Recent patents on nucleoside and nucleotide inhibitors for HCV.

Hepatitis C virus (HCV) infection is a leading cause of liver diseases such as cirrhosis and hepatocellular carcinoma. There are estimated 170 million people worldwide chronically infected with the virus. The lack of highly effective and safe therapeutics for HCV infection has spurred intensive efforts to develop anti-HCV drugs as evidenced by the large number of new patent applications filed each year. Nucleoside and nucleotide inhibitors are the analogues of DNA or RNA substrates, and they inhibit viral polymerases by acting as chain terminators, viral mutagens, or simple competitive inhibitors. The successful development of various nucleoside and nucleotide inhibitors for the treatment of HIV and HBV infections has prompted the drug industry to seek similar strategies for HCV. This review summarizes recently issued or published patents covering nucleoside and nucleotide inhibitors for HCV. The claimed chemical structures and available biological activities, mechanism of action, and drug resistance profiles are discussed. The development status of several promising nucleoside inhibitors is also described.

The duration of immobilization causes the changing pharmacodynamics of mivacurium and rocuronium in rabbits.

In the clinical setting, in patients with a cast, it is not known whether the monitoring of the neuromuscular paralysis induced by either mivacurium or rocuronium in the contralateral limb is the correct interpretation. We compared the dose-response relationships and the neuromuscular blocking effects of mivacurium and rocuronium in 56 anesthetized rabbits immobilized in a plaster cast for 2, 4, and 6 wk. Train-of-four stimuli were simultaneously applied every 10 s to both common peroneal nerves, and the force of contraction of both tibialis anterior muscles was measured. Immobilization was associated with a rightward shift of the mivacurium and rocuronium dose-response curves after the duration of the immobilized limb, whereas no shift occurred in the contralateral limb. The 50% effective dose values for 0, 2, 4, and 6 wk of immobilization in the immobilized limb of mivacurium were 15.1 +/- 1.4, 18.2 +/- 1.5, 21.5 +/- 1.9, and 27.8 +/- 2.5 microg/kg, respectively, and they were unchanged in the contralateral limb. The calculated 50% effective dose values for the correspondence of rocuronium were 48.1 +/- 4.1, 56.2 +/- 4.2, 64.8 +/- 4.9, and 75.1 +/- 5.5 microg/kg, respectively, and they were unchanged in the contralateral limb. The rabbits receiving mivacurium and rocuronium had a significantly accelerated recovery from neuromuscular blockade compared with the placebo group in the immobilized limb after the immobilized duration, whereas there were no differences in the contralateral limb. The results of the present study showed that immobilization disuse atrophy produced by casting led to the development of resistance to both mivacurium and rocuronium; however, no resistance was shown in the contralateral limb. The peripheral nerve stimulator could be applied on the nonimmobilized limb, which might be associated with a normal recording if either mivacurium or rocuronium was used as neuromuscular relaxants.