glucuronyl-glucosamine-glycan-sulfate and ruboxistaurin

Chronic kidney failure remains a major health problem worldwide. Although current treatment is focused on the renin-angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment.

Topics: Amides; Anticoagulants; Antihypertensive Agents; Bicarbonates; Chronic Disease; Enzyme Inhibitors; Fumarates; Glycosaminoglycans; Humans; Indoles; Iron Chelating Agents; Kidney Diseases; Kidney Failure, Chronic; Maleimides; Pentoxifylline; Phosphodiesterase Inhibitors; Protein Kinase C; Pyridones; Renin; Renin-Angiotensin System

Despite the worldwide epidemic of chronic kidney disease complicating diabetes mellitus, current therapies directed against nephroprogression are limited to angiotensin conversion or receptor blockade. Nonetheless, additional therapeutic possibilities are slowly emerging. The diversity of therapies currently in development reflects the pathogenic complexity of diabetic nephropathy. The three most important candidate drugs currently in development include a glycosaminoglycan, a protein kinase C (PKC) inhibitor and an inhibitor of advanced glycation. In targeting primary mechanisms by which hyperglycaemia contributes to diabetic complications, these drugs could provide risk reduction complementary to the partial reduction proven for ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers). Glycosaminoglycans act to restore glycoproteins present in reduced amounts in the glomerular basement membrane and mesangium of diabetic animal models. Components of the drug sulodexide prevent pathological changes and proteinuria in diabetic rats. Reductions in albuminuria, a hallmark of early diabetic kidney disease, have been reported in initial human trials. In the US, a multicentre phase II study has been completed, with an interim analysis indicating reduction in urinary albumin losses. Pivotal phase II trials have begun in patients with type 2 diabetes. A second metabolic pathway of diabetic complications is overexpression of PKC. Several activators of this family of intracellular kinases have been identified and PKC activation may result in tissue damage through a variety of mechanisms. In animal models, the inhibitor ruboxistaurin reduces albuminuria, diabetic histological changes and kidney injury. Like sulodexide, drug development of ruboxistaurin has reached completion of a phase II evaluation with mixed results. The third metabolic target is the nonenzymatic formulation of advanced glycation end-products (AGEs) through well described biochemical pathways. Multiple pathways lead to AGE accumulation in tissues in diabetes and diverse AGE products are formed. AGE deposition has been implicated in animal models of diabetic nephropathy. The leading AGE inhibitor currently in development is pyridoxamine, which has multiple actions that inhibit glycation. Pyridoxamine is an efficient AGE inhibitor in experimental diabetes. A phase II study in diabetic patients with nephropathy reported mixed efficacy results and a favourable safety prof

Topics: Animals; Diabetic Nephropathies; Drugs, Investigational; Glycation End Products, Advanced; Glycosaminoglycans; Humans; Indoles; Maleimides; Protein Kinase C; Protein Kinase Inhibitors; Pyridoxamine; Renal Agents; Treatment Outcome

Although treatments for diabetic kidney disease are available, many patients still have progressive disease. More effective therapies are urgently needed. Novel agents currently under evaluation in clinical trials are described in this review. Sulodexide, a mixture of three glycosaminoglycans, appears to prevent diabetic nephropathy in experimental models by ameliorating abnormalities in the glomerular basement membrane and mesangial matrix. Pyridoxamine is an inhibitor of advanced glycation end-product (AGE) formation derived from vitamin B(6). Alagebrium is an AGE cross-link breaker. AGEs injure the kidneys and other vascular targets by mechanisms such as oxidative stress, inflammation, and protein cross-linking, among others. By inhibiting AGE formation or breaking AGE cross-links, experimental models have demonstrated kidney protection. Ruboxistaurin is an inhibitor of protein kinase C beta (PKC-beta), a mediator of signal transduction that leads to cell growth, fibrosis, and tissue injury. In diabetes, PKC-beta is up-regulated and activated in the kidney. Ruboxistaurin prevents diabetic kidney disease in animal models. These agents have appeared promising (by reduction of albuminuria and preservation of kidney function) in phase II studies. To determine whether clinical outcomes (mortality, renal, and cardiovascular events) are improved beyond the current standard of care, phase III trials are planned.

Topics: Animals; Diabetic Nephropathies; Disease Progression; Enzyme Inhibitors; Glycation End Products, Advanced; Glycosaminoglycans; Humans; Indoles; Maleimides; Models, Animal; Protein Kinase C; Pyridoxamine; Renal Agents; Thiazoles