Pharmacokinetic evaluation of besifovir for the treatment of HBV infection

Introduction: Besifovir (LB80380) is a relatively new oral acyclic nucleotide phosphonate. We reviewed the pharmacokinetic characteristics of LB80380 and discussed its role in the treatment of chronic hepatitis B infection.

Areas covered: LB80380 is a prodrug of LB80331 and LB80317. It is rapidly absorbed when taken orally. Escalating doses of besifovir produce linear increase of the plasma concentration. Doses above 60mg are effective for inhibiting HBV in human. Using 60mg as an example, the maximal concentration of LB80331 in plasma is 397 ng/mL. The time required to reach maximal concentration in plasma and elimination half-life are 2.0 and 3.0 h, respectively. Besifovir and its metabolites are mainly excreted via the kidneys. Its antiviral efficacy is non-inferior to ETV 0.5mg daily. It is generally safe in terms of renal and bone toxicity. The most common adverse event is carnitine depletion which affects almost all patients on besifovir requiring carnitine supplementation.

Expert opinion: Besifovir demonstrated predictable pharmacokinetic characteristics in human subjects. Few clinical studies on besifovir have been conducted. More data are expected particularly for special populations. The adverse events upon long term exposure should be monitored. Large scale head-to-head trials comparing besifovir with existing NA, especially tenofovir alafenamide, should be conducted.     

Window of opportunity treatment in breast cancer

Window of opportunity therapies, which involve short‐term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone‐receptor positive breast cancer, a 2‐week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision‐making regarding treatment options. Changes in short‐term biomarker endpoints such as cell proliferation measured by Ki‐67 can act as surrogate markers of long‐term outcomes. Paired tissues obtained pre‐ and post‐investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.     

Rigid membranes of Malayan ovalocytes: a likely genetic barrier against malaria

A high frequency of nonhemolytic hereditary ovalocytosis in Malayan aborigines is thought to result from reduced susceptibility of affected individuals to malaria. Indeed, Kidson et al. recently showed that ovalocytes from Melanesians in Papua New Guinea are resistant to infection in culture by the malarial parasite Plasmodium falciparum. In order to determine if protection against parasitic invasion in these ovalocytes might be the result of some altered membrane material property in these unusual cells, we measured their membrane and cellular deformability characteristics using an ektacytometer . Ovalocytic red cells were found to be much less deformable in comparison to normal discoid red cells. Similar measurements on isolated membrane preparations revealed a marked reduction in ovalocytic membrane deformability. To produce equal deformation of ovalocytic and normal membranes, ovalocytes required an 8-10-fold increase in applied shear stress, indicating that their membrane was capable of deforming under sufficient stress. To test the possibility that this increased membrane rigidity might confer resistance to parasitic invasion, we performed an in vitro invasion assay using Plasmodium falciparum merozoites and Malayan ovalocytes of varying deformability from seven different donors. The level of infection of the ovalocytes ranged from 1% to 35% of that in control cells, and the extent of inhibition appeared to be closely related to the reduction in membrane deformability. Moreover, we were able to induce similar resistance to parasitic invasion in nonovalocytic normal red cells by increasing their membrane rigidity with graded exposure to a protein crosslinking agent. Our findings suggest that resistance to parasite invasion of Malayan ovalocytes is the result of a genetic mutation that causes increased membrane rigidity.     

Synergistic Inhibition on Acetylcholinesterase by the Combination of Berberine and Palmatine Originally Isolated from Chinese Medicinal Herbs

Alzheimer’s disease is a multi-factorial neurodegenerative disorder devastatingly affecting the aged population worldwide. Previous studies have shown that medicinal herbs used in traditional Chinese medicine might be benefit to Alzheimer’s disease patients. Berberine and palmatine, two isoquinoline alkaloids found in several medicinal herbs, were used for memory enhancement in China. In this study, the inhibitory effects of combined berberine and palmatine on acetylcholinesteras were evaluated using recombinant human acetylcholinesterase. Our results showed that the combination of berberine and palmatine inhibited acetylcholinesterase in a mixed competitive pattern. By the median-effect principle, the calculated combination index of the combination was less than 1, suggesting that berberine and plamatine inhibited acetylcholinesterase synergistically. Furthermore, the drug-reducing index of berberine and palmatine were 2.98 and 2.66, respectively. Taken together, the results showed that the combination of the two alkaloids might potentially be developed as a more effective therapeutic strategy for Alzheimer’s disease patients.     

The application of the theory of planned behavior to help-seeking intention in a Chinese society

Purpose

This study tested the efficacy of Ajzen’s theory of planned behavior (TPB) in explaining intention to seek mental health services and compared the traditional TPB model with a TPB partial mediation model. It also aimed to understand factors related to intention to seek mental health services in Macao to inform local policies.

Method

The present study consisted of two phases: (a) a pilot study to develop belief-based measures used in the main study, and (b) a cross-sectional study to investigate the application of TPB in understanding help-seeking intention. In the main study, 337 Macao residents (age range 18–65) participated in a survey conducted in the community.

Results

The TPB partial mediation model was better than the traditional TPB model in explaining help-seeking intention in Macao. The model also suggested that attitude, subjective norm, and perceived behavioral control were all significant predictors of help-seeking intention. However, symptom severity, prior help-seeking, and gender did not significantly directly predict help-seeking intention.

Conclusion

Preference for the TPB partial mediation model may be culturally relevant. The implications of the findings are discussed in relation to the salient beliefs about help-seeking. Limitations and recommendations for future research are provided.