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Glaucoma, a leading cause of irreversible blindness, affects about 70 million people globally. Its treatment focuses on reducing intraocular pressure. Acetazolamide, a potent anti-glaucoma drug, is currently used only systemically due to low solubility and permeation, which cause severe side effects. Developing topical medications with acetazolamide requires robust analytical methods for its detection in biological samples. In this context, this study aimed to develop a method to quantify acetazolamide in rabbit vitreous humor samples. The method involved a simple, fast, inexpensive, and environmentally friendly protein precipitation step for sample preparation, needing just 50 μL of sample and 200 μL of organic solvent, with adequate recovery. This was combined with high-performance liquid chromatography coupled to tandem mass spectrometry, enabling highly sensitive (LOQ of 5 ng/mL) quantification within only 5 min. The method proved to be selective, precise, and accurate, with well-fitted analytical curves, with no carryover, and no matrix effect impacting reliability. The method was successfully applied to analyze vitreous humor samples from rabbits in pharmacokinetic studies, monitoring drug release from intravitreal implants. Results showed a controlled release profile, with a maximum drug concentration (Cmax) of 426.01 ± 64.57 ng/mL, time to reach Cmax (Tmax) of 28 days, and area under the curve (AUC0-42 and AUC0-∞) of 7722.66 ± 1125.96 ng days/mL and 8998.11 ± 1311.92 ng days/mL, respectively. The device demonstrated significantly slower elimination, ensuring therapeutic levels for an extended period when compared to intravitreal injection., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christian Fernandes reports financial support was provided by Coordination of Higher Education Personnel Improvement, National Council for Scientific and Technological Development and Minas Gerais State Foundation of Support to the Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute mountain sickness (AMS) occurs due to rapid altitude ascents and/or insufficient acclimatization. Acetazolamide (AZ) is commonly prescribed for AMS prophylaxis but inhibits exercise performance. Methazolamide (MZ), an analogous drug, has similar prophylactic benefits but does not impair isolated muscle mass exercise performance in normoxia. We sought to compare whole body exercise performance in acute hypoxia (fraction of inspired oxygen, [Formula: see text] = 0.15) between AZ, MZ, and placebo (PLA). Fifteen healthy participants completed five testing visits: day 1 for maximal exercise test, day 2 for familiarization, and days 3 - 5 were the experimental visits. Each experimental visit involved a 5-km hypoxic cycling time trial (TT) performed after a 2-day dosing protocol of either AZ (250 mg three times a day), MZ (100 mg twice a day), or PLA (three times a day); the order was randomized and double-blinded. Before exercise, capillary blood samples were taken, and maximal voluntary contractions of quadriceps were performed. AZ and MZ resulted in a partially compensated metabolic acidosis at rest compared with PLA [capillary hydrogen ions (H + ) 47 ± 3, 43 ± 2, and 39 ± 2 nmol for AZ, MZ, and PLA respectively, P < 0.01]. Time to complete 5 km with PLA (562 ± 32 s, P < 0.01) was significantly faster than AZ and MZ (577 ± 38 vs. 581 ± 37 s, respectively), with no differences between AZ and MZ ( P = 0.96). There were no differences in average ventilation (124 ± 27, 127 ± 24, 127 ± 19 L/min) and oxyhemoglobin saturation (87 ± 2, 88 ± 2, 88 ± 3%) between AZ, MZ, and PLA, respectively ( P > 0.05). Overall, both AZ and MZ impair whole body exercise performance in acute normobaric hypoxia. NEW & NOTEWORTHY Administration of acetazolamide (AZ) and methazolamide (MZ) both resulted in a significantly slower 5-km time trial in acute normobaric hypoxia compared with a placebo. Both drugs lead to a partially compensated metabolic acidosis, but ventilation and oxyhemoglobin saturation were not different across the conditions. Overall, acetazolamide and methazolamide both impaired whole body exercise performance in acute normobaric hypoxia but potentially have different mechanisms of action.

This study aims to formulate and evaluate Eudragit nanoparticles-laden hydrogel contact lenses for controlled delivery of acetazolamide (ACZ) using experimental design. Eudragit S-100 was selected for the preparation of nanoparticles. The optimization of Eudragit S100 concentration (X1), polyvinyl alcohol concentration (X2), and the sonication time (X3) was attempted by applying a central composite experimental design. Mean size of nanoparticles (nm), percent in vitro drug release and drug leaching from the ACZ-ENs laden contact lens were considered as dependent variables. Nanoparticles-laden contact lens was prepared through the direct loading method and characterized. Optimum check-point formulation was selected based on validated quadratic polynomial equations developed using response surface methodology. The optimized formulation of ACZ-ENs exhibited spherical shape with a size of 244.3 nm and a zeta potential of -13.2 mV. The entrapment efficiency of nanoparticles was found to be 82.7 ± 1.21%. Transparent contact lenses loaded ACZ-ENs were successfully prepared using the free radical polymerization technique. ACZ-ENs incorporated in contact lens exhibited a swelling of 83.4 ± 0.82% and transmittance of 80.1 ± 1.23%. ACZ-ENs showed a significantly lower burst release of the drug when incorporated in the contact lens and release was sustained over a period of 24 h. The sterilized formulation of ACZ-ENs laden contact lens did not show any sign of toxicity in rabbit eyes. ACZ-ENs incorporated in contact lens could be considered as a potential alternative in glaucoma patients due to their ability to provide sustained drug release and thus enhance patient compliance.

Background: Topiramate is often considered as a second-line medication for the treatment of pseudotumor cerebri syndrome (PTCS), but limited studies exist that evaluate its efficacy in children., Methods: Retrospective study of patients aged <21 years with PTCS who were treated with topiramate alone or in combination with acetazolamide was performed. Data regarding clinical courses and visual outcomes were recorded., Results: A total of 46 patients were identified. Three (6.5%) patients were treated with topiramate alone, 31 (67.4%) transitioned to topiramate from acetazolamide, and 12 (26.1%) took both topiramate and acetazolamide concurrently. The median time to resolution of papilledema on topiramate was 0.57 years (interquartile range 0.32 to 0.84). Among eyes with papilledema graded on the Frisen scale at topiramate initiation, 40 of 57 (70.2%) were grade 1, nine of 57 (15.8%) were grade 2, and eight of 57 (14.0%) were grade 3. Twenty-seven of 46 (58.7%) reported headache improvement after starting topiramate. The mean dose of topiramate was 1.3 ± 0.8 mg/kg/day. The most common side effect was patient report of cognitive slowing (10 of 46 [21.7%]). All patients on topiramate monotherapy who were compliant with treatment and follow-up had resolution of papilledema with no evidence of visual function loss., Conclusions: Topiramate can effectively treat PTCS in children with mild to moderate papilledema or in those unable to tolerate acetazolamide. More research is needed to assess the efficacy of topiramate for higher grade papilledema., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Breast cancer treatment has been a global puzzle, and targeted strategies based on the hypoxic tumor microenvironment (TME) have attracted extensive attention. As a signature transcription factor overexpressed in hypoxia tumor, hypoxia-inducible factor-1 (HIF-1) contribute to cancer progression. Compound 7-(3-(2-chloro-1H-benzo[d]1midazole-1-yl) propoxy)-2-(3,4,5-trime-thoxyphenyl)-4H-chromen-4-one, synthesized and named FB15 in our earlier research, a potential inhibitor of HIF-1α signaling pathway, has been proved a promising drug candidate for many kinds of cancer chemotherapy. However, the poor solubility and undesirable pharmacokinetics of FB15 leads to limited treatment efficacy of tumor, which ultimately restricts its potential clinical applications. Carbonic anhydrase IX (CAIX), a tumor cell transmembrane protein, was overexpressed in hypoxia tumor site. Acetazolamide (AZA), a highly selective ligand targeting CAIX, can be utilized to delivery FB15 to hypoxia tumor site., Methods: In this study, we prepared and characterized FB15 loaded nano-mixed micelles with the AZA conjugated poloxamer 188 (AZA-P188) and D-a-Tocopherol Polyethylene 1000 Glycol Succinate (TPGS), denoted as, AZA-P188/TPGS@FB15. Its delivery efficiency in vitro and in vivo was assessed by in vitro drug release, cytotoxicity assay, cellular uptake, and in vivo pharmacokinetics and fluorescence imaging. Finally, therapeutic effect of AZA-P188/TPGS@FB15 was investigated using a preclinical breast cancer subcutaneous graft model in vivo., Results: In vitro studies revealed that AZA-P188/TPGS@FB15 could efficiently target breast cancer cells mediated by CAIX receptor, trigger FB15 release in response to acidic condition, and enhance cellular uptake and cytotoxicity against breast cancer cells. The pharmacokinetic studies showed that FB15-loaded AZA-functionalized micelles exhibited significantly increased AUC 0-t over free FB15. In vivo imaging demonstrated that AZA-functionalized micelles significantly increased the drug distribution in the tumor site. In vivo experiments confirmed that AZA-P188/TPGS@FB15 exhibited superior inhibition of tumor growth in nude mice with good biosafety., Conclusion: AZA-P188/TPGS@FB15 hold promise as a potentially effective therapeutic way for breast cancer. Its targeted delivery system utilizing AZA as a carrier shows potential for improving the efficacy of FB15 in cancer therapy., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Liu et al.)

Central Retinal Artery Occlusion (CRAO) is a serious ophthalmic emergency characterized by sudden, painless vision loss in one eye. This condition leads to rapid and significant visual impairment if not treated promptly. This case illustrates an adult man with hypertension presented with unilateral, painless, sudden vision loss occurring 13 hours before admission. Examination revealed a visual acuity of 1-meter counting finger in the affected eye, a cherry red spot, and a pale retina. Diagnosed with CRAO, immediate interventions included ocular massage, and acetazolamide loading alongside systemic antihypertensive medication. Visual acuity improved significantly, with the patient able to see 5/30 on the nasal side and can maintain this visual acuity until 6 months follow-up. Immediate and aggressive treatment for CRAO can lead to significant visual recovery even when initiated beyond the traditionally recommended time frame, underscoring the need for quick recognition and intervention in CRAO cases., Competing Interests: The authors declare no competing interests., (Copyright: Muhammad Indra Mahardika Iridika Humeri et al.)

A woman in her mid-60s who is a high hypermetrope presented with bilateral eye pain and headache approximately 1 hour after taking a single dose of a widely available decongestant containing paracetamol, guaifenesin and phenylephrine hydrochloride for coryzal symptoms. She had previous successful bilateral peripheral iridotomies performed for narrow angles. At presentation, her intraocular pressures (IOPs) were significantly raised at 72 mm Hg and 66 mm Hg in the right and left eye, respectively, with bilateral corneal oedema. Her IOP was normalised with urgent treatment using 500 mg intravenous acetazolamide, pilocarpine 2%, dexamethasone 0.1% and IOP-lowering drops. She was listed for cataract surgery and was advised to avoid the precipitating agent and other over-the-counter decongestants. This is the first reported case of bilateral angle closure triggered by a decongestant with such a combination of ingredients. Clinicians should be aware of this rare side effect for prompt diagnosis and management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The complex structure of the eye poses challenges in delivering drugs effectively, which can be circumvented by employing nanotechnologies. The present study aimed to prepareacetazolamide-loadedleciplex (ACZ - LP) using a simple one-step fabrication approach followed byoptimization employing a 3 2 Full Factorial Design. The ACZ - LP demonstrated high entrapment efficiency (93.25 ± 2.32 %), average diameter was recorded around 171.03 ± 3.32 with monodisperse size distribution and zeta potential of 41.33 ± 2.10 mV. Invitro release and ex vivo permeation studies of prepared formulation demonstrated an initial burst release in 1 h followed by sustained release pattern as compared to plain acetazolamide solution. Moreover, an ex vivo corneal drug retention (27.05 ± 1.20 %) and in vitro mucoadhesive studies with different concentration of mucin indicated strong electrostatic bonding confirming the mucoadhesive characteristics of the formulation. Additionally, the histopathological studies ensured that the formulation was non-irritant and nontoxic while and HET-CAM ensured substantial tolerability of the formulation. The in vivo pharmacodynamic investigation carried out on a rabbit model demonstrated that treatment with ACZ - LP resulted in a significant and prolonged reduction in intraocular pressure as compared to plain acetazolamide solution, acetazolamide oral tablet, and Brinzox®. In summary, the ACZ - LP is anefficient and versatile drug delivery approach which demonstrates significant potential in controlling glaucoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Limited evidence exists regarding efficacy and safety of diuretic regimens in ambulatory, congestion-refractory, chronic heart failure (CHF) patients., Objectives: The authors sought to compare the potency and safety of commonly used diuretic regimens in CHF patients., Methods: A prospective, randomized, open-label, crossover study conducted in NYHA functional class II to IV CHF patients, treated in an ambulatory day-care unit. Each patient received 3 different diuretic regimens: intravenous (IV) furosemide 250 mg; IV furosemide 250 mg plus oral metolazone 5 mg; and IV furosemide 250 mg plus IV acetazolamide 500 mg. Treatments were administered once a week, in 1 of 6 randomized sequences. The primary endpoint was total sodium excretion, and the secondary was total urinary volume excreted, both measured for 6 hours post-treatment initiation., Results: A total of 42 patients were recruited. Administration of furosemide plus metolazone resulted in the highest weight of sodium excreted, 4,691 mg (95% CI: 4,153-5,229 mg) compared with furosemide alone, 3,835 mg (95% CI: 3,279-4,392 mg; P = 0.015) and to furosemide plus acetazolamide 3,584 mg (95% CI: 3,020-4,148 mg; P = 0.001). Furosemide plus metolazone resulted in 1.84 L of urine (95% CI: 1.63-2.05 L), compared with 1.58 L (95% CI: 1.37-1.8); P = 0.039 collected following administration of furosemide plus acetazolamide and 1.71 L (95% CI: 1.49-1.93 L) following furosemide alone. The incidence of worsening renal function was significantly higher when adding metolazone (39%) to furosemide compared with furosemide alone (16%) and to furosemide plus acetazolamide (2.6%) (P < 0.001)., Conclusions: In ambulatory CHF patients, furosemide plus metolazone resulted in a significantly higher natriuresis compared with IV furosemide alone or furosemide plus acetazolamide., Competing Interests: Funding Support and Author Disclosures Dr Abbo has been a consultant for Edwards Life Sciences; and has received speaker honoraria from Boehringer Ingelheim. Dr Kristensen has been a consultant for Bayer; and has received speaker honoraria from AstraZeneca. Dr Caspi has received speaker honoraria from AstraZeneca, Novo Nordisk, and Pfizer; and has received consultancy honoraria from Vectorious medical technologies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Idiopathic intracranial hypertension (IIH) is a disorder that primarily affects obese women of reproductive age. The exact pathogenesis of IIH is unknown though multiple etiologies have been proposed., Case Presentation: We report a case of IIH triggered by first-time Ramadan intermittent fasting (RIF) in an 18-year-old woman. Our patient developed new onset headaches, diplopia, and pulsatile tinnitus with examination notable for bilateral papilledema and lumbar puncture revealing an elevated opening pressure. Her symptoms resolved after cessation of RIF, apart from persistent left sided tinnitus which later resolved with acetazolamide administration., Conclusion: This case report uniquely illustrates that RIF may provoke symptomatic IIH. We hypothesize that a decreased concentration of glucagon-like peptide-1 (GLP-1) induced by fasting results in decreased GLP-1 receptor activation in the choroid plexus, allowing for increased CSF secretion into the ventricles invoking increased intracranial pressure (ICP). This theoretical mechanism provides further insight as to the possible underlying pathophysiology of IIH.

Background: The carbonic anhydrase inhibitor acetazolamide stimulates ventilation through metabolic acidosis mediated by renal bicarbonate excretion. In animal models, acetazolamide attenuates acute hypoxia-induced pulmonary hypertension (PH), but its efficacy in treating patients with PH due to pulmonary vascular disease (PVD) is unknown., Methods: 28 PVD patients (15 pulmonary arterial hypertension, 13 distal chronic thromboembolic PH), 13 women, mean±SD age 61.6±15.0 years stable on PVD medications, were randomised in a double-blind crossover protocol to 5 weeks acetazolamide (250mg b.i.d) or placebo separated by a ≥2 week washout period. Primary endpoint was the change in 6-minute walk distance (6MWD) at 5 weeks. Additional endpoints included safety, tolerability, WHO functional class, quality of life, arterial blood gases, and hemodynamics (by echocardiography)., Results: Acetazolamide had no effect on 6MWD compared to placebo (treatment effect: mean change [95%CI] -18 [-40 to 4]m, p=0.102) but increased arterial blood oxygenation through hyperventilation induced by metabolic acidosis. Other measures including pulmonary hemodynamics were unchanged. No severe adverse effects occurred, side effects that occurred significantly more frequently with acetazolamide vs. placebo were change in taste (22/0%), paraesthesia (37/4%) and mild dyspnea (26/4%)., Conclusions: In patients with PVD, acetazolamide did not change 6MWD compared to placebo despite improved blood oxygenation. Some patients reported a tolerable increase in dyspnoea during acetazolamide treatment, related to hyperventilation, induced by the mild drug-induced metabolic acidosis. Our findings do not support the use of acetazolamide to improve exercise in patients with PVD at this dosing., Gov Identifier: NCT02755298., Competing Interests: Conflicts of interest None of the authors report any conflict of interest in direct relation to this manuscript. Prof. Dr. med. S. Ulrich reports grants from Johnson and Johnson SA, Switzerland, during the conduct of the study; grants from Zurich Lung, grants from Orpha Swiss, personal fees from Actelion SA, Switzerland, personal fees from MSD Switzerland, outside the submitted work. Dr. Swenson reports that he has a patent: METHODS OF TREATING PULMONARY DISEASE USING ACETAZOLAMIDE AND STRUCTURALLY RELATED DERIVATIVES issued by the US government with the the patent designation US Patent No. 8,614,236, (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Morning glory disc anomaly is a rare congenital anomaly affecting the optic disc and is frequently associated with retinal detachment. This report presents a unique case of a 10-year-old boy with morning glory disc anomaly and serous retinal detachment, treated with oral acetazolamide. Remarkably, half of the retina exhibiting bullous detachment was reattached leading to full recovery of vision within a few days after starting acetazol-amide treatment. There was no recurrence after discontinuation of medication. Oral acetazolamide can be considered an alternative treatment option for retinal detachment associated with morning glory disc anomaly of non-rhegmatogenous origin. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:415-417.] .

Glaucoma, the second most common cause of blindness worldwide, requires the development of new and effective treatments. This study introduces a novel controlled-release system utilizing elastin-like recombinamers (ELR) and the Supercritical Antisolvent (SAS) technique with supercritical CO2. Acetazolamide (AZM), a class IV drug with limited solubility and permeability, is successfully encapsulated in an amphiphilic ELR at three different ELR:AZM ratios, yielding up to 62 %. Scanning electron microscopy (SEM) reveals spherical microparticles that disintegrate into monodisperse nanoparticles measuring approximately 42 nm under physiological conditions. The nanoparticles, as observed via Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM), do not exhibit aggregates, a fact confirmed by the zeta potential displaying a value of -33 mV over a period of 30 days. Transcorneal permeation tests demonstrate a 10 % higher permeation level compared to the control solution, which increases to 30 % after 2 h. Ocular irritation tests demonstrate no adverse effects or damage. Intraocular pressure (IOP) tests conducted on hypertensive rabbits indicate greater effectiveness for all three analyzed formulations, suggesting enhanced drug bioavailability during treatment. Consequently, the combination of recombinant biopolymers and high-pressure techniques represents a promising approach for advancing glaucoma therapy, emphasizing its potential clinical significance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Urine alkalization is one of the standard treatments to prevent acute kidney injury in patients receiving high-dose methotrexate. Carbonic anhydrase inhibitors are promising adjuvants/substitutes with advantages such as faster urine alkalization time and prevention of fluid overload. However, there is limited and contradictory evidence on its efficacy and safety. We aimed to compare the efficacy and safety of carbonic anhydrase inhibitors to standard treatments in adult patients receiving high-dose methotrexate., Methods: The protocol was registered at PROSPERO (CRD42022352802) in August 2021. We evaluated the use of carbonic anhydrase inhibitors in combination with standard treatment compared to standard treatment alone. We excluded articles irrelevant to the efficacy and safety of acetazolamide in patients receiving high dose methotrexate and/or did not provide sufficient data regarding doses, recruitment criteria, and follow-up period. Two authors performed the data extraction independently., Results: Among 198 articles retrieved, six observational studies met all eligibility criteria. Four studies with five datasets (totaling 558 patients/cycles) had enough data to be included in the meta-analysis. We independently report the results from the two remaining studies. The results did not show a significant difference between acetazolamide versus standard treatment in acute kidney injury (AKI) rate (OR = 0.79, 95% CI 0.48-1.29, P = 0.34, I 2  = 0%). Regarding the time to urine pH goal, there was no significant time difference between the two groups (Mean Difference = 0.07, 95% CI - 1.9 to 2.04, P = 0.95, I 2  = 25%). Furthermore, our meta-analysis showed that acetazolamide did not reduce length of stay (Mean Difference = 0.75, 95% CI - 0.8 to 2.31, P = 0.34, I 2  = 0%). In one study, the only reported side effect of acetazolamide was hypokalemia (nearly 50% in the acetazolamide group)., Conclusions: This systematic review showed no significant difference between acetazolamide and standard care treatment regarding urine alkalinization time and AKI rate in adult patients receiving high dose methotrexate. We suggest performing a large blinded, randomized, controlled trial to evaluate the potential benefits of this low-cost medication., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

We report the case of a 32-year-old male who presented with an acute myopic shift as a result of uveal effusion following a single administration of 250 mg acetazolamide. The drug was discontinued and following cycloplegia and topical steroid therapy, we observed progressive deepening of the anterior chamber, reopening of the iridocorneal angle, and complete resolution of the myopic shift after 5 days. A literature review since 1956 identified 23 cases, including ours, which developed a myopic shift after a median time of 24 h (3 - 24) following a median dose of 500 mg (125 - 1000) acetazolamide, with about a third complicated by angle closure ocular hypertension. This presumed idiosyncratic reaction can occur without prior drug exposure and independent of the phakic status. Treatment options include systematic drug withdrawal associated with cycloplegia, anti-glaucomatous agents, and/or corticosteroids. Full recovery is achieved within about 5 days (2 - 14). Given the widespread use of acetazolamide, awareness of this idiosyncratic reaction is crucial to avoid complications of acute angle-closure glaucoma., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Recent evidence suggests that acetazolamide may be beneficial as an adjunctive diuretic therapy in patients with acute decompensated heart failure (HF). We aim to pool all the studies conducted until now and provide updated evidence regarding the role of acetazolamide as adjunctive diuretic in patients with acute decompensated HF., Methods: PubMed/Medline, Cochrane Library, and Scopus were searched from inception until July 2023, for randomized and nonrandomized studies evaluating acetazolamide as add-on diuretic in patients with acute decompensated HF. Data about natriuresis, urine output, decongestion, and the clinical signs of congestion were extracted, pooled, and analyzed. Data were pooled using a random effects model. Results were presented as risk ratios (RRs), odds ratios (ORs), or weighted mean differences (WMD) with 95% confidence intervals (95% CIs). Certainty of evidence was assessed using the grading of recommendation, assessment, development, and evaluation (GRADE) approach. A P value of < 0.05 was considered significant in all cases., Results: A total of 5 studies (n = 684 patients) were included with a median follow-up time of 3 months. Pooled analysis demonstrated significantly increased natriuresis (MD 55.07, 95% CI 35.1-77.04, P < 0.00001; I 2 = 54%; moderate certainty), urine output (MD 1.04, 95% CI 0.10-1.97, P = 0.03; I 2 = 79%; moderate certainty) and decongestion [odds ratio (OR) 1.62, 95% CI 1.14-2.31, P = 0.007; I 2 = 0%; high certainty] in the acetazolamide group, as compared with controls. There was no significant difference in ascites (RR 0.56, 95% CI 0.23-1.36, P = 0.20; I 2 = 0%; low certainty), edema (RR 1.02, 95% CI 0.52-2.0, P = 0.95; I 2 = 45%; very low certainty), raised jugular venous pressure (JVP) (RR 0.86, 95% CI 0.63-1.17, P = 0.35; I 2 = 0%; low certainty), and pulmonary rales (RR 0.82, 95% CI 0.44-1.51, P = 0.52; I 2 = 25%; low certainty) between the two groups., Conclusions: Acetazolamide as an adjunctive diuretic significantly improves global surrogate endpoints for decongestion therapy but not all individual signs and symptoms of volume overload., Systematic Review Registration: This systematic review was prospectively registered on the PROSPERO ( https://www.crd.york.ac.uk/PROSPERO/ ), registration number CRD498330., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Consider IV Acetazolamide in addition to standard IV loop diuretic therapy in patients hospitalized for acute decompensated heart failure. 1 ., Competing Interests: Conflict of interest: Dr. Ge has served as a consultant for CSL Seqirus., (Copyright © 2024 by Family Physicians Inquiries Network, Inc.)

Primary intracranial hypertension (PIH) is characterized by clinical signs of increased intracranial pressure, papilledema, elevated opening pressure, and absence of mass lesion, hydrocephalus, or meningeal enhancement on neuroimaging. Visual changes are a common presenting feature and if untreated there is risk of irreversible vision loss. There have been recent proposed changes to the criteria for PIH along with studies looking at the differences in imaging characteristics between adult and pediatric PIH. The presence of transverse sinus stenosis alone was highly sensitive and specific for pediatric PIH. The Idiopathic Intracranial Hypertension Treatment Trial was an adult, multicenter study that examined the use of acetazolamide and weight loss on the course of PIH. The study confirmed many previously held beliefs including the most common presenting symptom in PIH is headache. Most patients present with bilateral papilledema with 58.2% of patients having symmetric Frisen scale grading and within one grade in 92.8%. Although diplopia is a common reported symptom, very few have evidence of cranial nerve palsy. Male gender, high-grade papilledema, and decreased visual acuity at presentation are risk factors for treatment failure. Acetazolamide use is associated with mild metabolic acidosis. During acetazolamide treatment, monitoring for hypokalemia or aplastic anemia is not recommended. Monitoring transaminases in the titration phase of treatment should be considered due to a case of transaminitis and pancreatitis with elevated lipase. Newer case reports have also seen associations of secondary intracranial hypertension with concurrent COVID-19 infection and MIS-C., Competing Interests: Conflict of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction : Systemic acetazolamide is an efficacious adjunct to topical therapy to lower intraocular pressure (IOP) in glaucomatous eyes. This article aims to provide a comprehensive review for how best to use the agent in ophthalmic practice. Areas covered : This article will review the history, mechanism of action, methods of observing efficacy, indications for IOP lowering, side effects, allergy information including discussion of limited cross-reactivity between antimicrobial and non-antimicrobial sulfonamides, formulations, dosing and monitoring of acetazolamide. To select articles for this review, an electronic search was conducted using the PubMed database and cross-referencing was conducted for relevant literature. Expert opinion : The benefits of oral carbonic anhydrase inhibitor therapy can outweigh the risks in many circumstances. It is important that eye care practitioners work together with a patient's primary care practitioner to monitor for and mitigate risks. Greater education is needed with regard to the allergy profile of these powerful agents. Though not often a first-line option, oral carbonic anhydrase inhibitors remain pivotal and play in important role in delivery of eye care.

Rationale: Metastasis of neoplasms to the eye is quite uncommon. In this case report, we describe a patient where primary esophageal cancer was diagnosed by fine needle aspiration biopsy (FNAB) of an iris tumor., Patient Concerns: A 70-year-old male complained of redness and discomfort in the right eye., Diagnosis and Interventions: The patient's right eye was diagnosed as idiopathic uveitis, and a topical steroid was administered. As vitreous opacities were observed even after topical therapy, oral prednisolone was administered. On slit-lamp examination of the right eye, an iris mass with neovascularization was seen in the anterior chamber. A metastatic tumor was suspected, and FNAB was performed. Histology revealed squamous cell carcinoma. Systemic workup revealed esophageal cancer with several metastases. Best-corrected visual acuity decreased to 20/400, and intraocular pressure was 40 mmHg in the right eye. Two iris tumors with neovascularization were present extending into the anterior chamber with posterior iris synechiae and 360 degree peripheral anterior synechiae. Intraocular pressure in the right eye was medically managed with hypotensive eye drops and oral acetazolamide. Iris metastases were treated with 40 Gray of radiation therapy and concurrent chemotherapy., Outcomes: The tumor regressed, but intraocular pressure was refractory to treatment because of 360 degree goniosynechial closure. The right eye lost light perception six months after treatment commenced, and the patient died 9 months after the onset of therapy due to multiple systemic metastases., Lessons: This is a rare case of masquerade syndrome without systemic symptoms in which FNAB of an iris tumor led to a diagnosis of metastatic esophageal squamous cell carcinoma. Although the patient lost his sight due to uncontrollable ocular hypertension, systemic chemotherapy, and radiation therapy were initially effective in the treatment of the metastatic iris tumor. As the prognosis of patients with metastatic iris tumors is poor, it is important for ophthalmologists to consider such diagnoses and conduct systemic investigations when necessary., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Using N-isopropyl-p-[123I]-iodoamphetamine(123I-IMP) and single-photon emission computed tomography (SPECT), the relationship between cerebrovascular reserve and the 123I-IMP redistribution phenomenon was investigated.The 50 patients who matched the inclusion criteria were divided into control and ischemia groups, and the redistribution phenomenon was examined on resting images. The delayed images showed higher 123I-IMP accumulation in lesions in the middle cerebral artery(MCA) area and anterior cerebral artery(ACA) area, these watershed areas in the ischemia group than in the control group, confirming that the redistribution phenomenon exists with statistical significance (Wilcoxon test; control group vs ischemic group in the ACA area[P = .002], ACA-MCA watershed area(P = .014), MCA area(P = .025), and MCA-posterior cerebral artery(PCA) watershed area(P = .002). The patients were then divided into 4 types according to the Kuroda grading system, and the difference in the redistribution phenomenon was investigated between type III and the other 3 types.Compared with type I and type II, type III had a significantly lower rate of decrease in the radioisotope (RI) count, verifying the redistribution phenomenon (Student t test: type I vs type III in the ACA area(P = .008), ACA-MCA watershed area(P = .009), MCA area(P < .001), and MCA-PCA watershed area(P = .002); type II vs type III in the ACA area(P = .004), ACA-MCA watershed area(P = .2575), MCA area(P < .001), and MCA-PCA watershed area(P < .001). No significant difference between type III and type IV was observed in any area [(Student t test: type III vs type IV in the ACA area(P = .07), ACA-MCA watershed area(P = .38), MCA area(P = .05), and MCA-PCA watershed area(P = .24)].The redistribution phenomenon is associated with resting cerebral blood flow (CBF), but not necessarily with cerebral vascular reactivity (CVR)., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Spontaneous cerebrospinal fluid (CSF) leaks represent a unique subset of skull base pathology and require distinctive management. Perioperative evaluation and management of intracranial hypertension are essential in preventing further erosion of the skull base and development of recurrent leak. The objective of this study is to evaluate the safety and utility of an expedited protocol for recording and managing intracranial hypertension following endoscopic repair of spontaneous CSF leaks., Methods: Prospectively collected data was reviewed in patients undergoing endoscopic repair of spontaneous CSF leaks between January 2017 and March 2020. A standard intracranial pressure monitoring protocol was compared to an expedited protocol (EP), and data regarding the two groups was compared for leak location, short-term success of skull base repair, complications, hospital length of stay, and cost-based analysis., Results: Fifty-five patients (standard protocol, n = 28 vs. EP, n = 27) were included in the study. Leak location was similar between cohorts, with the lateral recess being the most common locations in both groups (37.9% vs. 40.6%; P = .90). Postoperative complications (3.6% vs. 7.4%; P = .53) and ventriculoperitoneal shunt rate (32.1% vs. 22.2%; P = .41) were similar among cohorts. There was no difference in lumbar drain complications (0% vs. 7.4%; P = .14) or recurrent leak (7.1% vs. 0%; P = .16). Length of stay was shorter in the EP group [median(interquartile range): 3(1) vs. 2 (1); P < .01]. Total hospital charges were similar between groups (median (USD/$1,000): 83.57 ± 49.58 vs. 83.93 ± 46.11; P = .18)., Conclusion: An expedited monitoring protocol shortened hospital stay without increased risk of complications., Level of Evidence: III Laryngoscope, 131:E408-E412, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Although ultratrail races are increasing in popularity, there is a dearth of data regarding illnesses and medical care at these events. Data about injuries and illnesses for races taking place in the Himalayas, where the nearest medical facility can be hundreds of miles away, are even harder to find. This study aimed to describe the injuries and illnesses befalling the participants of a 7-stage 212 km (132 mi) trail race at high altitude., Methods: Ethical approval was obtained from Nepal Research Health Council. A retrospective study of the record of medical encounters among the 100 participants competing in the Manaslu trail race in Nepal from 2014 to 2016 was performed. Diagnoses were classified into various categories. Informed consent was taken from all participants., Results: Acute diarrhea was the most common ailment reported among the participants (18%), followed closely by musculoskeletal problems (17%). Altitude illness made up 6% of care provided. Approximately 35% of the athletes were using acetazolamide as prophylaxis for high altitude illnesses. The 1 case needing evacuation in the 3 iterations was high altitude pulmonary edema., Conclusions: Ultratrail races at high altitude pose a challenge in terms of provision of medical care in a remote setting with limited resources. However, most of the illnesses are minor in nature and easily managed by the race doctor. Knowledge of common illnesses among travelers to the area can help aid in preparation and provision of proper care, especially in remote settings with limited resources., (Copyright © 2020 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Background: Acetazolamide is the most common medication used for acute mountain sickness prevention, with speculation that a reduced dose may be as efficacious as standard dosing with fewer side effects., Methods: This double-blind, randomized, controlled noninferiority trial compared acetazolamide 62.5 mg twice daily to the standard dose acetazolamide 125 mg twice daily starting the evening prior to ascent from 1240 m (4100 ft) to 3810 m (12,570 ft) over 4 hours. The primary outcome was acute mountain sickness incidence (ie, headache, Lake Louise Questionnaire ≥3, and another symptom)., Results: A total of 106 participants were analyzed, with 51 (48%) randomized to 125 mg and 55 (52%) to 62.5 mg, with a combined acute mountain sickness incidence of 53 (50%) and mean severity of 3 (± 2.1). The 62.5-mg group failed to fall within the prespecified 26% noninferiority margin for acute mountain sickness incidence (62.5 mg = 30 [55%] vs 125 mg = 23 [45%], 95% confidence interval [CI] -11% to 30%). Participants in the 62.5-mg group had a higher risk of acute mountain sickness (odds ratio = 1.5, 95% CI 0.7-3.2) and moderate acute mountain sickness (odds ratio = 1.8, 95% CI 0.6-5.9), with a number needed to harm (NNH) of 9, with a number needed to treat (NNT) in the 125-mg group of 4.8. Increased acute mountain sickness incidence and symptom severity corresponded to lower weight-based and body mass index dosing, with similar side effects between groups., Conclusion: Acetazolamide 62.5 mg twice daily failed to demonstrate equal effectiveness to 125 mg twice daily for prevention of acute mountain sickness. With increased risk and no demonstrable symptomatic or physiologic benefits, acetazolamide 62.5 mg twice daily should not be recommended for acute mountain sickness prevention., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Improved ocular delivery of a poorly soluble anti-glaucoma drug, acetazolamide (ACZ), in a stable nanosuspension (NS) was the main target of the study. The anionic polypeptide, poly-γ-glutamic acid (PG) and the glycosaminoglycan, hyaluronic acid, were used to stabilize ACZ-NS prepared using the antisolvent precipitation (AS-PT) coupled with sonication technique. To endue in site biocompatibility with high tolerability, soya lecithin (SL) phospholipid has been also combined with polyvinyl alcohol (PVA). NS with uniform PS in the range 100-300 nm, high ζ > ±20 mV, and enhanced saturation solubility were produced. Targeting solvent removal with control on future particle growth, post-production processing of NS was done using spray drying. The carriers' composition and amount relative to ACZ-NS were optimized to allow for the production of a redispersible dry crystalline powder. Particles crystallinity was confirmed using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) in liquid and spray dried NS. The modified Draize test proved the safety and tolerability following application to rabbit eyes accompanying an efficient ocular hypotensive activity using a steroid glaucoma model., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The purpose of this study was to assess whole brain and regional patterns of cerebrovascular reactivity (CVR) abnormalities in HIV-infected women using quantitative whole brain arterial spin labeling (ASL). We hypothesized that HIV-infected women would demonstrate decreased regional brain CVR despite viral suppression. This cross-sectional study recruited subjects from the Bay Area Women's Interagency Health Study (WIHS)-a cohort study designed to investigate the progression of HIV disease in women. In addition to conventional noncontrast cerebral MRI sequences, perfusion imaging was performed before and after the administration of intravenous acetazolamide. CVR was measured by comparing quantitative ASL brain perfusion before and after administration of intravenous acetazolamide. In order to validate and corroborate ASL-based whole brain and regional perfusion, phase-contrast (PC) imaging was also performed through the major neck vessels. FLAIR and susceptibility weighted sequences were performed to assess for white matter injury and microbleeds, respectively. Ten HIV-infected women and seven uninfected, age-matched controls were evaluated. Significant group differences were present in whole brain and regional CVR between HIV-infected and uninfected women. These regional differences were significant in the frontal lobe and basal ganglia. CVR measurements were not significantly impacted by the degree of white matter signal abnormality or presence of microbleeds. Despite complete viral suppression, dysfunction of the neurovascular unit persists in the HIV population. Given the lack of association between CVR and traditional imaging markers of small vessel disease, CVR quantification may provide an early biomarker of pre-morbid vascular disease.

Central retinal artery occlusion (CRAO) is a rare but blinding disorder. We present a case of a 81-year-old woman with multiple cardiovascular comorbidities admitted to the emergency department due to sudden, painless vision loss on left eye (oculus sinister (OS)) on awakening. The patient also reported long standing fatigue associated with effort that started 4 months before admission. She presented best corrected visual acuity of counting fingers OS. Funduscopy OS revealed macular oedema with cherry red spot pattern. Blood cultures came positive for Streptococcus gallolyticus in the context of a bacteremia and native mitral valve vegetation identified on transoesophageal echocardiography. CRAO of embolic origin was admitted in the context of an infective endocarditis. CRAO can be the first manifestation of a potentially fatal systemic condition and thus multidisciplinary approach is warranted with close collaboration between ophthalmologists and internists in order to provide proper management and the best possible treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Arterial spin labelling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that may provide fully quantitative regional cerebral blood flow (rCBF) images. However, before its application in clinical routine, ASL needs to be validated against the clinical gold standard, 15 O-H 2 O positron emission tomography (PET). We aimed to compare the two techniques by performing simultaneous quantitative ASL-MRI and 15 O-H 2 O-PET examinations in a hybrid PET/MRI scanner. Duplicate rCBF measurements were performed in healthy young subjects ( n  = 14) in rest, during hyperventilation, and after acetazolamide (post-ACZ), yielding 63 combined PET/MRI datasets in total. Average global CBF by ASL-MRI and 15 O-H 2 O-PET was not significantly different in any state (40.0 ± 6.5 and 40.6 ± 4.1 mL/100 g/min, respectively in rest, 24.5 ± 5.1 and 23.4 ± 4.8 mL/100 g/min, respectively, during hyperventilation, and 59.1 ± 10.4 and 64.7 ± 10.0 mL/100 g/min, respectively, post-ACZ). Overall, strong correlation between the two methods was found across all states (slope = 1.01, R 2  = 0.82), while the correlations within individual states and of reactivity measures were weaker, in particular in rest (R 2  = 0.05, p  = 0.03). Regional distribution was similar, although ASL yielded higher perfusion and absolute reactivity in highly vascularized areas. In conclusion, ASL-MRI and 15 O-H 2 O-PET measurements of rCBF are highly correlated across different perfusion states, but with variable correlation within and between hemodynamic states, and systematic differences in regional distribution.

Idiopathic intracranial hypertension (IIH) is a condition associated with poor vision and headaches that can cause disability and reduced quality of life. The onset of IIH is typically associated with sudden weight gain and obesity, which may be due to first-generation or second-generation antipsychotics. This case involved the use of quetiapine in an obese, 28-year-old woman; she gained significant weight after starting the antipsychotic and later developed headaches and blurred vision. Reducing quetiapine and administering acetazolamide significantly improved her symptoms within 4 weeks. This case reminds physicians to consider IIH as a cause of headache and vision loss in patients who have gained weight after starting or increasing quetiapine., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite the well documented increased risk of thrombosis in patients with cancer and during chemotherapy, cerebral venous sinus thrombosis (CVT) remains a rare entity. We present a rare case of cerebrospinal fluid (CSF) rhinorrhoea secondary to a left transverse sinus thrombus which occurred 2 years previously during chemotherapy for breast cancer. The patient underwent a three-layer repair using Neuro-Patch, septal cartilage and middle turbinate pedicle flap and was started on acetazolamide. There was no recurrence at 1-year follow-up. Raised intracranial pressure secondary to cerebral venous occlusion can erode the base of skull and predispose to CSF leaks. Despite the theoretical risk, there have been no cases reported where CSF leaks have occurred following chemotherapy induced CVT. We describe the first case and discuss pathophysiology and management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Idiopathic intracranial hypertension typically presents with holocephalic headache associated with nausea, vomiting and bilateral papilledema. Involvement of the sixth cranial nerve is relatively common. The involvement of other cranial nerves, however, is rare in this disorder. We describe a patient with idiopathic intracranial hypertension who presented with episodic unilateral retro-orbital pain and multiple cranial nerve abnormalities without papilledema. Imaging studies excluded alternate diagnoses, and the immediate resolution of symptoms after lumbar puncture confirmed that these symptoms were due to intracranial hypertension. Atypical presentations of such a disabling yet treatable disorder is very important to recognise and address., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Acetazolamide (AZM) is used for various conditions (eg, altitude sickness, sleep apnoea, glaucoma), but therapy is often limited by its side effect profile. Our objective was to estimate the risk of commonly reported side effects based on meta-analyses. We hypothesised that these risks are dose-dependent., Methods: We queried MEDLINE/EMBASE (Medical Literature Analysis and Retrieval System Online/Excerpta Medica dataBASE) up until 04/10/2019, including any randomised placebo-controlled trial in which adults received oral AZM versus placebo reporting side effects. Eligibility assessment was performed by two independent reviewers. Data were abstracted by one reviewer who verified key entries at a second time point. For side effects reported by > 3 studies a pooled effect estimate was calculated, and heterogeneity assessed via I 2 ; for outcomes reported by > 5 studies effect modification by total daily dose (EMbyTDD; <400 mg/d, 400-600 mg/d, >600 mg/d) was assessed via meta-regression. For pre-specified, primary outcomes (paraesthesias, taste disturbances, polyuria and fatigue) additional subgroup analyses were performed using demographics, intervention details, laboratory changes and risk of bias., Results: We included 42 studies in the meta-analyses (N subjects =1274/1211 in AZM/placebo groups). AZM increased the risk of all primary outcomes (p<0.01, I 2 ≤16% and low-to-moderate quality of evidence for all)-the numbers needed to harm (95% CI; n Studies ) for each were: paraesthesias 2.3 (95% CI 2 to 2.7; n=39), dysgeusia 18 (95% CI 10 to 38, n=22), polyuria 17 (95% CI 9 to 49; n=22), fatigue 11 (95% CI 6 to 24; n=14). The risk for paraesthesias (beta=1.8 (95% CI 1.1 to 2.9); P EMbyTDD =0.01) and dysgeusia (beta=3.1 (95% CI 1.2 to 8.2); P EMbyTDD =0.02) increased with higher AZM doses; the risk of fatigue also increased with higher dose but non-significantly (beta=2.6 (95% CI 0.7 to 9.4); P EMbyTDD =0.14)., Discussion: This comprehensive meta-analysis of low-to-moderate quality evidence defines risk of common AZM side effects and corroborates dose dependence of some side effects. These results may inform clinical decision making and support efforts to establish the lowest effective dose of AZM for various conditions., Competing Interests: Competing interests: CNS and JO have nothing to declare. RLO reports personal fees from Novartis, outside the submitted work. BAE reports grants from Heart Foundation of Australia, during the conduct of the study; grants from National Health and Medical Research Council of Australia, other from Apnimed, outside the submitted work. As an Officer of the ATS, AM relinquished all outside personal income since 2012. ResMed provided a philanthropic donation to UC San Diego in support of a sleep centre., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To compare the clinical outcome of intravitreal dexamethasone implant versus oral acetazolamide in patients with cystoid macular edema (CME) secondary to retinitis pigmentosa (RP). Design: Multicenter, prospective, propensity-score-matched, comparative study. Methods: Eyes with RP and CME were treated either with intravitreal dexamethasone implant or with oral acetazolamide (500 mg/day). Patients were evaluated monthly and followed up for 12 months. Primary outcome measures were changes in central retinal thickness and best corrected visual acuity (BCVA). Adverse events were recorded. Results: Propensity score matching resulted in 2 groups of 30 eyes each. All patients completed 12 months of follow-up. Mean central retinal thickness decreased from 535 μm at baseline to 208 μm at month 12 in the dexamethasone implant group and from 519 to 339 μm in the oral acetazolamide group ( P  < 0.001, Student's t -test). Mean BCVA average change from baseline during the study (area-under-the-curve approach) was -0.084 logarithm of the minimum angle of resolution (logMAR) (+4.2 letters) in the dexamethasone implant group and -0.032 (+1.6 letters) in the oral acetazolamide group ( P  < 0.05, Mann-Whitney U test). Patients in the dexamethasone implant group required on average 1.7 treatments during 1 year of therapy. Conclusions: In this study, intravitreal dexamethasone implant produced better anatomic and functional improvements over oral acetazolamide in patients affected by CME secondary to RP. Larger, randomized clinical trials with longer follow-up are warranted to confirm these data.

Cerebral collaterals is crucially important in the pathophysiology of acute ischemic stroke and associated with outcome after reperfusion therapy. We explored the effectiveness of collateral augmentation treatment with a combination of acetazolamide (ACZ) and head-down tilt (HDT) in the transient middle cerebral artery occlusion (MCAO) rat model. Transient MCAO was induced in all animals for 1.5 h, followed by reperfusion for 22.5 h. Seventy-two male Wistar rats were divided into four treatment groups: control, ACZ, HDT, and combination. Twenty sham rats, which underwent surgery, were randomly allocated to these groups. Twenty-four hours after MCAO or sham surgery, we measured the infarction volume, brain edema (aquaporin-4 [AQP4], and brain water content), and neurological deficits (Garcia and Longa tests). Collateral augmentation treatments were associated with reduced infarction volume, less brain edema, and better neurological outcomes compared with untreated animals. More specifically, ACZ and HDT treatments resulted in small infarction volumes, and HDT was associated with a low AQP4 expression and improved neurological score, while the combination of ACZ and HDT improved neurological scores and reduced brain water content. This study shows that collateral augmentation treatments are associated with a better stroke prognosis compared with untreated animals after transient MCAO. The combination of ACZ and HDT seems to have some synergistic effect, but was not proven to be superior to HDT treatment alone., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Acetazolamide (AZ) is a medication commonly used to prevent acute mountain sickness (AMS) during rapid ascent to high altitude. However, it is unclear whether AZ use impairs exercise performance; previous literature regarding this topic is equivocal. The purpose of this study was to evaluate the impact of AZ on time-trial (TT) performance during a 30-h exposure to hypobaric hypoxia equivalent to 3,500-m altitude. Ten men [sea-level peak oxygen consumption (VO 2 peak): 50.8 ± 6.5 mL·kg -1 ·min -1 ; body fat %: 20.6 ± 5.2%] completed 2 30-h exposures at 3,500 m. In a crossover study design, subjects were given 500 mg/day of either AZ or a placebo. Exercise testing was completed 2 h and 24 h after ascent and consisted of 15-min steady-state treadmill walking at 40%-45% sea-level VO 2 peak, followed by a 2-mile self-paced treadmill TT. AMS was assessed after ~12 h and 22 h at 3,500 m. The incidence of AMS decreased from 40% with placebo to 0% with AZ. Oxygen saturation was higher ( P < 0.05) in AZ versus placebo trials at the end of the TT after 2 h (85 ± 3% vs. 79 ± 3%) and 24 h (86 ± 3% vs. 81 ± 4%). There was no difference in time to complete 2 miles between AZ and PL after 2 h (20.7 ± 3.2 vs. 22.7 ± 5.0 min, P > 0.05) or 24 h (21.5 ± 3.4 vs. 21.1 ± 2.9 min, P > 0.05) of exposure to altitude. Our results suggest that AZ (500 mg/day) does not negatively impact endurance exercise performance at 3,500 m. NEW & NOTEWORTHY To our knowledge, this is the first study to examine the impact of acetazolamide (500 mg/day) versus placebo on self-paced, peak-effort exercise performance using a short-duration exercise test in a hypobaric hypoxic environment with a repeated-measures design. In the present study, acetazolamide did not impact exercise performance after 2-h or 24-h exposure to 3,500-m simulated altitude.

We present the case of a 42-year-old man with moyamoya disease presenting for cerebral revascularization surgery who developed critical hyperkalemia following a single intravenous (iv) dose of 1000 mg of acetazolamide 1 day preoperatively for a cerebrovascular reactivity study. His potassium increased from 5.1 to 6.7 mmol/L. Prompt treatment of this abnormality allowed this patient to undergo surgery the next day uneventfully. A paradoxical, critical increase in potassium can result from a single 1000-mg iv dose of acetazolamide.

The information regarding fetal effects of acetazolamide use during pregnancy and lactation is sparse. We report the clinical and pharmacodynamic characteristics of maternal acetazolamide use and the timing of its effects on acid-base balance in three cases who presented with metabolic acidosis in the newborn period. We found that the infants' clinical status soon after birth was inconsistently correlated with maternal drug dose and concentrations of medication in maternal serum. However, there was low transfer of the drug in breast milk and its use did not affect clinical symptomatology. We also present a review of literature on this subject to help consolidate our current knowledge on this topic.

According to the "chloride theory" for heart failure (HF) pathophysiology, manipulation of the serum chloride concentration is an important therapeutic target. This study determined the short- and long-term effects of acetazolamide (Diamox), a potential chloride-regaining diuretic, on peripheral blood, serum electrolytes, and renal function. Effects of low-dose Diamox (250-500 mg/day) were evaluated in 30 HF patients for whom Diamox was added as de-novo/add-on decongestion therapy for acutely worsening HF (n = 18) or as modification therapy for serum hypochloremia in stable HF ( < 100 mEq/L; n = 12). Peripheral hematologic tests were performed at baseline, and at short- ( ≤ 10 days) and long-term ( ~ 60 days) time-points. In all 30 study patients of both groups, the serum chloride concentration increased in the short-term and even further over the long-term. The serum potassium concentration constantly decreased throughout the study period. Both the blood urea nitrogen and serum creatinine concentrations increased in the short-term, but returned to baseline levels over the long-term. Responders to Diamox (n = 13; defined by HF resolution and body weight loss ≥ 1 kg) in the decongestion group exhibited reduced serum b-type natriuretic peptide levels and a markedly increased serum chloride concentration, but the hemoglobin/hematocrit and serum creatinine concentrations did not change after treatment. In conclusion, acetazolamide is a potent candidate "chloride-regaining diuretic" for treating HF patients under the "chloride theory". Its effect to enhance the serum chloride concentration occurred within 10 days and persisted for at least ~ 60 days. Plasma volume and renal function were preserved under adequate diuretic treatment with acetazolamide.

Objective: To compare the physiological and biochemical effects of a single intravenous dose of furosemide or acetazolamide in critically ill patients., Design: Single centre, pilot randomised controlled trial., Setting: Large tertiary adult intensive care unit (ICU)., Participants: Twenty-six adult ICU patients deemed to require diuretic therapy., Intervention: Single dose of intravenous 40 mg furosemide or 500 mg acetazolamide., Main Outcome Measures: Data were collected on urine output, cumulative fluid balance, and serum and urine biochemistry for 6 hours before and 6 hours after diuretic administration., Results: Study patients had a median age of 55 years (IQR, 50-66) and median APACHE III score of 44 (IQR, 37-52). Furosemide caused a much greater increase in-urine output and much greater median mass chloride excretion (121.7 mmol [IQR, 81.1-144.6] v 23.3 mmol [IQR, 20.4-57.3]; P < 0.01) than acetazolamide. Furosemide also resulted in a progressively more negative fluid balance while acetazolamide resulted in greater alkalinisation of the urine (change in median urinary pH, +2 [IQR, 1.75-2.12] v 0 [IQR, 0-0.5]; P = 0.02). In keeping with this effect, furosemide alkalinised and acetazolamide acidified plasma (change in median serum pH, +0.03 [IQR, 0.01-0.04] v -0.01 [IQR, -0.04 to 0]; P = 0.01; change in median serum HCO 3 -, +1.5 mmol/L [IQR, 0.75-2] v -2 mmol/L [IQR, -3 to 0]; P < 0.01)., Conclusions: Furosemide is a more potent diuretic and chloriuretic agent than acetazolamide in critically ill patients, and achieves a threefold greater negative fluid balance. Compared with acetazolamide, furosemide acidifies urine and alkalinises plasma. Our findings imply that combination therapy might be a more physiological approach to diuresis in critically ill patients.

Background: The associations among cortisol levels, body water status, and acute mountain sickness (AMS) remain unclear. We investigated associations between AMS prevalence and severity with resting saliva cortisol levels at low altitude (LA) and high altitude (HA) and with fluid balance during a HA stay. Methods: Twenty-two physically fit and healthy participants (12 women, 10 men) were transported to HA (Testa Grigia, 3480 m). In the late afternoon at LA, on the next day 3-4 hours after arrival at HA and in the morning after an overnight stay, heart rate, oxygen saturation, and systolic and diastolic blood pressures were measured in a sitting position after 10 minutes of rest; cortisol levels were quantified in saliva samples taken pre-ascent and 3-4 hours after arrival at HA. AMS was scored with the 1993 Lake Louise Score (LLS, cut-off ≥3). Urine volume and fluid and food intake were recorded during the altitude stay. Results: Pre-ascent cortisol levels were associated with fluid retention during the altitude stay ( r 2  = 0.33, p  < 0.05) and both were positively related to the LLS ( r 2  = 0.49 and r 2  = 0.26, p  < 0.05, respectively). Conclusions: In conclusion, resting LA cortisol levels and fluid retention upon rapid exposure to altitude seem to be associated with AMS. This suggests a potential link among cortisol homeostasis, fluid balance, and AMS risk.

Background: Acetazolamide is the most common medication used for prevention of acute mountain sickness (AMS), usually administered the day or night before ascent. The objective of this study was to evaluate the efficacy of day of ascent dosing of acetazolamide for AMS prevention. Methods: Double-blind, randomized, controlled noninferiority trial of acetazolamide 125 mg twice daily beginning either the night before or the morning of ascent. Healthy low altitude adults ascended from 1240 m (4100 ft) to 3810 m (12,570 ft) during summer 2018 on White Mountain, California. Primary outcome was incidence of AMS with the two different dosing patterns, assessed by the 1993 Lake Louise Questionnaire (LLQ) of ≥3 with headache and a minimum of 1 for other symptom. Results: One hundred four participants completed the study, with 54 (52%) randomized to night before acetazolamide and 50 (48%) to day of ascent dosing, without differences in baseline characteristics. There was 9% greater incidence of AMS in the day of ascent acetazolamide group (48.0% vs. 39%, 95% confidence interval [CI] -11.8 to 30, p  = 0.46, number needed to treat [NNT] = 5.6 vs. 3.7), with the CI just surpassing the predetermined 26% noninferiority margin. There was a lower incidence of severe AMS (1993 LLQ >5) in the day of ascent group ( n  = 5, 10%, NNT = 2.3) compared with night before dosing ( n  = 12, 22%, NNT = 3.1) (95% CI -28 to 3.6), and lower average symptom severity in the day of ascent group (3 vs. 3.5, 95% CI -0.5 to 1.4). Conclusions: Day of ascent acetazolamide demonstrated higher rates of AMS compared with traditional dosing by a small margin. With similar rates of severe AMS and overall symptom severity, the potential for improved convenience and compliance may support day of ascent use.

Background: Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior., Methods: Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids., Results: Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice., Conclusions: Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

Background: Severe carotid and intracranial artery stenosis disease (CIAD) is major risk for perioperative stroke in coronary artery bypass grafting. Then, preoperative risk assessment is quite important., Case Presentation: A 58-years old Japanese woman with bilateral carotid stenosis and bilateral middle cerebral artery occlusion was suffered from worsening effort angina due to severe three coronary vessel disease. Magnetic resonance imaging angiography demonstrated severe carotid and intracranial vessel stenosis. Selective carotid/cerebral angiography also showed severe stenosis and delayed filling of the right internal carotid artery and moderate stenosis of the left internal carotid artery, with occlusion of the bilateral middle cerebral arteries. However, quantitative evaluation with brain perfusion, single-photon emission computed tomography (SPECT) with acetazolamide showed depleted cerebral perfusion volume and vascular responses, particularly in the left middle cerebral artery area. However, both sides of MCA reserve cerebral blood flow was maintained at > 34 ml/100 g/min. So, we finally considered that her cerebral perfusion reserve was maintained a certain level and could tolerate open heart surgery. Then, she underwent off-pump coronary artery grafting. Before sternotomy, prophylactic intra-aortic balloon pump support was used to minimize possible perioperative stroke. As a result, hemodynamic status and brain regional oxygen saturation were stable throughout the operation, and recovered uneventfully., Conclusions: Preoperative quantitative evaluation using brain perfusion SPECT with acetazolamide is useful in assessing hemodynamic cerebrovascular risk in patients with severe obstructive CIAD. Off pump coronary artery bypass grafting with intra aortic balloon pump assist is a good option for prevention of cerebrovascular morbidity in ischemic heart disease with severe CIAD.

Purpose: To describe a case of intraocular pressure fluctuation during haemodialysis in a patient with previously treated proliferative diabetic retinopathy and previous unilateral angle neovascularisation., Case Description: A 63-year-old male with end-stage renal disease on maintenance haemodialysis and recurrent episodes of symptomatic intraocular pressure rise during dialysis sessions. Higher intraocular pressure spikes occurred in the eye with previous angle new vessels., Outcome: Topical antihypertensive drops failed to control the intraocular pressure. Due to multiple co-morbidities, options of medical management were deemed unsuitable; those included intravenous mannitol, systemic acetazolamide and intravenous glucose. Furthermore, modifications of his dialysis prescription did not lead to satisfactory results. As a consequence, the patient underwent trabeculectomy with mitomycin C. Adequate control of his intraocular pressure was achieved post-operatively., Conclusion: Intraocular pressure fluctuations during haemodialysis are not fully understood, and management can be quite challenging to the treating ophthalmologists and nephrologists. In this case report, we discuss some of those difficulties and different treatment options.

In rats, we recently showed how a chronic metabolic acidosis simultaneously reduced urinary oxalate excretion and promoted oxalate secretion by the distal colon leading to the proposition that acid-base disturbances may trigger changes to renal and intestinal oxalate handling. The present study sought to reproduce and extend these observations using the mouse model, where the availability of targeted gene knockouts (KOs) would offer future opportunities to reveal some of the underlying transporters and mechanisms involved. Mice were provided with a sustained load of acid (NH 4 Cl), base (NaHCO 3 ) or the carbonic anhydrase inhibitor acetazolamide (ATZ) for 7 days after which time the impacts on urinary oxalate excretion and its transport by the intestine were evaluated. Mice consuming NH 4 Cl developed a metabolic acidosis but urinary oxalate was only reduced 46% and not statistically different from the control group, while provision of NaHCO 3 provoked a significant 2.6-fold increase in oxalate excretion. For mice receiving ATZ, the rate of urinary oxalate excretion did not change significantly. Critically, none of these treatments altered the fluxes of oxalate (or chloride) across the distal ileum, cecum or distal colon. Hence, we were unable to produce the same effects of a metabolic acidosis in mice that we had previously found in rats, failing to find any evidence of the 'gut-kidney axis' influencing oxalate handling in response to various acid-base challenges. Despite the potential advantages offered by KO mice, this model species is not suitable for exploring how acid-base status regulates oxalate handling between the kidney and intestine.

Background : Intraretinal cystoid spaces (IRCS) are fluid-filled spaces seen in some retinal dystrophies and often treated with carbonic anhydrase inhibitors. The purpose of this study is to report an unexpected bilateral improvement in the IRCS after discontinuation of therapy. Material and Methods : We identified from our records 23 patients with retinal dystrophy and IRCS who had been treated with topical and/or oral carbonic anhydrase inhibitors. All subjects had regular follow-up with OCT and previous genetic testing. Results : We identified four (17%) patients who experienced a bilateral and symmetrical paradoxical improvement in IRCS size and visual acuity after discontinuation of carbonic anhydrase inhibitors. Two were mutations in RS1 , one in CLN3 and another in NR2E3 . All patients were followed for at least three years (range 39-63 months). None had systemic abnormalities. Conclusions : Patients with IRCS may exhibit a paradoxical response after discontinuation of carbonic anhydrase inhibitors. Although the pathophysiology of these phenomena is unclear, stopping treatment may be an option in patients who cease to improve or get worse on treatment.

Idiopathic intracranial hypertension (IIH) is a disorder affecting both the pediatric and adult population. Investigations and treatments may differ considerably. There are no evidence-based guidelines for treatment. During a national multidisciplinary meeting in Stockholm January 2018 IIH experts from several Swedish regions met to discuss how to manage this patient group. These guidelines are based on this meeting and a review of current medical knowledge. To summarize: All patients should be investigated and treated for underlying factors that could be the cause of high intracranial pressure (ICP) (such as obesity, secondary causes such as intracranial tumors or other factors reported to affect ICP). When treating IIH the preservation of vision is crucial. Follow-up depends on visual status. In case of acute risk of visual impairment prompt surgical intervention must be considered. Symptomatic treatment of headache is recommended.