The goal of the present study is to optimize acetazolamide-loaded solid lipid nanoparticles (AZM-loaded SLNs) using central composite design (CCD) for prolonged ocular delivery. The emulsion solvent evaporation process was used to develop AZM-loaded SLNs. The optimal formulation parameters influencing particle size, entrapment efficiency, and percentage drug release were determined using a CCD, and the effects of these variables on the formulation were examined. Furthermore, the particle size, entrapment effectiveness, and in-vitro drug release were carried out, along with FTIR, XRD, DSC, SEM, and TEM, which were used to determine structural and physicochemical properties. The ex-vivo corneal permeability investigations were used to assess drug penetration, and in-vivo experiments in rabbit eyes were conducted to assess the impact on reducing intraocular pressure. Moreover, hemocompatibility, sterility, and eye irritation were also used to evaluate the formulation's safety features. The optimized AZM-loaded SLNs had a drug entrapment efficiency of 89.45%, a particle size of 110.3 nm, and a prolonged drug release of 87.76% in a 24 h period. The drug's effective incorporation into the lipid carrier particles was verified by FTIR, XRD, DSC, SEM, and TEM. Ex-vivo corneal permeation showed that it was significantly higher than both the pure drug and the marketed formulation. Additionally, the in-vivo studies showed a reduction in the intraocular pressure (IOP) during 24 h. A promising nanocarrier system for prolonged ocular administration and better glaucoma patient management has been represented by the developed AZM-loaded SLNs.

Pediatric moyamoya disease (MMD) is a progressive steno-occlusive arteriopathy that carries a high risk of recurrent ischemic stroke and neurocognitive decline if left untreated, with a more aggressive course in children under 4 years of age than in older children or adults. This narrative review critically synthesizes original clinical studies published between 2018 and 2026 to provide an evidence-based surgical decision-making framework. A literature search of PubMed/MEDLINE was performed, including only original articles (case series >10 patients, cohort studies) reporting surgical outcomes in children ≤18 years with MMD or moyamoya syndrome. In large contemporary series, indirect revascularization achieves postoperative stroke-free survival rates exceeding 95% and 20-year event-free survival of 97% in young children. Direct or combined bypass provides superior angiographic revascularization but does not significantly lower the long-term stroke rate compared with indirect techniques. Preoperative assessment of cerebrovascular reactivity using BOLD MRI or SPECT with acetazolamide is the strongest predictor of surgical benefit. Preliminary machine learning models using intraoperative arterial blood pressure waveforms can predict postoperative neurological events with an AUROC of 0.738. A four-step surgical algorithm based on age, hemodynamic status and vascular anatomy is proposed. Priorities for future research include an international pediatric registry, validation of AI-based risk stratification tools, and randomized comparisons of direct versus indirect bypass in children aged 4-8 years.

Idiopathic intracranial hypertension (IIH) management often involves acetazolamide and topiramate, both carbonic anhydrase inhibitors. Their concurrent use poses a high, yet clinically under-recognized, risk of additive metabolic acidosis. We report a 44-year-old female with IIH who developed insidious, clinically significant hyperchloremic metabolic acidosis and profound weight loss (24% reduction) following prolonged combination therapy. Her clinical presentation mimicked malignancy, prompting extensive diagnostic screening before the pharmacodynamic interaction was identified. Acetazolamide discontinuation led to biochemical resolution. To systematically evaluate this interaction, we conducted a disproportionality analysis using the FDA Adverse Event Monitoring System (AEMS). The analysis corroborated strong safety signals for metabolic acidosis in combination therapy (ROR: 45.56, 95% CI: 28.66-72.43). This study highlights a distinct, chronic trajectory of acetazolamide-topiramate-induced acidosis. Clinicians must exercise heightened vigilance and enforce routine biochemical monitoring when co-prescribing these agents to prevent desirable therapeutic weight loss from transitioning into a debilitating adverse event.

Rationale: Chronic prescription opioid use can exert ventilatory depression and increase loop gain to induce sleep disordered breathing (SDB). Alternative therapies to mitigate opioid-associated SDB are needed. Objective: We sought to examine whether oral acetazolamide (ACZ) will reduce SDB in opioid-associated SDB by reductions in plant and/or by increasing cerebrovascular responsiveness to CO2 (CCR) Methods: Nine adults with opioid-associated SDB were randomized to receive oral ACZ or placebo, in crossover fashion, for 6 days, with multiple measurements of awake CCR to hypercapnia on day 4, followed by measurements of apneic threshold, plant and controller gains (components of loop gain), using noninvasive mechanical ventilation during NREM sleep, and subsequent overnight polysomnography while still on the drug. Serum opioid and serum total CO2 levels confirmed use of opioid drug and ACZ, respectively. Measurements and Main Results: Compared with placebo, ACZ significantly reduced SDB severity (apnea-hypopnea index, 25.2±8.3/hour vs.32.2±8.2/hour, p=0.03; central apnea-hypopnea index 0.9±0.3/hour vs. 5.0±1.1/hour, p=0.006, i.e. reduced 22% and 82%, respectively, with increased oxygen saturations). The reduction in SDB severity was accompanied with a significant reduction in plant gain with ACZ vs. placebo (4.0±0.7 mmHg vs.6.6±0.6 mmHg/L/min, p<0.001), driven by ACZ-induced metabolic acidosis leading to increased eupneic minute ventilation (10.0±1.4 L/min vs. 6.8±0.5 L/min, p=0.04), and reduced eupneic end-tidal CO2 (33.1±1.2 mmHg vs. 41.6±1.1 mmHg, p<0.001). In contrast, the controller gain and CCR were unchanged with ACZ vs. placebo. Conclusions: Acetazolamide significantly mitigates opioid-associated sleep disordered breathing via reduction in plant gain but without alterations in ventilatory chemoresponsiveness or cerebrovascular responsiveness.

In this study, novel pyrrolidine-based compounds bearing indole, chromone, and benzoylthiourea pharmacophores were rationally designed, synthesized, and evaluated as dual inhibitors of carbonic anhydrase I/II (hCA I, hCA II) and acetylcholinesterase (AChE). The target compounds were synthesized via imine azomethine ylide 1,3-dipolar cycloaddition and in selected cases, benzoyl isothiocyanate condensation reactions. Their structures were fully characterized using FTIR, NMR, microanalysis, and single-crystal X-ray diffraction (for 1ba). Compound 2ad (hCA I, Ki = 35.56 ± 5.10 nM, hCA II, Ki = 31.10 ± 4.84 nM) exhibited remarkable inhibitory activity against both hCA I and hCA II, outperforming the reference acetazolamide (AZA) (hCA I, Ki = 303.45 ± 10.21 nM, hCA II, Ki = 240.15 ± 8.65 nM). Compounds 1aa and 2bd demonstrated potent AChE inhibitory activity, displaying approximately 3-fold and 4-fold higher potency than tacrine (TAC), with Ki values of 47.92 ± 8.25 nM, and 35.04 ± 7.69 nM, respectively. An in silico approach, including molecular docking and ADMET analyses, was employed to elucidate the binding interactions and pharmacokinetic profiles of the synthesized compounds. Docking simulations revealed that compound 2ad showed favorable binding affinities toward hCA I and hCA II (-8.24 and -10.09 kcal/mol, respectively), while compounds 2bd and 1aa showed highly favorable binding energies toward AChE (-12.48 and -11.56 kcal/mol, respectively), forming stable interactions comparable to reference inhibitors. Furthermore, ADMET predictions indicated good oral absorption and favorable drug-likeness properties, although optimization may be required to enhance blood-brain barrier (BBB) permeability. The experimental and computational findings support the strong interaction potential of compound 2ad toward hCA II, whereas compounds 2bd and 1aa exhibit high binding affinity toward AChE, in agreement with the experimental inhibition data.

Marfan syndrome (MFS) is a connective tissue disorder classically associated with cardiovascular, musculoskeletal, and ocular manifestations. Neurological involvement is increasingly recognized and is most commonly related to spontaneous intracranial hypotension secondary to dural ectasia and cerebrospinal fluid (CSF) leakage. By contrast, idiopathic intracranial hypertension (IIH) is exceptionally rare in pediatric patients with MFS. We report the case of an 8-year-old girl with Marfan syndrome presenting with neck pain, diplopia, bilateral papilledema, and bilateral sixth cranial nerve palsy. Brain MRI demonstrated optic nerve tortuosity, distension of the perioptic subarachnoid spaces, and partial empty sella, while venous sinus thrombosis and spinal CSF leakage were excluded. Lumbar puncture confirmed markedly elevated CSF opening pressure (48 cmH2O), consistent with IIH. CSF and plasma neurofilament light chain levels were elevated, whereas anti-MOG antibodies and autoimmune investigations were negative. The patient showed rapid clinical improvement following therapeutic CSF drainage and acetazolamide treatment. To the best of our knowledge, this represents only the second report of pediatric IIH associated with Marfan syndrome. Our patient developed idiopathic intracranial hypertension, an uncommon neurological manifestation in this condition. Through this case, we aim to highlight the diagnostic challenges, discuss the possible pathophysiological mechanisms underlying this rare association and emphasize the importance of considering intracranial hypertension in the differential diagnosis of children with Marfan syndrome presenting with neuro-ophthalmological symptoms.

This study examined whether Ginkgo biloba (GB), used as an adjunct to acetazolamide (Az) for acute mountain sickness (AMS) prevention, affected endurance and cognitive performance under normobaric hypoxia in male mountaineers. This randomized, double-blind, placebo-controlled crossover trial included four sessions and two supplementation phases (GB and placebo) separated by a 1-week washout period. Testing was conducted under normobaric hypoxic conditions (13% O2). Twelve healthy male mountaineers (aged 18-44) with prior high-altitude experience (above 4000 m), a history of AMS, and regular aerobic training were included. Participants received GB (200 mg/day) or a placebo for 5 days, with Az (125 mg, three doses) administered during the final 2 days of each phase. GB supplementation was associated with a significantly longer time to exhaustion (p = 0.019) and lower ratings of perceived exertion (p = 0.020) during treadmill exercise to exhaustion under hypoxia. However, no significant between-condition differences were observed for the Feeling Scale, Felt Arousal Scale, heart rate, or peripheral oxygen saturation during the endurance test. No significant differences were found in choice reaction time or Stroop Color-Word Test outcomes. In conclusion, GB supplementation for 5 days was associated with a longer time to exhaustion under simulated altitude in male mountaineers using Az for AMS prevention, while no significant between-condition differences were observed in cognitive outcomes. The endurance finding is preliminary and should be regarded as exploratory pending confirmation in larger studies. Because Az was administered in both conditions, the effect of GB without Az cannot be determined from this design. Trial Registration: The trial was registered in the Iranian Clinical Trial Registry (www.irct.behdasht.gov.ir, IRCT ID: IRCT20230711058744N1).