Aim: The British Pharmacological Society and UK Medical Schools Council Prescription Safety Assessment (BPS/MSC PSA) is an electronic platform developed for assessing the prescription skills of medical students. Our aim was to investigate the feasibility of the PSA in addressing prescribing competencies among junior doctors in a hospital setting. Methods: The Department of Clinical Pharmacology at Odense University Hospital (OUH) established a Danish translated program using the BPS/MSC PSA platform. We launched a formal three year program in 2021, potentially assessing all first-year doctors at OUH and Esbjerg Regional Hospital. Participation was mandatory, followed by a survey (not mandatory). Results: During the period of 2021 to 2023 n= 364 doctors were invited, from which n=246 participated. The compliance rate increased from 38% in 2021 to 88% in 2023. The mean assessment score (points normalized to percentage) across n=246 participants was 71%, and 94% achieved a score of at least 50%. The survey was distributed to n=402 with 90 responses (22%) from which n=71 completed the questionnaire. Of these, 64% stated that the purpose with the assessment was clear. The two questions about difficulty level and the number of questions had similar evaluations. The majority of respondents found that the questions were of clinical relevance. Conclusion: It is feasible to translate and implement the PSA in a Danish hospital setting. The program provides insight into the prescribing competencies of junior doctors and the participants are generally positive.

Fung and colleagues observed improvements in Prescribing Safety Assessment (PSA) pass rates following targeted teaching interventions in their medical school cohorts. They showed that the PSA captured the effect of the intervention providing further evidence of its validity as a test of prescribing competence, and its sensitivity as an instrument to measure this. It also demonstrates that a dedicated prescribing assessment can influence the design of student learning pathways and encourage the development of authentic prescribing tasks in undergraduate medical training. In contrast, the Applied Knowledge Test (AKT), which necessarily tests multiple domains and areas of practice and knowledge, exclusively with single-best-answer (SBA) questions, did not detect the educational impact of this intervention. The PSA focuses on various aspects of prescribing skills including drug selection, dosing, timing and frequency of administration; as well as providing information to patients, recognising adverse drug reactions, dose calculations, monitoring, prescription review and planning management. It uses a testing approach that more closely aligned with prescribing practice including simulation of electronic prescribing in ‘white space’ fields, avoiding the potential cuing effects of SBA questions, and using a semi-open book design, in which the candidates use the key resource that they will use in practice – the British National Formulary. Fung and colleagues’ findings underscore the importance of passing the PSA as a measure of competence to enter practice and the complementarity of the PSA and the AKT in determining this.

Abstract Aim: To assess cardiac event incidence and trends by sex and age in young patients on psychopharmacological treatment in Sweden. Methods: This nationwide incidence study encompassed data from Swedish registers (2006–2018). Patients aged 5–30 years were exposed to one or more psychotropic medications (attention deficit hyperactivity disorder medications, antihistamines, selective serotonin reuptake inhibitors, other antidepressants, anxiolytics, antipsychotics, hypnotics/sedatives). Annual incidences, trends, and mean incidences of cardiac events (cardiac arrest, arrhythmias, fainting/collapse, sudden death) and recurrent events were calculated. Results: Among those exposed (n=875,430, 2,647,957 patient-years, 55% female), 26,750 cardiac events were identified. The mean annual incidence of cardiac events and first-ever events were 0.98% and 0.80%, respectively, showing significant upward annual trends of 4.26% and 2.48%, respectively (p<0.001). The highest incidences were among females aged 15–19 years (1.50%) and those exposed to polypharmacy (1.63%), anxiolytics (1.53%), or antihistamines (1.27%). The mean annual incidences of cardiac arrest and arrythmias, for both sexes, were 0.01% and 0.51%, respectively. Fainting/collapse accounted for about half of all events, occurring more often in females. The pattern of rising annual incidence remained after excluding fainting/collapse. In all, 21.1% of events were recurrent. Sudden death occurred in thirteen patients. Conclusions: The mean annual incidence of cardiac events among young patients receiving psychopharmacological treatment was low, 0.98%, with an upward trend of 4.26% annually. Incidence was highest in females and patients exposed to polypharmacy. Our study highlights the need for more knowledge regarding the possible association between exposure to psychopharmacological treatment and cardiac events.

Spotlight Commentary: Examining Safety Profiles of Topical Ocular MedicationLorena Karla Šklebar1,2, Robert Likić2,3, Sonja Jandroković1,21 Department of ophthalmology, University Hospital Centre Zagreb, Zagreb, Croatia2 University of Zagreb, School of medicine, Zagreb, Croatia3 Division for clinical pharmacology and therapeutics, Department of internal medicine, University Hospital Centre Zagreb, Zagreb, CroatiaKeywords: eye drops; systemic side effect; ocular side effect; safety profile; topical ocular medicationWord count: 1085Table count: 1Figure count: 0Topical medications are frequently used in treating a wide range of ocular diseases due to their efficiency in delivery directly to the afflicted area. However, localized administration cannot prevent side effects, both local and systemic, which can sometimes be overlooked or underestimated. The aim of this spotlight commentary is to provide a review of safety profiles of topical ocular medications, analysing their effect on the ocular structures as well as their systemic and environmental impacts. 1Although topical ocular medications are designed for localized treatment and are administered directly on the surface of the eye, there is a significant systemic absorption of these drugs through several pathways. The first of two major pathways is from the lacrimal sac through the nasolacrimal duct into the nasopharynx where drugs can be systemically absorbed through the nasal mucosa. This pathway can easily be circumvented by manually providing pressure to the medial canthus or by closing the eyes for 5 minutes after the instillation of each drop, which will cause compression on the nasolacrimal duct. The other major pathway for systemic absorption is through the conjunctiva and conjunctival blood vessels. Minor pathways of systemic drug delivery are through the pharynx, gastrointestinal tract, skin of the cheeks and the eyelids, aqueous humour, and inner ocular tissues. Special care must be taken when treating the paediatric patients who have a much higher risk of developing systemic side effects, due to inadequate dosage and increased systemic permeability of the drugs. 2Localised adverse effects of topical ocular medications commonly arise due to preservatives, which are used in eye drops and ointments in order to prolong their shelf life and guard against microbiological contamination. Benzalkonium chloride (BAC) is the most used preservative in ophthalmic medications. Clinical studies have extensively examined the toxic effects of BAC, revealing that its prolonged use causes time- and dose-dependent cytotoxicity on the ocular surface, leading to tear film instability and the development of ocular surface disease, dry eye, and Meibomian gland dysfunction 3,4. Therefore, the European Medicine Agency recommends avoiding preservatives in patients who have pre-existing ocular surface disease or who develop dry eye or ocular irritation over time. 3Among eye drops, the most commonly discussed side effects, both local (as stated in Table 1) and systemic, in certain groups of topical ocular medications, pertain to antiglaucoma eyedrops, such as β receptor blockers, α receptor agonists and pilocarpine. Due to their chronic usage, physicians must take special care in choosing the right therapy for their patients as well as monitor for potential adverse events. β receptor blockers have a major limitation in their usage due to their frequent systemic side effects, although they are a potent antiglaucoma medications. Targeting β1-receptor causes reduced cardiac contractility and heart rate, bradycardia, and a blood pressure decrease and β2-receptor targeting leads to exacerbated asthma and chronic obstructive pulmonary disease symptoms. Additionally, central nervous system symptoms such as headaches, depression, and confusion may occur. Betaxolol is a selective β1-receptor antagonist which therefore causes fewer side effects to the respiratory system. 5 When α2 adrenergic agonists are applied, systemic side effects such as dry mouth, dizziness, fatigue, and drowsiness may occur, particularly in patients predisposed to bradycardia.6Excessive use of pilocarpine can also have numerous adverse effects due to its parasympathomimetic action which includes excessive sweating, drooling, bronchospasm, vomiting, diarrhea, stomach-ache, bradycardia, a drop in blood pressure, hallucinations and depression.Special caution also must be taken when prescribing topical ocular or systemic steroid medication. Because of their potential to change the microstructure of the trabecular meshwork, they can induce a rise in intraocular pressure by decreasing aqueous humour outflow and potentially causing the development of steroid induced glaucoma. Prolonged use of topical corticosteroids can also induce cataract formation and increase susceptibility to infection. If used in eyes with epithelial defects, they can inhibit growth factors and delay wound healing.Another group of eye drops which can have substantial systemic effects are mydriatics, such as phenylephrine and atropine. Phenylephrine, a selective α1-receptor, is applied in the form of eye drops for dilating the pupils during ophthalmological examinations. Due to its sympathomimetic effect it can cause major cardiovascular side effects, especially when administered in patients with pre-existing hypertension conditions.7 Atropine is a muscarinic receptor antagonist often used in ophthalmology in the form of eye drops for its mydriatic and cycloplegic effect. When systemically absorbed, it can potentially cause side effects like mouth and eye dryness, flushed skin and face, fever, tachycardia, delirium or restlessness, urinary retention, and constipation. If used in higher doses or over a longer period, in severe cases, central anticholinergic syndrome may occur, which is characterized by confusion, agitation, and hallucinations.8 Mydriatics also affect inner ocular structures. Phenylephrine is linked with a decrease in choroidal thickness, while atropine eye drops are associated with an increase in choroidal thickness. This necessitates careful monitoring of patients on long-term topical therapies for any alterations in choroidal structure because of their potential effect on visual function.9Other eyedrops, such as antiallergics, can also be sometimes used in treating eye conditions. Topical H1-receptor blockers and mast cell stabilizers in the form of antiallergic eye drops infrequently cause systemic side effects following ocular use. When they do occur, these side effects are usually mild, presenting as dry mouth, nausea, headache, or drowsiness.7The environmental effect is another part of pharmaceutical safety profiles which cannot be disregarded. Inappropriate disposal of drugs, including eye medications, poses a significant risk to public health and environmental sustainability by contaminating water supplies and disrupting ecosystems.10 Other than the drug itself, its packaging can also cause substantial waste, as is the case with monodose eye drops. These eyedrops are stored in small single-use containers, in order to prevent microbial growth which can occur in standard eye drop bottles after opening. However, their disposal creates a lot of waste. 11 Pharmaceutical companies should provide education and raise awareness among healthcare providers and patients about how to properly manage pharmaceutical waste.In conclusion, although topical ocular medication is the foundation of ophthalmic treatment, before prescribing physicians must be aware of their safety profiles. Although they are generally considered safe, their potential adverse effects on ocular and systemic health highlights challenges in the management of ocular diseases. Healthcare practitioners should choose preservative-free formulations where possible, monitor for both local and systemic side effects, and act responsibly while taking into consideration the environmental implications of pharmaceutical use. These safety concerns should be further investigated in future studies with the goal of improving therapeutic outcomes for patients while minimizing risks.

Aims: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor (TKI) used to treat various cancers, including hepatocellular carcinoma (HCC). LEN therapy for HCC is associated with a high incidence of adverse events, including hypertension (HTN). However, the risk factors associated with LEN therapy remain unclear. This study aimed to investigate the incidence of LEN-induced HTN (LENiHTN) and the relationship between the incidence of HTN and patient demographics in patients with HCC receiving LEN therapy. Methods: This was a single-centre, retrospective study of patients with HCC who received LEN therapy between 19 April 2018 and 30 September 2020. The observation period was from 1 week before the start to 1 month after the end of LEN administration. Results: In total, 75 patients with HCC were enrolled. LENiHTN of any grade was found in 74.7% of patients. The use of two or more antihypertensive agents before starting LEN was more common (P = 0.007); serum potassium (K), and albumin–bilirubin score (ALBI) were lower (P = 0.013 and 0.038, respectively); and albumin (Alb) was higher (P = 0.025). The cut-off values of K, Alb, and ALBI for HTN were estimated to be 4.1 mEq L-1, 3.1 g dL-1, and -1.736, respectively. In the multivariate analysis, K and ALBI were independent risk factors for LENiHTN. Conclusion: Low K and high ALBI were independent risk factors for LENiHTN. Systematic evaluation of HTN risk and early intervention for HTN prevention among high-risk patients can markedly enhance the efficacy and utilisation of LEN therapy.

A document by Francis Williams. Click on the document to view its contents.

The use of tramadol and other opioids for pain management has been accompanied by a multitude of challenges and concerns worldwide. The use of tramadol saw a decline in Denmark during 2017-2019 accompanied by a slight increase in the use of morphine and oxycodone. Using the Danish National Prescription Registry and utilizing data until and including 2023, we aimed to provide updated data on the utilization patterns of tramadol and other opioids in Denmark. We found a 35% decline in the use of tramadol from 2017-2023 most likely due to media attention, regulatory actions, health campaigns, and targeted education of physicians and patients by the Danish health authorities. This decline was accompanied by an increase in the number of new (+90%) and current users of morphine (+57%) which surpassed those of tramadol, oxycodone, and other opioids in 2023.

Aim Recording the indication for a medicine in the prescription supports communication. In May 2023 our district hospitals made the free-text indication field in prescriptions compulsory for all medicines in the inpatient prescribing system. This study aimed to evaluate the effect of introducing a compulsory indication field in an inpatient prescribing system. Methods Text in the indication field was manually classified as an indication, ‘other text’, ‘rubbish text’, ‘to be determined’, and ‘blank’. Prescribing data were extracted from the district data warehouse. The change in proportion of prescriptions with an indication was compared for eight-weeks after introduction of a compulsory indication field to an equivalent eight-weeks in 2022. Secondary outcomes included patient outcomes, medication cessation, and indication recording before discharge. Results We analysed 81,634 prescriptions before and 82,726 after indications were made compulsory. The proportion of prescriptions with an indication increased from 29.2% to 75.6%. ‘Rubbish text’ increased from 0% to 2.3%, ‘other text’ from 2.5% to 14.7%, and ‘to be determined’ from 0.0% to 6.6%. Of 5,557 prescriptions with ‘to be determined’ initially, 18.1% were ceased and 2.7% had an indication before discharge. There was minimal change in patient outcomes. Conclusion Introducing a compulsory indication field increased the proportion of medicines with an indication from 29% to 76%, with only a small increase in ‘rubbish text’. The carefully selected compulsory field improved information quality but did not alter medicine use or patient outcomes. Compulsory fields should be combined with improvements in other components of care to improve medicine use.

Background & Aims: The potential of mechanistic biomarkers to improve prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration, as well as to characterize their natural variability and impact of diurnal variation. Methods: Serum samples from 227 healthy volunteers were recruited as part of a cross-sectional study; of these, 25 subjects had weekly serial sampling over 3 weeks, while 23 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), High Mobility Group Box-1 (HMGB1), total Keratin-18 (K18), caspase-cleaved Keratin-18 (ccK18), Glutamate Dehydrogenase (GLDH) and Macrophage Colony-Stimulating Factor-1 (CSF-1) were assayed. Results: Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models. Intra-individual variability was found to be non-significant, and there was no significant impact of diurnal variation. Conclusions: Reference intervals for novel DILI biomarkers have been described. An upper limit of a reference range might represent the most appropriate mechanism to utilize these data. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification as required by regulatory authorities.

Residual neuromuscular blockade (RNB) commonly occurs when using neuromuscular blockers and increases the risk for pulmonary complications, such as airway obstruction and severe hypoxemia, in extubated patients. Rocuronium exhibits a high variability in recovery time, contributing to an increased risk for RNB. This study aimed to identify and characterize the sources of variability in rocuronium exposure and response via a population pharmacokinetic/pharmacodynamic (PK/PD) analysis and to apply the developed PK/PD model to investigate clinical implications. A nonlinear mixed-effect model was developed for rocuronium in patients undergoing general anaesthesia, using doses of 0.3–1.2 mg/kg. Plasma concentrations and the neuromuscular block [train of four ratio] were assessed up to 6 h after dosing. The influence of age, body mass index, renal function, and sex on PK and PD was explored. Simulations were performed to predict the recovery time. A two-compartment model with linear elimination and an indirect sigmoid I-max model was used to describe PK and PD. The transfer rate into the periphery increases with age. The predicted recovery time was significantly longer in older subjects compared to young adults following single bolus administrations of doses ≥ 0.7 mg/kg. Our findings suggest that geriatric patients take slightly longer to recover than younger adults due to an age-dependent increase in tissue uptake. However, a priori dose adjustments for rocuronium in elderly patients are not feasible, since age contribution is overshadowed by the overall variability in the recovery time.

Low-Dose Amitriptyline: A Potential Therapeutic Option for Chronic Pain in Older PeopleTakayuki Suga, DDS, PhD1; Trang Thi Huyen Tu, DDS, PhD1,2; Motoko Watanabe, DDS, PhD1; Takahiko Nagamine MD, PhD1,3; and Akira Toyofuku, DDS, PhD11 Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo2 Department of Basic Dental Sciences, Faculty of Odonto- stomatology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam3 Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Yamaguchi, Japan.Word count:798Acknowledgements: noneConflict of interest statement: There are no conflicts of interest to declare.Keywords: psychopharmacology, safety Pharmacology, chronic pain, antidepressive agents, older adultCorrespondence to:Takayuki Suga, DDS, PhD1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.Phone number: +81358035898; Fax: +81358035898; Email: suga.ompm@tmd.ac.jpThe use of antidepressants in older adults with chronic pain is controversial. We found Dr. Narayan et al.’s article, titled “Efficacy and Safety of Antidepressants for Pain in Older Adults: A Systematic Review and Meta-Analysis,” on the use of antidepressants in older people with chronic pain to be highly engaging. (Narayan et al., 2024) They conducted a systematic review and meta-analysis on the efficacy and safety of antidepressants for chronic pain in older people. Due to various limitations, they concluded that the benefits and harms of antidepressant medicines for most types of chronic pain, especially knee OA, are unclear.Conducting clinical research with older adults poses challenges, often excluding them due to pre-existing conditions. Randomized controlled trials (RCTs) in this population are particularly difficult for several reasons:1. Comorbidities and Polypharmacy: older people often have multiple chronic conditions and take various medications, complicating group allocation, the isolation of the intervention’s effects and increasing the risk of drug interactions.2. Heterogeneity and Follow-up Challenges: Due to mobility impairments and other factors, it is difficult for older people to make regular visits to hospitals conducting RCTs, leading to high dropout rates.3. Ethical Considerations: The older people are often regarded as a vulnerable population, requiring ethical considerations when involving them in risk-related interventions.Despite these challenges, studies using real-world data suggest that, when used carefully, antidepressants might help manage chronic pain in older adults, particularly for conditions like burning mouth syndrome (BMS).BMS, a common type of chronic orofacial pain affecting mainly postmenopausal women, has uncertain pathophysiology.We previously reported that low doses of amitriptyline are effective in managing pain in older people with BMS. (Suga et al., 2019) Furthermore, even in patients over 80 years old, amitriptyline demonstrates efficacy when used in low doses with careful administration. (Watanabe et al., 2022) Regarding common side effects, managing these side effects in elderly patients will be effective through regular visits and examination. (Suga et al., 2019; Watanabe et al., 2022) Hence, it is crucial to monitor for anticholinergic side effects such as drowsiness, dry mouth, and constipation, as well as potential falls due to dizziness and any changes in cognitive function in clinical assessment.A therapeutic window exists for the dosages of amitriptyline that are effective in managing chronic pain, indicating that its efficacy is not dose-dependent. (Nagamine, 2024) In contrast to the doses used in psychiatry for depression (typically 100 mg/day or more), amitriptyline is effective at doses of 5-20 mg/day in the treatment of BMS. The use of amitriptyline at this dosage is considerably lower than the doses employed in the RCTs included in the authors’ study, suggesting a reduced risk of side effects and withdrawal symptoms.The challenges of administering antidepressants to older people with chronic pain are not limited to concerns about side effects but also encompass issues related to their overall efficacy in this population. Serotonin’s role in pain modulation is complex, as it can either exacerbate or alleviate pain depending on the receptor subtype activated. This bidirectional effect is attributed to the distinct pathways involved in serotonin-mediated pain processing, with some receptors promoting analgesia and others enhancing nociception. (Bannister & Dickenson, 2016) Additionally, the elevation of serotonin levels might disrupt the delicate equilibrium with dopamine, thus hindering pain inhibition via the reward pathway. Therefore, increasing serotonin levels alone may exacerbate pain rather than produce therapeutic benefits.Moreover, chronic pain modulation involves not only serotonin but also other monoamines, such as dopamine and noradrenaline. Consequently, antidepressants that modulate serotonergic, noradrenergic, or dopaminergic pathways may exhibit therapeutic potential in managing chronic pain. (Bannister & Dickenson, 2016) This is also reflected in the study by Narayan et al., which demonstrated the efficacy of duloxetine, a dual serotonin and noradrenaline reuptake inhibitor, albeit with a modest effect size. Amitriptyline, which similarly targets both serotonin and noradrenaline, and to some dopamine transporters, may offer superior efficacy compared to other antidepressants. However, as previously mentioned, its therapeutic effect does not appear to be dose-dependent, suggesting that there may be an optimal therapeutic window at lower doses. Although not specifically in older people, other reports have also demonstrated the effectiveness of low-dose amitriptyline (5-25 mg/day) in managing conditions such as lower back pain, chronic neck pain, and chest pain. (Maarrawi et al., 2018; Park et al., 2013; Urquhart et al., 2018) Given the above, it is conceivable that low doses of certain antidepressants, such as amitriptyline, may be effective and safe for patients with other types of chronic pain. Research on the use of antidepressants for chronic pain in older people is still limited; therefore, as the authors have pointed out, there is a need for more prospective studies and numerous real-world investigations. In conclusion, careful clinical management and the accumulation of treatment data are essential for the effective treatment of chronic pain in older people using antidepressants.ReferencesBannister, K., & Dickenson, A. H. (2016). What do monoamines do in pain modulation? Curr Opin Support Palliat Care , 10 (2), 143-148. https://doi.org/10.1097/SPC.0000000000000207Maarrawi, J., Abdel Hay, J., Kobaiter-Maarrawi, S., Tabet, P., Peyron, R., & Garcia-Larrea, L. (2018). Randomized double-blind controlled study of bedtime low-dose amitriptyline in chronic neck pain. Eur J Pain , 22 (6), 1180-1187. https://doi.org/10.1002/ejp.1206Nagamine, T. (2024). Amitriptyline at low dose for burning mouth syndrome. Oral Diseases , 30 (7), 4650-4652. https://doi.org/10.1111/odi.14966Narayan, S. W., Naganathan, V., Vizza, L., Underwood, M., Ivers, R., McLachlan, A. J., Zhou, L., Singh, R., Tao, S., Xi, X., & Abdel Shaheed, C. (2024). Efficacy and safety of antidepressants for pain in older adults: A systematic review and meta-analysis. Br J Clin Pharmacol . https://doi.org/10.1111/bcp.16234Park, S. W., Lee, H., Lee, H. J., Park, J. C., Shin, S. K., Lee, S. K., Lee, Y. C., & Kim, J. E. (2013). Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain. World J Gastroenterol , 19 (30), 4958-4965. https://doi.org/10.3748/wjg.v19.i30.4958Suga, T., Takenoshita, M., Watanabe, T., Tu, T. T. H., Mikuzuki, L., Hong, C., Miura, K., Yoshikawa, T., Nagamine, T., & Toyofuku, A. (2019). Therapeutic Dose of Amitriptyline for Older Patients with Burning Mouth Syndrome. Neuropsychiatric Disease and Treatment ,Volume 15 , 3599-3607. https://doi.org/10.2147/ndt.S235669Urquhart, D. M., Wluka, A. E., van Tulder, M., Heritier, S., Forbes, A., Fong, C., Wang, Y., Sim, M. R., Gibson, S. J., Arnold, C., & Cicuttini, F. M. (2018). Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial. JAMA Intern Med ,178 (11), 1474-1481. https://doi.org/10.1001/jamainternmed.2018.4222Watanabe, M., Takao, C., Liu, Z., Nayanar, G., Suga, T., Hong, C., Tu, T. T. H., Yoshikawa, T., Takenoshita, M., Motomura, H., Nagamine, T., & Toyofuku, A. (2022). The Effectiveness and Adverse Events of Amitriptyline and Aripiprazole in Very Elderly Patients With BMS.Frontiers in Pain Research , 3 . https://doi.org/10.3389/fpain.2022.809207

Early approval mechanisms, such as conditional approval in the EU, have been used extensively to provide timely access to therapeutic innovations to cancer patients with unmet medical needs. While based on promising early evidence, such approvals are challenging from many perspectives due to the lack of comprehensive data. The limitation typically relates to data that demonstrates clinical benefit via particular endpoints and is only acceptable when the early evidence is particularly convincing to assume that the benefits of early access are greater than the potential harms. This paper describes the requirements for conditional approval and reviews common pitfalls in oncology, such as misunderstandings about the strength of evidence from exploratory trials and secondary analyses, lack of planning, and opportunities to improve communication. Thereafter, we present a framework (“EDGE”) on how to improve the submission and evaluation of drug applications for conditional approval in the EU.

Background Study on the effect of hydroxychloroquine (HCQ) in treating children with chronic immune thrombocytopenia (ITP) is limited. The association between ANA positivity and its efficacy is not clear. Methods This was a retrospective cohort study on chronic ITP children. We compared the clinical characteristics of patients who received HCQ with those who didn’t, as well as patients who responded to HCQ at 3 months with those who didn’t. Mixed-effects models were performed to assess the effect of HCQ on platelet counts and the association between ANA and its efficacy. Records of side effects associated with HCQ were reviewed. Results A total of 191 children with chronic ITP were included in this study, involved 42 patients who received HCQ. In patients who received HCQ, 69.0% of patients achieved complete response /response at the last follow-up, with a higher frequency than in patients who didn’t (69.0% vs. 48.3%). The overall response rate was 56.8% at 3 months and 40.5% at 1 year. Our results showed no difference in ANA positivity between patients with response to HCQ and those without. HCQ was effective for increasing platelet counts (mean difference: 23.82×109/L; 95% CI: 7.44 ~ 40.21), but the association between ANA positivity and its efficacy was not found. Side effects were recorded in 6 of 42 patients (14.3%). Conclusions HCQ was associated with increased platelet counts in chronic ITP children. The baseline ANA level was not found to have an interaction effect on this efficacy. Side effects of HCQ should be concerned.

This is just an editorial and does not include an abstract