Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.

BACKGROUND: Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed. RESULTS: A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups. CONCLUSIONS: The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).

In acute decompensated HF, adding acetazolamide to IV loop diuretics reduced congestion at 3 d across eGFR levels.

SOURCE CITATION: Meekers E, Dauw J, Martens P, et al. Renal function and decongestion with acetazolamide in acute decompensated heart failure: the ADVOR trial. Eur Heart J. 2023;44:3672-3682. 37623428.

Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial.

BACKGROUND: Acetazolamide inhibits proximal tubular sodium reabsorption and improved decongestion in the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. It remains unclear whether the decongestive effects of acetazolamide differ across the spectrum of left ventricular ejection fraction (LVEF). METHODS: This is a prespecified analysis of the randomized, double-blind, placebo-controlled ADVOR trial that enrolled 519 patients with acute heart failure (HF), clinical signs of volume overload (eg, edema, pleural effusion, or ascites), NTproBNP (N-terminal pro-B-type natriuretic peptide) >1000 ng/L, or BNP (B-type natriuretic peptide) >250 ng/mL to receive intravenous acetazolamide (500 mg once daily) or placebo in addition to standardized intravenous loop diuretics (twice that of the oral home maintenance dose). Randomization was stratified according to LVEF (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload within 3 days from randomization without the need for mandatory escalation of decongestive therapy because of poor urine output. RESULTS: Median LVEF was 45% (25th to 75th percentile; 30% to 55%), and 43% had an LVEF ≤40%. Patients with lower LVEF were younger and more likely to be male with a higher prevalence of ischemic heart disease, higher NTproBNP, less atrial fibrillation, and lower estimated glomerular filtration rate. No interaction on the overall beneficial treatment effect of acetazolamide to the primary end point of successful decongestion (OR, 1.77 [95% CI, 1.18-2.63]; P=0.005; all P values for interaction >0.401) was found when LVEF was assessed per randomization stratum (≤40% or >40%), or as HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction, or on a continuous scale. Acetazolamide resulted in improved diuretic response measured by higher cumulative diuresis and natriuresis and shortened length of stay without treatment effect modification by baseline LVEF (all P values for interaction >0.160). CONCLUSIONS: When added to treatment with loop diuretics in patients with acute decompensated HF, acetazolamide improves the incidence of successful decongestion and diuretic response, and shortens length of stay without treatment effect modification by baseline LVEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03505788.

Combination pharmacological therapy targeting multiple mechanisms of sleep apnoea: a randomised controlled cross-over trial.

RATIONALE: Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone. METHODS: In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions. Outcomes were assessed at baseline and night 3 of each treatment period. Mixed model analysis compared the reduction in Apnoea-Hypopnoea Index (AHI) from baseline between AtoOxy-plus-acetazolamide and AtoOxy (primary outcome). Secondary outcomes included hypoxic burden and arousal index. RESULTS: Although AtoOxy lowered AHI by 49 (33, 62)%baseline (estimate (95% CI)) vs placebo, and acetazolamide lowered AHI by+34 (14, 50)%baseline vs placebo, AtoOxy-plus-acetazolamide was not superior to AtoOxy alone (difference: -2 (-18, 11)%baseline, primary outcome p=0.8). Likewise, the hypoxic burden was lowered with AtoOxy (+58 (37, 71)%baseline) and acetazolamide (+37 (5, 58)%baseline), but no added benefit versus AtoOxy occurred when combined (difference: -13 (-5, 39)%baseline). Arousal index was also modestly reduced with each intervention (11%baseline-16%baseline). Mechanistic analyses revealed that similar traits (ie, higher baseline compensation, lower loop gain) were associated with both AtoOxy and acetazolamide efficacy. CONCLUSIONS: While AtoOxy halved AHI, and acetazolamide lowered AHI by a third, the combination of these leading experimental interventions provided no greater efficacy than AtoOxy alone. Failure of acetazolamide to further increase efficacy suggests overlapping physiological mechanisms. TRIAL REGISTRATION NUMBER: NCT03892772.

Comparative study of stability and activity of wild-type and mutant human carbonic anhydrase II enzymes using molecular dynamics and docking simulations.

The human carbonic anhydrase II (HCA II) enzyme is a cytosolic protein located in the membrane of red blood cells that reversible hydration of carbon dioxide (CO2). Considering the critical role of the HCA II and the effects of some mutations on the activity and stability of the enzyme in humans, several computational methods are used to study the structure and dynamics of the wild-type and the mutant enzymes with three ligands, CO2, 4-nitrophenyl acetate and acetazolamide. Our results of MD simulation of a wild-type enzyme with 4-nitrophenyl acetate show that it created essential effects on the fluctuation of this enzyme and made it more unstable and less compact than the same enzyme without ligand. In the MD of the mutant enzyme with 4-nitrophenyl acetate ligand, no significant difference is observed between with and without ligand. The affinity of the wild-type enzyme to the 4-nitrophenyl acetate is notably higher than the mutant enzyme with the same ligand. Furthermore, results showed that wild-type and mutant enzymes with CO2 are more favorable in stability and flexibility than the same enzymes without ligand. The MD results of wild-type with acetazolamide indicate instability compare without ligand, but in MD of mutant enzyme with acetazolamide show that it more stable and compact than the same enzyme without ligand. Finally, Comparing protein trajectories to assess the impact of ligands on the stability and activity of HCA II enzymes can have medical applications and can in the engineering and design of new variants of carbonic anhydrase enzyme.

Effects of acetazolamide combined with remote ischemic preconditioning on risk of acute mountain sickness: a randomized clinical trial.

BACKGROUND: We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). METHODS: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. RESULTS: The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07-0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3- 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. CONCLUSIONS: The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05023941.

Neurological manifestations in PMM2-congenital disorders of glycosylation (PMM2-CDG): Insights into clinico-radiological characteristics, recommendations for follow-up, and future directions.

PURPOSE: In the absence of prospective data on neurological symptoms, disease outcome, or guidelines for system specific management in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG), we aimed to collect and review natural history data. METHODS: Fifty-one molecularly confirmed individuals with PMM2-CDG enrolled in the Frontiers of Congenital Disorders of Glycosylation natural history study were reviewed. In addition, we prospectively reviewed a smaller cohort of these individuals with PMM2-CDG on off-label acetazolamide treatment. RESULTS: Mean age at diagnosis was 28.04 months. Developmental delay is a constant phenotype. Neurological manifestation included ataxia (90.2%), myopathy (82.4%), seizures (56.9%), neuropathy (52.9%), microcephaly (19.1%), extrapyramidal symptoms (27.5%), stroke-like episodes (SLE) (15.7%), and spasticity (13.7%). Progressive cerebellar atrophy is the characteristic neuroimaging finding. Additionally, supratentorial white matter changes were noted in adult age. No correlation was observed between the seizure severity and SLE risk, although all patients with SLE have had seizures in the past. "Off-label" acetazolamide therapy in a smaller sub-cohort resulted in improvement in speech fluency but did not show statistically significant improvement in objective ataxia scores. CONCLUSION: Clinical and radiological findings suggest both neurodevelopmental and neurodegenerative pathophysiology. Seizures may manifest at any age and are responsive to levetiracetam monotherapy in most cases. Febrile seizure is the most common trigger for SLEs. Acetazolamide is well tolerated.

Acetazolamide therapy in patients with acute heart failure: a systematic review and meta-analysis of randomized controlled trials.

Acute heart failure (AHF) often leads to unfavorable outcomes due to fluid overload. While diuretics are the cornerstone treatment, acetazolamide may enhance diuretic efficiency by reducing sodium reabsorption. We performed a systematic review and meta-analysis on the effects of acetazolamide as an add-on therapy in patients with AHF compared to diuretic therapy. PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCT). A random-effects model was employed to compute mean differences and risk ratios. Statistical analysis was performed using R software. The GRADE approach was used to rate the certainty of the evidence. We included 4 RCTs with 634 patients aged 68 to 81 years. Over a mean follow-up of 3 days to 34 months, acetazolamide significantly increased diuresis (MD 899.2 mL; 95% CI 249.5 to 1549; p < 0.01) and natriuresis (MD 72.44 mmol/L; 95% CI 39.4 to 105.4; p < 0.01) after 48 h of its administration. No association was found between acetazolamide use and WRF (RR 2.4; 95% CI 0.4 to 14.2; p = 0.3) or all-cause mortality (RR 1.2; 95% CI 0.8 to 1.9; p = 0.3). Clinical decongestion was significantly higher in the intervention group (RR 1.35; 95% CI 1.09 to 1.68; p = 0.01). Acetazolamide is an effective add-on therapy in patients with AHF, increasing diuresis, natriuresis, and clinical decongestion, but it was not associated with differences in mortality.

Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.

Using modified Fenn diagrams to assess ventilatory acclimatization during ascent to high altitude: Effect of acetazolamide.

High altitude (HA) ascent imposes systemic hypoxia and associated risk of acute mountain sickness. Acute hypoxia elicits a hypoxic ventilatory response (HVR), which is augmented with chronic HA exposure (i.e., ventilatory acclimatization; VA). However, laboratory-based HVR tests lack portability and feasibility in field studies. As an alternative, we aimed to characterize area under the curve (AUC) calculations on Fenn diagrams, modified by plotting portable measurements of end-tidal carbon dioxide ( P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) against peripheral oxygen saturation ( S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) to characterize and quantify VA during incremental ascent to HA (n = 46). Secondarily, these participants were compared with a separate group following the identical ascent profile whilst self-administering a prophylactic oral dose of acetazolamide (Az; 125 mg BID; n = 20) during ascent. First, morning P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ measurements were collected on 46 acetazolamide-free (NAz) lowland participants during an incremental ascent over 10 days to 5160 m in the Nepal Himalaya. AUC was calculated from individually constructed Fenn diagrams, with a trichotomized split on ranked values characterizing the smallest, medium, and largest magnitudes of AUC, representing high (n = 15), moderate (n = 16), and low (n = 15) degrees of acclimatization. After characterizing the range of response magnitudes, we further demonstrated that AUC magnitudes were significantly smaller in the Az group compared to the NAz group (P = 0.0021), suggesting improved VA. These results suggest that calculating AUC on modified Fenn diagrams has utility in assessing VA in large groups of trekkers during incremental ascent to HA, due to the associated portability and congruency with known physiology, although this novel analytical method requires further validation in controlled experiments. HIGHLIGHTS: What is the central question of this study? What are the characteristics of a novel methodological approach to assess ventilatory acclimatization (VA) with incremental ascent to high altitude (HA)? What is the main finding and its importance? Area under the curve (AUC) magnitudes calculated from modified Fenn diagrams were significantly smaller in trekkers taking an oral prophylactic dose of acetazolamide compared to an acetazolamide-free group, suggesting improved VA. During incremental HA ascent, quantifying AUC using modified Fenn diagrams is feasible to assess VA in large groups of trekkers with ascent, although this novel analytical method requires further validation in controlled experiments.

Effects of furosemide, acetazolamide and amiloride on renal cortical and medullary tissue oxygenation in non-anaesthetised healthy sheep.

It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.

Acetazolamide as an effective treatment for pilomotor seizures in autoimmune encephalitis.

Pilomotor seizures are strongly associated with autoimmune encephalitis (AE), particularly anti-LGI1 encephalitis. The carbonic anhydrase inhibitor acetazolamide may have special efficacy for treating AE-associated pilomotor seizures. Six patients with AE (five anti-LGI1, one seronegative) and temporal lobe pilomotor seizures (five with seizures inducible by hyperventilation) were treated with acetazolamide, administered in a cycling (2-days-ON, 4-days-OFF) regimen to offset tolerance. Seizures were assessed during epilepsy monitoring unit (EMU) recordings in four inpatients (one of whom also maintained an outpatient seizure diary chronicling 1203 seizures over 1079 days); two outpatients self-reported seizure frequencies. The extended diary revealed an inverse correlation between acetazolamide and proportion of seizures/day: 6%, 2% (days 1, 2 ON); 3%, 13%, 31%, 45% (days 1, 2, 3, 4 OFF). This patient later developed focal status epilepticus upon wean of antiseizure medications during a seropositive AE relapse that was remarkably aborted with acetazolamide monotherapy. The other three EMU patients averaged .56 seizures/day ON, and 3.81 seizures/day OFF (p = .004). The two outpatients reported seizure reductions from 3-5/day to 2/week, and 15-20/day to none, respectively, after initiation of cycling acetazolamide. Likely related to cerebral CO2/pH sensitivity, acetazolamide can be unusually effective in controlling pilomotor seizures in AE, chronically or in acute settings.

A CAIX Dual-Targeting Small-Molecule Probe for Noninvasive Imaging of ccRCC.

Carbonic anhydrase IX (CAIX), a zinc metal transmembrane protein, is highly expressed in 95% of clear cell renal cell carcinomas (ccRCCs). A positron emission tomography (PET) probe designed to target CAIX in nuclear medicine imaging technology can achieve precise positioning, is noninvasive, and can be used to monitor CAIX expression in lesions in real time. In this study, we constructed a novel acetazolamide dual-targeted small-molecule probe [68Ga]Ga-LF-4, which targets CAIX by binding to a specific amino acid sequence. After attenuation correction, the radiolabeling yield reached 66.95 ± 0.57% (n = 5) after 15 min of reaction and the radiochemical purity reached 99% (n = 5). [68Ga]Ga-LF-4 has good in vitro and in vivo stability, and in vivo safety and high affinity for CAIX, with a Kd value of 6.62 nM. Moreover, [68Ga]Ga-LF-4 could be quickly cleared from the blood in vivo. The biodistribution study revealed that the [68Ga]Ga-LF-4 signal was concentrated in the heart, lung, and kidney after administration, which was the same as that observed in the micro-PET/CT study. In a ccRCC patient-derived xenograft (PDX) model, the signal significantly accumulated in the tumor after administration, where it was retained for up to 4 h. After competitive blockade with LF-4, uptake at the tumor site was significantly reduced. The SUVmax of the probe [68Ga]Ga-LF-4 at the ccRCC tumor site was three times greater than that in the PC3 group with low CAIX expression at 30 min (ccRCC vs PC3:1.86 ± 0.03 vs 0.62 ± 0.01, t = 48.2, P < 0.0001). These results indicate that [68Ga]Ga-LF-4 is a novel small-molecule probe that targets CAIX and can be used to image localized and metastatic ccRCC lesions.

Systemic lupus erythematosus with chronic persistent intracranial hypertension: A case report.

OBJECTIVE: The aim is to investigate the clinical characteristics of systemic lupus erythematosus with intracranial hypertension. METHODS: The clinical characteristics of one case of systemic lupus erythematosus with chronic persistent intracranial hypertension were analyzed, and related literature was reviewed by searching Medline and Wanfang databases. RESULTS: Intracranial hypertension in SLE patients may occur at the onset or during the course of the disease. Our patient was diagnosed with IH 3 years after the onset of SLE. Headache and papilledema were the most common symptoms of intracranial hypertension, followed by nausea or vomiting, vision changes, and cerebral palsy. Our patient had a headache and cranial hypertension that lasted for years, but no papilledema was found. Corticosteroid is currently the mainstay of the treatment of IIH in patients with SLE, and immunosuppressive agents, acetazolamide, intravenous mannitol and furosemide are also used. However, our patient did not respond to these treatments and presents the characteristics of chronic persistent intracranial hypertension. CONCLUSION: Systemic lupus erythematosus with intracranial hypertension is a rare manifestation of SLE, which is not completely parallel to SLE activity. Headache and papilledema were the most common presenting symptoms. Different from previous reported cases, our patient had poor response to treatments, showing chronic and persistent characteristics.

Acetazolamide-induced pulmonary oedema: A disproportionality analysis from the EudraVigilance database.

To our knowledge, no prior study has analysed a possible association between acetazolamide and pulmonary oedema. The aim of this study was to use data from the EudraVigilance to detect a safety signal for acetazolamide-induced pulmonary oedema. We performed a disproportionality analysis (case-noncase method), calculating reporting odds ratios (RORs) up to 22 February 2024. Among 11 684 208 spontaneous cases of adverse reactions registered in EudraVigilance, 38 275 were pulmonary oedemas. Acetazolamide was involved in 31 cases. In more than half of those cases, the patients received a single dose of acetazolamide after undergoing cataract surgery: latency was 10-90 min. Remarkably, there were five cases of positive rechallenge and six cases resulted in death. The ROR for acetazolamide was 3.63 (95% CI 2.55-5.17). Disproportionality was also observed in VigiBase®: ROR 4.44 (95% CI 3.34-5.90). Our study confirms a signal that suggests a risk of serious pulmonary oedema associated with acetazolamide.

Spatial coefficient of variation of arterial spin labeling magnetic resonance imaging can predict decreased cerebrovascular reactivity measured by acetazolamide challenge single-photon emission tomography.

PURPOSE: The aim of this study was to investigate whether the spatial coefficient of variation of arterial spin labeling (ASL-CoV) acquired in clinical settings can be used to estimate decreased cerebrovascular reactivity (CVR) measured with single-photon emission computed tomography (SPECT) and acetazolamide challenge in patients with atherosclerotic stenosis of intra- or extracranial arteries. METHODS: We evaluated the data of 27 atherosclerotic stenosis patients who underwent pseudocontinuous ASL and SPECT. After spatial normalization, regional values were measured using the distributed middle cerebral artery territorial atlas of each patient. We performed comparisons, correlations, and receiver operating characteristic (ROC) curve analyses between ASL-cerebral blood blow (CBF), ASL-CoV, SPECT-CBF and SPECT-CVR. RESULTS: Although the ASL-CBF values were positively correlated with SPECT-CBF values (r = 0.48, 95% confidence interval (CI) = 0.28-0.64), no significant difference in ASL-CBF values was detected between regions with and without decreased CVR. However, regions with decreased CVR had significantly greater ASL-CoV values than regions without decreased CVR. SPECT-CVR was negatively correlated with ASL-CoV (ρ = -0.29, 95% CI = -0.49 - -0.06). The area under the ROC curve of ASL-CoV in predicting decreased CVR (0.66, 95% CI = 0.51-0.81) was greater than that of ASL-CBF (0.51, 95% CI = 0.34-0.68). An ASL-CoV threshold value of 42% achieved a high specificity of 0.93 (sensitivity = 0.42, positive predictive value = 0.77, and negative predictive value = 0.75). CONCLUSION: ASL-CoV acquired by single postlabeling delay without an acetazolamide challenge may aid in the identification of patients with decreased CVR on SPECT.

Effects of 5-Week Oral Acetazolamide on Incremental Cycling Exercise in Pulmonary Arterial and Chronic Thromboembolic Pulmonary Hypertension: A Randomized Placebo-Controlled, Double-Blinded, Crossover Trial.

INTRODUCTION: Acetazolamide (AZA) improves nocturnal and daytime blood oxygenation in patients with pulmonary vascular disease (PVD), defined as pulmonary arterial and distal chronic thromboembolic pulmonary hypertension (CTEPH), and may improve exercise performance. METHODS: We investigated the effect of 5 weeks of AZA (250 mg bid) versus placebo on maximal load during incremental cycling ramp exercise in patients with PVD studied in a randomized controlled, double-blind, crossover design, separated by > 2 weeks of washout. RESULTS: Twenty-five patients (12 pulmonary arterial hypertension, 13 CTEPH, 40% women, age 62 ± 15 years) completed the trial according to the protocol. Maximum load was similar after 5 weeks of AZA versus placebo (113 ± 9 vs. 117 ± 9 watts [W]), mean difference -4 W (95% CI: -9 to 1, p = 0.138). With AZA, maximum (max)-exercise partial pressure of O2 (PaO2) was significantly higher by 1.1 kPa (95% CI: 0.5-1.8, p = 0.003), while arterial pH and partial pressure of CO2 were significantly lower. Gas exchange threshold was reached at a higher load with AZA (108 ± 8 W vs. 97 ± 8 W) and was therefore delayed by 11 W (95% CI: 3-19, p = 0.013), while the ventilatory equivalent for O2 and CO2 were significantly higher at both the max-exercise and gas exchange threshold with AZA versus placebo. CONCLUSION: AZA for 5 weeks did not significantly change maximum exercise capacity in patients with PVD despite a significant increase in PaO2. The beneficial effects of increased blood oxygenation may have been diminished by increased ventilation due to AZA-induced metabolic acidosis and increased dyspnea.

Congenital nephrogenic diabetes insipidus treated with acetazolamide.

Congenital nephrogenic diabetes insipidus (CNDI) is a rare disorder. The condition is characterised by an inability of distal nephron segments to respond to normal or raised concentrations of serum antidiuretic hormone. In this report, we describe the case of a 13-year-old male known with CNDI who experienced a pedestrian vehicle accident leading to coma following a head injury. Intra-operatively, severe hypernatraemia and polyuria were observed. Following an inadequate response to conventional therapy, acetazolamide was prescribed resulting in an immediate response to therapy. To the best of our knowledge, acetazolamide has not been previously documented as a therapeutic option for CNDI. Additional research is necessary before considering the recommendation of acetazolamide for cases of NDI that do not respond adequately to conventional treatments.

Acetazolamide and human carbonic anhydrases: retrospect, review and discussion of an intimate relationship.

Acetazolamide (AZM) is a strong pharmacological sulphonamide-type (R-SO2-NH2, pKa 7.2) inhibitor of the activity of several carbonic anhydrase (CA) isoforms, notably of renal CA II (Ki, 12 nM) and CA IV (Ki, 74 nM). AZM is clinically used for about eighty years in various diseases including epilepsy and glaucoma. Pharmacological AZM increases temporarily the urinary excretion of bicarbonate (HCO3-) and sodium ions (Na+) and sustainably the urinary pH. AZM is excreted almost unchanged over several hours at high rates in the urine. Closely parallel concentrations of circulating and excretory AZM are observed upon administration of therapeutical doses of AZM. In a proof-of-principle study, we investigated the effects of the ingestion of a 250-mg AZM-containing tablet by a healthy volunteer on the urinary excretion of organic and inorganic substances over 5 h (range, 0, 0.5, 1, 1.5, 2, 3, 4, 5 h). Measured analytes included: AZM, amino acids and their metabolites such as guanidinoacetate, i.e. the precursor of creatine, of asymmetrically (ADMA) and symmetrically (SDMA) dimethylated arginine, nitrite (O = N-O-, pKa 3.4) and nitrate (O2N-O-, pKa -1.37), the major metabolites of nitric oxide (NO), the C-H acidic malondialdehyde (MDA; (CHO)2CH2, pKa 4.5), and creatinine for correction of analytes excretion. All analytes were measured by validated isotopologues using gas chromatography-mass spectrometry (GC-MS) methods. AZM excretion in the urine reached its maximum value after 2 h and was fairly stable for the next 3 h. Time series analysis by the ARIMA method was performed. AZM ingestion increased temporarily the urinary excretion of the amino acids Leu + Ile, nitrite and nitrate, decreased temporarily the urinary excretion of other amino acids. AZM decreased sustainably the urinary excretion of MDA, a biomarker of oxidative stress (i.e. lipid peroxidation). Whether this decrease is due to inhibition of the excretion of MDA or attenuation of oxidative stress by AZM is unknown. The acute and chronic effects of AZM on the urinary excretion of electrolytes and physiological substances reported in the literature are discussed in depth in the light of its extraordinary pharmacokinetics and pharmacodynamics. Tolerance development/drug resistance to AZM in chronic use and potential mechanisms are also addressed.

Paediatric idiopathic intracranial hypertension: Epidemiology, clinical features and treatment outcomes in a tertiary care centre in Western Australia.

AIM: This retrospective study aims to analyse the epidemiology, clinical and neuroimaging features, treatment modalities, and outcomes of paediatric idiopathic intracranial hypertension (IIH) in a tertiary care centre in Australia. METHODS: Using the International Classification of Diseases Diagnostic Criteria for IIH, we identified and analysed a cohort of children diagnosed with IIH over a 5-year period (2017-2022). Data on patient demographics, symptomatology, examination findings, investigative results, treatments and outcomes were collected from medical records and electronic health records. RESULTS: A total of 45 cases were analysed. The pre-pubertal group saw a male predominance and the post-pubertal a female one. Increased body mass index was an associated comorbidity in majority of patients. Headaches (89%) and visual symptoms (56%) were the most common symptoms, with tinnitus also seen in 20% of patients. Papilledema was detected in 91% of the cases examined. The commonest neuroimaging features were optic nerve sheath distention (78%) and empty sella (49%). Acetazolamide was the primary treatment, with most patients responding well. Only a minority required surgical intervention. Long-term resolution of headaches was achieved in 89% of patients. CONCLUSIONS: The incidence of paediatric IIH in the West Australian population appears relatively high. It presents with subtle symptoms, emphasising the need for increased awareness among health-care providers. Younger children may represent a distinct subgroup with unique clinical features. Timely diagnosis and aggressive medical management lead to favourable outcomes. However, weight loss interventions showed limited effectiveness. This study underscores the importance of early recognition and management of paediatric IIH to optimise patient outcomes.