Drug therapy in pregnancy may cause anxiety to both physicians and patients due to uncertainty regarding dosing and safety. Nevertheless, the need for medication is high given that maternal chronic illnesses such as hypertension or diabetes are on the rise1. In a national study in the United States over 33 years, the prevalence of prescription medication use by pregnant women in the first trimester increased by 62.5% between the first 2 years of the study and the last 2 years2. Furthermore, the average number of medications used anytime in pregnancy has increased two-fold 2. More recent research from different countries has found that medications are widely used in pregnancy, with the prevalence of using at least one drug ranging from 60 to 90 percent, excluding vitamins and minerals 3-5. Prescription of drugs with potential teratogenicity has also increased in pregnancy, including folate antagonists or angiotensin converting enzyme inhibitors3,4. This suggests that many women go into pregnancy with chronic conditions that require medications, including those may pose some degrees of risk to the fetus, since the maternal benefit may outweigh the risk or if the pregnancy is unplanned. Successful treatment of pregnant patients requires a correct diagnosis and providing treatment that not only is effective but also balances risks and benefits, as maternal health is the best defense for fetal health. However, concomitant health conditions, and the intrinsic complex physiological changes associated to pregnancy can make prescribing in this population a particularly challenging balancing act. Very few drugs have specific pregnancy dosing regimens supported by scientific evidence in spite of well-known pharmacokinetics changes during pregnancy affecting a large proportion of medications (Table 1)6-10. Data on drug efficacy and safety is sorely lacking for pregnant women, even for drugs that have been available for decades. Pregnant patients are commonly excluded from clinical trials during the drug development process due to ethical and safety concerns, which implies that the majority of drug therapy data in pregnancy have been extrapolated from males and to a much lesser extent, from non-pregnant females11. However, using extrapolated data in pregnancy has a number of major drawbacks such as that the extrapolation commonly fails to account for the changes in drug metabolism related to pregnancy 6. Multiple physiological changes in pregnancy, including those affecting pharmacokinetics, must be considered when prescribing. Furthermore, these changes can also be affected by genetic variability10. Some drugs need to be used at higher doses in pregnancy due to increasing metabolic demand. A classic example is thyroid hormone, which requires a 30 to 45 percent higher dose in order to maintain euthyroid state due to limited compensation in pregnant patients with underlying thyroid disease 12. One of the biggest physiologic changes in pregnancy is the expansion of plasma volume by approximately 50 percent due to hormone-mediated vasodilation, leading to activation of the renin-angiotensin-aldosterone system10. This change results in and increased volume of distribution for hydrophilic drugs and reduced peak concentrations 6. Increased glomerular filtration rate in pregnancy also increases elimination of renally cleared drugs; a classic example of this effect is lithium13. Changes in hepatic enzyme activity in pregnancy, including upregulation of cytochrome P450 and glucuronidation, are another cause of increased metabolism and elimination of drugs14. Increased metabolism of lamotrigine by glucuronidation results in low drug levels in pregnancy and this can be further affected by polymorphism of UDP-glucuronosyltransferases 15. One strategy to address changes in drug metabolism is to use therapeutic drug monitoring (TDM) with blood levels; however, TDM analysis is not readily available for the majority of drugs used in pregnancy, limiting the usefulness of this strategy in clinical practice. Furthermore, lower total drug levels do not necessarily translate to less free drug due to volume expansion in pregnancy leading to relative hypoalbuminemia 6. For some drugs, many clinicians modify the dosing regimen on their own based on limited pharmacokinetic data. For example, labelatol, a common antihypertensive used in pregnancy, has a half-life of only 1.7 ± 0.27 hours in patients in the 3rd trimester of pregnancy, compared to 6-8 hours outside of pregnancy16. This difference leads many clinicians to prescribe labelatol three times per day based on patient response instead of twice-per-day as per drug monograph16. However, there is considerable variation among clinicians due to lack of scientific evidence. For example, in patients diagnosed with acute pulmonary embolism, twice-per-day dosing and once-per-day dosing of low molecular weight heparin are both commonly used 17. Enoxaparin once-per-day versus twice-per-day in a population pharmacokinetics study both achieved target plasma concentration in pregnancy18; however, once daily regimen has not been universally adopted in clinical practice and no similar data are available for other low molecular weight heparins. Pregnancy is also a vulnerable period for the occurrence of cardiac events. In particular consideration must be given to patients known to have long QT syndrome or on QT prolonging drugs. The adrenergic nature of labor and delivery may lead to catecholaminergic polymorphic ventricular tachycardia in these patients. Furthermore, patients with congenital long QT syndrome are also at risk during a nine-month post-partum period 19. Treatment with beta-blockers are the mainstay of therapy during pregnancy and in the post-partum period19. There is a lack of data for therapeutics that may be urgently needed intrapartum that may prolong the QT interval in susceptible patients. For example, oxytocin and carbetocin are both known to prolong the QT interval but may be required for prevention or treatment of postpartum hemorrhage20,21. Clinical guidelines for using oxytocin for augmentation or induction of labour are lacking and some obstetricians may choose to do an elective Caesarian section to avoid prolonged oxytocin in these patients although this is not evidence based due to lack of studies. In addition to the challenges in proper prescribing in pregnancy, the information on teratogenicity of drugs is also limited. Management of the care of a pregnant patient must balance the benefits of treating the maternal medical condition with possible adverse effects on the fetus. Clinicians must rely on animal data, data from pregnancy registries, and published case control studies and case reports to make these risk/benefit assessments. These resources are by no means ideal as results are confounded by recall bias, selection bias, and inconsistency, as well as lack of ability to extrapolate safety between species 22. Other than a few specific drugs with clear evidence of harm, many drugs have limited information, leading to variable practice among clinicians and inconsistent information provided to patients. For example, while angiotensin-converting enzyme inhibitor induced fetopathy has been described since the 1990s and accepted by medical community consistently23, the risk of maternal corticosteroid use with increased risk of cleft lip and palate has not been consistent among studies24,25. In addition, long term corticosteroid use is also linked to increased risk of preeclampsia which needs to be taken into consideration for treatment and monitoring26. The US Food and Drug Administration recognized the limitation of the prior FDA classifications for medication use in pregnancy (A, B, C, D, X category system). Thus, the “Pregnancy and Lactation Labeling Rule” went into effect by the FDA in June 2015, requesting manufacturers to provide available information regarding risks in pregnancy and lactation in a narrative summary; however, according to a recent survey, less than 50 percent of prescribers were aware of this change, while more than half deemed the narrative summary not helpful 27. Lack of quality data is one of the barriers identified in this survey. In addition to the rating systems used in various jurisdictions, an evidence-based medicine classification system has been developed by toxicologists, which can be used to assist clinical decision making. Unfortunately, all of the currently available systems are of limited utility due to reliance on small studies and inability to be updated frequently with new data22. Since the thalidomide story in the 1960s, much advancement has been made in medical therapy in pregnant women. However there remains a significant knowledge gap in pharmacological information which may expose patients to either toxicity or under treatment with reduced efficacy. In addition, numerous commonly used medications lack concrete data on teratogenicity. Supported by the NIH, the Pediatric Trials Network is currently conducting a multicentre trial studying the pharmacokinetics and safety of commonly used drugs in lactating women and breastfeeding infants in North America (NCT03511118); similar studies in pregnancy are also warranted to guide appropriate dosing. Long term data on children with fetal exposure for developmental toxicity are also urgently needed, and while some data for newer medications is systematically collected by international registries, in general information on fetal risks of maternal exposures is limited to incidental data obtained from accidental exposures. Finally, making all up-to-date information readily available to clinicians should also be a priority. References1. Sun AJ, Li S, Zhang CA, Jensen TK, Lindahl-Jacobsen R, Eisenberg ML. Parental comorbidity and medication use in the USA: a panel study of 785 000 live births. Hum Reprod.Mar 18 2020.2. Mitchell AA, Gilboa SM, Werler MM, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. American journal of obstetrics and gynecology. Jul 2011;205(1):51 e51-58.3. Ventura M, Maraschini A, D’Aloja P, et al. Drug prescribing during pregnancy in a central region of Italy, 2008-2012. BMC Public Health. May 15 2018;18(1):623.4. Engeland A, Bjorge T, Klungsoyr K, Hjellvik V, Skurtveit S, Furu K. Trends in prescription drug use during pregnancy and postpartum in Norway, 2005 to 2015.Pharmacoepidemiology and drug safety. Sep 2018;27(9):995-1004.5. Lutz BH, Miranda VIA, Silveira MPT, et al. Medication Use among Pregnant Women from the 2015 Pelotas (Brazil) Birth Cohort Study. International journal of environmental research and public health. Feb 5 2020;17(3).6. Koren G, Pariente G. Pregnancy- Associated Changes in Pharmacokinetics and their Clinical Implications.Pharmaceutical research. Feb 12 2018;35(3):61.7. Yerby MS, Friel PN, McCormick K, et al. Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding. Epilepsy research. Apr 1990;5(3):223-228.8. Prevost RR, Akl SA, Whybrew WD, Sibai BM. Oral nifedipine pharmacokinetics in pregnancy-induced hypertension. Pharmacotherapy. 1992;12(3):174-177.9. Philipson A. Pharmacokinetics of ampicillin during pregnancy. J Infect Dis. Sep 1977;136(3):370-376.10. Blackburn S. Chapter 9. Cardiovascular System. Maternal, Fetal, & Neonatal Physiology . 5th ed. London, United Kingdom: Elsevier; 2018:251-259.11. Huybrechts KF, Bateman BT, Hernandez-Diaz S. Use of real-world evidence from healthcare utilization data to evaluate drug safety during pregnancy.Pharmacoepidemiology and drug safety. Jul 2019;28(7):906-922.12. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. Mar 2017;27(3):315-389.13. Wesseloo R, Wierdsma AI, van Kamp IL, et al. Lithium dosing strategies during pregnancy and the postpartum period. The British journal of psychiatry : the journal of mental science. Jul 2017;211(1):31-36.14. Betcher HK, George AL, Jr. Pharmacogenomics in pregnancy. Seminars in perinatology. Jan 25 2020:151222.15. Milosheska D, Lorber B, Vovk T, Kastelic M, Dolzan V, Grabnar I. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. British journal of clinical pharmacology. Aug 2016;82(2):399-411.16. Rogers RC, Sibai BM, Whybrew WD. Labetalol pharmacokinetics in pregnancy-induced hypertension.American journal of obstetrics and gynecology. Feb 1990;162(2):362-366.17. Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood advances. Nov 27 2018;2(22):3317-3359.18. Patel JP, Green B, Patel RK, Marsh MS, Davies JG, Arya R. Population pharmacokinetics of enoxaparin during the antenatal period. Circulation. Sep 24 2013;128(13):1462-1469.19. Garg L, Garg J, Krishnamoorthy P, et al. Influence of Pregnancy in Patients With Congenital Long QT Syndrome. Cardiology in review. Jul/Aug 2017;25(4):197-201.20. Clunies-Ross N, Roston TM, Taylor J, et al. The Effect of Carbetocin Dose on Transmural Dispersion of Myocardial Repolarization in Healthy Parturients Scheduled for Elective Cesarean Delivery Under Spinal Anesthesia: A Prospective, Randomized Clinical Trial. Anesthesia and analgesia. Mar 5 2020.21. Liou SC, Chen C, Wong SY, Wong KM. Ventricular tachycardia after oxytocin injection in patients with prolonged Q-T interval syndrome–report of two cases. Acta anaesthesiologica Sinica. Mar 1998;36(1):49-52.22. Wilmer E, Chai S, Kroumpouzos G. Drug safety: Pregnancy rating classifications and controversies.Clinics in dermatology. May-Jun 2016;34(3):401-409.23. Barr M, Jr., Cohen MM, Jr. ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection.Teratology. Nov 1991;44(5):485-495.24. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies.American journal of medical genetics. Sep 17 1999;86(3):242-244.25. Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology. Nov 1997;56(5):335-340.26. Cai E, Czuzoj-Shulman N, Abenhaim HA. Maternal and fetal outcomes in pregnancies with long-term corticosteroid use. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet. Aug 20 2019:1-8.27. Namazy J, Chambers C, Sahin L, et al. Clinicians’ Perspective of The New Pregnancy and Lactation Labeling Final Rule (PLLR): Results from an AAAAI/FDA Survey. The journal of allergy and clinical immunology. In practice. Feb 18 2020.

Fluvoxamine for COVID-19 ICU patients?Vladimir TrkuljaDepartment of PharmacologyZagreb University School of MedicineŠalata 11, Zagreb, Croativladimir.trkulja@mef.hrNumber of words: 800Number of figures/tables: 1To the Editor,I read with interest a recently BJCP-accepted manuscript on the use of fluvoxamine in COVID-19 patients who needed admission to an intensive care unit (ICU) 1. It was instructive to read about the pre-existing clinical experience and about possible mechanisms of presumed benefits of fluvoxamine in COVID-19. However, attention needs to be drawn to the suggested effect of fluvoxamine quantified as a 40% reduction in instantaneous risk of death. The authors report1 on a cohort (n=51) of patients who, upon ICU admission, were treated with oral fluvoxamine added to the standard of care (SoC) (3x100 mg/day over 15 days, then 2x50 mg/day over 7 days), and who were compared to a cohort (n=51) of SoC-only patients. The two cohorts were said to be matched 1. Based on reported data 1, it appears that the patients were matched exactly in respect to gender and COVID-19 vaccination status, and, seemingly, on a rather narrow age-caliper, but the matching method was not reported 1; not reported was also a measure of matching adequacy – standardized difference (d ), a preferred method of balance assessment (adequate if d <0.1) since independent of the sample size 2. Based on the reported data1, for example, the fluvoxamine – SoC d regarding body mass index was -0.30 (-0.31 in women and -0.29 in men); also, d=-0.122 regarding history of diabetes,d= -0.350 regarding history of treated hypertension,d=-0.11 regarding on-admission APACHE score – all suggesting a considerable imbalance between the two cohorts (lower values in the fluvoxamine cohort). The authors provide Kaplan-Meier curves of time-to-death (or ICU discharge) but without the numbers at risk1. Still, data could be read from the graphs and curves reconstructed (Figure 1A):(i) the first marked difference between the treated and controls occurs during the first 7 days of observation – 3 patients died and 3 were censored in the former, and 11 died and 4 were censored the latter cohort (Figure 1A). This difference in deaths (3 vs. 11) did not change over the entire later period since the overall difference in the number of deaths was 9 (30/51 in treated vs. 39/51 in controls). This would indicate a very rapid-onset (and subsequently “lost”) effect of fluvoxamine, which does not seem pharmacologically plausible. The assumed fluvoxamine mechanisms1 are not of the immediate-onset type; with a 3x100 mg/day dosing, elimination half-life is likely to extend well beyond 30 hours, hence steady-state would be achieved only after 7-10 days 3. Combined with the baseline imbalance between groups, this indicates that the initial separation of the two curves – more or less preserved throughout the entire subsequent period - was likely not attributable to fluvoxamine; (ii) after day 21, and particularly after day 28, the numbers at risk were very low, and after day 35 there were no further events (Figure 1A), hence accounting for the entire curve is likely misleading 4; (iii) although the curves do not cross (Figure 1A), they indicate a possibility that hazard ratio varied over time. Hazard ratio as generated in a Cox proportional hazard model (as done by the authors) is an average of values that can change over time5; it is also inherently prone to selection bias and, even in absence of confounding its interpretation is not straightforward5. This holds for randomized and particularly for non-randomized settings 5. Reconstructed data depicted in Figure 1A were used to fit a complementary log-log model for continuous time process taking into account the first 35 days (no events after that point): the method treats time as a continuous but more “coarsely” measured variable, in intervals of identical length (in this case 7-day intervals, i.e., weeks); based on assumption of constant hazard within the interval, the method provides period-specific (for weeks 1-5) hazard ratios 6, which is likely a preferable option 5. Figure 1B depicts estimated probabilities of death and HRs: it is only during week 1 that the hazard appeared lower in treated – a period during which, as elaborated, fluvoxamine most likely had no effect. Finally, authors fitted a multivariable Cox model 1to substantiate the fluvoxamine effect. With a total of 15 independents in a study with 102 subjects, the model was likely overfitted and susceptible to bias arising from over(unnecessary)-adjustments 7. But more importantly, it included adjustment for renal replacement therapy (RRT), which was actually one of the outcomes. Inadequacy of adjustments for post-exposure outcomes as if they were baseline covariates has been extensively elaborated 8 and almost inevitably results in a considerable bias, regardless of whether the respective variable was actually a mediator or a collider 8. Such adjustments require implementation of marginal structural models or some of the g-estimation methods 9.Overall, the reported difference between the two cohorts of patients is more likely bias arising from design and analysis than evidence supporting a causal effect of fluvoxamine.ReferencesČalušić M, Marčec R, Lukša L et al. Safety and efficacy of fluvoxamine in COVID-19 ICU patients: an open label, prospective cohort trial with matched controls. Br J Clin Pharmacol . 2021; doi: 10.1111/bcp.15126.Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci . 2010; 25(1):1-21.Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther . 2000; 85 (1):11-28.Machin D, Cheung YB, Parmar MKB, eds. Survival analysis: a practical approach . 2nd ed. Chichester, West Sussex: John Wiley & Sons Ltd; 2006. p.38.Hernan MA. The hazards of hazard ratios. Epidemiology 2010; 21(1):13-15.Prentice RL, Gloecker LA. Regression analysis of grouped survival data with application to breast cancer data. Biometrics 1978; 34(1):57-67.Schisterman EF, Core SF, Platt RW. Overadjustment bias and unnecessary adjustment in epidemiological studies. Epidemiology 2009; 20(4):488-495.Greenland S. Quantifying biases in causal models: classical confounding vs collider-stratification bias. Epidemiology 2003; 14(4):300-306.Hernan MA, Robins JM, eds. Causal inference: What if . 1st ed. CRC Press LLC; 2019.Figure 1 . Summary of re-analysis of survival data published in ref. 1. A . Reconstructed curves of Kaplan-Meier product-limit estimates. Data1 were read using a digitizing software, and were re-analyzed and curves were drawn using JMP 13 software (SAS Institute Inc., Cary, NC). Upward oriented ticks indicate censorings, downward oriented ticks indicate failures. ICU – intensive care unit. B . Estimated probabilities of death during weeks 1 to 5 by treatment (Fluvox – fluvoxamine) and period-specific hazard ratios (HR) with confidence intervals. A complementary log-log model was fitted to reconstituted data using SAS 9.4 for Windows (SAS Inc., Cary, NC).

Re letter to British Journal of Clinical Pharmacology

Aim: Two recommendations for hemodialysis in lithium poisoning, one from the Extracorporeal TReatments in Poisoning (EXTRIP) workgroup and a single center retrospective one (Paris), differ. We compared outcomes in lithium poisoning based on these criteria with a primary outcome of worsening neurological symptoms in patients where EXTRIP and Paris criteria were discordant. Methods: Poison center data were queried for lithium poisoned patients for whom hemodialysis was either recommended or performed. Patients were categorized according to EXTRIP and Paris criteria and excluded if the peak lithium concentration was <1.2 mmol/L or if neurological follow-up was unavailable. Comparative analyses were only performed when both criteria could be assessed. Results: 219 patients were analyzed. Paris criteria were applied in 70 and EXTRIP criteria in 178. 42 patients were excluded because Paris criteria could not be applied. When Paris and EXTRIP both supported hemodialysis, 50/57 (88%) of patients who received hemodialysis improved, as did all 3 who did not receive hemodialysis. When Paris and EXTRIP opposed hemodialysis, all non-dialyzed patients did well. Among the 86 patients for whom EXTRIP supported hemodialysis but Paris did not, 4/19 (21%) patients not dialyzed deteriorated (p=0.02; OR=8.7, 95%CI=1.5-51.8), one of whom died. All 8 patients for whom Paris criteria supported hemodialysis but EXTRIP did not were dialyzed and improved. Conclusion: When the EXTRIP and Paris criteria are discordant, EXTRIP criteria outperforms the Paris criteria at identifying potentially ill patients who might benefit from hemodialysis.

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.

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.

This study aimed to examine gabapentin utilization trends among older adults with different cognitive statuses and investigate concurrent medication use of potentially inappropriate medications. Data were extracted from National Alzheimer’s Coordinating Center Uniform Data Set (2006-2019). We estimated the yearly prevalence of gabapentin use, both overall and within subgroups defined by cognitive status [normal, mild cognitive impairment, and dementia] and demographics [age and sex] for participants aged 65+. Additionally, we assessed the prevalence of concurrent use of gabapentin with opioids, combined opioids and benzodiazepine, antidepressant, and antipsychotic. Participants reported gabapentin use increased from 2006 to 2019 in both overall and every participant subgroup. About 10-30% of gabapentin users reported to concurrently use of opioids, and more than 50% gabapentin users with dementia reported to concurrently use gabapentin with antidepressants. Given increasing use among older adults, rigorous studies are needed to examine the safety of gabapentin in this population.

Aim: The effect of the Dutch nationwide adjustment of reduced 6-TGN target values (from 600-1200 pmol/8x108 RBC to 320-630 pmol/8x108 RBC) on toxicity and clinical outcome of thiopurine treatment in patients with inflammatory bowel disease (IBD) has not yet been established. Therefore the authors determined the incidence of toxicity-induced discontinuations and efficacy at both target concentrations. Methods: This retrospective study was performed in IBD patients treated with azathioprine or mercaptopurine. Two groups were defined: the former target (FT) group with target concentrations of 600-1200 pmol/8x10^8 RBC and the adjusted target (AT) group with target concentrations of 320-630 pmol/8x10^8 RBC. Patients were followed for maximum 52 weeks or until discontinuation of thiopurine therapy. Data were collected from the local hospital electronic health software of Rijnstate Hospital. Results: 151 patients were included, 76 in the FT group and 75 in the AT group. At week 52, 100 out of 150 patients (66%) of the total population discontinued thiopurine therapy. Forty-eight of this discontinuations were due toxicity (48%). The estimated cumulative incidence of toxicity was higher in the FT group compared to the AT group (47% and 35% respectively, p=0.25). No loss of efficacy was seen in the AT group. Conclusion: Reduction of the target range may lead to less toxicity induced discontinuations. In addition, this study did not find any indication that the reduction of the target range diminished efficacy.

Gene therapy medicinal products have the potential to provide curative treatment to many diseases with current limited therapeutic options. As advanced therapy medicinal products (ATMPs), these therapies undergo a centralised, single European Union authorisation by the European Medicines Agency, but the risks, and potential harm to the environment and population at large are weighted in each application, and different interpretations at national level exist. A streamlined procedure is now in place to facilitate a consistent approach for the assessment of the environmental risks of medicines containing genetically modified organisms. This article provides an overview of basic requirements across the EU, an overview of the new streamlined process and discusses available guidance for developers. All these initiatives are aimed to remove hurdles for ATMP developers and facilitate faster access to patients.

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.

A document by Thomas Svare Ehlers. Click on the document to view its contents.

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.

Aim: Infantile haemangioma (IH) is the most common benign tumour in children. Since 2014, propranolol has become the first-choice therapy and currently Hemangiol® is the only approved drug for complicated haemangioma. This post-marketing study reported the use of Hemangiol® for IH in paediatric practice. Method and Results: From January 2014 to November 2018, 94 children (median age 4 [0;21] months; 75% female) treated with Hemangiol® for proliferative IH were enrolled in the study. The systematic paediatric cardiology consultation never contraindicated beta-blockers. Two Hemangiol® initiation protocols were used: a conventional ambulatory 3-week titration phase protocol (N=76, 80.9%), and a rapid initiation protocol with a 48-hour dose escalation in conventional hospitalization for severe proliferative IH (N=18, 19.1%). In both protocols, the haemodynamic tolerance was good. The mean maintenance dose of Hemangiol® was 2.7±0.8 mg/kg/day, with a median treatment duration of 7 [1.5;19] months. Adverse events (AEs) have been found in 25 (26,6%) patients including 8 (8.5%) patients with serious AEs (uncontrolled bronchial hyperreactivity, N=5; serious hypoglycaemia, N=3). Some patients had one or more AEs, a total of 24 non-serious AEs was reported in 19 patients (sleep disturbances, N=9; respiratory disorders, N=5; digestive disorders, N=6). No cardiac adverse event was reported. Conclusion: This post-marketing surveillance drug study supports the good tolerance of Hemangiol® in children with IH. A rapid initiation protocol is of interest when treatment is urgent. The pre-therapeutic paediatric cardiology consultation should not be systematic but only indicated on specific patients. ClinicalTrials.gov: NCT 04105517.

Background: 64 million pharmacy filled multicompartment medication compliance aids (MCAs) are dispensed by pharmacies in England each year as a method to improve medication adherence. Despite the widespread use of MCAs and evidence that their use may be associated with harm there is no national consensus regarding MCA provision by acute hospital Trusts in England. Aim: To determine current practice for initiation and supply of MCAs in acute hospital Trusts in England and the potential consequences for patients and hospitals. Methods: A 26 item survey was distributed to all acute hospital Trusts in England. The questionnaire covered policy, initiation, supply and review of MCAs; alternatives offered; and pharmacy staffing and capacity related to MCAs. Results: 72 out of 138 (52%) Trusts responded to the survey. 60/70 (86%) had a policy for the provision of MCAs. 33/55 (60%) that supplied MCAs on discharge supplied a different prescription length for MCA vs. non-MCA prescriptions. 49/55 (89%) Trusts provided only one brand of MCA. 47/55 (85%) MCA-supplying Trusts identified frequent difficulties with MCAs and 13/55 (24%) reported employing staff specifically to complete MCAs. 30/35 (86%) MCA-initiating Trusts had an assessment process for initiation, with care agency request as the most common reason. Conclusion: There is a lack of a national approach to MCA provision and initiation by acute hospital Trusts in England. This leads to significant variation in care and has the potential to put MCA users at an increased risk of medication related harm.

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.

Aim: The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes. Methods: Data source were request forms for routine therapeutic drug monitoring of TPM. Concentration dependent adverse drug reactions (ADRs) were evaluated in 1,721 samples taken pre-dose. Seizure frequency analysis was performed in 294 samples of monotherapy. Statistics: Prism 5.0, GraphPad Instatt: Mann–Whitney U test for median plasma level (PL). χ2-test for seizure frequency and for distribution of PL according to TR 5-20 mg/L and intervals <2, 2-5, 5-10, 10-20, >20 mg/L. Results: Better seizure control was found in children both in whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs 5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L. Seizure-free children had higher PL than those with seizure yearly: median (lower, upper quartile) [mg/L]: 5.5 (3.4-6.5) vs 4.7 (4.3-7.95). No difference was found in adults. Seizure control was poorer in all patients with PL <2 mg/L compared to 5-10 mg/L; and 10-20 mg/L; further in PL within 5-10 mg/L vs 10-20 mg/L; and in the period 2003-2005. ADRs reported in 38 samples (2.8%) were without relation to PL. Conclusions: Change of TR is not recommended.

Introduction: Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment, benznidazole (BZN) and nifurtimox (NF). Treating CD infected patients, especially children and women of reproductive age, is vital in order to prevent long term sequelae such as heart and gastrointestinal disfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Finally, treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response. Areas covered: This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Conclusion: Early diagnosis and treatment of CD, especially in pediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drugs development.

Title:Tranexamic acid-associated fatal status epilepticus in a paediatric patientAuthor:Dr Santosh Patel MD, FRCA, PG Dip (Med Edu)Consultant AnaesthetistDepartment of anaesthesiaTawam hospitalAl AinUnited Arab EmiratesCorrespondence address: as above.Email: skpatel@seha.aeFunding: No source of funding to declareConflicts of interest: Nothing to declareDear Editor,I have read with interest a case report and literature review published in the British journal of pharmacology on tranexamic acid (TXA) associated SE in a 4-year child who underwent tonsillectomy.1 I would like to congratulate the authors for reporting the case despite the fatal outcome. Considering that the use of TXA is expanding to minimise blood loss in a wide range of surgeries, an evidence-based therapeutic approach for its associated seizures is of paramount importance.The authors described in their report (also mentioned in Table 2) and concluded that general anaesthetics, propofol and halogenated inhaled anaesthetics are considered the first line of management of TXA-associated seizures due to their direct activity at glycine receptors. In support of their statement, they have quoted three references (references 35,45,46 in their report). However, in their articles, the authors did not recommend the use of general anaesthetics (propofol and halogenated inhalational anaesthetics) as the first line of treatment for TXA-related seizures. It is valuable to point out to the readers that their conclusion is not valid and needs clarification and correction.TXA-associated hyperexcitability of neural networks is because it is a competitive antagonist of glycine and GABAA receptors.2 Following IV TXA administration, not all seizures progress to status epilepticus. Although TXA-related seizures commonly manifest as generalised tonic-clonic activity, focal seizures have been reported; which are not an indication for the use of general anaesthetics. Refractory status epileptics (RSE) and super RSE are uncommon following IV TXA although this is a common feature following intrathecal TXA.3Propofol’s anticonvulsant, hypnotic, sedative and anaesthetic effects are mediated via multiple complex molecular mechanisms, including modulation of GABAA and glycine receptors. GABAA receptor modulation by propofol has distinct dose-dependent effects likely involving multiple sites of action; clinical concentrations of propofol potentiate GABA-activated currents, increase open channel frequency, and reduce the rate of desensitization, while intermediate concentrations directly activate GABAA channels, and even higher concentrations inhibit receptor function.4Propofol can cause neuroexcitatory effects, including tonic-clonic seizures, particularly during the start or weaning from propofol infusion.5 Among the various mechanisms that have been proposed for these neuroexcitatory symptoms are antagonism of glycine and dopamine receptors, hyposensitization of GABAergic pathways and dysregulated inhibition of NMDA glutamate receptors.6Its use is associated with side effects, including hypotension (and the associated use of vasopressors) and respiratory depression. With prolonged infusion, propofol infusion syndrome (PIS) may occur, which may contribute to morbidity and mortality of RSE. Children are more susceptible to developing this complication. Propofol infusion therapy is not recommended as the first line of treatment for TXA-associated seizures, and its use is reserved for severe cases in children.Inhalational anaesthetics are beneficial for the control of seizure activity via inhibition of NMDA excitotoxicity and potentiation of inhibitory functions of GABAA and glycine receptors. However, it is essential to highlight that there are several limitations to the use of inhalational anaesthetic agents. First, the only clinical evidence of their use is from the minimal number of case reports. Second, TXA-related seizures often manifest in the postoperative period in the recovery room or in ICU, where delivery and scavenging of inhalational agents via ventilator may not be feasible. Third effective end-tidal concentration and optimal therapeutic duration are not known. Finally, in higher concentrations, they cause cardiac depression and cerebral vasodilation. Therefore, their use is limited as salvage therapy for the management of TXA-associated RSE and super RSE.In summary, the authors’ conclusion is incorrect, and clinicians should follow currently available evidence-based professional guidelines to manage TXA-associated status epilepticus.8,9References:1. Aboul-Fotouh S, Habib MZ, Magdy SM, Hassan BEE. Tranexamic acid-associated fatal status epilepticus in a paediatric non-cardiac surgery: A case report and literature review. Bri J Clin Pharmacol 2022;1-6. doi:10.1111/bcp.152962. Lecker I, Wang D, Whissell P, et al. Tranexamic acid-associated seizures: causes and treatment. Ann of Neurol 2015;79(1):18-26. doi:10.1002/ana.245583. Patel S, Robertson B, McConachie I. (2019). Catastrophic drug errors involving tranexamic acid administered during spinal anaesthesia.Anaesthesia ,74(7),904-14 https://doi.org/10.1111/anae.146624. Platholi J, Hemmings H. (2022). Effects of general anesthetica on synaptic transmission and spasticity. Currt Neuropharmacol2022;20(1):27-54. doi: 10.2174/1570159X19666210803105232.5. Walder B, Tramèr MR, Seeck M. (2002). Seizure-like phenomena and propofol: a systematic review. Neurology 2002; 58(9):1327-32. 10.1212/wnl.58.9.13276. Pantelakis L, Alvarez V, Gex G, Godio M. Severe neuroexcitatory reaction: A rare and underrecognized life-threatening complication of propofol-induced anesthesia. The Neurohospitalist2021;11(1):49-53. doi: 10.1177/1941874420929536.7. Godec S, Gradisek MJ, Mirkovic T etal. Ventriculolumbar perfusion and inhalational anesthesia with sevoflurane in an accidental intrathecal injection of tranexamic acid: unreported treatment options. Reg Anesthe Pain Med 2022;47(1):65-68 10.1136/rapm-2021-1024988. Nelson SE, Varelas PN. Status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Continuum (Minneap Minn). 2018;24(6):1683-1707.9. Vossler DG, Bainbridge JL, Boggs JG etal.. Treatment of refractory convulsive status epilepticus: a comprehensive review by the American Epilepsy Society Treatments Committee. Epilepsy Curr.2020;20(5):245-64.