This review describes specific strategies for targeting to the central nervous system (CNS). Systemically administered drugs can reach the brain by crossing one of two physiological barriers resistant to free diffusion of most molecules from blood to CNS: the endothelial blood-brain barrier or the epithelial blood-cerebrospinal fluid barrier. These tissues constitute both transport and enzymatic barriers. The most common strategy for designing effective prodrugs relies on the increase of parent drug lipophilicity. However, increasing lipophilicity without a concomitant increase in rate and selectivity of prodrug bioconversion in the brain will result in failure. In these regards, consideration of the enzymes present in brain tissue and in the barriers is essential for a successful approach. Nasal administration of lipophilic prodrugs can be a promising alternative non-invasive route to improve brain targeting of the parent drugs due to fast absorption and rapid onset of drug action. The carrier-mediated absorption of drugs and prodrugs across epithelial and endothelial barriers is emerging as another novel trend in biotherapeutics. Several specific transporters have been identified in boundary tissues between blood and CNS compartments. Some of them are involved in the active supply of nutrients and have been used to explore prodrug approaches with improved brain delivery. The feasibility of CNS uptake of appropriately designed prodrugs via these transporters is described in detail.

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Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progressive gait and limb ataxia, but in most cases is also accompanied by a severe hypertrophic cardiomyopathy. This life threatening symptom can be ameliorated by the administration of idebenone, a short chain quinone antioxidant, supporting additional evidence that oxidative stress plays a major role in the pathogenesis of this disease. In this study we analyze the combinatorial effect of different antioxidants on cell viability of FRDA fibroblasts and of RAT-1 immortalized fibroblasts exposed to oxidative stress. We find that an equimolar mixture of idebenone and vitamin E is more potent than each of the compound alone. Increased potency was also obtained with a novel synthetic antioxidant (Fe-Aox29) combining the active groups from both idebenone and vitamin E. These results indicate, that idebenone and vitamin E might act synergistically to counteract oxidative stress in fibroblasts from FRDA patients.

The Flaviviridae virus family presents linear, plus sense, single-stranded RNA genome of 9.6 to 12.3-kilobases in length and is responsible for about seventy diseases, of which thirteen in humans. The viruses belonging to this family, are divided in three different genera, showing a great similarity in virion morphology, genome organization and replication strategy:1) Hepacivirus [Hepatitis C Virus (HCV)], Flavivirus [e.g. Yellow Fever Virus (YFV), Dengue Fever Virus (DFV), West Nile Virus (WNV)], and Pestivirus [Bovine Viral Diarrhea Virus (BVDV), Border Disease Virus (BDV)]. [2][3][4][5] Bovine viral diarrhea virus (BVDV), the prototype representative of the Pestivirus genus, is ubiquitous and causes a range of clinical manifestations, including abortion, teratogenesis, respiratory problems, chronic wasting syndrome, immune system dysfunction, and predisposition to secondary viral and bacterial infections. 5)Regardless of the availability of vaccines 6) against BVDV and the increasingly elaborate eradication or control of programs, BVDV continues to be a financial burden to the farming industry. An alternative approach against BVDV infections could be the use of antiviral agents that specifically inhibit the replication of the virus. Although not suited to treat large herds, it could be important to have selective anti-Pestivirus compounds on hand.Recently, a number of selective anti-BVDV compounds have been reported. These include the following: polymerase inhibitors i.e. N-propyl-N-[2-(2H-1,2,4-triazino[5,6-b]indol-3-ylthio)ethyl]-1-propanamine (VP32947), 7) a thiazole urea derivative, 8) a cyclic urea derivative 9) and inhibitors of the NS3/NS4A protease, for example, a boron-modified peptidyl mimetic.10) Aromatic cationic molecules have also been reported to inhibit BVDV replication, although the mechanism of action remains to be elucidated.11) Other BVDV inhibitors target cellular enzymes such as the a-glucosidase 12-14) and inosine monophosphate dehydrogenase (IMPDH).15) Recently, a new highly selective BVDV polymerase inhibitor of pestivirus replication, 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP), was reported. 16)Like BVDV, HCV also belongs to the Flaviviridae family. It is an important cause of chronic hepatitis throughout the world and is the most common factor involved in the development of liver cirrhosis and hepatocellular carcinoma. 17,18) The licensed therapy based on the combination of pegylated interferon-a with the broad spectrum antiviral agent ribavirin, has a limited efficacy (about 60%) and there are important side effects associated with the therapy. Therefore, highly effective and selective inhibitors of HCV replication are urgently required. 19) BVDV is considered to be a valuable surrogate virus model for identifying and characterizing antiviral agents for use against HCV. 20) In some aspects of viral replication, BVDV is more advantageous than the currently used HCV replicon systems 21,22) because this latter does not present a complete replication cycle thus...

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