Snowdon (United States)

Jaroslav Matějka, Život sira Winstona, Vydavatelstvo politickej literatúry, Bratislava 1968, 662 str.

The European Free Trade Association and the Crisis of European Integration, Graduate Institute of International Studies, Geneva, Michael Joseph Ltd., Londýn 1968, 323 str.

K otázce směnitelnosti měny

Novel therapeutics are greatly needed that target specific pathological receptors and pathways involved in Neuropathic Pain (NP). Extending our previous work published in this Journal on Group I metabotropic glutamate receptor (mGluR) modulators, we now investigate the therapeutic potential of niclosamide in modulating aberrant glutamate transmission in NP. Calcium mobilization assays and cross-receptor selectivity experiments are conducted to characterize the pharmacological activity of niclosamide. A focused series of niclosamide analogues is then prepared to elucidate key structural determinants that emerged from computational molecular modeling analysis on drug-receptor interactions. Finally, niclosamide and a carbamate derivative are studied to assess their efficacy in an NP-evoked mechanical hyperalgesia model in rats. Niclosamide is a low-nanomolar allosteric antagonist of Group I mGluRs with high selectivity for Group I over homologous Group III mGluRs. The phenolic hydroxyl group of niclosamide forms a crucial hydrogen bond with mGluR1/5. Its bioactive coplanar conformation is further stabilized by the nitro substituent on the B ring and an intramolecular bond. Mechanical hyperalgesia in NP rats is reversed by niclosamide through three different dosing routes. To our knowledge, this is the first report of the salicylanilide class of compounds as potential treatments for NP.

Drug repositioning strategies were employed to explore new therapeutic indications for existing drugs that may exhibit dual negative mGluR1/5 modulating activities as potential treatments for neuropathic pain. A customized in silico-in vitro-in vivo drug repositioning scheme was assembled and implemented to search available drug libraries for compounds with dual mGluR1/5 antagonistic activities, that were then evaluated using in vitro functional assays and, for validated hits, in an established animal model for neuropathic pain. Tizoxanide, the primary active metabolite of the FDA approved drug nitazoxanide, fit in silico pharmacophore models constructed for both mGluR1 and mGluR5. Subsequent calcium (Ca++) mobilization functional assays confirmed that tizoxanide exhibited appreciable antagonist activity for both mGluR1 and mGluR5 (IC50 = 1.8μM and 1.2μM, respectively). The in vivo efficacy of nitazoxanide administered by intraperitoneal injection was demonstrated in a rat model for neuropathic pain. The major aim of the present study was to demonstrate the utility of an in silico-in vitro-in vivo drug repositioning protocol to facilitate the repurposing of approved drugs for new therapeutic indications. As an example, this particular investigation successfully identified nitazoxanide and its metabolite tizoxanide as dual mGluR1/5 negative modulators. A key finding is the vital importance for drug screening libraries to include the structures of drug active metabolites, such as those emanating from prodrugs which are estimated to represent 5-7% of marketed drugs.

John Lewis Gaddis: The Cold War: A New History. 1st ed. New York: The Penguin Press, 2005, 333 stran, ISBN 1-59420-062-9.