pyrimidinones and Peripheral-Nervous-System-Diseases

Successful treatment of chronic hepatitis B (CHB) often requires long-term oral nucleoside/nucleotide agents which can be associated with viral resistance, patient non-compliance and adverse effects. Telbivudine is one of the more potent options available, with a 6.5- to 6.6-log copies/ml hepatitis B DNA reduction at 12 weeks in an early viral kinetic study, a potency comparable to entecavir. It is also one of the few drugs in the treatment of CHB under FDA pregnancy Category B.. The efficacy and safety profile of telbivudine in compensated and decompensated CHB patients compared to other agents are discussed. Viral resistance, characteristic adverse effects including elevation in creatine kinase and peripheral neuropathy in telbivudine treatment are reviewed. Infrequent but significant adverse effects of other nucleoside/nucleotide analogs are highlighted.. Readers are provided the latest update on the clinical profile of long-term use of telbivudine.. Long-term telbivudine treatment offers effective viral suppression to CHB patients with certain baseline characteristics and on-treatment virologic response. Creatine kinase elevation is not a good predictor of muscle-related adverse effects with nucleoside/nucleotide analogs. But significant myopathy and neuropathy have been reported in a small number of patients receiving telbivudine.

Topics: Adult; Antiviral Agents; Biomarkers; Creatine Kinase; Double-Blind Method; Drug Resistance, Viral; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Isoenzymes; Male; Multicenter Studies as Topic; Muscular Diseases; Nucleosides; Peripheral Nervous System Diseases; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine

Topics: Antiviral Agents; Hepatitis B, Chronic; Humans; Nucleosides; Peripheral Nervous System Diseases; Pyrimidinones; Rhabdomyolysis; Telbivudine; Thymidine

Cold hypersensitivity is a common sensory abnormality accompanying peripheral neuropathies and is difficult to treat. Progress has been made in understanding peripheral mechanisms underlying neuropathic pain but little is known concerning peripheral mechanisms of cold hypersensitivity. The aim of this study was to analyze the contribution of uninjured primary afferents to the cold hypersensitivity that develops in neuropathic rats. Rats with a lumbar 5 (L5) and L6 spinal nerve ligation (SNL, Chung model) but not sham, developed mechanical allodynia, evidenced by decreased paw withdrawal thresholds and increased magnitude of response to von Frey stimulation. Cold hypersensitivity also developed in SNL but not sham rats, evidenced by enhanced nociceptive behaviors induced by placement on a cold plate (6 degrees C) or application of icilin (a transient receptor potential M8 (TRPM8)/transient receptor potential A1 (TRPA1) receptor agonist) to nerve-injured hind paws. Single fiber recordings demonstrated that the mean conduction velocities of intact L4 cutaneous A delta- and C-fibers were not different between naive and SNL rats; however, mechanical thresholds of the A delta- but not the C-fibers were significantly decreased in SNL compared with naive. There was a higher prevalence of C-mechanoheat-cold (CMHC) fibers in SNL compared with naive, but the overall percentage of cold-sensitive C-fibers was not significantly increased compared with naive. This was in contrast to the numerous changes in A delta-fibers: the percentage of L4 cold sensitive A delta-, but not C-fibers, was significantly increased, the percentage of L4 icilin-sensitive A delta-, but not C-fibers, was significantly increased, the icilin-induced activity of L4 A delta-, but not C-fibers, was significantly increased. Icilin-induced activity was blocked by the TRPA1 antagonist Ruthenium Red. The results indicate plasticity in both A delta- and C-uninjured fibers, but A delta fibers appear to provide a major contribution to cold hypersensitivity in neuropathic rats.

Topics: Action Potentials; Analysis of Variance; Animals; Calcium; Cold Temperature; Disease Models, Animal; Dose-Response Relationship, Drug; Ganglia, Spinal; Hyperalgesia; Male; Nerve Fibers; Neural Conduction; Neuronal Plasticity; Neurons, Afferent; Pain Threshold; Peripheral Nervous System Diseases; Physical Stimulation; Pyrimidinones; Rats; Rats, Sprague-Dawley; Reaction Time; Statistics, Nonparametric