Drugs in Context

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Authors: José Antonio Magaña Serrano, José Angel Cigarroa López, Adolfo Chávez Mendoza, Juan Betuel Ivey-Miranda, Genaro Hiram Mendoza Zavala, Luis Olmos Domínguez, Sergio Armando Chávez Leal, José Ernesto Pombo Bartelt, Eduardo Heberto Herrera-Garza, Gerardo Mercado Leal, Rodolfo Parra Michel, Luisa Fernanda Aguilera Mora, Patricia Lenny Nuriulu Escobar

The authors wish to make the following corrections to their article: Magaña Serrano JA, Cigarroa López JA, Chávez Mendoza A, Ivey-Miranda JB, Mendoza Zavala GH, Olmos Domínguez L, Chávez Leal SA, Pombo Bartelt JE, Herrera-Garza EH, Mercado Leal G, Parra Michel R, Aguilera Mora LF, Nuriulu Escobar PL. Corrigendum: Vulnerable period in heart failure: a window of opportunity for the optimization of treatment – a statement by Mexican experts. Drugs Context. 2024;13:2023-8-1. https://doi.org/10.7573/dic.2023-8-1

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Authors: Kayla R Stover, Taylor E Jordan, Jamie L Wagner, Katie E Barber

Invasive fungal infections pose significant morbidity and mortality risks, particularly those caused by moulds. Available antifungal classes are limited by toxicities and are increasingly susceptible to resistance, particularly amongst challenging fungal pathogens. The purpose of this case series and literature review was to characterize the use of a high-dose lipid formulation of amphotericin B. A case series is presented including patients who received high-dose lipid formulation amphotericin B (≥7.5 mg/kg/day) between June 2012 and August 2021. Additionally, a systematic literature review was conducted by searching the PubMed database for English-language studies involving individuals who received high-dose amphotericin B therapy (≥7.5 mg/kg) using lipid formulations. Nine patients were included in the case series, receiving an average of 8.9 ± 1.3 mg/kg liposomal amphotericin B over a mean of 11.0 ± 10.8 days predominantly for mould infections including Mucorales, aspergillosis and Fusarium. The patients were primarily cared for in intensive care units, with varying treatment histories and outcomes. A total of 11 studies (n=260 patients) met inclusion criteria for the literature review. Responses to high-dose liposomal amphotericin B ranged from 8% to 100%, often showing favourable outcomes. High doses of liposomal amphotericin B were well tolerated both in the case series and in published literature, with serum creatinine changes being the most commonly reported adverse event. However, multi-patient studies continue to report less than favourable (range 8–62%) response rates. High-dose liposomal amphotericin B, either alone or in combination with other antifungal agents, might be a viable strategy for managing invasive fungal infections when few treatment choices exist. 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

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Authors: Iñaki Izquierdo, Laia Casas, Susana Cabrera, Alberto Fernandez

The off-label use of second-generation antihistamines, used outside of the formal indications authorized by regulatory authorities, in different age groups, doses or in special populations, is very common for many allergic, autoimmune and dermatological diseases. The off-label use of rupatadine (a second-generation antihistamine with PAF antagonist activity) in these conditions is reviewed here, including in combination with immunotherapy in the treatment of food allergy or allergic rhinitis, at high doses in chronic urticaria, and with prescriptions of less common but challenging conditions such as skin pruritus or mast cell activation disorders like mastocytosis. Rupatadine use is reviewed herein to confirm if its off-label management is supported by well-designed clinical trials or by published real-world cases. This review will contribute to increasing compliance and achieving better results in clinical practice. Off-label use of rupatadine should be left to the discretion of the prescribing healthcare professional after careful clinical evaluation.

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Authors: Tiago Torres, Paulo Varela, Pedro Mendes Bastos, Sofia Magina, Martinha Henrique, Paulo Ferreira

Background: Real-world evidence plays a pivotal role in validating the efficacy of biologic drugs beyond the controlled environment of randomized trials. This study aimed to evaluate the effectiveness of tildrakizumab in treating moderate-to-severe psoriasis within a real-world setting over a 52-week period in Portugal. Methods: This multicentric, prospective, observational study included adult patients with moderate-to-severe psoriasis. All participants received tildrakizumab 100 mg at weeks 0 and 4, followed by a maintenance dose every 12 weeks, and were monitored for 52 weeks. Primary endpoints were determined based on Psoriasis Area and Severity Index (PASI) assessments at baseline, 16 (±2) weeks, 28 (±2) weeks and 52 (±2) weeks. Results: A total of 54 patients were enrolled in the study (56% men, mean age of 50.3 ± 14.4 years). Half of the sample (n=27) had no prior experience with biologic treatments. About 74% of patients (n=40) presented at least one comorbidity during the study, with psoriatic arthritis being the most prevalent (29.6%). By week 52, there was a significant decrease in the mean PASI from 17.8±10.3 at baseline to 1.3±1.9 (p<0.001), indicating an overall improvement of 93%. By week 52, more than 85% of patients attained PASI ≤5, more than 80% reached PASI ≤3, and nearly 60% achieved PASI ≤1. Infections were observed in 9.3% of patients, and one patient required hospitalization (1.9%). The cumulative proportion of patients continuing treatment at 52 weeks was 88.9%. Conclusions: This study demonstrates that tildrakizumab is an effective and safe agent for the treatment of moderateto- severe psoriasis in a diverse, real-world setting.

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Authors: Tirsit Ketsela Zeleke, Bekalu Dessie Alamirew, Zegaye Agmassie Bazezew, Muluken Adela Alemu, Abdisa Gemedi Jara, Rahel Belete Abeb

Background: Low levels of living standards amongst street dwellers worldwide limit their access to conventional healthcare services, resulting in self-medication use for the treatment of an illness. Nevertheless, self-medication use has risks, including adverse drug reactions, increased polypharmacy, drug resistance, drug dependence, drug interactions and incorrect diagnosis. Ethiopia has a large street-dwelling community; however, there are no studies conducted in Ethiopia assessing self-medication use amongst street dwellers. This study provides insight into self-medication use and predictors amongst street dwellers in Ethiopia. Methods: A community-based, multicentre cross-sectional study was conducted amongst street dwellers from 1 September 2022 to 1 February 2023 at community drug-retail outlets in the three major cities in the Amhara region of Ethiopia. The data were obtained using an interviewer-administered questionnaire. Frequencies and percentages of descriptive statistics were calculated. Bivariable and multivariable logistic regression analyses were employed to indicate predictors of self-medication use. To determine statistical significance, a 95% confidence interval with a p value below 0.05 was utilized. Results: The prevalence of self-medication use was 67.4%. Time and financial savings were reported as the reasons for most self-medication use. The most commonly reported illnesses for which people sought self-medication were gastrointestinal diseases. Low monthly income (adjusted OR 3.72, 95% CI 2.34–5.91) and residing near sewage areas (adjusted OR 3.37, 95% CI 2.03–5.58) were significantly associated with self-medication use. Conclusion: Street dwellers had a high rate of self-medication use. Residing near sewage areas and having a low level of income were factors in self-medication use. Gastrointestinal diseases, respiratory ailments and dermatological conditions were the most frequently reported complaints, whereas antimicrobials and anthelmintics were the most commonly used medications. We recommend that healthcare services enhance outreach programmes to the most vulnerable people, such as street dwellers, especially those with lower monthly incomes and who live near sewage areas, to reduce self-medication rates.

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Authors: Michael Langworthy, Peter Lascarides, Wilson Ngai, Kevin Steele, Yili Huang

Background: Clinical trials on the use of viscosupplementation with hyaluronic acid (HA) in patients with knee osteoarthritis (KOA) are inconsistent, making it challenging to determine its value in clinical practice. One issue is the availability of various HA products on the market; differences in their chemical features can impact patient outcomes. Herein, we assess the efficacy and safety of three once-weekly intra-articular (IA) injections of Hylan G-F 20, a high-molecular-weight and highly crosslinked HA product, in patients with KOA. We hypothesized that Hylan G-F 20 would provide significant pain relief with no increased safety risk compared with IA saline (placebo). Methods: This was a 26-week, patient-blinded and evaluator-blinded, single-centre, randomized placebocontrolled trial. Men or women ≥18 years of age with Larsen grade II or III KOA were included. Patients received IA injections of either Hylan G-F 20 or placebo once a week for 3 weeks. The primary endpoints were the week 12 and 26 visits. Primary efficacy outcomes included visual analogue scale (VAS) pain scores, patient activity level and an overall assessment of clinical condition. Secondary outcomes included adverse events (AEs) that emerged during treatment. The primary analysis included the intention-to-treat population. An alpha level of 0.05 was used in the statistical analysis. Results: Thirty patients were included in the intentionto- treat population (15 per group). All efficacy outcomes were statistically significant in favour of Hylan G-F 20, except night pain and inactivity stiffness, for both patientassessed (all p=0.0001 at week 12) and evaluator-assessed (all p=0.0001 at week 12 and p=0.0004–0.0180 at week 26) measurements. There was also a greater proportion of symptom-free patients and those with a >50% improvement in their VAS scores, except night pain, in the Hylan G-F 20 group (p=0.001–0.003 in patient-assessed scores and p<0.0001 to 0.002 in evaluator-assessed scores at week 12). Two patients, one in each group, experienced an AE; no sequelae occurred, and no special treatment was required for either AE. No patients withdrew from the study prematurely due to an AE. Conclusion: In patients with chronic idiopathic KOA, Hylan G-F 20 provides significant improvements in pain relief compared with placebo with no added safety concerns.

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Authors: Bernardo Rossini, Nicola Cecchi, Felice Clemente, Maria Rosaria De Paolis, Stefan Hohaus, Vanessa Innao, Mariano Lucignano, Roberto Massaiu, Giovanna Palumbo, Gian Matteo Rigolin, Francesca Gaia Rossi, Luisa Verga, Attilio Guarini

Castleman disease (CD) is a group of lymphoproliferative disorders that share common histopathological features yet have widely different aetiologies, clinical features and grades of severity as well as treatments and outcomes. Siltuximab is currently the only therapy approved by the FDA and EMA for idiopathic multicentric CD and is recommended as first-line therapy in treatment guidelines. Despite the extensive characterization of siltuximab treatment in clinical trials, available evidence from real-world practice is still scant. This collection of clinical experiences focuses on patients treated with siltuximab therapy, particularly regarding the idiopathic multicentric CD diagnostic work-up, and on treatment administration in patients with complex disease entering differential diagnosis with CD or concomitant diseases. Thus, these data help further characterize and improve the use of siltuximab in real practice in terms of effectiveness and safety of long-term administration as well as consequences of treatment interruption.

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Authors: José Antonio Magaña Serrano, José Angel Cigarroa López, Adolfo Chávez Mendoza, Juan Betuel Ivey-Miranda, Genaro Hiram Mendoza Zavala, Luis Olmos Domínguez, Sergio Armando Chávez Leal, José Ernesto Pombo Bartelt, Eduardo Heberto Herrera-Garza, Gerardo Mercado Leal, Rodolfo Parra Michel, Luisa Fernanda Aguilera Mora, Patricia Lenny Nuriulu Escobar

Acute heart failure (HF) is associated with poor prognosis. After the acute event, there is a vulnerable period during which the patient has a marked risk of readmission or death. Therefore, early optimization of treatment is mandatory during the vulnerable period. The objective of this article is to provide recommendations to address the management of patients with HF during the vulnerable period from a practical point of view. A group of Mexican experts met to prepare a consensus document. The vulnerable period, with a duration of up to 6 months after the acute event – either hospitalization, visit to the emergency department or the outpatient clinic/day hospital – represents a real window of opportunity to improve outcomes for these patients. To best individualize the recommendations, the management strategies were divided into three periods (early, intermediate and late vulnerable period), including not only therapeutic options but also evaluation and education. Importantly, the recommendations are addressed to the entire cardiology team, including physicians and nurses, but also other specialists implicated in the management of these patients. In conclusion, this document represents an opportunity to improve the management of this population at high risk, with the aim of reducing the burden of HF.

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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

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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/

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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

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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.

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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

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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/

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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

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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.

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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.

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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/

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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.

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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

1

Authors: Jennifer N Clements

The authors wish to make the following corrections to their article: Clements JN. Diabetes: how to manage chronic kidney disease. Drugs Context. 2022;11:2021-9-10. https://doi.org/10.7573/dic.2021-9-10

4

Authors: Kamile Johnson, Mark T Sawkin

The logistical management of an injectable therapy for the treatment of HIV can be expensive, time consuming, frustrating and riddled with barriers. In this Commentary, we describe our experiences to date with acquiring, storing, handling, administering and billing for long-acting cabotegravir and rilpivirine through four scenarios, each of which have presented their own unique obstacles and learning curves. At the time of writing, we have successfully transitioned four patients from the CUSTOMIZE trial to long-acting cabotegravir and rilpivirine. In doing so, we encountered a variety of barriers to acquiring, handling and administering the medication for both insured and uninsured patients; it is expensive, on a limited number of insurance formularies, and often requires a prior authorization from the provider. Cold-chain handling of the injectable therapy, along with individual patient characteristics, present barriers to management and administration of this therapy. Whilst a seemingly very attractive option for the treatment of HIV-1 infection in adults, long-acting cabotegravir and rilpivirine present a variety of challenges to pharmacists, providers and clinic staff on how to obtain it for and administer it to the patient. We plan to continue documenting our experiences, progress and successes, or lack thereof, in order to fine-tune our process and share with others.

5

Authors: Milena Murray, Fatima Khaleq, E Paul O’Donnell

Proper transitions of care for people with HIV (PWH) are necessary to ensure continuity of care, medication adherence and maintenance of successful clinical outcomes. Three transitions of care may lead to suboptimal outcomes if PWH are not correctly engaged: adolescent to adult, prison to society and the postpartum period. The management of these care transitions is a vital part of engagement in treatment. Evidence highlighting the gaps in care transitions provides a potential framework to optimize outcomes for PWH.

6

Authors: Maurício de Almeida Ferreira, José Alexandre Mendonça

Background: Testosterone replacement therapy (TRT) is one of the main lines of treatment for men with hypogonadism. This study sought to evaluate the influence of TRT in men with late-onset hypogonadism (LOH), regarding fatigue, coronary artery disease (CAD), carotid intima-media thickness (CIMT) and cardiovascular risk. Methods: This study compared men with LOH already on TRT for >1 year to newly diagnosed men with LOH who recently started TRT (controls). We included men aged >18 years with clinical manifestations of testosterone deficiency and testosterone levels of <300 ng/dL documented in two separate occasions. Results: A total of 33 patients were included in the study group and 30 in the control group. Mean age was 49.1 years (±11.5) in those already under TRT for >1 year and 45 (±12.2) years in the control group (p=0.18). CAD was present in 14 (46.7%) patients in the control group and in 3 (9.1%) in the study group (p<0.001). TRT >1 year was not associated with lower rates of CAD in multivariable analysis. Fatigue Severity Score was significantly higher in the control group (39.2±15.0), compared to TRT >1 year (23.5±8.1; p<0.001). In a multivariable analysis adjusted for age and hypertension, TRT >1 year was associated with a 14.8-point decrease in Fatigue Severity Score (p<0.001). Overall, there were no differences between the study group and the control group regarding cardiovascular risk (p=0.31). Conclusion: TRT for >1 year was associated with significantly lower fatigue scores. No differences were observed regarding CIMT, CAD and cardiovascular risk according to the WHO-ISH scale.

7

Authors: Javier Martin de Carpi

Paediatric ulcerative colitis (UC) can cause malnutrition and growth retardation but its treatment can be limited by the potential adverse events of corticosteroids and anti-TNF agents in children. However, adsorptive granulocyte monocyte/macrophage apheresis (GMA) using Adacolumn® reduces intestinal inflammation through multiple immunomodulatory effects. This case series shows the safety and efficacy of GMA in paediatric UC, illustrating several GMA uses: in chronically active UC, for corticosteroid reduction in steroid-dependent UC, in UC with secondary loss of response to anti-TNF therapy, as bridge therapy in UC with failure of anti-TNF therapy, and to substitute toxic drug treatments.

7

Authors: Laura Cristina Vargas López, David Chavez Gallegos

Background: Pharmacy practice (PP) research is a new discipline that studies the scope of interventions and health services performed by pharmacists. Information on PP in Latin America is available; however, to date, it has not been methodically analysed. It is critical to understand the current level of evolution of pharmaceutical activities to support evidence-based decision-making. Methods: We performed a review of PP literature published in five databases, of which two were international and three were focused on Latin America. The data obtained were qualitative, such that the strategies used for data search and collection were structured by PRISMA guidelines, and data synthesis and analysis were conducted through a narrative review. Results: Of the 1863 articles found in the initial search, 108 were included in the final analysis. The majority of these were conducted in Brazil (n=73, 74%) and Colombia (n=14, 13%). The interventions and services most frequently reported were dispensing (n=24, 22%), clinical pharmacy services (n=21, 19%) and pharmaceutical care (n=21, 19%). Most studies focused on only one key strategic area (n=94, 87%), specifically on health services provision. Conclusion: PP in Latin America follows worldwide trends to some extent with regard to the inclusion of clinical pharmacy and pharmaceutical care. However, the region also demonstrates particularities, including the heterogenous level of development amongst its countries. It is vital for Latin American pharmacists to publish their activities, interventions and services in order to generate a solid evidence base to evaluate practice and support informed decision-making.

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Authors: Susana Puig, Carlos Serra-Guillén, Gemma Pérez-Pastor, Álvaro Martínez-Domenech, Ricardo Fernández-de-Misa Cabrera

Sonidegib is a Hedgehog signalling pathway inhibitor approved for use in patients with advanced basal cell carcinoma (BCC) not eligible for surgery or radiotherapy. This report describes clinical experience with sonidegib in two patients with locally advanced BCC (one with a tumour adjacent to the right eye and the other with a tumour associated with the left ear) and in one patient with Gorlin syndrome. Two of the patients had recurrent and intractable tumours. Treatment with sonidegib 200 mg/day led to remission in both patients with locally advanced BCC within 7 months and to a reduction in the size and number of lesions after 4 months in the patient with Gorlin syndrome. Adverse effects reported in these patients were cramps, alopecia, ageusia and weight loss, all of which were mild and consistent with the known toxicity profile for sonidegib. Sonidegib has an important role to play in the effective treatment of challenging cases of advanced BCC. In parallel, a need remains to improve management protocols for patients with advanced BCC, particularly through earlier intervention and a multidisciplinary team approach.

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Authors: Cristóbal Morales, Juan Francisco Merino-Torres, Paloma Moreno-Moreno, María Lainez, Iñigo Tejado, Alfredo Yoldi, Sonsoles Gutiérrez Medina, Alfonso Soto, Manuel A Botana, Virginia Bellido, Irene Caballero

Background: This study aims to evaluate dapagliflozin in patients with type 2 diabetes (T2D) in clinical practice in Spain. Methods: This is a retrospective study including adults with T2D under stable antidiabetic therapy, with either dapagliflozin or sitagliptin ≥6 months, before inclusion. Data about the effectiveness and safety of dapagliflozin are presented. Results: A total of 594 patients (61.8±9.9 years, 21.7% cardiovascular disease) were included. After 6 months, HbA1c, weight, blood pressure, urine albumin-to-creatinine ratio and uric acid significantly decreased (1.63%, 2.88 kg, 4.82/2.70 mmHg, −17.38 mg/g and −0.30 mg/dL, respectively), whereas glomerular filtration rate and haematocrit significantly increased (3.72 mL/min/1.73 m2 and 1.8%, respectively). No cases of hypoglycaemia, diabetic ketoacidosis, Fournier gangrene, fractures or amputations were reported. Conclusion: Thus, dapagliflozin provides a comprehensive cardiometabolic protection in patients with T2D.

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Authors: Daniel Lee

Background: Dyslipidaemia is a common metabolic condition occurring in people with HIV (PWH), whether treated or untreated with antiretroviral therapy (ART). As people live longer with HIV, ongoing lipid abnormalities may contribute to increased cardiovascular disease risk. This article aims to provide a narrative updated review on the clinical evaluation and management of dyslipidaemia in PWH. Methods: A PubMed search was performed with Clinical Queries using the key term “HIV dyslipidemia”. The search strategy included clinical trials, randomized controlled trials, observational studies and reviews. The search was restricted to the English literature and the population of PWH. Results: HIV infection causes dysregulation of metabolic processes, including lipid metabolism, thus leading to dyslipidaemia. The main lipid changes seen in untreated HIV infection are elevated triglyceride levels but lower total, LDL and HDL-cholesterol levels. Treatment of HIV infection with ART often leads to a ‘return to health’ increase in total cholesterol and LDL-cholesterol back towards pre-HIV infection levels. However, specific ART may cause a further increase in triglyceride and cholesterol levels. The treatment of dyslipidaemia is similar in both HIV and non-HIV populations and includes both non-pharmacological and pharmacological options, with a few caveats. Conclusions: The management of dyslipidaemia is aimed at reducing cardiovascular risk via the utilization of non-pharmacological and pharmacological interventions. Whilst treatment options are similar, awareness of the impact of polypharmacy and drug interactions between ART and lipid-lowering medications in addition to close monitoring for adverse events is key to being successful in managing dyslipidaemia in PWH.

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Authors: Muskaan Sachdeva, Marissa Joseph

Atopic dermatitis (AD) is a chronic inflammatory cutaneous disease prevalent in all skin types but can differ in pathogenesis and clinical presentation. It has been documented in the literature that AD is more prevalent in Asian and Black individuals than in white individuals. Genetic variations as well as cultural and socioeconomic factors have important implications for susceptibility to AD and response to treatment in skin of colour. In this narrative review, we discuss differences in the epidemiology, pathophysiology, clinical presentation and treatment of AD in skin of colour. Additionally, we highlight the need for greater inclusivity of non-white ethnic groups in clinical trials to develop targeted treatments for diverse populations. Moreover, awareness of differences in AD presentation amongst non-white individuals may encourage patients to seek medical care earlier, leading to timely management and improved outcomes.

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Authors: Rajesh R Tampi, Deena J Tampi, Syeda Arshiya Farheen, Mahwish Adnan, Dhweeja Dasarathy

Prazosin, a centrally acting α1 adrenoceptor antagonist, has been included in two published algorithms amongst the list of medications that may be used in the management of behavioural and psychological symptoms of dementia (BPSD). However, a review of PubMed, Ovid and Cochrane Collaboration found that there was only one small published randomized controlled trial (RCT) that evaluated the use of prazosin amongst individuals with BPSD. Evidence from this good quality RCT indicates that prazosin appears to benefit individuals with agitation and aggression amongst individuals with BPSD and this medication is well tolerated. When compared to other treatments for BPSD, including atypical antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, repetitive transcranial magnetic stimulation and electroconvulsive therapy, where there are multiple studies for each of these treatment modalities, the data for the use of prazosin for BPSD are limited to just one good quality RCT. Given the limitations in available data, the routine use of prazosin for the treatment of BPSD cannot be recommended at this time. However, prazosin may be used for the management of agitation and aggression amongst individuals with dementia when other medication classes, like acetylcholinesterase inhibitors, memantine, antidepressants and/or atypical antipsychotics, have been ineffective or not tolerated.

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Authors: Maria Cecilia Rivitti-Machado, Renata Ferreira Magalhães, Roberto Souto da Silva, Gleison V Duarte, Fabiana ZS Bosnich, Roberto Gaspar Tunala, Francisco José Forestiero

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with a significant negative impact on the quality of life of patients. Methods: We conducted a systematic review to assess current treatment for HS, with a special focus on therapies approved or used in Brazil. We used the PICO framework to improve the research process. The systematic review was reported in line with the PRISMA statement checklist. The search was conducted with clinical questions on two global databases (PubMed (MEDLINE) and Google Scholar) and three databases especially selected to retrieve Brazilian outcomes (BVS, SCIELO and REDALYC). Results: Overall, 4640 articles were screened, 182 articles were analysed and 70 were used in a thematic qualitative analysis. Of these, 12 articles were from Brazil. The evidencebased literature was largely limited to case reports, case series, observational studies and expert opinion. Topical therapy, lifestyle interventions and oral antibiotics appeared as effective measures for mild HS. However, moderate-to-severe HS remains refractory to conventional treatments. Conclusion: Some biologic agents, such as adalimumab, infliximab, ustekinumab and secukinumab, have been shown to be effective in the management of moderate-to-severe HS that failed conventional treatment and demonstrated a good tolerability and safety profile.

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Authors: Claire Chiang, Madison Ward, Melinda Gooderham

Acne vulgaris is a prevalent dermatological condition worldwide but is especially challenging to treat in individuals with skin of colour (SOC). Corresponding to Fitzpatrick skin phototypes III–VI, people of African, Asian, Middle Eastern and Hispanic ethnicity are considered to have SOC. With the additional risk of postinflammatory hyperpigmentation (PIH) as a consequence of inflammatory acne or its respective treatment, managing acne in this population holds significant importance. PIH adversely impacts self-esteem and quality of life and, thus, is usually the patient’s priority of treatment. Available acne treatments are similar for all skin types. However, some are more beneficial for individuals with SOC, in particular by targeting both active acne lesions and PIH. The acne treatment literature was searched for topical and systemic treatments that were specifically studied in the SOC population. These treatments included topical agents, such as retinoids and azelaic acid, in addition to topical antibiotics and benzoyl peroxide. Newer formulations and combined regimens reported effective in reducing lesions are less likely to induce PIH and may treat pre-existing PIH. Moisturiser use, titrating doses and patient education are strategies to minimize irritation and improve adherence. In addition, systemic therapies, including oral antibiotics, isotretinoin, oral contraceptives and spironolactone, are efficacious for refractory acne or more severe cases but specific studies in SOC are lacking. Chemical peels may improve acne and target PIH directly. Overall, based on limited evidence, topical and systemic therapies are well tolerated in the SOC population but efficacy should be balanced with the risk of adverse effects. This narrative review aims to highlight formulations and combination therapies that are effective and safe for treating acne and PIH in patients with SOC.

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Authors: Juan Bautista Blaquier, Gonzalo Recondo

Several oncogenic mechanisms have been identified for MET, including MET amplification, fusions, mutations in the tyrosine kinase domain and exon 14 skipping alterations. MET exon 14 mutations are found in about 3–5% of non-small-cell lung cancers. Dysregulation of the MET receptor leads to cell proliferation and survival by activation of the PI3K–AKT–TOR and RAS–RAF–MET–ERK canonical pathways. Targeting the MET tyrosine kinase domain in the setting of MET exon 14 mutations using effective MET tyrosine kinase inhibitors is a current targeted therapy option for patients with metastatic lung cancer. In this Review, we focus on the management of patients with MET exon 14 skipping alterations by addressing the biology of the MET receptor and exon 14 skipping mutations, current treatment strategies, and sequential treatment options based on resistance mechanisms to MET inhibitors in patients with non-small-cell lung cancer.

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Authors: Giulio Metro, Andrea De Giglio, Biagio Ricciuti, Marco Siringo, Daniele Marinelli, Alain Gelibter, Federica Pecci, Rossana Berardi, Luca Cantini, Alessandro Di Federico, Elisa Andrini, Mirta Mosca, Giuseppe Lamberti, Marta Brambilla, Giannis Mountzios

EGFR exon 20 insertion mutations (Ex20ins) and HER2 mutations characterize an oncogene-addicted subtype of non-small-cell lung cancer (NSCLC) typically associated with a never or light smoking history, female sex, and adenocarcinoma histology. Nevertheless, Ex20ins-mutant and HER2-mutant advanced NSCLCs are still difficult to treat for various reasons. First, there is a need for sophisticated diagnostic tools (e.g. next-generation sequencing) that could allow the identification of these relatively rare molecular drivers. Second, highly active targeted drugs that might support a significant change in patients’ prognosis when used as first-line therapy are required. In fact, although a few targeted drugs have so far demonstrated antitumour activity for these patients, mainly selective human epidermal receptor-tyrosine kinase inhibitors such as poziotinib and mobocertinib (for both molecular alterations), monoclonal antibodies such as amivantamab (for Ex20ins), and antibody–drug conjugates such as trastuzumab deruxtecan (for HER2 mutants), they are mostly confined for clinical use in pretreated patients. Finally, Ex20ins-targeted or HER2-targeted drugs might be difficult to access in different countries or regions worldwide. In the present review, we provide a concise but comprehensive summary of the challenges that lie ahead as we move towards personalized treatment of Ex20ins-mutant and HER2-mutant advanced NSCLC, also suggesting a treatment algorithm that could be followed for patients with these genetic aberrations. This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue: https://www.drugsincontext.com/special_issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/

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Authors: Eric R Ocheretyaner, Maria Kofman, Elaena Quattrocchi

Migraine headaches are widespread, debilitating and considered a main cause of disability worldwide. Symptoms of migraines include unilateral, pulsating pain that can last for hours to days, frequently associated with photophobia and phonophobia, nausea, or vomiting, and often aggravated by physical activity. The Canadian Headache Society and American Headache Society guidelines suggest strong evidence of the efficacy of triptans, acetaminophen, aspirin, diclofenac sodium, naproxen and ibuprofen for the acute treatment of migraines. The use of calcitonin gene-related peptide (CGRP) antagonists for the treatment and prevention of migraines has been gaining utilization since the approval of the first agent in this class in 2018. There are increasing available options for the acute treatment of migraines. The purpose of this article is to provide a narrative review of the pharmacological and clinical characteristics of ubrogepant and rimegepant and to discuss their implications for use.

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Authors: Juan José Cerezo-Manchado, Olga Meca Birlanga, Luis García de Guadiana Romualdo, Ignacio Gil-Ortega, Antonio Martínez Francés, Teodoro Iturbe-Hernandez

COVID-19 increases the risk of atrial fibrillation (AF) and thrombotic complications, particularly in severe cases, leading to higher mortality rates. Anticoagulation is the cornerstone to reduce thromboembolic risk in patients with AF. Considering the risk of hepatotoxicity in patients with severe COVID-19 as well as the risk of drug–drug interactions, drug-induced hepatotoxicity and bleeding, the ANIBAL protocol was developed to facilitate the anticoagulation approach at discharge after COVID-19 hospitalization. However, since the publication of the original algorithm, relevant changes have occurred. First, treatment of COVID-19 pneumonia has been modified with the use of dexamethasone or remdesivir during the first week in patients that require oxygen therapy, and of dexamethasone and/or tocilizumab or baricitinib during the second week in patients that necessitate supplementary oxygen or with a high inflammation state, respectively. On the other hand, metabolic syndrome is common in patients with AF as well as metabolic-associated fatty liver disease, and this could negatively impact the prognosis of patients with COVID-19, including high transaminase levels in patients treated with immunomodulators. The EHRA guidelines update also introduce some interesting changes in drug–drug interaction patterns with the reduction of the level of the interaction with dexamethasone, which is of paramount importance in this clinical context. Considering the new information, the protocol, named ANIBAL II, has been updated. In this new protocol, the anticoagulant of choice in patients with AF after COVID-19 hospitalization is provided according to three scenarios: with/without dexamethasone treatment at discharge and normal hepatic function, transaminases ≤2 times the upper limit of normal, or transaminases >2 times the upper limit of normal.

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Authors: Kam Lun Hon, Alexander KC Leung, Wing Hang Leung, Karen Ka Yan Leung, Kai Ning Cheong, Pamela PW Lee

Background: Many syndromes are associated with exaggerated inflammation. Children with hyperinflammatory syndromes often present with vague and non-specific symptoms that pose diagnostic and management challenges. The recent literature seems biased towards referring these syndromes only to the multisystem inflammatory syndrome in children (MIS-C) that is associated with COVID-19. The purpose of this paper is to provide an updated narrative review on the pathophysiology, manifestations and management approaches for common hyperinflammatory syndromes. Methods: An extensive PubMed search of all publications in the English literature was performed with Clinical Queries for various hyperinflammatory syndromes and conditions using the undermentioned Medical Subject Headings: “hyperinflammation”, “hyperinflammatory syndromes”, “sepsis syndrome”, “severe inflammatory response syndrome” and “acute respiratory distress syndrome”. Categories were limited to reviews and clinical trials for the age range from birth to 18 years. Results: The criteria, presentation and management of these hyperinflammatory syndromes are described. Hyperinflammatory syndromes refer to a basket of inflammatory syndromes often associated with multisystem involvement and aberrant cytokine release and should be differentiated from autoinflammatory, autoimmune and hyperimmune syndromes. The major subtypes of hyperinflammatory syndromes, including macrophage activation syndrome, haemophagocytic lymphohistiocytosis, cytokine release syndrome and cytokine storm syndrome, are described. MIS-C associated with SARS-CoV-2 represents the latest addition. It must be understood that the syndrome is not exclusive to COVID-19 but could be caused by various viral infections. Early recognition, prompt and proactive treatment can reduce potential complications and improve outcomes and survival rates in paediatric patients. Anti-inflammatory medications for the management of these syndromes are described. Conclusion: The incidence of these hyperinflammatory conditions is generally low in comparison to other disease conditions. Except for paediatric inflammatory multisystem syndrome/MIS-C, the mortality is high and the hospital stay is prolonged in affected patients. Acute and critical care physicians must be aware of these conditions and their initial management. Corticosteroids are often used in the initial phrase but various disease-specific drugs and biologics are needed in subsequent management and expert management of these often-difficult conditions is crucial.

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Authors: Francesco Serra, Paolo Pedrazzoli, Silvia Brugnatelli, Anna Pagani, Salvatore Corallo, Giovanni Rosti, Riccardo Caccialanza, Jacopo Viganò, Ornella Carminati

Gastric cancer is the sixth most common malignancy in the world. However, its mortality has been decreasing in the last years thanks to improvement in diagnostics and therapeutics. Nevertheless, the high rate of malnutrition in patients with gastric cancer still has a major impact on the overall survival and quality of life of patients. The narrative review presents the most recent data on nutritional support in the resectable stages of gastric cancer, with a particular focus on perioperative strategies, and discusses malnutrition in gastric cancer, nutritional support before and after surgery, and the relationship between nutritional support and chemotherapy. Despite the predominantly methodological limitations related to the difficulty of performing randomized controlled trials on nutritional support in cancer patients, this review highlights important points. Nutritional counselling is essential starting from diagnosis. In limited or locally advanced forms (about 40% of cases), the therapeutic cornerstone is represented by gastric surgery. In most of these cases, perioperative chemotherapy is also indicated. Of note, nutritional support varies before and after surgery. In the preoperative period, the goal is to prepare the body for surgery, with available evidence recommending the prescription of immunonutrition (both oral and artificial, as appropriate). In the postoperative period, on the other hand, the objective is to facilitate recovery and adaptation to the new anatomy; an early and combined strategy (oral and enteral) seems to be the most suitable to pursue this. Unfortunately, rigorous data on the relationship between nutritional support and chemotherapy treatments used in resectable gastric cancer are not available. In the absence of strong scientific evidence, it may be useful to adopt a personalized multidisciplinary strategy for each patient wherein the chemotherapy programme is modulated based on nutritional status.

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Authors: Rajesh R Tampi, Deena J Tampi, Syeda Arshiya Farheen, Sochima I Ochije, Pallavi Joshi

Propranolol is a β-adrenergic antagonist used in the management of hypertension, cardiac arrhythmia, and angina pectoris. There is some evidence that propranolol may benefit individuals with behavioural and psychological symptoms of dementia (BPSD). A total of three case series, one randomized controlled trial and one case report were identified (from a literature search of three major databases: PubMed, Ovid, and Cochrane collaboration) that assessed the use of propranolol for the management of BPSD. From these studies, it appears that propranolol improves BPSD, including agitation and aggression. Propranolol is also well tolerated with no significant bradycardia or hypotension noted in these studies. Current data on the use of propranolol for the management of BPSD are limited in comparison to other pharmacological agents (atypical antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, and cannabinoids) and treatment modalities (repetitive transcranial magnetic stimulation and electroconvulsive therapy). The efficacy and safety of these treatments among individuals with BPSD has been evaluated in multiple controlled studies. In clinical practice, the routine use of propranolol among people with BPSD cannot be recommended at this time given the limited data. However, propranolol can be trialled among individuals with BPSD when symptoms have not responded adequately to other medications. Propranolol may also be used prior to embarking on trials of repetitive transcranial magnetic stimulation and electroconvulsive therapy among people with BPSD given the greater acceptance of this medication in the general population.

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Authors: Howard Busch, George J Wan, John Niewoehner, Parul Houston, Yujie Su, Cassie Clinton, Mary P Panaccio

Introduction: Repository corticotropin injection (RCI, Acthar® Gel) is a naturally sourced mixture of adrenocorticotropic hormone analogues and other pituitary peptides with anti-inflammatory and immunomodulatory effects. In a recent clinical trial, RCI was safe and effective for the treatment of refractory rheumatoid arthritis (RA). This study aims to describe real-world use and outcomes of patients with RA who were prescribed RCI in clinical practice through retrospective analysis of an electronic medical record database. Methods: Patients with RA who were prescribed RCI were identified through the ColumbusTM electronic medical record repository, representing approximately 100 rheumatology practices. Demographics, medications, comorbidities, disease histories, laboratory evaluations, clinical outcomes and patient-reported outcomes were evaluated from 12 months pre-RCI to 12 months post-RCI initiation. Results: The RCI cohort (n=63) comprised predominantly white women, aged 54 years on average, at 6 years from RA diagnosis, with high disease activity at baseline according to Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) scores. Within the 12 months pre-RCI initiation, 87% of patients were prescribed disease-modifying antirheumatic drugs and 67% were prescribed glucocorticoids. Twelve months post- RCI initiation, glucocorticoid, opioid and non-steroidal antiinflammatory drug prescriptions decreased; disease-modifying antirheumatic drug prescriptions remained stable. Reductions in CDAI, RAPID3, physician global assessment, tender joint count, swollen joint count, and pain visual analogue scale scores were observed 12 months post-RCI initiation. Few discontinuations were due to side effects. Study limitations included small sample size and incomplete electronic medical record data. Conclusion: These findings support the safety and effectiveness of RCI for short-term adjunctive treatment of refractory RA and provide patient-management insights from routine clinical practice.

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Authors: Sarah L Anderson, Joel C Marrs

Atherosclerotic cardiovascular disease (ASCVD) commonly affects people with type 2 diabetes (T2D). Historically, traditional cardiovascular (CV) risk-lowering therapies in patients with T2D and ASCVD have included antiplatelet agents, blood pressure-lowering therapies, lipid-lowering therapies and healthy lifestyle modifications. In the past decade, multiple antihyperglycaemic agents have emerged as CV risk-lowering therapies in this population as well. This article provides a narrative review on the current non-glycaemic and glycaemic treatment options for CV risk reduction in patients with T2D and ASCVD. The FDA requirement that all new antihyperglycaemic agents undergo cardiovascular outcomes trials has demonstrated increasing evidence to support the role of glucagon-like peptide 1 (GLP1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors as first-line agents for both glycaemic control and CV risk reduction in this population.

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Authors: Rachel N Lowe, Briana Williams, Liza Claus

Hypoglycaemia is a complication associated with the management of both type 1 and type 2 diabetes. Despite newer technologies to help minimize the risk of hypoglycaemia, it remains a barrier for some patients to achieve optimal glycaemic control. In this review, the definitions and risk factors for hypoglycaemia will be briefly discussed and an in-depth review of the management for a conscious or unconscious patient in the outpatient and inpatient settings is provided. Rapid-acting glucose is the preferred treatment for a conscious patient regardless of the setting. For an unconscious patient, glucagon is preferred if the patient does not have intravenous (IV) access and dextrose can be used for patients with IV access. Until recently, there was only one formulation of glucagon, which had limitations due to the multiple steps required for reconstitution prior to administration in an emergency setting. This review also discusses the different glucagon formulations currently available for the management of hypoglycaemia.

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Authors: Michael Kennelly, Ronald Wielage, Denise Shortino, Elizabeth Thomas, Paul N Mudd Jr

Background: Few randomized controlled trials evaluate the long-term efficacy and safety of pharmacotherapy for overactive bladder (OAB). This network meta-analysis compares the long-term (52-week) efficacy and safety of vibegron, mirabegron and anticholinergics for the treatment of OAB. Methods: A systematic literature review and network meta-analysis were conducted following PRISMA guidelines using MEDLINE, Embase and Cochrane Central Register of Controlled Trials and terms related to OAB. Efficacy outcomes included change from baseline to week 48–52 in mean daily total urinary incontinence (UI) episodes, mean daily number of micturitions and volume voided/micturition. Efficacy outcomes were analysed using Bayesian models. Commonly reported adverse events (AEs) are described. Results: Of 2098 hits retrieved, 5 publications and 1 study report describing 5 unique randomized controlled trials were included in the analyses. Mean (95% credible interval) change from baseline in total UI episodes for vibegron 75 mg (–2.2; –2.9 to –1.5) showed a significantly greater reduction than mirabegron 50 mg (–1.3; –1.9 to –0.8) and tolterodine 4 mg extended release (–1.6; –2.1 to –1.1). No significant differences were observed between vibegron and comparators for daily micturitions or volume voided/micturition. Within the manuscripts, the 4 most common AEs (range) for anticholinergics included dry mouth (5.2–90.0%), constipation (7.7–65.0%), blurred vision (3.8–35.0%) and hypertension (8.6–9.6%); the 4 most commonly reported AEs for β3-adrenergic agonists included hypertension (8.8–9.2%), urinary tract infection (5.9–6.6%), headache (5.5%) and nasopharyngitis (4.8–5.2%). Conclusion: Vibegron was associated with significantly greater improvement in daily total UI episodes at 52 weeks than mirabegron and tolterodine. When reported, the most common AE for anticholinergics was dry mouth and for β3-adrenergic agonists was hypertension. Hypertension incidence was similar between drug classes.

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Authors: Megha Gandhi, Emily Fargo, Lalita Prasad-Reddy, Katherine M Mahoney, Diana Isaacs

Diabetic peripheral neuropathy (DPN) is a major complication of diabetes mellitus. Tight glycaemic management focused on lowering haemoglobin A1C and increasing time in the target glucose range along with metabolic risk factor management form the cornerstone of DPN prevention. However, there is limited evidence supporting the efficacy of glycaemic and metabolic control in reducing the symptoms and complications of DPN, including pain once painful DPN develops. DPN treatments include pharmacological agents and non-pharmacological interventions such as foot care and lifestyle modifications. Pharmacological agents primarily address pain symptoms, which affect 25–35% of people with DPN. First-line agents include the anticonvulsants pregabalin and gabapentin, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine, and secondary amine tricyclic antidepressants, including nortriptyline and desipramine. All agents have unique pharmacological, safety and clinical profiles, and agent selection should be guided by the presence of comorbidities, potential for adverse effects, drug interactions and costs. Even with the current treatment options, people are commonly prescribed less than the recommended dose of medications, leading to poor management of DPN symptoms and treatment discontinuation. By keeping up with the latest therapy algorithms and treatment options, healthcare professionals can improve the care for people with DPN.

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Authors: Andrea De Giglio, Alessandro Di Federico, Chiara Deiana, Biagio Ricciuti, Marta Brambilla, Giulio Metro

The therapeutic approach to patients affected by advanced non-small-cell lung cancer (NSCLC) is facing rapid and continuous evolution. In recent years, the emergence of new treatment strategies, such as immunotherapy and tyrosine kinase inhibitors, has revolutionized the treatment algorithm and the prognosis of patients with NSCLC. In the nononcogene- addicted disease, immune-checkpoint inhibitors, either as single agents or combined with chemotherapy, outperformed standard chemotherapy in both untreated and previously treated patients. However, many patients still do not derive the expected benefit from current treatments. Despite representing the only biomarker currently used in clinical practice to guide treatment selection, PD-L1 expression has been proven an imperfect predictor of immunotherapy outcomes. The evaluation of clinical factors remains essential to detect patients that would benefit the most from a particular treatment approach, but the identification of additional biological and molecular predictive tools is a priority. Herein, we provide a comprehensive though concise review of the current treatment approaches to advanced NSCLC in patients without molecular driver alterations, with an additional focus on special populations, concomitant medications, and other considerations that might be useful for daily clinical practice.

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Authors: Ngan Thi Tran, Pranee Sutcharitchan, Jindaporn Janprasit, Ponlapat Rojnuckarin, Noppawan Phumala Morales, Rataya Luechapudiporn

Background: Hyperfunctional platelets play important roles in thromboembolism in patients with β-thalassaemia/ haemoglobin E (β-thal/HbE). Our previous study revealed ex vivo inhibitory effects of deferiprone on normal platelets. Herein, we aimed to investigate the in vivo effects on platelets in patients with β-thal/HbE. Methods: A prospective, self-controlled clinical study on 30 patients with β-thal/HbE who had received therapeutic deferiprone (20.8–94.5 mg/kg/day) was conducted. The study included a 4-week washout period followed by 4 and 12 weeks of deferiprone treatment. Platelet aggregation was performed by a turbidimetric method. Levels of deferiprone and soluble platelet (sP)-selectin in serum were measured by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kit, respectively. Results: The washout period significantly enhanced platelet hyperactivity both in patients who had undergone splenectomy and in those who had not. At 2 hours following the administration of a single dose of deferiprone, platelet sensitivity to ADP and arachidonic acid was significantly reduced. The inhibitory effects of deferiprone were gradually increased over the period of 4 and 12 weeks. Deferiprone also depressed sP-selectin levels, but the effect was stable over longer follow-up periods. Correlation analysis demonstrated the relationship between serum levels of deferiprone, sP-selectin, and platelet activities induced by ADP and arachidonic acid. Conclusion: We first demonstrated the in vivo antiplatelet effect and benefit of short-term treatment of deferiprone in patients with β-thal/HbE. The impact on thrombotic outcomes deserves further study.

15

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

Background: Pediculosis capitis is a common human parasitic infestation in childhood. This article aims to provide a narrative updated review on the management of pediculosis capitis. Methods: A PubMed search was performed with Clinical Queries using the key terms “pediculosis capitis” OR “head lice” OR “head louse”. The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies and reviews published within the past 10 years. The search was restricted to articles published in English literature. The information retrieved from the search was used in the compilation of the present article. Results: Topical permethrin and pyrethrin formulated with piperonyl butoxide are the pediculicides of choice in areas where resistance to these products is low. When resistance to these products is suspected based on local levels of resistance or when treatment with these products fails despite their correct use, and reinfestation does not seem to be responsible, other topical treatment options include malathion, benzyl alcohol, dimethicone, spinosad and ivermectin. Wet combing should be considered for children younger than 2 years. Oral ivermectin and trimethoprim/sulfamethoxazole should be reserved for patients who do not respond to appropriate topical pediculicides. Conclusion: Many topical pediculicides are effective for the treatment of pediculosis capitis. The use of some of these pediculicides is limited for safety reasons, especially in children younger than 2 years. Resistance to pediculicides, especially those with a neurotoxic mode of action, is another concern which may limit the use of some of these pediculicides. New products should be evaluated for effectiveness and safety. Wet combing is time-consuming and should not be used as the sole intervention in the general population.

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Authors: Eleanor Liu, Nasar Aslam, Gaurav Nigam, Jimmy K Limdi

Inflammatory bowel diseases, comprising ulcerative colitis (UC) and Crohn’s disease, are chronic, immune-mediated and progressive inflammatory disorders affecting the gastrointestinal tract. Tofacitinib is the first oral small-molecule Janus kinase (JAK) inhibitor licensed and approved by the National Institute for Health and Care Excellence (NICE) for use in moderately-to-severely active UC after intolerance, inadequate response, or loss of response to conventional treatment or biologic therapy. The pivotal OCTAVE studies demonstrated the efficacy and safety of tofacitinib for the induction and maintenance of remission in UC. A growing body of evidence from real-world data supports the positive clinical and endoscopic benefits observed with tofacitinib treatment in the OCTAVE trials. This narrative review summarizes the current literature regarding the mechanism of action of tofacitinib, data from registrational trials, emerging real-world evidence, and an overview of the most recent safety evidence. We explore evolving treatment paradigms including the use of tofacitinib in the COVID-19 era, pregnancy and extraintestinal manifestations as well as the emerging concept of combining tofacitinib with biological therapy. We will also present a brief overview of the next generation of JAK inhibitors in the pipeline.

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Authors: Federica Pecci, Luca Cantini, Giulio Metro, Biagio Ricciuti, Giuseppe Lamberti, Ammad Ahmad Farooqi, Rossana Berardi

The treatment of non-small-cell lung cancer (NSCLC) harbouring EGFR mutations has witnessed some major breakthroughs in the last years. On the one hand, the recent advent of the third-generation tyrosine kinase inhibitor (TKI) osimertinib has reshaped the therapeutic algorithm both in the first-line and adjuvant settings for patients with common activating Ex19del and L858R EGFR mutations. On the other hand, the availability of new comprehensive next-generation sequencing panels, to be used on tumour tissue or on liquid biopsy, has revealed the existence of uncommon as well as compound mutations that partially explain the onset of resistance. Nevertheless, dissecting the biological mechanisms underlying primary and secondary resistance to EGFR-TKIs is crucial to developing alternative therapeutic strategies and further improving patient outcomes. Herein, we provide an updated and comprehensive summary of the latest advancements in the quest for compounds targeting EGFR-mutant advanced non-small-cell lung cancer, discussing the biological rationale underlying the development of a forefront combination of TKI and/or new antibody–drug conjugates. We also suggest a treatment algorithm that could be followed considering the latest published data.

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Authors: Julianna Rivich Kluemper, Alexandria Smith, Brooke Wobeter

Diabetes mellitus is a chronic condition affecting 1 out of every 11 people worldwide. Monitoring of blood glucose allows for therapeutic lifestyle and pharmacotherapy changes to reduce the occurrence of hyperglycaemia and hypoglycaemia. Advancements in technology over the past two decades have increased patient and clinician access to glucose data and trends with continuous glucose monitoring (CGM) systems. This narrative review seeks to investigate the efficacy and safety of CGM for the management of diabetes. In type 1 diabetes (T1DM) and type 2 diabetes, efficacy studies of real-time CGM (rtCGM) or intermittently scanned CGM (isCGM) have shown a decrease in HbA1C (0.3–0.6%) over traditional self-monitoring blood glucose. Percent time in the target glucose range also improved (6.8–17.6%). Rates of hypoglycaemia, including severe hypoglycaemia, decreased in studies of rtCGM and isCGM with most available data in T1DM. In pregnant women with T1DM, rtCGM has shown modest improvements in HbA1C and time in target glucose range and decreased risk of neonatal complications. Multiple studies have shown that the use of rtCGM or isCGM increased diabetes treatment satisfaction amongst patients. Head-to-head studies of rtCGM and isCGM are limited but one study indicates that a CGM system with alarms may be preferred in T1DM to reduce the risk of hypoglycaemia. Selection of a CGM device should depend on patient-specific factors and insurance coverage. The results of one study show that the benefits of CGM device use were not sustained after discontinuing use. Increasing widespread and long-term access to CGM devices is necessary to improve the management of diabetes amongst the greater population.

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

Background: Tinea versicolor is a common superficial fungal infection of the skin with various clinical manifestations. This review aims to familiarize physicians with the clinical features, diagnosis and management of tinea versicolor. Methods: A search was conducted in July 2022 in PubMed Clinical Queries using the key terms “tinea versicolor” OR “pityriasis versicolor”. The search strategy included all clinical trials, observational studies and reviews published within the past 10 years. Results: Tinea versicolor is caused by Malassezia species, notably M. globosa, M. furfur and M. sympodialis. The condition is characterized by scaly hypopigmented or hyperpigmented macules/patches, primarily located on the upper trunk, neck and upper arms. The diagnosis is usually based on characteristic clinical features. If necessary, a potassium hydroxide preparation test can be performed to reveal numerous short, stubby hyphae intermixed with clusters of spores. Most patients with tinea versicolor respond to topical antifungal therapy, which has a better safety profile (fewer adverse events, fewer drug interactions) and lower cost compared to systemic treatment and is therefore the treatment of choice. Oral antifungal therapy is typically reserved for patients with extensive disease, frequent recurrences or disease that is refractory to topical therapy. Advantages of oral antifungal therapy include increased patient compliance, shorter duration of treatment, increased convenience, less time involved with therapy and reduced recurrence rates. On the other hand, oral antifungal therapy is associated with higher cost, greater adverse events and potential drug–drug interactions and is therefore not the first-line treatment for tinea versicolor. Long-term intermittent prophylactic therapy should be considered for patients with frequent recurrence of the disease. Conclusion: Selection of antifungal agents depends on several factors, including efficacy, safety, local availability, ease of administration, likelihood of compliance and potential drug interactions of the antifungal agent.

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Authors: Martina Burlando, Riccardo Castelli, Emanuele Cozzani, Aurora Parodi

The authors wish to make the following corrections to their article: Burlando M, Castelli R, Cozzani E, Parodi A. Treatment of moderate-to-severe plaque psoriasis with tildrakizumab in the real-life setting. Drugs in Context 2021; 10: 2021-2-6. DOI: 10.7573/dic.2021-2-6

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Authors: Daniele Orsucci, Marco Vista

Letter to the Editor in response to Finsterer J, Scorza FA, Scorza CA. Presentation and pathophysiology of neuro-COVID. Drugs Context. 2021;10:2021-6-5. https://doi.org/10.7573/dic.2021-6-5

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Authors: Sergey V Efimov, Natallia V Matsiyeuskaya, Olga V Boytsova, Lyudmila Yu Akhieva, Elena I Kvasova, Francisco Harrison, Yulia S Karpova, Anton Tikhonov, Nadezhda F Khomyakova, Tim Hardman, Jean-François Rossi

The authors wish to make the following corrections to their article: Efimov SV, Matsiyeuskaya NV, Boytsova OV, et al. Corrigendum: The effect of azoximer bromide (Polyoxidonium®) in patients hospitalized with coronavirus disease (COVID-19): an open-label, multicentre, interventional clinical study. Drugs in Context 2021; 10: 2021-11-1. DOI: 10.7573/dic.2020-11-1

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Authors: Xavier Garcia-Moll, Vivencio Barrios, Josep Franch-Nadal

Traditionally, patients with type 2 diabetes have been stratified according to cardiovascular (CV) risk to requiring either primary prevention (those without atherosclerotic CV disease) or secondary prevention (those with atherosclerotic CV disease in any of the vascular beds). However, this classification is misleading and arbitrary, as not all patients requiring secondary prevention have the same risk for such events, which also holds true for those requiring primary prevention (i.e. CV risk ranges from moderate to very high). In addition, in some cases, the definitions of primary and secondary prevention do not rely on symptoms but rather on the results of supplementary tests. Furthermore, patients with type 2 diabetes may also develop heart failure or chronic kidney disease. Importantly, reducing CV risk stratification to primary and secondary prevention does not provide a comprehensive approach for the management of patients with diabetes, leading to an underuse of drugs with proven CV benefit regardless of the presence of atherosclerotic CV disease. Therefore, patients with diabetes should be treated according to their CV risk considered as a continuum and not simply as falling within primary or secondary prevention.

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Authors: Kristin M Holland, Lara DePadilla, Derrick W Gervin, Erin M Parker, Marcienne Wright

The United States drug overdose epidemic has reached an all-time high, with 2020 provisional mortality data indicating that over 90,000 lives were lost to drug overdose in the 12-months ending in December 2020. The overdose epidemic has evolved over time with respect to the substances involved in overdose deaths and also with respect to the geographic distribution and epidemiology of deaths involving specific substances. Thus, a nimble approach to addressing the epidemic and preventing future overdoses is needed. CDC’s response to the overdose epidemic supports implementation efforts at the state and local levels, where partners can better detect and respond to the evolving drug overdose landscape and implement prevention measures that meet their needs. CDC’s framework for responding to the overdose epidemic focuses on five areas: (1) conducting surveillance and research; (2) building state, local and tribal capacity; (3) supporting providers, health systems and payers; (4) partnering with public safety; and (5) empowering consumers to make safe choices. Central to informing the implementation of evidence-based strategies to prevent drug overdose is rigorous research that undergirds the evidence. This Commentary describes recent investments in overdose prevention research and outlines opportunities for ensuring that future research efforts allow for the flexibility necessary to effectively respond to the continually evolving epidemic.

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Authors: Martina Burlando, Riccardo Castelli, Emanuele Cozzani, Aurora Parodi

Background: Tildrakizumab is a high-affinity, humanized IgG1κ monoclonal antibody targeting the p19 subunit of IL-23, which is a key regulatory cytokine in psoriasis. Based on evidence from clinical trials, tildrakizumab is approved for the treatment of moderate-to-severe plaque psoriasis in patients eligible for systemic therapy. Methods: We report our clinical experience with 26 patients followed up to 24 weeks. Results: No adverse event was observed and no patient discontinued tildrakizumab. Whilst no patient had a Psoriasis Area and Severity Index (PASI) score of <5 at baseline, at week 4, 8 (32%) patients had a PASI score of <3 and 6 of these had a PASI score of 0. At week 12, 19 (79%) patients had a PASI score of <5 and, among these, 18 had a PASI score of <3 of whom 16 had a PASI score of 0. At week 24, 22 (96%) patients had a PASI score of <3 and 20 (87%) had a PASI score of 0. Quality of life was improved after 4 weeks and through the whole period of observation. Conclusion: Our experience in the real-life setting confirms the efficacy and safety of tildrakizumab as demonstrated by clinical trials.

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Authors: Sarah L Anderson, Matteo Bassetti, Arduino A Mangoni

The year 2020 was dominated by the COVID-19 pandemic, bringing with it unprecedented advancements in the fields of healthcare and therapeutic interventions as well as in vaccine and drug development. Nevertheless, several other advancements in various fields of medicine also deserve attention. Herein, the Senior Editors of Drugs in Context provide us with their expert opinion on the events of 2020 and what lies ahead in 2021.

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Authors: Sarah M Michienzi, Mikayla Johnson, Thomas D Chiampas, Eric Wenzler, Rodrigo M Burgos, Renata O Smith, Melissa E Badowski

Although tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) have been evaluated in various clinical trials, limited safety and efficacy data exist in real-world settings. The goal of this retrospective analysis is to assess changes in virological suppression, immunological status, renal function, weight and body mass index (BMI) amongst people living with HIV who switched from a TDF-based to a TAF-based regimen. Of 130 patients included in the final analysis, 53 patients experienced an increase in their viral load upon switching from TDF to TAF therapy whilst 62 patients remained undetectable. For those who experienced a viral blip, 33 (62%) resuppressed by the time of last follow-up, 15 (28%) patients did not have additional labs beyond the last follow-up and concern for failure occurred in 5 (9%) patients. No differences in immunological function, renal function, weight or BMI were observed from before switching to the last follow-up. Although a loss of virological suppression was found upon switching to TAF at subsequent follow-up visits, resuppression ultimately occurred in most patients.

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Authors: Ana Victoria Carro Martínez, Lydia Montolio Chiva, Montserrat Robustillo Villarino

Drug therapy of immune-mediated inflammatory arthropathies is not always satisfactory, and there is a risk of adverse events. Granulocyte and monocyte/macrophage apheresis (GMA) is a non-pharmacological therapeutic option that is beneficial and very well tolerated. GMA involves passing blood through a column with cellulose acetate beads to remove increased and activated myeloid lineage cells and improve the cytokine profile. The technique reduces pain and inflammation. We present four clinical reports that illustrate the clinical uses of GMA with the medical device Adacolumn® in patients with different backgrounds and immune-mediated inflammatory arthritis. The results were positive, and no adverse events were reported.

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Authors: Anna R Morgan, Michelle A Hendricks, Sanae El Ibrahimi, Sara E Hallvik, Brigit Hatch, Caitlin Dickinson, Dagan Wright, Michael A Fischer

The United States faces an opioid crisis with an unprecedented and increasing death rate from opioid overdose. Successfully reducing the rates of opioid use disorder (OUD) and overdose will require the engagement of frontline clinicians to prescribe opioids more safely and to build their capacity to treat patients with OUD using evidence-based approaches. The COVID-19 pandemic has created significant challenges for patients, clinicians and health systems and has been associated with increasing risks of overdoses and deaths. Herein, we review a multidisciplinary project designed to implement and evaluate clinic-based interventions in Oregon, USA, to improve pain management, opioid prescribing and treatment of OUD. The intervention, called Improving PaIn aNd OPiOId MaNagemenT in Primary Care (PINPOINT), combines practice facilitation, academic detailing and education through the Oregon ECHO Network. Implementation of PINPOINT has occurred across the Oregon Rural Practice-based Research Network and has involved 49 clinic sites to date. To evaluate the impact of the intervention, the research team created the Provider Results of Opioid Management and Prescribing Training (PROMPT), a dataset that links information from the state prescription drug monitoring program, all-payer claims database, emergency medical services, vital records and substance use disorder treatment system. The PROMPT dataset will allow evaluation of the impact of the intervention at both the clinician and clinic levels. Due to the constraints of the COVID-19 pandemic, elements of both implementation and evaluation required significant adaptations to continue to meet the original project goals.

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Authors: Giovanna Malara, Gabriella Fabbrocini, Caterina Trifirò, Martina Burlando

Background: Dimethyl fumarate (DMF) is an oral systemic agent approved for the treatment of moderate-to-severe psoriasis vulgaris. It has a favourable tolerability profile, but it is associated with a high incidence of mild and reversible adverse events. The aim of the article is to describe a clinical experience aimed at increasing tolerability. Patients and methods: A group of patients was treated with DMF with a titration schedule, according to clinical practice, although a personalization of the step-up timing was allowed. The highest dose was the minimal effective dose or the maximal tolerated doses. Results: DMF treatment was effective in reducing the disease severity and improving the quality of life. DMF was well tolerated as only mild, mainly gastrointestinal, adverse events occurred in these patients. In addition, the up-titration schedule seemed to provide a reduced incidence of adverse events compared with the fixed dose. Conclusion: Our experience suggested that the recommended up-titration schedule of DMF, adjusted and personalized according to patient needs and physician opinion, provided a relevant clinical benefit and was well tolerated.

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Authors: Rajesh R Tampi, Brent P Forester, Marc Agronin

Alzheimer’s disease (AD) is the most common cause for dementia worldwide. Until recently, all approved treatments for AD were symptomatic and not disease modifying. On 7 June 2021, the US FDA approved aducanumab, a human IgG1 anti-Aβ monoclonal antibody selective for Aβ aggregates, as the first disease-modifying treatment for AD. Aducanumab is approved in the United States for the treatment of mild cognitive impairment or mild-dementia stage of AD. In this Editorial, we review the trial data for aducanumab in the treatment of AD and the controversies that its approval has generated.

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Authors: Peter MB English

The vaccination campaign in the United Kingdom has been extremely successful. Bold decisions were made to order vaccines early, before we knew if they would be effective, and to vary from the manufacturers’ recommendations by extending the ‘prime-boost’ interval between the first and second doses of the AstraZeneca and Pfizer-BioNTech vaccines. These decisions were controversial at the time but have contributed enormously to the effectiveness of the vaccination programme. This is a personal perspective on the approach to COVID-19 vaccination in the United Kingdom.

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Authors: Valeria Nucera MD, Elisabetta Gerratana MD, Manuela Giallanza MD, Laura La Corte MD, Donatella Sangari MD, Fabiola Atzeni MD, PhD

Interstitial lung diseases (ILDs) are some of the first and most serious complications of connective tissue diseases (CTDs). However, the pathogenesis of CTD-related ILDs (CTD-ILDs) is still unclear and their treatment often depends on functional and radiographic disease progression as well as on patient age and comorbidities. It can be difficult to manage CTD-ILDs due to their heterogeneous nature, the lack of robust therapeutic data, and the few well-defined outcome measures. This review focuses on cyclophosphamide due to its crucial role in the treatment of systemic sclerosis-related ILD, particularly in the case of patients with progressive ILD. This narrative review was performed using PubMed, Medline, and Cochrane Library databases to retrieve English language papers published between 2000 and April 2020 concerning the treatment of CTD-ILDs with cyclophosphamide.

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Authors: Kam Lun Hon, Wun Fung Hui, Alexander KC Leung

Background: Poisoning causes significant morbidity and sometimes mortality in children worldwide. The clinical skill of toxidrome recognition followed by the timely administration of an antidote specific for the poison is essential for the management of children with suspected poisoning. This is a narrative review on antidotes for toxidromes in paediatric practice. Methods: A literature search was conducted on PubMed with the keywords “antidote”, “poisoning”, “intoxication”, “children” and “pediatric”. The search was customized by applying the appropriate filters (species: humans; age: birth to 18 years) to obtain the most relevant articles for this review article. Results: Toxidrome recognition may offer a rapid guide to possible toxicology diagnosis such that the specific antidote can be administered in a timely manner. This article summarizes toxidromes and their respective antidotes in paediatric poisoning, with an emphasis on the symptomatology and source of exposure. The antidote and specific management for each toxidrome are discussed. Antidotes are only available for a limited number of poisons responsible for intoxication. Antidotes for common poisonings include N-acetyl cysteine for paracetamol and sodium thiosulphate for poisoning by cyanide. Conclusion: Poisoning is a common cause of paediatric injury. Physicians should be familiar with the recognition of common toxidromes and promptly use specific antidotes for the management of childhood toxidromes.

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Authors: Rodrigo M Burgos, Melissa E Badowski, Emily Drwiega, Samaneh Ghassemi, Nikki Griffith, Fischer Herald, Mikayla Johnson, Renata O Smith, Sarah M Michienzi

The unprecedented toll of severe acute respiratory syndrome coronavirus 2, the virus responsible for coronavirus 2019 disease (COVID-19), jumpstarted the race towards the development and distribution of effective treatment and prevention options. With an urgent need to slow viral transmission, lessen disease severity, and reduce mortality, biopharmaceutical companies rapidly began investigating potential COVID-19 vaccinations. While typical vaccine development can take upwards of 10–15 years, COVID-19 vaccines were developed in less than a year after the identification of COVID-19. To accomplish this feat, clinical development, manufacturing scale-up and distribution are occurring in parallel for the four COVID-19 vaccine front-runners. This remarkable opportunity will forever change the drug development process and would not be possible without tremendous dedication from the public and private sectors, researchers, and clinical trial volunteers. However, many challenges still lie ahead. Comprehensive plans for equitable vaccine education, distribution, administration and post-marketing surveillance must be implemented successfully to overcome vaccine hesitancy, supply-chain obstacles and healthcare provider shortages in an already overburdened healthcare system. We are moving forward at a remarkable pace but worldwide immunity through vaccination will take time to achieve. Thus, current prevention efforts of masking, hand hygiene and social distancing must remain in effect for the foreseeable future. We must remain diligent and not fatigue in our efforts. Ending the COVID-19 pandemic cannot rest on the promise of vaccination alone – it will require a continued, robust and multi-faceted approach to disease treatment and prevention.

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Authors: Kam Lun Hon, Karen Ka Yan Leung, Felix Oberender, Alexander KC Leung

Background: Septic shock is a common critical illness associated with high morbidity and mortality in children. This article provides an updated narrative review on the management of septic shock in paediatric practice. Methods: A PubMed search was performed using the following Medical Subject Headings: “sepsis”, “septic shock” and “systemic inflammatory response syndrome”. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies and reviews. The search was limited to the English literature and specific to children. Results: Septic shock is associated with high mortality and morbidity. The outcome can be improved if the diagnosis is made promptly and treatment initiated without delay. Early treatment with antimicrobial therapy, fluid therapy and vasoactive medications, and rapid recognition of the source of sepsis and control are the key recommendations from paediatric sepsis management guidelines. Conclusion: Most of the current paediatric sepsis guideline recommendations are based on the adult population; therefore, the research gaps in paediatric sepsis management should be addressed.

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Authors: Tiago Torres, Margarida Gonçalo, Maria João Paiva Lopes, Cristina Claro, Leonor Ramos, Manuela Selores, Pedro Mendes Bastos, Joana Rocha, Rodrigo Carvalho, Alberto Mota, Paulo Filipe on Behalf of the Atopic Dermatitis Group of the Portuguese Society of Dermatology and Venereology

Atopic dermatitis is a highly prevalent chronic, immune-mediated inflammatory skin disease with a significant burden on patients, families and healthcare systems. This article presents recommendations developed by the Atopic Dermatitis Group of the Portuguese Society of Dermatology and Venereology addressing several clinical questions that arise in the management and care of moderate-to-severe atopic dermatitis with biologic agents and Janus kinase (JAK) inhibitors based on the available evidence. The recommendations were generated after a thorough evaluation of existing guidelines on the treatment of atopic dermatitis, publications concerning new biologics and JAK inhibitors not yet incorporated into existing guidelines, and expert-based recommendations. It also includes considerations on atopic dermatitis severity, indications for initiating biologic agents and JAK inhibitors, parameters to be considered in the treatment choice, in particular treatment goals, and recommendations for the use, screening and monitoring of these therapies.

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Authors: Omar Castaneda-Puglianini, Julio C Chavez

Immunotherapy has revolutionized the treatment of cancers. There are several approaches, including naked monoclonal antibodies, antibody–drug conjugates, immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies with important success. Bispecific antibodies represent a novel immunotherapeutic approach for the treatment of several malignancies, in particular non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Early-phase studies have shown encouraging clinical activity in poor-risk B cell NHL and MM. Several constructs are currently available and in clinical development for the treatment of these malignancies. Here, we present a narrative review of the most current data on bispecific antibodies in B cell NHL and MM.

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Authors: Karen Ka Yan Leung, Kam Lun Hon, Wun Fung Hui, Alexander KC Leung, Chi Kong Li

Background: With advancements in the field of oncology, cancer survival rates have improved dramatically but modern cancer treatments also come with an increasing number of disease and treatment-associated complications. This article provides an updated narrative review on the pathophysiology, clinical presentations and latest management strategies for common paediatric oncological emergencies. Methods: An extensive PubMed® search of all human studies in the English literature was performed in Clinical Queries for different oncology syndromes and conditions using the following Medical Subject Headings: “tumour lysis syndrome”, “hyperleukocytosis”, “disseminated intravascular coagulation”, “superior mediastinal syndrome”, “superior vena cava syndrome”, “sepsis”, “severe inflammatory response syndrome”, “acute respiratory distress syndrome”, “posterior reversible encephalopathy syndrome” and “reversible posterior leukoencephalopathy syndrome”. Categories were limited to clinical trials and reviews for ages from birth to 18 years. Results: The general description, presentation and management of these oncologic emergencies are systematically described. Early recognition along with prompt and proactive treatment can reduce the chances of potential complications and improve the clinical outcomes, thereby improving not only survival rates in oncology patients but also their clinical outcomes and quality of life. Conclusions: Oncologic emergencies are associated with significant mortality and morbidity. Healthcare professionals involved with the care of oncology patients must be vigilant of these emergencies.

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Authors: Rajesh R Tampi, Pallavi Joshi, Gargi Bhattacharya, Sheila Gupta

Objectives: This narrative review aims to synthesize information from the literature regarding older-age bipolar disorder (OABD) in order to provide up-to-date information on this important illness. Methods: We searched Ovid (Medline, Embase and PsychInfo) on October 1, 2020, using the keywords “bipolar disorder”, “older adults” and “elderly” to identify relevant articles on OABD. Additionally, the bibliography of identified articles was reviewed for pertinent studies. Discussions: OABD is a term that is used to describe bipolar disorder (BD) occurring amongst individuals ≥50 years of age. Evidence indicates that OABD accounts for a quarter of all cases of BD. When compared to individuals with early-onset BD, individuals with OABD have a greater association with cerebrovascular disease and other neurological disorders, less family history of mood disorders, and utilize almost four times the total amount of mental health services. In addition, they are four times more likely to have psychiatric hospitalizations when compared to age-matched controls. Despite a dearth of controlled studies on the use of pharmacotherapy amongst individuals with OABD, available evidence from mixed-age studies indicates the efficacy of commonly used medications in individuals with early-onset BD. Additionally, psychosocial treatments have been found to be effective as adjunctive management strategies amongst individuals with OABD. Furthermore, electroconvulsive therapy may be effective in the treatment of refractory cases of OABD. Conclusions: There is a great need for an improved understanding of the phenomenology and neurobiology of OABD. Additionally, research into effective treatments for this serious psychiatric disorder will mitigate the suffering of individuals with OABD.

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Authors: Caterina Vacchi PhD, Andreina Manfredi MD, Giulia Cassone PhD, Gian Luca Erre MD, Carlo Salvarani MD, Marco Sebastiani MD

Interstitial lung disease (ILD) represents a severe pulmonary complication of connective tissue diseases, rheumatoid arthritis (RA), and antineutrophil cytoplasmic antibodyassociated vasculitis. Treatment of ILD, mainly based on immunosuppression, remains challenging. Rituximab (RTX), a monoclonal antibody binding to CD20, is considered a valuable therapeutic choice in cases of refractory ILD. Here, we review the available efficacy and safety data on the use of RTX in the treatment of rheumatic disease-related ILD. Despite controversial efficacy data, RTX seems to be able to stabilize or improve ILD related to RA and antisynthetase syndrome and in established and severe ILD complicating systemic sclerosis. Fewer data are available regarding ILD related to Sjögren syndrome, systemic lupus erythematosus, and antineutrophil cytoplasmic antibody-associated vasculitis. To date, few prospective studies are available and randomized trials are still ongoing with the purpose of exploring the role of RTX in this condition, including the supposed relationship between efficacy and ILD radiologic patterns and safety data, up to now derived mainly from RA studies. Despite an overall acceptable safety profile, concerns remain regarding an increased infectious disease risk in patients with ILD as well as possible lung toxicity and the increased rate of immune-mediated reactions in patients with connective tissue diseases. In conclusion, RTX is a relevant therapeutic option for rheumatic disease-related ILD despite the existing uncertainties; ongoing trials are expected to clarify its use.

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Authors: Jason HS Kim, Joseph M Lam

Infantile haemangiomas (IHs) are relatively common benign vascular tumours found in the paediatric population. They have varying sizes and involve different depths in the skin leading to various colours, shapes and textures. Although considered harmless in most cases, they may lead to life-threatening complications or cause permanent disfigurations and organ dysfunction. For problematic IHs, the treatment options include oral and topical beta-blockers, systemic corticosteroids, laser treatment, and surgery. In this narrative review, the treatment options for problematic IH are compared and delivered concisely to facilitate the clinical decisions from practitioners, including those in primary care settings. Oral propranolol is currently considered the first-line intervention for problematic IHs. For superficial lesions, there is robust evidence for the use of topical timolol maleate. Systemic corticosteroids are sometimes used in specific situations such as resistance or contraindications to beta-blockers. Surgical excision can be considered in cases requiring urgent intervention such as airway obstruction; this can be done alongside laser therapies for the removal of residual tissue or when reconstructing areas of deformity. The combination of multiple treatment modalities may lead to a more rapid clinical response.

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Authors: Gian Luca Erre MD, PhD, Marco Sebastiani PhD, Andreina Manfredi MD, Elisabetta Gerratana MD, Fabiola Atzeni MD, Giuseppe Passiu MD, Arduino A Mangoni MD

Fibrosing interstitial lung disease (ILD) is one of the most important causes of morbidity and mortality in patients with connective tissue diseases (CTDs), which include systemic sclerosis, rheumatoid arthritis, Sjögren’s syndrome, idiopathic inflammatory myositis and systemic lupus erythematosus. The treatment of CTD-ILDs is challenging due to the paucity of proven effective treatments. Recently, two antifibrotic drugs conditionally approved for use in patients with idiopathic pulmonary fibrosis, nintedanib and pirfenidone, have been trialled in CTD-ILDs based on overlapping pathological and clinical features between the two diseases. In this narrative review, we discuss the experimental evidence and clinical trials investigating the efficacy and safety of antifibrotic drugs in patients with CTD-ILDs and the potential mechanisms of action involved. Results from clinical trials suggest that nintedanib use retards lung function decline in progressive fibrotic CTD-ILDs. By contrast, the evidence for the efficacy of pirfenidone in these groups is not equally compelling. Further, well-designed randomized clinical trials are needed to evaluate the efficacy and safety of individual antifibrotic drugs in specific CTD-ILD subgroups.

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Authors: Silvia Natoli

Objective: Ketamine is an anaesthetic agent with a unique dissociative profile and pharmacological effects ranging from the induction and maintenance of anaesthesia to analgesia and sedation, depending on the dose. This article provides information for the clinical use of ketamine in anaesthesia, in both conventional and special circumstances. Methods: This is a non-systematic review of the literature, through a PubMed search up to February 2021. Results: With a favourable pharmacokinetic profile, ketamine is used in hospital and prehospital settings for emergency situations. It is suitable for patients with many heart conditions and, unlike other anaesthetics, its potential for cardiorespiratory depression is low. Furthermore, it may be used when venous access is difficult as it may be administered through various routes. Ketamine is the anaesthetic of choice for patients with bronchospasm thanks to its bronchodilatory and anti-inflammatory properties. Conclusion: With a favourable pharmacokinetic profile, ketamine is used in hospital and prehospital settings for emergency situations and is suitable for patients with many cardiac and respiratory conditions.

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Authors: Theresa NH Leung, James WCH Cheng, Anthony KC Chan

Obstructive sleep apnoea syndrome (OSAS) is defined as the intermittent reduction or cessation of airflow due to partial or complete obstruction of the upper airway during sleep. Paediatric OSAS has specific contributing factors, presenting symptoms and management strategies in various age groups. Untreated OSAS can lead to detrimental effects on neurocognitive development and cardiovascular and metabolic functions of a growing child. In the past decade, practice guidelines have been developed to guide the evaluation and management of OSAS. This article provides a narrative review on the current diagnostic and treatment options for paediatric OSAS. Alternative diagnostic tools other than the standard polysomnography are discussed. Adenotonsillectomy is considered the first-line therapy yet it is not suitable for treatment of all OSAS cases. Nocturnal non-invasive positive airway pressure ventilation is effective and could be the priority treatment for patients with complex comorbidities, residual OSAS post-adenotonsillectomy or obesity. However, intolerance and non-adherence are major challenges of positive airway pressure therapy especially in young children. There is increasing evidence for watchful waiting and other gentler alternative treatment options in mild OSAS. The role of anti-inflammatory drugs as the primary or adjunctive treatment is discussed. Other treatment options, including weight reduction, orthodontic procedures and myofunctional therapy, are indicated for selected patients. Nevertheless, the successful management of paediatric OSAS often requires a multidisciplinary team approach.

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Authors: Amalia Leceta, Aintzane García, Ander Sologuren, Cristina Campo

Background: Bilastine, a non-sedating H1-antihistamine, is indicated to treat the symptoms of allergic disorders (e.g. rhinoconjunctivitis and urticaria) in adults and adolescents and, more recently, in children. Following its marketing approval, many questions regarding the ideal use of bilastine in various clinical practice situations have been received by the Medical Information Department (MID) of Faes Farma Spain. This article is an update of a previous review, with a focus on recent clinical information on the use of bilastine in paediatric and other populations. Methods: Results of recent clinical studies in paediatric and other populations as well as questions received and responses provided by the Faes Farma MID. Results: The information regarding the use of bilastine in paediatric patients is the most relevant aspect of this updated review. The stepwise approval of the paediatric formulations in various countries started with the European Medicines Agency approval in 2017 in accordance with a 2009 Paediatric Investigation Plan, followed by approval in other countries. The queries that are most commonly received by the Faes Farma MID include the potential for drug interactions involving bilastine and other frequently used drugs, and the use of bilastine in special populations or to treat specific symptoms related to allergic conditions. As the concomitant use of many medications is not permitted during clinical trials, the advice provided regarding the concomitant use of other medications with bilastine considers the pharmacological properties of both the drug in question and bilastine, as well as expert opinion. Likewise, advice regarding the use of bilastine in special populations (e.g. patients with renal impairment, obesity, lactose intolerance, and elderly or pregnant individuals) or to treat specific symptoms (e.g. treatment-resistant urticaria, pruritus or BASCULE syndrome) considers the best evidence from a variety of sources, including clinical studies, real-world experience, guideline recommendations and expert opinion. Conclusion: This updated review provides current data regarding the best use of bilastine in specific situations and patients and identifies areas in which further knowledge is required. Although decisions regarding the use of bilastine may be aided by expert opinion that relies on knowledge of the underlying science, additional research and evidence are required to answer certain queries regarding the use of bilastine.

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Authors: James S Leung

Background: Asthma is the most common chronic disease of childhood and a major source of childhood health burden worldwide. These burdens are particularly marked when children experience characteristic ‘symptom flare-ups’ or acute asthma exacerbations (AAEs). AAE are associated with significant health and economic impacts, including acute Emergency Department visits, occasional hospitalizations, and rarely, death. To treat children with AAE, several medications have been studied and used. Methods: We conducted a narrative review of the literature with the primary objective of understanding the evidence of their efficacy. We present this efficacy evidence in the context of a general stepwise management pathway for paediatric AAEs. This framework is developed from the combined recommendations of eight established (inter)national paediatric guidelines. Discussion: Management of paediatric AAE centres around four major care goals: (1) immediate and objective assessment of AAE severity; (2) prompt and effective medical interventions to decrease respiratory distress and improve oxygenation; (3) appropriate disposition of patient; and (4) safe discharge plans. Several medications are currently recommended with varying efficacies, including heliox, systemic corticosteroids, first-line bronchodilators (salbutamol/albuterol), adjunctive bronchodilators (ipratropium bromide, magnesium sulfate) and second-line bronchodilators (aminophylline, i.v. salbutamol, i.v. terbutaline, epinephrine, ketamine). Care of children with AAE is further enhanced using clinical severity scoring, pathway-driven care and after-event discharge planning. Conclusions: AAEs in children are primarily managed by medications supported by a growing body of literature. Continued efforts to study the efficacy of second-line bronchodilators, integrate AAE management with long-term asthma control and provide fair/equitable care are required.

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Authors: Francisca Gonçalves, Egídio Freitas, Tiago Torres

Background: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide. AD pathogenesis is multifactorial, involving environmental and genetic factors. IL-13 stands out as one of the main cytokines in the pathophysiology of AD. Currently, dupilumab, which targets both IL-4 and IL-13 signalling, is the only biologic agent approved for the treatment of moderate-to-severe AD. New targeted biologic therapies are being developed, such as lebrikizumab and tralokinumab, two selective IL-13 inhibitors. This article reviews the role of IL-13 in AD and the most recent data on lebrikizumab and tralokinumab. Methods: A narrative review of the literature was written after retrieving relevant articles in the PubMed database (up until December 2020) using the following keywords present in the title, abstract or body: atopic dermatitis; interleukin 13; IL-13; tralokinumab; lebrikizumab, biologic therapy. Discussion: A phase IIb trial showed that all three dosing regimens evaluated (lebrikizumab 125 mg every 4 weeks (Q4W), 250 mg Q4W or 250 mg every 2 weeks) achieved rapid and dose-dependent efficacy concerning the signs and symptoms of AD, with a statistically significant improvement, at week 16. Tralokinumab was studied in three phase III clinical trials and reached its primary endpoints at week 16 (ECZTRA 1 and 2 in monotherapy and ECZTRA 3 with concomitant topical corticosteroids), with response maintained over time. Both lebrikizumab and tralokinumab exhibited good safety profiles in AD trials, with adverse effects usually being comparable between the control and treatment groups. Conclusion: The evidence supports the hypothesis that selective antagonism of IL-13 is sufficient to control AD, providing an improvement in the patient’s quality of life. Therefore, the development of lebrikizumab and tralokinumab represents a new and exciting phase in the management of AD.

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

Background: Acne vulgaris is the most common skin disease that can lead to disfigurement and psychological distress. This article aims to provide a narrative updated review on the management of acne vulgaris. Methods: A PubMed search was performed with Clinical Queries using the key term “acne”. The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies and reviews. The search was restricted to articles published in English. Results: Treatments of acne include proper skin care, topical medications, oral medications and procedural therapies. Topical agents are the first-line treatment for mild-to-moderate acne and can be used as combination therapy for more severe acne. Systemic therapies are usually prescribed for the initial treatment of moderate-to-severe acne as well as for acne that is refractory to topical therapies. Conclusion: Topical retinoids are the drugs of choice for the treatment and maintenance therapy of patients with mild-to-moderate acne vulgaris. Depending on the severity of the acne, topical retinoids may be used alone or in combination with benzoyl peroxide and topical or oral antibiotics. Oral antibiotics are an important therapy for inflammatory acne unresponsive to topical therapy. Neither topical nor oral antibiotics should be used as monotherapy. Oral contraceptives and/or spironolactone are useful for many women with acne. Oral isotretinoin is the drug of choice for severe, extensive, nodular acne vulgaris but is also often used in moderate cases where scarring is evident, acne-related psychosocial distress is significant or other treatment modalities have failed.

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Authors: Constantine E Kosmas, Dafni Pantou, Andreas Sourlas, Evangelia J Papakonstantinou, Rogers Echavarria Uceta, Eliscer Guzman

Cardiovascular disease (CVD) represents the leading cause of death worldwide. The role of low-density lipoprotein-cholesterol (LDL-C) in the pathophysiology of atherosclerosis and CVD has been well recognized. Statins are the standard of care for the management of hypercholesterolaemia, and their effectiveness in lowering LDL-C and reducing CVD risk in both primary and secondary prevention has been well established. However, several patients fail to attain optimal LDL-C goals or are intolerant to statins, especially at high doses. PCSK9 inhibitors, bempedoic acid, inclisiran, ANGPTL3 inhibitors, PPARβ/δ agonists and LXR agonists are novel or upcoming LDL-C-lowering agents that have shown promising beneficial results. This review aims to present and discuss the current clinical and scientific data pertaining to the new and emerging lipid-modifying LDL-C-lowering drugs.

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Authors: Xenophon Kassianides BSc (Hons), MBBS, MRCP(UK), Sunil Bhandari MBChB, MRCP, FRCP, PhD, M Clin Edu, FHEA

Third-generation intravenous (i.v.) iron preparations are safe and efficacious and are increasingly used in the treatment of iron-deficiency anaemia. Hypophosphataemia is emerging as an established side-effect following the administration of certain compounds. Symptoms of hypophosphataemia can be masked by their similarity to those of iron-deficiency anaemia and both acute and chronic hypophosphataemia can be detrimental. Hypophosphataemia appears to be linked to imbalances in the metabolism of the phosphatonin fibroblast growth factor 23. In this narrative review, we discuss the possible pathophysiology behind this phenomenon, the studies comparing third-generation i.v. iron compounds, and the potential implications of the changes in fibroblast growth factor 23 and hypophosphataemia. We also present an algorithm of how to approach such patients requiring i.v. iron in anticipation of hypophosphataemia and how the impact related to it can be minimized.

1

Authors: Felicia Pantò MD, Liboria Adamo BSc, Carla Giordano MD, Carmelo Licciardello MD

The authors wish to make the following corrections to their article: Pantò F, Adamo L, Giordano C, Licciardello C. Efficacy and safety of photodynamic therapy with RLP068 for diabetic foot ulcers: a review of the literature and clinical experience. Drugs in Context 2020; 9: 2019-10-3. DOI: 10.7573/dic.2019-10-3

3

Authors: Antonio Ruggiero MD, Alberto Romano MD, Giorgio Attinà MD

Europe is now the epicenter of the COVID-19 outbreak. Many concerns have arisen about the management and treatment of children with cancer while researchers are wondering how to deal with this devastating pandemic. In view of the epidemiological and clinical characteristics of the COVID-19 outbreak, it is fundamental to stress that the behavior and hygiene rules adopted by children with cancer must be respected and implemented in order to continue to safeguard their health for the current pandemic.

4

Authors: Silvia Pilar González Rodríguez MD, PhD

The changes that occur in sex hormone levels, body composition, and lipid/lipoprotein levels during the menopause transition, together with vascular remodeling, increase the risk of cardiovascular disease (CVD) in postmenopausal women. Any treatments prescribed for concomitant conditions during menopause should not exacerbate CVD risk factors. Ospemifene is the first non-hormonal, non-estrogenic drug approved to treat moderate-to-severe vulvovaginal atrophy (VVA), a component of genitourinary syndrome of menopause, in women unsuited to receive vaginal estrogen therapy. This case study reports the experience of a postmenopausal woman with VVA who required escalation from local therapy and presented CVD risk factors (family history and hypertension). During the first 6 months of ospemifene treatment, and before initiating concomitant simvastatin for persistently elevated total cholesterol concentrations, improvements were observed in several lipid parameters (decreases of 11% in total cholesterol, 16% in low density lipoprotein cholesterol, and 15% in triglycerides) which may have been attributable at least in part to ospemifene. Improvements in lipid parameters during ospemifene treatment for VVA may contribute toward reducing long-term CVD risk.

5

Authors: Steven King-fan Loo MBChB, FRCP, Kam Lun Hon MBBS, MD, FAAP, FCCM, Alexander KC Leung MBBS, FRCPC, FRCP (UK & Irel), FRCPCH, FAAP, Tak Cheung Yung MBBS, MRCPCH, Man Ching Yam MBChB, MRCPCH

We have managed two anonymized siblings with Kawasaki disease (KD). The occurrence of KD in the elder brother alerted us to the occurrence of incomplete KD in the younger brother. Both siblings were treated with intravenous immunoglobulin and a high dose of dipyridamole with resolution of the coronary artery aneurysm. Dipyridamole was used instead of aspirin because both siblings were glucose-6-phosphate dehydrogenase deficient for which aspirin was contraindicated. To prevent damage to the coronary arteries, treatment should be started as soon as the diagnosis is made. There have been a lot of advances in medical therapy in recent years, which are reviewed together with conventional proven therapy for KD. Early diagnosis and prompt treatment are important to achieve optimal treatment outcome in KD. Family history of KD among siblings enables clinicians for an earlier diagnosis so as to prevent the disease complications particularly in patients with incomplete features.

5

Authors: Santiago Palacios MD, PhD

The menopause-related decline in estrogen levels leads to an array of genital, sexual, and urinary symptoms collectively known as genitourinary syndrome of menopause. The constellation of symptoms associated with vulvar and vaginal atrophy (VVA) can have a profoundly detrimental effect on a woman’s sexual function, relationships, and quality of life. Ospemifene is a selective estrogen receptor modulator indicated for treatment of moderate-to-severe symptomatic VVA in postmenopausal women who are not candidates for local vaginal estrogen therapy or have contraindications for estrogen products. Ospemifene is administered orally, thus avoiding the inconveniences of local therapy, and can be used in women with VVA and a history of breast cancer after completing all (including adjuvant) breast cancer treatment. As well as restoring vaginal health in symptomatic VVA, ospemifene may have collateral benefits of importance to postmenopausal women. In this Special Issue entitled “Treatment of Vulvar and Vaginal Atrophy: Clinical Experience with Ospemifene,” illustrative case studies examine the experiences of women with VVA during treatment with ospemifene. Specific topics include the effects of ospemifene on bone markers; its use in breast cancer survivors and in women with dyslipidemia, urinary incontinence, or VVA-related sexual dysfunction; and its concomitant use with laser therapy.

5

Authors: Antonio Ruggiero MD, Palma Maurizi MD, Silvia Triarico MD, Michele Antonio Capozza MD, Stefano Mastrangelo MD, Giorgio Attinà MD

Infantile haemangiomas (IHs) are the most common benign tumours of childhood; despite the benign histology, prognosis depends on severity of visceral involvement, with a mortality rate ranging from 50 to 90%. In this paper, we describe two infants with multifocal infantile haemangiomatosis and hepatic involvement. This condition should receive appropriate management as it can be potentially lethal due to the high risk of systemic complications such as cardiac or fulminant hepatic failure and abdominal compartment syndrome. Both cases presented with liver involvement, but only the infant who had an excellent response to propranolol is still alive. A review of current therapeutic approaches is also presented even though there are, at present, no uniform guidelines for treatment, despite the relative frequency of infantile haemangiomatosis and the potential severe complications.

6

Authors: Rodolfo Sacco MD, PhD, Vincenzo Messina MD, Umberto Vespasiani Gentilucci MD, Luigi Elio Adinolfi MD, Antonio Ascione MD, Giorgio Barbarini MD, Angelo Barlattani MD, Giuseppe Cariti MD, Raffaele Cozzolongo MD, Basilio Fimiani MD, Ruggiero Francavilla MD, Caterina Furlan MD, Giovanni Garrucciu MD, Vincenzo Iovinella MD, Luca Rinaldi MD, Massimo Marignani MD, Paola Begini MD, Valeria Pace Palitti MD, Adriano M Pellicelli MD, Gaetano Scifo MD, Antonio Facciorusso MD, Luca Giacomelli PhD, Aashni Shah BSc, Gaetano Bertino MD, Serena Perazzo MD, Giampaolo Bresci MD, Antonio Izzi MD

Background: The once-daily oral combination of daclatasvir (DCV) and sofosbuvir (SOF), with or without ribavirin (RBV), is effective and well tolerated in patients with hepatitis C virus (HCV). However, further field-practice studies are necessary to investigate the effectiveness and safety of the DCV+SOF combination in diverse subpopulations of patients with HCV, including those who are more challenging to treat such as patients with a genotype 3 (G3) infection. The aim of this retrospective, multicenter, field-practice study was to investigate the therapeutic efficacy and safety of the oral combination of DCV and SOF, with or without RBV (DCV+SOF±RBV), in a large unselected cohort of patients with chronic HCV infection (CHC). Patients and methods: Consecutive patients received DCV+SOF±RBV for 12 or 24 weeks. The efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12). Safety factors were also considered. Results: A total of 620 patients were included in this study; the predominant genotype was G3 (55.3%). Of the total sample, 248 (40%) patients were treated with DCV+SOF+RBV and 372 (60%) did not receive RBV. The majority of patients assessed at week 12 (98%, 596/608) achieved SVR12. Among G3 patients, 98.8% (335/339) achieved SVR12. The most common adverse event was elevated bilirubin (30.6%), recorded in 4.9% of cases as a grade 3–4 adverse event. Conclusion: This study shows the high pan-genotypic effectiveness and safety of the DCV+SOF±RBV combination in a large, unselected sample of CHC patients with G1–4, including a wide proportion of G3 CHC patients.

6

Authors: Ana Rosa Jurado López MD, PhD, Francisca Molero Rodríguez MD

The pathophysiological changes associated with hypoestrogenism of menopause, a condition known as genitourinary syndrome of menopause, are responsible for the hallmark symptoms of vulvovaginal atrophy (VVA), namely dyspareunia secondary to vaginal dryness. Many postmenopausal women with VVA find sexual relations to be challenging or impossible. Ospemifene has estrogen-like effects on the vaginal epithelium, and is indicated to treat moderate-to-severe symptomatic VVA (Europe) or moderate-to-severe symptomatic dyspareunia and vaginal dryness (United States) in postmenopausal women. The case studies presented in this article follow the progress of two women who began treatment with ospemifene for the main presenting symptom of dyspareunia. Both women had concerns about the impact of their symptomatology on new relationships. The patient in case 1 experienced relevant improvement within 3 months of treatment start and, by 1 year, dyspareunia was absent. Vaginal lubricants were no longer required. The patient in case 2 experienced relevant improvement within 4 weeks of starting ospemifene. At 15 months, with the use of a lubricant for vaginal penetration, she could enjoy sexual intercourse without pain. At the time of writing, she had been receiving ospemifene continuously for more than 2 years with effective symptom relief and good tolerability.

6

Authors: Mariella Lilue MD, Santiago Palacios MD, PhD, María del Carmen Pingarrón Santofimia MD

Women with breast cancer are at a higher risk of developing vulvar and vaginal atrophy (VVA), a major component of the genitourinary syndrome of menopause, due to the combined estrogen-depleting effects of chemotherapy, adjuvant hormone therapy, and menopause. Ospemifene is approved to treat VVA in postmenopausal women with a history of breast cancer after completion of all breast cancer (including adjuvant) treatments. This article examines the background characteristics and outcomes in two postmenopausal women with a history of breast cancer who were treated with ospemifene for VVA. In the first case, a 78-year-old postmenopausal woman developed VVA while on aromatase inhibitor therapy for breast cancer. In the second case, a 54-year-old woman developed VVA many years after completing breast cancer therapy but not long after menopause. Both women had meaningful symptomatic improvement within 3 months of starting ospemifene treatment. Further improvement allowed each woman to resume sexual relations which had been a concern at presentation. Mammography and breast ultrasound imaging indicated no changes in breast tissue during treatment. Ospemifene is a useful therapeutic option for postmenopausal women with VVA and a history of breast cancer.

7

Authors: George J Wan PhD, Ishveen Chopra PhD, John Niewoehner PharmD, Samuel F Hunter MD, PhD

Background: Relapses are common in patients with multiple sclerosis (MS) even after the use of disease-modifying therapies. Repository corticotropin injection (RCI), plasmapheresis (PMP), and intravenous immunoglobulin (IVIg) may be utilized as alternative therapies in the management of MS relapse. There is a lack of health economic studies on these alternative therapies for the acute exacerbations of MS. The objective of this study was to estimate the cost per response of RCI compared with PMP or IVIg from the United States (US) commercial payer perspective. Methods: Costs and response rates were sourced from published peer-reviewed observational studies. The cost of care included MS-related inpatient, outpatient, and medication costs. Treatment response was defined as no evidence of additional relapse treatment or procedure claims within 30 days after treatment. The cost per response for each treatment was calculated by dividing the total annual cost of care by the proportion of patients with resolved relapse for each treatment. The incremental cost per response ratio was calculated by dividing the difference in costs and the proportion of responses for RCI versus PMP or IVIg. One-way sensitivity analysis (OWSA) was conducted for both costs and response rates. All included costs were inflated to the 2019 US dollars. Results: With a lower total annual cost of care and a higher response rate, RCI had a lower cost per response (US$141,970) compared with PMP or IVIg (US$253,331). RCI had a lower cost per response even when more stringent estimates for RCI were applied in the OWSA. The annual cost of care had a greater influence on the cost per response in the OWSA. Conclusions: Based on the estimates from the real-world evidence, our economic evaluation suggests that RCI may have real-world clinical and economic benefits for patients with MS relapse who fail on corticosteroid therapy.

7

Authors: Adam Kisling MD, Jason Jones MD, Caleb Hixson DO FCAP, David Hostler MD MPH FACP, Jordanna Hostler MD FACP

A 55-year-old woman with cough-variant asthma presented for 1 month of worsening wheezing, cough, and dyspnea refractory to treatment. Initial laboratory findings revealed profound peripheral eosinophilia, and a chest computed tomography showed bi-apical consolidation. Bronchio-alveolar lavage demonstrated alveolar eosinophilia. She was diagnosed with idiopathic chronic eosinophilic pneumonia (ICEP). Her peripheral eosinophilia and respiratory symptoms improved rapidly with high-dose systemic corticosteroid therapy. However, she was intolerant to corticosteroid monotherapy due to non-compliance and psychological adverse effects. Mepolizumab was initiated as a steroid-sparing agent, resulting in successful therapy for 2 years without relapse or adverse effects. Mepolizumab is an interleukin-5 (IL-5) antagonist monoclonal antibody, which is a targeted therapy for diseases mediated by eosinophil activity and eosinophil proliferation. Mepolizumab is typically used in ICEP refractory to steroids, but this case supports its use in cases of glucocorticoid intolerance. Further study of IL-5 antagonist therapies for ICEP may identify an alternative treatment modality for patients in whom the adverse effects of corticosteroids pose a challenge.

7

Authors: Fernanda Gomes Gonçalves Chaer MD, Juliana Miranda de Lucena Valim MD, Rogério Castro Reis MD, Giselle Burlamaqui Klautau PhD, Branca Dias Batista de Souza MSc

Background: Brazil is a country with a high burden of tuberculosis (TB). The immunomodulatory effect of biological therapies is associated with an increased risk of infection. This study evaluated the frequency of TB infection in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), and psoriatic arthritis (PsA) after the use of biologic agents in a single center of rheumatology. Methods: In this observational study, 161 consecutive adult patients with RA, JIA, AS, and PsA using biological therapy were followed up during 55 months to evaluate the occurrence of TB infection throughout treatment. All patients were screened for latent TB infection (LTBI), and TB disease was excluded before introduction of biological therapy. Patients with LTBI received prophylaxis with isoniazid before the start of biological treatment. Results: Of 161 patients on biologics, 31 (19.25%) had positive tuberculin skin test (TST) and received LTBI treatment. Eleven (6.8%) cases of TB were detected in patients on biologics, six (54.5%) had AS, one had PsA (9.09%), two had RA (18.18%), and two had JIA (18.18%). Regarding the use of different biologics, six (54.5%) patients received adalimumab, three (27.2%) infliximab, one (9.09%) etanercept, and one (9.09%) tocilizumab. Conclusion: In this study, the frequency of TB infection among 161 patients on biologics, during 55 months of follow-up, was 6.8%. Compared with the national registry of patients receiving biologics (BiobadaBrasil — January 01, 2009 to May 31, 2013), a higher incidence of TB (6.8 versus 0.44%) was found in this sample of patients receiving biological therapy. This study highlights that in a country with high TB burden, the possibility of TB infection in a patient receiving biological therapy should always be considered, even after prophylaxis with isoniazid.

7

Authors: Edgardo Kaplinsky MD

Heart failure (HF) continues to be a major global health problem with a notable impact in terms of morbidity and mortality and so, in consequence, with a large unmet necessity for new therapies. The inhibition of sodium–glucose cotransporter 2 (SGLT2) causes glycosuria and natriuresis, leading to reductions in hyperglycemia (antidiabetic effect), body weight, and blood pressure. In this context, outcome trials have been shown to reduce hospitalizations for HF in patients with type 2 diabetes mellitus treated with SGLT2 inhibitors. The underlying protective cardiovascular (CV) mechanisms of these agents are complex, multifactorial, and not entirely understood as, in addition to a diuretic-like function, SGLT2 inhibitors may mitigate glycemic-related toxicity, promote ketogenesis, increase hematocrit, and exert antihypertrophic, antifibrotic, and antiremodeling properties. The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial enrolled 4744 patients with HF and reduced ejection fraction (EF) who were receiving excellent guideline-directed treatment before the addition of dapagliflozin (a SGLT2 inhibitor) or placebo. The DAPA-HF trial clearly showed that dapagliflozin was superior to placebo at preventing CV deaths and HF events. The relative and absolute risk reductions in death and hospitalizations were consistent across subgroups including patients with and without diabetes; so, in consequence, dapagliflozin represents the first in a new class of drug for HF with reduced EF. The recently published Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction (DEFINE-HF) trial is also described in this review as well as the thought-to-be mechanisms of action of SGLT2 inhibitors beyond their known glucose-lowering effects. There is a vast, ambitious, and promising ongoing clinical investigation program with dapagliflozin and other SGLT2 inhibitors, which may result in changes to the therapeutic approach to HF in a relatively short time.

7

Authors: Felicia Pantò MD, Liboria Adamo BSc, Carla Giordano MD, Carmelo Licciardello MD

This article is the second part of a literature review concerning diabetic foot ulcers (DFUs) and the use of antimicrobial photodynamic therapy (PDT). PDT involves the topical application of a photosensitiser into the tissue, followed by illumination that induces the formation of reactive oxygen species (ROS). PDT provides bacterial inactivation and promotes wound healing, and it can be used to manage the infection and microbial colonisation of DFUs. It has pivotal advantages in comparison with chemotherapeutics, such as no potential to induce resistance, and a wide spectrum of activity. Tetracationic Zn(II) phthalocyanine derivatives have been developed for PDT. Among these, we would like to focus on RLP068, whose antimicrobial activity has been widely demonstrated in preclinical studies and in a clinical trial. This article reports previously published evidence and presents four unpublished clinical cases of DFUs treated in the real-life setting with PDT.

8

Authors: Leocadio Rodriguez-Mañas MD, PhD

Urinary tract infections (UTIs) are common in the elderly, and cover a range of conditions from asymptomatic bacteriuria to urosepsis. Risk factors for developing symptomatic UTIs include immunosenescence, exposure to nosocomial pathogens, multiple comorbidities, and a history of UTIs. European guidelines on urological infections recommend antimicrobial treatment only for symptomatic UTIs. Non-antimicrobial options to treat and prevent UTIs include among others cranberry products, OM-89 Escherichia coli bacterial lysate vaccine, and estrogen therapy in postmenopausal women, although evidence for their efficacy is weak. Another nonantimicrobial option to control and prevent UTIs is a medical device (Utipro Plus®) containing xyloglucan, gelatin, propolis, and extracts of Hibiscus sabdariffa. The device acts in the intestine as a mechanical barrier to protect against invasion by uropathogenic E. coli strains. A randomized controlled trial of Utipro Plus® in patients with uncomplicated UTIs provided good-quality evidence of its efficacy compared with placebo. In an observational study of Utipro Plus® in patients with recurrent UTIs, more than 80% women reported a return to their pre-UTI clinical status and about 30% transitioned from symptomatic UTIs to asymptomatic bacteriuria. New treatment strategies that offer a safe and effective non-antimicrobial means of managing UTIs could have an important role in the elderly.

8

Authors: Sandra Ferreira MD, Tiago Torres MD, PhD

Atopic dermatitis (AD) is a common, chronic, inflammatory skin disorder with high physical and emotional burden. Robust evidence suggests that interleukin (IL)-4 and IL- 13 are key cytokines in the immunopathogenesis of AD. New emerging agents include dupilumab, a fully human monoclonal antibody directed against the IL-4 receptor a subunit that blocks both IL-4 and IL-13 signaling and has shown significant efficacy in patients with moderate-tosevere AD. Dupilumab is approved for the treatment of moderate-to-severe AD, moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma, and chronic rhinosinusitis with nasal polyps. Data from phase phase 2 and 3 studies have revealed that dupilumab generally has a low rate of adverse events, although an increased incidence of mild-to-moderate conjunctivitis has been reported for dupilumab compared with placebo. The present paper reviews the data of dupilumab-associated conjunctivitis and risk factors in adults with moderate-to-severe AD and other atopic diseases in dupilumab clinical trials and addresses the characteristics and treatment options available for this clinically highly relevant condition. Additionally, it presents data from ten studies in the real-life setting with dupilumab. Dupilumab-associated conjunctivitis incidence is higher in AD, although most cases are mild-to-moderate and have good response to topical treatment, with no need to suspend dupilumab therapy.

9

Authors: Namrata Singhania MD, Saurabh Bansal MD, Shreya Mohandas, Divya P Nimmatoori MD, Abutaleb A Ejaz MD, Girish Singhania MD

Renin–angiotensin–aldosterone system (RAAS) inhibitors are the key medications for patients with heart failure and chronic kidney disease. Multiple randomized controlled trials have demonstrated their benefits in an outpatient setting for the treatment of chronic heart failure. Additional advantages in acute heart failure treatment during inpatient hospitalization are less clear but a small number of non-randomized studies have favored their use. Conditions that result in stoppage of RAAS inhibitors during inpatient stay are an increase in serum creatinine, hyperkalemia, and hemodynamic instability such as hypotension. The role of RAAS inhibitors in chronic kidney disease has also been documented in multiple randomized controlled trials, with their use in hypertension and proteinuria being unambiguous. This narrative review summarizes the role of RAAS inhibitors in acute and chronic heart failure and chronic kidney disease.

9

Authors: Antonio Ruggiero MD, Anna Ariano MD, Silvia Triarico MD, Michele Antonio Capozza MD, Alberto Romano MD, Palma Maurizi MD, Stefano Mastrangelo MD, Giorgio Attinà MD

Despite advances in the treatment of brain tumors, the prognosis of children with recurrent malignant brain tumors remains poor. Etoposide (VP-16), an inhibitor of nuclear enzyme deoxyribonucleic acid (DNA)-topoisomerase II, has shown activity in brain tumors. Its efficacy appears schedule dependent but, to date, the most effective schedule of administration has not been well defined. Temozolomide (TMZ), like VP-16, penetrates the blood–brain barrier and has activity against malignant brain tumors. This novel alkylating agent is rapidly absorbed and is highly bioavailable after oral administration. The antitumor activity of TMZ has been shown to be schedule dependent. Based on the evidence of different mechanisms of cytotoxicity, TMZ and VP-16 have been utilized in combination in patients with malignant brain tumors. This review evaluates the results derived from the combination use of TMZ and oral VP-16. The reported data suggest potential activity of oral VP-16 and TMZ alone or in combination. Further clinical trials are needed to explore and confirm their promising activity in relapsed brain neoplasms.

9

Authors: Santiago Palacios PhD, MD, Marieta Ramirez MD, Mariella Lilue MD

Background: Calcium is an essential macronutrient; however, currently supplements are often associated with gastrointestinal (GI) adverse events. The authors investigated the tolerability of a new delivery system for calcium supplementation, based on the functionalization of calcium carbonate (CaCO3) particles by casein proteins, in a randomized, prospective, double-blind, active comparator clinical trial. Methods: Around 208 postmenopausal women were enrolled and randomized 1:1:1:1 to one of the four calcium supplements, taken for 30 days: (1) microencapsulated CaCO3 (microCaCO3) with a 90:10 mineral to protein ratio; (2) microCaCO3 with a 95:5 mineral to protein ratio; (3) conventional CaCO3 tablets; and (4) calcium citrate tablets (CaCitr). The Gastrointestinal Symptom Rating Scale (GSRS) questionnaire was used to evaluate the GI tolerability and the Treatment Satisfaction Questionnaire for Medication (TSQM) to analyze the satisfaction of the participants with the use of the calcium supplements. Results: The mean GSRS scores at baseline differed among the groups from 3.95 to 5.35 without statistical significance. After 1 month use of supplements, the group given microCaCO3 with a 90:10 mineral to protein ratio, showed the lowest mean GSRS score (6.07), while the group given conventional CaCO3 showed the highest score (11.86). According to the completed TSQM questionnaire, the use of supplements was easier for both microCaCO3 groups in comparison with conventional supplements. Conclusions: The microCaCO3 supplement has shown promising results in the context of GI tolerability and patient satisfaction in the use of supplements compared to conventional calcium supplements. The reduction of GI adverse events may increase the compliance to calcium supplements especially important among groups at risk of calcium deficiency.

9

Authors: Luca Giacomelli PhD, Alessandra Moglia PharmD, Gianedoardo Losa PharmD, Pietro Quaglino MD

The skin is the largest organ in the human body; beyond its regulatory and sensory roles, it is meant to protect and act like a barrier against foreign matter. Products intended to restore the skin health should reintegrate the structure of the stratum corneum in which the corneocytes are surrounded by the intercellular lipid lamellae that maintain both corneum integrity and skin permeability barrier. Capilen is a specific liposomal formulation based on a technology through which highly concentrated fresh plant extracts are conveyed into a jelly-like liposomal vehicle and combined with plant-derived omega-3, -6, -7, and -9 fatty acids, phospholipids, and precursors of ceramides. Its components have been widely investigated and produced clinical benefits in atopic dermatitis, bedsores, scars, inflammatory lesions of the skin, and generally whenever signs of xerosis cutis were present. Liposomes contribute to restore the surface lipid layer of the skin and to deliver substances in the activity site. This liposomal cream was proven to limit and delay the occurrence of radiodermatitis in breast cancer patients, and as an add-on provided complete healing of bedsore lesions in geriatric subjects.

10

Authors: Hae-Jin Suh Oh MD, Ángeles Flórez Menéndez PhD, Víctor Sacristán Santos MD, Francisca Fernández Ribeiro PharmD, Lucía Vilanova-Trillo DNP, Manuel Constenla Figueiras PhD, Manuel Pereiro Ferreiros PhD

Background: Despite growing interest in cutaneous adverse events (CAEs) and their management in patients with cancer, they are often underreported and there are no extensive data on their impact on quality of life (QoL). Healthcare professionals should consider this issue in order to minimize its negative impact on QoL and improve patient outcomes. This study evaluates the impact of CAEs on QoL in outpatients receiving anticancer drugs and aims to determine the differences in QoL between conventional chemotherapy versus targeted therapies. Methods: A total of 114 cancer patients with CAEs were included in this observational, cross-sectional study. Patient-reported outcomes instruments (Functional Assessment of Cancer Therapy – General, Dermatology Life Quality Index, and Skindex-16) were used. Results: Mean scores in QoL indices were 65.3±13.4, 8.4±5, and 30.8±16.9 in Functional Assessment of Cancer Therapy – General, Dermatology Life Quality Index, and Skindex-16, respectively. The CAEs that had the greatest impact on dermatologic-related QoL were hand–foot skin reaction, rash, palmo-plantar erythrodysesthesia, and papulopustular eruption. No significant differences in QoL indices according to the type of treatment (conventional chemotherapy versus targeted therapy) were observed. Conclusions: CAEs, and particularly hand–foot toxicities, rashes, and papulopustular eruptions, can have an impact on QoL in outpatients receiving anticancer drugs as evaluated with three different patient-reported outcomes instruments. No differences in QoL related to CAEs were observed between conventional chemotherapy and targeted therapy.

10

Authors: María del Carmen Pingarrón Santofimia MD, Silvia Pilar González Rodríguez MD, PhD, Mariella Lilue MD, Santiago Palacios MD, PhD

Selective estrogen receptor modulators (SERMs) exhibit varying agonist/antagonist activities on estrogen receptors in tissues, although most SERMs, including ospemifene, have agonist effects on bone. In this article, outcomes in relation to bone homeostasis, bone mineral density (BMD), and osteopenia– osteoporosis are examined in postmenopausal women during treatment with ospemifene for vulvar and vaginal atrophy (VVA), a component of the genitourinary syndrome of menopause. In cases 1 and 2, the women had established osteopenia or osteoporosis before the start of ospemifene treatment. After 6 months’ and 7 months’ treatment, respectively, marked reductions were observed in bone resorption (decreased levels of carboxy-terminal cross-linking telopeptide of type-1 collagen). The woman in case 3 had normal bone marker data and BMD prior to starting treatment with ospemifene. After 1 year, bone biomarkers and densitometry indicated improved bone health. Ospemifene 60 mg daily for treatment of VVA in postmenopausal women appears to benefit bone health although, because current evidence is based mainly on bone biomarkers, long-term studies are required to confirm this potential.

11

Authors: Alexander KC Leung MBBS, FRCPC, FRCP (UK and Irel), FRCPCH, FAAP, Kam Lun Hon MD, FAAP, FCCM, Winnie CW Chu MD, FRCR

Background: In the pediatric age group, approximately 7.5% of upper respiratory tract infections (URIs) are complicated by acute bacterial sinusitis (ABS). Despite its prevalence, ABS is often overlooked in young children. The diagnosis and management present unique challenges in primary care. This is an updated narrative review on the evaluation, diagnosis, and management of ABS. Methods: A PubMed search was performed using the key term ‘acute sinusitis’. The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies, and reviews. The search was restricted to the English literature and children. Results: Haemophilus influenzae (non-typeable), Streptococcus pneumoniae, and Moraxella catarrhalis are the major pathogens in uncomplicated ABS in otherwise healthy children. In complicated ABS, polymicrobial infections are common. The diagnosis of acute sinusitis is mainly clinical and based on stringent criteria, including persistent symptoms and signs of a URI beyond 10 days, without appreciable improvement; a URI with high fever and purulent nasal discharge at onset lasting for at least 3 consecutive days; and biphasic or worsening symptoms. Conclusion: Data from high-quality studies on the management of ABS are limited. The present consensus is that amoxicillin-clavulanate, at a standard dose of 45 mg/kg/day orally, is the drug of choice for most cases of uncomplicated ABS in children in whom antibacterial resistance is not suspected. Alternatively, oral amoxicillin 90 mg/kg/day can be administered. For those with severe ABS or uncomplicated acute sinusitis who are at risk for severe disease or antibiotic resistance, oral high-dose amoxicillin-clavulanate (90 mg/kg/day) is the drug of choice.

11

Authors: Tatum Kutzer DO, Michelle Dick MD, Trevor Scudamore MD, Mark Wiener MD, Thomas Schwartz MD

Antidepressant treatment has been evolving and changing since the 1950s following the discovery of the classic antidepressant treatments including tricyclic antidepressants and monoamine oxidase inhibitors. The heterogeneity of the disorder became apparent in the beginning when individuals remained symptomatic despite medication compliance. This spurred further research in order to understand the neurobiology underlying the disorder. Subsequently, newer medications were designed to target specific neurotransmitters and areas of the brain involved in symptom development and maintenance. Our original review article looked at both classic and modern antidepressant medications used in the treatment of major depressive disorder. This manuscript is an update to the original review and serves to provide clinicians with information about novel antidepressant medications, augmentation strategies with atypical antipsychotics, over-the-counter medications, as well as nonpharmaceutical treatments that should be considered when treating each individual patient who remains symptomatic despite treatment efforts.

11

Authors: Clara Ferreira MD, Alexandra Azevedo MD, Miguel Nogueira MD, Tiago Torres MD, PhD

The onset of psoriasis collides with women’s reproductive timeframe, and pregnancy brings challenges to its treatment. Indeed, the health of both mother and foetus must be considered. When choosing to treat pregnant women affected by psoriasis with pharmacological therapy, it is important to be aware of all possible options and their repercussions. Although there are several pharmacological therapies available, pregnancy brings ethical concerns and any pharmacological approach must be well thought out. The data available in humans are limited, and further investigation on this matter is needed. Within biological therapies, certolizumab pegol has recently been identified as a promising approach during pregnancy because it has been shown to have no late active placental transfer and no clear signs of foetal harm. This article aims to review the impact of psoriasis during pregnancy, how the disease can be managed pharmacologically during this period according to the available armamentarium, and the possible effects of the therapeutic options for the mother and the foetus.

11

Authors: Sonam Puri MD, Michael Shafique MD

Immunotherapy has revolutionized cancer treatment. In non-small-cell lung cancer (NSCLC), monotherapy with immune checkpoint inhibitors has improved survival in metastatic disease. Combinations of immune checkpoint inhibitors have shown synergy in preclinical models and are being studied as part of the treatment armamentarium in NSCLC. This review discusses the rationale, outcomes, and challenges of combination immune checkpoint blockade. Despite the challenges, this paper also presents some solutions and ways to improve our understanding and implementation of such combinations in the future.

12

Authors: John C Stevenson MB BS, FRCP, FESC, MFSEM, Serge Rozenberg MD, PhD, Silvia Maffei MD, Christian Egarter Prof Dr Med, Petra Stute Prof Dr Med, Thomas Römer Prof Dr Med

Optimizing menopausal hormone therapy (MHT) requires an awareness of the benefits and risks associated with the available treatments. This narrative review, which is based on the proceedings of an Advisory Board meeting and supplemented by relevant articles identified in literature searches, examines the role of progestogens in MHT, with the aim of providing practical recommendations for prescribing physicians. Progestogens are an essential component of MHT in menopausal women with a uterus to prevent endometrial hyperplasia and reduce the risk of cancer associated with using unopposed estrogen. Progestogens include natural progesterone, dydrogesterone (a stereoisomer of progesterone), and a range of synthetic compounds. Structural differences and varying affinities for other steroid receptors (androgen, glucocorticoid, and mineralocorticoid) confer a unique biological and clinical profile to each progestogen that must be considered during treatment selection. MHT, including the progestogen component, should be tailored to each woman, starting with an estrogen and a progestogen that has the safest profile with respect to breast cancer and cardiovascular effects, while addressing patient-specific needs, risk factors, and treatment goals. Micronized progesterone and dydrogesterone appear to be the safest options, with lower associated cardiovascular, thromboembolic, and breast cancer risks compared with other progestogens, and are the first-choice options for use in ‘special situations,’ such as in women with high-density breast tissue, diabetes, obesity, smoking, and risk factors for venous thromboembolism, among others.

12

Authors: Alexander KC Leung MBBS, FRCPC, FRCP (UK and Irel), FRCPCH, FAAP, Joseph M Lam MD, FRCPC, Kin Fon Leong MBBS, MRCPCH, Kam Lun Hon MD, FAAP, FCCM

Background: Tinea corporis is a common fungal infection that mimics many other annular lesions. Physicians must familiarize themselves with this condition and its treatment. Objective: This article aimed to provide a narrative updated review on the evaluation, diagnosis, and treatment of tinea corporis. Methods: A PubMed search was performed with Clinical Queries using the key term ‘tinea corporis.’ The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies, and reviews. The search was restricted to the English language. The information retrieved from the mentioned search was used in the compilation of the present article. Results: Tinea corporis typically presents as a well-demarcated, sharply circumscribed, oval or circular, mildly erythematous, scaly patch or plaque with a raised leading edge. Mild pruritus is common. The diagnosis is often clinical but can be difficult with prior use of medications, such as calcineurin inhibitors or corticosteroids. Dermoscopy is a useful and non-invasive diagnostic tool. If necessary, the diagnosis can be confirmed by microscopic examination of potassium hydroxide wetmount preparations of skin scrapings from the active border of the lesion. Fungal culture is the gold standard to diagnose dermatophytosis especially if the diagnosis is in doubt and results of other tests are inconclusive or the infection is widespread, severe, or resistant to treatment. The standard treatment of tinea corporis is with topical antifungals. Systemic antifungal treatment is indicated if the lesion is multiple, extensive, deep, recurrent, chronic, or unresponsive to topical antifungal treatment, or if the patient is immunodeficient. Conclusion: The diagnosis of tinea corporis is usually clinical and should pose no problem to the physician provided the lesion is typical. However, many clinical variants of tinea corporis exist, rendering the diagnosis difficult especially with prior use of medications, such as calcineurin inhibitors or corticosteroids. As such, physicians must be familiar with this condition so that an accurate diagnosis can be made and appropriate treatment initiated.

12

Authors: Luis Miguel Juárez-Salcedo MD, Diego Conde-Royo MD, Keina Quiroz-Cervantes MD, Samir Dalia MD

The identification of the CD20 antigen in 1979 was the first step in what would become a therapeutic milestone opening the use of immunotherapy in hematological diseases. This protein is expressed on the surface of developing B cells, but not the early progenitors or mature plasma cells. In 1997, rituximab was approved by the Food and Drug Administration, and since then it has revolutionized the treatment of B-cell malignancies. It is used as a monotherapy and in combination, at induction, at relapsed, and also in maintenance. Indolent non-Hodgkin lymphomas are characterized by a long and non-aggressive course. In this group of lymphomas, rituximab represented a great therapeutic improvement, achieving lasting responses with few adverse effects. Nowadays, second-generation molecules are emerging that may have important advantages compared to rituximab, as well as biosimilars that represent an important cost-effective option.

13

Authors: Philippe Lehert Dr Ir PhD, Cassandra Szoeke MD, GAICD, PhD, FRACP, AMA(M), MBBS

Aim: To assess the non-inferiority of pitolisant, a new compound for the relief of excessive daytime sleepiness (EDS) and cataplexy in narcolepsy, compared with modafinil. Methods: Randomized controlled trials (RCTs) in narcolepsy were searched systematically. Network meta-analysis (NMA) compared the efficacy and safety of pitolisant and modafinil. The main endpoints are Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), the number of cataplexies, and overall safety. Results: Of 312 articles after removing duplicates, 10 RCTs were eligible for NMA. For ESS, a non-significant superior beneficial decrease (−0.69, [−2.18, 0.79]) showed non-inferiority of pitolisant (non-inferiority margin [NIM]=1, p=0.015). An MWT beneficial increase (2.12 minutes [−0.95, 5.19]; p=0.18) showed non-inferiority of pitolisant (NIM=−1). For cataplexy, the mean beneficial effect of pitolisant was significant, providing evidence of pitolisant superiority in addition to non-inferiority. The risk ratio (RR) of treatment-suspected adverse events for pitolisant/ modafinil was 0.86 [0.44, 1.24] favoring pitolisant, confirming non-inferiority considering a safety margin of RR=1.25 (tolerance of 25%). Conclusions: Pitolisant is non-inferior to modafinil in relieving EDS, but superior to modafinil in reducing cataplexy, outranking modafinil in narcolepsy type-1 patients. Despite a slight superiority of pitolisant in EDS relief, both drugs perform equally in narcolepsy type-2 patients.

13

Authors: Gabriela Antelo MD, Cinta Hierro MD, MSc, Juan Pablo Fernández MD, Eduardo Baena MD, Cristina Bugés MD, Laura Layos MD, José Luis Manzano MD, Mónica Caro MD, Ricard Mesia MD, PhD

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumours, which can be classified into neuroendocrine tumours (NETs), neuroendocrine carcinomas (NECs) and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). To date, there is no consensus regarding the optimal therapy, which usually depends on the primary location and classification, according to morphological features of differentiation and proliferation rates. Nevertheless, multidisciplinary strategies combining medical treatments and locoregional strategies have yielded better efficacy results. Here, we report the case of a patient diagnosed with a nonfunctional rectal NECs with metastatic widespread to pelvic lymph nodes and bilateral lung metastases. The patient received three cycles of platinumetoposide, concomitantly with palliative radiotherapy. Although CT scan after three cycles showed a significant partial response, there was an early fatal progression only 3 months after having stopped systemic therapy. As formerly described in the literature, this case highlights the aggressive behaviour of NECs, rare tumours that often present in advanced stages at diagnosis. Lately, new insights into the molecular biology of NECs have unveiled the possibility of using novel drugs, such as targeted agents or immunotherapy, in molecularly selected subgroups of patients. In this review, we discuss the current management of this rare entity and provide an overview of the most relevant molecular findings, whilst illustrating the potential value that prescreening panels can offer, searching for actionable targets (MSI/dMMR, PD-L1, BRAFv600E) to guide therapy with promising agents that could fill a void in this disease.

14

Authors: Wing Lum Cheung MBBS, MRCPCH, Kam Lun Hon MBBS, MD (CUHK), FAAP, FCCM, Cheuk Man Fung MBChB, MRCPCH, Alexander KC Leung MBBS, FRCPC, FRCP (UK & Irel), FRCPCH, FAAP

Background: Tumor lysis syndrome (TLS) is the most common life-threatening oncological emergency encountered by physicians treating children with lymphoproliferative malignancies. Healthcare providers should be aware of the condition in order to prevent occurrence and prompt timely management to avoid severe consequences. Objective: To provide an update on the current understanding, evaluation, and management of tumor lysis syndrome in childhood malignancies. Methods: A PubMed search was performed in Clinical Queries using the keywords ‘tumor lysis syndrome’ and ‘malignancies’ with Category limited to clinical trials and reviews for ages from birth to 18 years. Results: There were 22 clinical trials and 37 reviews under the search criteria. TLS is characterized by acute electrolyte and metabolic disturbances resulting from massive and abrupt release of cellular contents into the circulation due to breakdown of tumor cells. If left untreated, it can lead to multiorgan compromise and eventually death. Apart from close monitoring and medical therapies, early recognition of risk factors for development of TLS is also necessary for successful management. Conclusions: Prophylactic measures to patients at risk of TLS include aggressive fluid management and judicious use of diuretics and hypouricemic agents. Both allopurinol and urate oxidase are effective in reducing serum uric acid. Allopurinol should be used as prophylaxis in low-risk cases while urate oxidase should be used as treatment in intermediate to highrisk cases. There is no evidence on better drug of choice among different urate oxidases. The routine use of diuretics and urine alkalinization are not recommended. Correction of electrolytes and use of renal replacement therapy may also be required during treatment of TLS.

15

Authors: Diego Conde-Royo MD, Luis Miguel Juárez-Salcedo MD, Samir Dalia MD

Therapeutic options for relapsed/refractory B-cell acute lymphoblastic leukemia have evolved in the past few years. The FDA has approved three novel therapies for this disease: inotuzumab ozogamicin (an anti-CD22 antibody–drug conjugate), blinatumomab (a bispecific T-cell engager), and chimeric antigen receptor T-cell therapy. Although these novel immunotherapies have revolutionized the therapeutic landscape, it is important to understand the crucial aspects of administration, especially toxicity. In this article, we review the unique toxicities and adverse effects of blinatumomab and inotuzumab ozogamicin and provide recommendations for prevention of adverse effects as well as the management options for each medication.

15

Authors: Benjamin Crooks MA MBBS, Tom Barnes MBBS BSc, Jimmy K Limdi FRCP FACG

Inflammatory bowel diseases, comprising Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, relapsing and remitting immune-mediated inflammatory diseases affecting the gastrointestinal tract. Vedolizumab is the first licensed drug in a group of ‘gut-selective’ biological agents used to treat inflammatory bowel diseases. The GEMINI registrational trials established the efficacy of vedolizumab for the induction and maintenance of remission in both CD and UC, with the most favourable results in tumour necrosis factor (TNF)-antagonist-naive patients. In recent years, a wealth of ‘real-world’ data has emerged supporting positive clinical, endoscopic and histological outcomes in patients treated with vedolizumab (VDZ) as well as reassuring safety data. More recently, the results of the first head-to-head trials of VDZ and TNF antagonists have been reported, as well as the results of a number of studies exploring the role of therapeutic drug monitoring with VDZ. This review brings together data reported on VDZ to date, including from the GEMINI trials, real-world data and emerging studies regarding therapeutic drug monitoring and immunogenicity. The safety profile of VDZ is also reviewed. Evolving treatment paradigms are explored, including data regarding the role of VDZ in perianal CD, post-operative complications and recurrence, extraintestinal manifestations and pregnancy.

22

Authors: Rebecca Hedrick MD, Samuel Korouri BA, Emile Tadros BS, Tarneem Darwish MD, Veronica Cortez RN, OD, Desiree Triay RN, Mia Pasini RN, MSN, Linda Olanisa LCSW, Nathalie Herrera MD, Sophia Hanna BA, MA, Asher Kimchi MD, Michele Hamilton MD, Itai Danovitch MD, MBA, Waguih William IsHak MD, FAPA

Objective: The purpose of this paper is to review the literature on the impact of antidepressants on depressive symptom severity, quality of life (QoL), morbidity, and mortality in patients with heart failure (HF). Methods: Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Reporting Items for Systematic Reviews and Meta-Analyses guidelines, studies published from December 1969 to December 2019 that pertain to depression and HF were identified through the use of the PubMed and PsycINFO databases, using the keywords: ‘antidepressant*’ and ‘heart failure.’ Two authors independently conducted a focused analysis and reached a final consensus on 17 studies that met the specific selection criteria and passed the study quality checks. Results: Studies varied in types of antidepressants used as well as in study designs. Ten studies were analyzed for the impact of antidepressant medications on depressive symptom severity. Five of these were randomized controlled trials (RCTs), out of which sertraline and paroxetine showed a significant reduction in depressive symptoms despite the small samples utilized. Four of the 17 studies addressed QoL as part of their outcomes showing no difference for escitalopram (RCT), significantly greater improvements for paroxetine controlled release (RCT), statistical significance for sertraline compared to control (pilot study), and showing significant improvement before and after treatment (open-label trial) for nefazodone. Thirteen of the 17 studies included measures of morbidity and mortality. Although early analyses have pointed to an association of antidepressant use and mortality particularly with fluoxetine, the reviewed studies showed no increase in mortality for antidepressants, and secondary analyses showed improved mortality in patients who achieved remission of depressive symptoms. Conclusion: Out of the various antidepressants studied, which included sertraline, paroxetine, escitalopram, citalopram, bupropion, nefazodone, and nortriptyline, selective serotonin reuptake inhibitors seem to be a safe treatment option for patients with depression and HF. However, due to the variety of study designs as well as the mixed results for each antidepressant, more information for reducing depression severity, morbidity, and mortality and improving quality of life in patients with HF should be examined using robust large sample RCTs.

29

Authors: Sarah M Michienzi PharmD, Melissa E Badowski PharmD

Severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) quickly became a global pandemic and has been responsible, so far, for infecting 5.8 million and claiming the lives of more than 350,000. While certain medications initially garnered attention as potential treatment options, further studies failed to demonstrate great promise but did demonstrate the need to reduce the cytokine storm experienced by patients with this potentially life-threatening virus. Unfortunately, there is no cure on the horizon, but members of the medical community are beginning to evaluate the potential role of vitamins and supplements as potential treatment options or addition to other treatments. The goal of this narrative review is to evaluate current and ongoing clinical trials of vitamins and supplements, alone or in combination with each other or other therapies, for the treatment of coronavirus disease-2019 (COVID-19).