Up to 170 million people are infected with Hepatitis C Virus worldwide. Chronic HCV infection is the leading cause of fibrosis, cirrhosis and liver cancer. Treatment options are currently limited to interferon based therapies alone or in conjunction with direct acting antivirals (DAA) such as viral protease inhibitors. While the implementation of DAAs has increased the effective cure rate of HCV infected individuals, treatment is far from being complete or ideal. New DAAs with unique modes of action will be necessary to compliment our current repertoire of anti-HCV therapies. Previously our lab identified three dihydropyridines (DHP) as potent HCV replication inhibitors. We investigated and characterized the anti-HCV properties of nine additional DHP compounds. We also show that DHP compounds inhibit IRES dependent translation in full-length HCV. This inhibition of two separate steps of the viral life cycle may be a unique feature of DHPs making them superior DAAs. Among these DHPs, efonidipine emerged as the most effective HCV replication and translation inhibitor with the least toxicity. Using a real-time evolution strategy, we developed and characterized a mutant virus which was resistant to DHPs and several other drugs which modify intracellular calcium stores. Our results further the understanding of DHP inhibition of HCV providing a solid basis for investigation of more structurally related compounds as potent inhibitors of HCV.

Universiẗat, Diss.--Bonn, 1998.

Regensburg, Univ., Diss., 2002. / Computerdatei im Fernzugriff.

Regensburg, Univ., Diss., 2002. / Computerdatei im Fernzugriff.

Regensburg, Universiẗat, Diss., 2002.

Proefschrift Rijksuniversiteit Groningen.

Braunschweig, Techn. Univ., Diss., 1994.

1,4-Dihydropyridines (DHPs) are a classification of compounds used as calcium channel blockers in the treatment of various conditions. These compounds readily undergo photodegradation. The degradants produced have no pharmaceutical activity and render the drugs ineffective. DHPs also exhibit polymorphism. Nifedipine and Nimodipine are two such drugs. This study aimed to monitor the photodegradation of these two drugs and to establish the effect of particle size, polymorphism and β-Cyclodextrin (β-CD) on the rate of photodegradation. Different polymorphs (namely the amorphous and stable crystalline polymorphs) of the two drugs were prepared for use in the study. Mixtures of each drug with β-CD were also prepared for photostability studies. The mixtures were prepared in a 1:1 molar ratio. The rate of photodegradation was studied with a 500 W metal halide lamp in accordance to ICH guidelines. The study employed samples on a small scale where degradation was analysed with High Performance Liquid Chromatography, and also samples on a larger scale where degradation was monitored with Powder X-ray Diffraction. The two sets of results of observing the degradation process by two analytical techniques where compared in terms of their quantification methods. The extent of photodegradation was suitably modelled and fitted using the Avrami-Erofeyev kinetic equation. Smaller particle size showed increased photodegradation for Nimodipine; the effect was insignificant for Nifedipine however. For both drugs it was found that the amorphous polymorph underwent faster photodegradation. The study showed that β-CD caused an increase in photodegradation for both drugs under these experimental conditions.

Univ., Habil.-Schr.--Halle-Wittenberg, 2000.

Fatigue and skeletal muscle weakness are problems associated with congestive heart failure. Research does not support the theory that the affected cardiac function is responsible for the fatigue. During skeletal muscle fatigue, calcium handling is altered. Thus, the fatigue associated with congestive heart failure could be attributed to altered calcium handling. The main proteins involved in calcium release are the ryanodine receptor (RyR) and the dihydropyridine receptor (DHPR). The main proteins involved in calcium uptake are the fast and slow isoforms of sarco(endo)plasmic reticulum calcium ATPase (SERCA 1 and SERCA 2 respectively). Calsequestrin (Csq) and calmodulin (CaM) play regulatory roles in calcium handling. Changes in the levels of these proteins could explain alterations in calcium handling and subsequent muscle function. The purpose of this study was to use a genetic model of heart failure, the SHHF rat, to examine the levels of regulatory calcium handling proteins to determine if changes in the amounts of RyR, DHPR, SERCA1, SERCA2, Csq and CaM are altered in congestive heart failure. A significant decrease was found in the amounts of RyR, DHPR, and SERCA 1 of the SHHF gastrocnemius and diaphragm samples in comparison to the control. There was no significant difference found in the amounts of CaM or SERCA 2 between the two groups. Csq was not found to be statistically different between the two groups of the gastrocnemius samples. However, there was an increase in Csq in the SHHF diaphragm samples in comparison to the control. In conclusion, the calcium handling proteins are affected in the genetic model of heart failure. These changes could explain previous reports of altered calcium handling within the skeletal muscles of congestive heart failure animals. / Master of Science