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Arquivos de Neuro-psiquiatria May 2022Idiopathic Intracranial Hypertension (IIH) is a secondary headache with a steadily growing incidence. Currently, there is little evidence to guide the treatment of IIH. (Review)
Review
BACKGROUND
Idiopathic Intracranial Hypertension (IIH) is a secondary headache with a steadily growing incidence. Currently, there is little evidence to guide the treatment of IIH.
OBJECTIVE
To review the pathophysiology of IIH, with focus on the role of obesity as a risk factor, and the implications for new therapeutic perspectives.
METHODS
in this narrative review, we summarized the current knowledge on treatment options highlighting available evidence for managing intracranial hypertension, obesity, and headache.
RESULTS
Clinical Presentation: headache is the most common symptom and a significant cause of quality-of-life impairment. Visual loss is common in the diagnosis. Pathophysiology: there is no unified theory able to explain all symptoms and the evolution of the disease. There is growing data pointing to metabolic changes and obesity with a central role in IIH pathophysiology. Treatment: most published data on IIH treatment is related to pressure control and protection from visual loss. Acetazolamide and cerebrospinal fluid diversion are the best options available. Optic nerve sheath fenestration might be useful to temporally control the pressure over the optic nerve and thus protect from visual deterioration. Recently, venous sinus stenting has proven to be a safe option in selected cases. Finally, bariatric surgery has proven to effectively control elevated intracranial pressure.
CONCLUSION
IIH is a potential cause of high disability. Early recognition is important, and treatment should be tailored to the needs of each case. There is a lack of research on headache management, which might persist after ICP control.
Topics: Acetazolamide; Headache; Humans; Intracranial Hypertension; Obesity; Pseudotumor Cerebri; Vision Disorders
PubMed: 35976300
DOI: 10.1590/0004-282X-ANP-2022-S110 -
Expert Opinion on Therapeutic Targets 2023Four different genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) are present in bacteria, α-, β-, γ- and ι-CAs. They play relevant functions related... (Review)
Review
INTRODUCTION
Four different genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) are present in bacteria, α-, β-, γ- and ι-CAs. They play relevant functions related to CO, HCO/H ions homeostasis, being involved in metabolic biosynthetic pathways, pH regulation, and represent virulence and survival factors for bacteria in various niches. Bacterial CAs started to be considered druggable targets in the last decade, as their inhibition impairs survival, growth, and virulence of these pathogens.
AREAS COVERED
Significant advances were registered in the last years for designing effective inhibitors of sulfonamide type for α-CA, α-CA, vacomycin-resistant enterococci (VRE) α- and γ-CAs, for which the in vivo validation has also been achieved. MIC-s in the range of 0.25-4.0 µg/mL for wild type and drug resistant strains, and of 0.007-2.0 µg/mL for VRE were observed for some 1,3,4-thiadiazole-2-sulfonamides, and acetazolamide was effective in gut decolonization from VRE.
EXPERT OPINION
Targeting bacterial CAs from other pathogens, among which , , , serovar Typhimurium, , , , , , , , , , may lead to novel antibacterials devoid of drug resistance problems.
Topics: Humans; Carbonic Anhydrase Inhibitors; Acetazolamide; Sulfonamides; Carbonic Anhydrases; Bacteria; Anti-Bacterial Agents; Sulfanilamide; Structure-Activity Relationship
PubMed: 37747071
DOI: 10.1080/14728222.2023.2263914 -
Revue Medicale Suisse Oct 2023Acute heart failure is a leading cause of hospitalisations with an increasing economic and public health burden. Management of acute heart failure involves the use of... (Randomized Controlled Trial)
Randomized Controlled Trial
Acute heart failure is a leading cause of hospitalisations with an increasing economic and public health burden. Management of acute heart failure involves the use of diuretics to treat congestion and improve morbimortality. Despite current guidelines, numerous patients maintain congestion and often leave the hospital setting with incomplete volume depletion, leading to an increased risk of rehospitalisation. A recent multicentric randomised controlled trial studied the administration of acetazolamide in addition to standard care with loop diuretics in the acute setting. There was a significantly faster decongestion, based on a pragmatic clinical score, with very few side effects.
Topics: Humans; Acetazolamide; Diuretics; Heart Failure; Drug-Related Side Effects and Adverse Reactions; Hospitalization
PubMed: 37878100
DOI: 10.53738/REVMED.2023.19.847.2002 -
European Heart Journal Jun 2023Acetazolamide inhibits proximal tubular sodium and bicarbonate re-absorption and improved decongestive response in acute heart failure in the ADVOR trial. It is unknown... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Acetazolamide inhibits proximal tubular sodium and bicarbonate re-absorption and improved decongestive response in acute heart failure in the ADVOR trial. It is unknown whether bicarbonate levels alter the decongestive response to acetazolamide.
METHODS AND RESULTS
This is a sub-analysis of the randomized, double-blind, placebo-controlled ADVOR trial that randomized 519 patients with acute heart failure and volume overload in a 1:1 ratio to intravenous acetazolamide (500 mg/day) or matching placebo on top of standardized intravenous loop diuretics (dose equivalent of twice oral maintenance dose). The primary endpoint was complete decongestion after 3 days of treatment (morning of day 4). Impact of baseline HCO3 levels on the treatment effect of acetazolamide was assessed. : Of the 519 enrolled patients, 516 (99.4%) had a baseline HCO3 measurement. Continuous HCO3 modelling illustrated a higher proportional treatment effect for acetazolamide if baseline HCO3 ≥ 27 mmol/l. A total of 234 (45%) had a baseline HCO3 ≥ 27 mmol/l. Randomization towards acetazolamide improved decongestive response over the entire range of baseline HCO3- levels (P = 0.004); however, patients with elevated baseline HCO3 exhibited a significant higher response to acetazolamide [primary endpoint: no vs. elevated HCO3; OR 1.37 (0.79-2.37) vs. OR 2.39 (1.35-4.22), P-interaction = 0.065), with higher proportional diuretic and natriuretic response (both P-interaction < 0.001), greater reduction in congestion score on consecutive days (treatment × time by HCO3-interaction <0.001) and length of stay (P-interaction = 0.019). The larger proportional treatment effect was mainly explained by the development of diminished decongestive response in the placebo arm (loop diuretics only), both with regard to reaching the primary endpoint of decongestion as well as reduction in congestion score. Development of elevated HCO3 further worsened decongestive response in the placebo arm (P-interaction = 0.041). A loop diuretic only strategy was associated with an increase in the HCO3 during the treatment phase which was prevented by acetazolamide (day 3: placebo 74.8% vs. acetazolamide 41.3%, P < 0.001).
CONCLUSION
Acetazolamide improves decongestive response over the entire range of HCO3- levels; however, the treatment response is magnified in patients with baseline or loop diuretic-induced elevated HCO3 (marker of proximal nephron NaHCO3 retention) by specifically counteracting this component of diuretic resistance.
Topics: Humans; Acetazolamide; Sodium Potassium Chloride Symporter Inhibitors; Bicarbonates; Diuretics; Heart Failure; Treatment Outcome
PubMed: 37138385
DOI: 10.1093/eurheartj/ehad236 -
European Journal of Heart Failure Sep 2023Both acetazolamide and sodium-glucose cotransporter 2 (SGLT2) inhibitors block sodium reabsorption in the proximal renal tubule primarily through inhibition of... (Review)
Review
Similarities and distinctions between acetazolamide and sodium-glucose cotransporter 2 inhibitors in patients with acute heart failure: Key insights into ADVOR and EMPULSE.
Both acetazolamide and sodium-glucose cotransporter 2 (SGLT2) inhibitors block sodium reabsorption in the proximal renal tubule primarily through inhibition of sodium-hydrogen exchanger isoform 3 (NHE3), but neither SGLT2 inhibitors nor acetazolamide produce a sustained natriuresis due to compensatory upregulation of sodium reabsorption at distal nephron sites. Nevertheless, acetazolamide and SGLT2 inhibitors have been used as adjunctive therapy to loop diuretics in states where NHE3 is upregulated, e.g. acute heart failure. Two randomized controlled trials have been carried out with acetazolamide in acute heart failure (DIURESIS-CHF and ADVOR). In ADVOR, acetazolamide improved physical signs of fluid retention, but this finding could not be explained by the modest observed diuretic effect. Acetazolamide did not produce a natriuresis in the DIURESIS-CHF trial, and in ADVOR, immediate effects on symptoms and body weight were not reported, and the drug had no effect on morbidity or mortality after 90 days. Three randomized controlled trials have been carried out with empagliflozin (EMPAG-HF, EMPA-RESPONSE-AHF and EMPULSE) in acute heart failure. The EMPULSE trial did not report effects on diuresis or in changes in physical signs of congestion during the first week of treatment, but in EMPAG-HF and EMPA-RESPONSE-AHF, empagliflozin had no effect of dyspnoea, urinary sodium excretion or body weight during the first 4 days. In the EMPULSE trial, empagliflozin improved health status at 15 days and reduced the risk of worsening heart failure events at 90 days, but these effects are similar in magnitude and time course to the early statistical significance on the risk of heart failure hospitalizations achieved within 14-30 days in the major trials of SGLT2 inhibitors in patients with chronic heart failure. Neurohormonal inhibitors produce this early effect in the absence of a diuresis. Additionally, in numerous randomized controlled trials, in-hospital diuretic intensification has not reduced the risk of major heart failure events, even when treatment is sustained. These findings, taken collectively, suggest that any immediate diuretic effects of acetazolamide and SGLT2 inhibitors in acute heart failure are not likely to influence the short- or long-term clinical course of patients.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Heart Failure; Acetazolamide; Sodium-Hydrogen Exchanger 3; Diuretics; Sodium; Body Weight; Glucose; Diabetes Mellitus, Type 2
PubMed: 37403655
DOI: 10.1002/ejhf.2968 -
High Altitude Medicine & Biology Mar 2023Doherty, Connor J., Jou-Chung Chang, Benjamin P. Thompson, Erik R. Swenson, Glen E. Foster, and Paolo B. Dominelli. The impact of acetazolamide and methazolamide on... (Review)
Review
Doherty, Connor J., Jou-Chung Chang, Benjamin P. Thompson, Erik R. Swenson, Glen E. Foster, and Paolo B. Dominelli. The impact of acetazolamide and methazolamide on exercise performance in normoxia and hypoxia. . 24:7-18, 2023.-Carbonic anhydrase (CA) inhibitors are commonly prescribed for acute mountain sickness (AMS). In this review, we sought to examine how two CA inhibitors, acetazolamide (AZ) and methazolamide (MZ), affect exercise performance in normoxia and hypoxia. First, we briefly describe the role of CA inhibition in facilitating the increase in ventilation and arterial oxygenation in preventing and treating AMS. Next, we detail how AZ affects exercise performance in normoxia and hypoxia and this is followed by a discussion on MZ. We emphasize that the overarching focus of the review is how the two drugs potentially affect exercise performance, rather than their ability to prevent/treat AMS , their interrelationship will be discussed. Overall, we suggest that AZ hinders exercise performance in normoxia, but may be beneficial in hypoxia. Based upon head-to-head studies of AZ and MZ in humans on diaphragmatic and locomotor strength in normoxia, MZ may be a better CA inhibitor when exercise performance is crucial at high altitude.
Topics: Humans; Acetazolamide; Methazolamide; Carbonic Anhydrase Inhibitors; Hypoxia; Altitude Sickness; Acute Disease
PubMed: 36802203
DOI: 10.1089/ham.2022.0134 -
Molecules (Basel, Switzerland) Apr 2023The development of heterocyclic derivatives has progressed considerably over the past decades, and many new carbonic anhydrase inhibitors (CAIs) fall into this field. In... (Review)
Review
The development of heterocyclic derivatives has progressed considerably over the past decades, and many new carbonic anhydrase inhibitors (CAIs) fall into this field. In particular, five-membered heterocyclic sulfonamides have been generally shown to be more effective inhibitors compared to six-membered rings ones. Despite the importance of oxygen and nitrogen five-membered heterocyclic aromatic rings in medicinal chemistry, the installation of sulfonamide moiety on such heterocycles has not received much attention. On the other hand, 1,3,4-thiadiazole/thiadiazoline ring-bearing sulfonamides are the scaffolds which have been widely used in a variety of pharmaceutically important CAIs such as acetazolamide, metazolamide and their many derivatives obtained by using the tail approach. Here, we reviewed the field focusing on the diverse biological activities of these CAIs, such as antiglaucoma, antiepileptic, antitumor and antiinfective properties. This review highlights developments involving five-membered heterocyclic sulfonamides over the last years, with a focus on their pharmacological/clinical applications.
Topics: Carbonic Anhydrase Inhibitors; Sulfonamides; Structure-Activity Relationship; Acetazolamide; Anticonvulsants; Sulfanilamide; Dermatologic Agents
PubMed: 37049983
DOI: 10.3390/molecules28073220 -
Brain Sciences Jan 2023Acetazolamide, a carbonic anhydrase inhibitor, is used to treat a variety of ailments. It has been highlighted for its potential to benefit people with bipolar... (Review)
Review
Acetazolamide, a carbonic anhydrase inhibitor, is used to treat a variety of ailments. It has been highlighted for its potential to benefit people with bipolar disorders, for whom there are clear current unmet treatment needs. This scoping review sought to synthesise all available evidence related to the potential effects of acetazolamide on symptoms related to bipolar disorder, acceptability and tolerability, and intervention characteristics (e.g., dose and duration). Following publication of the review protocol, the Pubmed, Embase, and PsycInfo databases were searched (all dated to 31 August 2022). A systematic approach was undertaken to identify eligible articles and extract relevant data from these. Five studies were included, assessing a total of 50 patients treated with acetazolamide. Most patients were from two open-label trials, while the others were case reports. Approximately one third of patients were experiencing psychosis or mania before treatment initiation, and one third had refractory depression. Forty-four percent of patients were estimated to achieve a response (not seemingly affected by the baseline episode type, acetazolamide dose, or duration), while a further 22% appeared to experience minimal benefits from the intervention. Acetazolamide was generally reported to be tolerated well and acceptable for up to 2 years, although reporting for acceptability and tolerability was suboptimal. The reviewed evidence is extremely limited in size and methodology (e.g., no randomised studies, blinding, or standardised outcome assessment). We posit that the current findings are sufficiently encouraging to recommend substantive clinical trials, but we emphasise that at present, the evidence is exceedingly preliminary, and there remains evident uncertainty as to whether acetazolamide could be a viable treatment for bipolar disorders.
PubMed: 36672121
DOI: 10.3390/brainsci13010140 -
Journal of Enzyme Inhibition and... Dec 2024Acetazolamide (AZM) is a strong pharmacological sulphonamide-type (R-SO-NH, p 7.2) inhibitor of the activity of several carbonic anhydrase (CA) isoforms, notably of... (Review)
Review
Acetazolamide (AZM) is a strong pharmacological sulphonamide-type (R-SO-NH, p 7.2) inhibitor of the activity of several carbonic anhydrase (CA) isoforms, notably of renal CA II (, 12 nM) and CA IV (, 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 (HCO) 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, p 3.4) and nitrate (ON-O, p -1.37), the major metabolites of nitric oxide (NO), the C-H acidic malondialdehyde (MDA; (CHO)CH, p 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.
Topics: Humans; Acetazolamide; Nitrites; Nitrates; Carbonic Anhydrases; Amino Acids
PubMed: 38078375
DOI: 10.1080/14756366.2023.2291336