Background: Alagebrium (ALT-711) has been shown to improve renal dysfunction in animal models of diabetes. Methods: To test its effects in diabetic nephropathy (DN), ALT-711 was administered (1 mg/kg daily i.p.) to 9-week-old female db/db mice (n = 15, group A1) for 3 weeks and to 3-month-old (n = 15, group A2), 7-month-old (n = 7, group A3), and 12-month-old (n = 5, group A4) female db/db mice for 12 weeks, while a similar number of diabetic and nondiabetic mice were used as controls. The ΕN-carboxymethyllysine (CML) levels in serum, urine, skin, and kidney tissue were measured by enzyme-linked immunosorbent assay. The renal morphometric parameters were assessed by electron and light microscopy. Results: By the 3rd week of treatment, the serum CML level decreased by 41%, and the urinary CML concentration increased by 138% from baseline, while the urinary albumin/creatinine ratio was lower (p < 0.05) in diabetic and nondiabetic group A1 mice. After 3 months of treatment, serum, skin, and kidney CML levels and urinary albumin/creatinine ratio were lower (p < 0.05) and the urinary CML levels higher (p < 0.05) in treated group A2, A3, and A4 animals compared with groups which received phosphate-buffered saline, with a similar pattern observed in nondiabetic mice. The renal morphological parameters characteristic of DN decreased in treated compared with untreated mice. Conclusion: Alagebrium may prevent, delay, and/or reverse established DN in db/db mice by reducing the systemic advanced glycation end product pools and facilitating the urinary excretion of advanced glycation end products.

Ritz E, Rychlik I, Locatelli F, Halimi S: End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis 1999;34:795–808.
UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.
Peppa M, Uribarri J, Vlassara H: Advanced glycoxidation: a new risk factor for cardiovascular disease? Cardiovasc Toxicol 2002;2:275–287.
Peppa M, Uribarri J, Vlassara H: Glucose and the advanced glycosylation end products; in Johnstone MT, Veves A (eds): Diabetes and Cardiovascular Disease, ed 2. Totowa, Humana Press, 2005, pp 81–102.
Forbes JM, Cooper ME, Oldfield MD, Thomas MC: Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol 2003;14(Suppl 3):S254–S258.
Vasan S, Foiles P, Founds H: Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. Arch Biochem Biophys 2003;419:89–96.
Wolffenbuttel BH, Boulanger CM, Crijns F, Huijberts MS, Poitevin P, Swennen GN, Vasan S, Egan JJ, Ulrich P, Cerami A, Levy BI: Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci USA 1998;95:4630–4634.
Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, de Groof RC, Lakatta EG: Improved arterial compliance by a novel advanced glycation end product crosslink breaker. Circulation 2001;104:1464–1470.
Vaitkevicius PV, Lane M, Spurgeon H, Ingram DK, Roth GS, Egan JJ, Vasan S, Wagle DR, Ulrich P, Brines M, Wuerth JP, Cerami A, Lakatta EG: A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci USA 2001;98:1171–1175.
Susic D, Varagic J, Ahn J, Fröhlich ED: Cardiovascular and renal effects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats. Am J Hypertens 2004;17:328–333.
Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ: An advanced glycation end product cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 2000;97:2809–2813.
Candido R, Forbes JM, Thomas MC, Thallas V, Dean RG, Burns WC, Tikellis C, Ritchie RH, Twigg SM, Cooper ME, Burrell LM: A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. Circ Res 2003;92:785–792.
Forbes JM, Thallas V, Thomas MC, Founds HW, Burns WC, Jerums G, Cooper ME: The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J 2003;17:1762–1764.
Peppa M, Brem H, Ehrlich P, Zhang JG, Cai W, Li Z, Croitoru A, Thung S, Vlassara H: Adverse effects of dietary glycotoxins on wound healing in genetically diabetic mice. Diabetes 2003;52:2805–2813.
Weibel ER: Stereological Methods. Practical Methods for Biological Morphometry. London, Academic Press, 1979, vol 1, pp 44–45.
Basgen JM, Steffes MW, Stillman AE, Mauer M: Estimating glomerular number in situ using magnetic resonance imaging and biopsy. Kidney Int 1994;45:1668–1672.
Fioretto P, Steffes MW, Sutherland DE, Mauer M: Sequential renal biopsies in insulin-dependent diabetic patients: structural factors associated with clinical progression. Kidney Int 1995;48:1929–1935.
Nakamura S, Makita Z, Ishikawa S, Yasumura K, Fujii W, Yanagisawa K, Kawata T, Koike T: Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. Diabetes 1997;46:895–899.
Saito A, Nagai R, Tanuma A, Hama H, Cho K, Takeda T, Yoshida Y, Toda T, Shimizu F, Horiuchi S, Gejyo F: Role of megalin in endocytosis of advanced glycation end products: implications for a novel protein binding to both megalin and advanced glycation end products. J Am Soc Nephrol 2003;14:1123–1131.
Price DL, Rhett PM, Thorpe SR, Baynes JW: Chelating activity of advanced glycation end product inhibitors. J Biol Chem 2001;276:48967–48972.
Fukami K, Ueda S, Yamagishi SI, Kato S, Inagaki Y, Takeichi M, Motomiya Y, Bucala R, Iida S, Tamaki K, Imaizumi T, Cooper M, Okuda S: AGEs activate mesangial TGF-β-Smad signaling via an angiotensin II type I receptor interaction. Kidney Int 2004;66:2137–2147.
Thallas-Bonke V, Lindschau C, Rizkalla B, Bach LA, Boner G, Meier M, Haller H, Cooper ME, Forbes JM: Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway. Diabetes 2004;53:2921–2930.
Monnier VM, Bautista O, Kenny D, Sell DR, Fogarty J, Dahms W, Cleary PA, Lachin J, Genuth S: Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial. Diabetes 1999;48:870–880.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.