PubMed · 14460804
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T KUROTSU. 1962. [Final lecture].. https://pubmed.ncbi.nlm.nih.gov/14460804/
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The central nervous system (CNS) activity has been investigated by using a topological substructural molecular approach (TOPS-MODE). A discriminant analysis to classify CNS and non-CNS drugs was developed on a data set (302 compounds) of great structural variability where more than 81% (247/302) were well classified. Randic's orthogonalization procedures was carried out to allow the interpretation of the model and to avoid the collinearity among descriptors. The discriminant model was assessed by a leave-n-out (when n varies from 2 to 20) cross-validation procedure (79.94% of correct classification), an external prediction set composed by 78 CNS/non-CNS drugs (80.77% of correct classification) and a 5-fold full cross-validation (removing 78 compounds in each cycle, 80.00% of good classification). With this methodology was demonstrated that the hydrophobicity increase the CNS activity, while the dipole moment and the polar surface area decrease it; evidencing the capacity of the TOPS-MODE descriptors to estimate CNS activity for new drug candidates. The structural contributions to the CNS activity for two compounds are presented on the basis of fragment contributions. The model has also been able to identify potential structural pharmacophore, showing its possibilities in the lead generation and optimization processes.
The authors present and discuss a new protocol for active multiple sclerosis (MS) patients. A double blind randomized controlled multicenter study was planned to study the effects of a combination regimen therapy: cyclophosphamide plus beta interferon versus beta interferon alone on both relapsing-remitting and secondary MS patients with active disease. The primary endpoint of this study is the number of new gadolinium enhancing lesions at MRI evaluation. Secondary endpoints are new T2 lesions, new T1 lesions, T2 lesion load, T1 lesion load, cerebral atrophy, number of patients who were relapse-free, number of patients who improved, yearly relapses, quality of life, disability and cognitive impairment, frequency of neutralizing antibodies, safety of the combination therapy (cyclophosphamide + beta interferon). The study will enroll 225 patients in 25 Italian MS centers. Eligible for the study are patients with either relapsing-remitting or secondary MS according McDonald criteria on 6-24 months beta interferon treatment with active disease (new gadolinium enhancing lesion or who experienced a new relapse on beta interferon treatment). Clinical evaluation will be performed every 4 months, MRI yearly. Vital signs and eventual adverse events will be collected monthly. The study will last 36 months, 12 for the enrollment phase and 24 for the treatment phase. The study will start on April 2004.
The development of ultrafast sequences has led to a significant improvement in fetal MRI. Imaging protocols have to be adjusted to the rapidly developing fetal central nervous system (CNS) and to the clinical question. Sequence parameters must be changed to cope with the respective developmental stage, to produce images free from motion artefacts and to provide optimum visualization of the region and focus of interest. In contrast to postnatal studies, every suspect fetal CNS abnormality requires examination of the whole fetus and the extrafetal intrauterine structures including the uterus. This approach covers both aspects of fetal CNS disorders: isolated and complex malformations and cerebral lesions arising from the impaired integrity of the feto-placental unit.