losartan-potassium and idebenone

Friedreich ataxia (FA) is a progressive genetic neurological disorder associated with degeneration of the dorsal columns, spinocerebellar tracts and other regions of the nervous system. The disorder results from mutations in the gene referred to as FXN. Almost all mutations are expansions of an intronic GAA repeat in this gene, which gives rise to decreased transcription of the gene product (called frataxin). Following these discoveries, drug discovery has moved at a rapid pace. Therapeutic trials in the next 5 years are expected to address amelioration of the effects of frataxin deficiency and methods for increasing frataxin expression. These therapies are directed at all levels of biochemical dysfunction in FA. Agents such as idebenone potentially improve mitochondrial function and decrease production of reactive oxygen species. Idebenone is presently in a phase III trial in the US and in Europe, with the primary outcome measure being neurological function. Deferiprone, an atypical iron chelator, may decrease build-up of toxic iron in the mitochondria in patients. It has entered a phase II trial in Europe, Australia and Canada directed toward improvement of neurological abilities. Finally, targeted histone deacetylase (HDAC) inhibitors and erythropoietin increase levels of frataxin when used in vitro, suggesting that they may provide methods for increasing frataxin levels in patients. Erythropoietin has been tested in a small phase II trial in Austria, while HDAC inhibitors are still at a preclinical stage. Symptomatic therapies are also in use for specific symptoms such as spasticity (baclofen). Thus, there is substantial optimism for development of new therapies for FA in the near future, and we suggest that one or several may be available over the next few years. However, continued development of new therapies will require creation of new, more sensitive measures for neurological dysfunction in FA, and clinically relevant measures of cardiac dysfunction.

Topics: Animals; Antioxidants; Deferiprone; Enzyme Inhibitors; Erythropoietin; Friedreich Ataxia; Histone Deacetylase Inhibitors; Humans; Iron Chelating Agents; Organophosphorus Compounds; Pyridones; Recombinant Proteins; Ubiquinone

Minimal objective evidence exists regarding management of Friedreich's ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy-darbepoetin alfa, idebenone, and riboflavin-in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45 years of age (average 28 ± 8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat ≥400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7 ± 8.3) on the scale for the assessment and rating of ataxia and 94.3 ± 27.2 g/m(2) in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150 μg darbepoetin alfa every 2 or 3 weeks, 10-20 mg/kg/day idebenone, and 10-15 mg/kg/day riboflavin for 32 ± 19.4 months (range of 8-56 months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2 years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA.

Topics: Adolescent; Adult; Antioxidants; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Female; Friedreich Ataxia; Hematinics; Humans; Male; Middle Aged; Pilot Projects; Riboflavin; Ubiquinone; Young Adult

Friedreich ataxia is a rare disease caused by GAA-trinucleotide-repeat expansions in the frataxin gene, leading to marked reduction of qualitatively normal frataxin protein. Recently, human recombinant erythropoietin was reported to increase frataxin levels in patients with Friedreich ataxia.. We performed a 6-month, randomized placebo-controlled, double-blind, dose-response pilot trial to assess the safety and efficacy of erythropoietin in increasing frataxin levels. Sixteen adult patient with Friedreich ataxia were randomly assigned to erythropoietin (n = 11) or matching placebo (n = 5). All patients continued Idebenone treatment (5 mg/kg/day). Treatment consisted of a 6-month scaling-up phase, in which erythropoietin was administered intravenously at the following doses: 20,000 IU every 3 weeks, 40,000 IU every 3 weeks, and 40,000 IU every 2 weeks.. Erythropoietin treatment was safe and well tolerated, but did not result in any significant hematological, clinical, or biochemical effects in Friedreich ataxia patients.

Topics: Adult; Antioxidants; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Male; Recombinant Proteins; Statistics, Nonparametric; Time Factors; Treatment Outcome; Ubiquinone; Young Adult

Diarrhea and anemia are side effects of mycophenolic acid (MPA), but underlying mechanisms are not fully understood. Gene expression of major-alpha-hemoglobin and catalase was suppressed in livers of mycophenolate mofetil (MMF)-treated rats, suggesting MPA attenuates cellular defense against reactive oxygen species (ROS). We investigated whether the antioxidant idebenone might alleviate MPA-related side effects.. Rats were treated as follows: group 1: controls; group 2: idebenone; group 3: MMF; and group 4: MMF/idebenone. Blood was collected weekly to determine cell counts, hemoglobin, MPA, plasma albumin, total protein, creatinine, and urea concentrations. On day 28 RNA was extracted from liver, kidneys, and bone marrow (BM). Colon and jejunum were examined histologically.. High-dose MMF-treated rats developed diarrhea, dehydration, and weight loss. After a week, a significant decrease (P=0.001) in erythrocyte count and hemoglobin concentration was observed that was not influenced by idebenone. Degenerative changes in the jejunum were slightly attenuated by idebenone. Idebenone did not influence MPA-induced suppression of catalase. A significant suppression of major-alpha-hemoglobin and the erythropoietin (EPO)-receptor in BM of MMF-treated groups and almost complete absence of hemopoietic progenitor cells were observed. EPO-mRNA was markedly upregulated in the MMF-group and even more in the MMF/idebenone-group.. Idebenone showed minimal benefit on MMF-related diarrhea and anemia. BM of MMF-treated rats revealed erythroid aplasia as a possible reason for anemia. Marked upregulation of EPO-mRNA presumably reflects a compensatory mechanism. Because ROS have the potential to suppress EPO expression, it can be hypothesized that enhanced EPO-mRNA expression in MMF/idebenone-treated rats is caused by antagonism of ROS.

Topics: Animals; Antioxidants; Catalase; Colon; DNA, Complementary; Erythropoietin; Female; Gene Expression Regulation; Hemoglobins; Immunosuppressive Agents; Jejunum; Models, Animal; Mycophenolic Acid; Rats; Rats, Wistar; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; Ubiquinone