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Comparing the Molecular Pharmacological Properties of Existing beta-Blockers to Determine the Theoretically Most "Ideal" Anti-Cancer beta-Blocker.There is increasing evidence, from cellular, animal and human epidemiological studies, linking β-blockers with reductions in cancer growth and metastasis. Propranolol is the most investigated β-blocker for cancer; although as many different off-patent β-blockers exist, there is little commercial incentive to drive comparative clinical trials. To minimize any chance of endogenous β-agonist driven cancer growth or metastasis, theoretically, the "ideal" anti-cancer β-blocker would have high affinity, no partial agonism, and long duration of action at β2-adrenoceptors (and for some cancers, additionally at β1 or β3-AR). Using CHO cells stably expressing the wildtype and polymorphic variants of the human β1 and β1-adrenoceptors, this study assessed 35 β-blockers for the affinity and duration of binding (using 3H-CGP12177 whole cell binding) and intrinsic efficacy (CRE-gene transcription). Despite high affinity, some β-blockers had a short binding duration (e.g., alprenolol, bupranolol, levobunolol, nadolol and oxprenolol). Other compounds had substantial partial agonism (e.g., cyanopindolol, bucindolol, pindolol, pronethalol and xamoterol) and other compounds had a biphasic washout (e.g., bucindolol, timolol, carpindolol, and CGP12177) for reasons unknown. Considering all 3 factors, carazolol and ICI118551 may be more "ideal" than propranolol; however, carvedilol, with higher affinity and substantially longer duration of β2 (and β1) receptor binding than propranolol whilst maintaining low partial agonism, may be the most theoretically optimal. Furthermore, it is already widely used in cardiovascular medicine as an off-patent tablet. Thus, carvedilol may have more optimal molecular pharmacological characteristics for an "anti-cancer" β-blocker than propranolol and could enter prospective comparative clinical trials without needing any further clinical workup.
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Predicting compounds that interact with the 2 known agonist-induced conformations of the human beta1-adrenoceptorThe β1-adrenoceptor exists in at least 2 agonist-stabilized conformational ensembles: a "catecholamine" ensemble induced via the intrahelical binding site through which catecholamines and most agonists act and a "secondary" ensemble of conformations through which CGP12177 stimulates agonist responses. Several β-ligands stimulate agonist responses through both conformations, resulting in biphasic concentration responses, but little is known about the structure-activity relationship of such ligands. Using a structure-activity hypothesis built on the predicted poses CGP12177 and 3 biphasic agonists (alprenolol, oxprenolol, and bucindolol), predictions based on ligand similarity and structural compatibility reasoning were made about 11 other β1-ligands not yet tested for secondary conformation interaction and examined in radioligand binding and functional assays using human β1- and β2-adrenoceptors. Although the predictions matched with pharmacology in only 6/11 of cases, 3 novel compounds were found to induce an active-state secondary conformation. A CGP12177 derivative (methyl-pyrrole replacing the cyclic urea motif) retained catecholamine site antagonism with secondary site activation. Carteolol (related to CGP12177) and bunitrolol (similar to alprenolol) activated both conformations with biphasic concentration responses. Bunolol (CGP12177 derivative lacking nitrogen in the bicyclic system), as predicted, was a neutral antagonist with no secondary site activation. Moprolol and some bucindolol analogs appeared as conventional agonists, whereas other alprenolol and bucindolol analogs lost all receptor interaction. In a β1-adrenoceptor mutant (β1-V189T-L195Q-W199Y) where secondary site CGP12177 and pindolol interaction is lost, the 3 novel secondary-site compounds were also no longer able to stimulate secondary conformation responses, suggesting that there is a common TM4 secondary conformation-inducing interaction site. SIGNIFICANCE STATEMENT: The β1-adrenoceptor exists in 2 agonist-stabilized, pharmacologically distinguishable conformations. This study pinpointed the interaction site through which the alternative conformation is stabilized and suggested and evaluated additional ligands, thus providing possible molecular determinants.
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Closing the gap in acute NIV: A scalable nurse-led approach to optimising time-critical care.Introduction The 2023 BTS RSU audit demonstrated a lower all-cause mortality for hospitals with an RSU and enhanced staffing ratios. At Sherwood Forest Hospitals (SHFT), an acute NIV nurse-led outreach and retrieval service, based on an RSU with enhanced staffing and central monitoring of observations, has been in place for over 8 years. However, data demonstrated our median gas and door-to-mask times were 03:29hrs, and 04:15hrs respectively, with delays noted in performing and interpretation of blood gases. Methods We created a digital tracker focusing on gas and door-to-mask times as our improvement measures. Following process mapping and root cause analysis, we redesigned our referrals process and developed an early assessment model for all acute patients. Acute NIV nurses perform an early clinical review at the initial identification of possible NIV patients, optimising patient care, ensuring timely blood gases and earlier ringfencing of RSU beds. Adopting and supplementing the BTS care bundle,2 we added 3 additional locally conceived standards to match our new delivery model and created a checklist to ensure consistency and completeness. We audited the utilisation of our standards before and after the intervention. Results Audit data demonstrated that pre-intervention, only 10% of sampled patients from 2024 received all elements of the care bundle, improving to 74%. Delivery of acute NIV improved with a reduction in both gas and door-to-mask times of 43 minutes and 1 hour 09 minutes, respectively. Conclusion Early results demonstrate an improvement in treatment times. The development of the locally enhanced care bundle enabled the reduction in variation of care and empowered the team to utilise their skills, experience and knowledge. We believe the continuous development of our acute NIV nurse model to now include earlier optimisation and identification of patients is sustainable, cost-effective and applicable to similar services.
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Establishing real world quality standards for domiciliary non-invasive ventilation.Introduction Chronic Obstructive Pulmonary Disease (COPD) places a significant burden on healthcare. Non-invasive ventilation (NIV) is an established treatment for acute respiratory failure in COPD, with comprehensive guidelines.1 However, evidence for its use in the domiciliary setting is more recent, with no standardised criteria for initiating or monitoring treatment. Trials such as HOT-HMV2 demonstrated clinical benefit but excluded patients with BMI >35 or obstructive sleep apnoea (OSA), highlighting limited real-world applicability. We hypothesised that testing local standards in real-world COPD populations could offer insight into realistic expectations for national domiciliary NIV services. Objectives We developed local criteria for domiciliary NIV initiation and follow-up, assessing their feasibility in routine care to inform service design. We also characterised our COPD population to evaluate how well existing research2 applies to real-world patients. Methods This retrospective observational study used cross-sectional and longitudinal data from 181 COPD patients initiated on domiciliary NIV between 1st July 2021 and 1st July 2024 within an NHS trust. Seven local standards (table 1) were defined using clinical reasoning alongside available guidelines. Demographics were evaluated at initiation. Patients with ≥12 months of follow-up (n=107) were assessed for hospital readmission, comparing admissions in the year before and after NIV initiation. Results Demographics: 62% female, mean BMI 34 (n=138), 48% BMI >35. 35% had OSA, 67% ≥1 additional respiratory diagnoses. Performance against quality standards was variable (see table 1). However, there was a 33% reduction in hospital admissions among patients with ≥12 months follow-up, and 81% attended ≥3 respiratory clinics in the first year on treatment. Conclusions This study trialled proposed quality standards and examined the real-world COPD population. Our findings show that trial populations do not reflect real-world COPD cohorts, limiting research generalisability. Many standards proved overly ambitious, highlighting the need for evidence-based, achievable national guidelines. These findings support the need for a national audit to inform realistic, standardised domiciliary NIV pathways.
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Semaglutide-associated drug-induced liver injury: a case report and review of the literatureSemaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to manage type 2 diabetes and, since 2021, for weight loss in individuals with obesity or weight-related comorbidities. It works by enhancing insulin secretion, delaying gastric emptying and reducing appetite. Common side effects include hypoglycaemia, gastrointestinal disturbances, nausea, weight loss and cholelithiasis. While some studies have noted an association with acute kidney injury, reports of liver injury are rare. We present a rare case of drug-induced liver injury in a middle-aged female, associated with transient liver failure after semaglutide use. She presented one month after starting the medication with rapidly worsening liver function tests. Investigations, including a non-invasive liver screen, viral studies, ultrasound and CT imaging, revealed no clear cause. A liver biopsy supported the diagnosis of drug-induced liver injury. The patient improved with supportive treatment and withdrawal of semaglutide. This case underscores the importance of clinician awareness given its increasing, and often unregulated, use for weight loss.
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A Comparison of the Molecular Pharmacological Properties of Current Short, Long, and Ultra‐Long‐Acting β2‐Agonists Used for Asthma and COPDβ-agonists have been used in asthma for 120 years. There are two recent changes: ultra-long-acting agonists for COPD and new asthma guidelines recommending formoterol/ICS inhalers phasing out short-acting salbutamol inhalers. Few studies directly compare the molecular pharmacological properties of short (salbutamol, terbutaline, fenoterol), long (formoterol, salmeterol), and ultra-long-acting (indacaterol, olodaterol, vilanterol) β2-agonists. Here, the in vitro molecular pharmacological properties of affinity, selectivity, intrinsic efficacy, and duration of β2-agonists at human β2 and β1-adrenoceptors and the 4 β2-polymorphisms stably expressed in CHO cells were directly compared using radioligand binding and functional studies. Whilst short-acting drugs were similar, there was huge variation and complete overlap in the molecular pharmacological properties of drugs labeled as long and ultra-long-acting β2-agonists. Salmeterol and vilanterol were highly β2-selective (> 1000-fold) whereas indacaterol was similar to salbutamol (40-fold). Formoterol and indacaterol were the most efficacious, whereas salmeterol had the longest duration of binding. Salmeterol and vilanterol utilize a β2-specific exosite (β2-H296-K305) for high affinity and selectivity (that does not affect intrinsic efficacy or duration) whilst the β2-selectivity of formoterol and olodaterol resides elsewhere. Duration of binding closely correlated with lipophilicity. β2-polymorphisms had no substantial effect on β2-agonist properties. Comparison with other β-ligands suggests that affinity and duration could both be improved further. However, given the very wide range of molecular pharmacological properties of β-agonists that are clinically effective and widely used, non-pharmacological properties (physiochemical, patient factors, devices and combination inhaler availability) may be as important in final clinical patient outcomes as the molecular pharmacological properties of the individual β2-agonists themselves.
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CASE STUDY: THE USE OF SUBCUTANEOUS CLONIDINE FOR PAIN RELIEF IN COMPLEX CANCER PAIN.Pain is a common symptom in the terminal phase of a cancer patient, and the World Cancer Declaration sets a target for universally available pain control by 2025. Cancer pain can be complex to manage due to the different pathological mechanisms occurring, particularly as it advances and is progressively resisting current analgesia. This case report focuses on the use of clonidine in the palliative care setting, where opioid and non-opioid approaches to analgesia have not controlled the intensifying pain. Sharing this study aims to further the experience base of its utility in complex cancer pain management. The α2A-adrenergic receptor agonist, clonidine, is increasingly being recognised as an effective adjuvant medication for pain and agitation in patients in end-of-life care. This is due to its anti-nociceptive properties and non-opioid action. Evidence of its use in a palliative setting, and relevant pharmacokinetic safety profile, is limited. However, a recent retrospective study in the UK has shown it to be a promising drug due to being well tolerated and its symptomatic benefits. Clonidine was titrated in response to reported and observed pain behaviours, to serve as an adjuvant to opioids. It was noted that there was a significant decrease in opioid usage in correlation with an increased dosage of clonidine. Despite the complicating factor of COVID-19, the patient reported a clinical benefit of clonidine in terms of their pain and comfort. Review of the patient’s integrated Palliative Care Outcome Scale indicated maintained scores with introduction of clonidine compared to prior use of opioids.
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The Association Between Psychosocial Factors and Decision Making Regarding Primary Treatment in Older Women With Early-Stage Breast Cancer.Background: Breast cancer is increasingly prevalent among older adults, who are likely to have numerous comorbidities and unique psychosocial challenges. Aims: The aim of this study was to measure the prevalence of psychosocial factors in a cohort of older women diagnosed with early-stage operable breast cancer and the influence these factors may have on treatment decisions. Methods: As part of a prospective study in three UK centres, 199 patients with a new diagnosis of early-stage operable primary breast cancer, aged ≥ 70 years (mean 77, range 68-93) were recruited. A cancer-specific Comprehensive Geriatric Assessment (CGA) was conducted within 6 weeks of diagnosis. Association between treatment decision and psychosocial aspects (as measured by the 'psychosocial support', 'social activity' and 'social support' domains) of the CGA was determined. Treatment decision was not guided by this study and was determined usual conventional methods as per the breast multi-disciplinary team. Results: Scores for 'psychosocial support' averaged 82.1/102, 'social activity' averaged 13.5/24, and 'social support' averaged 43.3/72; with a higher score indicating a more positive outcome. There was no association between total scores in these domains and the type of treatment received. A lower score in three individual questions was associated with a higher likelihood of non-surgical treatment. Conclusions: While no direct link emerged between overall psychosocial scores and treatment decisions using CGA, specific sub-questions displayed associations with non-surgical treatment. This study is the only one of its kind to our knowledge. This may have implications for the design of a pre-CGA screening tool.
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Intracardiac echocardiography versus transesophageal echocardiography guidance on left atrial appendage occlusion in patients with atrial fibrillation: A systematic review and meta-analysisBackground: Intracardiac echocardiography (ICE) is an innovative technique that has emerged as an alternative to transesophageal echocardiography (TEE) to guide the implantation of a left atrial appendage occlusion (LAAO) device in patients with nonvalvular atrial fibrillation (AF) who cannot tolerate anticoagulants. Purpose: We aim to review the clinical efficacy and safety of ICE compared to TEE to guide the implantation of LAAO devices in patients with AF. Methods: We conducted comprehensive searches across PubMed, CENTRAL, Web of Science, Scopus, and EMBASE until March 2024. Pooled data were reported using risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, along with a 95% confidence interval (CI). This systematic review and meta-analysis was registered with PROSPERO ID: CRD42024542537. Results: We included 19 studies involving 44,706 patients. ICE was associated with a statistically significant high procedure success rate compared to TEE (RR: 1.0055 with 95% CI [1.0006, 1.0104], p = 0.01), but there was no difference in procedure duration (MD: 3.07 with 95% CI [-4.67, 10.80], p = 0.44) between the two groups. However, compared to the ICE group, patients undergoing LAAO under TEE guidance required more than one device more often (RR: 1.39 with 95% CI [1.23, 1.57], p < 0.01). The TEE group also reported a reduced incidence of pericardial effusion compared to the ICE group (RR: 0.65 with 95% CI [0.50, 0.85], p < 0.01). Conclusion: Our meta-analysis concluded that ICE can be a viable alternative to TEE for guiding LAAO, particularly in patients unsuitable for general anesthesia. It can also reduce the need for GA and adverse effects and resources associated with it, require fewer devices, and demonstrate comparable safety and efficacy outcomes, though it may increase the risk of pericardial effusion. Further prospective trials are warranted.
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The Promising Role of Probiotics in the Prevention of Cardiovascular Risk Factors and Their Implication in Reducing Coronary Artery Disease: A Literature Review.Coronary artery disease (CAD) remains one of the most common causes of mortality across the globe, which is strongly associated with modifiable risk factors such as hypertension, hyperlipidemia, type 2 diabetes, and obesity. The role of the gut microbiota in influencing these factors has been established recently. Probiotics, which can modulate gut microbiota, have been investigated as a potential strategy to reduce cardiovascular risk. This review aims to evaluate current evidence on the role of probiotics in reducing CAD risk factors and to explore the mechanisms through which probiotics may support cardiovascular health. This narrative review was conducted using studies published within the last five years. The search included databases such as PubMed, Google Scholar, Medline, and ResearchGate. The selection focused on randomized controlled trials (RCTs), meta-analyses, and reviews that examined the impact of probiotics on CAD and its associated risk factors. Findings from several RCTs and meta-analyses show that probiotic supplementation is associated with improved lipid profiles (including lower LDL-C and triglycerides), better glycemic control, reduced inflammatory markers, and modest reductions in blood pressure and obesity measures. However, results across studies vary due to differences in sample size, duration, probiotic strains, and measured outcomes. Probiotics may offer a beneficial, non-pharmacological option to support conventional CAD therapies, particularly by targeting key modifiable risk factors. While early results are encouraging, further large-scale, long-term studies are necessary to confirm their clinical effectiveness and guide standardized recommendations.
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An Audit Of Oxygen Prescribing Practices In Respiratory Wards Of A Tertiary Care Hospital In Nottinghamshire, Uk.Background: This audit primarily assesses compliance with the British Thoracic Society guidelines (BTS) for oxygen prescriptions in the Respiratory Department at King's Mill Hospital. The results of this audit aim to guide the strategies to improve the oxygen prescription practices in the Trust. Methods: We collected the data on oxygen prescriptions, from the electronic prescribing system, of all the patients admitted in the three respiratory wards of King's Mill Hospital over the period of one week. This data was then recorded and analysed using Audit management and Tracking© (AMAT). Results: The overall compliance score to BTS guidelines for oxygen prescription was 12.2%. Out of the 152 patients, only 8 (5%) had oxygen therapy prescribed and a target oxygen saturation range was identified. No patient had an identifiable oxygen delivery method on their prescription. Conclusions: The current practices of oxygen prescription at the respiratory department of King's Mill Hospital are suboptimal. These findings highlight the risk of serious potential consequences and the opportunity to implement safe prescribing measures for oxygen, like other prescribed medications.
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Retrospective study on pain management pathway for patients with suspected renal/ ureteric colic in a U.K. accidents and emergency department: A quality improvement project.Competing Interests: No competing interests were disclosed. Background: In acute settings around the globe, renal/ureteric colic remains one of the most common diagnoses for patients presenting with loin-to-groin pain. Even though management spans from medical expulsive therapies to surgical options, pain as a significant component of a patient's presentation must be dealt with quickly, decisively, and safely, as it can be excruciating and its effects on overall health are dire. This study aimed to explore compliance with the National Institute for Health and Care Excellence (NICE) guidelines for pain management in patients with suspected renal/ureteric colic. It includes the use of nonsteroidal anti-inflammatory drugs (NSAIDs), intravenous paracetamol, and opioids as first-, second-, and third-line analgesics, respectively, and does not offer antispasmodics. In the event of deviations from the standard, the aim was to put in corrective measures, followed by re-exploration of compliance with patient care. Methods: This study involved a single healthcare facility with the study type being retrospective before interventions and prospective after interventions. In the first cycle, we retrieved and analysed 78 patients records whom had been suspected to have renal/ureteric colic between July and September 2022. The inclusion criteria were documented complaints of "flank/loin-to-groin pain" and diagnosis prior to performing diagnostic tests. We surveyed the first-, second-, and third-line painkillers issued, and whether an antispasmodic was given. We collected and entered data into a Microsoft Excel file and correlated it with NICE standards. Having found deviations from the standard, we conducted interventions, allowed time for clinicians to adapt, and re-explored compliance using patient case records [n=58] between February and May 2023. Results: In the 1 st cycle, 78 patients were suspected of having renal/ureteric colic. M: F = 1.2:1. Non-contrast computerized tomography of the kidney ureters and bladder (NC-CTKUB) confirmed 87% of patients with stones and 3% had no stones. NC-CTKUB was not performed in 9% of patients because they were young, and urinalysis showed no microscopic hematuria. One patient had discharged against medical advise before the NC-CTKUB was performed. Compliance with the NICE pain management guidelines for suspected renal/ureteric colic was full in 23% of cases but unsatisfactory in 78% of cases. In the 2 nd cycle, M: F = 1.5:1, NC-CTKUB was not re-audited, as the first cycle study yielded excellent results, and our action plan resulted in an NICE pain management compliance rate of 56%. Although our interventions resulted in improvements of more than twice the initial results, work still needs to be performed. Conclusion: Clinicians' ability to correctly diagnose renal/ureteric colic is remarkable. However, the pain management compliance rate indicates room for improvement. This may be due to the limited awareness of the NICE guideline or the fact that the clinical team has an affinity for certain analgesics compared to others. We propose the need to consider select variables to existing standard guidelines to enhance compliance for improved patient care. (Copyright: © 2024 Ojo C et al.)
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Worldwide trends in the quality and breadth of clinical investigations of medical devices over the past decade: a scoping review and evidence map.Background Recent regulatory developments in Europe have enhanced the requirements for clinical investigations of medical devices, partly in response to a perceived need for a higher level of evidence that is publicly available. This scoping review aims to map published clinical investigations of medical devices by device type and clinical specialty and summarise key trial design aspects. Methods We developed a search for EMBASE that identified clinical investigations of medical devices during two discrete 3-month periods at the end of 2012 and of 2022. Core information from observational studies was extracted along with details on study design in interventional studies. We developed an evidence map of published studies across device type and clinical specialty and summarised study design aspects. Results We included 682 studies from 2012 and 1682 studies from 2022. Around a quarter of studies were interventional and the remainder being observational and primary outcomes of effectiveness were more common than efficacy. Key study design aspects were frequently unreported, including sample size justification, registration, randomisation technique and funders. Our evidence map demonstrated that predominantly, investigations were of implants and were in a cardiovascular setting. Clinical investigations were broadly similar between 2012 and 2022, though there was a reduction in the proportion of cardiovascular studies, a move in the share of studies coming out of Europe and North America towards Asia and a general improvement in the quality of study design reported. Conclusions Implanted devices in cardiovascular disease and orthopaedics are the focus of a large proportion of published clinical investigations of medical devices. Reporting of key study design aspects of clinical investigations of medical devices are improving but are still below expected requirements.
