Maan H. Harbi

Background/Objectives: Narcolepsy type 1 (NT1) results from loss of hypothalamic orexin neurons. Selective orexin-2 receptor (OX2R) agonists now permit direct receptor-level restoration of deficient signaling, but recent broad reviews do not fully integrate the post-approval, trial-specific efficacy, prescribing, and safety evidence. This review asks what benefits and risks are supported by current data, which toxicities appear class-related versus molecule-specific, and how OX2R agonism should be positioned clinically. Methods: We performed a targeted narrative review of peer-reviewed human studies, major guidelines, trial registries, and regulatory documents updated through 16 October 2026. Peer-reviewed trials and regulatory sources were prioritized; conference- or sponsor-reported data were used only when peer-reviewed evidence was unavailable and were identified as provisional. Results: In the pivotal phase 3 trials, oveporexton produced placebo-adjusted improvements in MWT sleep latency of 13.8–20.1 min, ESS reductions of 8.0–9.8 points, and weekly cataplexy incidence-rate ratios of 0.25–0.38. Clinically important safety considerations include insomnia, urinary frequency/urgency, CPK elevations, CYP3A interactions, and measurable abuse potential. Alixorexton phase 2 data support OX2R agonism as a developing drug class, whereas firazorexton illustrates molecule-specific hepatotoxic risk. Conclusions: OX2R agonists are best described as mechanism-based pharmacological restoration of orexin signaling, not proven disease-modifying therapy. Their comparative clinical position remains uncertain because head-to-head trials with established therapies are lacking.

Background. Experimental pharmacology requires students to interpret laboratory findings, identify affected physiological pathways, and infer underlying drug mechanisms. While artificial intelligence (AI) is increasingly explored in health professions education, concerns remain regarding passive learning and overreliance on generated answers. This study evaluated the feasibility, acceptability, and short-term outcomes of a structured, multi-component practical designed to support active reasoning in antithrombotic pharmacology. Methods. A single-group pre-post educational intervention was conducted among 44 second-year PharmD students. The intervention included a baseline assessment, an experimental logic mini-brief, an AI-supported mechanistic reasoning practical using a standardized reasoning prompt, an independent post-test, and a perception survey. The primary outcome was total assessment score change. Secondary outcomes included domain-specific scores, performance during the AI-supported practical, confidence, perceived AI helpfulness, student perceptions, and associations between practical performance and learning outcomes. Results. Total assessment scores improved significantly from 76.82% ± 25.06% at baseline to 85.80% ± 21.27% after the intervention, with a mean gain of 8.98 ± 20.53 percentage points (Wilcoxon signed-rank test, Z = −2.597, p = 0.009, r = 0.39). Significant pre-post improvements were observed in coagulation pharmacology (p = 0.001, r = 0.49) and a smaller uncorrected improvement occurred in platelet pharmacology (p = 0.048, r = 0.30), while experimental reasoning scores increased numerically but did not reach statistical significance (p = 0.219, r = 0.19). Among AI-supported practical completers (n = 43), the mean Step 3 reasoning score was 17.88 ± 4.01 out of 21 (85.1% ± 19.1%). Accuracy was highest for experimental interpretation (87.0%), followed by mechanism or pathway identification (85.0%) and drug-class identification (83.4%). Step 3 performance was positively associated with post-test score (Spearman’s rho = 0.606, p < 0.001). The core perception and acceptability items showed excellent internal consistency (Cronbach’s alpha = 0.935), and student perceptions were generally favorable. Conclusion. A multi-component pharmacology practical containing an AI-guided reasoning prompt was feasible, acceptable, and associated with improved short-term assessment scores. Given the single-group pre-post design, we cannot isolate the specific AI contribution from co-occurring instructional elements, such as the mini-brief, case-based practice, and retrieval-practice testing effects. Controlled studies are needed to assess causal efficacy and long-term retention.

Narcolepsy type 1 (NT1) is caused by loss of hypothalamic orexin (hypocretin) neurons and consequent deficiency of orexin signalling. Conventional pharmacotherapy improves excessive daytime sleepiness, cataplexy, or disturbed nocturnal sleep through downstream monoaminergic, histaminergic, or GABA-related mechanisms but does not correct the underlying neurochemical lesion. Selective orexin-2 receptor (OX2R) agonists act directly at the receptor normally engaged by the missing peptide. Danavorexton established proof of mechanism; firazorexton (TAK-994) confirmed oral efficacy but was discontinued for idiosyncratic hepatotoxicity; and oveporexton produced large, sustained improvements in wakefulness, sleepiness, cataplexy, and broader disease measures across two pivotal phase 3 trials, leading to its approval (August 2026) as the first OX2R agonist for NT1. This review appraises OX2R biology, oveporexton's clinical pharmacology, class safety versus molecule-specific toxicity, and the emerging pipeline, and argues that the class is best framed as functional restoration of orexin signalling rather than proven disease modification.

Background: Ibrutinib is widely used in B-cell malignancies, yet real-world safety data remain heterogeneous, particularly in underrepresented regional populations. Objective: To characterize the adverse-event profile and severity and explore factors associated with Grade 3–5 toxicity and permanent treatment discontinuation among patients receiving ibrutinib in routine clinical practice. Methods: A retrospective cohort study was conducted at King Abdullah Medical City, Makkah, Saudi Arabia, with follow-up through December 2025. Adult patients with B-cell malignancies who received ibrutinib and had sufficient clinical documentation for safety-outcome ascertainment were included. The primary endpoint was the occurrence of at least one Grade 3–5 adverse event according to CTCAE v5.0. Secondary outcomes included dose modifications, permanent treatment discontinuation, factors associated with toxicity, and temporal adverse-event patterns. Results: Among 57 patients, all 57 (100%) experienced at least one adverse event and 41 (71.9%) experienced at least one Grade 3–5 adverse event. Neutropenia and hypertension were the most frequent severe toxicities. Dose modification occurred in 47 patients (82.5%), and permanent discontinuation occurred in 17 (29.8%). In reduced Firth penalized-likelihood models adjusted for starting-dose category, pre-existing ischemic heart disease was associated with permanent discontinuation (aOR 6.25, 95% profile-likelihood CI 1.29–39.19; p = 0.023), while creatinine clearance 90 days) periods ( p = 0.004), although an equal-window sensitivity analysis comparing days 0–90 with days 91–180 was not significant ( p = 0.240). Conclusion: Ibrutinib was associated with substantial toxicity and frequent treatment modification in routine clinical practice. Pre-existing ischemic heart disease and impaired renal function emerged as exploratory markers of treatment vulnerability. The temporal findings support continued surveillance throughout therapy but do not establish a phase-specific monitoring strategy.

Background/Objectives: Elevated lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor associated with atherosclerotic cardiovascular disease and calcific aortic valve disease. Historically, therapeutic options for reducing Lp(a) have been limited. This study aimed to characterize the clinical development landscape of emerging Lp(a)-targeted therapies, evaluate endpoint assessment strategies, and summarize available efficacy evidence from investigational agents. Methods: A qualitative clinical trial landscape review was conducted using ClinicalTrials.gov. Interventional Phase I–III studies evaluating therapies specifically targeting Lp(a) were identified through a structured registry search performed on 5 November 2025. Eligible studies were screened according to predefined inclusion and exclusion criteria. Extracted data included trial characteristics, therapeutic class, endpoint methodologies, and published efficacy outcomes. Data were synthesized narratively. Results: Twenty clinical trials met the eligibility criteria. Three therapeutic classes were identified: antisense oligonucleotides (ASOs), small interfering RNA (siRNA)-based therapies, and small-molecule inhibitors. Pelacarsen represented the sole ASO program, whereas siRNA-based therapies constituted the largest therapeutic category. Five studies were designed as cardiovascular outcomes trials. Percent change from baseline in circulating Lp(a) concentration was the most frequently used efficacy endpoint. Published data demonstrated substantial reductions in Lp(a) concentrations across all major therapeutic platforms. Available non-head-to-head published evidence showed substantial Lp(a) reductions across several investigational agents, including siRNA-based therapies, pelacarsen, and muvalaplin, although differences between studies preclude direct comparison between therapeutic platforms. Conclusions: The Lp(a) therapeutic landscape has rapidly evolved, with RNA-based therapies demonstrating unprecedented reductions in circulating Lp(a) concentrations. Ongoing cardiovascular outcomes trials will determine whether these reductions translate into meaningful cardiovascular benefits, establish Lp(a) as a therapeutic target in cardiovascular prevention and clarify the long-term safety and risk–benefit profile of Lp(a)-targeted therapies.

Background: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide, (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as an effective therapy for obesity and type 2 diabetes mellitus (T2DM). Its dual-incretin mechanism may offer enhanced metabolic benefits compared with selective GLP-1 receptor agonists such as semaglutide. Methods: A structured narrative review of clinical trials, real-world observational studies, and contextual cardiovascular outcome analyses was conducted. Literature was sourced from ClinicalTrials.gov and relevant scientific databases to compare tirzepatide and semaglutide across weight, glycemic, cardiometabolic, and safety outcomes. Results: Across completed head-to-head randomized trials, tirzepatide consistently achieved greater reductions in body weight, and HbA1c than semaglutide in individuals with obesity or T2DM. Semaglutide, however, has the most mature evidence for cardiovascular risk reduction, as demonstrated in the SUSTAIN-6, PIONEER-6, and SELECT trials. The SURPASS-CVOT trial established cardiovascular non-inferiority for tirzepatide compared with dulaglutide, alongside improvements in cardiometabolic risk factors. Real-world studies reported heterogeneous cardiovascular outcomes. Conclusion: Tirzepatide demonstrates superior metabolic efficacy in direct comparative trials, whereas semaglutide currently has the strongest evidence for cardiovascular benefit. Treatment selection should be individualized based on clinical priorities and patient characteristics.

Introduction: Cardiac amyloidosis, primarily comprising transthyretin amyloid cardiomyopathy (ATTR-CM) and light-chain amyloidosis with cardiac involvement (AL-cardiac), is an increasingly recognized contributor to the global heart failure burden. Management has shifted from supportive care to disease-modifying agents targeting specific stages of the amyloid cascade. This registry-based review qualitatively characterizes the current pharmacological clinical trial landscape through a registry-based analysis. Methods: A structured qualitative analysis of ClinicalTrials.gov was conducted for interventional trials registered between January 2015 and November 2025. Following PRISMA principles, studies were screened to include pharmacological interventions with explicit cardiac targeting while excluding neuropathy-dominant amyloidosis. Trial-level data regarding therapeutic classes, study phases, enrollment, and primary outcome domains were extracted and synthesized. Results: A total of 18 trials met the inclusion criteria (14 ATTR-CM; 4 AL-cardiac), representing a total enrollment of 4924 participants across 11 unique agents. Five therapeutic classes were identified: amyloid-clearing monoclonal antibodies (44.4% of trials), TTR silencers, TTR stabilizers, fibril-modifying agents, and cardiac phenotype-directed therapies. Monoclonal antibodies represented the largest class by both trial count and enrollment (3075 participants). Clinical events (n = 7) and safety/tolerability (n = 5) were the most frequent primary outcome domains. ATTR-CM trials dominated the landscape, accounting for 77.7% of the total study population, while parallel-group placebo-controlled designs were the most common study architecture (n = 10). Conclusions: The therapeutic landscape for cardiac amyloidosis is transitioning toward stage-specific, mechanism-based interventions. While ATTR-CM currently dominates research efforts, the expansion of silencers and monoclonal antibodies reflects an increasing capacity to intercept the amyloid cascade at distinct molecular checkpoints. However, significant heterogeneity in outcome measures and the shift toward diagnosing milder disease pose challenges for demonstrating clinical efficacy. Future priorities include standardized progression markers and addressing barriers to global access for these high-cost therapies.

Introduction: Cardiac amyloidosis, primarily comprising transthyretin amyloid cardiomyopathy (ATTR-CM) and light-chain (AL) subtypes, is an increasingly recognized contributor to the global heart failure burden. Management has shifted from supportive care to disease-modifying agents targeting specific stages of the amyloid cascade. This systematic review qualitatively characterizes the current pharmacological clinical trial landscape through a registry-based analysis. Methods: A qualitative systematic analysis of ClinicalTrials.gov was conducted for interventional trials registered between January 2015 and November 2025. Following PRISMA principles, studies were screened to include pharmacological interventions with explicit cardiac targeting while excluding neuropathy-dominant amyloidosis. Trial-level data regarding therapeutic classes, study phases, enrollment, and primary outcome domains were extracted and synthesized. Results: Eighteen trials met the inclusion criteria (14 ATTR-CM; 4 AL-cardiac), representing a total enrollment of 4,924 participants across 11 unique agents. Five therapeutic classes were identified: amyloid-clearing monoclonal antibodies (44.4% of trials), TTR silencers, TTR stabilizers, fibril-modifying agents, and cardiac phenotype–directed therapies. Monoclonal antibodies represented the largest class by both trial count and enrollment (3,075 participants). Clinical events (n=7) and safety/tolerability (n=5) were the most frequent primary outcome domains. ATTR-CM trials dominated the landscape, accounting for 77.7% of the total study population, while parallel-group placebo-controlled designs were the most common study architecture (n=10). Conclusion: The therapeutic landscape for cardiac amyloidosis is transitioning toward stage-specific, mechanism-based interventions. While ATTR-CM currently dominates research efforts, the expansion of silencers and monoclonal antibodies reflects an increasing capacity to intercept the amyloid cascade at distinct molecular checkpoints. However, significant heterogeneity in outcome measures and the shift toward diagnosing milder disease pose challenges for demonstrating clinical efficacy. Future priorities include standardized progression markers and addressing barriers to global access for these high-cost therapies.

Background: Childhood blindness is a significant global health concern, consistently identified in existing research as stemming from rare genetic and congenital disorders. With the technological advances of the 21^st century which have positively impacted many areas of human life, healthcare included, recent advances in gene therapy and pharmacological interventions have served to spur clinical research in this area. The primary focus of the current study was to use data from ClinicalTrials.gov to carry out a preliminary exploration and and descriptive analysis of clinical trials focusing on the treatment of childhood blindness. Methods: A cross-sectional analysis was conducted using data from ClinicalTrials.gov. The initial search for data in ClinicalTrials.gov yielded a total of 110 studies under blindness-related conditions. Upon further cross-examination of these studies based on the inclusion criteria, only five interventional trials (published between 2012 and 2023) specifically targeting childhood blindness met the inclusion criteria and were therefore included. Key trial characteristics studied conditions, intervention types, outcome measures, study phases, and enrollment sizes were extracted and analyzed descriptively. Results: Across the five included trials, a majority of trials investigated rare genetic conditions, including Leber Congenital Amaurosis, Wolfram Syndrome, and Osteoporosis Pseudoglioma. On interventions, the most commonly used approaches for handling childhood blindness include gene therapy vectors like AAV RPE65, antisense oligonucleotides like QR-110, and repurposed pharmacological agents such as lithium and dantrolene sodium. All studies included children within their target populations, and most were early-phase (Phase 1/2) trials with small sample sizes (11– 26 participants). Primary outcomes focused on safety, while secondary outcomes assessed visual function and biochemical changes. Conclusion: Although limited in number, current clinical trials represent a promising shift toward targeted therapies for childhood blindness. The dominance of early-phase studies highlights the need for expanded, multicenter, and later-phase trials. Future research should aim to improve trial accessibility, standardize outcome measures, and ensure ethical conduct in pediatric populations.

Despite the growing prevalence of off-label prescribing, there is limited research exploring pharmacists’ actual knowledge and practices, particularly in the Saudi context. Existing literature mainly focuses on physicians, leaving a gap in understanding pharmacists’ readiness to handle such prescriptions. This study aimed to assess the knowledge and practices of pharmacy staff in Saudi Arabia regarding off-label drug use and examined the impact of education, age, gender, and experience on these outcomes. A cross-sectional survey was conducted over 6 months (February–July 2024) targeting registered pharmacy staff working in healthcare settings in Riyadh and Jeddah, Saudi Arabia. Participants completed a content validated, structured questionnaire designed to assess their knowledge and practices related to off-label drug use. The survey also captured demographic and professional data, including age, gender, education level, hospital type, and years of experience. Among 302 pharmacy staff, the mean knowledge score was 54.7 ± 22.3, indicating moderate knowledge while Practice scores were higher (mean 68.2 ± 17.8), with over 75% correctly managing off-label prescriptions. Logistic regression showed hospital level as a significant predictor, staff in tertiary hospitals were more knowledgeable (OR = 4.5) and practiced better (OR = 3.6). Demographics had no significant impact. No association was found between self-rated knowledge and actual knowledge, but poor self-rated familiarity strongly correlated with poor practice ( P < .0001). These findings underscore the need for SFDA-aligned training and regulatory initiatives to improve off-label prescribing, especially in primary and secondary care. Periodic national assessments are essential to monitor and enhance pharmacy staff competence amid ongoing healthcare reforms.