Selection, optimization, and pharmacokinetic properties of a novel, potent antiviral locked nucleic acid-based antisense oligomer targeting hepatitis C virus internal ribosome entry site

We have screened 47 locked nucleic acid (LNA) antisense oligonucleotides (ASOs) targeting conserved (>95% homology) sequences in the hepatitis C virus (HCV) genome using the subgenomic HCV replicon assay and generated both antiviral (50% effective concentration [EC(50)]) and cytotoxic (50% cytotoxic concentration [CC(50)]) dose-response curves to allow measurement of the selectivity index (SI). This comprehensive approach has identified an LNA ASO with potent antiviral activity (EC(50) = 4 nM) and low cytotoxicity (CC(50) >880 nM) targeting the 25- to 40-nucleotide region (nt) of the HCV internal ribosome entry site (IRES) containing the distal and proximal miR-122 binding sites. LNA ASOs targeting previously known accessible regions of the IRES, namely, loop III and the initiation codon in loop IV, had poor SI values. We optimized the LNA ASO sequence by performing a 1-nucleotide walk through the 25- to 40-nt region and show that the boundaries for antiviral efficacy are extremely precise. Furthermore, we have optimized the format for the LNA ASO using different gapmer and mixomer patterns and show that RNase H is required for antiviral activity. We demonstrate that RNase H-refractory ASOs targeting the 25- to 40-nt region have no antiviral effect, revealing important regulatory features of the 25- to 40-nt region and suggesting that RNase H-refractory LNA ASOs can act as potential surrogates for proviral functions of miR-122. We confirm the antisense mechanism of action using mismatched LNA ASOs. Finally, we have performed pharmacokinetic experiments to demonstrate that the LNA ASOs have a very long half-life (>5 days) and attain hepatic maximum concentrations >100 times the concentration required for in vitro antiviral activity.     

Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients

Russell C, Conn V, Ashbaugh C, Madsen R, Wakefield M, Webb A, Coffey D, Peace L. Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
Clin Transplant 2011: 25: 864–870. © 2010 John Wiley & Sons A/S. Abstract: Background: Immunosuppressive medication non‐adherence is one of the most prevalent but preventable causes of poor outcomes in adult renal transplant recipients, yet there is a paucity of studies testing interventions in this area. Methods: Using a randomized controlled trial design, 30 adult renal transplant recipients were screened for medication non‐adherence using electronic monitoring. Fifteen non‐adherent participants were randomized to receive either a continuous self‐improvement intervention or attention control management. The six‐month continuous self‐improvement intervention involved the participant and clinical nurse specialist collaboratively identifying the person’s life routines, important people, and possible solutions to enhance medication taking. The participant then received individual monthly medication taking feedback delivered via a graphic printout of daily medication taking generated from electronic monitoring. Results: The mean medication adherence score for the continuous self‐improvement intervention group (n = 8) was statistically significantly higher than the attention control group’s (n = 5) mean medication adherence score (p = 0.03). The continuous self‐improvement intervention effect size (Cohen’s d) was large at 1.4. Participants’ perceptions of the intervention were highly favorable. Conclusions: The continuous self‐improvement intervention shows promise as an effective and feasible approach to improve medication adherence in adult renal transplant recipients. A fully‐powered study with a diverse sample is needed to confirm these preliminary findings.     

Ivermectin: uses and impact 20 years on

PURPOSE OF REVIEW: Ivermectin was first discovered and used in veterinary medicine over 20 years ago. This review highlights some of the recent published research from 2005 through June 2006 on the use of ivermectin in both helminth and arthropod infection. RECENT FINDINGS: In recent years, several published studies have detailed the expanding role for ivermectin in multiple endo and ectoparasitic infections, including scabies, pediculosis, soil transmitted helminths, gnathostomiasis and myiasis. In addition, there is increasing experience with parenteral ivermectin for the treatment of disseminated strongyloidiasis. The success of ivermectin in reducing Onchocerca volvulus and Wuchereria bancrofti transmission through universal treatment in disease control programs continues to be well documented, but recent epidemiologic data describe suboptimal response to ivermectin by O. volvulus in a minority of individuals, the molecular markers for which are currently under investigation. SUMMARY: Over 20 years of research and clinical use have advanced ivermectin from its beginnings as a veterinary anthelmintic to its significant role in several successful disease control programs. Nevertheless, further research is needed to understand the basis for suboptimal response and to better define optimal drug regimens for varying diseases.     

Randomized double blind placebo-controlled trial of a Chinese herbal therapy (CH100) in chronic hepatitis C

BACKGROUND AND AIM: Hepatitis C virus (HCV) is a common infection with serious health consequences. Alternative therapies are often used for hepatitis C. The aim of the present study was to examine CH100, a Chinese herbal remedy, for efficacy in therapy of chronic HCV. METHODS: A randomized double blind placebo-controlled study in a tertiary outpatient clinic of CH100 over 24 weeks with 24 weeks follow-up in patients with chronic HCV infection. Alanine aminotransferase (ALT), HCV-RNA, quality of life (by SF-36) and side-effects were examined regularly. Ninety-seven patients were enrolled of which 91 were suitable for analysis. RESULTS: No significant differences were observed between patients receiving CH100 (n = 61) or placebo (n = 30) at baseline or during follow-up in either ALT or viral titer. However, patients receiving CH100 had a fall in mean ALT over time (P = 0.05 at week 4, P = 0.26 at week 12, and P = 0.04 at week 24), with reversion to baseline during post-treatment follow up. No significant side-effects were observed although mild complaints were common. Quality of life scores improved in both groups with time, and bodily pain significantly improved in CH100 recipients. CONCLUSION: CH100 appears to be no better than placebo in the treatment of patients with chronic HCV infection.