172 research outputs found
Use of the Court of Protection's welfare jurisdiction by supervisory bodies in England and Wales
Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis
This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection model
Is ‘activist’ a dirty word? Place identity, activism and unconventional gas development across three continents
Communities respond to unconventional gas in a variety of ways. In some communities, industry has held a social license, while in other areas, industrial development has been slowed, halted, or prevented by social resistance. Repeatedly, across multiple nations and communities, we have observed that social identities that either incorporate or eschew activism intersect with perceptions of this development's effect on place identity to either foster or discourage opposition. Particularly interesting are cases in which fracking is perceived to threaten local place identity, but where activism conflicts with social identity. To mobilise different sectors of the population, it often appears important for local residents to be perceived as ‘regular citizens’ and not as activists. We explore how intersection of social identities and place identity shaped the different ways in which communities in Australia, Canada, the Netherlands, and the United States have responded to unconventional gas development. Communities resisting development often see ‘activism’ as something that ‘outsiders’ do and that must be rejected as insufficiently objective and neutral. This view of activism and activists produces specific forms of resistance that differ from typical ‘activist’ actions, in which ‘knowledge’, ‘information’, neutrality, and objectivity are particularly important.</p
Antidepressant and antipsychotic prescribing in patients with type 2 diabetes in Scotland: a time-trend analysis from 2004-2021
Aims:
Prescribing of antidepressant and antipsychotic drugs in general populations has increased in the United Kingdom, but prescribing trends in people with type 2 diabetes (T2D) have not previously been investigated. The aim of this study was to describe time trends in annual prevalence of antidepressant and antipsychotic drug prescribing in adult patients with T2D.
Methods:
We conducted repeated annual cross-sectional analysesof a population-based diabetes registry with 99% coverage, derived from primary and secondary care data in Scotland, from 2004 to 2021. For each cross-sectional calendar year time period, we calculated the prevalence of antidepressant and antipsychotic drug prescribing, overall and by sociodemographic characteristics and drug subtype.
Results:
The number of patients with a T2D diagnosis in Scotland increased from 161 915 in 2004 to 309 288 in 2021. Prevalence of antidepressant and antipsychotic prescribing in patients with T2D increased markedly between 2004 and 2021 (from 20.0 per 100 person-years to 33.3 per 100 person-years and from 2.8 per 100 person-years to 4.7 per 100 person-years, respectively). We observed this pattern for all drug subtypes except for first-generation antipsychotics, prescribing of which remained largely stable. The degree of increase, as well as the overall prevalence of prescribing, differed by age, sex, socioeconomic status and subtype of drug class.
Conclusions:
There has been a marked increase in the prevalence of antidepressant and antipsychotic prescribing in patients with T2D in Scotland. Further research should identify the reasons for this increase, including indication for use and the extent to which this reflects increases in incident prescribing rather than increased duration
Primary care and health inequality : Difference-in-difference study comparing England and Ontario
BACKGROUND: It is not known whether equity-oriented primary care investment that seeks to scale up the delivery of effective care in disadvantaged communities can reduce health inequality within high-income settings that have pre-existing universal primary care systems. We provide some non-randomised controlled evidence by comparing health inequality trends between two similar jurisdictions-one of which implemented equity-oriented primary care investment in the mid-to-late 2000s as part of a cross-government strategy for reducing health inequality (England), and one which invested in primary care without any explicit equity objective (Ontario, Canada). METHODS: We analysed whole-population data on 32,482 neighbourhoods (with mean population size of approximately 1,500 people) in England, and 18,961 neighbourhoods (with mean population size of approximately 700 people) in Ontario. We examined trends in mortality amenable to healthcare by decile groups of neighbourhood deprivation within each jurisdiction. We used linear models to estimate absolute and relative gaps in amenable mortality between most and least deprived groups, considering the gradient between these extremes, and evaluated difference-in-difference comparisons between the two jurisdictions. RESULTS: Inequality trends were comparable in both jurisdictions from 2004-6 but diverged from 2007-11. Compared with Ontario, the absolute gap in amenable mortality in England fell between 2004-6 and 2007-11 by 19.8 per 100,000 population (95% CI: 4.8 to 34.9); and the relative gap in amenable mortality fell by 10 percentage points (95% CI: 1 to 19). The biggest divergence occurred in the most deprived decile group of neighbourhoods. DISCUSSION: In comparison to Ontario, England succeeded in reducing absolute socioeconomic gaps in mortality amenable to healthcare from 2007 to 2011, and preventing them from growing in relative terms. Equity-oriented primary care reform in England in the mid-to-late 2000s may have helped to reduce socioeconomic inequality in health, though other explanations for this divergence are possible and further research is needed on the specific causal mechanisms
2,4-Diaminopyrimidines as Potent Inhibitors of Trypanosoma brucei and Identification of Molecular Targets by a Chemical Proteomics Approach
The protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT) or sleeping sickness, a fatal disease affecting nearly half a million people in sub-Saharan Africa. Current treatments for HAT have very poor safety profiles and are difficult to administer. There is an urgent need for new, safe and effective treatments for sleeping sickness. This work describes the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide or SCYX-5070, as potent inhibitors of T. brucei growth in vitro and also in animal models for HAT. To determine the parasite proteins responsible for interaction with SCYX-5070 and related compounds, affinity pull-downs were performed followed by sequence analysis and parasite genome database searching. The work revealed that mitogen-activated protein kinases (MAPKs) and cdc2-related kinases (CRKs) are the major proteins specifically bound to the immobilized compound, suggesting their potential participation in the pharmacological effects of 2,4-diaminopyrimidines against trypanosomatid protozoan parasites. These data strongly support the use of 2,4-diminipyrimidines as leads for the development of new drug candidates for the treatment of HAT
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis
SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis
Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT
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