Introduction: In critically ill patients, Transfusion Related Acute Lung Injury (TRALI) remains the leading cause of transfusion-related fatalities in critical care setting and associated with inflammation and oxidative stress state. Recent research raised the potential efficacy of high dose intravenous ascorbic acid in critically ill patients. Objective: The aim of this trial was to investigate the effect of high dose intravenous ascorbic acid (VC) as a targeted therapy for TRALI in terms of serum proinflammatory (interleukin-8, interleukin-1β, C-reactive protein), anti-inflammatory (interleukin-10), oxidative stress (superoxide dismutase, malondialdehyde) markers, and plasma VC levels. Secondary outcomes were oxygenation (PaO2/FiO2 ratio), vasopressor use, duration of mechanical ventilation, ICU length of stay, 7-days mortality and 28-days mortality. Methods: Eighty critically ill patients with TRALI (n=80) were randomized to receive 2.5gm/6hr intravenous vitamin C for 96 hours (ASTRALI group) or placebo. Patients were followed-up to measure the outcomes initially (T0) and at the end of treatment (T96). Results: When compared to control group, ASTRALI group at T96, showed significantly higher median of interleukin-10 (31.6 ± 25.8 Vs. 17.7 ± 12.0 pg/mL, p<0.0001) levels and superoxide dismutase (12876 ± 4627 U/L Vs. 5895 ± 6632 U/L, p<0.0001) activities, lower median C-reactive protein (76 ± 50 Vs. 89 ± 56 mg/L, p=0.033), interleukin-8 (11.8 ± 7.3, 35.5 ± 19.8 pg/mL, p<0.0001), and malondialdehyde (0.197 ± 0.034 Vs. 0.234 ± 0.074 µM/L, p=0.002) levels. Conclusion: High dose ascorbic acid was associated with significantly reduced oxidative stress, reduced pro-inflammatory markers except IL-1β, elevated anti-inflammatory marker, and elevated plasma VC levels

A document by Emma Magavern. Click on the document to view its contents.

Drug-related adverse reactions are among the main reasons for harm to patients under care worldwide and even their deaths. The pharmacovigilance system has been proven to be an effective method of avoiding or alleviating such adverse events. In 2019, after two decades of implementation of the drug-related adverse reaction reporting system, China formally implemented a pharmacovigilance system with the Pharmacovigilance Quality Management Standards and a series of supporting technical documents created to improve the safety of medication given to patients. China’s pharmacovigilance system has faced many problems and challenges during its implementation. This spontaneous reporting system is the main source of data for China’s medication vigilance activities, but it has not provided sufficiently powerful evidence for regulatory decision-making. In conformity to the health-centered drug regulatory concept, the Chinese government has accelerated the speed of examination and approval of urgently needed clinical drugs and orphan drugs along with the requirement to improve the safety supervision of these drugs after their listing. China’s marketing authorization holders（MAHs）must strengthen its pharmacovigilance capabilities as the primary responsible department for drug safety. Chinese medical schools generally lack professional courses on pharmacovigilance. The regulatory authorities have recognized such problems and have made efforts to improve the professional capacity of pharmacovigilance personnel and to strengthen cooperation with stakeholders through the implementation of an action plan of medication surveillance and the establishment of patient-based adverse events reporting system and active surveillance systems, which will help China bridge the gap to bring its pharmacovigilance practice up to standards.

Objectives We aim to seek expert opinion and gain consensus on the risks associated with a range of prescribing scenarios, preventable using e-prescribing systems, to inform the development of a simulation tool to evaluate the risk and safety of e-prescribing systems (ePRaSE). Methods We conducted a two-round eDelphi survey where expert participants were asked to score pre-designed prescribing scenarios using a five-point Likert scale to ascertain the likelihood of occurrence of the prescribing event, likelihood of occurrence of harm and the severity of the harm. Results Twenty four experts consented to participate with fifteen participants and thirteen participants completing rounds 1 and 2 respectively. Experts agreed on the level of risk associated with 136 out of 178 clinical scenarios with 131 scenarios categorised as high or extreme risk. Discussion We identified 131 extreme or high-risk prescribing scenarios that may be prevented using e-prescribing clinical decision support. The prescribing scenarios represent a variety of categories, with drug-disease contraindications, being the most frequent representing 37 (27%) scenarios and antimicrobial agents being the most common drug class representing 28 (21%) of the scenarios. Conclusion Our eDelphi study has achieved expert consensus on the risk associated with a range of clinical scenarios with most of the scenarios categorised as extreme or high risk. These prescribing scenarios represent the breadth of preventable prescribing error categories involving both basic and advanced clinical decision support. We will use the findings of this study to inform the development of the e-prescribing risk and safety evaluation tool.

Paracetamol overdose is common in developed countries but less than 10% involve large ingestions exceeding 30g or 500mg/kg. High dose acetylcysteine (NAC) has been proposed in patients taking large paracetamol overdoses based on reports of hepatotoxicity despite early initiation of NAC treatment with the commonly used 300 mg/kg intravenous acetylcysteine regimen. The evidence from cohorts of patients treated with the standard NAC regimen after large paracetamol overdoses shows that it is effective in most patients. Small studies in patients whose paracetamol concentration are above the 300mg/L nomogram line show that modification of the standard NAC regimen to provide a total of 400-500 mg/kg NAC over 21-22h may reduce the risk of hepatotoxicity (peak ALT>1000 IU/L) but the impact on development of hepatic failure, liver transplantation and mortality with this approach is presently unknown. Better risk stratification of patients taking paracetamol overdose may allow higher dose NAC and adjunctive treatments such as CYP2E1 inhibition and extracorporeal removal of paracetamol to be targeted to those patients at the highest risk of hepatotoxicity after a large paracetamol overdose.

The propellants used in metered-dose inhalers (MDIs) are powerful greenhouse gases, which account for approximately 13% of the NHS’s carbon footprint related to the delivery of care. Most MDI use is in salbutamol relievers in patients with poorly controlled disease. The UK lags behind in this regard with greater reliance on salbutamol MDI and correspondingly greater greenhouse gas emissions; roughly treble our European neighbours’. There has been a broad switch towards MDIs in the UK over the last 20 years to reduce financial costs such that two-thirds of asthma patients in the UK are on treatment dominated by salbutamol MDI. Strategies that replace overuse of reliever MDIs with regimes emphasising inhaled corticosteroids have the potential to improve asthma control alongside significant reductions in greenhouse gas emissions. Real-world evidence shows that once-daily long-acting combination dry-powder inhalers can improve compliance, asthma control and reduce the carbon footprint of care. Similarly, maintenance and reliever therapy (MART) which uses combination reliever and inhaled steroids in one device (usually a dry-powder inhaler) can simplify therapy, improve asthma control and reduce greenhouse gas emissions. Both treatment strategies are popular with patients, most of whom are willing to change treatment to reduce their carbon footprint. By focussing on patients who are currently using high amounts of salbutamol MDI, and prioritising inhaled steroids via dry-powder inhalers, there are golden opportunities to make asthma care more effective, safer and greener.

Aim: The placebo effect and the specific effect are often thought to add up (additive model). Whether this is true or whether there is an interaction between the two, can modify the external validity of a trial. This assumption of additivity was tested by Kleijnen et al. in 1994 but the data produced since then has not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held. Methods: We searched Medline and Psychinfo up to 10/01/2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in BPD with analysis of variance or covariance. Results: 30 studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity). Conclusion: Evidence of additivity between placebo and specific features of treatments was rare in our sample. For ailments that are placebo-responsive, pragmatic trials should be preferred to increase their external validity.

It is unfortunately true that clinicians lack the necessary evidence to know how to use medications properly in large sections of the population, and we do not have optimal drugs to use in many Neglected Tropical Diseases (NTDs). NTD’s often disproportionately affect neglected populations such as children and pregnant women. As reliable access to safe, effective preventives and treatments can break the cycle of poverty, illness, and ensuing debility that further perpetuates poverty, it is of paramount importance to investigate and develop new medicines for neglected populations suffering from NTDs. Furthermore, there is not only a need to develop and evaluate novel therapies, but also to ensure that these are affordable, available, and adapted to the communities who need them. With this editorial, the British Pharmacological Society hereby launches a call for high-quality articles focusing on NTDs in special populations, to facilitate the reversal of this dual neglect.

Low- and middle-income countries (LMIC) face unique challenges with regard to the establishment of robust pharmacovigilance systems capable of generating data to inform healthcare policy and practice. These include the limited integration and reliance of pharmacovigilance systems across LMIC despite recent efforts to harmonize pharmacovigilance rules and regulations in several regional economic communities; the need to translate reporting tools into numerous local languages; low numbers of healthcare providers relative to number of patients, with very short consultation times; scarcity of well-trained pharmacovigilance personnel with little or no budgetary support for these activities from national governments; high turnover of pharmacovigilance staff whose training involves a substantial amount of resources; little awareness of pharmacovigilance among healthcare workers, decision makers and consumers; very low spontaneous reporting rates with poor quality reports which hinders robust signal detection analyses; little collaboration between public health programmes and national medicines regulatory authorities; limited investment in pharmacovigilance activities especially during mass drug administration for neglected tropical diseases; high uptake of herbal and traditional medication, mostly by self-medication; disruptive political conflicts jeopardizing fragile systems; and little or no access to drug utilization data which makes it difficult to reliably estimate the true safety risks of medicine use. This review summarises the specific challenges and areas of progress in pharmacovigilance in LMIC with special focus on the situation in Africa.

Aim. Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)-related adverse events (AE). Guidelines recommend FP dosing adjusted to genotype-predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798, rs56038477). We evaluated relationship between three further DPYD polymorphisms [c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265)] and the risk of severe AEs. Methods. Consecutive FP-treated adult patients were genotyped for “standard” and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0-2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining three tested polymorphisms). Results. Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n=127) than in controls (n=376) [OR=5.20 (95%CI 1.88-14.3), Bayesian OR=5.24 (95% CrI 3.06-9.12)]. Odds tended to be higher in *6 c.2194G>A variant carries (n=58) than in controls (n=432) [OR=1.88 (0.95-3.73), Bayesian OR=1.90 (1.03-3.56)]. *9A c.85T>G did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls). Conclusion. DPYD c.496A>G variant might need to be considered for inclusion in the DPYD genotyping panel.

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.

A document by Christopher Threapleton. Click on the document to view its contents.

Aim: The risk-benefit profile of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (Covid-19) is still a matter of debate. With growing evidence on the protective effect of this group of commonly used antihypertensives in Covid-19, we aimed to thoroughly investigate the association between the use of major classes of antihypertensive medications and Covid-19 outcomes in comparison with the use of ACEIs and ARBs. Methods: We conducted a population-based study in patients with pre-existing hypertension in the UK Biobank. Multivariable logistic regression analysis was performed adjusting for a wide range of confounders. Results: The use of either beta-blockers (BBs), calcium-channel blockers (CCBs), or diuretics was associated with a higher risk of Covid-19 hospitalization compared to ACEI use (adjusted OR, 1.63; 95% CI, 1.40 to 1.90) and ARB use (adjusted OR, 1.50; 95% CI, 1.27 to 1.77). The risk of 28-day mortality among Covid-19 patients was also increased among users of BBs, CCBs or diuretics when compared to ACEI users (adjusted OR, 1.64; 95% CI, 1.23 to 2.19) but not when compared to ARB users (adjusted OR, 1.18; 95% CI, 0.87 to 1.59). However, no associations were observed when the same analysis was conducted among hospitalized Covid-19 patients only. Conclusion: Our results suggest protective effects of blocking of the renin-angiotensin-aldosterone system on Covid-19 hospitalization and mortality among patients with pharmaceutically treated hypertension, which should be addressed by randomized controlled trials. If confirmed, this finding could have high clinical relevance for treating hypertension during the SARS-CoV-2 pandemic.

There is paucity of evidence to support clinical decision making and counseling related to medication use in pregnancy. Despite multiple efforts from legislative bodies and advocacy groups, the inclusion of pregnant women in clinical drug trials assessing efficacy and safety remains scarce. Pregnancy can be complicated by multiple co-morbidities that require pharmacological intervention; these interventions primarily target the pregnant women but also sometimes have secondary effects for the fetus. The U.S. Food and Drug Administration has issued multiple guidance documents on incorporating pregnant women in clinical trials to aid pharmaceutical companies in designing a protocol to ensure safety and adherence to ethical standards. Advances in pediatric pharmacology studies provide lessons for researchers on the best practice of designing clinical trials with inclusion of patients from special populations. In this review, we present the status of pregnant women in clinical trials, highlighting the ethical stigma and possible future directives.

AIM Ropeginterferon alfa-2b is a new site-specific conjugated 40 kDa branched polyethylene-glycol recombinant interferon (IFN). The aim of the study was to determine its safety, pharmacokinetics (PK) and pharmacodynamic (PD). METHODS Ropeginterferon alfa-2b was evaluated first in human in 48 healthy male volunteers after a single dose subcutaneous injection by either 24, 48, 90, 180, 225, 270mcg of the product or 180mcg of marketed pegylated (peg)-IFN alfa-2a. Within each dosing group, 6 subjects received ropeginterferon alfa-2b and 2 subjects received peg-IFN alfa-2a. RESULTS Dose-related increases in ropeginterferon alfa-2b PK parameters (Cmax, AUC, and AUC0-t) were observed over the dose range 24 to 270mcg. The geometric mean values for these PK parameters of ropeginterferon alfa-2b were higher than that of peg-IFN alfa-2a at the 180mcg dose level of 176%, 166%, and 182%, respectively. Mean PD parameters (Emax, Tmax, and AUC0-t) for ropeginterferon alfa-2b increased with dose for both biomarkers neopterin and 2’, 5’-OAS. Ropeginterferon alfa-2b has similar PD profiles as peg-IFN alfa-2a. The treatment related adverse events are similar between the two study drugs, but the overall incidence was numerically lower for ropeginterferon alfa-2b (83%) than peg-IFN alfa-2a (100%) at the 180mcg dose level. CONCLUSIONS Single subcutaneous dose of Ropeginterferon alfa-2b of up to 270mcg is safe and well tolerated. It displays dose related increase in PK and PD parameters, potentially less frequent injection, and better safety profiles. Ropeginterferon alfa-2b is being developed for diseases in which previous peg-IFN use has been limited by side effects.

Background: For diseases with a genetic cause genomics can deliver improved diagnostics and facilitate access to targeted treatments. Drug pharmacodynamics and pharmacokinetics are often dependent on genetic variation underlying these processes. As pharmacogenomics comes of age it may be the first way in which genomics is utilised at a population level. Still required is guidance and standards of how genomic information can be communicated within the health record, and how clinicians should be alerted to variation impacting the use of medicines. Methods: The Professional Record Standards Body commissioned by National Health Service England developed guidance on using pharmacogenomics information in clinical practice. We conducted research with those implementing pharmacogenomics in England and internationally to produce guidance and recommendations for a systems-based approach. Results: A consensus viewpoint is that systems need to be in place to ensure the safe provision of pharmacogenomics information that is curated, actionable and up-to-date. Standards should be established with respect to notification and information exchange, which could impact new or existing prescribing and these must be in keeping with routine practice. Alerting systems should contribute to safer practices. Conclusion: Ensuring pharmacogenetics information is available to make use of medicines safer will require major effort of which this guidance is a beginning. Standards are required to ensure useful genomic information within the health record can be communicated to clinicians in the right format and times to be actioned successfully. A multidisciplinary group of stakeholders must be engaged in developing pharmacogenomic standards to support the most appropriate prescribing.

Aims Theophylline clearance in patients with chronic liver diseases (CLDs), chronic hepatitis (CH) and liver cirrhosis (LC), was evaluated by population pharmacokinetic (PPK) analysis. Methods PPK analysis included 433 minimum steady-state concentrations from 192 Japanese bronchial asthma patients and was performed using NONMEM. The severity of LC was assessed by the Child-Pugh (CP) class and model for end-stage liver disease (MELD) score. Results Two final models (CP and MELD models) were obtained, and described apparent theophylline clearance (CL/F) as follows: CP model: CL/F=0.0473×0.874CH×0.697CPA×0.592CPB×0.441CPC, MELD model: CL/F=0.0472×0.876CH×0.687MELD < 10×0.568MELD 10-14×0.487MELD 15-19×0.417MELD 20-24×0.328MELD ≥ 25. The CP model showed that mean CL/F in patients without CLDs, and with CH, and LC with CP class A, B, and C was 0.0473, 0.0413, 0.0330, 0.0280, and 0.0209 L/h kg-1, respectively. The MELD model predicted that CL/F in patients without CLDs, and with CH, and LC with a MELD score of < 10, 10-14, 15-19, 20-24, and ≥ 25 was 0.0472, 0.0413, 0.0324, 0.0268, 0.0230, 0.0197, and 0.0155 L/h kg-1, respectively. Conclusions CL/F in various stages of LC was evaluated and a change in CL/F was highly dependent on the severity of CLDs in both models. The MELD model classified LC into 5 categories, and subdivided CP class C patients into 3 further categories. The MELD model provided a more accurate and precise description of CL/F than the CP model, particularly in high-severity LC patients.

Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1 (COX1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on- and off-target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified platelet mRNA sequencing to test the hypothesis that aspirin’s effects on the platelet transcriptome are associated with platelet function. We prospectively recruited 74 adult volunteers for a randomized cross over study of 81- vs. 325 mg/day, each for 4 weeks. Using mRNA sequencing of purified platelets collected before and after each 4-week exposure, we identified 208 aspirin-responsive genes with no evidence for dosage effects. In independent cohorts of healthy volunteers and patients with diabetes we validated aspirin’s effects on five genes: EIF2S3, CHRNB1, EPAS1, SLC9A3R2, and HLA-DRA. Functional characterization of the effects of aspirin on mRNA as well as platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor of protein synthesis. Database searches for small molecules that mimicked the effects of aspirin on platelet gene expression in vitro identified aspirin but no other molecules that share aspirin’s known mechanisms of action. The effects of aspirin on platelet mRNA were correlated with higher levels of platelet function both at baseline and after aspirin exposure – an effect that counteracts aspirin’s known antiplatelet effect. In summary, this work collectively demonstrates a dose-independent effect of aspirin on the platelet transcriptome that counteracts the well-known antiplatelet effects of aspirin.