Acute high-altitude hypoxia (AHH) disrupts systemic homeostasis and alters the pharmacokinetic (PK) profiles of drugs, yet the role of the organic anion transport network in mediating altered drug disposition and the link to regulation by the Remote Sensing and Signaling Theory remain unclear. Moreover, the underlying mechanisms governing the PK of acetazolamide (ACZ), an FDA-approved therapeutic agent for high-altitude illness, remain unelucidated. This study aimed to clarify the effects of AHH on the PK of ACZ, identify the organic anion transport network involved, and characterize perturbations in renal metabolism. Results demonstrated that AHH markedly altered ACZ PK: with a 3.27-fold increase in AUC0-∞ and a 2.62-fold prolongation in t1/2. For the first time, ACZ was confirmed as a specific substrate of organic anion transporter 1, multidrug resistance-related protein (MRP4), and breast cancer resistance protein. Mechanistically, AHH dysregulated these transporters, including upregulating breast cancer resistance protein, downregulating organic anion transporters, organic anion transporting polypeptides, MRPs, and P-glycoprotein via transcriptional regulation of nuclear receptors (hypoxia-inducible factor-1α, Pregnane X receptor, constitutive androstane receptor, and hepatocyte nuclear factor-4α), a finding validated in acute hypoxic Caco-2 cells and AHH rat models. Renal metabolomics further revealed profound perturbations in organic anion metabolism, notably, indoxyl sulfate, hippuric acid, and kynurenic acid were decreased by 56.84%, 88.53%, and 69.77%, respectively, whereas estrone glucuronide was elevated 4.78-fold, and these 4 metabolites were identified as novel renal tissue-specific biomarkers of AHH-induced renal organic anion transport network dysfunction. Collectively, this study elucidates organic anionic drug disposition mechanisms under AHH, validates Remote Sensing and Signaling Theory by linking organic anion transport network to drug metabolism crosstalk, and provides evidence for personalized pharmacotherapy of high-altitude sickness. SIGNIFICANCE STATEMENT: This study uncovers how acute high-altitude hypoxia dysregulates the organic anion transport network to disrupt acetazolamide (ACZ) disposition and renal metabolic homeostasis. It first identifies ACZ as an organic anion transporter 1/multidrug resistance-related protein 4/breast cancer resistance protein substrate and defines indoxyl sulfate, hippuric acid, kynurenic acid, and estrone glucuronide as endogenous renal tissue-specific biomarkers for organic anion transport network dysfunction. Filling the gap in understanding acute high-altitude hypoxia-mediated organic anion transport network regulation, this work validates the Remote Sensing and Signaling Theory and provides critical insights for optimizing ACZ pharmacotherapy and exploring metabolic homeostasis in high-altitude environments.

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.