Research progress on the nucleoside/nucleotide-loaded nanomedicines / 浙江大学学报·医学版

Nucleoside drugs play an essential role in treating major diseases such as tumor and viral infections, and have been widely applied in clinics. However, the effectiveness and application of nucleoside drugs are significantly limited by their intrinsic properties such as low bioavailability, lack of targeting ability, and inability to enter the cells. Nanocarriers can improve the physiological properties of nucleoside drugs by improving drug delivery efficiency and availability, maintaining drug efficacy and system stability, adjusting the binding ability of the carrier and drug molecules, as well as modifying specific molecules to achieve active targeting. Starting from the design strategy of nucleoside drug nanodelivery systems, the design and therapeutic effect of these nanomedicines are described in this review, and the future development directions of nucleoside/nucleotide-loaded nanomedicines are also discussed.

The anti-ZIKA virus activity of tenofovir disoproxil fumarate in vitro / 药学学报

Tenofovir disoproxil fumarate (TDF) is a nucleoside analogue that has been widely used for clinical treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. The aim of this study was to investigate whether TDF has anti-Zika virus (ZIKV) activity in vitro. The inhibitory effect of TDF on ZIKV was detected by plaque reduction assay. Then, the anti-ZIKV activity of TDF at RNA level and protein level was verified by real time quantitative PCR and Western blot. Finally, MTT assay was used to determine the cytotoxicity of TDF. Our results showed that TDF not only reduced the formation of plaque after ZIKV infection, but also inhibited the replication of ZIKV RNA or expression of ZIKV NS2B protein. The 50% effective concentration (EC50) of TDF in inhibition of ZIKV replication were 14.96-27.47 μmol·L-1, while that of ribavirin was 56.01 ± 12.16 μmol·L-1, which served as the positive control. The cytotoxicity of TDF and ribavirin in Vero cells were very low, with their 50% cytotoxic concentration (CC50) values being greater than 500 μmol·L-1. The therapeutic index of TDF calculated by CC50/EC50 was greater than 18.20, which was significantly higher than that of ribavirin. The results suggest that TDF has good anti-ZIKV activity in vitro and is expected to become a candidate drug for anti-ZIKV therapy.

Clinical analysis of viral hepatitis B recurrence after liver transplantation for HBV-related liver diseases / 中华器官移植杂志

Objective This study focused on the recurrence risks of viral hepatitis B (VHB) after liver transplantation for hepatitis B virus (HBV)-related liver diseases.Methods A total of 599 patients undergoing liver transplantation due to HBV-related liver disease [hepatic cellular cancer (HCC),decompensated liver cirrhosis (DLC),acute liver failure (ALF)] were included in this study.All patients included in this study have been followed up for at least 12 months for liver biochemistry and HBV testing,altogether with the clinical presentation and outcomes.Treatment protocols about prevention of VHB recurrence in perioperative period and after liver transplantation,the time interval and influencing factors of VHB recurrence,and the disease prognosis were analyzed.Results Of the 599 patients,VHB recurrence were observed in 36 cases.The rate of VHB recurrence was 7.2％ (23/319),5.6％ (13/232) and 0 (0/48) for HCC,DLC and ALF,respectively.The rate of VHB recurrence was 2.3％,5.5％ and 6％ for 1 year,5 years and 8 years,respectively.The rate of VHB recurrence in the lamivudine group was significantly higher than in enticavir group and combination therapy group [16.5％ (22/133),2.9％ (8/280),3.2％ (6/186),respectively,P ＜ 0.05].Conclusion HCC and DLC as liver transplantation indication are independent risk factors for VHB recurrance after liver transplantatuib.For liver transplantation patients with HBV-related liver disease,entecavir monotherapy and combination therapy (lamivudine and adefovir,or tenofovir are both more effective on the prophylaxis of VHB recurrance than lamivudine monotherapy.

Clinical analysis of viral hepatitis B recurrence after liver transplantation for HBV-related liver diseases / 中华器官移植杂志

Objective To study the recurrence risks of viral hepatitis B (VHB) after liver transplantation for hepatitis B virus (HBV)-related liver diseases.Methods A total of 599 patients undergoing liver transplantation due to HBV-related liver disease [hepatic cellular cancer (HCC),decompensated liver cirrhosis (DLC),acute liver failure (ALF)] were included in this study.All patients included in this study have been followed up for at least 12 month for liver biochemistry and HBV testing,altogether with the clinic presentation and outcomes.Treatment protocols about prevention of VHB recurrence in perioperative period and after liver transplantation,the time interval and influence factors of VHB recurrence,and the disease prognosis were analyzed.Results Of the 599 patients,36 cases of VHB recurrence were observed.The rate of VHB recurrence was 7.2％ (23/319),5.6％ (13/232) and 0 (0/48) for HCC,DLC and ALF,respectively.The rates of VHB recurrence were 2.3％,5.5％,6％ for 1 year,5 years and 8 years,respectively.The rate of VHB recurrence in the lamivudine group was significantly higher than in enticavir group and combination therapy group [16.5％ (22/133),2.9％ (8/280),and 3.2％ (6/186),respectively,P＜0.05 for all].Conclusion HCC and DLC as liver transplant indications are independent risk factors for VHB recurrence after liver transplant.For liver transplant patients with HBV-related liver disease,entecavir monotherapy and combination therapy (lamivudine and adefovir,or tenofovir) are both more effective on the prophylaxis of VHB recurrence than lamivudine monotherapy.

Clinical efficacy of application of hepatitis B surface antigen-positive donor liver in liver transplantation / 器官移植

Objective To evaluate the clinical efficacy of application of hepatitis B surface antigen (HBsAg)-positive donor liver in adult liver transplantation. Methods Clinical efficacy of 28 recipients with liver diseases induced by virus B hepatitis (hepatitis B) undergoing liver transplantation using HBsAg-positive donor liver from July 2012 to October 2015 was retrospectively analyzed. Clinical prognosis and postoperative complications of the recipients were summarized. The changing features of serum levels of HBsAg and hepatitis B virus (HBV) DNA was investigated. Results After liver transplantation, 28 recipients were orally administered with entecavir to prevent the recurrence of hepatitis B. During perioperative period, 2 recipients died from sepsis and acute heart failure. During postoperative follow-up, 2 cases died from the recurrence of hepatocellular carcinoma (liver cancer). The remaining 24 patients were followed up for 12-26 months. Throughout the follow-up, 24 recipients were positive for serum HBsAg. After treatment, the titre of HBV DNA was significantly declined to <1×102 copies/mL at postoperative 12 months. No graft dysfunction induced by hepatitis B recurrence occurred in 24 recipients alive. Conclusions As a marginal donor liver, HBsAg-positive liver graft is safe for liver transplantation in the recipients with hepatitis B-related liver diseases. Postoperatively, anti-HBV treatment should be strengthened and intimate follow-up should be delivered.

Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade

Although much advancement has been achieved in the treatment of chronic hepatitis B, antiviral resistance is still a challenging issue. Previous generation antiviral agents have already developed resistance in a number of patients, and it is still being used especially in resource limited countries. Once antiviral resistance occurs, it predisposes to subsequent resistance, resulting in multidrug resistance. Therefore, prevention of initial antiviral resistance is the most important strategy, and appropriate choice and modification of therapy would be the cornerstone in avoiding treatment failures. Until now, management of antiviral resistance has been evolving from sequential therapy to combination therapy. In the era of tenofovir, the paradigm shifts again, and we have to decide when to switch and when to combine on the basis of newly emerging clinical data. We expect future eradication of chronic hepatitis B virus infection by proper prevention and optimal management of antiviral resistance.

Entecavir / Entecavir

Es un análogo nucleósido de guanosina con actividad selectiva contra hepatitis B, que ha surgido como una opción terapéutica en pacientes que desarrollan resistencia a la lamivudina con un perfil de seguridad similar a esta, encontrándose prácticamente ausencia de resistencia en casos de tratamiento por 1 año con una dosis de 1mg/día.

It is a nucleoside analogue of guanosine with selective activity against hepatitis B. It has come out as a therapeutic option for patients who develop resistance to Lamivudine with a security profile similar to this medicine. There is absence of resistance in case of 1 year treatments with a dosage of 1mg/day.

Telbivudina / Telbivudina

Es un análogo nucleósido sintético de la timidina, cuyo nombre químico es 1-( 2-deoxy-ß-L-ribofuranosyl)-5metiluracil, y ejerce su acción a través de la inactivación de la ADN polimerasa del virus de la Hepatitis B, mediante la inhibición competitiva de su sustrato natural , el 5-trifosfato timidina. Fue recientemente aprobado por el FDA para el tratamiento de la hepatitis B.

Telbivudine´s chemical name is 1-(2-deoxy-ß-Lribofuranosyl)-5-metiluracil. It is a synthetic nucleoside analogue of timidine with activity against HBV DNA Polymerase by competing with the natural substrate, timidine 5-triphosphate. It was recently approved by the FDA for hepatitis B treatment.