Off-label Research Articles

Adverse drug reactions in paediatric surgery: prospective study on frequency and risk related factors

BackgroundPaediatric patients are especially prone to experiencing adverse drug reactions (ADRs), and the surgical environment gathers many conditions for such reactions to occur. Additionally, little information exists in the literature on ADRs in the paediatric surgical population. We aimed to quantify the ADR frequency in this population, and to investigate the characteristics and risk factors associated with ADR development.MethodsA prospective observational study was conducted in a cohort of 311 paediatric patients, aged 1–16 years, admitted for surgery at a tertiary referral hospital in Spain (2019–2021). Incidence rates were used to assess ADR frequency. Odds ratios (ORs) were calculated to evaluate the influence of potential risk factors on ADR development.ResultsDistinct ADRs (103) were detected in 80 patients (25.7%). The most frequent being hypotension (N = 32; 35%), nausea (N = 16; 15.5%), and emergence delirium (N = 16; 15.5%). Most ADRs occurred because of drug-drug interactions. The combination of sevoflurane and fentanyl was responsible for most of these events (N = 32; 31.1%). The variable most robustly associated to ADR development, was the number of off-label drugs prescribed per patient (OR = 2.99; 95% CI 1.73 to 5.16), followed by the number of drugs prescribed per patient (OR = 1.26, 95% CI 1.13 to 1.41), and older age (OR = 1.26, 95% CI 1.07 to 1.49). The severity of ADRs was assessed according to the criteria of Venulet and the Spanish Pharmacovigilance System. According to both methods, only four ADRs (3.9%) were considered serious.ConclusionsADRs have a high incidence rate in the paediatric surgical population. The off-label use of drugs is a key risk factor for ADRs development.

Pharmacovigilance Strategies to Address Resistance to Antibiotics and Inappropriate Use-A Narrative Review.

The spread of antimicrobial resistance (AMR) is a global challenge. Close and continuous surveillance for quick detection of AMR can be difficult, especially in remote places. This narrative review focuses on the contributions of pharmacovigilance (PV) as an auxiliary tool for identifying and monitoring the ineffectiveness, resistance, and inappropriate use of antibiotics (ABs). The terms "drug ineffective", "therapeutic failure", "drug resistance", "pathogen resistance", and "multidrug resistance" were found in PV databases and dictionaries, denoting ineffectiveness. These terms cover a range of problems that should be better investigated because they are useful in warning about possible causes of AMR. "Medication errors", especially those related to dose and indication, and "Off-label use" are highlighted in the literature, suggesting inappropriate use of ABs. Hence, the included studies show that the terms of interest related to AMR and use are not only present but frequent in PV surveillance programs. This review illustrates the feasibility of using PV as a complementary tool for antimicrobial stewardship activities, especially in scenarios where other resources are scarce.

PCSK9 inhibitor in acute ischemic stroke patient receiving mechanical thrombectomy: early outcomes and safety.

Lipid-lowering therapies are mainstays in reducing recurrence after acute ischemic stroke (AIS). Evolocumab, a Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, is a promising lipid-lowering agent known to decrease LDL cholesterol and mitigate vascular events alongside statins. However, its effects on the early functional outcomes post-mechanical thrombectomy (MT) remain unclear. This study aimed to assess the short-term effects and incidence of bleeding events after the early, off-label use of PCSK9 inhibitors in AIS patients undergoing MT. We retrospectively analyzed patients who had MT at a Regional Stroke Center from December 2018 to April 2023. Our primary outcome was discharge functional outcomes. Secondary outcomes included early neurologic deterioration (END), symptomatic intracerebral hemorrhage (sICH), 3-month functional outcomes, 3-month recurrence rate, and lipid profiles. Of 261 patients (mean age 69.2 ± 11.7, men 42.9%), 42 were administered evolocumab peri-procedurally. While baseline characteristics were similar between the two groups, evolocumab group demonstrated improved discharge outcomes, with a lower mean NIHSS (8.8 ± 6.8 vs. 12.4 ± 9.8, p = 0.02) and a higher percentage of patients with discharge mRS ≤ 3 (52.4% vs. 35.6%, p = 0.041). The 3-month follow-up show a non-significant trend toward an improved outcome in the evolocumab group. Multivariable analysis indicated that evolocumab had a potential impact on favorable discharge outcomes (aOR 1.98[0.94-4.22] for mRS ≤ 3 and 0.47[0.27-0.84] for lower ordinal mRS). Notably, evolocuamb users exhibited fewer instances of END and sICH, although they do not reach statistical significance. Additionally, the evolocumab group demonstrated potential benefits in LDL cholesterol reduction over time. Early use of evolocumab in AIS patients undergoing MT appeared to be safe and associated with better early functional outcomes. The potential benefit of the PCSK9 inhibitor shown here warrants further prospective studies.

Evaluating the efficacy and safety of letermovir compared to valganciclovir for the prevention of human cytomegalovirus disease in adult lung transplant recipients.

Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p=.370). The median (interquartile range) white blood cell (WBC) count was3.1 (2.1-5.6)at LET initiation which increased to5.1 (3.9-7.2)at the end of follow-up (p <.001). For VGCV controls, WBC was4.8 (3.4-7.2)at baseline and5.4 (3.6-7.2)at the end of follow-up; this difference was not statistically significant (p=.395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.

Impact of a national audit on child and adolescent psychiatrists' prescribing practices.

A look back review of South Kerry Child and Adolescent Mental Health Services (CAMHS) in Ireland, known as the 'Maskey report' (MR), highlighted substandard prescribing practices. The aim of this 'Maskey Impact Study' (MIS) was to explore changes to child and adolescent psychiatrists' prescribing practices following the MR. The study was cross-sectional and mixed method. A study specific questionnaire was distributed electronically to psychiatrists working in CAMHS (n = 160). 102 psychiatrists participated in the study (response rate 63.8%). Perceived improvement in prescribing practices included improved medical record keeping (63.7%), consent documentation (53.9%), medication information provision (41.2%) and physical health monitoring (60.8%). However, 43.1% of psychiatrists reported a reluctance to prescribe medication even when clinically indicated and 50% were more likely to avoid off-label use. Most respondents reported increased stress levels (80.4%) with higher stress being significantly associated with reticence in prescribing (χ2 = 11.746, p < .001) and avoiding off-label use (χ2 = 15.392, p < 0.001). Thematic analysis highlighted increased medication hesitancy, enforced 'meaningless' bureaucracy and medication mistrust among families. Although improvements reported are welcomed, the increased hesitancy of medication use, avoidance of prescribing more than one medication, and avoidance of off-label use, is of concern with potential unintended adverse consequences. Reluctance in prescribing may deprive youth of access to evidence-based treatments and limit exposure of NCHDs to the safe practice of consultant-initiated psychopharmacology. Further research will be important to determine if this impacts clinical care. Continued education in psychopharmacology is essential along with increased public awareness of the evidence for medication, to help restore public confidence and trust in psychopharmacology.

Off-label use of Lumen-apposing metal stents for treatment of short benign biliary strictures

BackgroundEndoscopic stenting is the mainstay of treatment for benign biliary strictures. There is a not-negligible rate of recurrence and stent migration. Lumen-apposing metal stents (LAMS) have a unique design with short length, large diameter and wide flanges which make them less prone to migration. AimsTo describe the intraluminal use of LAMS to treat short benign biliary strictures. MethodsAll consecutive patients who underwent bi-flanged LAMS placement for benign biliary strictures, in approximately 6 years, were retrospectively included. Primary outcomes were technical and clinical success; secondary outcomes were number of endoscopic procedures, adverse events evaluation and stricture recurrence during follow-up. ResultsSeventy patients (35 male, mean age 67) were enrolled; bilio-enteric anastomotic stricture was the most common etiology. Technical and clinical success were 100 % and 85.7 %, respectively. Patients with post-surgical stricture had a higher success rate than patients with non-surgical stricture or with bilio-enteric anastomotic stricture (90.4 %, 86.3 % and 81.4 %, respectively). Adverse events were 12/70 (17.1 %): stent migration was the most frequent (8/70, 11.4 %). Stricture recurrence was found in 10/54 patients (18.5 %). ConclusionLAMS placement could be safe and effective treatment for short benign biliary strictures in patients in which a significant caliber disproportion between stricture and the duct above was revealed.

A guide to antimicrobial options for common small ruminant diseases

There are few antibiotics approved for use in small ruminant species in the United States. According to the Animal Medicinal Drug Use Clarification Act (AMDUCA), extralabel drug use may only be employed under the direction of a licensed veterinar­ian in the context of a valid veterinarian-client-patient relation­ship. However, with the implementation of FDA Guidance for Industry #263, producers will no longer have access to antibiot­ics which were previously available over the counter and could have been utilized in an extralabel manner without veterinary oversight. The aim of this discussion is to provide veterinarians with a logical approach to selecting appropriate antibiotics for use in small ruminants.

Frequency, characteristics, predictors and treatment of relapsing myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD)

BackgroundMyelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have a monophasic or relapsing disease course. To date, factors that may predict a relapsing disease course remain largely unknown and only limited data exist regarding the efficacy of different utilized immunotherapy regimens at preventing or reducing relapses. ObjectivesTo assess the characteristics, predictors, and immunotherapy of relapsing MOGAD. MethodsThis multicenter retrospective analysis included all MOGAD cases at the University of Florida, Baylor College of Medicine and the University of California San Diego with minimum follow-up time of 6 months. Cox proportional hazards regression analyses, corrected for age and sex, were performed to evaluate hazard ratios (HR) of predictors of a relapsing disease course and to compare relapse hazards for utilized immunotherapies. ResultsThe majority of included participants (51/79 [64.6 %]) had a relapsing course, and of these individuals, 68.6 % (35/51) experienced their first relapse within the first year. However, 10/51 (19.6 %) participants experienced their first relapse ≥5 years (5–15 years) after the initial presentation. Predictors of a relapsing course were CSF pleocytosis (>150 cells/mm3; HR 3.3 [1.18 – 9.24]; p = 0.023), a pediatric disease onset at age < 9 years (HR 2.69 [1.07–6.75]; p = 0.035), and an initial presentation with the clinical syndrome of meningoencephalitis (HR 3.42 [1.28 – 9.17]; p = 0.015),. In participants with a relapsing course, 13/24 (54.2 %) patients remained relapse-free on rituximab, 4/8 (50 %) on mycophenolate mofetil, and 11/14 (78.6 %) on scheduled immunoglobulins. Patients treated with immunoglobulins had significantly fewer relapses compared to patients treated with other immunotherapies (HR: 0.1 [0.2 – 0.63]; p = 0.014). ConclusionsIn our cohort, the majority of MOGAD patients relapsed. The initial relapse occurred most frequently within the first year, but first relapses also took place over a decade after the initial presentation. Prepubertal onset, severe CSF pleocytosis, and the clinical syndrome of meningoencephalitis may be predictors of a relapsing course. Of the currently available off-label steroid-sparing treatments, scheduled immunoglobulins may be the most effective in relapse prevention.

Superficial Temporal Artery to Superior Cerebellar Artery STA (E-S*) s2 Bypass for Dolichoectatic Superior Cerebellar Artery Aneurysm After Failed Flow Diversion: 2-Dimensional Operative Video.

Flow diversion is a unique interventional tool with evolving roles in the treatment of intracranial aneurysms.1 Although flow diversion strategies can be highly effective in appropriately selected patients, their off-label use is controversial. As flow diversion indications have expanded, so has the incidence of treatment failure, resulting in an evolving subgroup of patients with atypical lesions that require complex salvage strategies, such as cerebrovascular bypass.2,3 We report a residual dolichoectatic superior cerebellar artery aneurysm in which flow diversion failed, which was treated through superficial temporal artery to superior cerebellar artery bypass.4,5 Being a single case report, institutional review board approval was not needed. Patient consent was obtained. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

Verapamil-Loaded Cubosomes for Enhancing Intranasal Drug Delivery: Development, Characterization, Ex Vivo Permeation, and Brain Biodistribution Studies

Verapamil hydrochloride (VRP), an antihypertensive calcium channel blocker drug has limited bioavailability and short half-life when taken orally. The present study was aimed at developing cubosomes containing VRP for enhancing its bioavailability and targeting to brain for cluster headache (CH) treatment as an off-label use. Factorial design was conducted to analyze the impact of different components on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and percent drug release. Various in-vitro characterizations were performed followed by pharmacokinetic and brain targeting studies. The results revealed the significant impact of glyceryl monooleate (GMO) on increasing EE%, PS, and ZP of cubosomes with a negative influence on VRP release. The remarkable effect of Poloxamer 407 (P407) on decreasing EE%, PS, and ZP of cubosomes was observed besides its influence on accelerating VRP release%. The DSC thermograms indicated the successful entrapment of the amorphous state of VRP inside the cubosomes. The design suggested an optimized formulation containing GMO (50% w/w) and P407 (5.5% w/w). Such formulation showed a significant increase in drug permeation through nasal mucosa with high Er value (2.26) when compared to VRP solution. Also, the histopathological study revealed the safety of the utilized components used in the cubosomes preparation. There was a significant enhancement in the VRP bioavailability when loaded in cubosomes owing to its sustained release favored by its direct transport to brain. The I.N optimized formulation had greater BTE% and DTP% at 183.53% and 90.19%, respectively in comparison of 41.80% and 59% for the I.N VRP solution.Graphical

Gabapentin as a novel adjunct for postoperative irritability after superior cavopulmonary connection operation in children.

Describing our institution's off-label use of gabapentin to treat irritability after superior cavopulmonary connection surgery and its impact on subsequent opiate and benzodiazepine requirements. This is a single-center retrospective cohort study including infants who underwent superior cavopulmonary connection operation between 2011 and 2019. Gabapentin was administered in 74 subjects (74/323, 22.9%) during the observation period, with a median (IQR) starting dose of 5.7 (3.3, 15.0) mg/kg/day and a maximum dose of 10.7 (5.5, 23.4) mg/kg/day. Infants who underwent surgery in 2015-19 were more likely to receive gabapentin compared with those who underwent surgery in 2011-14 (p < 0.0001). Infants prescribed gabapentin were younger at surgery (137 versus 146 days, p = 0.007) and had longer chest tube durations (1.8 versus 0.9 days, p < 0.001), as well as longer postoperative intensive care (5.8 versus 3.1 days, p < 0.0001) and hospital (11.5 versus 7.0 days, p < 0.0001) lengths of stays. The year of surgery was the only predisposing factor associated with gabapentin administration in multivariate analysis. In adjusted linear regression, infants prescribed gabapentin on postoperative day 0-4 (n = 64) had reduced benzodiazepine exposure in the following 3 days (-0.29 mg/kg, 95% CI -0.52 - -0.06, p = 0.01) compared with those not prescribed gabapentin, while no difference was seen in opioid exposure (p = 0.59). Gabapentin was used with increasing frequency during the study period. There was a modest reduction in benzodiazepine requirements associated with gabapentin administration and no reduction in opioid requirements. A randomised controlled trial could better assess gabapentin's benefits postoperatively in children with congenital heart disease.

STEP-CD study: ustekinumab use in paediatric Crohn's disease-a multicentre retrospective study from paediatric IBD Porto group of ESPGHAN.

Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause. Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.

Status and trends of legislative and regulatory regulation of off-label use of drugs: A review

The off-label use of drugs is a common practice worldwide. The legal basis for off-label medical use varies from country to country. Regulatory control of the pharmaceutical market in the off-label preventive and therapeutic practice at the international and national levels has become a breakthrough with the emergence of the coronavirus pandemic. The prospects for off-label use in the context of innovations in the legislation of public health in the Russian Federation are crucial. Professionally significant aspects of the use of medicinal products outside the Summary of Product Characteristics and the off-label use have been introduced by supranational regulatory authorities for the common market of medicinal products of the Eurasian Economic Union. Special attention should be paid to the regulatory control of the use of extemporaneous medicines as part of improving the government regulation of drug compounding in pharmacies. The active development of pharmacy activities in drug compounding within the framework of improving regulatory practice determines the relevance of actual off-label prescriptions and the use of extemporaneous formulations. Aim – to perform a systematic analysis of national, transnational legislative and regulatory documents regulating off-label use of medicinal products, determine the main conceptual components of the current regulatory pool and directions for future development in this area. Systematic analysis of the national legislative and regulatory pool of documents and the regulatory framework of the common market of medicinal products of the Eurasian Economic Union on the regulation of various aspects of the off-label use of medicinal products. Study of the components and identification of the main trends in the regulatory practice of prescriptions outside the Summary of Product Characteristics and the off-label use. An analytical search was carried out in the reference legal systems "ConsultantPlus" and "Garant" on the official websites of the Ministry of Health of Russia, the Eurasian Economic Union, the RusMed information resource of the National Library resource of Russia in medicine and pharmacy "Central Scientific Medical Library" was used. A logical generalization of the results on the current state of the legal framework and the development of conceptual proposals on the key directions of the prospective development of regulation, control, and supervisory activities of the pharmaceutical off-label use of medicinal products was made.

B-10 | Off-label Use of KA Micro Plug in PDA Closure in Premature Infants Weighing Less than 1500 Grams: Tips for Success

B-10 | Off-label Use of KA Micro Plug in PDA Closure in Premature Infants Weighing Less than 1500 Grams: Tips for Success

Paediatric off-label use of drugs in Gansu, China: a multicentre cross-sectional study

ObjectiveTo examine the current prevalence and cost of paediatric off-label drug prescriptions in Gansu, China, and the potential influencing factors.DesignThe prevalence of off-label prescriptions in paediatrics was evaluated according to...

Evaluating the Safety and Efficacy of Capromorelin in Rhesus Macaques (Macaca mulatta).

Nonhuman primates used in biomedical research may experience clinically significant weight loss for a variety of reasons. Episodes of anorexia (complete loss of appetite) or hyporexia (decreased appetite) can result in significant weight loss, potentially altering animal welfare and scientific studies. The FDA has approved several appetite stimulants for use in domestic species, but currently none are approved for use in NHP. Treatment of inappetence and weight loss in NHP often relies on the extralabel use of these compounds. Capromorelin is a ghrelin receptor agonist. As a growth hormone secretagogue, capromorelin increases appetite, leading to weight gain. Studies in several species have shown a positive correlation between capromorelin administration and weight gain; in 2017, an oral solution of capromorelin received FDA approval for use in dogs. We tested this solution in healthy adult rhesus macaques (n = 3 males and 3 females) for its effects on body weight and insulin like growth factor-1 (IGF-1). A control group (n = 2 males and 2 females) was used for comparison. Treated macaques received a 3mg/kg oral dose daily for 7 d. Clinical signs were observed daily. Weights were collected before, during and at the end of treatment. Blood was drawn before, during and after treatment for measurement of IGF-1 levels and standard hematology and biochemistry parameters. Baseline-adjusted mean body weights and IGF-1 levels were significantly higher in treated as compared with control monkeys after 7 d of beginning treatment (body weight of 10.5±0.1kg (mean ± SEM) and 10.1±0.1kg, respectively; IGF-1 of 758±43ng/mL and 639±22ng/mL, respectively). Capromorelin administration was not associated with appreciable changes in hematologic and biochemical values in treated macaques. These findings suggest that capromorelin may be useful for treating inappetence and weight loss in NHP, and based on blood analysis, a 7-d course of treatment does not appear to cause acute toxicity.

Risankizumab as a Therapeutic Approach for Recalcitrant Pyoderma Gangrenosum.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis that is challenging to diagnose and treat. Clinicians frequently use fast-acting corticosteroids, which are subsequently combined with slower-acting immunosuppressants to progressively taper the corticosteroid dosage. Current research is focused on the use of monoclonal antibodies (mAbs) directed against target molecules involved in the pathogenesis of PG. However, available data on their efficacy are based on sporadic case reports and clinical experiences, so the authors aimed to evaluate the efficacy of risankizumab, an anti-interleukin-23 mAb, in the management of two complex PG cases. The authors enrolled two patients with PG who were already treated with immunosuppressive therapies. Their management was based on the off-label use of an mAb directed against the p19 subunit of interleukin-23: risankizumab. Patients received subcutaneous injections of 150 mg at the start of treatment, at week 4, and then every 10 weeks thereafter. Systemic therapy was combined with local management of ulcers, based on the principles of TIME (tissue, infection, moisture balance, and epithelialization) applied to the inflammatory and noninflammatory phases of PG. Clinical resolution was obtained at week 24 for patient 1 and week 16 for patient 2 and was maintained until week 40, without adverse effects or disease recurrence. These clinical cases demonstrate that risankizumab is a valid tool in terms of efficacy and safety for complicated cases of multirefractory PG when provided in parallel with local personalized wound management.

The landscape of real-world evidence of rituximab utilization and clinical outcomes in patients with cancer, rheumatoid arthritis, and multiple sclerosis: A scoping review.

Rituximab (RTX) is an anti-CD20 monoclonal antibody that is used to treat various conditions in cancer, rheumatoid arthritis (RA), and multiple sclerosis (MS). Although RTX has been used in the United States for almost 3 decades, questions remain regarding its real-world utilization and effectiveness. To describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS. A broad search was conducted in MEDLINE, Embase, and CINAHL covering the period of January 2010 to June 2022. Two reviewers independently screened all identified records for each disease category (cancer, RA, MS) beginning with title review, followed by abstract, and full-text review to identify relevant publications to include in the final analysis. Data were extracted and summarized for each disease based on overall trends, similarities, and differences across included studies and stratified by disease state. A total of 260 studies met eligibility criteria, with 79 studies for the RA cohort, 144 for cancer, and 37 for MS. Across all disease cohorts, most studies (n = 189; 72.7%) were retrospective. 171 (65.8%) studies used hospital or electronic health record data as their data source and 65 (23.2%) used registry databases. Most studies (n = 153; 58.8%) assessed the effectiveness of RTX measured by disease-specific endpoints, followed by safety (n = 60; 23.1%), treatment patterns (n = 32; 12.3%), and descriptive analyses assessing treatment adherence and economic burden of disease (n = 16; 6.2%). Although safety was not the primary outcome for most studies, the majority of studies across all disease states still reported some form of safety measure. Conclusive statements on RTX's benefit varied across disease states, with MS having the most (n = 30; 81.1%) studies suggesting the drug's positive benefit. There were limited studies assessing RTX use, associated economic burden, and biosimilar switching. The findings underscore the need for health care providers to better understand the treatment landscape and utilization of RTX, particularly in terms of patient selection, timing of initiation, and long-term outcomes. Real-world evidence can help support health care decisions and treatment using rituximab.

Imrecoxib: Advances in Pharmacology and Therapeutics.

Imrecoxib, a cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), was discovered via the balanced inhibition strategy of COX-1/COX-2. It is indicated for the relief of painful symptoms of osteoarthritis. There have been some pharmacological and therapeutic advances since the approval of imrecoxib in 2011. However, an update review in this aspect is not yet available. Relevant literature until January 2024 was identified by search of PubMed, Web of science, Embase and CNKI. From the perspective of efficacy, imrecoxib provides relief of osteoarthritis symptoms, and potential off-label use for treatment of idiopathic pulmonary fibrosis, perioperative pain, hand-foot syndrome, axial spondyloarthritis, COVID-19, cartilage injury, and malignancies such as lung and colon cancer. From a safety point of view, imrecoxib showed adverse effects common to NSAIDs; however, it has lower incidence of new-onset hypertension than other types of selective COX-2 inhibitors, less gastrointestinal toxicities than non-selective NSAIDs, weaker risk of drug interaction than celecoxib, and more suitable for elderly patients due to balanced inhibition of COX-1/COX-2. From a pharmacoeconomic perspective, imrecoxib is more cost-effective than celecoxib and diclofenac for osteoarthritis patients. With the deepening of the disease pathophysiology study of osteoarthritis, new therapeutic schemes and pharmacological mechanisms are constantly discovered. In the field of osteoarthritis treatment, mechanisms other than the analgesic and anti-inflammatory effects of COX-2 inhibitors are also being explored. Taken together, imrecoxib is a moderate selective COX-2 inhibitor with some advantages, and there would be more clinical applications and research opportunities in the future.

“SEEK, AND YOU WILL FIND” - IMPLICATIONS OF PULMONARY HYPERTENSION DIAGNOSIS AND TREATMENT OF PATIENT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LEFT HEART FAILURE

Objective: The case report presents a patient with multimorbidity. A diagnosis of pulmonary hypertension was made during multiple hospitalizations due to bad compliance. The objective of this case report is to describe the difficulties involved in diagnosing pulmonary hypertension in a patient with chronic obstructive pulmonary disease and left heart failure. Design and method: Case report of patient with pulmonary hypertension, chronic obstructive pulmonary disease, left heart failure and multiple comorbidities. Observation of the patient's health condition during many hospitalizations led to further diagnosis of pulmonary hypertension and forced the modification of current treatment. Results: Patient went through many hospitalizations because of bad compliance to chronic obstructive pulmonary disease and left heart failure pharmacotherapy. The patient was hospitalized in our ward for chest pain. He also presented combination of nonspecific symptoms such as dyspnoea (including resting dyspnoea), exercise intolerance and peripheral oedema. Chest x-ray showed signs of pneumonia. Therefore, the diagnosis of pulmonary hypertension was not made during the first hospitalisations. Echocardiography was planned to exclude chronic coronary syndrome. It revealed patent ductus arteriosus, right ventriculum and pulmonary trunk dilation, tricuspid regurgitation and high probability of pulmonary hypertension (mean pulmonary artery pressure 46,5mmHg), without regional cardiac wall dysfunction. The next hospitalization was scheduled, during which cardiac catheterization was performed (pulmonary capillary wedge pressure 14,5 mmHg) and precapillary pulmonary hypertension was confirmed. After many consultations, excluding other causes, such as thromboembolic changes, chronic obstructive pulmonary disease was considered the most likely cause of precapillary pulmonary hypertension. Treatment of basal diseases has been modified, off-label treatment with sildenafil was started, and then due to ineffective treatment (deterioration of the patient's condition resulted in a transition from WHO functional class II to III) the patient was qualified for the bosentan clinical drug treatment program. Conclusions: Diagnosis of pulmonary hypertension can be difficult when symptoms of diseases from other systems are overlapping. This case shows the necessity of watchful observation of patients with multimorbidity, but also difficulties in maintaining good medical compliance. Pulmonary hypertension is still a rare diagnosis, but we should stay alerted about it.