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BMC Medicine Jan 2024We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain... (Randomized Controlled Trial)
Randomized Controlled 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 SpO 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; HCO 18.1 ~ 20.8 mmol/L) and improved SpO (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.
Topics: Humans; Altitude Sickness; Acetazolamide; Prospective Studies; Acute Disease; Hypoxia; Ischemic Preconditioning
PubMed: 38166913
DOI: 10.1186/s12916-023-03209-7 -
Expert Opinion on Drug Metabolism &... Mar 2024Carbonic anhydrases (CAs, EC 4.2.1.1) have been established drug targets for decades, with their inhibitors and activators possessing relevant pharmacological activity... (Review)
Review
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 , vancomycin resistant enterococci, , and 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.
Topics: Humans; Carbonic Anhydrase Inhibitors; Acetazolamide; Sulfonamides; Drug Interactions; Antineoplastic Agents; Structure-Activity Relationship; Phenylurea Compounds
PubMed: 38450431
DOI: 10.1080/17425255.2024.2328152 -
Haematologica Nov 2022Silent cerebral infarcts (SCI) are common in patients with sickle cell disease (SCD) and are thought to be caused by a mismatch between oxygen delivery and consumption....
Silent cerebral infarcts (SCI) are common in patients with sickle cell disease (SCD) and are thought to be caused by a mismatch between oxygen delivery and consumption. Functional cerebrovascular shunting is defined as reduced oxygen offloading due to the rapid transit of blood through the capillaries caused by increased flow and has been suggested as a potential mechanism underlying reduced oxygenation and SCI. We investigated the venous arterial spin labeling signal (VS) in the sagittal sinus as a proxy biomarker of cerebral functional shunting, and its association with hemodynamic imaging and hematological laboratory parameters. We included 28 children and 38 adults with SCD, and ten healthy racematched adult controls. VS, cerebral blood flow (CBF), velocity in the brain feeding arteries, oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) were measured before and after acetazolamide administration. VS was higher in patients with SCD compared to controls (P<0.01) and was increased after acetazolamide administration in all groups (P<0.01). VS was primarily predicted by CBF (P<0.01), but CBF-corrected VS was also associated with decreased CMRO2 (P<0.01). Additionally, higher disease severity defined by low hemoglobin and increased hemolysis was associated with higher CBF-corrected VS. Finally, CMRO2 was negatively correlated with fetal hemoglobin, and positively correlated with lactate dehydrogenase, which could be explained by changes in oxygen affinity. These findings provide evidence for cerebral functional shunting and encourage future studies investigating the potential link to aberrant capillary exchange in SCD.
Topics: Adult; Child; Humans; Magnetic Resonance Imaging; Acetazolamide; Brain; Anemia, Sickle Cell; Oxygen; Cerebral Infarction; Oxygen Consumption
PubMed: 35548868
DOI: 10.3324/haematol.2021.280183 -
The New England Journal of Medicine Dec 2022
Topics: Humans; Acetazolamide; Heart Failure; Diuretics; Acid-Base Imbalance
PubMed: 36577114
DOI: 10.1056/NEJMc2214165 -
The New England Journal of Medicine Dec 2022
Topics: Humans; Acetazolamide; Heart Failure; Diuretics; Acid-Base Imbalance
PubMed: 36577113
DOI: 10.1056/NEJMc2214165 -
The New England Journal of Medicine Dec 2022
Topics: Humans; Acetazolamide; Heart Failure; Diuretics; Acid-Base Imbalance
PubMed: 36577115
DOI: 10.1056/NEJMc2214165 -
Medical Hypothesis, Discovery &... 2022Macular edema (ME) is a vision-threatening condition that commonly develops as a consequence of ocular diseases, including age-related macular degeneration, retinal... (Review)
Review
BACKGROUND
Macular edema (ME) is a vision-threatening condition that commonly develops as a consequence of ocular diseases, including age-related macular degeneration, retinal vaso-occlusion of the central retinal vein and its branches, diabetic retinopathy, central serous chorioretinopathy, uveitis, retinitis pigmentosa, pseudophakia, ocular trauma, and drug toxicity. The treatment of ME remains challenging, although steroids and vascular endothelial growth factor inhibitors are available. Cost-effective therapy using a noninvasive administration route is required. This study aimed at reviewing the role of carbonic anhydrase inhibitors (CAIs) in the management of ME.
METHODS
A literature search was conducted using PubMed/MEDLINE and Google Scholar for studies from January 2000 to March 2022. The following keywords were used in various combinations: "macular edema", "carbonic anhydrase", "carbonic anhydrase inhibitors", "acetazolamide", "dorzolamide", and "brinzolamide".
RESULTS
Articles with high or medium clinical relevance were selected for this review. We found that multiple studies have demonstrated the relevance and efficacy rates of CAIs in the management of ME. Most published studies focused on acetazolamide and dorzolamide, with nearly all studies reporting therapeutic responses.
CONCLUSIONS
ME is the leading cause of vision loss and requires noninvasive and cost-effective pharmacotherapy. With progress in the understanding of ME, particularly the role of carbonic anhydrase as a key driver, CAIs are the focus of research. Further optimization of the choice of CAIs and retinal bioavailability, potentially with nanoparticle formulations, is required to enable the effective management of ME. Further research is warranted to address the therapeutic effects of CAIs in different formulations.
PubMed: 37641698
DOI: 10.51329/mehdiophthal1443 -
Journal of Helminthology Nov 2023Trichinellosis is a global food-borne disease caused by viviparous parasitic nematodes of the genus Due to the lack of effective, safe therapy and the documented...
Trichinellosis is a global food-borne disease caused by viviparous parasitic nematodes of the genus 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 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 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 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 adults and larvae. Acetazolamide-loaded AgNPs are a promising therapy against infection.
Topics: Male; Mice; Animals; Trichinellosis; Acetazolamide; Trichinella spiralis; Silver; Antioxidants; Metal Nanoparticles; Larva; Rodent Diseases
PubMed: 37970645
DOI: 10.1017/S0022149X23000731 -
JSLS : Journal of the Society of... 2022To perform a systematic review and meta-analysis to evaluate the efficacy of perioperative acetazolamide (ACTZ) administration with laparoscopy for reducing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
To perform a systematic review and meta-analysis to evaluate the efficacy of perioperative acetazolamide (ACTZ) administration with laparoscopy for reducing postoperative referred pain.
METHODS
The following databases were searched from inception to March 1, 2020: Cochrane, PubMed, PubMed Central, Ovid, and Embase. Electronic search used: Acetazolamide AND (laparoscopy OR laparoscopic OR Celioscopy OR Celioscopies OR Peritoneoscopy OR Peritoneoscopies). No limits or filters were used. We included only studies of patients who underwent abdominal laparoscopy (LSC), had a pain assessment at approximately 24 hours postoperatively, and included a treatment with ACTZ group and a no-treatment or minimal-treatment comparison group.
RESULTS
Five studies met inclusion criteria, with a combined total of 253 participants, 116 in the ACTZ group and 137 in the control group. A Bayesian hierarchical model was assumed for the study specific treatment effects. Posterior sampling was conducted via Markov Chain Monte Carlo methods, and posterior inference carried out on the hierarchical treatment effect. ACTZ significantly decreased average pain scores compared to control group by -0.726 points (95% confidence interval -1.175-0.264). The posterior probability that ACTZ decreases mean pain scores by ≥ 0.5 was 0.846.
CONCLUSION
Current available evidence demonstrates that perioperative ACTZ may provide a modest improvement in postoperative referred pain following LSC.
Topics: Acetazolamide; Bayes Theorem; Humans; Laparoscopy; Pain, Postoperative; Pain, Referred
PubMed: 36071992
DOI: 10.4293/JSLS.2022.00032 -
Sleep Apr 2023To assess altitude-induced sleep and nocturnal breathing disturbances in healthy lowlanders 40 y of age or older and the effects of preventive acetazolamide treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVES
To assess altitude-induced sleep and nocturnal breathing disturbances in healthy lowlanders 40 y of age or older and the effects of preventive acetazolamide treatment.
METHODS
Clinical examinations and polysomnography were performed at 760 m and in the first night after ascent to 3100 m in a subsample of participants of a larger trial evaluating altitude illness. Participants were randomized 1:1 to treatment with acetazolamide (375 mg/day) or placebo, starting 24 h before and while staying at 3100 m. The main outcomes were indices of sleep structure, oxygenation, and apnea/hypopnea index (AHI).
RESULTS
Per protocol analysis included 86 participants (mean ± SE 53 ± 7 y old, 66% female). In 43 individuals randomized to placebo, mean nocturnal pulse oximetry (SpO2) was 94.0 ± 0.4% at 760 m and 86.7 ± 0.4% at 3100 m, with mean change (95%CI) -7.3% (-8.0 to -6.5); oxygen desaturation index (ODI) was 5.0 ± 2.3 at 760 m and 29.2 ± 2.3 at 3100 m, change 24.2/h (18.8 to 24.5); AHI was 11.3 ± 2.4/h at 760 m and 23.5 ± 2.4/h at 3100 m, change 12.2/h (7.3 to 17.0). In 43 individuals randomized to acetazolamide, altitude-induced changes were mitigated. Mean differences (Δ, 95%CI) in altitude-induced changes were: ΔSpO2 2.3% (1.3 to 3.4), ΔODI -15.0/h (-22.6 to -7.4), ΔAHI -11.4/h (-18.3 to -4.6). Total sleep time, sleep efficiency, and N3-sleep fraction decreased with an ascent to 3100 m under placebo by 40 min (17 to 60), 5% (2 to 8), and 6% (2 to 11), respectively. Acetazolamide did not significantly change these outcomes.
CONCLUSIONS
During a night at 3100 m, healthy lowlanders aged 40 y or older revealed hypoxemia, sleep apnea, and disturbed sleep. Preventive acetazolamide treatment improved oxygenation and nocturnal breathing but had no effect on sleep duration and structure.
TRIAL REGISTRATION
The trial is registered at Clinical Trials, https://clinicaltrials.gov, NCT03561675.
Topics: Humans; Female; Male; Acetazolamide; Altitude; Sleep; Respiration
PubMed: 36356042
DOI: 10.1093/sleep/zsac269