Ocular pharmacokinetics of acetazolamide from intravitreal implants by high-performance liquid chromatography coupled to tandem mass spectrometry.

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.

The episodic ataxias.

The primary episodic ataxias (EAs) are a group of autosomal-dominant disorders characterized by transient recurrent incoordination and truncal instability, often triggered by physical exertion or emotional stress and variably associated with progressive baseline ataxia. There are now nine designated subtypes EA1-9 (OMIM) and late onset cerebellar ataxia with episodic features as newly designated SCA27B, based largely on genetic loci. Mutations have been identified in multiple individuals and families in 4 of the 9 EA subtypes, mostly with the onset before adulthood. This chapter focuses on the clinical assessment and management of EA, genetic diagnosis, and neurophysiologic consequences of the causative mutations in the best characterized EA syndromes: EA1 caused by mutations in KCNA1 encoding a neuronal voltage-gated potassium channel, EA2 caused by mutations in CACNA1A encoding a neuronal voltage-gated calcium channel, EA6 caused by mutations in SLC1A3 encoding a glutamate transporter that is also an anion channel, and SCA27B with late onset episodic ataxia caused by an intronic trinucleotide repeat in FGF14 encoding fibroblast growth factor 14 important in regulating the distribution of voltage-gated sodium channels in the cerebellar Purkinje and granule cells. The study of EA has illuminated previously unrecognized but important roles of ion channels and transporters in brain function with shared mechanisms underlying cerebellar ataxia, migraine, and epilepsy.

Acetazolamide suppresses the progression of hepatocellular carcinoma induced by diethylnitrosamine in Wistar albino rats.

Hepatocellular carcinoma (HCC) continues to be the most prevalent type of liver cancer worldwide. Diethylnitrosamine (DEN)-induced HCC is an extensively used hepatic cancer model in experimental animals. Acetazolamide (AZA) is a carbonic anhydrase enzyme inhibitor. This study aimed to assess the therapeutic mechanism of AZA against DEN-induced HCC. Thirty male Wistar albino rats were divided equally into three groups. Group I (C): control group, Group II (HCC): DEN-induced HCC, and Group III (HCC/AZA): AZA-treated HCC. Verification of the HCC induced by DEN was confirmed by elevated liver enzymes' activities, and increased α-fetoprotein (AFP) levels, as well as distinct liver architecture changes. On the other hand, the AZA-treated HCC group experienced decreases in the activities of serum liver enzymes and AFP levels, as well as, regulated liver architecture. Additionally, it downregulated p-p38 MAPK/p-JNK1/JNK2/p-C-Jun/p-NF-κB p65 protein expressions. Moreover, it ameliorated autophagy by controlling the expression of the p-AMPK/p-mTOR1/LC3 I/II proteins. Furthermore, it downregulated the relative gene expressions of carbonic anhydrase-IX (CAIX) and hexokinase-II (HKII). Histopathological examination of AZA-treated HCC liver tissues supported these findings. Conclusion: AZA provides a new dimension in ameliorating experimentally induced HCC through regulation of hepatic biomarkers, antioxidant status, inflammatory markers, and autophagy, mediated by amelioration of CAIX and HKII gene expressions.

Design and optimization of acetazolamide nanoparticle-laden contact lens using statistical experimental design for controlled ocular drug delivery.

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.

Acetazolamide as an Add-on Therapy Following Barbed Reposition Pharyngoplasty in Obstructive Sleep Apnea: A Randomized Controlled Trial.

Surgical interventions, like barbed reposition pharyngoplasty (BRP), are a valuable alternative for patients with obstructive sleep apnea (OSA) who are unable to tolerate continuous positive airway pressure (CPAP). However, predicting surgical success remains challenging, partly due to the contribution of non-anatomical factors. Therefore, combined medical treatment with acetazolamide, known to stabilize respiratory drive, may lead to superior surgical results. This double-blind, parallel-group randomized controlled trial evaluates the efficacy of acetazolamide as an add-on therapy to BRP in OSA. A total of 26 patients with moderate to severe OSA undergoing BRP were randomized to receive either acetazolamide or placebo post-surgery for 16 weeks. The group who was treated with BRP in combination with acetazolamide showed a reduction in AHI of 69.4%, significantly surpassing the 32.7% reduction of the BRP + placebo group (p < 0.01). The sleep apnea-specific hypoxic burden also decreased significantly in the group who was treated with BRP + acetazolamide (p < 0.01), but not in the group receiving BRP + placebo (p = 0.28). Based on these results, acetazolamide as an add-on therapy following BRP surgery shows promise in improving outcomes for OSA patients, addressing both anatomical and non-anatomical factors.

Role of Acetazolamide in Traumatic CSF Rhinorrhea and Otorrhea: A Randomized Controlled Trial.

Background Untreated cerebrospinal fluid (CSF) rhinorrhea and otorrhea can lead to adverse complications like meningitis and hence should not be overlooked. Acetazolamide reduces CSF production by 48%. The actual role of acetazolamide in the amelioration of traumatic CSF rhinorrhea and otorrhea is not clear as, till date, very few formal studies have been conducted. Aim of the study was to determine the role of acetazolamide in traumatic cerebrospinal fluid rhinorrhea and otorrhea. Materials and Methods A randomized controlled trial was conducted among 134 patients with head injuries presenting to the neurosurgery department of a tertiary care center in North India, with complaints of CSF rhinorrhea and otorrhea within 72 hours of traumatic injury. One-hundred thirty-four patients were randomized into intervention and control group. Comparative analysis was not possible in 58 patients as in due course they were either operated for head injury or lumbar drain was put due to excessive CSF leak; hence, forth comparative analysis was done in 76 patients. Out of these 76 patients, 44 patients belonged to the intervention group (Acetazolamide given) and 32 belong to the control group (Acetazolamide not given). The day of the stoppage of CSF Leak was the main endpoint of this study. Result Majority of the patients were in the age group of 21 to 30 years and were predominantly males. Road traffic accident was observed in 84 (75%) patients. There was no statistically significant difference noted in the mean number of days of CSF leak whether acetazolamide was given or not ( p = 0.344). The complication associated with CSF leak was meningitis. The percentage of patients developing meningitis was more after lumber drain insertion. Conclusion In our study, there was no advantage of adding acetazolamide to the conservative management of traumatic CSF leak. Therefore, the practice of routinely giving acetazolamide should be reconsidered.

Efficacy and Side Effects of Topiramate in Treatment of Children With Pseudotumor Cerebri Syndrome.

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.

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.

Clinical Characteristics, Therapeutic Options, and Outcomes in Hyperphosphatemic Tumoral Calcinosis: A Systematic Review.

This systematic review was performed to understand better the myriad presentations, various therapeutic options, response to therapy, and its clinical outcomes in hyperphosphatemic tumoral calcinosis (HTC). Full texts were selected according to strict inclusion criteria. All case reports of HTC wherein baseline phosphate was measured, treatment offered was mentioned, and information on follow-up and response to therapy that were available were included. A total of 43 of 188 eligible studies (N = 63 patients) met the inclusion criteria. A list of desired data was extracted and graded for methodological quality. A total of 63 individuals (Males = 33) were included from the 43 eligible case studies. The median age of the patients was 18 (IQR 8-32) years. The most frequently involved sites were the hip/gluteal region (34/63; 53.9%) followed by the elbow/forearm (26/63; 41.2%), and the shoulder (18/63; 28.5%). Three patients had conjunctival calcific deposits. The mean (SD) phosphate was 6.9 (1.1) mg/dL. Among the subjects, 36/63 (57.1%) underwent surgical excision with some form of medical therapy. Two patients underwent only surgical excision (2.1%). One patient was maintained on follow-up (1.6%) and 24/63 (38.1%) patients were treated with medical measures. The median (IQR) follow-up duration was 3 (1-9) years. Regression or reduction in lesion size was reported in 19/63 (30.2%) subjects; 20/63 (31.7%) showed progression, 24/63 (38.1%) had features of stable disease, and mortality was reported in 3 patients (4.7%). We report for the first time a detailed description of the clinical and therapeutic response of HTC. A combination of medical measures aimed at lowering serum phosphate appears to be the cornerstone of treatment, although clinical responses may vary.

Acetazolamide Tolerance in Acute Decompensated Heart Failure: An Observational Study.

Objectives: This real-life study aimed to evaluate the safety of acetazolamide (ACZ), a carbonic anhydrase inhibitor with diuretic effects. ACZ has recently been proven to improve decongestion in the context of patients hospitalized for acute heart failure (HF). However, data in terms of safety are lacking. Methods: We conducted a monocentric observational prospective study from November 2023 to February 2024 in a 12-bed cardiology department, recording adverse events (hypotension, severe metabolic acidosis, severe hypokalemia and renal events) during in-hospital HF treatment. All patients hospitalized for acute HF during the study period treated with ACZ (500 mg IV daily for 3 days) on top of IV furosemide (n = 28, 48.3%) were compared with patients who have been treated with IV furosemide alone (n = 30, 51.7%). Results: The patients treated with ACZ were younger than those without (median age 78 (range 67-86) vs. 85 (79-90) years, respectively, p = 0.01) and had less frequent chronic kidney disease (median estimated glomerular fraction rate (60 (35-65) vs. 38 (26-63) mL/min, p = 0.02). As concerned adverse events during HF treatment, there were no differences in the occurrences of hypotension (three patients [10.7%] in the ACZ group vs. four [13.3%], p = 0.8), renal events (four patients [14.3%] in the ACZ group vs. five [16.7%], p = 1) and severe hypokalemia (two [7.1%] in the ACZ group vs. three [10%], p = 1). No severe metabolic acidosis occurred in either group. Conclusions: Although the clinical characteristics differed at baseline, with younger age and better renal function in patients receiving ACZ, the tolerance profile did not significantly differ from patients receiving furosemide alone. Additional observational data are needed to further assess the safety of ACZ-furosemide combination in the in-hospital management of HF, especially in older, frail populations.

Peri-operative management of endoscopic endonasal cerebrospinal fluid leak repair: an international survey.

PURPOSE: Peri-operative management of nasal cerebrospinal fluid (CSF) leaks is not consensual due to limited evidence. The main aim of this study was to identify key factors in peri-operative management of endoscopic endonasal CSF leak repair among international experts. METHODS: A 60-item survey questionnaire collected opinions of members of international learned societies of ENT surgeons and neurosurgeons on nasal packing, post-operative instructions, antibiotic prophylaxis, and CSF volume depletion. RESULTS: The survey had 153 respondents (124 otorhinolaryngologists and 29 neurosurgeons). A resting position was recommended by 85% (130/151) of respondents for extended CSF leak of the anterior skull base, mainly in Fowler's position (72% (110/153)). Nasal packing was used by 85% (130/153) of respondents; 33.3% (51/153) used it to stabilize the reconstruction, and 22.2% (34/153) to prevent bleeding. It was usually removed after 48 h in 44.4% of cases (68/153). CSF depletion was considered by 47.1% (72/153) of respondents in case of CSF leak recurrence and by 34.6% (53/153) in cases of increased intracranial pressure. All respondents gave specific postoperative instructions to patients including driving, running, swimming, diving restrictions and flighting restrictions. In subgroup analysis, ENT surgeons more often recommended a resting position than neurosurgeons (71% vs. 37.9% ; p = 0.0008) and prescribed more antibiotics (82.3% vs. 21.4% ; p < 0.0001). CONCLUSION: Although postoperative management after CSF closure remains challenging and not codified, this international survey revealed some points of consensus concerning resting position and restriction of post-operative activities. Prospective clinical studies must be undertaken to evaluate their efficiency.

A case of middle-aged central sleep apnea due to Joubert syndrome with different treatment effects of oxygen and acetazolamide.

We report a case of severe central sleep apnea incidentally diagnosed during polysomnography for suspected obstructive sleep apnea. Characteristic clinical features included episodic hyperventilation followed by apnea from hypocapnia, which did not follow a Cheyne-Stokes pattern. Combined with the identification of cerebellar and brainstem malformations known as the "molar tooth sign" on a brain magnetic resonance imaging, developmental delay, and motor coordination problems, Joubert syndrome (a congenital disease) was first diagnosed at the age of 50 years. Central apneas were also observed during wakefulness, although not continuously. During sleep, continuous positive airway pressure and adaptive servo-ventilation were ineffective at the referring clinic and at our hospital. Supplemental oxygen decreased the frequency of central apneas and significantly shortened the duration of each central sleep apnea compared with room air. In contrast, the opposite response was observed with acetazolamide administration. CITATION: Murashima R, Shiota S, Sugiyama A, et al. A case of middle-aged central sleep apnea due to Joubert syndrome with different treatment effects of oxygen and acetazolamide. J Clin Sleep Med. 2024;20(10):1705-1710.

Fabrication of acetazolamide loaded leciplex for intraocular delivery: Optimization by 32 full factorial design, in vitro, ex vivo and in vivo pharmacodynamics.

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 32 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.

Management of Neisseria gonorrhoeae infection: from drug resistance to drug repurposing.

INTRODUCTION: Neisseria gonorrhoeae is a common sexually transmitted disease connected with extensive drug resistance to many antibiotics. Presently, only expanded spectrum cephalosporins (ceftriaxone and cefixime) and azithromycin remain useful for its management. AREAS COVERED: New chemotypes for the classical antibiotic drug target gyrase/topoisomerase IV afforded inhibitors with potent binding to these enzymes, with an inhibition mechanism distinct from that of fluoroquinolones, and thus less prone to mutations. The α-carbonic anhydrase from the genome of this bacterium (NgCAα) was also validated as an antibacterial target. EXPERT OPINION: By exploiting different subunits from the gyrase/topoisomerase IV as well as new chemotypes, two new antibiotics reached Phase II/III clinical trials, zoliflodacin and gepotidacin. They possess a novel inhibition mechanism, binding in distinct parts of the enzyme compared to the fluoroquinolones. Other chemotypes with inhibitory activity in these enzymes were also reported. NgCAα inhibitors belonging to a variety of classes were obtained, with several sulfonamides showing MIC values in the range of 0.25-4 µg/mL and significant activity in animal models of this infection. Acetazolamide and similar CA inhibitors might thus be repurposed as antiinfectives. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2016 to 2024.

Sterile Cerebrospinal Fluid Ascites With High Serum Ascites Albumin Gradient Treated With Acetazolamide.

Cerebrospinal fluid (CSF) ascites is a rare cause of ascites that presents in patients with ventriculoperitoneal (VP) shunts, treated by conversion to a ventriculoatrial shunt. Our case describes a patient presenting with CSF ascites almost 40 years after VP shunt placement, with fluid analysis showing elevated serum ascites albumin gradient, and response to acetazolamide therapy. As shown in this case, CSF ascites can present with elevated serum ascites albumin gradient and should be kept a differential diagnosis. Acetazolamide can be considered as a potential alternative treatment in patients who are not candidates for a VP to ventriculoatrial shunt conversion.

Acetazolamide As A Valuable Addition to Acute Heart Failure?

Consider IV Acetazolamide in addition to standard IV loop diuretic therapy in patients hospitalized for acute decompensated heart failure.1.

Morning Glory Anomaly With Serous Macular Detachment.

The morning glory (MG) disc anomaly is a congenital excavation of the posterior globe involving the optic disc, with a distinct appearance reminiscent of the MG flower. Various intracranial and ocular associations with MG have been documented. Conditions such as trans-sphenoidal encephalocele and hypoplasia of the intracranial vasculature have been observed in association with this anomaly. In this report, we present a case of MG optic disc anomaly accompanied by serous macular detachment.

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.

Diuresis Efficacy in Ambulatory Congested Heart Failure Patients: Intrapatient Comparison of 3 Diuretic Regimens (DEA-HF).

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.