-
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 -
Acute Myopic Shift after a Single Dose of Acetazolamide: A Case Report and Review of the Literature.Klinische Monatsblatter Fur... Apr 2024We report the case of a 32-year-old male who presented with an acute myopic shift as a result of uveal effusion following a single administration of 250 mg... (Review)
Review
We report the case of a 32-year-old male who presented with an acute myopic shift as a result of uveal effusion following a single administration of 250 mg acetazolamide. The drug was discontinued and following cycloplegia and topical steroid therapy, we observed progressive deepening of the anterior chamber, reopening of the iridocorneal angle, and complete resolution of the myopic shift after 5 days. A literature review since 1956 identified 23 cases, including ours, which developed a myopic shift after a median time of 24 h (3 - 24) following a median dose of 500 mg (125 - 1000) acetazolamide, with about a third complicated by angle closure ocular hypertension. This presumed idiosyncratic reaction can occur without prior drug exposure and independent of the phakic status. Treatment options include systematic drug withdrawal associated with cycloplegia, anti-glaucomatous agents, and/or corticosteroids. Full recovery is achieved within about 5 days (2 - 14). Given the widespread use of acetazolamide, awareness of this idiosyncratic reaction is crucial to avoid complications of acute angle-closure glaucoma.
Topics: Humans; Acetazolamide; Male; Adult; Myopia; Carbonic Anhydrase Inhibitors; Acute Disease; Treatment Outcome
PubMed: 38653306
DOI: 10.1055/a-2244-6160 -
Mikrochimica Acta May 2024The first electrochemical sensor application in the literature is described for the sensitive and selective determination of the selective Janus kinase (JAK)-1...
The first electrochemical sensor application in the literature is described for the sensitive and selective determination of the selective Janus kinase (JAK)-1 inhibitor abrocitinib (ABR). ABR is approved by the U.S. Food and Drug Administration (FDA) for the treatment of atopic dermatitis. The molecularly imprinted polymer (MIP)-based sensor was designed to incorporate zinc nanoflower (ZnNFs)-graphene oxide (GO) conjugate (ZnNFs@GO), synthesized from the root methanolic extract (RME) of the species Alkanna cappadocica Boiss. et Bal. to improve the porosity and effective surface area of the glassy carbon electrode (GCE). Furthermore, the MIP structure was prepared using ABR as a template molecule, 4-aminobenzoic acid (4-ABA) as a functional monomer, and other additional components. Scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to characterize the surface and structure of the synthesized nanomaterial and MIP-based surface. Among the electrochemical methods, cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were preferred for detailed electrochemical characterization, and differential pulse voltammetry (DPV) was preferred for all other electrochemical measurements using 5.0 mM [Fe(CN)] solution as the redox probe. The MIP-based sensor, which was the result of a detailed optimization phase, gave a linear response in the 1.0 × 10 - 1.0 × 10 M range in standard solution and serum sample. The obtained limit of detection (LOD) and limit of quantification (LOQ) values and recovery studies demonstrated the sensitivity, accuracy, and applicability of the sensor. Selectivity, the most important feature of the MIP-based sensor, was verified by imprinting factor calculations using ibrutinib, ruxolitinib, tofacitinib, zonisamide, and acetazolamide.
Topics: Molecularly Imprinted Polymers; Electrochemical Techniques; Limit of Detection; Zinc; Graphite; Humans; Aminoimidazole Carboxamide; Nanostructures; Electrodes
PubMed: 38730044
DOI: 10.1007/s00604-024-06404-2 -
Journal of Medicine and Life Dec 2023This study aimed to design, synthesize, and evaluate the cytotoxic activity of novel thiazole-sulfanilamide derivatives, specifically compounds M3, M4, and M5, through...
In silico study, synthesis, and antineoplastic evaluation of thiazole-based sulfonamide derivatives and their silver complexes with expected carbonic anhydrase inhibitory activity.
This study aimed to design, synthesize, and evaluate the cytotoxic activity of novel thiazole-sulfanilamide derivatives, specifically compounds M3, M4, and M5, through molecular docking and biological assays. The synthesis utilized essential chemical compounds, including sulfanilamide, chloro-acetyl chloride, thiourea, derivatives of benzaldehyde, and silver nitrate. The docking study was carried out using Molecular Operating Environment (MOE) software, and cytotoxic activity was predicted by MTT assay. The synthesized compounds demonstrated a reduction in the viability of cancer cells. Compound M5 had an IC50 of 18.53 µg/ml against MCF-7 cells, comparable to the IC50 of cisplatin. Additionally, compounds M3 and M4 had higher S scores than acetazolamide, indicating greater binding affinity to the active pocket of the receptor. Incorporating the thiazole ring in the synthesized compound augmented their flexibility and affinity for binding to the receptor. The inclusion of the metal complex additionally heightened the compounds' capacity to impede cellular growth.
Topics: Humans; Molecular Docking Simulation; Thiazoles; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Sulfonamides; Antineoplastic Agents; Sulfanilamides
PubMed: 38585528
DOI: 10.25122/jml-2023-0180 -
Journal of Taibah University Medical... Feb 2024The goal of this study was to design and enable development of anticancer sulfonamides by coupling amines and dansyl chloride with strategically selected substituents....
OBJECTIVES
The goal of this study was to design and enable development of anticancer sulfonamides by coupling amines and dansyl chloride with strategically selected substituents. The synthesized structures were characterized by NMR and mass spectrometry. In addition, molecular docking analysis was used to determine the binding ability of sulfonamides toward 1AZM, a possible drug target, as compared with that of the well-known drug acetazolamide.
METHODS
Sulfonamides were synthesized by coupling amines and dansyl chloride under highly favorable conditions. The designed sulfonamides incorporated strategically positioned substituents to impart diverse biological properties. The synthesized structures were validated with NMR and mass spectra. Molecular docking analysis was performed to evaluate the binding affinities of the synthesized sulfonamides with the potential drug target 1AZM.
RESULTS
The synthesis of sulfonamides through the coupling of amines and dansyl chloride was successfully achieved. The validation of the synthesized structures with NMR and mass spectra confirmed their chemical identities. Molecular docking analysis revealed that the synthesized sulfonamides displayed binding affinities ranging from -6.8 to -8.2 kcal/mol toward the potential drug target 1AZM. Importantly, all derivatives exhibited superior binding affinities to acetazolamide (-5.25 kcal/mol).
CONCLUSIONS
The coupling of amines and dansyl chloride enabled efficient, straightforward sulfonamide synthesis. The strategic design of sulfonamides with specific substituents endows diverse biological properties, including potential anti-cancer activity. The elucidation of the synthesized compounds with NMR and mass spectra confirmed their structures. Molecular docking analysis demonstrated that the synthesized sulfonamides exhibited favorable binding affinities toward the potential drug target 1AZM. Notably, all derivatives displayed higher binding affinities, ranging from -6.8 to -8.2 kcal/mol, than the recommended drug acetazolamide (-5.25 kcal/mol), thus suggesting their potential as highly effective analogues for further validation in cancer therapy.
PubMed: 38047237
DOI: 10.1016/j.jtumed.2023.10.006 -
Annals of Vascular Surgery Nov 2023Spinal cord ischemia (SCI) continues to be a devastating complication after repair of thoracoabdominal aortic aneurysms. The objective of this review is to present our...
BACKGROUND
Spinal cord ischemia (SCI) continues to be a devastating complication after repair of thoracoabdominal aortic aneurysms. The objective of this review is to present our single-center outcomes after the implementation of a standardized neuroprotective protocol following branched endovascular aortic repair.
METHODS
A standardized neuroprotective protocol including preoperative steroids, acetazolamide, intraoperative hemodynamic parameters, and postoperative treatment goals was initiated in November 2019. Physician-modified branched endovascular repairs were completed at a single center from 2012 to 2021 with outcomes reviewed both before (n = 107) and after (n = 67) the implementation of the neuroprotective protocol. The primary end point was the incidence of any SCI event at 30 days. Secondary end points included all-cause mortality, stroke, myocardial infarction, and renal failure at 30 days. Patients with Crawford extents I-III, renal failure, or necessitating emergent repair were deemed high risk for SCI events and underwent a subset analysis. Survivability after SCI was estimated using Kaplan-Meier tables.
RESULTS
Of the 174 consecutive patients treated, the 67 patients treated following implementation of the neuroprotective protocol were more likely to have experienced a prior myocardial infarction (26.9% vs. 14%; P = 0.0466) and have a history of chronic obstructive pulmonary disease (64.3% vs. 45.8%; P = 0.02). This group was more likely to be treated for paravisceral aneurysms (53.7% vs. 24.3%; P = 0.0002). Postprotocol implementation, spinal drain use was lower (6% vs. 38.3%; P = <0.0001) with 100% of these drains placed in urgent or unstaged thoracoabdominal aortic aneurysm repairs as a part of the protocol. Rates of any SCI event among all patients before and after implementation of the protocol were 9.3% (n = 10 of 107) and 6% (n = 4 of 67; P = 0.57), respectively. In comparison, the protocol significantly reduced SCI rates to 0 (0% vs. 17.1%; P = 0.0407) in high-risk patients. Frequency of renal failure was reduced (3% vs. 14%; P = 0.018) after initiation of the protocol. Patients in the postprotocol group had significantly improved 1-year mortality rate (9% vs. 27.1%; P = 0.0035) and renal failure rates (2% vs. 15%; P = 0.018). Regression models indicated that patients in the postprotocol group had lower likelihood of mortality and renal failure than patients in preprotocol group (P < 0.05) and that spinal drain reduced mortality (P < 0.1).
CONCLUSIONS
Implementation of a standardized neuroprotective protocol that focuses on medical management and fluid dynamics may significantly reduce risk of SCI after branched endovascular repairs, with the most significant improvement of SCI outcomes involving those at greatest risk for developing SCI. Also noteworthy, there was significant improvement to 1-year survivability after the implementation of this neuroprotective protocol.
Topics: Humans; Aortic Aneurysm, Thoracic; Aortic Aneurysm, Thoracoabdominal; Endovascular Aneurysm Repair; Endovascular Procedures; Myocardial Infarction; Renal Insufficiency; Retrospective Studies; Review Literature as Topic; Risk Factors; Spinal Cord Ischemia; Time Factors; Treatment Outcome
PubMed: 37659649
DOI: 10.1016/j.avsg.2023.08.006 -
Chinese Medicine May 2024The restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke....
BACKGROUND
The restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke. An-Gong-Niu-Huang-Wan (AGNHW) is a famous traditional compound Chinese medicine that has been used for over 220 years to treat acute ischaemic stroke; however, its role in the regulation of cerebral blood flow is still unclear. The aim of the present study was to investigate the regulatory effect of AGNHW on cerebral blood flow and microcirculation after ischaemic stroke and to elucidate the underlying mechanisms involved.
METHODS
Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (dMCAO) and randomly assigned to the sham, MCAO, or AGNHW groups. AGNHW was administered intragastrically 1 h after dMCAO. The rotarod test was utilized to evaluate behavioural function; TTC was used to determine the infarct volume; and ischaemic injury was assessed by detecting brain levels of SOD, MDA and NO. Then, cortical perfusion and acetazolamide-induced cerebrovascular reactivity were assessed using laser speckle contrast imaging, and the velocity and flux of red blood cells in cortical capillaries were detected using two-photon laser scanning microscopy. In addition, we employed RNA-Seq to identify variations in gene expression profiles and assessed endothelium-dependent changes in microcirculatory dysfunction by measuring vasoactive mediator levels.
RESULTS
AGNHW significantly increased cerebral blood flow, reduced the infarct volume, and promoted functional recovery after cerebral ischaemia. AGNHW increased the velocity and flux of red blood cells in capillaries and improved cerebrovascular reactivity in the ischaemic cortex. Furthermore, AGNHW regulated endothelium-dependent microcirculation, as evidenced by decreases in the expression of endothelins (Edn1, Edn3 and Ednrb) and the ratios of brain and serum TXB2/6-keto-PGF1α and ET-1/CGRP.
CONCLUSIONS
AGNHW improved cerebral hypoperfusion, regulated cerebrovascular reactivity and attenuated microcirculatory dysfunction within the ischaemic cortex after stroke. This outstanding effect was achieved by modulating the expression of genes related to vascular endothelial cell function and regulating endothelium-dependent vasoactive mediators.
PubMed: 38778375
DOI: 10.1186/s13020-024-00945-7 -
Journal of Vitreoretinal Diseases 2024To present a rare case of subfoveal choroidal neovascular membrane (CNVM) secondary to idiopathic intracranial hypertension. A case was evaluated. A 21-year-old woman...
To present a rare case of subfoveal choroidal neovascular membrane (CNVM) secondary to idiopathic intracranial hypertension. A case was evaluated. A 21-year-old woman presented with a 2-week history of painless blurred vision in the right eye. She described initial metamorphopsia and intermittent bitemporal headaches lasting 30 minutes. She denied pain with eye movements and a history of trauma. Her body mass index was 49 kg/m. The visual acuity (VA) was 20/320 OD and 20/20 OS; there was no relative afferent pupillary defect. A dilated fundus examination showed bilateral optic disc edema and a subfoveal CNVM in the right eye. The patient was started on oral acetazolamide 500 mg twice daily and treated with 2 intravitreal antivascular endothelial growth factor (anti-VEGF) injections. Three months later, the VA was 20/30 in the right eye and the disc edema had improved. CNVMs in the setting of idiopathic intracranial hypertension-related papilledema may be subfoveal and have an excellent response to anti-VEGF agents.
PubMed: 38465349
DOI: 10.1177/24741264231218539 -
Genes May 2024Pathogenic variants in the gene lead to severe, childhood-onset retinal degeneration leading to blindness in early adulthood. There are no approved therapies, and...
Pathogenic variants in the gene lead to severe, childhood-onset retinal degeneration leading to blindness in early adulthood. There are no approved therapies, and traditional adeno-associated viral vector-based gene therapy approaches are challenged by the existence of multiple CRB1 isoforms. Here, we describe three variants, including a novel, previously unreported variant that led to retinal degeneration. We offer a CRISPR-Cas-mediated DNA base editing strategy as a potential future therapeutic approach. This study is a retrospective case series. Clinical and genetic assessments were performed, including deep phenotyping by retinal imaging. In silico analyses were used to predict the pathogenicity of the novel variant and to determine whether the variants are amenable to DNA base editing strategies. Case 1 was a 24-year-old male with cone-rod dystrophy and retinal thickening typical of retinopathy. He had a relatively preserved central outer retinal structure and a best corrected visual acuity (BCVA) of 60 ETDRS letters in both eyes. Genetic testing revealed compound heterozygous variants in exon 9: c.2843G>A, p.(Cys948Tyr) and a novel variant, c.2833G>A, p.(Gly945Arg), which was predicted to likely be pathogenic by an in silico analysis. Cases 2 and 3 were two brothers, aged 20 and 24, who presented with severe cone-rod dystrophy and a significant disruption of the outer nuclear layers. The BCVA was reduced to hand movements in both eyes in Case 2 and to 42 ETDRS letters in both eyes in Case 3. Case 2 was also affected with marked cystoid macular lesions, which are common in CRB1 retinopathy, but responded well to treatment with oral acetazolamide. Genetic testing revealed two c.2234C>T, p.(Thr745Met) variants in both brothers. As G-to-A and C-to-T variants, all three variants are amenable to adenine base editors (ABEs) targeting the forward strand in the Case 1 variants and the reverse strand in Cases 2 and 3. Available PAM sites were detected for KKH-nSaCas9-ABE8e for the c.2843G>A variant, nSaCas9-ABE8e and KKH-nSaCas9-ABE8e for the c.2833G>A variant, and nSpCas9-ABE8e for the c.2234C>T variant. In this case series, we report three pathogenic variants, including a novel c.2833G>A variant associated with early-onset cone-rod dystrophy. We highlight the severity and rapid progression of the disease and offer ABEs as a potential future therapeutic approach for this devastating blinding condition.
Topics: Humans; Male; Gene Editing; Membrane Proteins; CRISPR-Cas Systems; Young Adult; Eye Proteins; Nerve Tissue Proteins; Adult; Cone-Rod Dystrophies; Female; Computer Simulation; Genetic Therapy; Retrospective Studies
PubMed: 38790254
DOI: 10.3390/genes15050625 -
Frontiers in Physiology 2023Hypoxia and old age impair postural control and may therefore enhance the risk of accidents. We investigated whether acetazolamide, the recommended drug for prevention...
Hypoxia and old age impair postural control and may therefore enhance the risk of accidents. We investigated whether acetazolamide, the recommended drug for prevention of acute mountain sickness, may prevent altitude-induced deterioration of postural control in older persons. In this parallel-design trial, 95 healthy volunteers, 40 years of age or older, living <1,000 m, were randomized to preventive therapy with acetazolamide (375 mg/d) or placebo starting 24 h before and during a 2-day sojourn at 3,100 m. Instability of postural control was quantified by a balance platform with the center of pressure path length (COPL) as primary outcome while pulse oximetry (SpO) was monitored. Effects of altitude and treatment on COPL were evaluated by ordered logistic regression. www.ClinicalTrials.gov NCT03536429. In participants taking placebo, ascent from 760 m to 3,100 m increased median COPL from 25.8 cm to 27.6 cm (odds ratio 3.80, 95%CI 2.53-5.70) and decreased SpO from 96% to 91% (odds ratio 0.0003, 95%CI 0.0002-0.0007); in participants taking acetazolamide, altitude ascent increased COPL from 24.6 cm to 27.3 cm (odds ratio 2.22, 95%CI 1.57-3.13), while SpO decreased from 96% to 93% (odds ratio 0.007, 95%CI 0.004-0.012). Altitude-induced increases in COPL were smaller with acetazolamide vs. placebo (odds ratio 0.58, 95%CI 0.34-0.99) while drops in SpO were mitigated (odds ratio 19.2, 95%CI 9.9-37.6). In healthy individuals, 40 years of age or older, postural control was impaired after spending a night at 3,100 m. The altitude-induced deterioration of postural control was mitigated by acetazolamide, most likely due to the associated improvement in oxygenation.
PubMed: 38250659
DOI: 10.3389/fphys.2023.1274111