fumarates and pirfenidone

Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in the pathogenesis of fibrosis. The renin-angiotensin-aldosterone system (RAAS) interacts with the potent Transforming Growth Factor β (TGFβ) pro-fibrotic pathway to mediate fibrosis in many cell and tissue types. RAAS consists of both classical and alternative pathways, which act to potentiate or antagonize fibrotic signaling mechanisms, respectively. This review provides an overview of recent literature describing the roles of RAAS in the pathogenesis of fibrosis, particularly in the liver, heart, kidney and skin, and with a focus on RAAS interactions with TGFβ signaling. Targeting RAAS to combat fibrosis represents a promising therapeutic approach, particularly given the lack of strategies for treating fibrosis as its own entity, thus animal and clinical studies to examine the impact of natural and synthetic substances to alter RAAS signaling as a means to treat fibrosis are reviewed as well.

Topics: Amides; Angiotensins; Animals; Benzimidazoles; Biphenyl Compounds; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Fumarates; Gene Expression Regulation; Humans; Kidney; Liver; Molecular Targeted Therapy; Myocardium; Pyridones; Renin-Angiotensin System; Signal Transduction; Skin; Tetrazoles; Transforming Growth Factor beta

Diabetic nephropathy is the most common and most rapidly growing cause of end-stage renal failure in developed countries. Diabetic nephropathy results from complex interactions between genetic, metabolic and hemodynamic factors. Improvements in our understanding of the pathogenesis of fibrosis associated with diabetic kidney disease have led to the identification of several novel targets for the treatment of diabetic nephropathy. Albuminuria is a useful clinical marker of diabetic nephropathy, as it can be used to predict a decline in renal function. A reduction in albuminuria might not, however, be reflective of a protective effect of therapies focused on ameliorating renal fibrosis. Although new strategies for slowing down the progression of several types of renal disease have emerged, the challenge of arresting the relentless progression of diabetic nephropathy remains. In this Review, we discuss novel pharmacological approaches that aim to improve the renal outcomes of diabetic nephropathy, including the use of direct renin inhibitors and statins. We also discuss the promise of using antifibrotic agents to treat diabetic nephropathy. The need for novel biomarkers of diabetic nephropathy is also highlighted.

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Biomarkers; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Protein Kinase C; Pyridones; Renin; Transforming Growth Factor beta

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

In 1993, interferon beta-1b, the first clinically proven disease-modifying agent for multiple sclerosis, was approved, with several comparable agents following close behind. These agents have been beneficial in reducing relapse events and MRI lesions, but all require parenteral administration, leading some otherwise eligible patients to decline such therapies. Oral agents have been studied for decades with mixed results, but a small number of medications currently being tested in phase II/III clinical trials have shown promise in efficacy and tolerability. This review assesses the results of the more thoroughly studied of these agents, some of which may soon be approved for use in multiple sclerosis.

Topics: Administration, Oral; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Cladribine; Clinical Trials as Topic; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Interferon beta-1b; Interferon-beta; Isoxazoles; Leflunomide; Minocycline; Multiple Sclerosis; Mycophenolic Acid; Propylene Glycols; Pyridones; Quinolones; Sphingosine

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR

Topics: Administration, Oral; Area Under Curve; Biological Availability; Cross-Over Studies; Delayed-Action Preparations; Fumarates; Healthy Volunteers; Humans; Pyridones; Solubility; Tablets; Therapeutic Equivalency