Cardiac Safety of Modified Vaccinia Ankara for Vaccination against Smallpox in a Young, Healthy Study Population

Background Conventional smallpox vaccines based on replicating vaccinia virus (VV) strains (e.g. Lister Elstree, NYCBOH) are associated with a high incidence of myo-/pericarditis, a severe inflammatory cardiac complication. A new smallpox vaccine candidate based on a nonreplicating Modified Vaccinia Ankara (MVA) poxvirus has been assessed for cardiac safety in a large placebo-controlled clinical trial. Methods Cardiac safety of one and two doses of MVA compared to placebo was assessed in 745 healthy subjects. Vaccinia-naive subjects received either one dose of MVA and one dose of placebo, two doses of MVA, or two doses of placebo by subcutaneous injection four weeks apart;vaccinia-experienced subjects received a single dose of MVA. Solicited and unsolicited adverse events (AE) and cardiac safety parameters (recorded as Adverse Events of Special Interest, AESI) were monitored after each injection. Results A total of 5 possibly related AESI (3 cases of palpitations, 2 of tachycardia) were reported during the study. No case of myo- or pericarditis occurred. One possibly related serious AE (SAE) was reported during the 6-month follow-up period (sarcoidosis). The most frequently observed AEs were injection site reactions. Conclusions Vaccination with MVA was safe and well tolerated and did not increase the risk for development of myo-/pericarditis

The pharmacokinetics of multiple inhaled NVA237 doses in patients with chronic obstructive pulmonary disease (COPD)

Objective: NVA237 (glycopyrronium bromide) is a once-daily long-acting muscarinic antagonist (LAMA) in development for the treatment of chronic obstructive pulmonary disease (COPD). This study investigated the pharmacokinetics (PK) of NVA237 following single and repeated once-daily inhalation in mild to moderate COPD patients. Methods: In this double-blind, parallel-group study, COPD patients were randomised to a 14-day treatment with NVA237 (25, 50, 100 or 200 μg) or placebo. Plasma concentration-time profiles and urinary excretion of NVA237 were determined on Days 1 and 14. Results: The median time to reach maximal plasma concentration (tmax) was 5 or 6.5 min post-inhalation. At steady state (Day 14), total and maximum systemic exposure (AUC0-24, Cmax) to NVA237 and urinary excretion of unchanged drug (Ae0-24) was approximately dose proportional over the 50 to 200 µg dose range. The average exposure was 1.4- to 1.7-fold higher on Day 14 compared with Day 1. The mean terminal elimination half-life (t½) of NVA237 ranged between 13 and 22 h. Steady-state plasma concentrations were reached within one week of treatment. Renal clearance (CLR) was similar across doses both after single and repeated dosing, ranging between 17.4 and 20.6 L/h. Urinary excretion of NVA237 enantiomers ([3S,2R]- and [3R,2S]-stereoisomers) was similar with respect to the amount excreted within 24 h and the excretion rate. Conclusions: The pharmacokinetics of NVA237 were consistent between doses with limited systemic accumulation at steady state after repeated once-daily inhalatio

Omalizumab Protects against Allergen-Induced Bronchoconstriction in Allergic (Immunoglobulin E-Mediated) Asthma

<p>Background: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE)</p>

Pharmacokinetic and pharmacodynamic comparison of subcutaneous intramuscular leuprolide acetate formulations in male subjects

Background: The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection. Methods: A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA ( n = 16) or IM-LA ( n = 16) in this phase I, open-label, parallel-group study. PK was assessed via LA concentrations, and PD via serum luteinizing hormone (LH) and testosterone (T) concentrations. Results: The initial surge of LA was higher for IM-LA than SC-LA (C max 27 ± 4.9 versus 19 ± 8.0 ng/ml, respectively), with a shorter t max (1.0 ± 0.4 versus 2.1 ± 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 56 versus 42 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by Day 35. Consequently, serum T began to increase by Day 42 in the IM-LA group, with only four subjects maintaining levels ⩽50 ng/dl, compared with 14 subjects in the SC-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ⩽50 ng/dl. Both SC-LA and IM-LA were well tolerated. Conclusions: Both formulations demonstrated consistent delivery of drug over 1 month; however, SC-LA provided a longer duration of action than expected based on the dosing interval. This profile suggests that SC-LA will provide effective suppression of T over a longer period of time, permitting greater injection scheduling flexibility

Patterns of local, intercontinental and interseasonal variation of soil bacterial and eukaryotic microbial communities

Although ongoing research has revealed some of the main drivers behind global spatial patterns of microbial communities, spatio-temporal dynamics of these communities still remain largely unexplored. Here, we investigate spatio-temporal variability of both bacterial and eukaryotic soil microbial communities at local and intercontinental scales. We compare how temporal variation in community composition scales with spatial variation in community composition, and explore the extent to which bacteria, protists, fungi and metazoa have similar patterns of temporal community dynamics. All soil microbial groups displayed a strong correlation between spatial distance and community dissimilarity, which was related to the ratio of organism to sample size. Temporal changes were variable, ranging from equal to local between-sample variation, to as large as that between communities several thousand kilometers apart. Moreover, significant correlations were found between bacterial and protist communities, as well as between protist and fungal communities, indicating that these microbial groups change in tandem, potentially driven by interactions between them. We conclude that temporal variation can be considerable in soil microbial communities, and that future studies need to consider temporal variation in order to reliably capture all drivers of soil microbiome changes

Related Adverse Events with a frequency of ≥2% in at least one study group; MedDRA Coding by System Organ Class and Preferred Term (Safety dataset).

<p>Fishers Exact test of comparison to Group 3; NS = Not Significant (p≥0.05);</p><p>* p< 0.05;</p><p>** p<0.01;</p><p>*** p < 0.001).</p><p>Related Adverse Events with a frequency of ≥2% in at least one study group; MedDRA Coding by System Organ Class and Preferred Term (Safety dataset).</p