AiZynth impact on medicinal chemistry practice at AstraZeneca.

AstraZeneca chemists have been using the AI retrosynthesis tool AiZynth for three years. In this article, we present seven examples of how medicinal chemists using AiZynth positively impacted their drug discovery programmes. These programmes run the gamut from early-stage hit confirmation to late-stage route optimisation efforts. We also discuss the different use cases for which AI retrosynthesis tools are best suited.

Management of migraine in children and adolescents.

Successful management of migraine in childhood and adolescence starts with making the correct diagnosis, assessing the impact of migraine on the child/adolescent's quality of life including impact on education, family life, and social activities. Understanding the child's and family's concerns and reasons for seeking medical advice is an important starting point in the management plan. Pharmacological treatment should go hand-in-hand with appropriate advice on maintaining a healthy life style, avoidance of triggers and aggravating factors, and exploring comorbid disorders that may influence response to treatment. Compared to those available for adult patients, pharmacologic treatment options for migraine in children and adolescents are relatively untested and limited at the present time. Therefore, an individual management plan on the appropriate use of medications, including the limitations of acute treatment and prevention of migraine, should be agreed and well understood by the patient, his/her carers, and school teachers, in order to achieve best results. Treatment of acute migraine episodes should be given as early as possible after onset of headache using an appropriate dose to child's age and weight and in the correct formulation and route of administration. Preventive treatment should be given regularly in a dose titrated to achieve maximum benefit with least adverse effect for at least 6-8 weeks before a judgment is made on its efficacy. Regular monitoring of treatment response can be facilitated by prospective headache diaries and follow-up.

The relationship between difficulties in the regulation of positive and negative emotions and binge-eating symptoms in young adults.

It is well-established that binge-eating (BE) is linked to emotion regulation (ER) difficulties. However, research to date has focused almost exclusively on difficulties regulating negative emotions, with little attention to the relationship between positive emotion dysregulation and BE. Further, research is inconclusive regarding which specific facets of ER difficulties are most strongly associated with BE behaviour. Therefore, the current study examined whether difficulties regulating both negative as well as positive emotions explained unique variance in BE among young adults. The study also aimed to identify which particular dimensions of negative and positive ER difficulties were most strongly related to BE symptoms. Participants (N = 449) ages 18-25 completed self-report measures of difficulties regulating positive and negative emotions, BE symptoms, and psychological distress. Hierarchical regression analyses showed that BE was related to difficulties regulating both positive emotions and negative emotions, after controlling for psychological distress and BMI. Lack of emotional clarity and lack of access to ER strategies when faced with strong negative emotions were the facets of negative ER difficulties most strongly associated with BE. Impulsivity when experiencing strong positive emotions was the facet of positive ER difficulties most strongly associated with BE. These findings support the ER model of BE and suggest that difficulties regulating both positive and negative emotions contribute to BE among young adults.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

A narrative review of course evaluation methods for continuing professional development: The case of paediatric and neonatal acute-care in-service courses in low and lower-middle income countries: BEME Guide No. 76.

BACKGROUND: Training a skilled healthcare workforce is an essential part in reaching the United Nations Sustainable Development Goal to end preventable deaths in children and neonates. The greatest burden of mortality lies in low and lower-middle income countries (LLMIC). Short term, in-service courses have been implemented in many LLMIC to improve the quality of care delivered, but the evaluation methods of these courses are inconsistent. METHOD: Studies describing evaluations of course and outcome measures were included if the course lasted seven days or less with postgraduate participants, included paediatric or neonatal acute or emergency training and was based in a LLMIC. This narrative review provides a detailed description of evaluation methods of course content, delivery and outcome measures based on 'Context, Input, Process and Product' (CIPP) and Kirkpatrick models. RESULTS: 5265 titles were screened with 93 articles included after full-text review and quality assessment. Evaluation methods are described: context, input, process, participant satisfaction, change in learning, behaviour, health system infrastructure and patient outcomes. CONCLUSIONS: Outcomes, including mortality and morbidity, are rightly considered the fundamental aim of acute-care courses in LLMIC. Course evaluation can be difficult, especially with low resources, but this review outlines what can be done to guide future course organisers in providing well-conducted courses with consistent outcome measures for maximum sustainable impact.

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

What is new in migraine management in children and young people?

For this narrative review, we found recent publications on the use and effectiveness of old therapies including nutraceuticals, such as riboflavin, vitamin D, magnesium, melatonin and talking therapies. Recent large trials of established conventional pharmaceuticals such as propranolol, pizotifen, topiramate and amitriptyline for childhood migraine have failed, but the use of a quasi-placebo in future trials could help. We reviewed the evidence for angiotensin antagonists including candesartan in adults, but found a lack of evidence for their use in children. There have been new developments in pharmaceuticals recently, including a more selective 5-HT1F agonist, lasmiditan, an effective acute treatment with no vasoconstrictor activity in adults, currently being tested in children. Also, a number of new calcitonin gene-related peptide (CGRP) antibodies and antagonists, with proven efficacy in acute treatment and/or prevention of migraine in adults, are undergoing trials in children. Peripheral nerve blocks and botulinum toxin are gaining popularity in adult practice, but we really need more good quality evidence for their effectiveness in children. Finally, electroceuticals, that is, therapeutic electric devices, are now marketed for acute and or preventative treatment, including an external trigeminal nerve stimulator (e-TNS), a non-invasive vagal nerve stimulator (nVNS), a single-pulse transcranial magnetic stimulator (sTMS) and a remote electrical neuromodulation device (REN). At the moment, evidence for their effectiveness in children is still lacking. So, there has been much progress, but mostly for adults. We are in urgent need of more migraine trials in children.

Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC).

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.

Chronic post-traumatic headache in pediatrics.

Both primary headaches and minor head injuries are common in children. If headache presents for the first time or becomes exacerbated soon after head injury it is described as post-traumatic headache (PTH). Acute PTH resolves within 3 months from injury, but chronic PTH continues beyond 3 months. The pathogenesis of PTH is not well understood. Several mechanisms were proposed such as axonal injuries and disturbances of cerebral metabolic processes. The clinical features of PTH are those of primary headache disorders such as migraine and tension-type headache and usually follow a favorable prognosis. Investigations and management should therefore be relevant to the type of headache and focused on clinical needs of the child.

Primary headaches in children under the age of 7 years.

Recurrent headache is increasingly recognised in young children. Migraine and tension-type headache feature commonly amongst the primary headache disorders seen at this age. Headaches at this age are more likely than in older patients to be 'unclassifiable', possibly a reflection of the difficulties in obtaining a detailed headache history from a young child. Together with recent epidemiological data this review highlights the more prevalent primary headache types with advice on making a focussed headache assessment and guidance on management in this age group.

Fifteen minute consultation: headache in children under 5 years of age.

Headache occurring in children under the age of 5 years may cause a high level of anxiety in both parents and medical professionals. Crucial to a consultation about this problem will be to actively seek out clues to sinister pathologies, and investigate or reassure as appropriate. Making a positive diagnosis of a primary headache disorder where one exists is also important; however, in young children, headache does not always conform to well-established diagnostic criteria. This short guide provides a practical overview using the scenario of a new referral to the outpatient clinic.

Going legal.

A 16-year-old girl is admitted with a paracetamol overdose, but refuses treatment. This article explores the legal, ethical and practical aspects of this case, which led ultimately to an application to the court for a judicial order.

Initial evaluation of EPSCALE, a rating scale that assesses the process of explanation and planning in the medical interview.

OBJECTIVE: to evaluate the content validity, internal consistency and generalisability of EPSCALE, a new rating scale to measure communication skills in explanation and planning. METHODS: content validity: consensus exercise and expert review. Internal consistency and generalisability: 124 clinical students undertaking 4 OSCE stations with simulated patients, with one observer (hospital specialist, GP or communication specialist) per station, during finals examinations. Internal consistency estimated by coefficient alpha, generalisability estimated by generalisability coefficient and variance components using EPSCALE. RESULTS: content validity was supported by consensus exercise and expert review. Internal consistency was high with a coefficient alpha of greater than 0.8 for all four explanation and planning stations in the finals exam. Generalisability coefficient for 4 OSCE stations was 0.50. CONCLUSIONS: this paper provides initial evidence that EPSCALE has content validity and high internal consistency when used to assess explanation and planning skills in the consultation. It defines the generalisability of this new rating scale. Further work is needed to explore the scale's validity by a range of other measures.

Newborn resuscitation training--which manikin.

Newborn Life Support (NLS) courses use manikins for demonstration and practise of skills required for newborn resuscitation. The aim of this study was to compare currently available manikins for physical characteristics and feedback during psychomotor tasks. Four testers reached a consensus opinion about these features for each of four manikins. Although Laerdal manikins were considered to provide the most realistic airway patency, feedback during mask ventilation and chest compressions, none of the manikins were individually considered to have ideal physical characteristics. Features of the 'ideal' manikin are proposed. Manufacturers should consider these features when developing manikins for training in newborn resuscitation.