29 research outputs found
Formulation, stabilisation and encapsulation of bacteriophage for phage therapy
Against a backdrop of global antibiotic resistance and increasing awareness of the importance of the
human microbiota, there has been resurgent interest in the potential use of bacteriophages for
therapeutic purposes, known as phage therapy. A number of phage therapy phase I and II clinical
trials have concluded, and shown phages donât present significant adverse safety concerns. These
clinical trials used simple phage suspensions without any formulation and phage stability was of
secondary concern. Phages have a limited stability in solution, and undergo a significant drop in
phage titre during processing and storage which is unacceptable if phages are to become regulated
pharmaceuticals, where stable dosage and well defined pharmacokinetics and pharmacodynamics
are de rigueur. Animal studies have shown that the efficacy of phage therapy outcomes depend on
the phage concentration (i.e. the dose) delivered at the site of infection, and their ability to target and
kill bacteria, arresting bacterial growth and clearing the infection. In addition, in vitro and animal
studies have shown the importance of using phage cocktails rather than single phage preparations to
achieve better therapy outcomes. The in vivo reduction of phage concentration due to interactions
with host antibodies or other clearance mechanisms may necessitate repeated dosing of phages, or
sustained release approaches. Modelling of phage-bacterium population dynamics reinforces these
points. Surprisingly little attention has been devoted to the effect of formulation on phage therapy
outcomes, given the need for phage cocktails, where each phage within a cocktail may require
significantly different formulation to retain a high enough infective dose.
This review firstly looks at the clinical needs and challenges (informed through a review of key animal
studies evaluating phage therapy) associated with treatment of acute and chronic infections and the
drivers for phage encapsulation. An important driver for formulation and encapsulation is shelf life and
storage of phage to ensure reproducible dosages. Other drivers include formulation of phage for
encapsulation in micro- and nanoparticles for effective delivery, encapsulation in stimuli responsive
systems for triggered controlled or sustained release at the targeted site of infection. Encapsulation of
phage (e.g. in liposomes) may also be used to increase the circulation time of phage for treating
systemic infections, for prophylactic treatment or to treat intracellular infections. We then proceed to
document approaches used in the published literature on the formulation and stabilisation of phage for
storage and encapsulation of bacteriophage in micro- and nanostructured materials using freeze
drying (lyophilization), spray drying, in emulsions e.g. ointments, polymeric microparticles,
nanoparticles and liposomes. As phage therapy moves forward towards Phase III clinical trials, the
review concludes by looking at promising new approaches for micro- and nanoencapsulation of
phages and how these may address gaps in the field
Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTICâHF: baseline characteristics and comparison with contemporary clinical trials
Aims:
The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTICâHF) trial. Here we describe the baseline characteristics of participants in GALACTICâHF and how these compare with other contemporary trials.
Methods and Results:
Adults with established HFrEF, New York Heart Association functional class (NYHA)ââ„âII, EF â€35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokineticâguided dosing: 25, 37.5 or 50âmg bid). 8256 patients [male (79%), nonâwhite (22%), mean age 65âyears] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NTâproBNP 1971âpg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTICâHF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressureâ<â100âmmHg (n = 1127), estimated glomerular filtration rate <â30âmL/min/1.73 m2 (n = 528), and treated with sacubitrilâvalsartan at baseline (n = 1594).
Conclusions:
GALACTICâHF enrolled a wellâtreated, highârisk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation
Siliceous scales of filose-amoebae (Pompholyxophryidae, Rotosphaerida) from deep Southern Ocean sediments, including first records for the Southern Hemisphere
The world of protists remains largely unexplored. A thorough electron-microscopic investigation of a few microlitres of deep-sea sediment from 2,964 m water depth near the South Sandwich Islands (Southern Ocean) revealed siliceous scales of filose-amoeba protist species, two of which have not been reported previously from Antarctica or from elsewhere in the Southern Hemisphere. However, all the species are known from other oceans and, in one case, from freshwater habitats. The Antarctic protistan scales belong to four species of filose amoebae: Pinaciophora fluviatilis Greef 1869, Pinaciophora denticulata Thomsen 1978, Pinaciophora multicosta Thomsen 1978 and Rabdiaster reticulata (Thomsen 1979) Mikrjukov 1999 nov. comb. Our study shows that (1) none of the species has been recorded from the Australasian biogeograpical region, (2) Pinaciophora multicosta and Rabdiaster reticulata are new records for the Southern Ocean and for the Southern Hemisphere as a whole, (3) prior to this investigation, Pinaciophora multicosta had been reported once only, from the Baltic Sea (Europe). These results highlight the problem of undersampling in the study of the global distribution of protists