Characteristics of AZD9708, a novel, selective β2-adrenoceptor agonist with rapid onset and long duration of action

Here we describe the pre-clinical pharmacological profile of AZD9708, a novel long-acting β₂-adrenoceptor agonist that has potential as a once-daily therapy for asthma and chronic obstructive pulmonary disease (COPD).AZD9708 is a potent and selective agonist at the human β₂-adrenoceptor, with selectivity over human β₁- and β₃-adrenoceptors of >500 and >24 fold, respectively. AZD9708 relaxes carbachol-induced contraction of human bronchial rings with a time to 90% of maximal relaxation of 13–20 min, similar to that seen with formoterol and quicker than salmeterol. In anesthetized guinea pigs, AZD9708 provides significant protection against histamine-induced airway constriction at 24 h after intratracheal and nebulized doses. This is longer than with intratracheal salmeterol, which is bronchoprotective for approximately 8 h, and formoterol, which is bronchoprotective for 8 and 12 h following nebulized and intratracheal dosing, respectively.AZD9708 also shows the potential for a greater therapeutic margin than widely used β₂-adrenoceptor agonists such as formoterol. At a defined efficacy dose that provides 80% bronchoprotection (ED₈₀), formoterol leads to a decrease in blood potassium levels in guinea pigs, whilst AZD9708 is not associated with significant reductions in potassium levels at doses up to 7 times the ED₈₀. [¹⁴C]AZD9708 is associated with extensive protein binding in both human (mean 1.0% free) and rat (mean 2.6% free) plasma.This pharmacological profile indicates the potential of AZD9708 to become an important addition to the range of bronchodilators available for the treatment of patients with obstructive airways disease.     

The ethics of extracorporeal membrane oxygenation in brain‐dead potential organ donors

Organ‐preserving extracorporeal membrane oxygenation (OP‐ECMO) is defined as the use of extracorporeal support for the primary purpose of preserving organs for transplantation, rather than to save the patient's life. This paper discusses the ethics of using OP‐ECMO in donation after brain determination of death (DBDD) to avoid the loss of organs for transplantation. We review case reports in the literature and analyze the ethical issues raised. We conclude that there is little additional ethical concern in continuing OP‐ECMO in patients already on ECMO if they become brain dead. The implementation of OP‐ECMO in hemodynamically unstable brain‐dead patients is ethically permissible in certain clinical situations but requires specific consent from relatives if the patient's wish to donate is not clear. If no evidence of a patient's wish to donate is available, OP‐ECMO is not recommended. In countries with presumed consent legislation, failure to opt out should be considered as a positive wish to donate. If a patient is not‐yet brain‐dead or is undergoing testing for brain death, OP‐ECMO is not recommended. Further research on OP‐ECMO is needed to better understand the attitudes of professionals, families, and lay people to ensure agreement on key ethical issues.     

Associations of context-specific sitting time with markers of cardiometabolic risk in Australian adults

Background

High volumes of sitting time are associated with an elevated risk of type 2 diabetes and cardiovascular disease, and with adverse cardiometabolic risk profiles. However, previous studies have predominately evaluated only total sitting or television (TV) viewing time, limiting inferences about the specific cardiometabolic health impacts of sitting accumulated in different contexts. We examined associations of sitting time in four contexts with cardiometabolic risk biomarkers in Australian adults.

Methods

Participants (n?=?3429; mean?±?SD age 58?±?10 years) were adults without clinically diagnosed diabetes or cardiovascular disease from the 2011–2012 Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Multiple linear regressions examined associations of self-reported context-specific sitting time (occupational, transportation, TV-viewing and leisure-time computer use) with a clustered cardiometabolic risk score (CMR) and with individual cardiometabolic risk biomarkers (waist circumference, BMI, resting blood pressure, triglycerides, HDL- and LDL-cholesterol, and fasting and 2-h post-load plasma glucose).

Results

Higher CMR was significantly associated with greater TV-viewing and computer sitting time (b [95%CI]?=?0.07 [0.04, 0.09] and 0.06 [0.03, 0.09]), and tended to be associated with higher occupational and transport sitting time (0.01 [??0.01, 0.03] and 0.03 [??0.00, 0.06]), after adjustment for potential confounders. Furthermore, keeping total sitting time constant, accruing sitting via TV-viewing and computer use was associated with significantly higher CMR (0.05 [0.02, 0.08] and 0.04 [0.01, 0.06]), accruing sitting in an occupational context was associated with significantly lower CMR (??0.03 [??0.05, ??0.01]), while no significant association was seen for transport sitting (0.00 [??0.03, 0.04]). Results varied somewhat between the respective biomarkers; however, higher sitting time in each domain tended to be associated detrimentally with individual biomarkers except for fasting glucose (non-significant associations) and systolic blood pressure (a beneficial association was observed). Overall, associations were stronger for TV-viewing and computer use, and weaker for occupational sitting.

Conclusions

Higher context-specific sitting times tended to be detrimentally associated, albeit modestly, with CMR and several cardiometabolic risk biomarkers. There was some evidence suggesting that the context in which people sit is relevant above and beyond total sitting time. Methodological issues notwithstanding, these findings may assist in identifying priorities for sitting-reduction initiatives, in order to achieve optimal cardiometabolic health benefits.

     

The effect on consent rates for deceased organ donation in Wales after the introduction of an opt-out system

Organ transplantation saves and transforms lives. Failure to secure consent for organ retrieval is widely regarded as the single most important obstacle to transplantation. A soft opt-out system of consent for deceased organ donation was introduced into Wales in December 2015, whilst England maintained the existing opt-in system. Cumulative data on consent rates in Wales were compared with those in England, using a two-sided sequential procedure that was powered to detect an absolute difference in consent rates between England and Wales of 10%. Supplementary risk-adjusted logistic regression analysis examined whether any difference in consent rates between the two nations could be attributed to variations in factors known to influence UK consent rates. Between 1 January 2016 and 31 December 2018, 8192 families of eligible donors in England and 474 in Wales were approached regarding organ donation, with overall consent rates of 65% and 68%, respectively. There was a steady upward trend in the proportion of families consenting to donation after brain death in Wales as compared with England and after 33 months, this reached statistical significance. No evidence of any change in the donation after circulatory death consent rate was observed. Risk-adjusted logistic regression analysis revealed that by the end of the study period the probability of consent to organ donation in Wales was higher than in England (OR [95%CI] 2.1 [1.26–3.41]). The introduction of a soft opt-out system of consent in Wales significantly increased organ donation consent though the impact was not immediate.     

Incorporation of Ophiobolin A into Novel Chemoembolization Particles for Cancer Cell Treatment

Purpose

To design and synthesize chemoembolization particles for the delivery of Ophiobolin A (OphA), a promising fungal-derived chemotherapeutic, directly at the tumour location. To investigate cell death mechanism of OphA on a Rhabdomyosarcoma cancer (RD) cell line. Rhabdomyosarcoma is the most common soft tissue sarcoma in children; with a 5-year survival rate of between 30 and 65%.

Methods

Multimodal chemoembolization particles were prepared by sintering mesoporous silica nanoparticles, prepared by the sol-gel method, onto the surface of polystyrene microspheres, prepared by suspension copolymerisation. The chemoembolization particles were subsequently loaded with OphA. The effects of OphA in vitro were characterised by flow cytometry and nanoparticle tracking analysis (NanoSight).

Results

High loading of OphA onto the chemoembolization particles was achieved. The subsequent release of OphA onto RD cells in culture showed a 70% reduction in cell viability. OphA caused RD cells to round up and their membrane to bleb and caused cell death via apoptosis. OphA caused both an increase in the number of microvesicles produced and an increase in DNA content within these microvesicles.

Conclusions

The prepared chemoembolization particles showed good efficacy against RD cells in culture.     

alpha-MSH acetylation in the pituitary gland of the sea bream (Sparus aurata L.) in response to different backgrounds, confinement and air exposure

MSH is a pituitary hormone derived by post-translational processing from POMC and involved in stress and background adaptation. N-terminal acetylation of MSH to monoacetyl alpha-MSH or diacetyl alpha-MSH increases the bioactivity of the peptide. The aim of this study was to characterize alpha-MSH acetylation in the sea bream (Sparus aurata L.) pituitary gland in response to the stressors air exposure and confinement, as well as in fish adapted for 15 days to a white, gray or black background. Pituitary homogenates were purified by reversed-phase HPLC (RP-HPLC). The alpha-MSH content of fractions was measured by RIA. Immunoreactive RP-HPLC fractions were further analyzed by electrospray mass spectrometry and the peptide sequence determined as SYSMEHFRWGKPV-NH2. In the pituitary gland of sea bream, des-, mono- and diacetyl alpha-MSH were identified. Then plasma alpha-MSH levels were measured in sea bream adapted to different backgrounds. Surprisingly, we found the highest plasma alpha-MSH levels in white-adapted as compared with black-adapted sea bream with intermediate values for gray-adapted fish. This observation is in contrast with results that have been obtained in eel, trout or terrestrial vertebrates. Next, des-, mono- and diacetyl alpha-MSH forms were measured in homogenates of the pituitary gland and in plasma of sea bream exposed to air, to confinement, or to different backgrounds. Monoacetyl alpha-MSH was the predominant form in all control and experimental groups. The lowest content of monoacetyl alpha-MSH relative to des- and diacetyl alpha-MSH was found in white-adapted fish. Levels of des- and diacetyl alpha-MSH forms were similar under all conditions. We observed that monoacetyl alpha-MSH is the most abundant isoform in the pituitary gland after background adaptation, confinement and air exposure, in sea bream. These data indicate that the physiologically most potent isoform of alpha-MSH may vary from species to species.