Drug-resistant Neisseria gonorrheae is becoming an increasingly concerning threat as cases continue to rise, highlighting the need for novel therapeutics. We, therefore, have further developed our previously established structure-activity relationship for derivatives of acetazolamide, an FDA-approved carbonic anhydrase inhibitor. A large cohort of acetazolamide-based analogs was investigated for their activity against N. gonorrheae and their binding to NgCAs. Lead compounds were carried forward for in vitro ADME evaluation before prioritizing two molecules, 18 and 33, for in vivo PK analysis. These compounds were orally bioavailable and metabolically stable, and exhibited low cytotoxicity against mammalian cell lines. When investigated for in vivo efficacy in an infected mouse model, 18 was found to significantly decrease gonococcal bioburden compared with the vehicle control. Our studies culminated in the finding that acetazolamide-based compounds can be developed as effective drugs against N. gonorrheae and may be an answer in the search for new therapeutics.

The limitations of conventional therapeutic approaches for treating ocular diseases such as glaucoma via the topical administration route are nowadays a constant challenge for researchers in the field of pharmaceutical technology. The present study shows the feasibility of developing nanocomposite hydrogel-based eye drops for the topical delivery of acetazolamide, underlining its potential benefits in the glaucoma treatment. In detail, hyaluronic acid hydrogels loaded with acetazolamide nanocrystals were developed and characterized in accordance with requirements for ocular administration. Nanocomposite hydrogels composition was optimized with hyaluronic acid 1.25% w/v and acetazolamide nanocrystals 5% w/v, showing a viscosity compatible with topical instillation (μ₀ < 30 mPa·s). Fourier-transform infrared spectroscopy and thermal analyses showed purely physical incorporation of the nanocrystals into the polymeric network. Microscopy analysis revealed a homogeneous morphology with uniform nanocrystal dispersion and no visible phase separation. Rheological characterization demonstrated enhanced mucoadhesive properties, attributed to physical entanglement between hyaluronic acid and mucin. In vitro release studies in simulated tear fluid showed a biphasic release profile with an initial burst followed by a sustained diffusion-controlled release over 72 h. In vivo studies in albino normotensive rabbits showed no signs of irritation or damage after topical ocular administration of nanocomposite hydrogels and demonstrated a significant reduction in intraocular pressure compared with normal saline solution, even at a low drug dose. Furthermore, the duration of the hypotensive effect tended to go beyond that of a commercial formulation tested as reference. Overall, the nanocomposite hydrogel emerges as a promising platform for ocular delivery of acetazolamide.

Eleven carbonic anhydrase isoforms are known to be present in different parts of the central nervous system and are involved in signal transduction, cerebral fluid homeostasis, bicarbonate generation, respiratory response to carbon dioxide, seizure activity, and fluid and ion compartmentation. Therefore, carbonic anhydrase inhibitors profoundly influence several neurological therapeutic approaches. Many CAIs, such as acetazolamide, zonisamide, topiramate, lacosamide, and levetiracetam are successfully used in cerebral pathologies. To improve the efficacy, selectivity, and to minimize the side effects, the bespoke medications are engineered using "one-tail approach" and their pharmacological mechanisms of actions are elucidated.

The acetazolamide challenge test is frequently performed to evaluate cerebral blood flow and reserve capacity in cerebrovascular disease. Most of its side effects are mild and transient. Acute pulmonary edema (PE) has never been reported to occur after acetazolamide challenge tests. Here, we present a case of acute noncardiogenic PE triggered by an acetazolamide challenge test. A 62-year-old man with carotid artery stenosis underwent an acetazolamide challenge test during an arterial spin labeling (ASL) magnetic resonance (MR) imaging study. The patient showed stable vital signs and no neurologic abnormalities. The patient had no pulmonary or cardiac problems that could induce acute PE. Routine laboratory findings, electrocardiography, and chest X-ray also produced normal findings. An acetazolamide challenge ASL MR study was performed with intravenous administration of 1 g of acetazolamide. Two hours after acetazolamide administration, sudden dyspnea and hypoxemia developed, and chest X-ray and computed tomography revealed diffuse PE. Immediately, the oxygen supply and furosemide treatment were initiated. The following day, the dyspnea and PE improved and the patient recovered completely. To the best of our knowledge, this is the first case report of acute noncardiogenic PE triggered by intravenous acetazolamide administration in an acetazolamide challenge test.

Hypervitaminosis A is relatively uncommon but may develop with excessive supplementation or medication use. We report a 17-year-old non-obese male presenting with symptomatic papilloedema and normal neuroimaging. Investigations excluded alternative causes, but a detailed history identified that he used a protein supplement containing significant amounts of vitamin A. Although there are potential confounding factors, the combination of the clinical presentation, deranged liver function tests, resolution following the diagnostic lumbar puncture, starting acetazolamide and stopping the supplements supported a diagnosis of vitamin A-induced intracranial hypertension. With the rising global use of dietary supplements, clinicians should routinely enquire about over-the-counter products in people with unexplained intracranial hypertension to reduce avoidable investigations, prolonged treatments and risk of visual morbidity.

Therapeutics for acute mountain sickness (AMS) remain limited, with no new drugs introduced since acetazolamide over half a century ago. Recently, H0802, whose target protein was unknown, was an FGF21 and GDF15 mRNA Expression regulator with promising anti-hypoxic effects. Given that FGF21 and GDF15 have been identified as key factors in hypoxia-related metabolic reprogramming, this study proposes a drug-discovery approach based on the RNA-regulation phenotypes of FGF21 and GDF15 to explore the structure-activity relationship of H0802. We designed and synthesized 28 new compounds and tested them on primary liver cells using mRNA expression of FGF21 and GDF15 as indicators. YXX0237 and YXX0248 emerged as the most promising candidates. They significantly increased FGF21 and GDF15 levels both in vitro and in vivo, thereby enhancing mice's hypoxia tolerance in closed hypoxia experiments. Preliminary safety tests showed that YXX0237 and YXX0248 have favorable safety profiles, with low cytotoxicity within the effective dose range, and their LD50 values in mice exceed 500 mg/kg. Pharmacokinetic studies revealed that YXX0237 has higher bioavailability than YXX0248, enters the bloodstream quickly, and maintains stable exposure. Overall, this research offers a new strategy for developing small molecules that enhance hypoxia tolerance by inducing the expression of FGF21 and GDF15. Structure-activity relationship analysis provides a foundation for further structural optimization of H0802 derivatives. YXX0237 could be a potential candidate for treating hypoxia-related diseases.

Intracranial hypertension can mimic acute meningitis, especially in immunosuppressed patients presenting with fever and meningism, often prompting urgent empirical treatment. Distinguishing infectious from non-infectious causes is crucial to avoid unnecessary antimicrobials and delayed diagnosis. We report a 20-year-old woman with systemic lupus erythematosus on rituximab and a recent corticosteroid taper who presented with fever, severe headache, photophobia, and neck stiffness. She was started on empirical antibiotics for suspected meningitis. Lumbar puncture showed a markedly raised opening pressure (43 cm H2O) with otherwise normal cerebrospinal fluid (CSF). Neuroimaging excluded structural lesions and cerebral venous sinus thrombosis, while ophthalmologic examination confirmed papilloedema. Her symptoms improved after a therapeutic lumbar puncture and acetazolamide. This case highlights the value of measuring CSF opening pressure and reconsidering the diagnosis in immunosuppressed patients with meningitic features.

Infants and children with KMT2A::AFF1+ leukemia have a dismal prognosis and are therefore in urgent need for more efficient and less aggressive therapy. In this study, we investigated three microRNAs that are downregulated in KMT2A::AFF1+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL): miR-194, miR-99b, and miR-125a-5p. When overexpressed, all three microRNAs impaired the survival of KMT2A::AFF1+ leukemic blasts and the maintenance of KMT2A::AFF1+ BCP-ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in KMT2A::AFF1+ BCP-ALL: CA5B, PPP3CA, and PPP2R5C. Importantly, using a drug-repurposing approach, we found that inhibition of CA5B, PPP3CA, and PP2A by acetazolamide, tacrolimus, and LB-100, respectively, showed high toxicity toward KMT2A::AFF1+ leukemic blasts and reduced leukemia burden in vivo. Furthermore, acetazolamide was able to prolong the survival of patient-derived xenotransplant models in combination with infant ALL induction therapy. This study highlights how the unique microRNA expression signature of patients with KMT2A::AFF1+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing. It also indicates potential new drug combinations for less toxic chemotherapy.

Pediatric pseudotumor cerebri syndrome (PTCS) is an uncommon cause of raised intracranial pressure in children. We report a case of PTCS temporally associated with standard-dose oral N-acetylcysteine (NAC). A 6-year-old boy (20 kg) presented with 1 week of worsening nocturnal headaches, vomiting, and photophobia. Examination revealed bilateral optic disc swelling. Brain magnetic resonance imaging and magnetic resonance venography were normal. Lumbar puncture showed an opening pressure of 80 cm H2O and normal cerebrospinal fluid composition. The patient had been treated with oral NAC 200 mg twice daily for 4 weeks before symptom onset. Acetazolamide and topiramate were started with no improvement; symptoms and papilledema improved rapidly within 24 hours of NAC discontinuation. The patient remained asymptomatic at 6 months of follow-up. This case suggests a possible association between therapeutic-dose NAC and intracranial hypertension. Clinicians should consider medication-induced PTCS in children who present with new-onset headaches and papilledema. Further pharmacovigilance and reporting are warranted.

Background and Clinical Significance: Acetazolamide is routinely used post-cataract surgery to prevent intraocular pressure (IOP) spikes. Rare non-cardiogenic pulmonary edema (NCPE) cases highlight its risks in elderly comorbid patients. This report details acetazolamide-induced NCPE and provides a review of current evidence from the literature. Case Presentation: A 74-year-old male with chronic kidney disease, atrial fibrillation, and aortic aneurysm repair received 250 mg oral acetazolamide post-cataract extraction. Clinical, imaging, and lab data were documented during Intensive Care Unit (ICU) stay. PubMed/Google Scholar review identified similar cases. Within 30 min, severe hypoxemia with SpO2 (peripheral oxygen saturation) of 77%, accompanied by tachypnea and hypertension, necessitated endotracheal intubation. Echocardiography showed preserved left ventricular (LV) function; computed tomography (CT) confirmed bilateral alveolar opacities without cardiomegaly or embolism, indicating permeability-mediated NCPE. Lung-protective mechanical ventilation and vasopressor therapy resulted in hemodynamic and respiratory stabilization. On day 4, ventilator-associated pneumonia (VAP) due to Acinetobacter baumannii resolved with targeted antibiotic therapy. The patient made a full recovery following ICU discharge. To date, nine prior cases have been reported, alongside 31 entries in EudraVigilance reflecting a 19.4% mortality rate. Conclusions: Rapid-onset NCPE from acetazolamide involves endothelial injury, distinct from cardiogenic pulmonary edema. Early recognition, drug cessation, and admission to the intensive care unit (ICU) are vital components of therapeutic intervention. Risk stratification and pharmacovigilance are recommended for perioperative safety.