Deuterium, the stable isotope of hydrogen, is known to medicinal chemists for its utility in mechanistic, spectroscopic, and tracer studies. In fact, well-known applications utilizing deuterium exist ...within every subdiscipline in pharmaceutical discovery and development. Recent emphasis on incorporation of deuterium into the active pharmaceutical ingredient has come about as a result of inquiries into the potential for substantial benefits of the deuterium kinetic isotope effect on the safety and disposition of the drug substance. This Perspective traces the author’s experience in reviving and expanding this potential utility, first suggested many decades prior by the discoverer of this, the simplest of all isotopes.
Patients with chest pain and concern for potential coronary ischemia are frequently referred to the emergency department (ED), resulting in substantial resource utilization and cost. The objective of ...this study was to implement a protocol for urgent care center (UCC) evaluation of potential acute coronary syndrome (ACS) and describe its performance.
This is a descriptive, retrospective review of consecutive cases included in a protocol for UCC evaluation of ACS.
Consecutive patient encounters from 4 urgent care facilities of our regional integrated health system were reviewed from a period spanning 4.5 months of the 2017 calendar year. The primary outcome was avoidance of an ED visit within 30 days of the index visit, and the primary safety outcome was serious adverse events (AEs) occurring in the UCC setting.
There were 802 patients evaluated, with a median age of 55 years, and 58% were female. Seventy-three (9.1%) patients were referred to the ED or hospitalized for any reason at the index visit, 10 (1.2%) of whom were ultimately diagnosed with ACS. Within 30 days, 56 (7.7%) of the remaining 729 patients had ED visits or hospitalization for any reason, 2 (0.2%) of whom received a diagnosis of ACS. Overall, 673 (83.9%) patients were managed without any ED visit. No serious AEs were recorded.
Our initial pilot data demonstrate the feasibility of an outpatient UCC evaluation for ACS without refuting the underlying premise of safety.
Rates of compulsory (also known as involuntary) detention under mental health legislation have been rising over several decades in countries including England. Avoiding such detentions should be a ...high priority given their potentially traumatic nature and departure from usual ethical principles of consent and collaboration. Those who have been detained previously are at high risk of being detained again, and thus a priority group for preventive interventions. In a very sparse literature, interventions based on crisis planning emerge as having more supporting evidence than other approaches to preventing compulsory detention.
We have adapted and manualised an intervention previously trialled in Zürich Switzerland, aimed at reducing future compulsory detentions among people being discharged following a psychiatric admission that has included a period of compulsory detention. A co-production group including people with relevant lived and clinical experience has co-designed the adaptations to the intervention, drawing on evidence on crisis planning and self-management and on qualitative interviews with service users and clinicians. We will conduct a randomised controlled feasibility trial of the intervention, randomising 80 participants to either the intervention in addition to usual care, or usual care only. Feasibility and acceptability of the intervention and trial procedures will be assessed through process evaluation (including rates of randomisation, recruitment, and retention) and qualitative interviews. We will also assess and report on planned trial outcomes. The planned primary outcome for a full trial is repeat compulsory detention within one year of randomisation, and secondary outcomes include compulsory detention within 2 years, and symptoms, service satisfaction, self-rated recovery, self-management confidence, and service engagement. A health economic evaluation is also included.
This feasibility study, and any subsequent full trial, will add to a currently limited literature on interventions to prevent involuntary detention, a goal valued highly by service users, carers, clinicians, and policymakers. There are significant potential impediments to recruiting and retaining this group, whose experiences of mental health care have often been negative and traumatising, and who are at high risk of disengagement.
ISRCTN, ISRCTN11627644. Registered 25th May 2022, https://www.isrctn.com/ISRCTN11627644 .
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High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of
N-(5-isopropyl-thiazol-2-yl)isobutyramide (
1). This compound is an equipotent inhibitor of ...cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC
50
=
ca. 320
nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.
The design, synthesis, and biological evaluation of potent isothiazole inhibitors of the TrkA kinase is presented.
The design, synthesis, and biological evaluation of potent inhibitors of the TrkA ...kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.
Lectures are a commonly used teaching method in higher education, but there is significant debate about the relative merits of different classroom practices. Various classroom observation tools have ...been developed to try to give insight into these practices, beyond the simple dichotomy of “traditional lecturing versus active learning”. Here we review of a selection of classroom observation protocols from an ethological perspective and describe how this informed the development of a new protocol, FILL+. We demonstrate that FILL+ can be applied reliably by undergraduate students after minimal training. We analysed a sample of 208 lecture recordings from Mathematics, Physics, and Veterinary Medicine and found a wide variety of classroom practices, e.g. on average lecturers spent 2.1% (± 2.6%) of the time asking questions, and 79.3% (± 19%) of the lecture talking, but individuals varied considerably. The FILL+ protocol has the potential to be widely used, both in research on effective teaching practices, and in informing discussion of pedagogical approaches within institutions and disciplines.
Mitogen-activated protein kinase phosphatase-4 (MKP-4) is a dual specificity phosphatase, which acts as a negative regulator of insulin-stimulated pathways
1. Here, we describe expression, ...purification, and biochemical characterization of MKP-4. We used the Baculovirus expression system and purification with a combination of affinity and gel filtration chromatography to generate pure MKP-4 and MKP-4/p38 complex. Both MKP-4 and the MKP-4/p38 complex exhibited moderate activity toward the surrogate substrates
p-nitrophenyl phosphate, 6, 8-difluoro-4-methylumbelliferyl phosphate, and 3-
O-methylfluorescein phosphate. The phosphatase activity could be inhibited by peroxovanate, a potent inhibitor of protein tyrosine phosphatases. We further determined kinetic parameters for the MKP-4 and the MKP-4/p38 by using spectrophotometric and fluorescence intensity methods. The MKP-4/p38 complex was found to provide substantially higher phosphatase activity than MKP-4 alone, similar to what has been shown for MKP-3. Our data allow the configuration of screens for modulators of MKP-4 activity.
Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic ...route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel
cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
Using structure-based drug design, 4-aminoimidazoles were prepared with potent inhibition of cdk5/p25 in enzyme and whole cell assays and selectivity over cdk2.
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