Drugs in Context

1

Authors: Xiaonan Yang, Visnu Lohsiriwat, Frank Chun Shin Chang, Tan Thiam Chye, Catherine J Howard, Liang Qiao, Steven W Shaw, Tu Nguyen Anh Tran, Chan Yung, Daniel Dellosa, Dinesh Nagrale

The authors wish to make the following corrections to their article: Yang X, Lohsiriwat V, Chang FCS, Chye TT, Howard CJ, Qiao L, Shaw SW, Tran TNA, Yung C, Dellosa D, Nagrale D. Real-world management of abnormal scarring using topical silicone gel: expert consensus and case series from the Asian SCARS Expert Group. Drugs Context. 2023;12:2023-4-3. https://doi.org/10.7573/dic.2023-4-3

3

Authors: Andrea De Giglio, Biagio Ricciuti, Giulio Metro

This Editorial by De Giglio, Ricciuti and Metro introduces the series Treatment of advanced non-small-cell lung cancer: one size does not fit all: https://www.drugsincontext.com/special_issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/

5

Authors: Tanyaporn Chantarojanasiri

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent chronic liver disorders worldwide. It is closely associated with metabolic syndrome components, including type 2 diabetes, hyperlipidaemia and obesity. To date, no effective drug treatment is available for NAFLD but several clinical trials suggested that silymarin, the active milk thistle extract, has well-documented antioxidant and hepatoprotective properties. In this case report, silymarin 140 mg twice daily decreased liver enzyme activity with a good safety profile in a patient with NAFLD and overweight, supporting silymarin as a promising supportive intervention aimed at normalizing liver activity in NAFLD. This article is part of the Current clinical use of silymarin in the treatment of toxic liver diseases: a case series Special Issue: https://www.drugsincontext.com/special_issues/current-clinical-use-of-silymarin-in-the-treatment-of-toxic-liver-diseases-a-case-series

5

Authors: Giacomo Caldarola, Arianna Zangrilli, Gerardo Palmisano, Mauro Bavetta, Gaia Moretta, Gianluca Pagnanelli, Vincenzo Panasiti, Luca Bianchi, Clara De Simone, Ketty Peris

Background: Data on the treatment of palmoplantar psoriasis (PP) are scarce, representing a therapeutic challenge. This study aims to assess the efficacy and safety of risankizumab in a population of patients with psoriasis with a palmoplantar involvement, over a 52- week treatment period. Methods: We performed a retrospective analysis in a cohort of patients with PP, with or without involvement of other skin sites. Palmoplantar Psoriasis Area and Severity Index (ppPASI) was assessed at baseline and after 4, 16, 28 and 52 weeks, to evaluate the PP severity. Results: Sixteen patients were enrolled. The rates of ppPASI90 responses constantly increased during the period of observation and were 18.7%, 62.2%, 75.0% and 81.2% at weeks 4, 16, 28 and 52, respectively. Only two patients suspended treatment because of ineffectiveness at week 16. Conclusion: Our data from a series of 16 patients reveal that risankizumab could represent an effective and safe therapeutic choice in patients with PP.

5

Authors: Ahmed Hashem

Non-alcoholic fatty liver disease (NAFLD) and its progressive form (non-alcoholic steatohepatitis; NASH) are the main reason for chronic liver disease in the general population, characterized by fat accumulation in hepatocytes (steatosis) and anomalies in liver biochemical analyses. To date, no pharmacological agents have been approved for NAFLD or NASH treatment. However, silymarin, the active ingredient in milk thistle, has been used in the last decades for the treatment of several liver diseases. In this case report, treatment with silymarin 140 mg three-times daily highlighted moderate efficacy and a good safety profile in the management of NASH and liver function, as it decreased serum AST and ALT levels over the treatment period with no side-effects, supporting silymarin as a promising supplemental intervention that can normalize liver activity in NAFLD and NASH. This article is part of the Current clinical use of silymarin in the treatment of toxic liver diseases: a case series. Special Issue: https://www.drugsincontext.com/special_issues/current-clinical-use-of-silymarin-in-the-treatment-of-toxic-liver-diseases-a-case-series

5

Authors: Yeong Yeh Lee, Vincent Tee

Non-alcoholic fatty liver disease is one of the main causes of elevated liver enzymes and chronic liver disease worldwide. It ranges from steatosis to steatohepatitis, leading to cirrhosis and related liver dysfunction. Silymarin is a herbal medicine, mostly used for liver disorders owing to its supposed hepatoprotective action. This report recommends silymarin in a patient with diabetes and grade II non-alcoholic steatohepatitis, confirming significant hepatoprotective effects as shown by the reduction of liver enzyme activities. This article is part of the Current clinical use of silymarin in the treatment of toxic liver diseases: a case series Special Issue: https://www.drugsincontext.com/special_issues/current-clinical-use-of-silymarin-in-the-treatment-of-toxic-liver-diseases-a-case-series

7

Authors: Bharat Saboo, Nimmi Mulwani, Anup Uttam Petare, Krishna Chaitanya Veligandla, Colette Stephen Pinto, Amey Mane, Rahul Rathod, Bhavesh Kotak

Background: Proton-pump inhibitors, along with a prokinetic agent, are widely used to provide symptomatic relief amongst patients with acid peptic disease (APD). This article evaluates the effectiveness and safety of the omeprazole–domperidone combination amongst patients with type 2 diabetes mellitus for the management of APD. Methods: PRIDE-2 (PRoton-pump Inhibitor in patients with type 2 DiabEtes mellitus) is a retrospective study reviewing electronic medical records of patients with type 2 diabetes mellitus and APD who were receiving the omeprazole–domperidone combination and visiting multiple Indian healthcare settings between March 2018 and April 2021. The effectiveness outcome of the therapy was evaluated in terms of resolution of APD symptoms at visit 5 (120 days after baseline visit) compared with visit 1 (baseline visit). Safety was determined in terms of reported adverse events (AEs) during the treatment period (120 days). Results: A total of 174 patients were included in the study. The mean age of the patients was 51.5±9.6 years, with the majority (59.8%) being men. A significant proportion of patients reported relief from APD symptoms, including abdominal pain (91.6%), epigastric burning (68.7%), nausea (89.5%), flatulence (100.0%), loss of appetite (93.6%), and altered bowel movements (94.7%) (p<0.001 for each) at visit 5 compared with visit 1. No serious AEs were reported. Conclusion: Omeprazole–domperidone combination was beneficial in providing symptomatic relief to patients with diabetes and APD. The combination therapy was well tolerated, with few reports of minor AEs.

7

Authors: Andrew Merker, Kartik Anne, Justin Rayyan, Milena Murray

Background: Recent recommendations by the American Society of Health System Pharmacists and Infectious Disease Society of America have provided guidance regarding vancomycin dosing and monitoring in serious infections (including methicillin-resistant Staphylococcus aureus); however, trough monitoring for uncomplicated acute bacterial skin and skin structure infections (ABSSSI) were not addressed. Vancomycin use appears to lead to a low incidence of acute kidney injury with short durations and a low trough goal (10–15 mg/L). Nevertheless, clinical studies have found no difference in clinical outcomes for ABSSSI regardless of vancomycin level. Therefore, it can be posed whether trough monitoring is necessary in this patient population. Methods: This is a retrospective cohort study comparing vancomycin therapy duration for ABSSSI in adult, general medicine patients who received scheduled vancomycin with an initial creatinine clearance rate of ≥50 mL/minute and had at least one vancomycin trough. The objective of this study was to determine if vancomycin treatment duration differs for patients with ABSSSI with a subtherapeutic vancomycin trough (ST; <10 mg/L) compared with therapeutic trough (TT; ≥10 mg/L). Results: There were 39 (67.2%) patients with ST compared with 19 (32.8%) with TT. A similar median vancomycin treatment duration for ST (48.25 hours) and TT (59.5 hours; p=0.65) was found. There was no statistical difference for hospital duration, time from last trough to vancomycin discontinuation, or incidence of acute kidney injury (p>0.05 for all). Conclusion: Patients with ST and TT had similar vancomycin durations and clinical outcomes. It may be prudent for institutions to address vancomycin trough laboratory stewardship and associated costs.

8

Authors: Nuria García, Pere Guiró, Jordi Galván, Nigel Crutchley, Morten Praestegaard, Lars Iversen, Tiago Torres

Background: In psoriasis, poor treatment adherence is frequently related to low efficacy and limited cosmetic acceptability from the patients’ perspective. This study aimed to characterize the sensorial attributes of a calcipotriol (CAL) and betamethasone dipropionate (BDP)-cream vehicle based on polyaphron dispersion (PAD) Technology and to compare them with the conventional ointment and oleogel formulations for psoriasis. Methods: A panel of 16 experts assessed sensory properties at four different stages: appearance, pick up, rub out and afterfeel. Descriptive sensory analysis was used to evaluate relevant attributes. Each attribute was rated on a line scale (range 0–100%). Active ingredients were not used because panellists were healthy volunteers, and vehicle formulations needed to be used instead. Results: CAL/BDP PAD-cream vehicle was evaluated as having a low stickiness, low grease behaviour, good wetness, and good spreadability. Ointment showed the least desirable behaviour regarding these properties. Moreover, once CAL/BDP PAD-cream vehicle was absorbed, the gloss disappeared quickly, leaving low stickiness and a low amount of residue. This afterfeel behaviour was not observed with ointment. The oleogel formulation had good sensory properties, similar to CAL/BDP PAD-cream vehicle, but with lower integrity of shape, lower wetness and higher greasiness. Conclusion: Overall, CAL/BDP PAD-cream vehicle has the desirable requirements for a topical product for the treatment of psoriasis, with better sensory properties than ointment and easier manipulation than oleogel, which may lead to greater acceptance and adherence.

8

Authors: Sarah L Anderson, Joel C Marrs

One in ten adults worldwide is living with diabetes, with 95% having type 2 diabetes (T2D). Sustained glycaemic control in people with T2D is difficult to achieve despite recent advances in T2D management with the advent of glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i). Tirzepatide represents a first-in-class agent as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP1RA to be approved in the USA and Europe for the treatment of T2D. This narrative review intends to list and discuss the glycaemic efficacy, key safety and weight loss outcomes related to the treatment of T2D with tirzepatide. Tirzepatide has been evaluated in five published clinical trials (n=6278) within the SURPASS clinical trial programme, with a focus on glycaemic control and weight loss. These trials have demonstrated significant improvements in glycosylated haemoglobin (–1.24% to –2.11% versus placebo and –0.6% to –1.14% versus active comparator) and weight (up to 15.5 kg versus placebo or active comparator) in patients with T2D. Notably, tirzepatide exhibited superior glycaemic control and weight loss when compared directly with a GLP1RA. Adverse events with the use of tirzepatide are similar to other approved GLP1RA and are predominantly gastrointestinal (nausea, vomiting). The tirzepatide cardiovascular outcomes trial (SURPASS-CVOT) is in progress and is expected to be completed in the fall of 2024. Tirzepatide represents an attractive new option and first-in-class agent for the treatment of T2D in people unable to achieve their glycaemic or weight management goals.

8

Authors: Carol Fernandez Hazim, Gustavo Duarte, Ana P Urena, Swati Jain, Rishabh Mishra, Timothy J Vittorio, Miguel Rodriguez-Guerra

Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a crucial role. There are robust guidelines with extensive evidence for the management of heart failure; however, clear guidance is needed for patients who do not respond to standard diuretic treatment. Diuretic resistance (DR) can be defined as an insufficient quantity of natriuresis with proper diuretic therapy. A combination of diuretic regimens is used to overcome DR and, more recently, SGLT2 inhibitors have been shown to improve diuresis. Despite DR being relatively common, it is challenging to treat and there remains a notable lack of substantial data guiding its management. Moreover, DR has been linked with poor prognosis. This review aims to expose the multiple approaches for treatment of patients with DR and the importance of intravascular volume expansion in the response to therapy.

9

Authors: Paulo Henrique Feitosa

The underdiagnosis of alpha-1 antitrypsin (AAT) deficiency (AATD) has been recognized for many years, yet little progress has been made in treatment of the disease. In this review, we summarize the AATD disease process as well as its diagnosis and treatment by AAT augmentation therapy. AATD is a rare autosomal disease that primarily affects the lungs and liver. AATD is associated with an increased susceptibility to developing pulmonary emphysema. The specific pharmacological treatment for AATD is intravenous administration of exogenous AAT. Augmentation therapy with AAT increases serum and pulmonary epithelial AAT levels, restores anti-elastase capacity, and decreases inflammatory mediators in the lung. Augmentation therapy reduces the loss of lung density over time, thus slowing progression of the disease. The effects of augmentation therapy on outcomes, such as frequency/duration of flare-ups, quality of life, lung function decline and mortality, are assessed. Wider testing for AATD, potentially through primary care physicians, could result in earlier treatment and better outcomes for individuals with AATD-induced lung respiratory disease.

9

Authors: Guido Mannaioni, Fabio Lugoboni

Opioid use disorder (OUD) is a serious medical condition with vast social, health and economic impact. Individuals with OUD are prescribed opioid agonist therapies, such as methadone, levomethadone, buprenorphine or naloxone/buprenorphine, to reduce the risks associated with illegal substance abuse, eventually leading to opioid use abstinence. The OUD population has peculiar frailties, mainly related to the psychiatric sphere, which may jeopardize their therapeutic course. Amongst the possible phenomena that may contribute to treatment failure, opioid agonist therapy misuse and diversion are of utmost importance, leading to serious repercussions for patients as well as for national health systems. To minimize the consequences related to these practices, it is necessary to implement cross-cutting precautions, from the formulation of abuse-deterrent drugs to the implementation of a national monitoring system that oversees the health situation and signals when action is needed. Based on these premises, this article focuses on data and insights concerning the Italian territory.

10

Authors: Muhammed Ahmed Elhadedy, Ghada El-Kannishy, Ayman F Refaie, Hussein A Sheashaa, Ahmed Halawa

Background: Secondary hyperparathyroidism is a common consequence of end-stage renal disease. Despite the efficacy of kidney transplantation in treating renal failure, many transplant recipients still suffer from persistent or tertiary hyperparathyroidism. Furthermore, the impact of secondary hyperparathyroidism therapy choices on other renal transplant outcomes is poorly understood. Methods: We retrieved the clinical data of 334 patients who received a kidney allograft between January 2007 and December 2014 at the Sheffield Teaching Hospitals, NHS Foundation Trust, United Kingdom. We identified three groups: parathyroidectomy group (34 patients), including patients who had parathyroidectomy before transplantation; cinacalcet group (31 patients), including patients who received cinacalcet before transplantation; and control group (269 patients), including patients who receive a transplant in the same period but did not have any evidence of hyperparathyroidism. We reviewed the demographic data, biochemical parameters and graft survival of all groups. Results: Patients who underwent parathyroidectomy before transplantation had significantly better posttransplant calcium and parathyroid hormone levels than patients in the cinacalcet group (p=0.003). In addition, a significantly lower number of patients had tertiary hyperparathyroidism in the parathyroidectomy group than in the cinacalcet group at 1 year of follow-up (p=0.001). However, short-term and long-term graft survival was comparable in all groups. Conclusions: Renal allograft survival was comparable in all groups. However, tertiary hyperparathyroidism was less likely to occur in patients who underwent parathyroidectomy than in those who were administered cinacalcet.

11

Authors: Edgardo Kaplinsky, Sergio Perrone, Alejandro Barbagelata

The nitric oxide (NO)–soluble guanylate cyclase (sGC)– cyclic guanosine monophosphate (cGMP) pathway is dysregulated in patients with heart failure (HF) resulting in myocardial and vascular dysfunction that contributes to its progression. Vericiguat is a novel direct sGC stimulator that targets in at least two ways the NO–sGC–cGMP pathway with the subsequent restoration of cGMP activity. The VICTORIA trial assessed the effects of vericiguat (versus placebo) in 5050 patients with chronic HF (NYHA class II–IV), left ventricular ejection fraction (LVEF) <45%, elevated natriuretic peptide levels and a recent HF decompensation (hospitalized or outpatient intravenous diuretics). After a median follow-up of 10.8 months, a lower risk (10% reduction) of the primary combined outcome (cardiovascular death or HF hospitalization) was achieved (HR 0.90, 95% CI 0.83–0.98; p=0.02). The composite endpoint was driven by HF hospitalizations (HR 0.9, 95% CI 0.81–1.00; p=0.048) whilst CV death reduction was not statistically significant on its own. The target dose was achieved in 89% of patients treated with vericiguat, and no significant differences were observed in the rates of syncope or hypotension. The VICTORIA trial showed that vericiguat was safe, well tolerated and without need of laboratory testing. The aim of this review is to provide comprehensive information about vericiguat in terms of its differential mechanism of action and clinical data particularly focused on the VICTORIA trial. A comparison is also made with DAPA-HF and EMPEROR-Reduced considering that, in all these contemporary trials, a new study medication was added to the standard triple HF therapy. This is a relevant issue because the VICTORIA trial had a significant but less powerful effect than DAPAHF and EMPEROR-Reduced on HF outcomes in a setting of more severe disease, higher event rate and shorter follow-up. In addition, relevant data on other previous studies are also provided in both HF with reduced LVEF (SOCRATES-Reduced) and HF with preserved LVEF (SOCRATES-Preserved and VITALITY-Preserved). This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment

11

Authors: Siddharth Chinta, Miguel Rodriguez-Guerra, Mohammed Shaban, Neelanjana Pandey, Maria Jaquez-Duran, Timothy J Vittorio

The SARS-CoV-2 pandemic is the most globally impacting health issue our world has faced over the last century. As of January 7, 2022, around 300 million cases have been reported worldwide, with over 5 million deaths. The SARS-CoV-2 infection causes a hyperactive host immune response leading to an excessive inflammatory reaction with the release of many cytokines — cytokine storm — commonly noticed in acute respiratory distress syndrome, sepsis and fulminant multiorgan failure. Since the beginning of the pandemic, the scientific medical community has worked on therapeutic procedures that interfere with the exaggerated immune response. Thromboembolic complications are widespread in patients who are critically ill with COVID-19. Anticoagulant therapy was initially considered a cornerstone in hospitalized patients and even in the early post-discharge period; however, later trials have aborted the clinical benefits except for suspicion of or confirmed thrombosis. Immunomodulatory therapies are still crucial in moderate to severe COVID-19. Immunomodulator therapies include various medications from steroids to hydroxychloroquine, tocilizumab and Anakinra. Anti-inflammatory agents, vitamin supplements and antimicrobial therapy had initial encouraging evidence, but there are limited data to review. Convalescent plasma, immunoglobulins, eculizumab, neutralizing IgG1 monoclonal antibodies and remdesivir have positively impacted inpatient mortality and hospital length of stay. Eventually, wide population vaccination was proven to be the best tool to overcome the SARS-CoV-2 pandemic and help humanity return to regular life. Many vaccines and various strategies have been used since December 2020. This review discusses how the SARS-CoV-2 pandemic has progressed and surged, and summarizes the safety and efficacy of the most used therapies and vaccines in the light of recent evidence.

11

Authors: Timothy C Hardman, Rob Aitchison, Richard Scaife, Jean Edwards, Gill Slater, on behalf of the Committee of the Pharmaceutical Contract Management Group

A workshop held at the 18th Annual Conference of the Pharmaceutical Contract Management Group in Krakow on 9 September 2022 asked over 200 delegates what the clinical trial landscape would look like in 2050. Issues considered included who will be running the pharmaceutical industry in 2050; how ‘health chips’, wearables and diagnostics will impact on finding the right patients to study; how will artificial intelligence be designing and controlling clinical trials; and what will the role of the Clinical Research Associate, the critical observer, documenter and conductor of a clinical trial need to look like by 2050. The consensus was that, by 2050, if you are working in clinical trials, you will be a data scientist. We can expect to see an increasing role of new technologies and a new three-phase registration model for novel therapies. The first phase will involve an aspect of quality evaluation and biological proof-of-concept probably involving more preclinical modelling and engineered human cell lines and fewer animal studies than currently used. Once registered, new products will enter a period of adaptive clinical development (delivered as a single study) intended to establish safety. This phase will most likely take around 1–2 years and explore tailored options for administration. Investigations will most likely be conducted in patients, possibly in a ‘patient-in-a-box’ setting (hospital or healthcare centre, virtual or microsite). On completion of safety licencing, drugs will begin an assessment of efficacy in partnership with those responsible for reimbursement – testing will be performed in patients, possibly where individual patient involvement in safety testing will offer some reimbursement deal for future treatment. Change is coming, though its precise form will likely depend on the creativity and vision of sponsors, regulators and payers.

11

Authors: Sofia Faria, Egídio Freitas, Tiago Torres

Alopecia areata (AA) is a chronic, tissue-specific autoimmune disorder, characterized by non-scaring hair loss, with a global prevalence of approximately 2%. Typically, it affects a young population, with initial onset frequently occurring before the age of 30 years. Even though the exact pathogenesis of AA remains unclear, the predominant hypothesis is the breakdown of immune privilege of the hair follicle, resulting in increased self-antigen and major histocompatibility complex expression in the follicular epithelium. The relapsing nature of the disease negatively impacts patients’ quality of life and makes them more susceptible to developing psychiatric comorbidities. Although many treatment modalities have been proposed, there are no currently available treatments able to induce and sustain disease remission. Traditional treatment modalities, despite being widely used, present limited results and a high risk of adverse effects. Hence, there exists an unfulfilled requirement for treatments that are both more efficient and safer. The latest understanding of the pathophysiology of AA and its connection to the JAK–STAT pathway has prompted the advancement of JAK inhibitors. These small-molecule agents function by obstructing the JAK–STAT intracellular signalling pathway. Baricitinib an orally administered, selective JAK1 and JAK2 inhibitor is a promising alternative to the available treatments, and is already approved for the treatment of AA.

12

Authors: Christoph Lübbert, Igor Dykukha, Jann-Patrick Pelz, Helen Yearley, Wolfgang Junker, Nina Gruber, Sibyll Escher, Katrin Biereth, Sima Melnik, Julia Puschmann

Background: Nirmatrelvir/ritonavir is authorized for the treatment of COVID-19 but has several contraindications and potential drug–drug interactions (pDDIs) due to ritonavir-induced irreversible inhibition of cytochrome P450 3A4. We aimed to assess the prevalence of individuals with one or more risk factors for severe COVID-19 along with contraindications and pDDIs due to ritonavir- containing COVID-19 therapy. Methods: Retrospective observational study of individuals with one or more risk factors according to Robert Koch Institute criteria for severe COVID-19 according to German statutory health insurance (SHI) claims data from the pre-pandemic years 2018–2019 based on the German Analysis Database for Evaluation and Health Services Research. Prevalence was extrapolated to the entire SHI population using age-adjusted and sex-adjusted multiplication factors. Results: Nearly 2.5 million fully insured adults, representing 61 million people in the German SHI population, were included in the analysis. In 2019, prevalence of individuals that would have been at risk of severe COVID-19 was 56.4%. Amongst them, the prevalence of contraindications for treatment with ritonavir-containing COVID-19 therapy was approximately 2% according to presence of somatic comorbidities (severe liver or kidney disease). Prevalence of intake of medicines contraindicated for their potential interactions with ritonavir-containing COVID-19 therapy was 16.5% according to Summary of Product Characteristics and 31.8% according to previously published data. The prevalence of individuals at risk of pDDIs during ritonavir- containing COVID-19 therapy without adjustment of their concomitant therapy was 56.0% and 44.3%, respectively. Prevalence data for 2018 were similar. Conclusion: Administering ritonavir-containing COVID- 19 therapy can be challenging as thorough medical record review and close monitoring are required. In some cases, ritonavir-containing treatment may not be appropriate due to contraindications, risk of pDDIs, or both. For those individuals, an alternative ritonavir-free treatment should be considered.

12

Authors: Yuko Hasebe, Yusuke Karasawa, Kazutaka Nozawa

Background: This study was aimed towards understanding the current status of dietary therapy for patients with pancreatic exocrine insufficiency (PEI) in Japan and its alignment with Japanese recommendations for high-fat intake and concomitant high-potency pancreatic enzyme replacement therapy (PERT) by surveying treating physicians and registered dietitians. Methods: The 19-item physicians’ online questionnaire collected data about the number of patients with PEI treated, methods used to assess PEI and nutritional status in patients with PEI, as well as provision of dietary guidance and details of treatment with PERT. The 10-item registered dietitians’ online questionnaire captured data about the provision of dietary guidance, including setting (inpatient or outpatient) and details of nutritional guidance provided to patients. Results: Overall, 35 physicians and 23 dietitians completed the respective questionnaires. The primary cause of PEI in patients treated by physicians during the previous month was chronic pancreatitis (80.5%). Of 30 (86%) physicians who reported implementing dietary guidance for patients with PEI, less than half (43%) followed national guidelines and most (83%) implemented a low-fat diet. The use of PERT in recently treated patients with PEI was low. Amongst 11 (48%) dietitians who reported providing dietary guidance to patients with chronic pancreatitis and PEI, 7 (64%) recommended restricting fat intake in patients with uncompensated chronic pancreatitis. Dietitians overall were more likely to provide guidance about alcohol avoidance (91%) than smoking cessation (48%) to appropriate patients. Conclusion: This survey suggests that additional educational efforts are required to align the management practices of physicians and registered dietitians with evidence-based clinical practice guidelines for Japanese patients with chronic pancreatitis and PEI.

13

Authors: Diogo Fonseca, Miguel Nogueira, Tiago Torres

Psoriatic arthritis is a chronic systemic inflammatory disease that presents with a variable clinical course and is typically associated with joint inflammation, together with cutaneous psoriasis. In recent decades, knowledge of the pathogenesis of psoriatic arthritis has advanced considerably and has allowed for development of new highly effective therapies, transforming the treatment landscape. Upadacitinib is a Janus kinase inhibitor (JAK) that is orally reversible with high selectivity for JAK1 and its signal transduction molecules. The results obtained in the phase III clinical trials (SELECT-PsA 1 and SELEC-PsA 2) demonstrated that upadacitinib was highly effective over placebo and non-inferior to adalimumab in several important domains of the disease. Improvements were observed in dactylitis, enthesitis and spondylitis as well as in physical function, pain, fatigue and overall quality of life. The safety profile of these results resembled that of adalimumab, apart from a slightly higher rate of herpes zoster infection, an increase of creatine kinase and an incidence of lymphopenia. However, none of these events was considered a serious adverse advent. Additionally, another analysis demonstrated that combining upadacitinib with methotrexate was associated with a similar efficacy to upadacitinib in monotherapy, both for patients that are naive to biologics treatment and for those previously treated with biologics. Therefore, upadacitinib is a new option for the treatment of psoriatic arthritis, presenting a series of beneficial characteristics. At this stage, it is important to collect long-term data to confirm the efficacy and safety profiles shown in clinical trials.

13

Authors: Enrique Casado, Ester Costa, Pedro Mezquita-Raya, Rubén Andújar-Espinosa, José Luis Neyro

As well as being essential for musculoskeletal health, vitamin D is involved in numerous other physiological processes. Poor vitamin D status is linked to a wide range of diseases, including cardiovascular disease, autoimmune conditions, pulmonary disorders and upper respiratory tract infections. While optimal target concentrations of serum 25-hydroxyvitamin D (25(OH)D) for health maintenance or therapeutic purposes are still the subject of debate, there is reasonable agreement that serum 25(OH)D levels <50 nmol/L (20 ng/mL) constitute vitamin D deficiency and that severe deficiency states (serum 25(OH)D levels <25-30 nmol/L ≈ 10-12 ng/ mL) should be avoided. Main strategies to maintain or improve vitamin D status are food supplementation and therapeutic use of medicinal forms of vitamin D. In this review, we examine evidence that implicates vitamin D deficiency in diverse conditions in the clinical settings of endocrinology, rheumatology, pneumology and reproductive health. Cholecalciferol (vitamin D3) is the most frequently used vitamin D supplement worldwide, though calcifediol (25-hydroxyvitamin D3) has recently become more widely available. Calcifediol is one step closer than cholecalciferol in the metabolic pathway to biologically active vitamin D. Pharmacokinetic differences between these vitamin D metabolites confer putative advantages for calcifediol in certain clinical situations. The clinical use of calcifediol is explored more closely through case studies, which illustrate its adjunctive role in the treatment of several vitamin D deficiency-related skeletal and extraskeletal diseases.

14

Authors: Barbara Tagliaferri, Ludovica Mollica, Raffella Palumbo, Claudia Leli, Alberto Malovini, Matteo Terzaghi, Erica Quaquarini, Cristina Teragni, Stefano Maccarone, Andrea Premoli, Federico Sottotetti

Background: Advanced breast cancer (ABC) is characterized by multidimensional clinical complexity that is usually not considered in randomized clinical trials. In the present real-life study, we investigated the link between clinical complexity and quality of life of patients with HR+/HER2– ABC treated with CDK4/6 inhibitors. Methods: We evaluated multimorbidity burden assessed with the Cumulative Illness Rating Scale (CIRS), polypharmacy and patient-reported outcomes (PROs). PROs were assessed at baseline (T0), after 3 months of therapy (T1), and at disease progression (T2) using EORTC QLC-C30 and QLQ-BR23 questionnaires. Baseline PROs and changes between T0 and T1 were evaluated amongst patients with different multimorbidity burden (CIRS <5 and ≥5) and polypharmacy (<2 or ≥2 drugs). Results: From January 2018 to January 2022, we enrolled 54 patients (median age 66 years, IQR 59–74). The median CIRS score was 5 (IQR 2–7), whilst the median number of drugs taken by patients was 2 (IQR 0–4). No changes in QLQ-C30 final scoring between T0 and T1 were observed in the overall cohort (p=0.8944). At T2, QLQ-C30 global score deteriorated with respect to baseline (p=0.0089). At baseline, patients with CIRS ≥5 had worse constipation than patients without comorbidities (p<0.05) and a lower trend in the median QLQ-C30 global score. Patients on ≥2 drugs had lower QLQ-C30 final scores and worse insomnia and constipation (p<0.05). No change in QLQ-C30 final score from T0 to T1 was observed (p>0.05). Conclusion: Multimorbidity and polypharmacy increase the clinical complexity of patients with ABC and may affect baseline PROs. The safety profile of CDK4/6 inhibitors seems to be maintained in this population. Further studies are needed to assess clinical complexity in patients with ABC. This article is part of the Tackling clinical complexity in breast cancer Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/

15

Authors: Federico Swedzky, Alejandro Barbagelata, Sergio Perrone, Edgardo Kaplinsky, Anique Ducharme

Circulatory support with extracorporeal membrane oxygenation (ECMO) is being increasingly used in several critical situations but evidence of its impact on outcomes is inconsistent. Understanding of the specific indications and appropriate timing of implantation of this technology might lead to improved results. Indeed, the line between success and futility may be sometimes very thin when facing a patient in critical condition. New techniques with lighter, simpler and effective devices are being developed. Hence, ECMO has become an accessible technology that is being increasingly used outside of the operating room by heart failure specialists, critical care cardiologists and intensivists. Proper timing of utilization and choice of device may lead to better outcomes. We herein aim to improve this knowledge gap by conducting a literature review to provide simple information, evidence-based indications and a practical approach for cardiologists who may encounter acutely ill adult patients that may be ECMO candidates. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment

15

Authors: Giampiero Porzio, Andreia Capela, Raffaele Giusti, Francesca Lo Bianco, Mirella Moro, Giulio Ravoni, Katarzyna Zułtak-Baczkowska

Underlying cancer pain has heterogenous aetiologies and mechanisms. It requires detailed and comprehensive pain assessment, combined with personalized treatment. A multidisciplinary team is essential to providing the best management of cancer pain at every disease stage, improving the quality of life and outcomes in patients with cancer. This narrative literature review emphasizes the value of providing all patients with multidisciplinary pain management in their preferred care setting. Real-life experiences are also reported to witness the efforts of physicians to properly manage cancer pain. This article is part of the Management of breakthrough cancer pain Special Issue: https://www.drugsincontext.com/special_issues/management-of-breakthrough-cancer-pain

15

Authors: Mikhail Kostinov, Oksana Svitich, Alexander Chuchalin, Natalya Abramova, Valery Osiptsov, Ekaterina Khromova, Dmitry Pakhomov, Vitaly Tatevosov, Anna Vlasenko, Vilia Gainitdinova, Kirill Mashilov, Nadezhda Kryukova, Irina Baranova, Anton Kostinov

Background: Although extensive research has been conducted on the role of local immunity in patients with SARS-CoV-2, little is known about the production and concentrations of secretory IgA (SIgA) in different mucosal compartments. This article aims to assess the secretion of SIgA in the nasal and pharyngeal compartments and saliva of patients with COVID-19 and to investigate the possibility and efficiency of correction of their secretion using combined intranasal and oral administration of a pharmaceutical containing antigens of opportunistic microorganisms. Methods: This study included 78 inpatients, aged between 18 and 60 years, who had confirmed COVID-19 with moderate lung involvement. The control group (n=45) received basic therapy, and the treatment group (n=33) was additionally administered the bacteria-based pharmaceutical Immunovac VP4 from day 1 to day 10 of hospitalization. SIgA levels were measured by ELISA at baseline and on days 14 and 30. Results: No systemic or local reactions associated with Immunovac VP4 were reported. We observed a statistically significant reduction in the duration of fever and hospitalization in patients who received Immunovac VP4 compared with those from the control group (p=0.03 and p=0.05, respectively). Changes over time in SIgA levels in nasal swabs were found to be significantly different in the two treatment groups (F=7.9, p[78.0]<0.001). On day 14 of observation, patients in the control group showed a statistically significant reduction in SIgA levels from baseline (p=0.02), whereas patients in the Immunovac VP4 group had stable SIgA levels (p=0.07). On day 30 after the start of treatment, there was a statistically significant increase in SIgA levels in the Immunovac VP4 group compared with baseline (from 77.7 (40.5–98.7) μg/L to 113.4 (39.8–156.7) μg/L; p=0.05) and the levels measured on day 14 (from 60.2 (23.3–102.9) μg/L to 113.4 (39.8–156.7) μg/L; p=0.03). The control group showed a statistically significant decrease in levels of nasal SIgA (to 37.3) on day 30 (p=0.007 for comparison with baseline values and p=0.04 for comparison with levels measured on day 14). Changes over time in SIgA levels measured in pharyngeal swabs were also different between the two treatment groups, and this difference reached statistical significance (F=6.5, p[73.0]=0.003). In the control group, this parameter did not change throughout the study (p=0.17 for a comparison between the levels measured on day 14 and the baseline values, and p=0.12 for a comparison between the levels measured on day 30 and the baseline values). In the Immunovac VP4 group, there was a statistically significant increase from baseline in SIgA levels on study day 30: from 1.5 (0.2–16.5) μg/L to 29.8 (3.6–106.8) μg/L (p=0.02). Changes over time in salivary SIgA did not show a significant difference between study groups (F=0.3, p[66.3]=0.75). Conclusion: As part of combination therapy, the bacteria-based immunostimulant agent Immunovac VP4 increases SIgA levels in the nasal and pharyngeal compartments and induces clinical improvement. Induced mucosal immunity is central to the prevention of respiratory infections, particularly in patients with post-COVID-19 syndrome.

15

Authors: Alejandro Bimbo Diaz, Jeremy Chow, Fan Kee Hoo, Kok Wei Koh, Gary Chin Keong Lee, Wee Siong Teo, Narayanaswamy Venketasubramanian, Chun-Chieh Wang, Radhika Mehta

Edoxaban, a once-daily, direct-acting oral anticoagulant, is approved to prevent stroke or systemic embolism in non-valvular atrial fibrillation (NVAF) and treat venous thromboembolism. The clinical benefit of edoxaban for stroke prevention in Asian patients with NVAF has been demonstrated in clinical and real-world studies. We share early clinical experiences with once-daily edoxaban and discuss its evidence-based use in patients with NVAF in Southeast Asia through several cases of patients at high risk, including frail patients, elderly patients with multiple comorbidities and patients with increased bleeding risk. These cases demonstrate the effectiveness and safety of once-daily edoxaban in patients with NVAF in Southeast Asia.

16

Authors: Katayoun Derakhchan, Zhen Lou, Hong Wang, Robert Baughman

Background: Prucalopride is a selective serotonin type 4 (5-HT4) receptor agonist indicated for treatment of chronic idiopathic constipation (CIC) in adults (2 mg orally, daily). 5-HT4 receptors are present in the central nervous system; therefore, non-clinical and clinical assessments were performed to evaluate the tissue distribution and abuse potential of prucalopride. Methods: In vitro receptor-ligand binding studies were performed to assess the affinity of prucalopride (≤1 mM) for peptide receptors, ion channels, monoamine neurotransmitters and 5-HT receptors. The tissue distribution of 14C-prucalopride (5 mg base-equivalent/kg) was investigated in rats. Behavioural assessments in mice, rats and dogs after treatment with single or repeated (up to 24 months) subcutaneous or oral doses of prucalopride (0.02–640 mg/kg across species) were performed. Treatment-emergent adverse events possibly indicative of abuse potential during prucalopride CIC clinical trials were evaluated. Results: Prucalopride showed no appreciable affinity for the receptors and ion channels investigated; its affinity (at ≤100 μM) for other 5-HT receptors was 150–10,000 times lower than that for the 5-HT4 receptor. In rats, <0.1% of the administered dose was found in the brain and concentrations were below the limit of detection within 24 hours. At supratherapeutic doses (≥20 mg/kg), mice and rats exhibited palpebral ptosis, and dogs exhibited salivation, eyelid tremors, decubitis, pedalling movements and sedation. All clinical treatment-emergent adverse events, possibly indicative of abuse potential, except dizziness, occurred in <1% of patients treated with prucalopride or placebo. Conclusion: This series of non-clinical and clinical studies suggest low abuse potential for prucalopride.

17

Authors: Teresa Guilera, Juan Pablo Chart Pascual, Maria del Carmen Blasco, Pilar Calvo Estopiñán, Rubén Asensio Piernas González, Isabel Ramírez Martínez, Cristóbal Rodríguez Moyano, Rita Prieto Pérez, Irene Gabarda-Inat, Juan L Prados-Ojeda, Marina Diaz-Marsà, Manuel Martín-Carrasco

Schizophrenia is a common debilitating disorder characterized by significant impairments in how reality is perceived, combined with behavioural changes. In this review, we describe the lurasidone development programme for adult and paediatric patients. Both the pharmacokinetic and pharmacodynamic characteristics of lurasidone are revisited. In addition, pivotal clinical studies conducted on both adults and children are summarized. Several clinical cases, which demonstrate the role of lurasidone in real-world practice, are also presented. Current clinical guidelines recommend lurasidone as the first-line treatment in the acute and long-term management of schizophrenia in both adult and paediatric populations.

19

Authors: Rosalba Torrisi, Flavia Jacobs, Chiara Miggiano, Rita De Sanctis, Armando Santoro

De novo metastatic breast cancer (dnMBC) accounts for ~6–10% of all breast cancers and for ~30% of MBC with increasing incidence over time. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) tumours are the most frequent subtype with a similar incidence to that observed amongst recurrent MBC (rMBC). Higher frequency of PI3KCA and ARID2 mutations and a lower frequency of ESR1 mutations and of genes involved in DNA damage, as compared with rMBC, have been reported in HR+/HER2– dnMBC; however, these are not correlating with prognosis, whilst tumour mutational burden is inversely correlated with outcome. Bone represents the most frequent metastatic site, being the single site in up to 60% of patients with dnMBC. HR+/HER2– dnMBC has been generally reported to have better outcomes than rMBC, with a median overall survival ranging from 26 months to nearly 5 years in patients with favourable features such as age <40 years and bone-only disease, but not when compared with patients with late recurring disease (≥2–5 years). Analyses of the de novo cohorts within randomized clinical trials and large real-world series report a better outcome after treatment with CDK4/6 inhibitors and endocrine agents as compared to rMBC. Despite the limitations of retrospective studies and controversial results of the randomized trials, locoregional treatment of the primary tumour after response to systemic therapy appears to confer a survival benefit, particularly in patients with favourable prognostic factors. Altogether genomic, biological and clinical findings highlight HR+/HER2– dnMBC as a peculiar entity as compared with rMBC and deserve a dedicated treatment algorithm. This article is part of the Tackling clinical complexity in breast cancer Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/

20

Authors: Alexander KC Leung, Benjamin Barankin, Joseph M Lam, Kin Fon Leong

Background: Guttate psoriasis is common and affects 0.5–2% of individuals in the paediatric age group. This review aims to familiarize physicians with the clinical manifestations, evaluation, diagnosis and proper management of guttate psoriasis. Methods: A search was conducted in July 2023 in PubMed Clinical Queries using the key term “guttate psoriasis”. The search strategy included all observational studies, clinical trials and reviews published within the past 10 years. The information retrieved from the search was used in the compilation of the present article. Results: Guttate psoriasis typically presents with an abrupt onset of numerous, small, scattered, tear-drop-shaped, scaly, erythematous, pruritic papules and plaques. Sites of predilection include the trunk and proximal extremities. There may be a history of preceding streptococcal infection. Koebner phenomenon is characteristic. Guttate psoriasis may spontaneously remit within 3–4 months with no residual scarring, may intermittently recur and, in 40–50% of cases, may persist and progress to chronic plaque psoriasis. Given the possibility for spontaneous remission within several months, active treatment may not be necessary except for cosmetic purposes or because of pruritus. On the other hand, given the high rates of persistence of guttate psoriasis and progression to chronic plaque psoriasis, some authors suggest active treatment of this condition. Conclusion: Various treatment options are available for guttate psoriasis. Triggering and exacerbating factors should be avoided if possible. Topical corticosteroids alone or in combination with other topical agents (e.g. tazarotene and vitamin D analogues) are the most rapid and efficient treatment for guttate psoriasis and are therefore the first-line treatment for mild cases. Other topical therapies include vitamin D analogues, calcineurin inhibitors, anthralin, coal tar and tazarotene. Ultraviolet phototherapy is the first-line therapy for moderate- to-severe guttate psoriasis, as it is more practical than topical therapy when treating widespread or numerous small lesions. Systemic immunosuppressive and immunomodulatory therapies (e.g. methotrexate, cyclosporine, retinoids, fumaric acid esters and biologics) may be considered for patients with moderate-to-severe guttate psoriasis who fail to respond to phototherapy and topical therapies.

23

Authors: Kayla R Stover, Brandon K Hawkins, J Myles Keck, Katie E Barber, David A Cretella

Invasive fungal infections are a strong contributor to healthcare costs, morbidity and mortality, especially amongst hospitalized patients. Historically, Candida was responsible for approximately 15% of all nosocomial bloodstream infections. In the past 10 years, the epidemiology of Candida species has altered, with increasing prevalence of resistant species. With rising fungal resistance, especially in Candida spp., the demand for novel antifungal therapies has exponentially increased over the last decade. Newer antifungal agents have become an attractive option for patients needing long-term therapy for infections or those requiring antifungal prophylaxis. Despite advances in coverage of non-Candida pathogens with newer agents, clinical scenarios involving multidrug-resistant fungal pathogens continue to arise in practice. Combination antifungal therapy can lead to a host of side-effects, some of which can be drug limiting. Additional antifungal therapies with enhanced fungal spectrum of activity and decreased rates of adverse effects are warranted. Fosmanogepix, ibrexafungerp, olorofim and rezafungin may help fill some of these gaps in the antifungal armamentarium. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections