studies. In: Creutzfeld W (ed) Acarbose for the treatment of diabetes mellitus. Springer, Berlin, pp 5–14

    Chapter  Google Scholar 

  • Sinkeidam EJ, Woutersen RA, Hollanders VMH, Til HP, Van Garderen-Hoetmer A, Bär A (1992) Subchronic and chronic toxicity/carcinogenicity feeding studies with lactitol in rats. J Am Coll Toxicol 11:165–188

    Article  Google Scholar 

  • Sunkara PS, Bowlin TL, Liu PS, Sjoerdsma A (1987) Antiretroviral activity of castanospermine and deoxynojirimycin, specific inhibitors of glycoprotein processing. Biochem Biophys Res Commun 148:206–210

    Article  PubMed  CAS  Google Scholar 

  • Suzuki T, Nagayabu T, Sato S, Abe T, Miyajima H, Matsuo T (1991) Effect of carbohydrates on oral toxicity of AO-128 in rats (in Japanese). Jpn Pharmacol Ther 19:13–19

    Google Scholar 

  • Til HP, Kuper CF, Falke He, De Groot AP, Suzuki T (1991) Subchronic (90-Day) oral toxicity study with AO-128 in dogs. Jpn Pharmacol Thet 19:209–231

    Google Scholar 

  • Tucker MJ (1979) The effect of long-term food restriction on tumours in rodents. Int J Cancer 23:803–807

    Article  PubMed  CAS  Google Scholar 

  • Yeung D, Oliver IT (1967) Gluconeogenesis from amino acids in neonatal rat liver. Biochem J 103:744–748

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. E. M. Bomhard
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institut für Klinische Pharmakologie, Bayer AG, Aprather Weg, 42096, Wuppertal, Germany

    Jochen Kuhlmann

  2. Krummacher Straße 200, 42115, Wuppertal, Germany

    Walter Puls

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Bomhard, E.M. (1996). Toxicology of Glucosidase Inhibitors. In: Kuhlmann, J., Puls, W. (eds) Oral Antidiabetics. Handbook of Experimental Pharmacology, vol 119. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-09127-2_20

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-09127-2_20

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-62456-1

  • Online ISBN: 978-3-662-09127-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation