eprodisate and Amyloidosis

Amyloidosis is a clinical disorder caused by extracellular deposition of proteins that are normally soluble as insoluble fibrils that damage different organs. More than 20 proteins can form amyloid deposits. All types of amyloid fibrils have a secondary structure with a β folded shape that is characteristic and makes them to adopt a green birefringence after stained with Congo red and viewed under cross-polarized light. Amyloidosis can be acquired or hereditary, systemic or localized, and are classified by the fibril precursor protein. Advances in the knowledge of the pathogenesis of amyloidosis allows the development of new diagnostic and therapeutical schemes that are currently under investigation.

Topics: Amyloid; Amyloidosis; Carboxylic Acids; Humans; Immunotherapy; Propane; Protein Conformation; Pyrrolidines; Sulfonic Acids

Amyloidoses represent an inhomogeneous group of diseases characterized by extracellular deposition of amyloid fibrils. AA amyloidosis is a serious life-threatening complication of chronic rheumatic diseases responsible for increased mortality due to organ failure or infection. The main component of amyloid is the serum amyloid A precursor protein (SAA) produced by the liver as an acute phase protein. This article presents the pathogenesis of amyloidosis, which is at the core of our understanding of treatment options. Effective anti-inflammatory therapy of rheumatic diseases is the best way to prevent AA amyloidosis. Early detection of this complication leads to treatment that can effectively retard the course of the disease and may even be accompanied by regression of amyloid deposits. New hope is offered by anti-TNF-alpha antibodies or by eprodisate, which blocks the proamyloidogenic interactions of glycosaminoglycans with SAA.

Topics: Amyloidosis; Anti-Inflammatory Agents; Early Diagnosis; Humans; Propane; Rheumatic Diseases; Sulfonic Acids; Tumor Necrosis Factor-alpha

Amyloid A (AA) amyloidosis can complicate chronic inflammatory diseases, chronic infections and recurrent periodic fever syndromes. Its treatment is challenging, given its heterogeneous spectrum of etiologies.. To review the available literature regarding treatment options for AA amyloidosis, particularly focusing on eprodisate, a newly developed inhibitor of fibrillogenesis.. A PubMed search was performed without any date limits, mainly using the search terms 'amyloidosis', 'colchicine', 'eprodisate', '1,3-propanedisulfonate', 'NC-503', 'Fibrillex' and 'TNF-blockers'.. Antibiotics and colchicine are effective in preventing and treating infection-related and familial Mediterranean fever-related AA amyloidosis, respectively. Recently, TNF-alpha blockers have emerged as effective agents in inflammatory AA amyloidosis. Eprodisate binds to the glycosaminoglycan binding site on amyloid fibrils, thus targeting amyloid fibril polymerization and tissue deposition. Eprodisate has possible applicability to other types of amyloidosis; the results of a recent randomized trial showed that it may slow the progression of AA amyloidosis-related renal disease but confirmatory studies are necessary.

Topics: Amyloidosis; Colchicine; Glycosaminoglycans; Humans; Immunosuppressive Agents; Propane; Serum Amyloid A Protein; Sulfonic Acids; Tumor Necrosis Factor-alpha

Topics: Amyloidosis; Biomarkers; Humans; Immunoglobulin Light Chains; Propane; Sulfonic Acids

Amyloid A (AA) amyloidosis is a complication of chronic inflammatory conditions that develops when proteolytic fragments of serum amyloid A protein (SAA) are deposited in tissues as amyloid fibrils. Amyloid deposition in the kidney causes progressive deterioration in renal function. Eprodisate is a member of a new class of compounds designed to interfere with interactions between amyloidogenic proteins and glycosaminoglycans and thereby inhibit polymerization of amyloid fibrils and deposition of the fibrils in tissues.. We performed a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of eprodisate in patients with AA amyloidosis and kidney involvement. We randomly assigned 183 patients from 27 centers to receive eprodisate or placebo for 24 months. The primary composite end point was an assessment of renal function or death. Disease was classified as worsened if any one of the following occurred: doubling of the serum creatinine level, reduction in creatinine clearance by 50% or more, progression to end-stage renal disease, or death.. At 24 months, disease was worsened in 24 of 89 patients who received eprodisate (27%) and 38 of 94 patients given placebo (40%, P=0.06); the hazard ratio for worsening disease with eprodisate treatment was 0.58 (95% confidence interval, 0.37 to 0.93; P=0.02). The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per minute per 1.73 m(2) of body-surface area per year in the eprodisate and the placebo groups, respectively (P=0.02). The drug had no significant effect on progression to end-stage renal disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95; P=0.94). The incidence of adverse events was similar in the two groups.. Eprodisate slows the decline of renal function in AA amyloidosis. (ClinicalTrials.gov number, NCT00035334.)

Topics: Amyloidosis; Arthritis, Rheumatoid; Creatinine; Disease Progression; Double-Blind Method; Familial Mediterranean Fever; Female; Glycosaminoglycans; Humans; Kaplan-Meier Estimate; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Propane; Proportional Hazards Models; Proteinuria; Serum Amyloid A Protein; Sulfonic Acids

Amyloid A protein quantification in fat tissue is a new immunochemical method for detecting AA amyloidosis, a rare but serious disease. The objective was to assess diagnostic performance in clinical AA amyloidosis.. Abdominal subcutaneous fat tissue of patients with AA amyloidosis was studied at the start of an international clinical trial with eprodisate (NC-503; 1,3-propanedisulfonate; Kiacta), an antiamyloid compound. All patients had renal findings, i.e. proteinuria (> or =1 g/day) or reduced creatinine clearance (20 - 60 ml/min). Controls were patients with other types of amyloidosis and arthritic patients without amyloidosis. Amyloid A protein was quantified by ELISA using monoclonal antihuman serum amyloid A antibodies. Congo red stained slides were scored by light microscopy in a semiquantitative way (0 to 4+).. Ample fat tissue (>50 mg) was available for analysis in 154 of 183 patients with AA amyloidosis and in 354 controls. The sensitivity of amyloid A protein quantification for detection of AA amyloidosis (>11.6 ng/mg fat tissue) was 84% (95% CI: 77 - 89%) and specificity 99% (95% CI: 98 - 100%). Amyloid A protein quantification and semiquantitative Congo red scoring were concordant. Men had lower amyloid A protein values than women (p < 0.0001) and patients with familial Mediterranean fever had lower values than patients with arthritis (p < 0.001) or other inflammatory diseases (p < 0.01).. Amyloid A protein quantification in fat tissue is a sensitive and specific method for detection of clinical AA amyloidosis. Advantages are independence from staining quality and observer experience, direct confirmation of amyloid AA type, and potential for quantitative monitoring of tissue amyloid over time.

Topics: Abdominal Fat; Adult; Aged; Aged, 80 and over; Amyloidosis; Case-Control Studies; Congo Red; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Propane; Serum Amyloid A Protein; Sulfonic Acids

Topics: Adalimumab; Aged; Amyloidosis; Animals; Cardiomyopathies; Humans; Male; Middle Aged; Propane; Sulfonic Acids

The amyloidoses constitute a group of diseases in which misfolding of extracellular proteins plays a fundamental role. The aggregation of normally soluble proteins into insoluble unbranching fibrils is the basic underlying pathology in amyloidosis. The process of amyloid formation generates toxic insoluble (in saline) protein aggregates that are deposited in tissues in the form of β- pleated sheets of fibrillary material. The amyloidoses are considered to be part of the so-called protein storage diseases (protein thesauroses). In addition, due to the unusual protein folding associated with amyloid, this group of diseases has been referred to as conformational and protein folding disorders. For many years amyloidosis was considered an extremely rare, somewhat mysterious disease. However, in recent years its pathogenesis, particularly that of renal amyloidosis, has been carefully dissected in the research laboratory using in vitro and, to a lesser extent, in vivo models. These have provided a molecular understanding of sequential events that take place in the renal mesangium leading to the formation of amyloid fibrils and eventual extrusion into the mesangial matrix, which itself becomes seriously damaged and, in due time, replaced by the fibrillary material. Amyloid, once considered to be an 'inert' substance, has been proven to be involved in crucial biological processes that result in the destruction and eventual replacement of normal renal constituents. Although there are more than two dozen recognized amyloid precursor proteins (and new ones being added to the list) that can be involved in the genesis of amyloid fibrils, the pathophysiologic mechanisms that occur in the renal mesangium are likely to be very similar, if not the same, regardless of the type of amyloidosis. Likewise, the same is true of amyloid formation in the renal vasculature. Mesangial cells are essentially smooth muscle cells and the events that take place in the mesangium and vasculature (where smooth muscle cells and/or pericytes are present) in the entire body responsible for the formation of amyloid are the same. In the renal interstitium, fibroblasts likely participate in the formation of amyloid, following a similar sequence of events as smooth muscle cells. Although much of the information gathered has been from in vitro systems, an in vivo model of renal amyloidosis has recently been designed to study renal amyloidogenesis. Crucial steps in the cascade of events that result i

Topics: Amyloid; Amyloidosis; Genetic Therapy; Glomerular Mesangium; Humans; Kidney Diseases; Mutation; Propane; Protein Precursors; Sulfonic Acids

Topics: Amyloidosis; Glycosaminoglycans; Humans; Immunoglobulin Light Chains; Prealbumin; Propane; Proteinuria; Serum Amyloid A Protein; Sulfonic Acids

Topics: Amyloidosis; Colchicine; Familial Mediterranean Fever; Humans; Kidney Diseases; Kidney Failure, Chronic; Propane; Proportional Hazards Models; Sulfonic Acids