Drug interactions of carbonic anhydrase inhibitors and activators.

INTRODUCTION: Carbonic anhydrases (CAs, EC 4.2.1.1) have been established drug targets for decades, with their inhibitors and activators possessing relevant pharmacological activity and applications in various fields. At least 11 sulfonamides/sulfamates are clinically used as diuretics, antiglaucoma, antiepileptic, or antiobesity agents and one derivative, SLC-0111, is in clinical trials as antitumor/antimetastatic agent. The activators were less investigated with no clinically used agent. AREAS COVERED: Drug interactions between CA inhibitors/activators and various other agents are reviewed in publications from the period March 2020 - January 2024. EXPERT OPINION: Drug interactions involving these agents revealed several interesting findings. Acetazolamide plus loop diuretics is highy effective in acute decompensated heart failure, whereas ocular diseases such as X-linked retinoschisis and macular edema were treated by acetazolamide plus bevacizumab or topical NSAIDs. Potent anti-infective effects of acetazolamide and other CAIs, alone or in combination with other agents were demonstrated for the management of Neisseria gonorrhoea, vancomycin resistant enterococci, Acanthamoeba castellanii, Trichinella spiralis, and Cryptococcus neoformans infections. Topiramate, in combination with phentermine is incresingly used for the management of obesity, whereas zonisamide plus levodopa is highly effective for Parkinson's disease. Acetazolamide, methazolamide, ethoxzolamide, and SLC-0111 showed synergistic antitumor/antimetastatic action in combination with many other antitumor drugs.

Idiopathic intracranial hypertension in two twin sisters.

Idiopathic intracranial hypertension (IIH) is a condition of unknown aetiology characterised by an increase in the intracranial pressure. Familial cases of IIH are rare and not well-understood. We present two monozygotic twins who developed IIH two years apart. The case involves two monozygotic female twins developing IIH in their 50s. They presented with a history of blurry vision and headaches. The diagnosis included the neurological, radiological and ophthalmological examination, excluding other causes. Both patients received treatment with acetazolamide, successfully resolving the papilloedema and restoring a normal visual field. This case highlights the occurrence of IIH among twins presenting at similar periods, emphasising the potential genetic influence. Clinicians should alert and educate the family regarding the risk factors and potential symptoms of this condition in the unlikely occurrence that other family members are affected.

Acetazolamide as an Adjunctive Diuretic Therapy for Patients with Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis.

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; I2 = 54%; moderate certainty), urine output (MD 1.04, 95% CI 0.10-1.97, P = 0.03; I2 = 79%; moderate certainty) and decongestion [odds ratio (OR) 1.62, 95% CI 1.14-2.31, P = 0.007; I2 = 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; I2 = 0%; low certainty), edema (RR 1.02, 95% CI 0.52-2.0, P = 0.95; I2 = 45%; very low certainty), raised jugular venous pressure (JVP) (RR 0.86, 95% CI 0.63-1.17, P = 0.35; I2 = 0%; low certainty), and pulmonary rales (RR 0.82, 95% CI 0.44-1.51, P = 0.52; I2 = 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.

Successful treatment approaches for tumoral calcinosis in children and young people: A condition of diverse pathogenesis.

BACKGROUND: Ectopic calcification is inappropriate biomineralization of soft tissues occurring due to genetic or acquired causes of hyperphosphataemia and rarely in normophosphataemic individuals. Tumoral Calcinosis (TC) is a rare metabolic bone disorder commonly presenting in childhood and adolescence with periarticular extra-capsular calcinosis. Three subtypes of TC have been recognised: primary hyperphosphataemic familial TC (HFTC), primary normophosphataemic familial TC and secondary TC most commonly seen in chronic renal failure. In the absence of established treatment, management is challenging due to variable success rates with medical therapies and recurrence following surgery. AIM: We outline the successful treatment approaches in four children with TC (2 normophosphatemic TC, 2 HFTC) aged 2.5-10 years at initial presentation. CASES: Patient 1 (P1) presented at 10 years with a painless lump behind the right knee, P2 with swelling of the right knee anteriorly at 9 years, P3 and P4 with pain and swelling over the right elbow at 5 and 2.5 years respectively. All patients were of Black African-Caribbean origin and were previously reported to be fit and well with no family history of TC. RESULTS: P1, P2 had normophosphataemic TC and P3, P4 had HFTC with genetically confirmed GALNT3 mutation. All four patients had initial surgical resection with TC confirmed on histology. P1 had complete surgical resection with no recurrence at 27 months post-operatively. P2 had significant overgrowth of the tumour following surgery and was subsequently successfully managed with 25 % topical sodium metabisulphite (total duration of 8 months with a 4 month gap during which there was recurrence). P3 had post-surgical recurrence of TC on the right elbow and a new lesion on left elbow which resolved with oral acetazolamide monotherapy (15-20 mg/kg/day). P4 had recurrence of right elbow lesion following surgery and developed an extensive new hip lesion on sevelamer therapy which resolved completely with additional acetazolamide therapy (18-33 mg/kg/day). Acetazolamide was well tolerated with normal growth for 5 years in P3 and 6.5 years in P4 and no recurrence of lesions. CONCLUSION: The frequent post-surgical recurrence in TC and successful medical therapy on the other hand indicates that medical management as first line therapy should be adopted. Monotherapies with topical 25 % sodium metabisulphite in normophosphataemic and oral acetazolamide in HFTC are effective treatment strategies which are well tolerated.

Pearls & Oy-sters: CACNA1A-Related Paroxysmal Tonic Upgaze With Ataxia Responsive to Acetazolamide.

A 9-month-old male infant was evaluated for sudden onset of paroxysmal episodes of forced, conjugate upward eye deviation. Extensive in-hospital evaluation including electrophysiology and neuroimaging studies were reassuring against seizures or a structural abnormality. Given the clinical presentation of sudden onset intermittent upward eye deviations, downbeating saccades, associated ataxia, and typical development, a clinical diagnosis of paroxysmal tonic upgaze (PTU) with ataxia was made. Targeted genetic testing of CACNA1A was performed, which revealed a variant of undetermined significance, which was later classified as a de novo pathogenic variant after protein modeling and parental testing performed. Off-label use of oral acetazolamide was prescribed, which led to dose-responsive decrease in the frequency and intensity of eye movement episodes. After 6 months of episode freedom at 2 years of age, acetazolamide was discontinued without return of episodes. Neurodevelopmental assessments revealed continued typical development. This case is presented to describe the diagnostic formulation, etiologic evaluation, and symptomatic treatment of CACNA1A-related PTU with ataxia.

Obstructive sleep apnea in those with idiopathic intracranial hypertension undergoing diagnostic in-laboratory polysomnography.

RATIONALE: The association of obstructive sleep apnea (OSA) with idiopathic intracranial hypertension (IIH) remains unclear, and few studies have used objective in-laboratory polysomnography (PSG) data. Thus, we used PSG data to examine the: 1) association between OSA, and its severity, with IIH and 2) sex differences in OSA severity in those with and without IIH. METHODS: We retrospectively analyzed diagnostic PSG data from January 2015 to August 2023 for patients who were diagnosed with IIH by a neuro-ophthalmologist using the modified Dandy criteria. We selected three age, sex, and body mass index (BMI) matched controls for each IIH patient. We examined potential associations of IIH with OSA using regression. Sex differences were analyzed using ANOVA. RESULTS: Of 3482 patients who underwent PSG, we analyzed 78 IIH patients (16 males) and 234 matched controls (48 males). Five (6.4 %) IIH and 39 (16.7 %) control patients had OSA, defined as AHI≥15. After adjusting for age, sex, BMI, and comorbidities, IIH was negatively associated with the presence of OSA (OR 0.29, 95%CI 0.10-0.87, p = 0.03). However, models that adjusted for acetazolamide use, with or without comorbidities, showed no significant relationship with OSA (OR 0.31, p = 0.20). Males with IIH had a significantly higher age (p = 0.020), OSA severity (p = 0.032), and arousal index (p = 0.046) compared to females with IIH. CONCLUSIONS: IIH treated with acetazolamide was not an independent risk factor for OSA presence or severity. The presence of IIH treated with acetazolamide likely does not warrant routine screening for OSA, but related risk factors may identify appropriate patients.

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.

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.

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.

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 and topiramate lower intracranial pressure through differential mechanisms: The effect of acute and chronic administration.

BACKGROUND AND PURPOSE: Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate. EXPERIMENTAL APPROACH: Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross-over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT-qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions. KEY RESULTS: We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24-h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium-dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes. CONCLUSIONS AND IMPLICATIONS: Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP.

Acetazolamide loaded-silver nanoparticles: A potential treatment for murine trichinellosis.

Trichinellosis is a global food-borne disease caused by viviparous parasitic nematodes of the genus Trichinella. Due to the lack of effective, safe therapy and the documented adverse effects of traditional therapy, this study aimed to evaluate the therapeutic effect of acetazolamide-loaded silver nanoparticles (AgNPs) on murine trichinellosis. Fifty male Swiss albino mice were divided into five groups of ten mice each: Group I, normal control group; Group II, infected with T. spiralis and not treated; Group III, infected and given AgNPs; Group IV, infected and treated with acetazolamide; and Group V, infected and treated with acetazolamide-loaded AgNPs. Mice were infected orally with 250 larvae. The efficacy was assessed by counting T. spiralis adults and larvae, measuring serum total antioxidant capacity, and observing the histopathological and ultrastructural alterations. Acetazolamide-loaded AgNPs treatment exhibited the highest percentage of reduction (84.72% and 80.74%) for the intestinal adults and the muscular larvae of T. spiralis-infected animals, respectively. Furthermore, during the intestinal and muscular phases, the serum of the same group had the best free-radical scavenging capacity (antioxidant capacity), which reduced tissue damage induced by oxidative stress. Histopathologically, the normal intestinal and muscular architecture was restored in the group treated with acetazolamide-loaded AgNPs, in addition to the reduced inflammatory infiltrate that alleviated inflammation compared to infected animals. Our results confirmed the marked destruction of the ultrastructural features of T. spiralis adults and larvae. Acetazolamide-loaded AgNPs are a promising therapy against T. spiralis infection.

A multi-arm, parallel, preclinical study investigating the potential benefits of acetazolamide, candesartan, and triciribine in combination with fluconazole for the treatment of cryptococcal meningoencephalitis.

Cryptococcus neoformans, an opportunistic fungal pathogen, primarily infects immunodeficient patients frequently causing cryptococcal meningoencephalitis (CM). Increased intracranial pressure (ICP) is a serious complication responsible for increased morbidity and mortality in CM patients. Non-invasive pharmacological agents that mitigate ICP could be beneficial in treating CM patients. The objective of the study was to investigate the efficacy of acetazolamide (AZA), candesartan (CAN), and triciribine (TCBN), in combination with the antifungal fluconazole, on C. neoformans-induced endothelial, brain, and lung injury in an experimental mouse model of CM. Our study shows that C. neoformans increases the expression of brain endothelial cell (BEC) junction proteins Claudin-5 (Cldn5) and VE-Cadherin to induce pathological cell-barrier remodeling and gap formation associated with increased Akt and p38 MAPK activation. All three agents inhibited C. neoformans-induced endothelial gap formation, only CAN and TCBN significantly reduced C. neoformans-induced Cldn5 expression, and only TCBN was effective in inhibiting Akt and p38MAPK. Interestingly, although C. neoformans did not cause brain or lung edema in mice, it induced lung and brain injuries, which were significantly reversed by AZA, CAN, or TCBN. Our study provides novel insights into the direct effects of C. neoformans on BECs in vitro, and the potential benefits of using AZA, CAN, or TCBN in the management of CM patients.

Should topiramate be initial therapy in the management of idiopathic intracranial hypertension?: A literature review.

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology that primarily affects obese women of childbearing age. Symptoms include disabling headaches, visual disturbances, and intracranial noises (pulsatile tinnitus). Currently, no standardized treatment guidelines are available and the current management focuses on weight loss and acetazolamide use. There is an increasing body of evidence suggesting that the initial use of topiramate may be considered in IIH treatment. Acetazolamide is the recommended initial treatment for IIH, with topiramate often used as a second-line agent. Topiramate has multiple benefits to indicate it would pose effective in IIH management. Through varying mechanisms, it leads to weight loss and improves migraine headache control, the most common headache phenotype in IIH. Topiramate also inhibits the carbonic anhydrase enzyme like acetazolamide to reduce intracranial pressure and treat papilledema. The safety profile of topiramate is comparable or superior to acetazolamide. To date, there are limited studies comparing topiramate to acetazolamide or other treatment modalities in IIH. Based on its varying mechanisms of action, topiramate is a strong potential treatment agent for IIH, yet acetazolamide is often chosen first-line. However, the data supporting use of acetazolamide or topiramate is inefficient to designate one agent preferred over the other. There is a need for further studies assessing topiramate use in the treatment of IIH, and comparing topiramate use to other treatment modalities.

Renal function and decongestion with acetazolamide in acute decompensated heart failure: the ADVOR trial.

BACKGROUND AND AIMS: In the ADVOR trial, acetazolamide improved decongestion in acute decompensated heart failure (ADHF). Whether the beneficial effects of acetazolamide are consistent across the entire range of renal function remains unclear. METHODS: This is a pre-specified analysis of the ADVOR trial that randomized 519 patients with ADHF to intravenous acetazolamide or matching placebo on top of intravenous loop diuretics. The main endpoints of decongestion, diuresis, natriuresis, and clinical outcomes are assessed according to baseline renal function. Changes in renal function are evaluated between treatment arms. RESULTS: On admission, median estimated glomerular filtration rate (eGFR) was 40 (30-52) mL/min/1.73 m². Acetazolamide consistently increased the likelihood of decongestion across the entire spectrum of eGFR (P-interaction = .977). Overall, natriuresis and diuresis were higher with acetazolamide, with a higher treatment effect for patients with low eGFR (both P-interaction < .007). Acetazolamide was associated with a higher incidence of worsening renal function (WRF; rise in creatinine ≥ 0.3 mg/dL) during the treatment period (40.5% vs. 18.9%; P < .001), but there was no difference in creatinine after 3 months (P = .565). This was not associated with a higher incidence of heart failure hospitalizations and mortality (P-interaction = .467). However, decongestion at discharge was associated with a lower incidence of adverse clinical outcomes irrespective of the onset of WRF (P-interaction = .805). CONCLUSIONS: Acetazolamide is associated with a higher rate of successful decongestion across the entire range of renal function with more pronounced effects regarding natriuresis and diuresis in patients with a lower eGFR. While WRF occurred more frequently with acetazolamide, this was not associated with adverse clinical outcomes. CLINICALTRIALS.GOV IDENTIFIER: NCT03505788.