This study systematically evaluates the efficacy, safety, tolerability, and contemporary clinical positioning of topical pilocarpine in the management of glaucoma and ocular hypertension. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed/MEDLINE, EMBASE, Cochrane CENTRAL via the Cochrane Library, Scopus, Web of Science Core Collection, and Google Scholar were searched from inception to 1 May 2026 without language restrictions. Randomized controlled trials and controlled observational studies in adults with glaucoma or ocular hypertension were eligible when topical pilocarpine, used alone or in combination, was compared with placebo, no treatment, laser trabeculoplasty, or other intraocular pressure (IOP)-lowering therapies. The primary outcome was mean change in IOP, and secondary outcomes included responder outcomes, ocular adverse events, discontinuation, visual field outcomes, medication burden, post-laser pressure spikes, and postoperative outcomes. Risk of bias was assessed with the Cochrane Risk of Bias 2.0 tool (RoB 2.0) for randomized studies and the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool for nonrandomized studies. We performed random-effects meta-analysis using raw mean difference in mmHg for continuous outcomes and risk ratio (RR) for binary safety outcomes, each reported with a 95% confidence interval (CI); certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Of the 38 studies that met the inclusion criteria, 34 contributed data to the quantitative meta-analysis. In the primary analysis, pilocarpine-containing regimens reduced IOP by an additional 1.16 mmHg compared to all comparators (95% CI 0.84 to 1.47; P < 0.001; I[2] = 50.7%). Subgroup analyses suggested larger pooled effects in placebo/no-treatment comparisons, ocular hypertension, primary open-angle glaucoma, and monotherapy studies; however, comparisons with beta-blockers and prostaglandin analogs require cautious interpretation because several large individual trials favored timolol or latanoprost for daily clinical use, tolerability, or dosing convenience. Pilocarpine was associated with a sevenfold higher risk of blurred vision (RR 7.33; 95% CI 3.30 to 16.29) and a sixfold higher risk of discontinuation due to adverse events (RR 6.07; 95% CI 3.69 to 10.00). Egger's test pointed to funnel plot asymmetry (P = 0.003), although the trim and fill method did not impute any missing studies. Pilocarpine lowers IOP effectively, but its modern role is limited by frequent dosing, miosis, blurred vision, accommodative symptoms, brow ache, and higher discontinuation. In current glaucoma care, prostaglandin analogs and selective laser trabeculoplasty are generally more consistent with first-line open-angle glaucoma management, whereas pilocarpine is better positioned for selected clinical scenarios, including angle-closure mechanisms, post-laser pressure-spike prophylaxis, selected postoperative angle-surgery settings, intolerance or nonresponse to other drug classes, and resource-limited settings where newer therapies are unavailable or unaffordable.

Leftover fentanyl patches can cause life-threatening opioid toxicity in opioid-naive individuals. In coma with miosis and hypoventilation, management should be guided by the opioid toxidrome, skin examination, patch removal, ventilatory support, and titrated naloxone, even when a routine urine opiate screen is negative.

As direct human experiments are often restricted by ethical concerns and safety risks, a cross-species physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model was developed to integrate pharmacokinetics (PKs) and pharmacodynamics of drugs using in vitro-in vivo extrapolation. Fentanyl and alfentanil, 2 μ-opioid receptor agonists with extensive clinical data, were selected as model drugs. Key in vitro parameters such as transport parameters across hCMEC/D3 cell monolayers (blood-brain barrier), hepatic metabolic clearance in liver microsomes, and unbound fractions in the brain were experimentally measured. PK and analgesic effects of the 2 drugs following an intravenous dose to mice were also documented. The affinity to receptor (Kd) to μ-opioid receptor were cited from the literature. A mouse PBPK-PD model was first constructed. It was assumed that the effects of the central nervous system were linked to unbound drug concentrations in brain parenchyma, which is illustrated using the Emax model. The developed PBPK-PD model, following validation using observations in mice, was extrapolated to rats and humans in sequence. The PK profiles and their central nervous system effects (such as analgesic effect, respiratory depression, and miosis) of fentanyl and alfentanil following intravenous administration to rats and humans were predicted and validated using observations. The results showed that the majority of observed values fell within the 5th-95th percentiles of simulations from 1000 virtual individuals. In conclusion, the developed cross-species PBPK-PD model, based on physiological parameters, in vitro PK/pharmacodynamic parameters, was successfully used to predict the PK and central nervous system effects of fentanyl and alfentanil in mice, rats, and humans, demonstrating the applicability and feasibility. SIGNIFICANCE STATEMENT: The developed cross-species physiologically based pharmacokinetic-pharmacodynamic model, based on physiological parameters, in vitro drug metabolic parameters, and in vitro pharmacokinetic parameters, was successfully used to predict the pharmacokinetic and central nervous system effects of fentanyl and alfentanil in mice, rats, and humans, demonstrating the applicability and feasibility.

Despite the usefulness of pupil size assessment as a proxy for subjects' state of mind in clinical and neuroscientific studies, its measure remains confined to non-ecological, controlled experiments where the subject fixates a stationary target. Here, we propose a novel method to assess pupil metrics based on a projective invariant, allowing the measurement to be insensitive to eye orientation, and to the video eye-tracker experimental setup. We used computer simulations to demonstrate the improvements achieved by the novel method in various scenarios. Finally, the new method was applied during a proof-of-concept free viewing experiment with a single subject that underwent a chemically induced miosis on one of his eyes. Limbus and pupil edges were manually labeled using a custom-made code developed to avoid perceptual bias of the edges' location. We demonstrated that the method tracks the pupil size independently of the eye orientation, negating the need to post-process the data as all solutions previously proposed. Our work could be used to continuously evaluate the pupil size, while relaxing the fixation constraint, paving the way to drastically increase the number of applications using pupil measurements in more ecological conditions.

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by muscle weakness, thrombocytopenia, spleen anomalies and short stature. They are due to mutations affecting the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1 and leading to aberrant Ca2+ homeostasis. Therapeutic approaches aiming to rebalance intracellular Ca2+ levels largely rescued the multi-systemic phenotype in Stim1R304W/+ mice harboring the most common TAM/STRMK mutation. However, the currently used biomarkers to follow disease progression are costly and inadequate for longitudinal studies. Here, we investigated the suitability of MYOM3 to serve as a robust blood-based biomarker for TAM/STRMK. Using only minimal blood volumes, we detected highly elevated circulating MYOM3 levels in plasma samples from Stim1R304W/+ mice and TAM/STRMK patients with different mutations, and we found that the MYOM3 levels were normalized in Stim1R304W/+ mice undergoing efficient therapies. We also identified skeletal muscle as the primary source of circulating MYOM3, a structural protein of the contractile unit in myofibers, and uncovered that MYOM3 is primarily expressed in regenerating muscle fibers and in fast-twitch type IIa fibers. Overall, this work emphasizes the utility of MYOM3 as a minimally-invasive biomarker for disorders involving myofiber degeneration, and highlights the ability of MYOM3 to detect early muscle dysfunction in TAM/STRMK and evaluate therapeutic efficiency.

Brimonidine ingestion in young children can cause rapid, severe central nervous system (CNS) depression, including miosis and hypotonia. Clinicians should maintain a high index of suspicion in toddlers presenting with unexplained drowsiness following exposure. Prompt airway management and supportive care are critical, as naloxone may improve symptoms in these cases.