**4. Conclusion**

performed at baseline and every 4 weeks until the end of the study. Patients enrolled in the

The primary efficacy end point was that the number of new Gad1 lesions appeared on T1 weighted sequences from weeks 4 to 24. This end point has been validated in many previous 6-month MS trials and was based on the diazoxide effects on microglia activation and bloodbrain barrier closing. Secondary MRI end points included cumulative number of lesions on T2-weighted sequences for all MRIs, cumulative number of lesions on T2-weighted sequences in the 6 months of the study (compared with the baseline MRI); cumulative number of combined unique active lesions (CUALs), addition of new or enlarged lesions on T2-weighted sequences that do not enhance with gadolinium and new Gad1 lesions for all MRIs; cumulative number of CUALs, addition of new or enlarged lesions on T2-weighted sequences that do not enhance with gadolinium and new Gad1 lesions in the 6 months after starting therapy (compared with the baseline MRI); number of patients without Gad1 lesions in T1-weighted sequences in the 6 months after starting therapy; and percentage brain volume change (PBVC). Secondary clinical end points also included the measurement of relapse-free status, relapse rate, number of relapses requiring corticosteroid treatment, time to first relapse during the trial, change in EDSS scale and quality of life. Secondary safety end points were monitorized during the 6 months of therapy up until 15 days after the last dose of diazoxide and included incidence, nature and severity of adverse events (AEs). Control of glucose levels, glycated

The results of the clinical trial showed no differences in the diazoxide groups in the primary end point or in the other MRI variables associated with the presence of new lesions [80]. However, an interesting decrease in the PBVC in the patients who received diazoxide com‐ pared with placebo was found. The number of new T2/Proton Density lesions converting to black holes was not different between arms. Finally, in accordance with the small sample size of the trial, no differences were detected in clinical variables of relapse-free status, relapse rate, number of relapses requiring corticosteroid treatment, change in EDSS or quality of life.

There were six serious adverse events during the study but only a case with autoimmune hypothyroidism was considered to be related to the therapy that was not discontinued. Regarding the described clinical effects of diazoxide on glycaemia, the detected glucose blood levels were always within the limits of normality. This confirms that the diazoxide doses used in this trial were lower than those that induce hyperglycaemic and hypotensive effects.

As commented above, at the doses tested, diazoxide does not seem to have a significant effect that impedes the appearance of new Gad1 lesions. However, although patients were randomly distributed within the groups, at the beginning of the study those patients receiving diazoxide presented a higher number of Gad1 lesions than patients included in the placebo group. This initial higher disease activity in the group treated with diazoxide was maintained throughout the trial. These findings confirm the need to perform an extensive and accurate selection of patients, in terms of the activity of the disease, which must be carried out prior to the clinical

follow-up study were subjected to an additional scan at week 48.

320 Trending Topics in Multiple Sclerosis

haemoglobin and blood pressure were also monitorized.

trial.

Neurodegenerative changes in MS such as demyelination and axonal loss take place early in the disease and independently from acute immuno-mediated inflammation. The reason why these focal demyelinating inflammatory lesions appear within the CNS still needs to be clarified, but diverse clinical presentations indicate the existence of different patterns of inflammation and neurodegeneration. Nevertheless, the molecular mechanisms underlying axonal damage in acute inflammation and chronic demyelination are potentially amenable to therapy. In this context, the pursuit of neuroprotective therapies in MS should provide new valid alternatives to significantly impact on disease progression. In this pursuit, the standard view of neuroprotection, which has long been mostly focused on neurons, is no longer valid. Instead, this view has been replaced by an integrative approach that recognizes the importance of dynamic interactions between immune cells, microglia, astrocytes and neurons.

A proper evaluation of neurodegenerative aspects in MS remains difficult. Also, for all mentioned drugs the neuroprotective effect has not been fully established. These issues could be better understood by applying well-established and new clinical and imaging parameters that require further preclinical and clinical investigations. Moreover, molecular characteriza‐ tion of the different MS clinical presentations must allow a pharmacogenomics classification of patients and development of personalized therapies. In this line, promising future ap‐ proaches will combine high-throughput techniques such as proteomics and genomics to investigate further MS neurodegenerative processes, in particular neuroinflammation.
