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

Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.

BackgroundInfluenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses.MethodsWe did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050.FindingsBetween Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis.InterpretationThe tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed.FundingBill &amp; Melinda Gates Foundation

Neglected Tropical Diseases of the Middle East and North Africa: Review of Their Prevalence, Distribution, and Opportunities for Control

The neglected tropical diseases (NTDs) are highly endemic but patchily distributed among the 20 countries and almost 400 million people of the Middle East and North Africa (MENA) region, and disproportionately affect an estimated 65 million people living on less than US$2 per day. Egypt has the largest number of people living in poverty of any MENA nation, while Yemen has the highest prevalence of people living in poverty. These two nations stand out for having suffered the highest rates of many NTDs, including the soil-transmitted nematode infections, filarial infections, schistosomiasis, fascioliasis, leprosy, and trachoma, although they should be recognized for recent measures aimed at NTD control. Leishmaniasis, especially cutaneous leishmaniasis, is endemic in Syria, Iran, Iraq, Libya, Morocco, and elsewhere in the region. Both zoonotic (Leishmania major) and anthroponotic (Leishmania tropica) forms are endemic in MENA in rural arid regions and urban regions, respectively. Other endemic zoonotic NTDs include cystic echinococcosis, fascioliasis, and brucellosis. Dengue is endemic in Saudi Arabia, where Rift Valley fever and Alkhurma hemorrhagic fever have also emerged. Great strides have been made towards elimination of several endemic NTDs, including lymphatic filariasis in Egypt and Yemen; schistosomiasis in Iran, Morocco, and Oman; and trachoma in Morocco, Algeria, Iran, Libya, Oman, Saudi Arabia, Tunisia, and the United Arab Emirates. A particularly noteworthy achievement is the long battle waged against schistosomiasis in Egypt, where prevalence has been brought down by regular praziquantel treatment. Conflict and human and animal migrations are key social determinants in preventing the control or elimination of NTDs in the MENA, while local political will, strengthened international and intersectoral cooperative efforts for surveillance, mass drug administration, and vaccination are essential for elimination

Severe Embryotoxicity of Artemisinin Derivatives in Experimental Animals, but Possibly Safe in Pregnant Women

molecule

Pre-clinical drug-drug interactions (DDIs) of gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine

Objective: To evaluate drug-drug interactions (DDIs) between gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs). Methods: In vitro supersomes were used to identify CYP isoenzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) involved in drug metabolism, and in vitro pooled cryopreserved primary human hepatocytes were employed to investigate DDIs. Results: The isoenzymes that showed drug degradation are listed in parentheses beside the respective drug: gefitinib (CYP2D6, 3A4, 1A2, 2C9, and 2C19), losartan (CYP2C9 and 3A4), citalopram (CYP2D6, 2C19, 3A4, and 2C9), fluoxetine (CYP2D6, 2C9, and 2C19), fluvoxamine (CYP2D6, 2C9, and 2C19), paroxetine (CYP2D6, 3A4, and 2C9), sertraline (CYP2D6, 2C9, 2C19, 1A2, and 3A4), and venlafaxine (CYP2D6 and 2C19).DDIs from human hepatocytes assays revealed that gefitinib had significant metabolic changes in (1:1) combination with paroxetine or sertraline (p-value ​= ​0.042 and 0.025 respectively) and (1:1:1) combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline (p-value ​= ​0.009, 0.027, 0.048, and 0.037 respectively). Losartan showed significant changes in (1:1:1) combination with gefitinib and fluoxetine or sertraline (p-value ​= ​0.026 and 0.008 respectively). Fluoxetine, fluvoxamine, and paroxetine underwent significant changes in (1:1:1) combination with gefitinib and losartan (p-value ​= ​0.003, 0.022, and 0.046 respectively). Sertraline had significant changes within all combinations: DDIs with gefitinib alone and in combination with gefitinib and losartan (p-value ​= ​0.009 and 0.008 respectively). Citalopram and venlafaxine appeared to be unaffected by any combination. Conclusion: The study provides a clear proof-of concept for in vitro metabolic DDI testing. While identifying compounds by their inhibition potential can help better predict their metabolism, it cannot resolve problems that arise from DDIs since the overall degree of effectiveness is unknown. As shown in this study, gefitinib has been identified as a weak CYP2C19 and 2D6 inhibitor, however, gefitinib can have significant DDIs with sertraline. Furthermore, multiple drug combinations (1:1:1) can change the significance of previously determined DDIs in (1:1) combination. Thus, in vitro assays can potentially provide better guidance for multidrug regimens with minimal risk for DDIs