Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis.
Effective therapies are needed for amyotrophic lateral sclerosis (ALS), a debilitating and fatal motor neuron disease. Cell and animal models of ALS are beginning to reveal possible principles governing the biology of motor neuron-selective vulnerability that implicate mitochondria and the mitochondrial permeability pore (mPTP). Proteins associated with the mPTP are known to be enriched in motor neurons and the genetic deletion of a major regulator of the mPTP has robust effects in ALS transgenic mice, delaying disease onset and extending survival. Thus, the mPTP is a rational, mechanism-based target for the development of drugs designed to treat ALS. Trophos SA has discovered olesoxime (TRO-19622), a small-molecule with a cholesterol-like structure, which has remarkable neuroprotective properties for motor neurons in cell culture and in rodents. Olesoxime appears to act on mitochondria, possibly at the mPTP. Phase I clinical trials of olesoxime have been completed successfully. Olesoxime is well tolerated and achieves levels predicted to be clinically effective when administered orally. It has been granted orphan drug status for the treatment of ALS in the US and for the treatment of spinal muscular atrophy in the EU. Phase II/III clinical trials are in progress in Europe. (+info)
Functional redundancy of steroid C26-monooxygenase activity in Mycobacterium tuberculosis revealed by biochemical and genetic analyses.
An evaluation of the use of serum 7-alpha-hydroxycholestenone as a diagnostic test of bile acid malabsorption causing watery diarrhea.
BACKGROUND: Bile acid malabsorption (BAM) is a recognized cause of watery diarrhea, often diagnosed empirically based on clinical response to cholestyramine. The radionuclide selenium-labelled homocholic acid-taurine whole body retention test is expensive, labour intensive and of limited availability. OBJECTIVE: To report on the clinical performance of serum 7-alphahydroxy-4-cholesten-3-one (7HCO) as a test of BAM in adult patients with unexplained diarrhea. METHODS: Patients with unexplained diarrhea were investigated over a three-year period. Final diagnosis was determined based on medical history and investigations, serum levels of 7HCO and response to cholestyramine. ROC analysis was used to determine the ideal upper reference range cut-off value to optimize sensitivity/specificity for BAM. Time of blood specimen collection was recorded to investigate possible variation in results throughout the working day. RESULTS: ROC analysis yielded a sensitivity/specificity of 90%/77% for type 1 BAM (ileal disease/resection) and 97%/74% for type 2 BAM (idiopathic) using 30 ng/mL as the upper limit of normal for serum 7HCO when compared with all other patients. Of 813 patients, 196 tested positive. Serum 7HCO levels were significantly higher in blood specimens that were collected between 12:00 and 13:00 (median 24 ng/mL) than in specimens collected between 09:00 and 10:00 (median 17 ng/mL) (P<0.05). CONCLUSION: Serum 7HCO testing is a simple, sensitive, noninvasive, inexpensive alternative to other more commonly used tests for BAM. Time of specimen collection, however, resulted in small but significant result variations and, although unlikely to have much impact on test value, it should ideally be standardized. (+info)