Diabetic complications

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Kador PF The role of aldose reductase in the development of diabetic complications. Med Res Rev 1988 8 325. 

Prevention of diabetic complications such as retinopathy, nephropathy, cardiomiopathy. 

Brownlee, M., Cerami, A. and Vlassara, H. (1988). Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N. Engl. J. Med. 318, 1315-1321. 

Other considerations such as demonstrating a direct correlation between the level of oxidative stress and tissue damage in diabetes and showing that antioxidant therapy leads to prevention, arrest or regression of diabetic complications are also important and must be the basis of future well-designed studies. 

Inhibitors of AR have been demonstrated to prevent a wide variety of biochemical, functional and structural alterations in animal models of diabetes. Early studies demonstrated arrest of both early cataract development and nerve conduction velocity. At least 30 clinical trials of AR inhibitors have been published involving nearly 1000 patients in total. However, there is little impressive data of their efficacy up to now but, rather than undermine the hypothesis linking excess polyol pathway activity to diabetic complications, it may reflect methodological difficulties and trial design errors. 

A relationship between polyol pathway activity and reduction in endothelium-dependent relaxation in aorta from chronic STZ-diabetic rats has recently been reported (Cameron and Cotter, 1992). In agreement with several previous studies (Oyama et al., 1986 Kamata et al., 1989), endothelial-dependent relaxation was defective in the diabetic rats but the deficit was prevented by prior treatment with an AR inhibitor. The mechanism underlying the defect has been speculated to be due to decreased production of endothelium-derived relaxing factor (EDRF) or nitric oxide, NO (Hattori et al., 1991). It has been speculated that these vascular abnormalities may lead to diminished blood flow in susceptible tissues and contribute to the development of some diabetic complications. NO is synthesized from the amino-acid L-arginine by a calcium-dependent NO synthase, which requires NADPH as a cofactor. Competition for NADPH from the polyol pathway would take place during times of sustained hyperglycaemia and... 

Aminoguanidine has been shown to prevent the formation of AGEs (Brownlee et al., 1986) and treatment with this drug prevents retinal pericyte loss in STZ-induced diabetic rats (Hammes et al., 1990). More recendy, functional and structural impairments in peripheral nerves are ameliorated by aminoguanidine in male Wistar rats (Yagihashi et al., 1992). These data surest that inhibitors of non-enzymatic glycosyiation may have a future role in the treatment of diabetic complications. 

Dvornik, D. (1987). Animal models of diabetic complications and their relation to aldose reductase inhibition. In Aldose Reductase Inhibition (ed. D. Porte) pp. 153-219. McGraw-Hill, New York. 

Wolff, S.P. (1987). The potential role of oxidative stress in diabetes and its complications novel implications for theory and therapy. In Diabetic Complications Scientific and Clinical Aspects (ed. M.J.C. Crabbe) pp. 167-221. Churchill Livingstone, Edinburgh. 

Sheetz, M. J. and King, G. L. Molecular understanding of hyperglycemia s adverse effects for diabetic complications. JAMA 288 2579-2588, 2002. 

N2. Nakata, H., Horita, K., and Eto, M., Alteration of lipoprotein(a) concentration with glycemic control in non-insulin-dependent diabetic subjects without diabetic complications. Metab., Clin. Exp. 42, 1323-1326 (1993). 

Ahmed N (2005) Advanced glycation endproducts - role in pathology of diabetic complications. Diabetes Res Clin Pract 67 3-21... 

Rhetsinine (2), isolated from the hot water extract of Evodia rutae-carpa (family Rutaceae), was found to inhibit aldose reductase with an IC50 value of 24.1 /rM furthermore, the isolate inhibited sorbitol accumulation by 79.3% at 100 This compound could find potential use in the treatment of diabetic complications. Tetramethylpyrazine (3), one of the active components in Qing Huo Yi Hao, displayed strong antioxidant and endothelial protective effects, which can be comparable as Qing Huo Yi Hao this result indicated that some therapeutic potential of Qing Huo Yi Hao for vascular complications of diabetes may be attributed to the presence of tetramethylpyrazine (3). ... 

Hypersensitivity to sulfonylureas diabetes complicated by ketoacidosis, with or without coma sole therapy of type 1 (insulin-dependent) diabetes mellitus diabetes when complicated by pregnancy. 

So it is likely that carnosine and other carbonyl scavengers might exert beneficial effects towards diabetes and its secondary complications (Hipkiss, 2005). Lee et ah (2005) have indeed demonstrated that dietary carnosine suppresses a number of diabetic complications in mice. 

Ahmed, N. and Thornalley, P. J. (2007). Advanced glycation endproducts What is their relevance to diabetic complications Diabetes Obes. Metab. 9, 233-246. 

Magalhaes, P. M., Appel, H. J., and Duarte, J. A. (2008). Involvement of advanced glycation end products in the pathogenesis of diabetic complications The protective role of regular physical activity. Eur. Rev. Aging Phys. Act. 5,17-29. 

Vander Jagt, D. L. (2008). Methylglyoxal, diabetes mellitus and diabetic complications. Drug Metabol. Drug Interact. 23, 93-124. 

Patients with both type 1 and type 2 diabetes are prone to complications. The specific chronic diabetic complications are due to microangiopathy and include neuropathy, retinopathy and nephropathy. Recent data stress the vital role of hyperglycaemia and oxidative stress in their pathophysiology. Premature atherosclerosis (which can be considered... 

Metformin works best in patients with significant hyperglycemia and is often considered first-line therapy in the treatment of mild to moderate type II overweight diabetics who demonstrate insulin resistance. The United Kingdom Prospective Diabetes Study demonstrated a marked reduction in cardiovascular comorbidities and diabetic complications in metformin-treated individuals. Metformin has also been used to treat hirsutism in individuals with polycystic ovarian syndrome and may enhance fertility in these women, perhaps by decreasing androgen levels and enhancing insulin sensitivity. 

Fidarestat is an aldose reductase inhibitor. It was being developed (Phase II/III) for complications of diabetes, but it seems to have been discontinued. Two other aldose reductase inhibitors, lidorestat and SPR-210, are currently in development for the treatment of diabetes complications (Figure 8.85). 

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