fumarates and Atrophy

Topics: Atrophy; Biomarkers; Brain; Cytoplasm; Diagnosis, Differential; Fumarate Hydratase; Fumarates; Humans; Metabolism, Inborn Errors; Mitochondria; Mutation; Prognosis

In the Phase 3 DEFINE study, delayed-release dimethyl fumarate (DMF) 240 mg twice (BID) and three times daily (TID) significantly reduced the mean number of new or enlarging T2-hyperintense lesions and gadolinium-enhancing (Gd+) lesion activity at 2 years in patients (MRI cohort; n = 540) with relapsing-remitting MS. The analyses described here expand on these results by considering additional MRI measures (number of T1-hypointense lesions; volume of T2-hyperintense, Gd+, and T1-hypointense lesions; brain atrophy), delineating the time course of the effects, and examining the generality of the effects across a diverse patient population. Reductions in lesion counts with delayed-release DMF BID and TID, respectively, vs. placebo were apparent by the first MRI assessment at 6 months [T2-hyperintense: 80 and 69 % reduction (both P < 0.0001); Gd+, 94 and 81 % reduction (both P < 0.0001); T1-hypointense: 58 % (P < 0.0001) and 48 % (P = 0.0005) reduction] and maintained at 1 and 2 years. Reductions in lesion volume were statistically significant beginning at 6 months for T2-hyperintense [P = 0.0002 (BID) and P = 0.0035 (TID)] and Gd+ lesions [P = 0.0059 (BID) and P = 0.0176 (TID)] and beginning at 1 year [P = 0.0126 (BID)] to 2 years [P = 0.0063 (TID)] for T1-hypointense lesions. Relative reductions in brain atrophy from baseline to 2 years (21 % reduction; P = 0.0449) and 6 months to 2 years (30 % reduction; P = 0.0214) were statistically significant for delayed-release DMF BID. The effect of delayed-release DMF on mean number of new or enlarging T2-hyperintense lesions and Gd+ lesion activity was consistent across pre-specified patient subpopulations. Collectively, these results suggest that delayed-release DMF favorably affects multiple aspects of MS pathophysiology.

Topics: Adolescent; Adult; Atrophy; Brain; Delayed-Action Preparations; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome; Young Adult

This case represents an individual with accelerating hypertension and declining kidney function associated with atherosclerotic renal artery stenosis. Key features include loss of GFR (reaching stage V CKD) during intensified antihypertensive drug therapy including agents that block the renin-angiotensin system and failure to appreciate the extent to which moderate renal artery stenosis was affecting his better kidney. Interpretation of duplex ultrasound studies was complicated by a discrepancy between near-normal peak systolic velocities and markedly abnormal segmental arterial waveforms. It was essential to recognize that both kidneys were abnormal and focus on recovery of perfusion to the better of these kidneys. Successful revascularization of one kidney allowed major improvement in GFR and BP control.

Topics: Aged; Amides; Antihypertensive Agents; Atherosclerosis; Atrophy; Blood Pressure; Carbazoles; Carvedilol; Disease Progression; Drug Therapy, Combination; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Propanolamines; Renal Artery Obstruction; Stents; Teaching Rounds

Scleroderma renal crisis (SRC) is an important complication of scleroderma associated with significant morbidity and mortality. Current treatment of patients with SRC focuses on renin-angiotensin-aldosterone system (RAAS) blockade, ideally using angiotensin-converting enzyme inhibitors. We present a case of SRC in a patient established on maximal tolerable RAAS-blocking treatment. Introduction of a selective endothelin-A receptor antagonist followed by a direct renin inhibitor provided excellent blood pressure control and complete abrogation of heavy proteinuria. This was associated with a decrease in kidney function, with serum creatinine level increasing by approximately 30%. This increase is considered acceptable after the introduction of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, is regarded as an indicator of drug efficacy, and confers longer term renal protection. Both endothelin receptor antagonism and direct renin inhibition offer alternate novel therapies for patients with SRC. Their ability to preserve or improve kidney function is unclear.

Topics: Amides; Antihypertensive Agents; Atrophy; Biomarkers; Biopsy; Endothelin Receptor Antagonists; Female; Fibrosis; Fumarates; Humans; Hypertension, Renal; Isoxazoles; Kidney; Middle Aged; Proteinuria; Pulmonary Fibrosis; Renal Insufficiency, Chronic; Renin; Scleroderma, Systemic; Thiophenes; Treatment Outcome

Effects in vitro of glutamate, aspartate, fumarate and malate on substrate activation kinetics of AMP-deaminase in denervated and contralateral gastrocnemius muscles of the frog, Rana hexadactyla were studied. Glutamate increase the enzyme activity of both muscles by increasing maximal velocity (V) and decreasing Michaelis-Menten constant (Km), whereas, aspartate did not show any significant effect. Fumarate and malate exerted mixed type of inhibition by decreasing V and increasing Km of enzymes in both muscle preparations. The inhibitor constant (Ki) values suggest that the denervated muscle enzyme was more sensitive to fumarate and malate as compared to the contralateral muscle enzyme.

Topics: AMP Deaminase; Animals; Aspartic Acid; Atrophy; Fumarates; Glutamates; Kinetics; Malates; Muscle Denervation; Muscles; Nucleotide Deaminases; Ranidae