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Climate change continues to pose a dangerous threat to human health. However, not only is health impacted by this crisis, healthcare itself adds to the problem, through significant contributions to greenhouse gas emissions. In the UK, the National Health Service (NHS) is responsible for an estimated 4% of the overall national carbon footprint. Medicines account for a quarter of this and whilst they are vital for health now, through sustainable use they can also positively influence the environmental health of the future. In this review, we explore how clinical pharmacologists and other health care professionals can practice sustainable medicines use or eco-pharmaco-stewardship. We will discuss current and near future environmental practices within the NHS, which we suspect will resonate with other health systems. We will suggest approaches for championing eco-pharmaco-stewardship in drug manufacturing, clinical practices and patient use, to achieve a more a sustainable healthcare system.

Peer reviewed: True, Objectives: To assess the risk of new-onset or worsening hyperglycaemia, hypertension, weight gain and hyperlipidaemia with systemic corticosteroid therapy (CST) as reported in published randomised control trial (RCT) studies. Data sources: Literature search using MEDLINE, EMBASE, Cochrane library, Web of Science and Scopus Study eligibility criteria: Published articles on results of RCT with a systemic CST arm with numerical data presented on adverse effect (AE). Participants and interventions: Reports of hyperglycaemia, hypertension, weight gain and hyperlipidaemia associated with systemic CST in patients or healthy volunteer’s ≥17 years of age. Study appraisal methods: Risk of bias tool, assessment at the level of AE and key study characteristics. Results: A total of 5446 articles were screened to include 118 studies with 152 systemic CST arms (total participants=17 113 among which 8569 participants treated with CST). Pooled prevalence of hyperglycaemia in the CST arms within the studies was 10% (95% CI 7% to 14%), with the highest prevalence in respiratory illnesses at 22% (95% CI 9% to 35%). Pooled prevalence of severe hyperglycaemia, hypertension, weight gain and hyperlipidaemia within the corticosteroid arms was 5% (95% CI 2% to 9%), 6% (95% CI 4% to 8%), 13% (95% CI 8% to 18%), 8% (95% CI 4% to 17%), respectively. CST was significantly associated hyperglycaemia, hypertension and weight gain as noted in double-blinded placebo-controlled parallel-arms studies: OR of 2.13 (95% CI 1.66 to 2.72), 1.68 (95% CI 0.96 to 2.95) and 5.20 (95% CI 2.10 to 12.90), respectively. Intravenous therapy posed higher risk than oral therapy: OR of 2.39 (95% CI 1.16 to 4.91). Limitations: There was significant heterogeneity in the AE definitions and quality of AE reporting in the primary studies and patient populations in the studies. The impact of cumulative dose effect on incidental AE could not be calculated. Conclusions and implications of key findings: Systemic CST use is associated with increased risk of metabolic AEs, which differs for each disease group and route of administration. PROSPERO registration number: CRD42020161270.

Patients with hypertensive emergencies, malignant hypertension and acute severe hypertension are managed heterogeneously in clinical practice. Initiating anti-hypertensive therapy and setting BP goal in acute settings requires important considerations which differ slightly across various diagnoses and clinical contexts. This position paper by British and Irish Hypertension Society, aims to provide clinicians a framework for diagnosing, evaluating, and managing patients with hypertensive crisis, based on the critical appraisal of available evidence and expert opinion.

Introduction Orthostatic hypotension (OH) is associated with cardiovascular mortality and morbidity. Non-pharmacological and pharmacological therapies are employed in the management of OH. The aim of this systematic review and meta-analysis is to provide an up-to-date review of the efficacy parameters of pharmacological therapies. Methods Medline, Embase, Cochrane Library, and Scopus were searched (inception-July 2021), and published articles with randomized control trials, meeting inclusion and exclusion criteria were quality assessed (Risk of Bias 2 tool). Assessment for trends in patient-related outcome measures and postural blood pressure improvement was undertaken. Studies reporting postural systolic blood pressure (SBP) before and after intervention in comparison to placebo were included in a meta-analysis using inverse -variance in a random-effects model. Results 19 articles were included in the systematic review. The orthostatic symptoms questionnaire (OHQ) was the most common patient-related outcome measure utilized in trials. Six studies included in the meta-analysis demonstrated that pharmacological therapies (pyridostigmine, midodrine, atomoxetine, yohimbine) improved postural SBP compared to placebo, with a mean rise of 12.50 mmHg [95% CI: 6.01, 18.98; p value

Vaccines have reduced the transmission and severity of COVID-19, but there remains a paucity of efficacious treatment for drug-resistant strains and more susceptible individuals, particularly those who mount a suboptimal vaccine response, either due to underlying health conditions or concomitant therapies. Repurposing existing drugs is a timely, safe and scientifically robust method for treating pandemics, such as COVID-19. Here, we review the pharmacology and scientific rationale for repurposing niclosamide, an anti-helminth already in human use as a treatment for COVID-19. In addition, its potent antiviral activity, niclosamide has shown pleiotropic anti-inflammatory, antibacterial, bronchodilatory and anticancer effects in numerous preclinical and early clinical studies. The advantages and rationale for nebulized and intranasal formulations of niclosamide, which target the site of the primary infection in COVID-19, are reviewed. Finally, we give an overview of ongoing clinical trials investigating niclosamide as a promising candidate against SARS-CoV-2.

Trendovi u razvoju farmakovigilancije.

Vaccines have reduced the transmission and severity of COVID-19 but there remains a paucity of efficacious treatment for drug resistant strains and more susceptible individuals. Repurposing existing drugs is a timely, safe and scientifically robust method for treating pandemics such as COVID-19. Here, we review the pharmacology and scientific rationale for repurposing niclosamide, an anti-helminth already in human use as a treatment for COVID-19. In addition to potent antiviral activity, niclosamide has shown pleiotropic anti-inflammatory, antibacterial, bronchodilatory and anticancer effects in numerous pre-clinical and early clinical studies. The advantages and rationale for nebulised and intranasal formulations of niclosamide, which target the site of primary infection in COVID-19, are reviewed. Finally, we discuss the TACTIC-E clinical trial, an international COVID-19 therapeutic platform trial for the use of licensed and novel therapeutic agents, which is investigating niclosamide as a promising candidate against SARS-CoV-2.

Climate change continues to pose a dangerous threat to human health. However, not only is health impacted by this crisis, healthcare itself adds to the problem, through significant contributions to green house gas emissions. In the UK, the National Health Service (NHS) is responsible for an estimated 4% of the overall national carbon footprint. Medicines account for a quarter of this and whilst they are vital in in health now, through sustainable use they can also positively influence the environmental health of the future. In this review, we explore how clinical pharmacologists and other health care professionals can practice sustainable medicines use or eco-pharmaco-stewardship. We will discuss current and near future environmental practices within the NHS, which we suspect will resonate with other health systems. We will suggest approaches for championing eco-pharmaco-stewardship in drug manufacturing, clinical practices and patient use, to achieve a more a sustainable healthcare system.

The last decade has witnessed the healthcare system going paperless with increased use of electronic healthcare records. Artificial intelligence tools including smartphones and smart watches have changed the landscape of day-to-day lives. Digitisation, decentralisation of healthcare and empowerment of allied healthcare providers and patients themselves have made shared clinical decision-making a reality. The year 2020 quickly turned into an unprecedented time in our lives with the entry of COVID-19. Amidst a pandemic, healthcare systems rapidly adapted and transformed, and changes that otherwise would have taken a decade, took a mere few weeks (Webster, Lancet 395:1180-1, 2020). This essay reviews evidence of transformation in the realm of hypertension management, namely diagnosis, lifestyle changes, therapeutics and prevention of hypertension at both individual and population levels, and presents an extrapolation of how this transformation might shape the next decade.

Introduction: Metabolic adverse events associated with corticosteroid therapy (CT) are seen as a necessary evil in the management of a wide variety of inflammatory conditions. Evidence on the burden of dysglycaemia associated with CT strategies is mostly based on case- control studies. The aim of this study was to quantify metabolic side effects of systemic steroids as reported in randomised clinical trials (RCT). Methods: We searched Medline, Embase, Cochrane Library, Web of Science and Scopus for studies reporting adverse effects of CT in trials since database inception to 13/01/2020. We used a standardised data extraction form to collect information from eligible studies using predefined inclusion and exclusion criteria. Cochrane risk of bias tool 2 (ROB2) was used to assess risk of bias in the RCTs. The study was registered prospectively with PROSPERO (CRD42020161270). Results: The search identified 5446 studies. In total 120 blinded studies were identified for the mixed method review of AEs. There was significant heterogeneity with respect to steroid dose, treatment duration, condition treated, exclusion criteria in the studies, data collection methods for adverse events (AE) and definition for specific AEs. A significant increase in cases of new onset diabetes, hyperglycaemia, episodes of rise in blood pressure (BP) was noted. Average adverse event rate for new onset of diabetes in the studies (N=21, 27 CT arms) was 4.8% (72 events in 1477 participants, range: 0.85%-18.75%). Event rate of hyperglycaemia in the CT arms was 11.8% approximately (53 CT arms, 222 events in 1854 participants, range: 2.5%-69%). Rise in BP was reported in 53 CT arms in 42 studies, with average event rate of 12.8% (160 events in 1251 participants, range: 0.94%-30.4%). Other significant AEs associated with steroid use included weight gain, dyslipidaemia, insomnia, infections, osteoporosis and fractures. Conclusions: Risk of new onset diabetes and worsening of diabetes control is significant in patients treated with CT, although available evidence to estimate risk is heterogenous. Both, alternatives to corticosteroids which do not elevate blood glucose and accurate estimation of risk of dysglycaemia from well-designed prospective RCTs are urgently required.

Objectives To determine if a specific immunomodulatory intervention reduces progression of COVID-19-related disease to organ failure or death, compared to standard of care (SoC). Trial design Randomised, parallel 3-arm (1:1:1 ratio), open-label, Phase IV platform trial of immunomodulatory therapies in patients with late stage 1 or stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical and/or radiological assessment. Participants Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a Risk count (as defined below) >3 OR ≥3 if risk count includes “Radiographic severity score >3”. A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >40 mg/L. Patients should be considered an appropriate subject for intervention with immunomodulatory therapies in the opinion of the investigator and be able to be maintained on venous thromboembolism prophylaxis during the inpatient dosing period, according to local guidelines. The complete inclusion and exclusion criteria as detailed in the additional file 1 should be fulfilled. Patients will be enrolled prior to the need for invasive mechanical ventilation, cardiac or renal support. Participants will be recruited across multiple centres including initially at Cambridge University Hospitals NHS Foundation Trust, King’s College Hospital NHS Foundation Trust, Guy’s and St Thomas’ NHS Foundation Trust, University Hospital of Wales, Gloucestershire Royal Hospitals NHS Foundation Trust and The Royal Wolverhampton NHS Trust. Intervention and comparator Each active comparator arm will be compared against standard of care (SoC). The immunomodulatory drugs were selected from a panel of licenced candidates by a drug evaluation committee, which considered potential efficacy, potential toxicity, scalability and novelty of each strategy. The initial active arms comprise baricitinib and ravulizumab. Baricitinib will be given 4 mg orally (once daily (OD)) on days 1-14 or until day of discharge. The dose will be reduced to 2 mg OD for patients aged > 75 years and those with an estimated Cockcroft Gault creatinine clearance of 30-60 ml/min. Ravulizumab will be administered intravenously once according to the licensed weight-based dosing regimen (see Additional file 1). Each active arm will be compared with standard of care alone. No comparisons will be made between active arms in this platform trial. Main outcomes The primary outcome is the incidence (from baseline up to Day 14) of any one of the events (whichever comes first): death, invasive mechanical ventilation, extra corporeal membrane oxygenation, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance Randomisation Eligible patients will be randomised using a central web-based randomisation service (Sealed Envelope) in a 1:1:1 ratio, stratified by site to one of the treatment arms or SoC. Blinding (masking) This is an open-label trial. Data analysis will not be blinded. Numbers to be randomised (sample size) There is no fixed sample size for this study. Serial interim analyses will be triggered by an Independent Data Monitoring Committee (IDMC), including analysis after 125 patients are recruited to each arm, 375 in total assuming 3 arms. Additional interim analyses are projected after 229 patients per arm, and potentially then after 469 per arm, but additional analyses may be triggered by the IDMC. Trial Status TACTIC-R Protocol version number 2.0 date May 20, 2020, recruitment began May 7, 2020 and the end trial will be the date 18 months after the last patient’s last visit. The recruitment end date cannot yet be accurately predicted. Trial registration Registered on EU Clinical Trials Register EudraCT Number: 2020-001354-22 Registered: 6 May 2020 It was registered on ClinicalTrials.gov (NCT04390464) and on ISRCTN (ISRCTN11188345) Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Medication nonadherence represents a modifiable risk factor for patients with hypertension. Identification of nonadherent patients could have significant clinical and economic implications in the management of uncontrolled hypertension. We analysed the results of 174 urinary adherence screens from patients referred to Addenbrooke's Hospital, Cambridge, for uncontrolled hypertension. Cases were identified for evaluation by results of liquid chromatography-tandem mass spectrometry of urine samples (males: 91; females: 83; age range: 17–87). We performed a binary logistic regression analysis for nonadherence using age, sex, and number of medications prescribed (both antihypertensives and non-antihypertensives separately) as independent predictors. Rates of nonadherence for individual antihypertensive drugs were calculated if prescribed to ≥10 patients. The overall rate of nonadherence to one or more prescribed antihypertensive medications was 40.3%. 14.4% of all patients were nonadherent to all prescribed antihypertensive medications (complete nonadherence), whereas 25.9% of all patients were nonadherent to at least 1, (but not all) prescribed antihypertensive medications (partial nonadherence). 72% of patients were prescribed ≥3 antihypertensives And for every increase in the number of antihypertensive medications prescribed, nonadherence increased with adjusted odds ratios of 2.9 (P