Drugs in Context

5

Authors: Yeong Yeh Lee, Vincent Tee

Elevated liver enzyme levels are a frequent incidental finding in primary care, and non-alcoholic fatty liver disease is the main cause of incidental elevation of liver enzymes worldwide. The features of the disease vary from simple steatosis, characterized by a benign prognosis, to non-alcoholic steatohepatitis and cirrhosis, increasing morbidity and mortality. In this case report, abnormal liver activity was incidentally detected during other medical assessments. The patient was treated with silymarin 140 mg three times daily, resulting in decreased serum liver enzyme levels over treatment with a good safety profile. This article is part of the Current clinical use of silymarin in the treatment of toxic liver diseases: a case series Special Issue: https://www.drugsincontext.com/special_issues/current-clinical-use-of-silymarin-in-the-treatment-of-toxic-liver-diseases-a-case-series

5

Authors: Aldo Torre

Metabolic-associated fatty liver disease (MAFLD) is the main condition of altered liver enzymes worldwide. With a constant increase in liver hospitalizations, MAFLD is the second cause of cirrhosis and soon will be the first cause of liver transplantation. Early recognition of MAFLD and a personalized approach are essential to its treatment. This case study presents personalized management of a patient with MAFLD with advanced fibrosis and severe steatosis. The impact of silymarin use, concomitant treatment with diet, exercise, insulin sensitizers and antifibrotic agents, was evaluated. 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.

7

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

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

8

Authors: Ana Martins, Ana Maria Lé, Tiago Torres

Psoriatic arthritis (PsA) is a heterogeneous disease that may develop in up to 30% of patients with psoriasis. PsA mainly involves peripheral joints; however, axial skeleton and entheses can also be involved. PsA is the result of a complex interplay between an individual’s genotype and environmental factors that triggers an immune response and leads to the production of a cytokine cascade. Even though there are about 17 targeted therapies for PsA, a significant percentage of patients fail to respond to such treatments, have a partial response or develop side-effects. This article aims to review the current knowledge on deucravacitinib, a new oral small molecule that selectively inhibits tyrosine kinase 2 (TYK2), for the treatment of PsA. TYK2, a member of the Janus kinase (JAK) family, is responsible for mediating intracellular signalling of cytokines involved in the pathogenesis of PsA and psoriasis, namely IL-12, IL-23, and type I interferons. Recently, deucravacitinib was approved by the FDA for the treatment of moderate-to-severe plaque psoriasis and is currently being evaluated in phase III clinical trials in PsA. In a phase II clinical trial, deucravacitinib showed sustained effectiveness in several domains of PsA, namely arthritis, enthesitis and dactylitis, was well tolerated, and had a favourable safety profile. In patients with psoriasis, deucravacitinib had shown a higher efficacy than placebo and apremilast. Deucravacitinib is a promising therapy, with a unique mechanism of action. Results from the phase III programme and studies evaluating long-term response and head-to-head comparisons with other targeted agents will be important to establishing the position of deucravacitinib in the management of PsA.

10

Authors: María Victoria Báez Cabanillas, Roberto Colque, Miguel Ángel Tibaldi, Edgardo Kaplinsky, Sergio Perrone, Alejandro Barbagelata

Tachycardia-induced cardiomyopathy is an entity characterized by reversible dysfunction of the left ventricle, which can be induced by different types of arrhythmia such as atrial fibrillation, atrial flutter, incessant supraventricular tachycardia and ventricular arrhythmia (more frequent causes). Correct identification of the causative arrhythmia and normalization of the heart rate (e.g through medical treatment, electrical cardioversion, ablation) can lead to recovery of left ventricular function. Tachycardia-induced cardiomyopathy should be suspected in patients with tachycardia and left ventricular dysfunction (heart failure setting), especially when there is no history of previous heart disease. Its usual phenotype is that of non-ischaemic/non-valvular dilated cardiomyopathy and it can occur in both children (main cause: permanent junctional reciprocating tachycardia) and adults (main cause: atrial fibrillation). With proper treatment, most cases recover within a few months, though there is a risk of relapse, especially when the causal arrhythmia reappears or its control is lost. This is a narrative review that comprehensively addresses the pathophysiology, clinical manifestations, and therapeutic management of tachycardia-induced cardiomyopathy. 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: Dhiraj Dhoot, Gaurav Kumar Jain, Mukesh Manjhi, Prashant Kesharwani, Namrata Mahadkar, Hanmant Barkate

Background: Due to changing face of dermatophytosis in India, many dermatologists practice different dosing patterns of itraconazole (ITZ). Recently, a new form of ITZ, super-bioavailable ITZ (SBITZ), has been commercialized to overcome the pharmacokinetic challenges of conventional ITZ (CITZ). Serum and sebum concentration of ITZ plays an important role in the management of dermatophytosis. Hence, the current study compares the rate and extent of serum and sebum concentration of SBITZ and CITZ at different dosing to determine their efficacy and safety in patients with dermatophytosis. Methods: This was an open-label, randomized, fourarm study including 40 adult patients diagnosed with glabrous tinea who were randomized equally into four groups to receive either CITZ-100-BD or CITZ-200-OD (2×100 mg capsules) or SBITZ-130-OD or SBITZ-100-OD (2×SBITZ-50 mg capsules) for 4 weeks. Serum and sebum samples were analysed at different time intervals along with clinical efficacy and safety. Results: For serum concentration, on day 28, the arithmetic mean and standard deviation (SD) for CITZ- 100-BD, CITZ-200-OD, SB-130-OD and SB100-OD were 1262±233.5 ng/mL, 1704±261.6 ng/mL, 1770±268.9 ng/mL and 1520±231.7 ng/mL, respectively, which was statistically significant for OD dosing of ITZ/SBITZ over CITZ-100- BD. Similarly, for sebum concentration, the arithmetic mean and SD for CITZ-100-BD, CITZ-200-OD, SB-130-OD and SB-100-OD were 1042±163.45 ng/mg, 1423±192.46 ng/ mg, 1534±227.55 ng/mg and 1107±182.35 ng/mg, respectively, which was statistically significant for SB-130-OD and CITZ-200-OD over CITZ-100-BD and SBITZ-100-OD dosing. No significant difference was noted between SBITZ-130 and CITZ-200 (p=0.25). Only two patients achieved complete cure in the SBITZ-130 group, whereas no patients achieved the same in other groups (p=0.47). All the dosages were very well tolerated with only 12 adverse events reported by ten patients in all groups. Conclusion: All formulations achieved desired serum and sebum concentrations required for efficacy in dermatophytosis, but SB 130 mg OD and CITZ 200 mg OD were statistically significant than other ITZ doses in achieving sebum concentration. Additionally, SBITZ 130 mg OD was bioequivalent to CITZ 200 mg OD and achieved similar results to those of CITZ 200 mg OD but at 35% lower drug concentrations.

11

Authors: Edgardo Kaplinsky, Sergio Perrone, Alejandro Barbagelata

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

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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.

13

Authors: Arturo Cuomo, Anastasios Boutis, Francesca Colonese, Davide Nocerino

Cancer pain requires careful comprehensive patient evaluation and an appropriate and personalized clinical approach by a trained multidisciplinary team. The proper assessment of breakthrough cancer pain (BTcP) is part of an all-inclusive multidimensional evaluation of the patient. The aim of this narrative review is to explore the relationship between high-rate BTcP, which strongly impacts healthrelated quality of life and tumour characteristics, in the face of novel approaches that should provide guidance for future clinical practice. The presentation of short, emblematic clinical reports also promotes knowledge of BTcP, which, despite the availability of numerous therapeutic approaches, remains underdiagnosed and undertreated. 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: Kimberly C Claeys, Melissa D Johnson

Novel diagnostic stewardship in infectious disease consists of interventions that modify ordering, processing, and reporting of diagnostic tests to provide the right test for the right patient, prompting the right action. The interventions work upstream and synergistically with traditional antimicrobial stewardship efforts. As diagnostic stewardship continues to gain public attention, it is critical that antimicrobial stewardship programmes not only learn how to effectively leverage diagnostic testing to improve antimicrobial use but also ensure that they are stakeholders and leaders in developing new diagnostic stewardship interventions within their institutions. This review will discuss the need for diagnostic and antimicrobial stewardship, the interplay of diagnostic and antimicrobial stewardship, evidence of benefit to antimicrobial stewardship programmes, and considerations for successfully engaging in diagnostic stewardship interventions. This article is part of the Antibiotic stewardship Special Issue: https://www.drugsincontext.com/special_issues/antimicrobial-stewardship-a-focus-on-the-need-for-moderation

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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: Andrea Beatriz De Lorenzi, Edgardo Kaplinsky, Marx Rivera Zambrano, Laia Tomás Chaume, Joan Monell Rosas

The role of sodium–glucose cotransporter 2 inhibitors (SLTG2i), developed initially as glucose-lowering agents, has represented a novelty in patients with heart failure (HF) and reduced ejection fraction (HFrEF) since dapagliflozin (DAPA-HF study) and empagliflozin (EMPERORReduced study) were able to reduce morbidity and mortality in this setting regardless of the presence or absence of diabetes. In previous large clinical trials (EMPA- REG OUTCOME study, CANVAS, DECLARE-TIMI 58), SGLT2i have been shown to attenuate HF progression expressed by reducing the risk of HF hospitalizations in patients with type 2 diabetes mellitus mostly without HF at baseline. This benefit was then corroborated with positive results in HF outcomes (cardiovascular mortality and HF hospitalizations) in patients with HF with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) trials. Several biological mechanisms apart from the glycosuria are attributed to these agents in this last context, including anti-inflammatory effects, reduction of fibrosis and apoptosis, improvement of myocardial metabolism, mitochondrial function optimization, and oxidative stress protection. Moreover, SGLT2i can also improve ventricular loading conditions by forcing diuresis and natriuresis, and by enhancing vascular and renal function. In addition, SGLT2i can reduce myocardial passive stiffness (diastolic function) by enforcing the phosphorylation of myofilament modulatory proteins. This article provided an overview of the main pathophysiological characteristics of HFpEF and of the diverse mechanisms of action of SGLT2i in this setting. The supporting clinical evidence of SGLT2i in HFpEF (EMPEROR-Preserved and DELIVER trials) is also reviewed. 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: Giorgia Guaitoli, Lodovica Zullo, Marcello Tiseo, Matthew Dankner, April AN Rose, Francesco Facchinetti

BRAF mutations are reported in about 3–5% of non-small-cell lung cancer (NSCLC), almost exclusively in adenocarcinoma histology, and are classified into three different classes. The segmentation of BRAF mutations into V600 (class 1) and non-V600 (classes 2 and 3) relies on their biological characteristics and is of interest for predicting the therapeutic benefit of targeted therapies and immunotherapy. Given the relative rarity of this molecular subset of disease, evidence supporting treatment choices is limited. This review aims to offer a comprehensive update about available therapeutic options for patients with NSCLC harbouring BRAF mutations to guide the physician in the choice of treatment strategies. We collected the most relevant available data, from single-arm phase II studies and retrospective analyses conducted in advanced NSCLC, regarding the efficacy of BRAF and MEK inhibitors in both V600 and non-V600 BRAF mutations. We included case reports and smaller experiences that could provide information on specific alterations. With respect to immunotherapy, we reviewed retrospective evidence on immune-checkpoint inhibitors in this molecular subset, whereas data about chemo-immunotherapy in this molecular subgroup are lacking. Moreover, we included the available, though limited, retrospective evidence of immunotherapy as consolidation after chemo-radiation for unresectable stage III BRAF-mutant NSCLC, and an overview of ongoing clinical trials in the peri-operative setting that could open new perspectives in the future.

4

Authors: Chiara Dallagiovanna, Laura Mensi, Luca Di Gesaro, Irene La Vecchia, Marco Reschini

Background: Due to high purity, recombinant human chorionic gonadotropin (hCG) is suitable for subcutaneous injection, and hence for self-administration, in assisted reproduction. To increase usability and reduce the risk of dosing errors, a prefilled pen was produced. We investigated the ease of administration and satisfaction with the product amongst patients and healthcare professionals. Methods: A survey was conducted amongst women with infertility who underwent in vitro fertilization treatments with recombinant hCG to trigger ovulation in various clinics in Italy. Results: A total of 276 Italian women were interviewed. The median score of preference for the prefilled pen in comparison with hCG powder to be reconstituted in the solvent was rated as 9 (range 8–10), and 125 women answered that the prefilled pen had major advantages. Reasons for preference of the prefilled pen were linked to ease of use and safety: avoidance of dosage mistakes and of concern of such, ease of administration, certainty that the drug is correctly taken, safe administration and no anxiety. The procedure for recombinant hCG administration through the prefilled pen was judged as easy by 80% of respondents, with a median score of 9 (range 8–10) for easiness on a 1–10 scale. Out of 276 respondents, 249 (90%) had no problem with the injection. Conclusion: Overall, the respondents reported a favourable perception of the prefilled pen with hCG, which was reported to be easy to use and perceived to prevent dosage mistakes.

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: Marco Vincenzo Lenti, Federico Sottotetti, Gino Roberto Corazza

Clinical complexity (CC) is an increasingly recognized feature of internal medicine patients who are often characterized by complex needs determined by both biological (i.e. intrinsic to the patient or disease biology) and non-biological (i.e. socioeconomic, cultural, environmental, behavioural) factors. Breast cancer, one of the most common malignancies worldwide, certainly represents an example of a complex disease. Nonetheless, the concept itself of CC and its possible determinants in breast cancer have been poorly addressed. We herein provide our view about the possible factors triggering CC, the key issues of CC and the related unmet needs in breast cancer.

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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: T Joseph Mattingly II, Shannon Weathers

Cost-of-illness (COI) studies attempt to measure and describe the costs associated or attributed to a specific disease, but there are several considerations for measuring and interpreting drug costs estimates. The complexity of the pharmaceutical supply chain and contractual relationships between manufacturers, wholesalers, pharmacies and payers create challenges for researchers attempting to include drug costs in COI analyses. This article aims to provide contextual information for a general audience interested in conducting or evaluating COI studies that may include drug costs and to describe key factors to consider when reviewing drug costs in the peer-reviewed literature.

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Authors: Francisco Nohales Alfonso

Three women with diverse gynaecological medical histories (one with endometriosis, one having had an episiotomy and obstetric anal sphincter injury during a recent delivery, and one having had a recent cystectomy of the left Bartholin gland) developed acute episodes of gynaecological pelvic pain. In each case, clinical investigations (including objective tools for assessing the source, nature and severity of the pain) were conducted early on, and a multimodal approach to therapy was introduced to control the pain and avoid central sensitization or chronicity. The multimodal approach included hormone therapy, antineuropathic medications, and corticosteroid or botulinum neurotoxin infiltrations in some of the patients according to their medical conditions but consistently included behavioural adjustments, physical interventions and a nutraceutical supplement (alpha-lipoic acid, palmitoylethanolamide and myrrh). In each case, the pelvic pain and associated dyspareunia (Marinoff scale 2 or 3) were largely resolved. These clinical cases support the results of clinical trials showing the benefits of alpha-lipoic acid + palmitoylethanolamide + myrrh for the management of gynaecological pelvic pain, enabling the reduction or withdrawal of other analgesic, anti-inflammatory and antineuropathic medications.

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Authors: Chiara Bertone, Antonella Mollicone, Stefano Russo, Paola Sasso, Romina Fasciani, Cinzia Riccardi, Mirella Lizzano, the ALI working group

Experiences from clinical practice suggest that hypochlorous acid (HOCl) used as adjuvant treatment can shorten the time to clinical resolution of blepharitis, particularly in relation to the ophthalmic complications that often occur with a blepharitis diagnosis. In addition, in clinical practice, HOCl adjuvant treatment also resulted in a viable option for the management of ophthalmic disorders other than blepharitis. This case series presents and discusses real-life experiences with using an HOCl ophthalmic spray to manage eye infections, further characterizing the use of HOCl for ophthalmic applications.

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Authors: Khalad Maliyar, Sonya J Abdulla

Rosacea is a common inflammatory skin disorder affecting the face. Common cutaneous symptoms include papules, pustules, persistent centrofacial erythema, telangiectasias, recurrent flushing, phymatous changes and a variety of ocular manifestations. Previous epidemiological studies have demonstrated that the incidence of rosacea is much lower in people with darker Fitzpatrick phototypes compared to fair-skinned individuals. In patients with darker skin, the centrofacial erythema can be masked and difficult to appreciate, impacting the ability for providers to make diagnoses and leading to misdiagnoses. Thus, it is difficult to say with certainty that the disparities in prevalence in rosacea amongst fair-skinned and darker individuals are true. The primary aim of this article is to raise awareness that rosacea is a global disease and to provide healthcare professionals with strategies to identify and manage rosacea amongst individuals with skin of colour.

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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: Stephanie Spivack, Stephen Pagkalinawan, Rafik Samuel, David E Koren

Although decreasing in prevalence, heavily treatment-experienced (HTE) persons with limited options for HIV treatment present unique complexities, even amongst experienced providers, as there is no single approach to successful management. HTE patients are described as those having two or less antiretroviral (ARV) classes available for use with limited fully active ARV agents within each class. A detailed understanding of the underlying processes that caused previous treatment failures, diagnostics to define resistance, resistance mechanisms and ARV pharmacology should all function in tandem to determine the next steps of clinical care. This narrative review provides an overview of the clinician approach to care, including diagnostics, approaches to regimen creation, relevant resources, and a broad array of both currently available and upcoming ARVs that may be used in regimens for HTE patients.

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Authors: Steven H Abman, Nicholas R Fox, M Ibrahim Malik, Sneha S Kelkar, Shelby L Corman, Sanika Rege, Jenna Bhaloo, Rachel Shah, Ren-Jay Shei, Dana Saporito, Nisreen Shamseddine, Erik DeBoer, George J Wan, on behalf of the NOTICE Study Investigators

Background: Inhaled nitric oxide (iNO) has been studied in patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 when it may be too late to impact disease course. This article aims to describe real-world iNO use and outcomes in patients with COVID-19 with mild-to-moderate ARDS in the United States. Methods: This was a retrospective medical chart review study that included patients who were ≥18 years old, hospitalized for COVID-19, met the Berlin ARDS definition, received iNO for ≥24 hours continuously during hospitalization, and had a partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F ratio) of >100 to ≤300 mmHg at iNO initiation. Outcomes included oxygenation parameters, physician-rated Clinical Global Impression–Improvement (CGI-I) scale scores, and adverse events. Response to iNO was defined as >20% improvement in P/F ratio. Results: Thirty-seven patients at six sites were included. A P/F ratio of ≤100 was the most common reason for exclusion (n=146; 83% of excluded patients). The mean P/F ratio (SD) increased from 136.7 (34.4) at baseline to 140.3 (53.2) at 48 hours and 151.8 (50.0) at 72 hours after iNO initiation. The response rate was 62% (n=23). During hospitalization, no patient experienced adverse events, including methemoglobinaemia, airway injury, or worsening pulmonary oedema associated with iNO. At discharge, 54.0% (n=20) of patients improved or remained stable according to the CGI-I. Conclusion: In patients hospitalized with COVID-19 and mild-to- moderate ARDS, iNO was associated with improvement in the P/F ratio with no reported toxicity. This study provides additional evidence supporting a favourable benefit–risk profile for iNO in the treatment of mild-to-moderate ARDS in patients with COVID-19 infection.

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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: Chrysanthi Batistaki, Michal Graczyk, Marcin Janecki, Agata Anna Lewandowska, Rita Moutinho, Kiriaki Vagdatli

The assessment and treatment of breakthrough cancer pain (BTcP) remain a major challenge in medicine due to its high impact on several aspects of health-related quality of life. BTcP should be carefully monitored in all cancer care settings by a multidisciplinary team to provide an appropriate and personalized clinical approach. The aim of this paper is to provide healthcare professionals involved in cancer pain management with a review of the relevant literature on the relationship between background cancer pain and BTcP which, by definition, occurs despite adequately controlled background cancer pain. The clinical cases presented contribute to a better understanding of this issue and underline its impact in daily clinical practice. 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: Federico Sottotetti, Elisa Ferraris, Barbara Tagliaferri, Raffaella Palumbo, Erica Quaquarini, Cristina Teragni, Emanuela Balletti, Claudia Leli, Andrea Premoli, Ludovica Mollica, Silvia Puglisi, Silvia Sardi, Alberto Malovini, Paolo Pedrazzoli, Antonio Bernardo

Tumour markers have no established role in the monitoring of the course of metastatic breast cancer during antineoplastic therapy, yet cancer antigen 15.3 (CA15.3) and carcinoembryonic antigen (CEA) are commonly used in clinical practice to aid in the early detection of progression of disease (PD). In our multicentre, prospective, real-life study, we enrolled 142 consecutive patients with advanced breast cancer receiving endocrine therapy in combination with a CDK4/6 inhibitor from January 2017 to October 2020; 75 patients had PD at the time of database closure. We measured serum marker concentrations at regular 4-month intervals together with radiological tumour response assessments and in cases of clinical suspicion of PD. Appropriate descriptive and inferential statistical methods were used to analyse serum marker level trends amongst prespecified subgroups and at specific time points (baseline, best radiologically documented tumour response and first detection of PD) in the subpopulation of patients with PD at the time of database closure. Notably, the median time from treatment initiation to best tumour response was 4.4 months. We evaluated the presence of an association between baseline CA15.3 and CEA levels and prespecified clinical characteristics but found no clinically meaningful correlation. We assessed marker level variations at the time of best radiologically documented disease response and PD: in the subgroup of patients who responded to treatment before progressing, we detected a statistically significant correlation with tumour marker variation between the time of best response and progression; this finding was not confirmed in the subgroup of patients that did not benefit from treatment. In conclusion, serum tumour marker flares can be useful in the early diagnosis of PD but should not be used as the sole factor prompting a change in treatment strategy without radiological confirmation.

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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: 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: S Mimi Mukherjee, Aimee Dawson

Due to worldwide increases in obesity and average maternal age, the incidence of gestational diabetes mellitus (GDM) is increasing. The primary treatment of GDM is medical nutrition therapy but approximately 15–30% of individuals need pharmacotherapy to reach blood glucose goals to minimize the adverse consequences of hyperglycaemia. In the past, regular and neutral protamine Hagedorn insulin were the mainstays of pharmacological treatment for GDM due to their well-established safety; however, because they are administered as injections and require strict timing of doses and meals to minimize hypoglycaemia, alternatives are often sought. The research around the treatment of GDM continues to evolve as insulin analogues and oral agents are studied in clinical trials. The short-term and long-term effects of treatment choices on both mothers and progeny are being evaluated, and this narrative review summarizes the current state of information available regarding the treatment of GDM.

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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: Elisa Andrini, Mirta Mosca, Linda Galvani, Francesca Sperandi, Biagio Ricciuti, Giulio Metro, Giuseppe Lamberti

Targeted therapy has dramatically changed the history and outcomes of oncogene-addicted non-small-cell lung cancer (NSCLC). RET rearrangements are typically observed in about 1–2% of NSCLC, resulting in constitutive activation of downstream signalling pathways commonly involved in cell growth and survival. RET-positive NSCLCs are generally associated with young age, non-smoking history, a high rate of brain metastases at diagnosis and an immunologically ‘cold’ tumour microenvironment. Multi-kinase inhibitors, such as cabozantinib, lenvatinib and vandetanib, showed limited efficacy but significant toxicity mainly linked to off-target effects. In contrast, two RET-selective tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, demonstrated high response rates and manageable safety profiles, and have received FDA approval for the treatment of advanced RET-positive NSCLC regardless of previous lines of treatment. Despite the initial high response rate to RET-TKIs, most patients inevitably develop disease progression due to acquired resistance mechanisms by both on-target or off-target mechanisms. To date, new potent and selective next-generation RET-TKIs are currently being evaluated in ongoing clinical trials in order to overcome resistance and improve efficacy and blood–brain barrier crossing. Genomic recharacterization at progression could help guide treatment choice or enrolment in clinical trials of specific next-generation RET inhibitors. Here, we review the biology, clinicopathological characteristics, targeted therapies and mechanisms of resistance of advanced NSCLC harbouring RET fusions to provide treatment guidance for these patients.

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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: 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: Andrea L Monteiro, Mary Smart, Christopher D Saffore, Todd A Lee, Sarette T Tilton, Michael A Fischer, A Simon Pickard

Introduction: Academic detailing (AD) is an educational outreach strategy to provide clinicians with current evidence-based information, which has been shown to change prescribing behaviours. The overall effectiveness of AD interventions is associated with prescriber satisfaction; however, most approaches use single items or nonvalidated measures. This study aims to develop and validate an instrument to assess prescriber satisfaction with AD interventions. Methods: A group of candidate items was generated and refined based on constructs identified through a literature review and in consultation with an expert panel. The initial instrument was piloted with 183 primary care providers who participated in an AD intervention on opioid-related pain management. To support the validity and reliability of the measure, psychometric properties were examined. Results: Ten candidate items were developed based on the following themes: acceptability, feasibility of implementation, usefulness, perception of efficacy, overall satisfaction, willingness to repeat and willingness to change. One item related to willingness to change did not contribute to assessing an individual’s ability and lowered the measure’s internal consistency and was therefore dropped. Conclusion: Results supported the validity and reliability of a refined 9-item measure of Provider Satisfaction with Academic Detailing (the PSAD). This measure should be considered for broad use across educational outreach programmes as a standardized measure to assess provider satisfaction and provide continuous quality improvement.

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Authors: Siddiq Moolla, Yvette Miller-Monthrope

Hyperpigmentation disorders, such as post-inflammatory hyperpigmentation and melasma, are common conditions affecting all skin types. These conditions are largely benign and are influenced by numerous endogenous and exogenous factors impacting melanocyte activity and melanin production. Current treatment modalities for these conditions fall into broad categories, including photoprotection, topical and systemic therapies, chemical peels, and laser or light-based therapies. Biological differences in skin of colour require additional consideration when deciding on treatment and management. This narrative review provides an inclusive summary of these conditions and compares the current treatment options with a specific focus on skin of colour. Photoprotection and sunscreens protective against both UV and visible light are recommended for all individuals. Topical therapy is the recommended first-line treatment, with the gold standard being hydroquinone, which can be used alone or in combination with other agents. Chemical peels and laser or light-based therapies are also effective adjunctive methods of treatment; however, caution should be taken when used in patients with richly pigmented skin due to the increased risk of post-inflammatory hyperpigmentation.

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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: Daniele Marinelli, Marco Siringo, Giulio Metro, Biagio Ricciuti, Alain J Gelibter

Oncogene addiction in non-small-cell lung cancer (NSCLC) has profound diagnostic and therapeutic implications. ALK, ROS1 and NTRK rearrangements are found in about 2–7%, 1–2% and 0.2% of unselected NSCLC samples, respectively; however, their frequency is markedly higher in younger and never-smoker patients with adenocarcinoma histology. Moreover, ALK, ROS1 and NTRK rearrangements are often mutually exclusive with other known driver alterations in NSCLC. Due to such a low frequency, diagnostic screening with accurate and inexpensive techniques such as immunohistochemistry is useful to identify positive cases; however, confirmation with fluorescent in situ hybridization or next-generation sequencing is often required due to higher specificity. In ALK-rearranged NSCLC, sequential treatment with second-generation and third-generation tyrosine kinase inhibitors leads to long-lasting disease control with most patients surviving beyond 5 years with metastatic disease. In ROS1-rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. NTRK1–3 fusions are extremely rare in unselected NSCLC. However, treatment with TRK inhibitors yields high response rates and durable disease control in most patients; diagnostic screening through multigene DNA/ RNA-based next-generation sequencing testing is therefore crucial to identify positive cases. 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: 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: 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: George Kassianos, Joan Puig-Barberà, Hannah Dinse, Martin Teufel, Özlem Türeci, Shanti Pather

Immunization programmes have been globally recognized as one of the most successful medical interventions against infectious diseases. Despite the proven efficacy and safety profiles of coronavirus disease 2019 (COVID-19) vaccines, there are still a substantial number of people who express vaccine hesitancy. Factors that influence vaccine decision-making are heterogenous, complex, and context specific and may be caused or amplified by uncontrolled online information or misinformation. With respect to COVID-19, the recent emergence of novel variants of concern that give rise to milder disease also drives vaccine hesitancy. Healthcare professionals remain one of the most trusted groups to advise and provide information to those ambivalent about COVID-19 vaccination and should be equipped with adequate resources and information as well as practical guidance to empower them to effectively discuss concerns. This article seeks to summarize the currently available information to address the most common concerns regarding COVID-19 vaccination.

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Authors: Emily K Hanners, Jessica Benitez-Burke, Melissa E Badowski

Background: People living with HIV (PLWH) and receiving antiretroviral therapy (ART) have a goal of achieving and maintaining viral suppression; however, low-level viraemia (LLV) (HIV-RNA viral load levels of 50–999 copies/mL) persists in certain patients despite consistent medication adherence, lack of drug interactions and no genotypic resistance. This is a narrative review of the growing evidence of LLV in PLWH to determine risk factors and ART management strategies and to discuss the implications of LLV on the development of future virological failure. Methods: A systematic, comprehensive literature search was completed in the English language using PubMed, Google Scholar and bibliography review to gather information about LLV in PLWH between July 2014 and June 2021. The following keywords were used as search terms: “low-level viremia”, “HIV”, “viral blip”, “intensification”, “genotyping”, “adherence” and “resistance.” Results: Of 66 studies examined, 39 were analysed and included in this review. All trials included were published between 2014 and 2021. Eleven studies assessed risk factors for LLV. Identified risk factors were low CD4+ T cell nadir counts at baseline, higher baseline viral load measurements, medication non-adherence, non-nucleoside reverse transcriptase inhibitor use and others. Three studies assessed genotyping and concluded that the interpretation of both historical RNA genotype resistance testing and current proviral DNA genotype resistance testing in patients with LLV is appropriate. Seven studies were evaluated and determined that modifying or intensifying ART regimens resulted in decreased incidence of virological failure. Conclusion: This compilation of reviewed data gives a framework for the management of PLWH with LLV. Currently, there are no clear or definitive treatment directions for LLV provided in guidelines. Complicating this topic further is the unclear and varying definitions of LLV. Future research is needed on this topic but patients presenting with LLV should have their medication adherence assessed, drug interactions checked and ART intensified, where appropriate.

1

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: Josef Finsterer, Fulvio Alexandre Scorza, Carla Alexandra Scorza

Letter to the Editor commenting on Orsucci D, Caldarazzo Ienco E, Nocita G, Napolitano A, Vista M. Neurological features of COVID-19 and their treatment: a review. Drugs Context. 2020;9:2020-5-1. https://doi.org/10.7573/dic.2020-5-1

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Authors: Gian Luca Erre MD, PhD, Arduino Aleksander Mangoni MD

This Editorial introduces the Special Issue on the efficacy and safety of current treatment strategies for patients with connective tissue disease-related interstitial lung disease, including the use of immunosuppressants, such as cyclophosphamide, mycophenolate mofetil and rituximab, and antifibrotic drugs.

3

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: Egídio Freitas, Tiago Torres

Bimekizumab, a humanized monoclonal IgG1 antibody being currently evaluated for multiple immune-mediated diseases, is mentioned in the recent report by Clarivate, Drugs to Watch in 2021, as one of the drugs to be observed in 2021. Due to its novel mechanism of action (dual inhibition of IL-17A and IL-17F), bimekizumab is considered a new therapeutic approach for the treatment of moderate-to-severe psoriasis. Bimekizumab has demonstrated superiority in all direct comparative clinical trials conducted, whether against ustekinumab (IL-12/23 inhibitor), adalimumab (TNF inhibitor) or secukinumab (IL-17A inhibitor), and has shown very encouraging results for the treatment of psoriatic arthritis. Since September 2020, the drug is being reviewed by the EMA and FDA for the treatment of psoriasis. Herein, the current status of bimekizumab is discussed.

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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: Francesco Serra, Carlotta Faverio, Angioletta Lasagna, Stefania Barruscotti, Tommaso Dominioni, Marco Benazzo, Paolo Pedrazzoli, Silvia Chiellino

The clinical management of BRAF-mutated metastatic melanoma had an important turning point after the introduction of the targeted therapy. Despite the efficacy and good tolerability of this treatment, the development of resistance mechanisms causes disease progression. The aim of this review is to investigate the role of treatment beyond progression and locoregional approaches in BRAF-mutated metastatic melanoma and provide oncologists dealing with this malignancy a useful road map on when and why to choose this strategy. The article is structured in the form of a narrative review reporting the most significant studies on the subject. Most of the available articles are represented by retrospective studies and case reports, leading to limitations in the final interpretations. Nevertheless, a correct analysis of the selected studies allows the drawing of some conclusions. In well-selected cases, treatment beyond progression could play an important role in the treatment sequence of patients with BRAF-mutated advanced melanoma and would seem to produce good disease control rates and positive survival outcomes. A careful evaluation of the radiological examinations and laboratory tests, based on the clinical conditions, allows the identification of which patients can benefit from this strategy. Such patients are those who, at the time of progression, have favourable features such as a lower performance status according to Eastern Cooperative Oncology Group (ECOG-PS), normal lactate dehydrogenase levels and lower disease burden. The clinical benefit is also consolidated by the addition of locoregional approaches. Locoregional approaches can include electrochemotherapy, radiotherapy or surgery, and their use provides local disease control and a better quality of life for patients.

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Authors: Tommaso Cai, Cristian Konstantinidis, Sam Ward

Recurrent urinary tract infections (UTIs) can profoundly impair patients’ quality of life and carry a substantial health resource burden. Although antibiotics are the mainstay of treatment, interest is growing in identifying antibiotic-sparing alternatives. Utipro® Plus is a medical device that acts as a mechanical barrier to protect the intestinal lumen against the adherence and invasion of uropathogenic strains of Escherichia coli. It is intended for the control and prevention of UTIs caused by E. coli and other Gram-negative uropathogens. Using illustrative case reports, this review documents outcomes in three women with recurrent UTIs who were treated with Utipro® Plus in clinical practice.

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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: 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: Giorgio Attinà, Alberto Romano, Silvia Triarico, Stefano Mastrangelo, Palma Maurizi, Antonio Ruggiero

Pain is one of the main symptoms reported by sick children, particularly by those suffering from cancer. Opioids are very useful in controlling this symptom but they are burdened with significant side effects that limit their use in children. Buprenorphine is a strong opioid that, due to its particular pharmacological characteristics, ensures excellent pain relief with fewer side effects than other opioids. The transdermal formulation allows for good pain control associated with optimal compliance by patients and few limitations on daily life. Unfortunately, transdermal buprenorphine use remains off-label for the control of chronic pain in children; therefore, it is desirable that new studies can validate its use in the paediatric population. This review aims to analyse the clinical advantages of transdermal buprenorphine in the paediatric population and the possible side effects registered in daily clinical practice.

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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: 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: 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

A clinical need for aetiotropic coronavirus disease (COVID-19) treatments is required. The immune modulator azoximer bromide (AZB; Polyoxidonium®) is indicated in Russia for use against acute viral infections and during remission. In this study, adults hospitalized with COVID-19 (n=32) received AZB and standard of care in an open-label, multicentre, interventional study. All patients were symptomatic; 22 had severe disease (National Early Warning Score ≥5) and required mechanical ventilation or respiratory support and 19 patients had co-morbidities. Patients received AZB 12 mg intravenously once daily for 3 days, then intramuscularly every other day (approximately ten injections) until discharge. The primary endpoint was the patient’s clinical status (7-point Ordinal Scale; OS) on day 15 versus that at baseline. The mean duration of hospitalization was 20 days. All patients were alive and discharged with normal oxygen saturation (SpO2) with no secondary infections or delayed mortality reported by the end-of-study visit (on day 28–72). A decrease in the mean OS and National Early Warning Score values was observed following treatment with AZB. A decrease in OS score was marked in patients identified as severe. Both sets of patients achieved similar scores, which can be classified as an improvement by day 9–10; SpO2 levels trended to normalization over time. By day 11–12, all patients had a normal body temperature. Serum C-reactive protein levels decreased in patients with severe and mild disease. Most patients had signs of pneumonia at baseline (n=27), with the majority recovering by days 10–12. No major toxicities were observed. AZB was safe and well tolerated when administered in addition to standard of care treatment for COVID-19. Further randomized, placebo-controlled studies are needed to elucidate any potential therapeutic effect in COVID-19.

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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: Alexander KC Leung, Kam Lun Hon

Background: Viral gastroenteritis is the most common diarrhoeal disorder seen in general practice and emergency departments. This article aims to provide a narrative updated review on the evaluation and management of viral gastroenteritis in children. Methods: A PubMed search was performed with Clinical Queries using the key term ‘viral gastroenteritis’. The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies and reviews. The search was restricted to the English literature and the paediatric population. Results: Acute viral gastroenteritis is usually self-limiting. However, it can lead to dehydration and electrolyte imbalance if not properly treated. Adequate fluids containing physiological concentrations of glucose and electrolytes should be provided to compensate for gastrointestinal losses and cover maintenance needs. Oral rehydration therapy is as effective as intravenous (IV) fluid therapy for rehydration for children with mild-to-moderate dehydration. Measurements of serum electrolytes, creatinine and glucose are usually not necessary and should only be considered in a subset of children with severe dehydration who require hospitalization and IV therapy. Judicious use of ondansetron can increase the success rate of oral rehydration therapy and minimize the need for IV therapy and hospitalization. Conclusion: Acute viral gastroenteritis is associated with substantial morbidity in developed countries and significant mortality in developing countries. Physicians should educate caregivers on proper personal hygiene and handwashing to prevent faecal to oral transmission of the pathogen as well as the importance of rotavirus vaccine in the prevention of rotavirus gastroenteritis. Several norovirus vaccines are currently undergoing clinical trials with promising results. It is hoped that development of an effective norovirus vaccine will further reduce the incidence of viral gastroenteritis.

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Authors: Elizabeth Van Nostrand, Alyssa Johnston, Steven M Albert, Andre L Brown, Jeanine M Buchanich, Brad Ray, Mark S Roberts

Background: Fatal and non-fatal events associated with drug misuse are skyrocketing in most United States jurisdictions, including Indiana. Historically, the role of the judiciary is to arrest, impose sanctions and protect society from harm. Adults arrested for drug abuse in Indiana can be sentenced to 1 of 17 correctional facilities. As an alternative, they may be eligible to participate in a problem-solving court (PSC) programme that refers individuals to treatment as a pretrial diversionary strategy. The aim of the study is to determine which interventions offered by PSCs and correctional facilities impact morbidity and mortality. The study began in 2019 and will end in 2023; therefore, the results in this manuscript are preliminary. Methods: The study cohort included two populations arrested for drug misuse: (1) adults sentenced to Indianan correctional facilities (1 January 2018 to 30 June 2021) and (2) adults participating in an Indiana PSC programme (1 January 2018 to 30 June 2021). The study used a mixed-methods design that integrated qualitative interviews of deputy wardens, PSC team members and service providers with the following quantitative datasets: sentencing information, emergency department visits, inpatient hospitalization admissions, prescription drug monitoring programme data and death records. The individuals will be followed at 2-week, 4-week, 6-month and 1-year intervals post-release. Difference-in-difference and time-toevent analyses will identify impactful interventions. A model will be created to show the effect of impactful interventions in Indiana counties that do not have PSCs. Results: Findings are preliminary. There is variability amongst correctional facilities regarding programme eligibility, provided services and provision of medication-assisted treatment. All correctional facilities were severely impacted by the COVID-19 pandemic. Conclusion: It is anticipated that the adoption of impactful interventions will lower opioid-related morbidity and mortality rates.

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Authors: Joan L Robinson

The goal of this narrative review of pharyngitis is to summarize the practical aspects of the management of sore throat in children in high- and middle-income countries. A traditional review of the literature was performed. Most cases of pharyngitis are viral and self-limited, although rarely viral pharyngitis due to Epstein–Barr leads to airway obstruction. Bacterial pharyngitis is usually due to group A streptococcus (GAS), occurs primarily in children aged 5–15 years, and presents as sore throat in the absence of rhinitis, laryngitis or cough. Again, most cases are self-limited; antibiotics hasten recovery by only 1–2 days. Guidelines vary by country, but antibiotics are commonly recommended for proven GAS pharyngitis as they may prevent rare but severe complications, in particular rheumatic fever (RF). In this era of antimicrobial stewardship, it should be extremely rare that antibiotics are prescribed for presumed GAS pharyngitis until GAS has been detected. Even with proven GAS pharyngitis, it is controversial whether children at low risk for RF should routinely be prescribed antibiotics as the number needed to treat to prevent one case of RF is undoubtedly very large. When treatment is offered, the antibiotics of choice are penicillin or amoxicillin as they are narrow spectrum and resistance resulting in clinical failure is yet to be documented. A 10-day oral course is recommended as shorter courses appear to be less likely to clear carriage of GAS. However, the evidence that one needs to clear carriage to prevent RF is low quality and indirect.

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Authors: Hichem Aouina, Anis Bamri, Aurélien Vesin, Karine Danno, Eléonore Aubry, Cécile Faure, Naoual Boujedaini

Background: Upper respiratory tract infections (URTIs) are a major cause of exacerbations in patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of Oscillococcinum® in the protection from URTIs in patients with COPD who had been vaccinated against influenza infection over the 2018–2019 winter season. Methods: Patients (n=106; mean ± standard deviation age: 66.0 ± 10.3 years; 89.6% men) were randomized into two groups: group V received influenza vaccination only and group OV received influenza vaccination plus Oscillococcinum® (one oral dose per week from inclusion in the study until the end of follow-up, with a maximum of 6 months follow-up over the winter season). The primary endpoint was the incidence rate of URTIs (number of URTIs/1000 patient-treatment exposure days) during follow-up compared between the two groups. Results: There was no significant difference in any of the demographic characteristics, baseline COPD, or clinical data between the two treatment groups (OV and V). The URTI incidence rate was significantly higher in group V than in group OV (2.9 versus 1.2 episodes/1000 treatment days, difference OV–V = −1.7; p=0.0312). There was a significant delay in occurrence of an URTI episode in the OV group versus the V group (mean ± standard error: 48.7 ± 3.0 versus 67.0 ± 2.8 days, respectively; p=0.0158). Limitations to this study include its small population size and the self-recording by patients of the number and duration of URTIs and exacerbations. Conclusion: Oscillococcinum may decrease the incidence rate and delay the appearance of URTIs in patients with COPD.

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

Background: Acute respiratory distress syndrome (ARDS) is a significant cause of mortality and morbidity amongst critically ill children. The purpose of this narrative review is to provide an up-to-date review on the evaluation and management of paediatric ARDS (PARDS). Methods: A PubMed search was performed with Clinical Queries using the key term “acute respiratory distress syndrome”. The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies and reviews. Google, Wikipedia and UpToDate were also searched to enrich the review. The search was restricted to the English literature and children. Discussion: Non-invasive positive pressure ventilation, lung-protective ventilation strategies, conservative fluid management and adequate nutritional support all have proven efficacy in the management of PARDS. The Pediatric Acute Lung Injury Consensus Conference recommends the use of corticosteroids, high-frequency oscillation ventilation and inhaled nitric oxide in selected scenarios. Partial liquid ventilation and surfactant are not considered efficacious based on evidence from clinical trials. Conclusion: PARDS is a serious but relatively rare cause of admission into the paediatric intensive care unit and is associated with high mortality. Non-invasive positive pressure ventilation, lung-protective ventilation strategies, conservative fluid management and adequate nutrition are advocated. As there has been a lack of progress in the management of PARDS in recent years, further well-designed, large-scale, randomized controlled trials in this field are urgently needed.

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Authors: Girija Narendrakumar Wagh, KM Kundavi Shankar, Sumitra Bachani

Background: Exogenous progesterone is a treatment option for obstetric indications associated with reduced progesterone activity. Oral natural micronized progesterone (NMP) is effective, although it requires multiple daily doses and may cause adverse events due to its active metabolites. A sustained-release formulation of NMP (NMP-SR) has been developed to overcome the limitations of conventional oral NMP. Methods: This narrative review examines the available evidence for oral NMP and NMP-SR in several obstetric indications of interest. Results: Literature searches identified 17 studies of oral NMP (luteal phase support during assisted reproduction, prevention of threatened miscarriage, prevention of preterm delivery), and clinical studies supporting use of NMP-SR (luteal phase support during intrauterine insemination, maintenance of high-risk pregnancy). Oral NMP was effective for luteal phase support during in vitro fertilization and intrauterine insemination, prevention of threatened miscarriage, and prevention of preterm delivery. NMP-SR was comparable to dydrogesterone for luteal phase support during intrauterine insemination and effectively maintained high-risk pregnancies. Oral NMP-SR was well tolerated. Conclusions: By releasing progesterone gradually and circumventing first-pass metabolism, NMP-SR elicits the desired therapeutic effect with benefits over conventional oral NMP in terms of bioavailability, once-daily dosing and improved tolerability. Oral NMP-SR appears to be a valuable option for treating obstetric conditions associated with insufficient progesterone exposure.

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Authors: Renato Vellucci, Gianluca De Rosa, Emanuele Piraccini

Background: Poor sleep may predict the increase and intensification of pain over time with increased insomnia symptoms being both a predictor and an indicator of worse pain outcomes and physical functioning status over time. However, the impact of different analgesic therapies on quality of life, functional recovery and sleep has been poorly assessed to date, whereas these evaluations may greatly help clinicians in the selection of treatment when dealing with patients with chronic pain (CP). Methods: To explore whether tapentadol-induced pain relief may drive improved sleep quality, we carried out a pooled analysis of real-world data collected from 487 patients with CP (mean age, 68.3 years; 57.7% women) suffering from a wide range of chronic musculoskeletal pain conditions and treated with tapentadol. Results: Following tapentadol treatment, patients experienced an 80% reduction in the frequency of very disturbed sleep as well as a 50% reduction in the predominant sleep complaint reported by patients with CP – that is, nocturnal awakenings. A significantly greater proportion of patients reported good/restful sleep at the end of the study period compared to baseline (72.4% versus 25.3%; p<0.01). This benefit was observed regardless of the clinical setting, treatment duration, posology or patient age and was associated with a higher proportion of patients reporting an improved global health status and good tolerability. Conclusion: The reduction in pain intensity provided by tapentadol fosters sleep quality and favours a better quality of life. Therefore, our findings provide the rationale for addressing sleep quality as a relevant outcome, complementary to pain relief in CP management.

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Authors: Russell Thompson, Sean Westbury, Dana Slape

This narrative review addresses scabies, a highly contagious, pruritic infestation of the skin caused by the mite Sarcoptes scabiei var hominis. Scabies is a common disorder that has a prevalence worldwide estimated to be between 200 and 300 million cases per year. Infestation is of greatest concern in children, the elderly, immunocompromised people and resource-poor endemic populations at risk of chronic complications. A diagnosis of scabies involves a clinical suspicion, a detailed targeted history, clinical examination and contact tracing. Dermoscopy and microscopy, where available, is confirmatory. Due to its infectivity and transmissibility, the management for scabies requires a multimodal approach: topical antiscabetic agents are the first line for most cases of childhood classic scabies and their contacts, which must also be identified and treated to prevent treatment failure and reacquisition. Environmental strategies to control fomite-related reinfestation are also recommended. Oral ivermectin, where available, is reserved for use in high-risk cases in children or in mass drug administration programmes in endemic communities. The prevention of downstream complications of scabies includes surveillance, early identification and prompt treatment for secondary bacterial infections, often superficial but can be serious and invasive with associated chronic morbidity and mortality. Post-scabetic itch and psychosocial stigma are typical sequelae of the scabies mite infestation. The early identification of patients with scabies and treatment of their contacts reduces community transmission. Although time consuming and labour intensive for caregivers, the implementation of appropriate treatment strategies usually results in prompt cure for the child and their contacts. Here, we provide a summary of treatments and recommendations for the management of paediatric scabies.

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Authors: George Kassianos MD, Ashis Banerjee MD, Florence Baron-Papillon MD, Alan W Hampson MD, Janet E McElhaney MD, Allison McGeer MD, Thierry Rigoine de Fougerolles MSc, Mitch Rothholz MD, Holly Seale MD, Litjen J Tan MD, Angus Thomson PhD, Olivier Vitoux MSc

Background: Many countries consistently fail to achieve the target influenza vaccine coverage rate (VCR) of 75% for populations at risk of complications, recommended by the World Health Organization and European Council. We aimed to identify factors for achieving a high VCR in the scope of four benchmark countries with high influenza VCRs: Australia, Canada, UK and USA. Methods: Publicly available evidence was first reviewed at a global level and then for each of the four countries. Semistructured interviews were then conducted with stakeholders meeting predefined criteria. Descriptive cluster analyses were performed to identify key factors and pillars for establishing and maintaining high VCRs. Results: No single factor led to a high VCR, and each benchmark country used a different combination of tailored approaches to achieve a high vaccine coverage. In each country, specific triggers were important to stimulate changes that led to improved vaccine coverage. A total of 42 key factors for a successful influenza vaccination programme were identified and clustered into five pillars: (1) Health Authority accountability and strengths of the influenza programme, (2) facilitated access to vaccination, (3) healthcare professional accountability and engagement, (4) awareness of the burden and severity of disease and (5) belief in influenza vaccination benefit. Each benchmark country has implemented multiple factors from each pillar. Conclusion: A wide range of factors were identified from an evaluation of four high-performing benchmark countries, classified into five pillars, thus providing a basis for countries with lower VCRs to tailor their own particular solutions to improve their influenza VCR.

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Authors: Alexander KC Leung, Kam Lun Hon

Background: Despite being a common problem in childhood, functional constipation is often difficult to manage. This article provides a narrative updated review on the evaluation, diagnosis and management of childhood functional constipation. Methods: A PubMed search was performed with Clinical Queries using the key term ‘functional constipation’. The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies and reviews. The search was restricted to the English literature and to the paediatric population. The information retrieved from the above search was used in the compilation of the present article. Results: A detailed history and thorough physical examination are important in the evaluation of a child with constipation to establish the diagnosis of functional constipation as per the Rome IV criteria and to catch ‘red flags’ suggestive of organic causes of constipation. These ‘red flags’ include delayed passage of meconium, ribbon stool, rectal bleeding/blood in the stool unless attributable to an anal fissure, failure to thrive, severe abdominal distension, absent anal wink/cremasteric reflex, tight and empty rectum on digital examination and explosive expulsion of liquid stool and gas on withdrawal of the finger, hair tuft/dimple/lipoma/haemangioma in the lumbosacral area, and an anteriorly displaced anus. For functional constipation, pharmacological therapy consists of faecal disimpaction and maintenance therapy. This can be effectively accomplished with oral medications, rectal medications or a combination of both. The most commonly used and most effective laxative is polyethylene glycol. Non-pharmacological management consists of education, behavioural modification and dietary interventions. The combination of pharmacological therapy and nonpharmacological management increases the chance of success. Conclusion: Polyethylene glycol is the medication of first choice for both disimpaction and maintenance therapy. If polyethylene glycol is not available or is poorly tolerated, lactulose is the preferred alternative. Other laxatives may be considered as second-line therapy if treatment with osmotic laxatives fails or is insufficient. Maintenance treatment should be continued for at least 2 months. Early treatment will result in a faster and shorter treatment course.

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Authors: Iris Y Sheng, Pedro Barata, Raafat Alameddine, Jorge A Garcia

Significant changes in the management of patients with de novo metastatic prostate cancer have led to the use of novel oral agents and docetaxel-based chemotherapy earlier in the natural history of their disease. Our main challenge is the lack of prospective randomized data comparing these regimens. It is clear that treatment intensification is needed. Yet, the heterogeneity of this patient population coupled with the lack of understanding of the specific biology for a given individual makes treatment selection challenging. The aim of this narrative review is to discuss the importance of defining advanced disease by volume, the necessity for treatment intensification, and the current and future landscape of metastatic hormone-sensitive prostate cancer management.

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Authors: Lauren Speakman, Sarah Michienzi, Melissa Badowski

Background: In the midst of the COVID-19 pandemic, there has been an information overload of health data (both accurate and inaccurate) available to the public. With vitamins and supplements being readily accessible, many have turned to using them in an effort to combat the virus. The purpose of this review was to analyse clinical trials regarding vitamins and supplements for the treatment of COVID-19 infections. Methods: Articles were identified through a literature search utilizing online databases and bibliographic review. Results: A total of seven articles were identified for review. All articles evaluated the use of vitamins and supplements for the treatment of COVID-19. Drug therapies included oral vitamin D, intravenous and oral vitamin C, oral vitamin D/magnesium/vitamin B12, oral zinc, oral combination zinc/ascorbic acid, and intravenous alpha-lipoic acid. The end points of each study varied, including the Sequential Organ Failure Assessment score, mortality, rate of intensive care unit (ICU) admissions, negativity of COVID-19 tests, oxygen requirements, and symptom burden. Conclusion: Of the vitamins and supplements that were studied, vitamin D presented the most promising data demonstrating significant decreases in oxygen requirements, need for ICU treatment, SARS-CoV-2 RNA test positivity, and mortality. All of these benefits were exhibited in hospitalized patients. Other vitamins and supplements that were evaluated in studies did not demonstrate any statistically significant benefits. Common shortcomings of the articles included generally small sample sizes, varying sites of study (which could determine the virus variant), a lack of standard of care as background therapy, and utilization of doses that were higher than standard.

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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: Alyssa P Gould, Hana R Winders, Kayla R Stover, P Brandon Bookstaver, Brooke Griffin, Christopher M Bland, Lea S Eiland, Milena Murray

This review is a comprehensive summary of treatment options for pregnant patients with less common bacterial, fungal, and viral infections. It offers guidance to clinicians based on the most recently published evidence-based research and expert recommendations. A search of MEDLINE (inception to March 2021) and the CDC website was performed. Liposomal amphotericin B is the preferred therapy for cryptococcosis, histoplasmosis, oesophageal candidiasis, and coccidioidomycosis, especially during the first trimester due to teratogenic concerns with azole antifungals. For oral candidiasis, clotrimazole troches or miconazole mucoadhesive buccal tablets are recommended. A β-lactam antimicrobial is preferred over doxycycline for various manifestations of Lyme disease and the drug of choice for Pneumocystis pneumonia is trimethoprim/sulfamethoxazole. Acyclovir is the preferred antiviral for varicella zoster virus. Fluoroquinolones, macrolides, and aminoglycosides should be avoided if possible and there are alternate agents available for an effective treatment regimen. There is a scarcity of clinical data in pregnant patients with less common bacterial, fungal and viral infections. This population lacks definitive recommendations in many clinical practice guidelines. The key to optimizing therapy is a comprehensive review of the available evidence and a careful balance of risks and benefits before final treatment decisions.

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Authors: Victoria Kulbokas, Kent A Hanson, Mary H Smart, Monika Rao Mandava, Todd A Lee, A Simon Pickard

Background: Academic detailing (AD) is a tailored, interactive educational outreach intervention that may improve patient outcomes. Insight into the design of AD interventions and the extent to which they are effective can help inform future AD-based programmes. The objective of this scoping review was to characterize opioid-focused AD interventions and describe their findings. Methods: A scoping review focused on AD interventions for opioids was conducted in PubMed, EMBASE and CINAHL databases through July 1, 2021. Studies were eligible for inclusion if written in English, included interactive opioid-focused educational interventions, and were conducted either in person, virtually or via telephone. Four independent reviewers reviewed titles and abstracts. Data extraction from full-text publications was completed using a standardized form. Results: Of 6086 articles initially identified, 22 articles met the inclusion criteria and 20 unique interventions were identified. The AD intervention was either delivered one-on-one (n=16) or in a small, interactive group setting (n=4). AD interventions varied in design. Effectiveness was evaluated in terms of opioid and naloxone prescribing rates, provider knowledge gaps, provider adherence to guidelines, and intervention feasibility. Sixteen (80%) interventions resulted in statistically significant improvement in one or more outcomes. Conclusion: Generally, opioid-related AD was effective and programmes were primarily conducted one-on-one between pharmacists and primary care providers for 16–30 minutes. A variety of metrics and outcomes were used to assess the success/effectiveness of AD interventions, which is an important consideration in future studies as no single metric captures the effectiveness of an educational outreach-based intervention for pain management.

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Authors: Ludovica Mollica, Claudia Leli, Silvia Puglisi, Silvia Sardi, Federico Sottotetti

Leptomeningeal carcinomatosis (LC) is a rare but challenging manifestation of advanced breast cancer with a severe impact on morbidity and mortality. We performed a systematic review of the evidence published over the last two decades, focusing on recent advances in the diagnostic and therapeutic options of LC. Lobular histology and a triple-negative intrinsic subtype are well-known risk factors for LC. Clinical manifestations are diverse and often aspecific. There is no gold standard for LC diagnosis: MRI and cerebrospinal fluid cytology are the most frequently used modalities despite the low accuracy. Current standard of care involves a multimodal strategy including systemic and intrathecal chemotherapy in combination with brain radiotherapy. Intrathecal chemotherapy has been widely used through the years despite the lack of data from randomized controlled trials and conflicting evidence on patient outcomes. No specific chemotherapeutic agent has shown superiority over others for both intrathecal and systemic treatment. Although endocrine therapy was heuristically considered unable to exert significant control on central nervous system metastatic disease, retrospective data suggest a favourable toxicity profile and even a possible positive impact on survival. In recent years, encouraging data on the use of targeted agents has emerged but further research in this field is required. Palliative treatment in the form of whole brain or stereotactic radiotherapy is associated with improvement in clinical manifestations and quality of life, with no proven impact on survival. The most investigated prognostic factors include performance status, non-triple-negative disease and multimodal treatment. Validation of prognostic scores is necessary to aid clinicians in the identification of patient subgroups that are most likely to benefit from an intensive therapeutic approach.

2

Authors: Matteo Bassetti MD, PhD, Paolo Pelosi MD, FERS, Chiara Robba MD, PhD, Antonio Vena MD, PhD, Daniele Roberto Giacobbe MD

Randomized controlled trials (RCTs) are the best way to find effective and acceptable safe treatments for COVID-19 and any possible future outbreak. However, caution is needed when comparing the number of participants in RCTs with that of patients with COVID-19 treated with compassionate and/or off-label drugs to support the hypothesis that the latter are preferred by clinicians as an alternative to the former.

4

Authors: Miguel Nogueira MD, Ron Vender MD, Tiago Torres MD, PhD

The pandemic known as coronavirus disease-19 (COVID-19) has quickly spread worldwide, with a significant impact on lives all over the world. The complexity related to the new coronavirus and the clinical syndrome it causes is not yet fully understood. The impact of COVID-19 on patients with psoriasis under biologic agents is continuously being observed in this rapidly changing pandemic. A case-by-case evaluation must be made by dermatologists, and the final decision should be discussed and decided by both the patient and the specialist. Observations reveal that immunosuppressive therapy may have a role in the treatment of this virus, placing emphasis on the scenario of safety through maintenance of therapy with biologic agents, especially when there are no signs or symptoms related to the infection or contact with an infected patient.

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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.

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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.

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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.

5

Authors: Zhiheng H He MD, PhD, Yan Li MD, Nitin Trivedi MD, Sabrina Gill MD, James V Hennessey MD

Excessive exogenous thyroid hormone ingestion may lead to severe thyrotoxicosis and cause potential harm. We have reviewed the literature and suggested that thyroid hormone supplementation should not be used to alleviate nonspecific complaints in patients with normal endogenous thyroid function. Failure to do so may cause serious harm, as demonstrated in one of the cases described here. In addition, treatment based on symptom relief only without biochemical measure may lead to overmedication – as reported from academic hospitals both in Canada and the United States. Given the risk of severe thyrotoxicosis from potential compounding errors, pharmacies providing a compounding service should be subject to more rigorous monitoring by the food and drug administration. Clinicians should also use local biochemical markers when titrating thyroid hormone supplements even though the normal thyroid function reference range has its limitation, failure to do so may result in iatrogenic thyrotoxicosis.

6

Authors: Gary L O’Brien BPharm, MPharm, Muireann McAlister BSc Pharmacy, Stephen Byrne BSc Pharmacy, PhD, James Gallagher BPharm, MPharm, PhD

Public discourse on medicine provision predominantly focuses on overall expenditure. However, current literature suggests measurement of alternative indicators can provide a method to benchmark or ameliorate medicine provision. Previous research has investigated the viability of using health-related outcome metrics, such as the number of patients treated, quality-adjusted life-year gain and life-year gain, to provide macro-level estimates on medicines’ societal contributions. This editorial provides an overview of the evolving healthcare landscape surrounding medicine usage estimation and valuation in Ireland and offers recommendations on how improved methods of measuring health-related outcomes may help ameliorate efficiencies and the sustainability of a healthcare system.

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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.

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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.

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Authors: Novin Nezamololama, BSc, MSc, Keira Fieldhouse, BSc, Kristy Metzger, BSc, Melinda Gooderham, MD, MSc, FRCPC

The Janus kinases (JAK) are a group of molecules, composed of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), which are key components within the JAK–signal transducers and activators of transcription pathway, where cytokine receptor signaling takes place. These molecules play a foundational role in the underlying pathogenesis of multiple immune-related conditions such as atopic dermatitis (AD), rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, and others. Thus far, JAK inhibitors for inflammatory conditions have only been marketed for the treatment of rheumatoid arthritis and psoriatic arthritis, but ongoing phase II and phase III clinical trials for other immune-mediated diseases, such as AD, have also shown promising results. This review summarizes the clinical data available from various trials and reports on the safety and efficacy of abrocitinib, baricitinib, and upadacitinib, the three oral systemic JAK inhibitors used in the treatment of AD. The safety and efficacy of JAK inhibitors for the treatment of AD are emerging in the literature. It is important that dermatologists are aware of any potential adverse events or risks associated with the use of JAK inhibitors in order to promote a higher standard of treatment and quality of living.

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Authors: Arpita Nag PhD, Rebecca Bornheimer BA, Gerry Oster PhD

Background: Chronic idiopathic constipation (CIC) is a common gastrointestinal disorder in community settings. Limited information exists on its treatment with the prosecretory agents linaclotide and lubiprostone. This retrospective cohort study investigated real-world pharmacotherapy patterns of linaclotide and lubiprostone. Methods: Patients (≥18 years) with CIC who received linaclotide or lubiprostone between January 2013 and December 2015 were identified in a United States health insurance claims database. Follow-up was from the date of the earliest claim for either drug to the end of continuous enrolment or switch to the alternative agent. Patterns of pharmacotherapy, evidence of irritable bowel syndrome (IBS), and concomitant use of selective serotonin reuptake inhibitors were examined using the International Classification of Diseases, Ninth or Tenth Revision, Clinical Modification codes and National Drug Codes. Results: In total, 43,164 and 17,743 patients with CIC received linaclotide and lubiprostone, respectively (~80% women, mean age ~47 years). Approximately 40% of subjects (linaclotide: 40.1%; lubiprostone: 37.6%) had evidence of IBS. Over a mean follow-up of 17 months, mean (standard deviation) treatment duration in patients without IBS was 6.6 (7.9) months for linaclotide and 4.5 (6.5) months for lubiprostone. Treatment episodes >180 days were more common with linaclotide (36.1%) than with lubiprostone (23.2%). At 12 months, Kaplan–Meier estimates of switching from lubiprostone to linaclotide and from linaclotide to lubiprostone were 13.4 and 5.6%, respectively. The number of patients receiving serotonin reuptake inhibitors was unchanged with treatment (~22%). Conclusions: Most patients with CIC receive linaclotide or lubiprostone for <6 months; few remain on therapy for >1 year. Additional research is warranted to understand the potential reason(s) for early discontinuation.

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Authors: Shivam Om Mittal MD

Tics and Tourette’s syndrome are common hyperkinetic movement disorders seen mostly in the pediatric age group. Tics are defined as sudden, rapid, recurrent, nonrhythmic motor movements or vocalization, generally preceded by urge. Tourette’s syndrome is defined as the presence of both motor and phonic tics for more than 1 year in patients with onset less than 18 years old. Most of these hyperkinetic movement disorders improve in adulthood. This review emphasizes the clinical pearls in the diagnosis and distinguishing it from other movement disorders. The treatment ranges from behavioral therapies, medical management, and also surgical treatment such as deep brain stimulation that is limited to refractory patients.

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Authors: Andrea Zlatkus CRHC, Todd Bixby RPh, Kavitha Goyal MD

As numerous biosimilar products are forecast to enter the US market in the coming years, health-system pharmacists will be faced with novel challenges while incorporating them into clinical practice. The current regulatory approval framework and guidance from the US Food and Drug Administration do not address many real-world scenarios that pharmacists will encounter. We provide an overview of the evolving healthcare landscape shaped by the entry of multiple biosimilars, including for a given reference product, and their impact on the healthsystem pharmacist with respect to formulary assessment, implementation, and education of various health-system stakeholders, including patients.

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Authors: Giuseppe Cicero MD PhD, Raffaele Addeo MD, Rossella De Luca PhD, Giuseppe Lo Re MD PhD, Leonardo Gulotta MD, Pierenrico Marchesa MD, Gaspare Gulotta MD PhD

Background: TAS-102 is an oral monotherapy, combining trifluridine and tipiracil hydrochloride, indicated for the treatment of pretreated metastatic colorectal cancer (mCRC). The aim of this real-life study is to evaluate the efficacy and safety of TAS-102 in heavily pretreated elderly patients with mCRC whose disease has progressed with standard therapies. Methods: In this retrospective observational study, we enrolled 50 elderly patients >70 years of age (median age 78 years) with a diagnosis of mCRC who were previously treated or were not considered candidates for treatment with other available therapies. Patients aged >70 years with advanced colorectal cancer and with an ECOG performance status of grade 0 (n=18) or grade 1 (n=32) were included. Overall survival and progression-free survival were the primary endpoints, whereas objective response rate, tolerability, and quality of life were the secondary endpoints. Results: Treatment with TAS-102 appeared to be well tolerated and side effects were generally mild, achieving disease control and a benefit on quality of life. The median overall survival was 6.7 (95% CI 5.7–11.3) and the median progression-free survival was 2.1 months (95% CI 1.2–3.2), estimated using the Kaplan– Meier method. Conclusion: TAS-102 represents a manageable and effective therapeutic opportunity and appeared to be well tolerated with generally mild side effects in elderly patients with mCRC who were heavily pretreated with standard therapies.

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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.

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Authors: José Alexandre Mendonça PhD, Lucas Nogueira Pansani MD, Mateus Basso Mimoto MD, Igor Tadeu Garcia Ferreira MD, Fernanda Bertucci Sanches MD, Thais de Campos Ferreira Pinto MD, Vania Aparecida Leandro-Merhi PhD, José Luis Braga de Aquino PhD

Background: Ultrasound (US) in psoriasis (PsO) and psoriatic arthritis (PsA) is an important tool in several situations to detect joint ecostructural damage as well as other tissue alterations, such as those that occur in the larger vessels. The objective of this study was to detect and correlate the changes that indicate the inflammatory and atherosclerotic process in two groups of patients, using nail US and carotid artery intima–media thickness radiofrequency (RF) software. Methods: A total of 30 patients diagnosed with (PsO) and (PsA) were selected. About 15 patients were present in each group, assigned by the Dermatology and Rheumatology Service of the Universidade Pontifícia Católica de Campinas, São Paulo, Brazil, and were assessed using carotid artery US (radiofrequency quality intima–media thickness [RF-QIMT]), joint US, clinical evaluation, and laboratory tests. Results: Spearman and Pearson correlations between US variables per group were Psoriasis Area and Severity Index (PASI) and loss of the nail pattern trilaminar: r=0.658, p=0.015; Framingham Score (FS) and Internal Resistance Index (IR): 0.351 to 0.526, p=0.034 to 0.002; the significant correlations by the Bayesian factor (BF) were those with a BF greater than 2.5, between QIMT expected with FS: r=0.677, BF=10.06, with total cholesterol: r=0.5232, BF=2.60, and QIMT-RF with low density lipoproteins: r=0.633, BF=3.70. Conclusion: The use of US in the evaluation of these patients showed significant correlations between clinical and laboratory measures, characterized by QIMT and FS as well as changes in nail insertion. Future studies may demonstrate an even better interaction.

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Authors: Joel C Marrs PharmD, MPH, Sarah L Anderson PharmD

Cardiovascular disease (CVD) is the leading cause of death worldwide and one key factor associated with the increased CVD risk is dyslipidemia. Statin therapy remains the first-line treatment to manage dyslipidemia, yet many patients do not achieve optimal low-density lipoprotein-cholesterol (LDL-C) levels even after taking moderate- or high-intensity statins; therefore, additional, non-statin therapy is often needed. Bempedoic acid is a prodrug that, once activated, decreases LDL-C levels by the inhibition of adenosine triphosphate citrate lyase in the liver. Five clinical trials have demonstrated the safety and efficacy of bempedoic acid and the bempedoic acid/ezetimibe combination in lowering LDL-C in patients with atherosclerotic CVD and heterozygous familial hypercholesterolemia and also in high-risk primary prevention, and statin-intolerant patients. Bempedoic acid has been demonstrated to lower LDL-C levels by 15–25% in clinical trials and up to 38% when combined with ezetimibe. In 2020, the FDA approved bempedoic acid. Furthermore, the combination of bempedoic acid with ezetimibe is FDA approved for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic CVD who require additional LDL-C lowering after maximally tolerated statin therapy. The ongoing CLEAR OUTCOMES trial aims to evaluate whether bempedoic acid can reduce cardiovascular events in patients with statin intolerance and results will be available in the next 3 years. This outcomes trial will be pivotal for determining the role of bempedoic acid in the non-statin lipid-lowering armamentarium.

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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.

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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.

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Authors: Joel C Marrs PharmD, MPH, Sarah L Anderson PharmD

More than 422 million people worldwide have diabetes, with 90–95% having type 2 diabetes (T2D). Glycemic control of T2D has demonstrated reductions in microvascular complications but recent data have demonstrated improvements in macrovascular outcomes with sodium–glucose cotransporter 2 (SGLT2) inhibitors. Ertugliflozin is the most recent SGLT2 inhibitor approved in the USA and Europe for the treatment of T2D. This narrative review aims to present and discuss the efficacy, safety, cardiovascular (CV), and renal outcomes related to the use of ertugliflozin in T2D. Ertugliflozin has been evaluated in eight clinical trials (n=5248) with a focus on glycemic control. These trials have demonstrated improvement in glycosylated hemoglobin (0.6–1%), fasting plasma glucose (30–50 mg/dL), 2-hour postprandial glucose (60–70 mg/dL), decreased body weight (2–3 kg), and lowering of blood pressure (3–5 mmHg) in patients with T2D when ertugliflozin is used as monotherapy or in addition to metformin, sitagliptin, insulin, and/or sulfonylureas. The findings from the VERTIS-CV trial (n=8246) were recently published and demonstrated that ertugliflozin use in patients with T2D and atherosclerotic CV disease is safe but did not demonstrate superiority in the lowering of major CV events compared to placebo. Other SGLT2 inhibitors, such as empagliflozin and canagliflozin, have demonstrated this benefit. The VERTIS-CV trial demonstrated that the use of ertugliflozin led to a decrease in the number of hospitalizations for heart failure and this lends further support that this benefit is a class effect of SGLT2 inhibitors.

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Authors: Paolo D’Agostino MSc, Alan Kent BSc (Hons), Eric Sharp MRSB, Fabian Schmidt Dipl.Kfm, Marco Turini MSc

Background: Mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) is a rare lymphoma localized in the skin. Due to its indolent nature and similarity to other skin conditions, diagnosis is often delayed or incorrect. Consequently, accurate calculations of incidence and prevalence are difficult to make. The treatment pathway taken by MF-CTCL patients can differ depending upon local healthcare systems, clinical policies and guidelines. Aims: This study aims to (1) provide an estimate for the prevalence of treated MF-CTCL patients in Spain, (2) describe the Spanish patient treatment pathways for MF-CTCL, including quantification of the distribution of patients between primary, secondary and tertiary care institutions, and (3) investigate and quantify the treatment preferences of physicians. Methodology: This study employed primary market research methodologies to facilitate the collection of patient numbers and treatment practices from healthcare professionals (HCPs) and patients. Limitations: Poor diagnosis of MF-CTCL may mean that actual prevalence levels in the broader population are higher than those estimated by this analysis of treated patients. This study was reliant upon accurate reporting by HCPs of patient numbers and their personal treatment practices. The rarity of the condition means the patient sample size is relatively small and limits possible accuracy of the quantitative analyses of patientderived data, although this is supplemented by HCP-derived data in the analysis. Findings: Around 75% of MF-CTCL patients in Spain report that the initial diagnosis by their general practitioner is incorrect. This is usually due to underestimation of severity or type of skin disease. Once they have been correctly diagnosed (usually by a dermatologist) in secondary care, the management of MF-CTCL is led by dermatologists. In 39% of patients, shared care teams are also involved in patient management. Following diagnosis, the majority of patient management is conducted by secondary or tertiary care centers. Conclusions: Incidence rates have increased in recent years, and possible reasons for this include improving levels of diagnosis. Survival in MF-CTCL has also increased over the last few decades. This trend appears to be reflected in the prevalence reported in this study, which is higher than suggested by some other estimates. However, it is still likely that there are further undiagnosed MF-CTCL patients in Spain due to the challenges of diagnosis at the primary care level.

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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.

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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.

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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.

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Authors: Lale Tokgözoglu MD, José Luis Zamorano MD

A meeting entitled ‘Current Perspective on the Use of Statins in the Treatment of Dyslipidemic Patients’ was held in Stresa, Italy, on 27–28th June 2019. The presentations covered the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines on dyslipidaemia, with discussion about the importance of controlling low-density lipoprotein cholesterol (LDL-C) and the pharmacological opportunities to reach the novel lipid goals. The roles of statins to manage dyslipidaemia in patients with different cardiovascular risks were also discussed. In particular, the efficacy and safety of pitavastatin for the treatment of dyslipidaemia were reviewed, highlighting its further advantages beyond LDL-C reduction. Therefore, the impact of statins on the glycaemic profile was discussed in view of the null/lower effect of pitavastatin as compared with other statins, as well as the interaction profile with other drugs commonly used. This meeting report summarizes the main messages of the discussion with a special focus on pitavastatin, whose main features in different settings are described.

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Authors: Attilio Giacosa MD, PhD, Antonella Riva PhD, Giovanna Petrangolini MSc, Pietro Allegrini MSc, Teresa Fazia PhD, Luisa Bernardinelli PhD, Clara Gasparri MSc, Milena Anna Faliva PhD, Gabriella Peroni BSc, Simone Perna PhD, Mariangela Rondanelli MD, PhD

Background: The treatment of symptomatic uncomplicated colonic diverticular disease (SUDD) is still under debate, and new data show a pathogenic role of dysbiosis and low-grade inflammation in intestinal mucosa. Recent research has highlighted the anti-inflammatory effects of botanical extracts such as Curcuma longa L. and Boswellia serrata Roxb. ex Colebr. The aim of this work is to investigate the potential role of a new delivery formulation of the association of curcumin and boswellia phytosome extracts (CBP) in SUDD. Methods: In a 30-day one-group longitudinal explanatory study, patients (men and women) were treated with an innovative association of CBP standardized extracts, 500 mg bid. Results: Treatment of SUDD with the association of CBP was followed by a significant decrease in abdominal pain (p<0.0001). The study group showed that CBP supplementation was efficacious within 10 days and that efficacy was maintained almost constant until the 30th day of intervention. Conclusion: A phytosome of curcumin and boswellia extracts may be useful for the relief of SUDD pain. However, controlled studies should be performed for final conclusions to be drawn.

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

Atrial fibrillation is a frequent complication among patients with severe coronavirus disease-2019 (COVID-19) infection. Both direct and indirect mechanisms through COVID-19 have been described to explain this relationship. COVID-19 infection increases the risk of developing both arterial and venous thrombotic complications through systemic coagulation activation, leading to increased mortality. Chronic oral anticoagulation is essential to reduce the thromboembolic risk among AF patients. Switching to low-molecular-weight heparin has been recommended during hospitalization for COVID-19 infection. Of note, at discharge, the prescription of direct oral anticoagulants may offer some advantages over vitamin K antagonists. However, oral anticoagulants should only be prescribed after the consideration of drug–drug interactions with antiviral therapies as well as of the risk of hepatotoxicity, which is common among individuals with severe COVID-19 pneumonia. Not all anticoagulants have the same risk of hepatotoxicity; dabigatran has shown a good efficacy and safety profile and could have a lower risk of hepatotoxicity. Furthermore, its metabolism by cytochrome P450 is absent and it has a specific reversal agent. Therefore, dabigatran may be considered as a first-line choice for oral anticoagulation at discharge after COVID-19 infection. In this review, the available information on the antithrombotic management of AF patients at discharge after COVID-19 infection is updated. In addition, a practical algorithm, considering renal and liver function, which facilitates the anticoagulation choice at discharge is presented. *The name of this great Carthaginian military general has been chosen for the protocol as a tribute by the authors, as they carry out their healthcare work in Cartagena

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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.

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Authors: Ramón Novell MD, Susanna Esteba-Castillo PhD, Emili Rodriguez PhD

Background: We evaluated Gamalate® B6 (GB6) in patients with borderline intellectual functioning (BIF) or mild intellectual development disability (IDD). Patients and methods: This was a prospective phase IV observational pilot study in 30 patients who underwent neuropsychological evaluation during treatment with GB6 for 12 weeks. Results: In comparison with baseline, the responses were positive, with a significant improvement in hyperactivity (51.7%), irritability (35.5%), and logorrhea (50%), and no sedative effect. The Clinical Global Impressions – Severity (CGI-S) score was much improved or very much improved in 73% of cases. Reaction time was better with fewer errors, thus indicating an improvement in attentional processes. A statistically significant result was obtained for the number of movements used to solve the problem and for the total number of correctly solved problems. Conclusion: In this pilot study, GB6 was effective and well tolerated in cases of ADHD and challenging behavior in young adults with borderline-to-mild BIF/IDD. However, given the small number of patients involved and the uncontrolled nature of the study, these results should be viewed cautiously.

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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.

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Authors: Kam Lun Hon MBBS, MD, Karen Ka Yan Leung MBBS, MRCPCH, Alexander KC Leung MBBS, FRCPC, FRCP (UK & Irel), FRCPCH, FAAP, Su Yun Qian MD, Vivian PY Chan MPharm, MSc (Clin Pharm), BPharm, BCPPS, BCNSP, Patrick Ip MBBS, FRCPCH (Hon), FRCPCH, Ian CK Wong BPharm (Hons), MSc, PhD, FRCPCH (Hon)

Many viral respiratory infections can cause severe acute respiratory symptoms leading to mortality and morbidity. In the spring of 2003, the severe acute respiratory syndrome (SARS) outbreak caused by SARS-CoV spread globally. In the summer of 2012, the Middle East respiratory syndrome (MERS) outbreak caused by MERS-CoV occurred in Saudi Arabia. In the winter of 2019, the coronavirus disease 2019 (COVID-19) outbreak caused by a novel coronavirus SARS-CoV- 2 occurred in China which rapidly spread worldwide causing a global pandemic. Up until 27 May 2020, there are 5.5 million confirmed cases of COVID-19 and 347,587 COVID-19 related deaths worldwide, and there has also been an unprecedented increase in socioeconomic and psychosocial issues related to COVID-19. This overview aims to review the current developments in preventive treatments and therapies for COVID-19. The development of vaccines for SARS-CoV-2 is ongoing and various clinical trials are currently underway around the world. It is hoped that existing antivirals including remdesivir and lopinavir-ritonavir might have roles in the treatment of COVID-19, but results from trials thus far have not been promising. COVID-19 causes a mild respiratory disease in the majority of cases, but in some cases, cytokine activation causes sepsis and acute respiratory distress syndrome, leading to morbidity and mortality. Immunomodulatory treatments and biologics are also being actively explored as therapeutics for COVID-19. On the other hand, the use of steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs) has been discouraged based on concerns about their adverse effects. Over the past two decades, coronaviruses have caused major epidemics and outbreaks worldwide, whilst modern medicine has been playing catch-up all along.

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Authors: Karel Pavelka MD PhD, Zoltán Szekanecz MD PhD DSc, Nemanja Damjanov MD PhD, Branimir Anić MD PhD, Matija Tomšič MD PhD, Vadim Mazurov MD PhD, Marija Maksimovic MD, Orsolya Nagy MD PhD, Jerzy Świerkot MD PhD, Tzvetanka Petranova MD PhD, Tiina Veldi MD, Asta Baranauskaitė MD PhD, Catalin Codreanu MD PhD, Daina Andersone MD PhD, Roy Fleischmann MD

Background: In the randomized, phase III, global SELECTCOMPARE study, upadacitinib 15 mg demonstrated efficacy at week 12 versus placebo and adalimumab with methotrexate (MTX) in patients with rheumatoid arthritis and inadequate response to MTX, which was maintained over 48 weeks. This post hoc analysis of SELECT-COMPARE reports the efficacy and safety of upadacitinib in Central and Eastern European (CEE) patients. Methods: Patients were randomized 2:2:1 to upadacitinib 15 mg once daily, placebo, or adalimumab 40 mg every other week, and continued MTX. Efficacy and safety were assessed through 48 weeks. Primary endpoints were the achievement of ≥20% improvement in American College of Rheumatology response criteria and Disease Activity Score in 28 joints with C-reactive protein <2.6 responses at week 12 for upadacitinib versus placebo. No statistical comparisons were conducted. Results: A total of 596 patients from 12 CEE countries were randomized. At week 12, a numerically greater proportion of patients receiving upadacitinib versus placebo or adalimumab achieved ≥20% improvement in American College of Rheumatology response criteria (72% versus 33% and 59%), Disease Activity Score in 28 joints with C-reactive protein <2.6 (26% versus 4% and 11%), low disease activity and remission, and improved physical function, with results maintained over 48 weeks. Upadacitinib treatment numerically inhibited structural progression versus placebo at week 26. Serious infection and herpes zoster rates were numerically higher with upadacitinib versus adalimumab (2.7 versus 1.7 and 2.3 versus 1.1 events/100 patient-years, respectively) over 48 weeks. Conclusion: Consistent with the global population of patients with rheumatoid arthritis and an inadequate response to MTX, in CEE patients, upadacitinib 15 mg demonstrated clinical and functional improvements versus placebo and adalimumab, radiographic improvements versus placebo, and reasonable safety, over 48 weeks.

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Authors: José Luis Hernández MD, PhD, Francisco S Lozano MD, PhD, Vincent Riambau MD, PhD, Manuel Almendro-Delia MD, PhD, Juan Cosín-Sales MD, PhD, Sergi Bellmunt-Montoya MD, PhD, Javier Garcia-Alegria MD, PhD, Xavier Garcia-Moll MD, FESC, FACC, Juan José Gomez-Doblas MD, PhD, José R Gonzalez-Juanatey MD, PhD, Carmen Suarez Fernández MD

Patients with peripheral artery disease (PAD) are at a high risk not only for the classical cardiovascular (CV) outcomes (major adverse cardiovascular events; MACE) but also for vascular limb events (major adverse limb events; MALE). Therefore, a comprehensive approach for these patients should include both goals. However, the traditional antithrombotic approach with only antiplatelet agents (single or dual antiplatelet therapy) does not sufficiently reduce the risk of recurrent thrombotic events. Importantly, the underlying cause of atherosclerosis in patients with PAD implies both platelet activation and the initiation and promotion of coagulation cascade, in which Factor Xa plays a key role. Therefore, to reduce residual vascular risk, it is necessary to address both targets. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial that included patients with stable atherosclerotic vascular disease, the rivaroxaban plus aspirin strategy (versus aspirin) markedly reduced the risk of both CV and limb outcomes, and related complications, with a good safety profile. In fact, the net clinical benefit outcome composed of MACE; MALE, including major amputation, and fatal or critical organ bleeding was significantly reduced by 28% with the COMPASS strategy, (hazard ratio: 0.72; 95% confidence interval: 0.59–0.87). Therefore, the rivaroxaban plus aspirin approach provides comprehensive protection and should be considered for most patients with PAD at high risk of such events.

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Authors: Nicola Wearne MBChB, FCP, MMed, Bianca Davidson MBChB, FCP, MMed, Marc Blockman MBChB, BPharm, PG Dip Int Res Ethics, MMed, Annoesjka Swart BScPharm, Erika SW Jones MBBCh, FCP, PhD

Human immunodeficiency virus (HIV) affects over 36 million people worldwide. Antiretroviral therapy (ART) is expanding and improving HIV viral suppression, resulting in increasing exposure to drugs and drug interactions. Polypharmacy is a common complication as people are living longer on ART, increasing the risk of drug toxicities. Polypharmacy is related not only to ART exposure and medication for opportunistic infections, but also to treatment of chronic lifestyle diseases. Acute kidney injury (AKI) is frequent in HIV and is commonly the result of sepsis, dehydration and drug toxicities. Furthermore, HIV itself increases the risk of chronic kidney disease (CKD). Drug treatment is often complicated in people living with HIV because of a greater incidence of AKI and/or CKD compared to the HIV-negative population. Impaired renal function affects drug interactions, drug toxicities and importantly drug dosing, requiring dose adjustment. This review discusses ART and its nephrotoxic effects, including drug–drug interactions. It aims to guide the clinician on dose adjustment in the setting of renal impairment and dialysis, for the commonly used drugs in patients with HIV.

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Authors: Elaena Quattrocchi BS, PharmD, FASHP, CDE, Tamara Goldberg BS, PharmD, BCPS, Nino Marzella BS, MS, PharmD

Despite the advances in diabetes management, people with diabetes are not reaching their target glycemic goals. Healthcare professionals often fail to initiate, escalate, or de-intensify therapy when indicated. There are several organizations that provide guidance on the management of diabetes to assist the practitioner in achieving improved glycemic control, and this can cause confusion to the practitioner on which organizations’ guidance to follow. Diabetes mellitus is associated with an elevated risk of cardiovascular disease, and there have been studies that suggest some antidiabetic medications increase cardiovascular risk and some reduce cardiovascular risk. Diabetes organizations recommend the individualization of treatment goals and choices of drug therapy that will be safe and effective. Healthcare professionals should be knowledgeable and equipped to decide on the best treatment regimen for each of their patients with type 2 diabetes (T2D) and be familiar with how to utilize the different organizations’ philosophies in treating their patients.

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Authors: Vincenzo Accurso MD, Marco Santoro MD, Salvatrice Mancuso MD, Marisante Napolitano MD, Florinda Di Piazza MD, Antonio Russo MD, Sergio Mario Siragusa MD

Accurso V, Santoro M, Mancuso S, Napolitano M, Di Piazza F, Russo A, Siragusa SM. Efficacy of ruxolitinib retreatment in a patient with high-risk myelofibrosis using the international prognostic scoring system. Drugs in Context 2019; 8: 212569. DOI: 10.7573/dic.212569

5

Authors: Sonia Brugnara MD, Mariacristina Sicher MD, Elena Maria Bonandini MD, Mattia Barbareschi MD, Carlo Renè Girardelli MD, Orazio Caffo MD

Systemic treatment for metastatic melanoma has advanced dramatically in recent years with an impressive increase in the rate of overall survival. The two main different strategies are targeted therapies (i.e. BRAF and MEK inhibitors) and immunotherapy with monoclonal antibodies against the immune checkpoint proteins programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Vitiligo often accompanies immunotherapy in melanoma patients and even correlates with tumor regression after checkpoint blockade. At present, a correlation between vitiligo onset and outcome from immunotherapy is acknowledged; however, evidence of a correlation between vitiligo and efficacy of combination-targeted therapy is lacking. We describe our experience in a patient who received dabrafenib and trametinib and developed vitiligo-like depigmentation after treatment cessation.

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Authors: Daniele Orsucci MD, Laura Maria Raglione MD, Monica Mazzoni MD, Marco Vista MD

Episodic ataxias (EAs) are characterized by recurrent, discrete episodes of vertigo and ataxia. EA1 and EA2 are the two most common forms. In the interictal interval, myokymia is typically present in EA1, whereas EA2 patients present with interictal nystagmus. Specific pharmacological therapies are available for EA1 and especially EA2. We briefly discuss the case of an Italian young man with EA2, with a novel de novo CACNA1A mutation, who in our opinion is particularly illustrative for introducing the therapeutic approach. Acetazolamide could fully suppress EA episodes in our patient. We also provide a perspective review of the topic. 4-Aminopyridine is another valid treatment option. For EA1 (and for rarer EAs), the therapeutic possibilities are more limited. Carbamazepine is probably the treatment of choice for EA1, but the optimal treatment plan is unknown. A better understanding of the molecular processes involved in the mediation of EAs will lead to more specific and efficacious therapies for this still elusive group of disorders.

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Authors: Donata Galbiati MD, Stefano Cavalieri MD, Salvatore Alfieri MD, Carlo Resteghini MD, Cristiana Bergamini MD, Ester Orlandi MD, Francesca Platini MD, Laura Locati MD, Luca Giacomelli PhD, Lisa Licitra MD, Paolo Bossi MD

Background: Unresectable or metastatic cutaneous squamous cell cancers (cSCCs) are rare but potentially life-threatening diseases. In this setting, systemic therapy has a palliative intent with limited benefit, but there is no established consensus regarding the proper management of this tumour. This retrospective study aimed to review outcomes in patients with non-curable cSCC treated with platinum-based chemotherapy and cetuximab. Methods: We considered 12 consecutive patients treated between June 2010 and March 2016. All patients had received previous treatment for the local disease. Results: The overall response rate was 50%, and the disease control rate was 67%. Median progression-free survival and overall survival were 6.6 (95% confidence interval [CI]: 1.9–8.4) and 14.6 (95% CI: 9.4–20.1) months, respectively. The median duration of response was 4.8 months (95% CI: 1.2–5.9). The most frequent toxicities were skin reactions (58%; grade 3: 25%) and anaemia (10%). No grade 4 toxicities were observed. Conclusions: Cetuximab and platinum-based chemotherapy were shown to be feasible and active in cSCC, with an acceptable toxicity profile, even if with a limited duration of response.

7

Authors: Felix Liriano, Candace Hatten MD, Thomas L Schwartz MD

Post-traumatic stress disorder (PTSD) continues to make headlines given multiple military engagements across the world and civilian traumas, and resultant PTSD development continues at an even pace. Currently, antidepressant and cognitive-behavioral therapy have the greatest evidence base but still do not yield a remission of PTSD symptoms in many patients. Off-label and novel treatments continue to be considered for more refractory and disabling cases of PTSD. Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder (MDD). Its mechanism is controversial regarding its potential to create anxiety, but the perceived benefit of a rapid reduction of symptoms makes it worthy for study in animal models of, and possibly human studies in, PTSD. The current literature and theoretical mechanism of action is discussed in this manuscript.

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Authors: Pietro Sollena MD, Maria Mannino MD, Francesco Tassone MD, Maria Alessandra Calegari MD, Ettore D’Argento MD, Ketty Peris MD

Nail toxicities, such as paronychia and pyogenic granuloma-like lesions, are well-recognized side effects of epidermal growth factor receptor inhibitor (EGFR-I) therapy that can significantly impair patient’s quality of life and compliance to anticancer treatment. Numerous therapeutic options are available, with variable rates of success. Recently, topical β-blockers have emerged as a novel, non-invasive treatment strategy. We tested the effectiveness of topical timolol 0.5% gel, twice daily, under occlusion for 30 days, on paronychia and periungual pyogenic granuloma-like lesions in 9 patients being treated with EGFR-I. We also reviewed the available literature on this topic, which is the use of topical β-blockers in the management of EGFR-I-induced nail toxicities. We assessed 25 lesions consistent with the diagnosis of EGFR-I-induced pyogenic granuloma-like lesions and paronychia (21 diagnosed as pyogenic granuloma-like, and four as paronychia). Thirteen of the 25 lesions achieved complete resolution, 9/25 reached at least improvement, and only 3/25 did not respond to the intervention. As for the review, four papers met the scope of our research. The results confirmed at least partial benefit in the majority of treated patients. Among current strategies, high-potency topical corticosteroids are a well-known treatment option especially for paronychia, targeting the inflammatory component of such lesions; nevertheless, the management of pyogenic granuloma-like lesion is often more complex and the success rate is variable. Nail plate avulsion and phenol chemical matricectomy are not highly effective and display some degree of invasiveness. Topical β-blockers seem to be promising alternatives, especially in fragile cancer patients who may be unsuitable candidates for an invasive procedure.

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Authors: Brian Ford MD, Alex McDonald MD, Shilpa Srinivasan MD, DFAPA

Anti-N-methyl D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis is among one of the most common autoimmune encephalitides. However, variations in clinical presentation and nonsequential multiphasic course often lead to delays in diagnosis. The mild encephalitis (ME) hypothesis suggests a pathogenetic mechanism of low-level neuroinflammation sharing symptom overlap between anti-NMDAR encephalitis and other psychiatric disorders including schizophrenia. Clinical symptoms of anti-NMDAR encephalitis may mimic schizophrenia and psychotic spectrum disorders or substanceinduced psychosis. Although initially described in association with ovarian teratomas in women, anti-NMDAR encephalitis has been reported in individuals without paraneoplastic association, as well as in males. It can affect all age groups but is usually lower in prevalence in individuals greater than 50 years old, and it affects females more than males. Clinical evaluation is supported by laboratory workup, which includes cerebrospinal fluid (CSF) assays. The latter often reveals lymphocytic pleocytosis or oligoclonal bands with normal to elevated CSF protein. CSF testing for anti-NMDAR antibodies facilitates diagnostic confirmation. Serum anti-NMDAR antibody assays are not as sensitive as CSF assays. Management includes symptomatic treatment and immunotherapy.

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Authors: Federico Lavorini MD, PhD

Inhalation therapy is likely to continue to dominate asthma and chronic obstructive pulmonary disease (COPD) treatment. The pressurised metered-dose inhaler (pMDI) accounts for most of the global inhaler market, but this kind of device is difficult to use properly. Dry powder inhalers (DPIs) have several advantages over pMDIs: they are breath-activated, easy and convenient to use, and environmentally friendly. The Easyhaler® (Orion; Finland) is a multidose reservoir-type DPI developed to efficiently deliver a wide range of medications, including fixed-dose combinations of bronchodilators and corticosteroids. Easyhaler shares a similar shape with the pMDI, and its performance is unaffected by moisture, dropping, vibration, and freezing/thawing. For these reasons, Easyhaler may be considered one of the most convenient inhalers for daily use in patients with asthma or COPD.

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Authors: Alpesh Amin MD, MBA, W Richey Neuman MD, MPH, Melissa Lingohr-Smith PhD, Brandy Menges PhD, Jay Lin PhD, MBA

Background: We evaluated whether the duration of hospital stay influences venous thromboembolism (VTE) prophylaxis patterns and VTE risk during hospitalization and post-discharge among patients hospitalized for acute illnesses in the USA. Methods: Patients hospitalized for acute illnesses were identified from the US MarketScan Commercial and Medicare databases (January 1, 2012–June 30, 2015). Patients were stratified by index hospital length of stay (LOS), with study groups with 1–3 day, 4–6 day, and ≥7 day LOSs. Use of VTE prophylaxis and VTE event rates during and after hospitalization (6-month follow-up) were evaluated. Results: Of the overall population, 8647 had a 1–3 day LOS, 5551 had a 4–6 day LOS, and 3697 had a ≥7 day LOS. A greater proportion of patients with a 1–3 day LOS (66.2%) did not receive any VTE prophylaxis in comparison to patients with a 4–6 day LOS (55.0%) and ≥7 day LOS (48.8%; p<0.001). Proportions of patients with VTE events during the index hospitalization increased with longer hospital LOS (1–3 day LOS: 0.5%; 4–6 day LOS: 1.3%; ≥7 day LOS: 5.4%), as did proportions of patients with VTE events during the 6-month follow-up (1–3 day LOS: 2.4%; 4–6 day LOS: 2.7%; ≥7 day LOS: 4.2%). Conclusion: Among this study population of hospitalized acutely ill patients in the USA, VTE pharmacologic prophylaxis was underutilized, regardless of the duration of hospital stay. However, the risk for VTE events was substantial, with nearly 10% of those with a ≥7 day LOS having suffered a VTE event within 6 months.

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Authors: Antonio Ruggiero MD, Anna Ariano MD, Silvia Triarico MD, Michele Antonio Capozza MD, Pietro Ferrara MD, Giorgio Attinà MD

During the neonatal period, there is physiological immaturity of organs, systems and metabolic pathways that influences the pharmacokinetics and pharmacodynamics of administered drugs, the dosage of which should be constantly amended, considering the progressive increase in weight and the maturation of the elimination pathways. In this article, we analyse the main pharmacokinetic aspects (absorption, distribution, metabolism and excretion) that exist during the neonatal period, to offer a description of the physiological background for variability in pharmacological dosing.

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Authors: Pilar I Beato-Víbora PhD, Francisco J Arroyo-Díez PhD

Hypoglycaemia is the more frequent complication of insulin therapy and the main barrier to tight glycaemic control. Injectable glucagon and oral intake of carbohydrates are the recommended treatments for severe and non-severe hypoglycaemia episodes, respectively. Nasal glucagon is currently being developed as a ready-to-use device, to simplify severe hypoglycaemia rescue. Stable forms of liquid glucagon could open the field for different approaches for mild to moderate hypoglycaemia treatment, such as mini-doses of glucagon or continuous subcutaneous glucagon infusion as a part of dual-hormone closed-loop systems. Pharmaceutical companies are developing stable forms of native glucagon or glucagon analogues for that purpose.

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Authors: Mohammed Awais Hameed MB, ChB, Indranil Dasgupta DM

Nonadherence is a common reason for treatment failure and treatment resistance. No matter how it is defined, it is a major issue in the management of chronic illnesses. There are numerous methods to assess adherence, each with its own strengths and weaknesses; however, no single method is considered the best. Nonadherence is common in patients with hypertension, and it is present in a large proportion of patients with uncontrolled blood pressure taking three or more antihypertensive agents. Availability of procedure-based treatment options for these patients has shed further light on this important issue with development of new methods to assess adherence. There is, however, no consensus on the management of nonadherence, which reflects the complex interplay of factors responsible for it.

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Authors: Michael E Røder

Glucagon-like receptor agonists (GLP-1RAs) are included in current national and international guidelines as second-line treatment especially in patients with type 2 diabetes and concomitant cardiovascular disease (CVD). First-generation GLP-1RAs were two- or once-daily injectables, but longeracting GLP-1RAs have now been developed for onceweekly administration – e.g., exenatide ER, dulaglutide and semaglutide. With semaglutide, the same prolongation principle as designed in liraglutide is used (spacer and fatty acid chain). However, the similarity to endogenous human GLP-1 is well preserved, sharing 94% homology. It is administered with a simple device and without resuspension before use. The efficacy and safety of semaglutide have been investigated in an extensive clinical development program including more than 9,000 patients with type 2 diabetes. Semaglutide has been compared head-to-head with a dipeptidyl peptidase-4 (DPP4)-inhibitor, GLP-1RAs and basal insulin. Further head-to-head studies are awaiting that compare semaglutide against a sodium-dependent-glucose transporter-2 (SGLT2)-inhibitor. In these studies, semaglutide was found to provide significant and clinically relevant reductions in HbA1c, fasting plasma glucose (FPG), glucose excursions, body weight and blood pressure. The reduction in glycaemic parameters was more pronounced than that in the comparator GLP-1RAs. The rate of hypoglycemia is very low during treatment with semaglutide if not combined with sulphonylureas or insulin. A cardiovascular outcome trial (CVOT) was performed before the approval of semaglutide, at the request of legal authorities. Not only non-inferiority was confirmed, but also superiority compared with placebo used in a population of patients with type 2 diabetes and CVD treated with oral antihyperglycaemic drugs (OADs) and/ or insulin with regard to the primary composite endpoint: death from cardiovascular (CV) causes, nonfatal myocardial infarction or nonfatal stroke. The safety of treatment with semaglutide in patients with type 2 diabetes has been extensively investigated. Overall, gastrointestinal side effects dominate, as observed with other GLP-1RAs, and was observed in the same range as for comparator GLP-1RAs. As observed with other GLP-1RAs, side effects such as nausea and vomiting diminished over time during continuous treatment. Regarding microvascular complications, an unexpected increase in diabetes-related retinopathy was observed in the CVOT; Semaglutide Unabated Sustainability in Treatment of Type 2 diabetes’ [SUSTAIN 6]), but not in other studies. The reason for this increase is not finally elucidated, but may be due to a nonspecific effect of a rapid decrease in glycaemic parameters in patients with preexisting retinopathy with high HbA1c at the start of the treatment. There is currently a warning in the Summary of Product Characteristics (SmPC) for semaglutide concerning treatment in patients with preexisting retinopathy. Further studies are needed to clarify this.

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Authors: Stefania Nicola MD, Giovanni Rolla MD, Luisa Brussino MD

Hereditary angioedema (HAE) is a rare genetic disorder, characterized by recurrent and unexpected potentially life-threatening mucosal swelling. The impairment underlying HAE could be a defect in C1-inhibitor activity, or in its serum concentration. Patients affected by HAE should be treated with on-demand or prophylactic drugs. Lifelong C1-inhibitor supplementation is sometimes required. In this review, we review the currently approved drugs for HAE due to C1-inhibitor defect and to describe those under research. In particular, we focused on the mechanisms of action, routes of administration, and efficacy of these therapies. A systematic review of the literature was performed using the PubMed database for original articles and clinical trials of HAE treatments from 2005 to 2019. The approved HAE treatments can minimize the risk of death, but they are not effective in complete healing from the disease. The new gene therapies seem to provide promising opportunities for the treatment of hereditary angioedema. However, there are still many unmet needs, including efficacy, route, and timing of administration.

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Authors: Miguel Nogueira MD, Tiago Torres MD, PhD

Psoriasis is a chronic, immune-mediated, inflammatory, and debilitating skin disease with significant impact on patients’ quality of life. Its pathogenesis is complex and not yet fully understood. However, the IL-23/IL-17 axis is currently considered the main pathogenic pathway in psoriasis. Guselkumab is a fully human immunoglobulin G1 λ (IgG1λ) monoclonal antibody (mAb) that binds to the p19 subunit of IL-23. It is the first of its class, already approved by the US Food and Drug Administration (FDA), as well as the European Medicines Agency (EMA) for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for either systemic therapy or phototherapy. Several clinical trials have demonstrated potential benefits of guselkumab over other already approved immunomodulators in terms of safety and efficacy. The results of the head-to-head trial ECLIPSE were recently released and are addressed in this review. They contribute to the increasing confidence in guselkumab, demonstrating great potential for long-term treatment of psoriasis. However, further long-term data and additional comparative studies will be essential for positioning guselkumab in the therapeutic armamentarium for psoriasis.

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Authors: Francesco Menzella MD, Mirella Biava Msc, Diego Bagnasco MD, PhD, Carla Galeone Msc, Anna Simonazzi MD, Patrizia Ruggiero Msc, Nicola Facciolongo MD

Severe refractory asthma is characterized by a higher risk of asthma-related symptoms, morbidities, and exacerbations. This disease also determines much greater healthcare costs and deterioration in health-related quality of life (HR-QoL). Another concern, which is currently much discussed, is the high percentage of patients needing regular use of oral corticosteroids (OCS), which can lead to several systemic side effects. Airway eosinophilia is present in the majority of asthmatic patients, and elevated levels of blood and sputum eosinophils are associated with worse control of asthma. Regarding severe refractory eosinophilic asthma, interleukin-5 (IL-5) plays a fundamental role in the inflammatory response, due to the profound effect on eosinophils biology. The advent of the biological therapies provided an effective strategy, even if the increased number of molecules with different targets raised the challenge of choosing the right therapy and avoid overlapping. When considering severe refractory eosinophilic asthma and anti-IL-5 treatments, it is not easy to define which drug to choose between mepolizumab, reslizumab, and benralizumab. In this article, we carried out an indirect comparison among literature data, especially between OCS reduction studies (ZONDA-SIRIUS) and pivotal studies (SIROCCO-MENSA), evaluating whether the clinical efficacy and the steroid-sparing effect of benralizumab may represent an advantage over other compounds. This data could help the clinician in the decision process of treatment choice, within the different available therapeutic options for eosinophilic refractory severe asthma.

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Authors: Martina Biggioggero MD, Andrea Becciolini MD, Chiara Crotti MD, Elena Agape MD, Ennio Giulio Favalli MD

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint involvement, extra-articular manifestations, comorbidities, and increased mortality. In the last few decades, the management of RA has been dramatically improved by the introduction of a treat-to-target approach aiming to prevent joint damage progression. Moreover, the increasing knowledge about disease pathogenesis allowed the development of a new drug class of biologic agents targeted on immune cells and proinflammatory cytokines involved in RA network. Despite the introduction of several targeted drugs, a significant proportion of RA patients still fail to achieve the clinical target; so, more recently the focus of research has been shifted toward the inhibition of kinases involved in the transduction of the inflammatory signal into immune cells. In particular, two Janus kinase (JAK) inhibitors, baricitinib and tofacitinib, have been licensed for the treatment of RA as a consequence of a very favorable profile observed in randomized controlled trials (RCTs) conducted across different RA subpopulations. Both these new compounds are active on the majority of four JAK family members (JAK1, JAK2, JAK3, and TYK2), whereas the most recent emerging approach is directed toward the development of JAK1 selective inhibitors (upadacitinib and filgotinib) with the aim to improve the safety profile by minimizing the effects on JAK3 and, especially, JAK2. In this narrative review, we discuss the rationale for JAK inhibition in RA, with a special focus on the role of JAK1 selective blockade and a detailed description of available data from the results of clinical trials on upadacitinib and filgotinib.

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Authors: Donatella Marino MD, Clizia Zichi MD, Marco Audisio MD, Elisa Sperti MD, Massimo Di Maio MD

For many years, sorafenib has been the only approved systemic treatment for advanced hepatocellular carcinoma (HCC). For over a decade, randomized controlled trials exploring the efficacy of new drugs both in first- and second-line treatment have failed to prove any survival benefit. However, in the past few years, several advances have been made especially in pretreated patients; phase III trials of regorafenib, cabozantinib, and ramucirumab in patients with elevated α-fetoprotein have demonstrated efficacy in patients progressing after or intolerant to sorafenib. In addition, early phase I and II trials have shown promising results of immunotherapy alone or in combination with tyrosine-kinase inhibitors or monoclonal antibodies in the same setting of patients. In this review, we will discuss the evidence on second-line options for HCC, focusing on the latest results that are currently refining the treatment scenario.

13

Authors: Vania Phuoc MD, Jose Sandoval-Sus MD, Julio C Chavez MD, MS

Double-hit lymphoma (DHL) is a rare type of aggressive B-cell lymphoma defined as a high-grade B-cell lymphoma (HGBCL) with the presence of MYC, BCL2 and/or BCL6 rearrangements. Patients usually present with rapidly progressive and advanced stage of disease and, commonly, with extranodal involvement. Typically, patients become refractory to standard R-CHOP, and more aggressive regimens such as DA-EPOCH-R, R-hyperCVAD or CODOX-R regimens are typically needed. MYC is considered an “undruggable” mutation. Recent evidence suggests that pathogenic mechanisms associated with MYC could be potential targets. In this review, we also discuss the role of hematopoietic stem cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell therapy in DHL. We also discuss the role of potential novel agents such as BCL2 inhibitors, checkpoint inhibitors, bromodomain and extraterminal (BET) family inhibitors, Pi3K inhibitors, and others.

14

Authors: Seyda Cankaya MD, Baris Cankaya MD, Ulkan Kilic PhD, Ertugrul Kilic PhD, Burak Yulug MD

Minocycline, a semisynthetic tetracycline-derived antibiotic, has been shown to exert anti-apoptotic, anti-inflammatory, and antioxidant effects. Furthermore, there is rapidly growing evidence suggesting that minocycline may have some neuroprotective activity in various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson’s disease (PD), Huntington’s disease, and multiple sclerosis. In this perspective review, we summarize the preclinical and clinical findings suggesting the neuroprotective role of minocycline in PD.

14

Authors: Carlos Henrique Ferreira Camargo MD, MSc, PhD, Hélio Afonso Ghizoni Teive MD, MSc, PhD

The term movement disorders encompasses all disorders hypokinetic and hyperkinetic, which were previously known as extrapyramidal syndromes. With the definition of movement disorders and their diagnostic criteria and classifications, new studies for therapeutics could be performed. New drugs were launched, functional neurosurgery was developed, and the introduction of botulinum toxin (BoNT) for hyperkinesias was introduced. BoNT is an important therapy for dystonia, tics, myoclonus, and tremors. The aim of this review is to present the new and well-established uses of BoNT for movement disorders.

15

Authors: Kanae Jennifer Nagao MBBS (Hons), FRACP, Neepa J Patel MD

Motor complications are responsible for the large burden of disability and poor quality of life in Parkinson’s disease (PD). The pulsatile nature of stimulation with oral dopaminergic therapies due to relatively short pharmacokinetic profiles and dysfunctional gastrointestinal absorption have been attributed to the development of PD motor complications. In this review, we will provide an overview of the pharmacologic and surgical therapies currently available and under investigation for the treatment of motor fluctuations and dyskinesia.

15

Authors: Alessandro Giallongo MD, Giuseppe Fabio Parisi MD, Amelia Licari MD, Giulio Pulvirenti MD, Caterina Cuppari MD, Carmelo Salpietro MD, Gian Luigi Marseglia MD, Salvatore Leonardi MD

The aim of precision medicine is setting up targeted therapies for selected patients that would ideally have high effectiveness and few side effects. This is made possible by targeted therapy drugs that selectively act on a specific pathway. Precision medicine is spreading to many medical specialties, and there is increasing interest in the context of allergic airway diseases, such as allergic rhinitis, chronic rhinosinusitis, and asthma. This review is an update of new targets in the treatment of childhood allergic upper airway diseases and asthma, including the most recent biologic drugs that have already been licensed or are in the pipeline to be tested with children.

16

Authors: Francesco Serra MD, Pietro Lapidari MD, Erica Quaquarini MD, Barbara Tagliaferri MD, Federico Sottotetti MD, Raffaella Palumbo MD, PhD

The purpose of this review is to summarize the background and latest evidence for the use of palbociclib, an oral, first-in-class, highly selective cyclin-dependent kinase 4/6 inhibitor, in advanced breast cancer, with a focus on some of the unanswered questions about the performance of this agent in clinical practice. The available clinical data from both controlled clinical trials and real-life experiences concerning palbociclib-based combinations in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) metastatic disease, including patient-reported outcomes and subgroup analyses, have been reviewed and discussed. Palbociclib significantly improved progression-free survival and clinical benefit rates when added to letrozole in postmenopausal women as initial endocrine-based therapy, and it prolonged progression-free survival and overall survival when added to fulvestrant in women who progressed on previous endocrine therapy in randomized clinical trials. Tolerability profile was manageable, with neutropenia occurring most commonly, without detrimental impact on quality of life. Available data from real-life experiences confirm the good performance of palbociclib in unselected, heavily pretreated populations. Palbociclib in combination with endocrine therapy is a valuable emerging option for patients with HR+/HER2– advanced or metastatic breast cancer. Further investigation is needed to provide solutions for palbociclib resistance and to identify the best sequence to use for the best patient benefit with a minimal toxicity.

18

Authors: Rudolf Hoermann, John E M Midgley, Rolf Larisch, Johannes W Dietrich

Levothyroxine (LT4) therapy has a long history, a well-defined pharmacological profile and a favourable safety record in the alleviation of hypothyroidism. However, questions remain in defining the threshold for the requirement of treatment in patients with subclinical hypothyroidism, assessing the dose adequacy of the drug, and selecting the best treatment mode (LT4 monotherapy versus liothyronine [LT3]/LT4 combinations) for subpopulations with persisting complaints. Supplied as a prodrug, LT4 is enzymatically converted into the biologically more active thyroid hormone, triiodothyronine (T3). Importantly, tetraiodothyronine (T4) to T3 conversion efficiency may be impaired in patients receiving LT4, resulting in a loss of thyroid-stimulating hormone (TSH)-mediated feedforward control of T3, alteration of the interlocking equilibria between serum concentrations of TSH, free thyroxine (FT4), and free triiodothyonine (FT3), and a decrease in FT3 to FT4 ratios. This downgrades the value of the TSH reference system derived in thyroid health for guiding the replacement dose in the treatment situation. Individualised conditionally defined setpoints may therefore provide appropriate biochemical targets to be clinically tested, together with a stronger focus on clinical presentation and future endpoint markers of tissue thyroid state. This cautionary note encompasses the use of aggregated statistical data from clinical trials which are not safely applicable to the individual level of patient care under these circumstances.