A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials.

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

[Parenteral nutrition in critically ill newborns]. / Alimentación parenteral en recién nacidos, críticamente enfermos

In nine critically ill newborns, five of them with intractable diarrhea and four surgical patients, we administered a 5% crystalline aminoacids solution (AA) and glucose in sufficient amount to provide 120 cal times kg. in 24 hours. Six of them recovered after receiving parenteral alimentation for 3 to 15 days, gained weight during or after treatment and were discharged from the hospital in good conditions. Three died, one of them presented septicemia and two pneumonia and pulmonary infarcts. The solution used generated few metabolic alterations, the acid-base status remained within normal range and there were not important changes in the sodium and potassium serum concentrations. On the contrary, children with hyponatremia and hypokalemia at the beginning of the treatment, normalized these constants within the first hours, as diarrhea ceased. The most frequent complications were infiltrations and reaction of the surrounding tissue of the catheterized vein and local skin infection. Only one patient died of septicemia, possibly caused by this proceeding. In summary, parenteral alimentation though not free from risk, seems to be a useful proceeding when oral feeding is impossible or inadvisable. The utmost danger is septicemia. Metabolic changes are minimal and they do not mean a risk for child's life; nevertheless, there is a need for long term studies to bring up definite conclusions. The solutions in actual use are probably not the most physiological for the newborn. It is necessary to adequate them according to the new advances made on child nourishment during his first days of life.