Paracetamol poisoning continues to be a worldwide problem and despite the availability of an affective antidote, N-acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from paracetamol, even in those receiving prompt NAC therapy, at high doses of paracetamol, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.
X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.
Introduction: Free-of-charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. Methods: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available MHRA Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. Results: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company-FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes; 37% had phase 2 data; and 19% were supported only by phase 1, retrospective observational studies, or pre-clinical data. Utilisation of company-FoC schemes increased on average by 50% per year, while MHRA EAMS showed little growth. Conclusion: Company-FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co-ordinate schemes. Motivations for company-FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or allow generation of further evidence.
Fomepizole is a promising new treatment for preventing liver injury following paracetamol (acetaminophen) overdose. However, we need robust clinical trials to be performed to demonstrate its effect on clinical outcomes that are important to our patients and important to healthcare providers. Until such trials are performed, the toxicology community should learn the lessons from the COVID pandemic – potential novel therapeutic options may be theoretically appealing, but their effectiveness needs to be assessed in robust clinical trials before they are used in clinical practice.
Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180mg QD, the highest tolerable dose tested in clinical trials: 240mg QD, and two precision dosing strategies targeting the median trough concentrations following 180mg QD, and 240mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS), and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240mg dosing strategy, with only a minor increase in the probability of developing toxicity.
Aim To describe the antiepileptic drug (AED) prescription pattern in pregnant women and women of childbearing age in the 2010-2019 period in the Lombardy region, Italy. Methods The Lombardy region administrative healthcare databases (2010-2019) were analysed. AEDs were classified as drugs belonging to the N03A subgroup of the Anatomical Therapeutic Chemical Classification System. Women 15-49 years old were considered as women of childbearing age, while exposure during pregnancy was estimated taking into account the 12 months before delivery (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM codes in the diagnosis record from 650 to 659). Results During 2019, 16,605 women of childbearing age (prevalence: 14.8‰) received at least one AED prescription. Pregabalin was the most widely used antiepileptic in women of childbearing age (22.3%), followed by valproic acid (20.0%). The prevalence of AED prescription in pregnant women was 3.8‰, and levetiracetam and lamotrigine (16.6%) were the most commonly prescribed drugs. The prevalence of AED prescription did not change from 2010 to 2019 in women of childbearing age or in pregnant women. Valproic acid was one of the most used AEDs in pregnancy until 2016, after which its prescription declined from 19% to 14% of AED users. Conclusions Despite the decrease in valproic acid prescription over time, this drug is still among the most used AEDs, in particular in women of childbearing age. Educational interventions for healthcare professionals and women are needed in order to reduce the risk of unplanned pregnancy.
A case of acute necrotising pancreatitis following the second dose of Pfizer-BioNTech COVID-19 mRNA vaccineAs of 22 June 2021, there have been about 400,000,000 doses of the Pfizer-BioNTech COVID-19 mRNA vaccine administered world-wide. At this time, 176 cases of pancreatitis have been reported in pharmacovigilance reports submitted to the WHO.1 No epidemiological link between the Pfizer-BioNTech COVID-19 mRNA vaccine and pancreatitis has been reported. We report a case of acute necrotising pancreatitis following the second dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. This case has been reported to the New Zealand Pharmacovigilance Centre and the patient has consented to publication of the case report.A 43-year-old, NZ European male was diagnosed with acute necrotising pancreatitis 10 hours following the administration of his second Pfizer-BioNTech COVID-19 mRNA vaccine. He has a background of atopy with seasonal rhinitis, eczema and asthma, all of which are ‘mild’. He takes no regular medications and takes as needed melatonin 2 mg nocte, cetirizine 10 mg for hay fever, and betamethasone and emollient cream for dermatitis. He has no family history of note and works in a senior professional role. He drinks six standard units of alcohol per week, has never been a tobacco smoker and does not use recreational drugs – and his employer undertakes regular drug testing.He had a previous episode of pancreatitis in 2011, precipitated by high alcohol intake during a holiday abroad. He is otherwise previously well. There is no family history of note, his father was a smoker and died of lung cancer in his 60s, his mother is well, he has two siblings and three children all of whom are well. He is not aware of any diseases of note in his extended family.In May 2021 he received his second dose of Pfizer-BioNTech COVID-19 mRNA vaccine, he was well at that time. Four hours after the dose he had two 330ml bottles of 5% alcohol beer with his dinner. Six hours after the dose he became unwell with nausea, epigastric pain, and vomiting. Ten hours after the dose blood tests on admission to hospital included: white cell count 18.5 x109/L (4 - 11), neutrophils 15.5 x109/L (1.9 - 7.5), lymphocytes 0.8 x109/L (1.0 - 4.0), CRP <3 mg/L (<5), lipase 23,750 U/L (10 – 70), and triglycerides 3.3 mmol/L. Acute pancreatitis was diagnosed. An ultrasound scan showed pancreatitis without evidence of cholelithiasis. He subsequently deteriorated and a computer tomography (CT) scan on 17 May, day 9 of the illness, showed severe necrotising pancreatitis with collections.During the admission under a specialist hepatobiliary surgical team, known causes of pancreatitis were excluded including: steroid use, trauma, family history of autoimmune conditions, and infection. He did not have the risk factors of obesity, smoking or heavy alcohol consumption. He had the risk factor of a previous episode of acute pancreatitis. The incidence of pancreatitis in New Zealand Europeans in this age group is approximately 50 per 100,000 per year.2 Idiopathic cases represent about 15% of these.Using the Naranjo criteria, the pancreatitis being ’caused’ by the Pfizer-BioNTech COVID-19 mRNA vaccine score was 6 ‘probable’.3 Clinical case discussion (including a hepatobiliary surgeon, gastroenterologist and clinical pharmacologist) concluded that while idiopathic pancreatitis could not be excluded, the onset of symptoms and findings were consistent with an acute precipitating event around the time the second vaccine dose was administered.In addition to the 176 cases reported in VigiBase™, searches of PubMed and Google Scholar™ identified two published case reports of pancreatitis following the Pfizer-BioNTech COVID-19 mRNA vaccine. These were following administration of the first dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. In one case symptoms developed several hours after vaccine administration and the other several days after vaccine administration.4,5Acute pancreatitis is a rare in patients with COVID-19 but characteristic patterns of illness have been reported.6 This raises the possibility that an immune response to either the virus or the vaccine could have common sequalae.This case of acute pancreatitis was temporally associated with the Pfizer-BioNTech COVID-19 mRNA vaccine suggesting a causal link. The characteristics of pancreatitis cases associated with the Pfizer-BioNTech COVID-19 mRNA vaccine should be examined to see if a consistent pattern is present.VigiAccess™ http://www.vigiaccess.org/ - accessed June 24, 2021.Pendharkar SA, Mathew J, Zhao J, Windsor JA, Exeter J, Petrov MS. Ethnic and geographic variations in the incidence of pancreatitis and post- pancreatitis diabetes mellitus in New Zealand: a nationwide population- based study. 2017;130(1450):14.Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther . 1981;30(2):239-245. doi:10.1038/clpt.1981.154Cieślewicz A, Dudek M, Krela-Kaźmierczak I, Jabłecka A, Lesiak M, Korzeniowska K. Pancreatic Injury after COVID-19 Vaccine—A Case Report. Vaccines . 2021;9(6):576. doi:10.3390/vaccines9060576Parkash O, Sharko A, Farooqi A, Ying GW, Sura P. Acute Pancreatitis: A Possible Side Effect of COVID-19 Vaccine. Cureus . Published online April 28, 2021. doi:10.7759/cureus.14741Bircakova B, Bruha R, Lambert L, Grusova G, Michalek P, Burgetova A. A bimodal pattern of the onset of COVID-19 related acute pancreatitis supports both the cytotoxic and immune-related pathogenesis – a systematic review. Scand J Gastroenterol . 2021;56(7):870-873. doi:10.1080/00365521.2021.1922751
Abstract Interleukin 6 (IL-6) is a circulating cytokine that is implicated in a range of inflammatory diseases. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL-6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines, and growth factors. The findings from this study support feedback effects of IL-6R signalling on reducing levels of a range of circulating cytokines and identify compensatory mechanisms that may be modulating its inflammatory effects. These results provide novel insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune diseases.
Aim: A better knowledge of opioid prescribing patterns would help to identify areas of potential improvement in cancer pain management. This study aimed to identify potential inappropriate use (PIU) of strong opioid analgesics in cancer outpatients in their last year of life. Methods: A retrospective cohort of cancer patients dead between 2011 and 2014 and who were exposed as outpatient to a strong opioid analgesic in the last year of life was identified in the “Echantillon Généraliste de Bénéficiaires” (a 1/97th random sample of the French general population). Prescribing patterns of strong opioids were analyzed and PIU was defined by at least one of these criteria: overlapping prescriptions; contraindicated prescriptions; lack of laxatives; potential drug interactions; prescription in patients hospitalized for opioid-related disorders. Factors associated with PIU were investigated through a multiple logistic regression model. Results: One third of the 2,236 patients (median age 72 years (IQR: 61-82), 44.1% of women) presented a PIU (insufficient laxative prescription (19.6% of patients), insufficient background treatment with transmucosal fentanyl (14.8%), overlapping prescriptions (2.6%)). The rate of PIU significantly decreased from 37.6% (2011) to 29.8% (2014). For patients with a duration of opioid use 3 months, factors associated with PIU were fentanyl prescription (aOR=2.36; 95% CI [1.86-3.00]) and previous use of strong opioid (aOR=1.88; [1.50-2.36]) Conclusion: In France, one third of cancer patients exposed to strong opioids experienced PIU and this proportion tended to decrease over time. There is still room for progress in cancer pain management at the end of life.
Abstract Background: Propofol may result in hypotension, bradycardia, and loss of protective reflexes, especially in elderly patients, while esketamine, a N-methyl-D-aspartate receptor antagonists, has analgesic, anaesthetic and sympathomimetic properties and is known to cause less cardiorespiratory depression. We hypothesized that esketamine may reduce the median effective concentration (EC50) of propofol and cause more stable haemodynamic responses during gastrointestinal endoscopy in elderly patients. Methods: Ninety elderly patients, aged 65-89 years, undergoing gastrointestinal endoscopy were randomly assigned into three groups: SK0.25 group (0.25 mg/kg esketamine), SK0.5 group (0.5 mg/kg esketamine) and saline control group. Anaesthesia was achieved by target-controlled infusion of propofol with an initial plasma concentration of 2.5 μg/ml with different bolus doses of esketamine during gastrointestinal endoscopy. The EC50 of propofol for gastrointestinal endoscopy was determined by using an up-and-down method of Dixon with an adjacent concentration gradient at 0.5μg/mL to prohibit purposeful movements. Cardiovascular parameters were also measured and recorded. Results: Propofol EC50 and its 95% confidence interval for gastrointestinal endoscopy in elderly patients were 1.71 (1.15-2.27) μg/mL in SK0.5 group, 2.45 (1.85-3.05) μg/mL in SK0.25 group and 3.69 (2.59-4.78) μg/mL in control group respectively (P < 0.05). The average percent change to baseline mean arterial pressure (MBP) was -19.7 (7.55), -15.2 (7.14) and -10.1 (6.73) with P＜0.001, in the control group, the SK0.25 group and the SK0.5 group, respectively. Conclusions: Combination medication of propofol with esketamine reduced the propofol EC50 during gastrointestinal endoscopy in elderly patients and caused more stable haemodynamic responses compared with single administration of propofol.
AIM: Influenza infection poses a severe threat to pregnant mothers, and antiviral treatment is recommended. However, the safety of neuraminidase-inhibitor antiviral medications during pregnancy has not been well described. METHODS: A systematic review and meta-analysis were performed to evaluate the adverse neonatal outcomes associated with exposure to neuraminidase inhibitors during pregnancy. The PubMed, Embase, and Cochrane Library databases were searched to identify potential studies for inclusion. RESULTS: Nine cohort studies that estimated adverse neonatal outcomes associated with exposure to neuraminidase-inhibitor medication during pregnancy were included. Exposure to a neuraminidase inhibitor during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.72–1.12, P = 0.341), low Apgar score (OR 0.96, 95% CI 0.77–1.2, P = 0.733), or preterm birth (OR 0.99, 95% CI 0.89–1.09, P = 0.771) compared with no exposure. However, exposure to a neuraminidase inhibitor was associated with a reduced risk of low birth weight (OR 0.79, 95% CI 0.68–0.92, P = 0.002) and giving birth to a small-for-gestational-age infant (OR 0.78, 95% CI 0.69–0.88, P < 0.001). Further analyses limited to oseltamivir exposure were consistent with the overall results. CONCLUSION: Exposure to neuraminidase-inhibitor medication during pregnancy does not appear to be associated with adverse neonatal outcomes. We recommend further studies to investigate this association, which will help clinicians determine whether to prescribe a neuraminidase inhibitor during pregnancy.
Chagas cardiomyopathy is the most prevalent non-ischemic cardiomyopathy in Latin America, with high morbidity and mortality even today. Treatment of these patients is based on the use of medications for heart failure. This study evaluated a cohort of patients with Chagas heart disease who used sacubitril valsartan at a referral hospital for the disease in Brazil. After six months, there was a symptomatic improvement in these individuals assessed by the NYHA classification, with a 44.3% reduction in the absolute number of patients classified as III-IV in the period (p 0.035), but without changes in the parameters on the echocardiogram for reverse ventricular remodeling and still high mortality rate and hospitalization. These results emphasize the importance of studying the use of sacubitril valsartan in chagas heart disease to better describe its effectiveness taking into account the peculiarities of these individuals.
Since the beginning of the COVID-19 pandemic, industry and healthcare providers have investigated methodologies to manage infection of SARS-CoV-2. One treatment breakthrough has been the introduction of monoclonal antibodies to prevent worsening SARS-CoV-2 infection in non-hospitalized patients diagnosed with COVID-19. These monoclonal antibodies, like bamlanivimab, bind to the SARS-CoV-2 spike protein and prevent its ability to binding to human ACE2 receptors. This is a case of a 91 year-old man with no prior seizure history who developed new-onset seizures after bamlanivimab infusion.
Improved global access to novel age-appropriate formulations for paediatric subsets, either of new chemical entities or existing drugs, is a priority to ensure that medicines meet the needs of these patients. However, despite regulatory incentives, the introduction to the market of paediatric formulations still lags behind adult products. This is mainly caused by additional complexities associated with the development of acceptable age-appropriate paediatric medicines. This position paper proposes the use of a paediatric Quality Target Product Profile (pQTPP) as an efficient tool to facilitate early planning and decision making during the children-centric formulation design for new chemical entities, or to repurpose/reformulate off-patent drugs. Essential key attributes of a paediatric formulation are suggested and described. Moreover, greater collaboration between formulation experts and clinical colleagues, including healthcare professionals, is advocated to lead to safe and effective, age-appropriate medicinal products. Acceptability testing should be a secondary endpoint in paediatric clinical trials to ensure post-marketing adherence is not compromised by a lack of acceptability. Not knowing the indications and the related age groups and potential dosing regimens early enough is still a major hurdle for efficient paediatric formulation development; however the proposed pQTPP could be a valuable collaborative tool for planning and decision making to expedite paediatric product development.
Approval of direct-acting oral anticoagulants (DOACs) for stroke prevention in atrial fibrillation (AF) was an important milestone, providing widened treatment choices along with the possibility for inter-drug switching after initiation. In addition to improved utilisation of oral anticoagulants (OACs) for stroke prevention, reports of switching among OACs are growing in the literature. Switching may influence clinical outcomes, healthcare costs and patient satisfaction. This review aimed to summarise the current literature on the pattern of OAC switching in patients with AF, including reasons for switching and clinical consequences following switching. We included articles published after 2013, following the introduction of apixaban; searched on June 27, 2020 from PubMed, Scopus and Embase. The review found that switching among OACs was common in clinical practice, significantly varying with the type of OAC. Studies reporting the reason for switching and clinical outcomes were comparatively limited. The reasons were often related to safety issues, poor anticoagulation control and ease of use. Factors that can increase the risk of bleeding and stroke were found to be associated with switching from vitamin K antagonists, but less for DOAC switching. Findings regarding bleeding outcomes following switching were inconsistent, possibly confounded with the type of OAC, reasons for switching and switching protocol. Despite the limited number of studies included and their relatively short follow-up periods, our review revealed that switching had minimal impact on stroke and other related thrombotic outcomes. Further prospective studies are needed to better understand possible reasons for switching and its influence on clinical outcomes.
Aim Antimicrobial resistance is an evolving phenomenon with alarming public health consequences. Antibiotic cycling is a widely known antimicrobial stewardship initiative which encompasses periodical shifts in empirical treatment protocols with the aim to limit selective pressures on bacterial populations. Nonetheless, mathematical models have challenged its presumable efficacy by favouring a higher heterogeneity in antibiotic administration. We present a review of the evidence regarding the actual impact of antimicrobial cycling on bacterial resistance control within hospitals. Methods A systematic literature review was conducted using the PubMed/MedLine, Embase, CINAHL Plus and Global Health databases. Results A systematic search process retrieved a sole randomised study, and so we broadened inclusion criteria to encompass quasi-experimental designs. Fifteen studies formed our dataset including seven prospective trials and eight before-and-after studies. Nine studies evaluated cycling versus a control group and produced conflicting results whilst three studies compared cycling with antibiotic mixing, with none of the strategies appearing superior. The rest evaluated resistance dynamics of each of the on-cycle antibiotics with contradictory findings. Research protocols differed in parameters such as the cycle length, the choice of antibiotics, the opportunity to de-escalate to narrow-spectrum agents and the measurement of indicators of collateral damage. This limited our ability to evaluate the replicability of findings and the overall policy effects. Conclusions Dearth of robust designs and standardised protocols limits our ability to reach safe conclusions. Nonetheless, in view of the available data we find no reason to believe that cycling should be expected to improve antibiotic resistance rates within hospitals.
Pregnant, or potentially pregnant women have historically been excluded from clinical trials of new medications. However, it is increasingly recognised that it is imperative to generate evidence from the population in whom the drugs are likely to be used in order to inform safe, evidence-based shared clinical decision making. Reluctance by researchers and regulators to perform such studies often relates to concerns about risk, particularly to the fetus. However, this must be offset against the risk of untreated disease or using a drug in pregnancy where safety, efficacy and dosing information are not known. This review summarises the historical perspective, the ethical and legal frameworks which inform the conduct of such research, then highlights examples of innovative practice which have enabled high quality, ethical research to proceed to inform the evidence-based use of medication in pregnancy.