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Journal of Medicinal Chemistry Jan 2024is an amoeba that inhabits soil and water in every part of the world. Acanthamoeba infection of the eye causes keratitis and can lead to a loss of vision. Current...
is an amoeba that inhabits soil and water in every part of the world. Acanthamoeba infection of the eye causes keratitis and can lead to a loss of vision. Current treatment options are only moderately effective, have multiple harmful side effects, and are tedious. In our study, we developed a novel drug screening method to define the inhibitory properties of potential new drugs against in vitro. We found that the clinically used carbonic anhydrase inhibitors, acetazolamide, ethoxzolamide, and dorzolamide, have promising antiamoebic properties.
Topics: Acanthamoeba castellanii; Carbonic Anhydrase Inhibitors; Amoeba; Drug Evaluation, Preclinical
PubMed: 38150360
DOI: 10.1021/acs.jmedchem.3c01020 -
Brain Sciences Dec 2023Acetazolamide is a non-competitive inhibitor of carbonic anhydrase, an enzyme expressed in different cells of the central nervous system (CNS) and involved in the... (Review)
Review
BACKGROUND
Acetazolamide is a non-competitive inhibitor of carbonic anhydrase, an enzyme expressed in different cells of the central nervous system (CNS) and involved in the regulation of cerebral blood flow (CBF). The aim of this review was to understand the effects of acetazolamide on CBF, intracranial pressure (ICP) and brain tissue oxygenation (PbtO) after an acute brain injury (ABI).
METHODS
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA), we performed a comprehensive, computer-based, literature research on the PubMed platform to identify studies that have reported the effects on CBF, ICP, or PbtO of acetazolamide administered either for therapeutic or diagnostic purposes in patients with subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, and hypoxic-ischemic encephalopathy.
RESULTS
From the initial search, 3430 records were identified and, through data selection, 11 of them were included for the qualitative analysis. No data on the effect of acetazolamide on ICP or PbtO were found. Cerebral vasomotor reactivity (VMR-i.e., the changing in vascular tone due to a vasoactive substance) to acetazolamide tends to change during the evolution of ABI, with the nadir occurring during the subacute stage. Moreover, VMR reduction was correlated with clinical outcome.
CONCLUSIONS
This systematic review showed that the available studies on the effects of acetazolamide on brain hemodynamics in patients with ABI are scarce. Further research is required to better understand the potential role of this drug in ABI patients.
PubMed: 38137126
DOI: 10.3390/brainsci13121678 -
Cells Dec 2023Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer's disease (AD), which triggers loss of brain vascular smooth muscle cells...
Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors.
Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer's disease (AD), which triggers loss of brain vascular smooth muscle cells (BVSMCs) in cerebral arteries, via poorly understood mechanisms, altering cerebral blood flow, brain waste clearance, and promoting cognitive impairment. We have previously shown that, in brain endothelial cells (ECs), vasculotropic Aβ species induce apoptosis through death receptors (DRs) DR4 and DR5 and mitochondria-mediated mechanisms, while FDA-approved carbonic anhydrase inhibitors (CAIs) prevent mitochondria-mediated EC apoptosis in vitro and in vivo. In this study, we analyzed Aβ-induced extrinsic and intrinsic (DR- and mitochondria-mediated) apoptotic pathways in BVSMC, aiming to unveil new therapeutic targets to prevent BVSMC stress and death. We show that both apoptotic pathways are activated in BVSMCs by oligomeric Aβ42 and and mitochondrial respiration is severely impaired. Importantly, the CAIs methazolamide (MTZ) and acetazolamide (ATZ) prevent the pro-apoptotic effects in BVSMCs, while reducing caspase 3 activation and Aβ deposition in the arterial walls of TgSwDI animals, a murine model of cerebral amyloid angiopathy (CAA). This study reveals new molecular targets and a promising therapeutic strategy against BVSMC dysfunction in AD, CAA, and ARIA (amyloid-related imaging abnormalities) complications of recently FDA-approved anti-Aβ antibodies.
Topics: Animals; Mice; Carbonic Anhydrase Inhibitors; Amyloid beta-Peptides; Endothelial Cells; Muscle, Smooth, Vascular; Alzheimer Disease; Cerebral Amyloid Angiopathy; Mitochondria; Receptors, Death Domain
PubMed: 38132159
DOI: 10.3390/cells12242840 -
Polish Archives of Internal Medicine Dec 2023
Topics: Humans; Diuretics; Acetazolamide; Chlorides; Heart Failure
PubMed: 38126245
DOI: 10.20452/pamw.16629 -
Polish Archives of Internal Medicine Dec 2023
Topics: Humans; Acetazolamide; Heart Failure; Disease Progression
PubMed: 38126242
DOI: 10.20452/pamw.16632 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Dec 2023To explore the effects of hypoxic and hypobaric conditions on blood gas and erythrocyte-related indicators in rats.
OBJECTIVES
To explore the effects of hypoxic and hypobaric conditions on blood gas and erythrocyte-related indicators in rats.
METHODS
SD male rats were exposed to low-pressure hypoxic conditions simulating an altitude of 6500 m in a small or a large experimental cabin. Abdominal aortic blood samples were collected and blood gas indicators, red blood cells (RBCs) count, and hemoglobin (Hb) content were measured. The effects of exposure to different hypoxia times, different hypoxia modes, normal oxygen recovery after hypoxia, and re-hypoxia after hypoxia preconditioning on blood gas indicators, RBCs count and Hb content were investigated.
RESULTS
The effect of blood gas indicators was correlated with the length of exposure time of hypoxia and the reoxygenation after leaving the cabin. Hypoxia caused acid-base imbalance and its severity was associated with the duration of hypoxia; hypoxia also led to an increase in RBCs count and Hb content, and the increase was also related to the time exposed to hypoxia. The effects of reoxygenation on acid-base imbalance in rats caged in a small animal cabin were more severe that those in a large experimental cabin. Acetazolamide alleviated the effects of reoxygenation after leaving the cabin. Different hypoxia modes and administration of acetazolamide had little effect on RBCs count and Hb content. Normal oxygen recovery can alleviate the reoxygenation and acid-base imbalance of hypoxic rats after leaving the cabin and improve the increase in red blood cell and hemoglobin content caused by hypoxia. The improvement of hypoxia preconditioning on post hypoxia reoxygenation is not significant, but it can alleviate the acid-base imbalance caused by hypoxia in rats and to some extent improve the increase in red blood cell and hemoglobin content caused by hypoxia.
CONCLUSIONS
Due to excessive ventilation and elevated RBCs count and Hb content after hypoxia reoxygenation, oxygen partial pressure and other oxygenation indicators in hypoxic rats are prone to become abnormal, while blood gas acid-base balance indicators are relatively stable, which are more suitable for evaluating the degree of hypoxia injury and related pharmacological effects in rats.
Topics: Rats; Animals; Male; Acetazolamide; Hypoxia; Oxygen; Erythrocytes; Hemoglobins; Acid-Base Imbalance
PubMed: 38105680
DOI: 10.3724/zdxbyxb-2023-0352 -
Ophthalmology. Retina Jun 2024To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to...
PURPOSE
To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to evaluate the efficacy of CAIs on visual acuity and cystoid fluid collections (CFC) in XRLS patients in Dutch and Belgian tertiary referral centers.
DESIGN
Retrospective cohort study.
PARTICIPANTS
Forty-two patients with XLRS.
METHODS
In total, 42 patients were enrolled. To be included, patients had to have previous treatment with an oral CAI (acetazolamide), a topical CAI (brinzolamide/dorzolamide), or a combination of an oral and a topical CAI for at least 4 consecutive weeks. We evaluated the effect of the CAI on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on OCT.
MAIN OUTCOME MEASURES
Central foveal thickness and BCVA.
RESULTS
The median age at the baseline visit of the patients in this cohort study was 14.7 (range, 43.6) years, with a median (interquartile range [IQR]) follow-up period of 4.0 (2.2-5.2) years. During the follow-up period, 25 patients were treated once with an oral CAI (60%), 24 patients were treated once with a topical CAI (57%), and 11 patients were treated once with a combination of both topical and oral CAI (26%). We observed a significant reduction of CFT for oral CAI by 14.37 μm per 100 mg per day (P < 0.001; 95% confidence interval [CI], -19.62 to -9.10 μm) and for topical CAI by 7.52 μm per drop per day (P = 0.017; 95% CI, -13.67 to -1.32 μm). The visual acuity changed significantly while on treatment with oral CAI by -0.0059 logMAR per 100 mg (P = 0.008; 95% CI, -0.010 to -0.0013 logMAR). Seven patients (17%) had side effects leading to treatment discontinuation.
CONCLUSIONS
Our data indicate that treatment with (oral) CAI may be beneficial for short-term management of CFC in patients with XLRS. Despite a significant reduction in CFT, the change in visual acuity was modest and not of clinical significance. Nonetheless, the anatomic improvement of the central retina in these patients may be of value to create an optimal retinal condition for future potential treatment options such as gene therapy.
FINANCIAL DISCLOSURE(S)
The authors have no proprietary or commercial interest in any materials discussed in this article.
Topics: Humans; Carbonic Anhydrase Inhibitors; Retinoschisis; Retrospective Studies; Visual Acuity; Male; Tomography, Optical Coherence; Adult; Adolescent; Female; Follow-Up Studies; Young Adult; Treatment Outcome; Child; Subretinal Fluid; Middle Aged; Sulfonamides; Administration, Oral
PubMed: 38104928
DOI: 10.1016/j.oret.2023.12.003 -
Journal of the American Heart... Dec 2023
Topics: Humans; Acetazolamide; Tomography, X-Ray Computed; Positron-Emission Tomography; Cerebrovascular Disorders; Hemodynamics
PubMed: 38084748
DOI: 10.1161/JAHA.123.032657 -
Journal of the American Heart... Dec 2023Staging of hemodynamic failure (HF) in symptomatic patients with cerebrovascular steno-occlusive disease is required to assess the risk of ischemic stroke. Since the...
Hemodynamic Failure Staging With Blood Oxygenation Level-Dependent Cerebrovascular Reactivity and Acetazolamide-Challenged (O-)HO-Positron Emission Tomography Across Individual Cerebrovascular Territories.
BACKGROUND
Staging of hemodynamic failure (HF) in symptomatic patients with cerebrovascular steno-occlusive disease is required to assess the risk of ischemic stroke. Since the gold standard positron emission tomography-based perfusion reserve is unsuitable as a routine clinical imaging tool, blood oxygenation level-dependent cerebrovascular reactivity (BOLD-CVR) with CO is a promising surrogate imaging approach. We investigated the accuracy of standardized BOLD-CVR to classify the extent of HF.
METHODS AND RESULTS
Patients with symptomatic unilateral cerebrovascular steno-occlusive disease, who underwent both an acetazolamide challenge (O-)HO-positron emission tomography and BOLD-CVR examination, were included. HF staging of vascular territories was assessed using qualitative inspection of the positron emission tomography perfusion reserve images. The optimum BOLD-CVR cutoff points between HF stages 0-1-2 were determined by comparing the quantitative BOLD-CVR data to the qualitative (O-)HO-positron emission tomography classification using the 3-dimensional accuracy index to the randomly assigned training and test data sets with the following determination of a single cutoff for clinical application. In the 2-case scenario, classifying data points as HF 0 or 1-2 and HF 0-1 or 2, BOLD-CVR showed an accuracy of >0.7 for all vascular territories for HF 1 and HF 2 cutoff points. In particular, the middle cerebral artery territory had an accuracy of 0.79 for HF 1 and 0.83 for HF 2, whereas the anterior cerebral artery had an accuracy of 0.78 for HF 1 and 0.82 for HF 2.
CONCLUSIONS
Standardized and clinically accessible BOLD-CVR examinations harbor sufficient data to provide specific cerebrovascular reactivity cutoff points for HF staging across individual vascular territories in symptomatic patients with unilateral cerebrovascular steno-occlusive disease.
Topics: Humans; Acetazolamide; Positron-Emission Tomography; Cerebrovascular Disorders; Middle Cerebral Artery; Hemodynamics; Cerebrovascular Circulation; Magnetic Resonance Imaging
PubMed: 38084716
DOI: 10.1161/JAHA.123.029491 -
Sports Medicine (Auckland, N.Z.) Apr 2024The (patho-)physiological responses to hypoxia are highly heterogeneous between individuals. In this review, we focused on the roles of sex differences, which emerge as... (Review)
Review
The (patho-)physiological responses to hypoxia are highly heterogeneous between individuals. In this review, we focused on the roles of sex differences, which emerge as important factors in the regulation of the body's reaction to hypoxia. Several aspects should be considered for future research on hypoxia-related sex differences, particularly altitude training and clinical applications of hypoxia, as these will affect the selection of the optimal dose regarding safety and efficiency. There are several implications, but there are no practical recommendations if/how women should behave differently from men to optimise the benefits or minimise the risks of these hypoxia-related practices. Here, we evaluate the scarce scientific evidence of distinct (patho)physiological responses and adaptations to high altitude/hypoxia, biomechanical/anatomical differences in uphill/downhill locomotion, which is highly relevant for exercising in mountainous environments, and potentially differential effects of altitude training in women. Based on these factors, we derive sex-specific recommendations for mountain sports and intermittent hypoxia conditioning: (1) Although higher vulnerabilities of women to acute mountain sickness have not been unambiguously shown, sex-dependent physiological reactions to hypoxia may contribute to an increased acute mountain sickness vulnerability in some women. Adequate acclimatisation, slow ascent speed and/or preventive medication (e.g. acetazolamide) are solutions. (2) Targeted training of the respiratory musculature could be a valuable preparation for altitude training in women. (3) Sex hormones influence hypoxia responses and hormonal-cycle and/or menstrual-cycle phases therefore may be factors in acclimatisation to altitude and efficiency of altitude training. As many of the recommendations or observations of the present work remain partly speculative, we join previous calls for further quality research on female athletes in sports to be extended to the field of altitude and hypoxia.
Topics: Humans; Hypoxia; Female; Altitude Sickness; Altitude; Acclimatization; Sex Factors; Mountaineering; Adaptation, Physiological; Physical Conditioning, Human; Male
PubMed: 38082199
DOI: 10.1007/s40279-023-01970-6