Aim: Residual neuromuscular blockade is a common complication after general anaesthesia. Sugammadex can reverse the action of aminosteroid neuromuscular blockers. Our study aimed to explore sugammadex safety issues in the real world and determine the spectrum of adverse reactions. Methods: All sugammadex-related adverse events reported in VigiBase between 2010 and 2019 were classified by group queries according to the Medical Dictionary for Regulatory Activities. A disproportionality analysis of data was performed using the information component (IC); positive IC values were deemed significant. Results: Overall, 16,219,410 adverse events were reported, and 2032 were associated with sugammadex. The most frequent reactions were recurrence of neuromuscular blockade (n = 54, IC: 6.74, 95% credibility interval [CI]: 6.33–7.10), laryngospasm (n = 53, IC: 6.05, IC025:5.64), bronchospasm (n = 119, IC: 5.63 , IC025:5.36), and bradycardia (n = 169, IC: 5.13, IC025:4.90). Fatal cases were more likely with cardiac disorders, especially in patients over 65 years. In addition, the common adverse drug reactions (ADRs) differed between different age groups (P < 0.01). The ADRs were higher between 0–17 years than in other age groups. The onset time of common ADRs was typically within one day, and 68.9% occurred within half an hour after sugammadex administration. Conclusions: Anaesthesiologists should carefully monitor the anaesthesia recovery period to correct the adverse drug reactions caused by sugammadex and recommend monitoring neuromuscular function throughout the anaesthesia process. Sugammadex should be used carefully in patients with cardiovascular diseases, and ECG and hemodynamic changes monitored after medication.

In this special issue of the British Journal of Clinical Pharmacology, we highlight innovative methodologies in pediatric drug development.

Ductopenia is often regarded as a chronic process where ≥50% of portal tracts lack bile ducts, which is also known as vanishing bile duct syndrome (VBDS). One etiology is drug-induced liver injury. Cloxacillin, an anti-staphylococcal penicillin, typically causes “bland” cholestasis. We present the first case of cloxacillin-induced acute ductopenia or VBDS and a review of published cloxacillin-induced liver injuries. A 66-year-old woman with no prior liver disease, but known penicillin allergy, was treated for post-carotid angioplasty staphylococcal infection with 6 weeks of cloxacillin. She presented with a two-week history of weakness and jaundice. Laboratory work-up showed elevated liver enzymes, hyperbilirubinemia, and eosinophilia. She required ICU transfer for hypotension and was started empirically on prednisone. Liver biopsy revealed severe centrilobular cholestasis, mild necroinflammation, and ductopenia with epithelial injury, but no ductular reaction. Two-months later, she was discharged on hydrocortisone and ursodiol with persistently elevated alkaline phosphatase and bilirubin. She was considered for liver transplantation but died of liver failure four months later. Four additional articles were found with histopathologic descriptions of cloxacillin-related liver injury. These included portal inflammation, cholestasis and mild necroinflammation. Clinical features were reported in two cases; both had mild symptoms with cholestatic liver enzymes and hyperbilirubinemia. Both patients recovered completely within 10-60 days. Cloxacillin-induced cholestasis can be secondary to acute ductopenia, which can result in worse clinical outcomes than previously described “bland” cholestasis. Liver biopsy is recommended to identify cases with acute VBDS.

Esomeprazole is a proton pump inhibitor being investigated for treatment of preeclampsia. Esomeprazole pharmacokinetics during pregnancy is unknown. We used data from 10 pregnant patients with preterm preeclampsia, and 49 non-pregnant individuals to develop a population pharmacokinetic model of esomeprazole. A two-compartment model described the data well. In pregnant patients after single dose, clearance was 42.2% (14.9%– 61.6%) lower compared to non-pregnant, most likely due to downregulation of CYP2C19. In non-pregnant after repeated dosing, clearance was 54.9% (48.2% – 63.5%) lower in extensive metabolizers and bioavailability was 33% (10.0% – 52.0%) higher compared to single dosing, which could be due to autoinhibition of CYP2C19. Esomeprazole pharmacokinetics during pregnancy appears to be more dependent on CYP3A4.

Aims: Voriconazole is the mainstay for the treatment for invasive fungal infections in heart transplant patients and significantly increase tacrolimus exposure because of drug-drug interaction (DDI). However, the magnitude of this DDI is highly variable and hard to predicted. The purpose of this study was to present the characteristics of DDI between tacrolimus and voriconazole, and further identify the predictors of tacrolimus dose modification. Methods: We retrospectively enrolled 69 heart transplant recipients without using voriconazole as the control and 68 patients received voriconazole treatment in voriconazole group. CYP3A4*1G, CYP3A5*3 and CYP2C19*2 or *3 were genotyped by Sanger sequencing. The requirement of tacrolimus dose for therapeutic concentrations and tacrolimus dose-corrected trough concentration (C0/D) before and after VRC administration were evaluated. Results: The DDI between tacrolimus and voriconazole was in a large inter-individual variability with more than ten-fold changes in tacrolimus dose (range 1.28–13.00) and C0/D (range 1.43–13.75). Besides, the fold changes of tacrolimus dose were associated with CYP2C19 genotype, which was significantly lower in CYP2C19 extensive metabolizers than that in CYP2C19 intermediate metabolizers or poor metabolizers (4.06±1.85 vs 5.49±2.47, p=0.0031). While no significant difference was found in both CYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19 genotype and hematocrit were independent predicting factors for tacrolimus dose modification after voriconazole co-therapy. Conclusions: This study provided a potential basis for comprehensive factors to adjust tacrolimus dosage when co-administrated with voriconazole in individual patients. CYP2C19 genotype and hematocrit should be considered in tailoring tacrolimus dose.

Aim: Pregnant women are hypothesized to have low adherence to prescribed medication, because of concerns about toxicity and harmful effects on the unborn child. However, very little is known about the actual adherence to prescribed medication during pregnancy. We determined to what extent women follow treatment recommendations regarding prescribed medication use in mid-pregnancy. Methods: Dutch women participating in the PRIDE Study completed a six-week diary on medication use. Additionally, pharmacy records were obtained. For each medication dispensed, we determined three measures of adherence: 1) whether use was reported in the diary (actual use), 2) difference between dispensing date and date of first reported use (initiation time), and 3) proportion of days with at least the correct number of doses taken (implementation adherence). Results: During the six-weeks study period, 235 of 816 women (29%) were prescribed medication. Actual use was highest for medications used for chronic conditions (88%; 95% confidence interval [95% CI] 81-93), followed by medication for pregnancy-related conditions (79%; 95% CI 71-86) and medication for occasional and short-time use (69%; 95% CI 60-77). We observed a ≥1 day delay in treatment initiation for 42% of medications dispensed for the first time in the study period. For medications that were actually used, mean implementation adherence was 74.2% (95% CI 69.3-79.2). Conclusion: Although actual use of medications dispensed was high, many pregnant women did not adhere to treatment recommendations. This non-adherence may impact maternal and child health and lead to exposure misclassification in studies in perinatal pharmacoepidemiology relying on administrative databases.

Aim: This systematic review aims to assess the safety profile of oxcarbazepine during pregnancy. Methods: Observational studies that included women who took oxcarbazepine anytime during pregnancy were included in our systematic review. The review did not include non-English articles, reviews, meta-analyses, case reports, and animal studies. Different online sources such as MEDLINE, Cochrane library, Virtual Health Library, etc. were searched for published and unpublished literature. Assessment of the risk of bias in observational studies was done using the Newcastle-Ottawa Scale. The meta-analyses were performed using a random-effect model. GRADE was used for the evaluation of the quality of evidence for the primary outcomes. Results: We included 19 cohort studies with a total number of 5,071,137 patients, of which 2,450 were exposed to oxcarbazepine either as monotherapy or polytherapy. The summary odds ratio (OR) was 1.69 (95% CI, 0.95-2.98) for congenital malformations following in-utero exposure to oxcarbazepine as compared to the control group of unexposed patients [seven studies (n=625)], and was 1.19 (95% CI, 0.67-2.12) when compared to those following lamotrigine (LTG) exposure during pregnancy [3 studies (n=591)]. In total, three studies (n=770) reported the association between in-utero oxcarbazepine exposure and fetal/perinatal deaths. The meta-analysis yielded a summary OR of 3.33 (95% CI, 1.70-6.51). Significance: Our systematic review will help healthcare providers and guideline developers regarding the treatment of epilepsy and other neurological disorders during pregnancy. More cohort studies with a higher sample size concerning oxcarbazepine use in pregnant patients are required to truly assess the in-utero safety profile of the drug.

Aim: Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. This study aimed to examine chiral status of the drugs withdrawn from the market. Methods: We searched the literature regarding withdrawn drugs between 1950-2020 due to safety-related issues and identified 395 drugs. We examined their chirality and assigned into one of three categories: achiral compound, chiral mixture, and pure enantiomer. We compared their distribution at ATC-1 level, duration on the market, and adverse drug reactions leading to their withdrawal. Results: We identified that 52.4% (n=207) of withdrawn drugs were achiral, whereas 27.6% (n=109) were chiral mixtures and 20.0% (n=79) were pure enantiomers. The mean duration on the market was 24.6±27.5 years. The groups did not differ in terms of mean duration on the market. Chiral mixtures were significantly more withdrawn than were achirals in cardiovascular system drugs (17.4% vs. 7.7%, p=0.01). In musculoskeletal system drugs, pure enantiomers were significantly less withdrawn (2.5%) compared to achirals (12.6%, p=0.01) and chiral mixtures (11.9%, p=0.03). Hepatotoxicity was significantly less common in pure enantiomers (5.4%) compared to chiral mixtures (12.7%, p=0.04) and achirals (17.0%, p<0.01). Cardiovascular toxicity was significantly more common in chiral mixtures (14.5%) compared to that in achiral drugs (7.5%, p=0.02). Conclusion: Our study showed slightly higher representation of chiral mixtures among withdrawn drugs over pure enantiomers. The assessment of withdrawal reasons further indicates higher tendency of chiral mixtures towards hepatotoxicity and cardiovascular toxicity.

Background Linezolid is often used for the infections caused by drug-resistant Gram-positive bacteria. Recent studies suggested that large between-subject variability (BSV) and within-subject variability could alter drug pharmacokinetics (PK) during linezolid therapy due to pathophysiological changes. Objective The review synthesized information on linezolid population PK studies and summarized the significant covariates that influence the PKs of linezolid. Methods A literature search was performed from PubMed, Web of Science, and Embase from their inception to 30 September 2021. Published studies were included if they contained data analyzing linezolid PK parameters in humans using a population approach with a nonlinear mixed-effects model. Results Twenty-five studies were included in adults and five studies in pediatric patients. One- and two-compartment models were the commonly used structural models for linezolid. Body size [weight, lean body weight, and body surface area], creatinine clearance (CLcr), and age significantly influenced linezolid PK. The median clearance (CL) values (range) in infants [0.128 L/h/kg (0.121-0.135)] and children [0.107 L/h/kg (0.088-0.151)] were higher than in adults [0.098 L/h/kg (0.044-0.237)]. For patients with severe renal impairment (CLcr ≤ 30 mL/min), the CL was 37.2% (15.2-55.3%) lower than in patients with normal renal function. Conclusion Linezolid’s optimal dosage could be adjusted based on the patient’s body size, renal function, and age. More studies are needed to explore the exact mechanism of elimination of linezolid and evaluate PK characteristics in pediatric patients.

Aims: To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs). Methods: More than 500 databases were searched between 1-Nov-2020 and 2-Oct-2021 to identify RCTs that were published after our baseline review. One reviewer extracted data with other reviewers verifying the extracted data for accuracy and completeness. Results: After screening 22,414 records, we included 24 and 21 RCTs in the qualitative and quantitative syntheses, respectively. The most investigated drug classes were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and anticoagulants, investigated by 10 and 11 studies respectively. In meta-analyses, ACEI/ARBs did not affect hospitalization length (mean difference/MD -0.42, 95% CI -1.83; 0.98 days, n=1183), COVID-19 severity (risk ratio/RR 0.90, 95% CI 0.71; 1.15, n=1661) and mortality (RR 0.92, 95% CI 0.58; 1.47, n=1646). Therapeutic anticoagulation also had no effect (hospitalization length MD -0.29, 95% CI -1.13 to 0.56 days, n=1449; severity RR 0.86, 95% CI 0.70;1.04, n=2696; and, mortality RR 0.93, 95% CI 0.77;1.13, n=5689). Other investigated drug classes were antiplatelets (aspirin, 2 trials), antithrombotics (sulodexide, 1 trial), calcium channel blockers (amlodipine, 1 trial) and lipid modifying drugs (atorvastatin, 1 trial). Conclusion: Moderate- to high-certainty RCT evidence suggests that cardiovascular drugs such as ACEIs/ARBs are not associated with poor COVID-19 outcomes, and should therefore not be discontinued. These cardiovascular drugs should also not be initiated to treat or prevent COVID-19 unless they are needed for an underlying currently approved therapeutic indication.

Benzalkonium chloride (BAC) is a quaternary ammonium compound commonly employed as a preservative in several multidose eye drops. Its use is associated with several adverse events, particularly when used chronically. Topically instilled BAC acts not only on superficial structures but also reaches deeper tissues (trabecular meshwork, optic nerve) and can be deleterious in patient under chronic treatment. In glaucomatous patients, BAC is the primary cause of ocular surface disease (OSD), and it can lead to significant morbidity, influence treatment compliance, quality of life, and surgical outcomes. Clinical and experimental evidence demonstrates that BAC causes instability of the tear layer, loss of goblet cells, apoptosis, subclinical neuroinflammation, and antibiotic resistance. Considering the validity of the alternative formulations (alternative preservatives or preservative-free formulations) it is unreasonable to persist in using such toxic compounds and, perhaps it is time for a moratorium on the use of BAC in eye drops.

Aim: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the hemodynamic response to dobutamine in critically ill neonates. Methods: Alleles in the known genetic single nucleotide polymorphisms in β1 and β2 adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Results: 26 neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8 – 60.7) bpm per AUC of 100 mg·h, p=0.0005. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C>T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2 – 42.9) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0116 and 33.2 (12.1 – 54.3) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0025, respectively. Conclusion: In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C>T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.

AIM: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS. This first-in-human study comprised of single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS. ESM-HDAC391 was well tolerated whilst showing robust targeted mechanistic engagement, as demonstrated by selective retention of compound and increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production. Importantly, common clinical HDACi toxicities were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible. In-depth characterisation of monocyte depletion in a transgenic mouse model (CES1/Es1elo) suggested that CSF1R loss on circulating cells contributes to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of CSF1R and downstream effects on cell differentiation. CONCLUSION. These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for the potential benefit of these molecules in myeloid-driven diseases.

Erythema nodosum (EN), the most form of panniculitis, is mainly caused by numerous infective (especially Beta-hemolytic streptococcal infections) and non-infective (especially sarcoidosis) diseases and drugs. EN associated with vaccines has been rarely reported. We describe herein, an original clinical observation of EN induced by BNT162b2, an mRNA vaccine. A 75-year-old woman presented with diffuse erythematous painful rounded nodular lesions, located symmetrically over her legs. Six days before, she had received the second dose of Covid-19 vaccine (BNT162b2 (Pfizer–BioNTech)), followed by a sudden asthenia, polyarthralgia, throbbing and edema over her lower limbs. She had been given the first dose of the same Covid-19 vaccine 29 days prior to the second without incident. General physical examination was normal. Skin examination showed multiple, erythematous tender, nodules, 10–30 mm in diameter, over the tibial area. Complete blood count, renal and hepatic tests, antistreptolysin O titer, antinuclear antibody, thyroid test and chest radiograph and PCR, were carried out, and found to be normal. Histopathology revealed infiltration of deep dermal vessels and subcutaneous fat with lymphomononuclear cells and neutrophils, consistent with erythema nodosum. Treatment with analgesics led to complete resolution of the lesion after three months. The patient has shown no relapse after follow-up for three months. In conclusion, to our knowledge, this is the first case of EN induced by the second dose of BNT162b2 (Pfizer–BioNTech) Covid-19 vaccine. It is important for clinicians to be aware of this rare, yet potential, adverse effect to this vaccine.

Several observational studies have examined the potential protective effect of angiotensin-converting enzyme inhibitor (ACE-I) use on the risk of age-related macular degeneration (AMD) and have reported contradictory results owing to confounding and time-related biases. We aimed to assess the risk of AMD in a base cohort of patients aged 40 and above with hypertension among new users of ACE-I compared to an active comparator cohort of new users of calcium channel blockers (CCB) using data obtained from IQVIA Medical Research database, a primary care database in the UK. In this study, 53,832 and 43,106 new users of ACE-I and CCB were included between 1995 and 2019, respectively. In an on-treatment analysis, patients were followed up from the time of index drug initiation to the date of AMD diagnosis, loss to follow-up, discontinuation or switch to the comparator drug. A comprehensive range of covariates were used to estimate propensity scores to weight and match new users of ACE-I and CCB. Standardized mortality ratio (SMR) weighted Cox proportional hazards model was used to estimate hazard ratios (HRs) of developing AMD. During a median follow-up of 2 years (interquartile range 1-5 years), the incidence rate of AMD was 2.4 and 2.2 per 1,000 person-years among the weighted new users of ACE-I and CCB, respectively. There was no association of ACE-I use on the risk of AMD compared to CCB use in either the propensity score weighted or matched, on-treatment analysis (aHR: 1.07 (95% CI 0.90-1.27) and 0.87 (0.71-1.07) respectively).

Background: Antiretroviral therapy reduces systemic inflammation and immune activation, but not to levels like HIV-negative. Limited drug penetration within tissues has been argued as potential mechanism of persistent inflammation. Data on the role of inflammation on plasma/intracellular (IC) pharmacokinetics (PK) of ARV drugs through to downregulation/expression of cytochrome P450 3A/membrane transport proteins are limited. Aim of this study was to investigate the correlation between inflammation markers and plasma/IC PK of different ARVs regimen in HIV-positive patients. Methods: We included in the study ART-treated HIV+ pts switching to 3 different ARV regimens: 1) DTG-based dual-therapy plus boosted-PIs, 2) DTG-based triple-therapy without PIs, 3) DRV/c-based triple-therapy. Plasma and IC ARV drugs concentration means at the end of dosing interval (T0), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL-6 and LPS were analysed. Results: 60 samples from pts included in the switching study were used for measuring plasma and IC concentrations of HIV drugs. No significative differences between CRP, sCD14, IL-6 and LPS values in 3 arms of therapy were observed. Significant correlation was observed between tenofovir plasma concentrations and sCD14 (p<0.001), DRV plasma concentration and sCD14 (p=0,07) and DRV IC/plasma ratio and Log10 IL-6 concentrations (p=0.04). Furthermore, in 24 pts on DTG-TT, we observed a negative trend between DTG IC concentrations and sCD14 (p=0.09). Conclusions: Our preliminary data support the hypothesis of lower IC concentrations of DRV and DTG in pts with higher plasma IM, suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.

Manuscript title:Sustainable medicines use in clinical practice – it is time to help the teacher

Objective: Our hypothesis was that the intervention would decrease (or at least not increase) the number of potentially inappropriate medications (PIMs) and the number of hospital readmissions within 30 days of discharge per hospital stay. Methods: A cohort of hospitalized older adults enrolled in the PAERPA integrated care pathway (the exposed cohort) was matched retrospectively with hospitalized older adults not enrolled in the pathway (unexposed cohort) between January 1st, 2015, and December 31st, 2018. It was an analysis of French health administrative database. The inclusion criteria for exposed patients were admission to an acute care department in general hospital, age 75 or over, at least three comorbidities or the prescription of diuretics or oral anticoagulants, discharge alive, and performance of a medication review. Results: For the study population (n=582), the mean ± standard deviation age was 82.9 ± 4.9, and 190 (65.3%) were women. Depending on the definition used, the overall median number of PIMs ranged from 2 [0;3] upon admission to 3 [0;3] at discharge. The intervention was not associated with a significant difference in the mean number of PIMs. Patients in the exposed cohort were half as likely to be readmitted to hospital within 30 days of discharge, relative to patients in the unexposed cohort. Conclusion: Our results show that a medication review was not associated with a decrease in the mean number of PIMs. However, the integrated care intervention including the medication review was associated with a reduction in the number of hospital readmissions at 30 days.