Pharmacokinetics, tissue distribution and mass balance of radiolabeled dihydroartemisinin in male rats

<p>Abstract</p> <p>Background</p> <p>Dihydroartemisinin (DHA), a powerful anti-malarial drug, has been used as monotherapy and artemisinin-based combination therapy (ACT) for more than decades. So far, however, the tissue distribution and metabolic profile of DHA data are not available from animal and humans.</p> <p>Methods</p> <p>Pharmacokinetics, tissue distribution, mass balance, and elimination of [¹⁴C] DHA have been studieded in rats following a single intravenous administration. Protein binding was performed with rat and human plasma. Drug concentrations were obtained up to 192 hr from measurements of total radioactivity and drug concentration to determine the contribution by the parent and metabolites to the total dose of drug injected from whole blood, plasma, urine and faecal samples.</p> <p>Results</p> <p>Drug was widely distributed after 1 hr and rapidly declined at 24 hr in all tissues except spleen until 96 hrs. Only 0.81% of the total radioactivity was detected in rat brain tissue. DHA revealed a high binding capacity with both rat and human plasma proteins (76–82%). The concentration of total radioactivity in the plasma fraction was less than 25% of that in blood total. Metabolism of DHA was observed with high excretion via bile into intestines and approximately 89–95% dose of all conjugations were accounted for in blood, urine and faeces. However, the majority of elimination of [¹⁴C] DHA was through urinary excretion (52% dose). The mean terminal half-lives of plasma and blood radioactivity (75.57–122.13 h) were significantly prolonged compared with that of unchanged DHA (1.03 h).</p> <p>Conclusion</p> <p>In rat brain, the total concentration of [¹⁴C] was 2-fold higher than that in plasma, indicating the radioactivity could easily penetrate the brain-blood barrier. Total radioactivity distributed in RBC was about three- to four-fold higher than that in plasma, suggesting that the powerful anti-malarial potency of DHA in the treatment of blood stage malaria may relate to the high RBC binding. Biliary excretion and multiple concentration peaks of DHA have been demonstrated with high urinary excretion due to a most likely drug re-absorption in the intestines (enterohepatic circulation). The long lasting metabolites of DHA (> 192 hr) in the rats may be also related to the enterohepatic circulation.</p

Intranasal administration of NDV-HXP-S COVID19 vaccines induces robust protective mucosal and systemic immunity in mice

With the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually changing and no end of this pandemic in sight, a next generation of vaccines preventing transmission and an equitable allocation is needed in order to reduce global disease burden. The NDV-HXP-S vaccine is based on recombinant Newcastle disease virus (NDV) stably expressing a membrane-anchored, optimized (with six proline mutations – Hexa Pro) spike protein1. Using the current influenza virus vaccine manufacturing facilities, this vaccine can be produced in embryonated eggs and thereby can meet the demands on a global scale at a low cost. Here, we report that mice vaccinated intranasally (i.n.) with different designs and regimens of our live NDV-HXP-S induced strong antibody response, displaying good systemic as well as mucosal immunity. Furthermore, the T and B cell responses in the lung were characterized via flow cytometry. It is important to emphasize, that we have been able to quickly adapt the vaccine to newly emerging variants of concern (VOC) of SARS-CoV-2. Please click Download on the upper right corner to see the full abstract

Development of a universal group 2 influenza virus vaccine using chimeric hemagglutinin constructs

The stalk domain of the hemagglutinin (HA) has become the prime target for universal influenza virus vaccine development in the last few years. Unlike the HA head domain, the immunosubdominant stalk domain is conserved to a higher level within each influenza virus HA group. Sequential vaccination with chimeric HA (cHA) vaccine constructs consisting of the same HA stalk and exotic head domains has proven to re-direct the immune response towards the stalk domain. This vaccination concept provides the basis for the development of more broadly cross-protective vaccines that are less affected by antigenic drift and shift, one of the main drawbacks of currently marketed influenza vaccines. Most influenza virus vaccines are licensed as inactivated split vaccines. They are manufactured based on HA content with little to no information and standardization of neuraminidase (NA) content. Virus inactivation is generally performed with alkylating agents such as formalin (FA) or β-propiolactone (βPL), rendering the virus unable to infect or replicate. Though safe, whole inactivated virus vaccines can be highly reactogenic. Virus splitting with detergents like sodium deoxycholate (SDCO) and Triton X-100 (TX-100), which dissociate the virus into smaller parts while maintaining a good immunogenicity profile, are typically employed. To date, there are several studies assessing the effect of a variety of inactivating and splitting agents on influenza viruses, but little is known about the impact of combining these agents on HA stalk conformation and NA activity. Please click Download on the upper right corner to see the full abstract

Chimeric Hemagglutinin Constructs Induce Broad Protection against Influenza B Virus Challenge in the Mouse Model.

Seasonal influenza virus epidemics represent a significant public health burden. Approximately 25% of all influenza virus infections are caused by type B viruses, and these infections can be severe, especially in children. Current influenza virus vaccines are an effective prophylaxis against infection but are impacted by rapid antigenic drift, which can lead to mismatches between vaccine strains and circulating strains. Here, we describe a broadly protective vaccine candidate based on chimeric hemagglutinins, consisting of globular head domains from exotic influenza A viruses and stalk domains from influenza B viruses. Sequential vaccination with these constructs in mice leads to the induction of broadly reactive antibodies that bind to the conserved stalk domain of influenza B virus hemagglutinin. Vaccinated mice are protected from lethal challenge with diverse influenza B viruses. Results from serum transfer experiments and antibody-dependent cell-mediated cytotoxicity (ADCC) assays indicate that this protection is antibody mediated and based on Fc effector functions. The present data suggest that chimeric hemagglutinin-based vaccination is a viable strategy to broadly protect against influenza B virus infection.IMPORTANCE While current influenza virus vaccines are effective, they are affected by mismatches between vaccine strains and circulating strains. Furthermore, the antiviral drug oseltamivir is less effective for treating influenza B virus infections than for treating influenza A virus infections. A vaccine that induces broad and long-lasting protection against influenza B viruses is therefore urgently needed

Trends of overweight and obesity among preschool children from 2013 to 2018: a cross-sectional study in Rhine-Neckar County and the City of Heidelberg, Germany

Background: Early childhood overweight and obesity is a growing public health concern worldwide. Few recent studies have addressed how time trends varied by sociodemographic characteristics at the regional level using large and high-quality data. This study determines how time trends vary in the prevalence of early childhood overweight and obesity by age, gender, and migration background at the regional level. Methods: We used a Kernel-density curve to describe the BMI distribution, and evaluated the trends of overweight and obesity by age, gender, and migration background using logistic regression. Results: Mean BMI and the overall prevalence of overweight and obesity increased among preschool children aged 4–6 years in the Rhine-Neckar County and the City of Heidelberg. After adjusting for age, sex, and migration background, trends of overweight significantly increased only among male children in the age 5 year group with migration background (P < 0.05), and an upward trend of obesity was observed only among male children in the age 5 year group and female children in the age 6 year group with migration background (P < 0.05). Conclusions: BMI distribution as well as general prevalence of overweight and obesity are still increasing among preschool children. Children with migration backgrounds, particularly male children in the age 5 year groups and female children in the age 6 year group should be prioritized. Health promotion strategies for children with migration backgrounds will help address this challenge