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Purpose of Review: To review the management of Idiopathic Intracranial Hypertension (IIH) with co-existing conditions affecting therapy: obesity, sulfa allergy, nephrolithiasis, and pregnancy. Recent Findings: The IIH-WT trial showed that bariatric surgery is currently the most effective method for obese patients with IIH to lose weight, leading to normalization of CSF pressure in many cases. Allergy to sulfonamide antibiotics does not preclude the use of acetazolamide; rather, penicillin allergy or multiple drug allergies are the strongest predictor of a hypersensitivity reaction. Carbonic anhydrase inhibitors should be avoided in individuals with a personal history of nephrolithiasis; the risk of renal stones increases with concomitant use of other medications with the potential for nephrolithiasis. Glucagon-like peptide-1 receptor antagonists (GLP-1RA) are promising non-surgical weight loss options although preliminary studies have not demonstrated considerable impact on papilledema, headache or vision. Women with IIH have high rates of pregnancy complications partly related to obesity. Recommendations for weight gain or loss during gestation are controversial. Recent studies show better outcomes in obese women who maintain or lose weight while pregnant including gestational diabetes, pre-eclampsia and emergency caesarian section. Summary: Progress continues in the search for the cause and best treatments for IIH. Larger multicenter trials of GLP-1RA are needed to determine their efficacy. [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy of intravitreal antivascular endothelial growth factor (anti-VEGF) agents with oral carbonic anhydrase inhibitors (CAIs) in treating cystoid macular edema (CME) secondary to retinitis pigmentosa (RP). Methods: This retrospective study analyzed 98 patients (98 eyes) with RP-CME: 47 (48.0%) received intravitreal anti-VEGF agents (Ranibizumab or Bevacizumab) and 51 (52.0%) were treated with oral CAIs (methazolamide 50 mg/day or acetazolamide 500 mg/day). Medical records were reviewed to assess best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) at baseline and at 1, 3, 6, and 12 months post-treatment using Generalized Estimation Equations (GEE). Adverse events and risk factors influencing visual prognosis were also evaluated. Results: Both groups showed significant improvement in BCVA and reduction in CMT at 1 and 3 months post-treatment compared to baseline (all p < 0.001). In the oral CAIs group, these improvements persisted until 6 months. However, by 12 months, neither group exhibited significant improvements in BCVA or CMT compared to baseline (all p > 0.05). Intragroup comparisons revealed that the oral CAIs group had significantly better BCVA and CMT improvements at 3 and 6 months than intravitreal anti-VEGF group (p < 0.001 for BCVA at 3 months, p = 0.003 for BCVA at 6 months; all p < 0.001 for CMT at both 3 and 6 months). No significant differences were found between the two groups in BCVA and CMT at 12 months or in IOP at any time point (all p > 0.05). Subgroup analysis indicated that oral acetazolamide was more effective than methazolamide in reducing CMT and improving BCVA at 3 and 6 months (p = 0.005 for BCVA at 3 months, p = 0.015 for BCVA at 6 months; p = 0.037 for CMT at 3 months, p < 0.001 for CMT at 6 months). There were no significant differences in outcomes between intravitreal Ranibizumab and Bevacizumab (all p > 0.05). Correlation analysis showed that worse BCVA at 12 months was associated with older age (r = 0.202, p = 0.046), higher baseline CMT (r = 0.353, p < 0.001), poorer baseline BCVA (r = 0.579, p < 0.001), but showed no correlation with genotype. Adverse effects from oral CAIs included tingling sensation (3.9%), altered taste (9.8%), and gastrointestinal upset (7.8%). The Ranibizumab group required an average of 3.7 ± 0.8 treatments, and the Bevacizumab group required an average of 3.8 ± 0.5 treatments over the course of 1 year without experiencing severe adverse effects. Conclusion: Both intravitreal anti-VEGF agents and oral CAIs effectively improved CMT and BCVA in RP-CME patients within the first 3 months of treatment. However, oral CAIs demonstrated superior anatomic and functional improvements at 6 months. Poorer BCVA prognosis was associated with older age, higher baseline CMT, poorer baseline visual acuity. Larger, randomized clinical trials with extended follow-up periods are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Human carbonic anhydrase IX (CAIX) plays a key role in maintaining pH homeostasis of malignant neoplasms, thus creating a favorable microenvironment for the growth, invasion, and metastasis of tumor cells. Recent studies have established that inhibition of CAIX expressed on the surface of tumor cells significantly increases the efficacy of classical chemotherapeutic agents and makes it possible to suppress the resistance of tumor cells to chemotherapy, as well as to increase their sensitivity to drugs (in particular, to reduce the required dose of cytostatic agents). In this work, we studied the ability of new CAIX inhibitors based on substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides, to potentiate the cytostatic effect of gefitinib (selective inhibitor of epidermal growth factor receptor tyrosine kinase domain) under hypoxic conditions. We investigated a combined effect of gefitinib and CAIX inhibitors 4-(3-phenyl-1,2,4-oxadiazol-5-yl)thiophene-2-sulfonamide (1), 4-(5-(thiophene-3-yl)-1,2,4-oxadiazol-3-yl)benzenesulfonamide (2), 4-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)thiophene-2-sulfonamide (3), and 4-(5-methyl-1,2,4-oxadiazol-3-yl)benzenesulfonamide (4) on gefitinib cytotoxicity, cell proliferation, activation of caspases-3/7, and cell cycle control in human lung adenocarcinoma A549 cells. It was found that the combinations of compounds 1 and 2 with gefitinib suppressed the invasive potential of A549 cells. Compound 1 had the greatest effect and can be considered as a promising candidate for further research. [ABSTRACT FROM AUTHOR]

We designed novel pre-drug compounds that transform into an active form that covalently modifies particular His residue in the active site, a difficult task to achieve, and applied to carbonic anhydrase (CAIX), a transmembrane protein, highly overexpressed in hypoxic solid tumors, important for cancer cell survival and proliferation because it acidifies tumor microenvironment helping invasion and metastases processes. The designed compounds have several functionalities: (1) primary sulfonamide group recognizing carbonic anhydrases (CA), (2) high-affinity moieties specifically recognizing CAIX among all CA isozymes, and (3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high initial affinity and selectivity for the disease target protein followed by complete irreversible inactivation of the protein via covalent modification. Our designed prodrug candidates bearing moderately active pre-vinylsulfone esters or weakly active carbamates optimized for mild covalent modification activity to avoid toxic non-specific modifications and selectively target CAIX. The lead inhibitors reached 2 pM affinity, the highest among known CAIX inhibitors. The strategy could be used for any disease drug target protein bearing a His residue in the vicinity of the active site. [ABSTRACT FROM AUTHOR]

Dorzolamide hydrochloride (DRZ) is a carbonic anhydrase inhibitor utilized in managing elevated intraocular pressure (IOP) associated with glaucoma. However, its clinical effectiveness is hindered by a short half-life, low residence time, and the need for frequent dosing, highlighting the necessity for innovative delivery systems. This work reviews recent advancements in DRZ delivery, particularly focusing on cyclodextrin complexation and nanotechnology applications. It explores the potential of cyclodextrin derivatives to enhance DRZ's bioavailability. DRZ cyclodextrin complexes or nanoparticulate systems maintain high drug concentrations in the eye while minimizing irritation and viscosity-related issues. Nanotechnology introduces nanoparticle-based carriers such as polymeric nanoparticles, solid lipid nanoparticles, liposomes, niosomes, and nanoemulsions. These formulations enable sustained drug release, improved corneal permeation, and enhanced patient compliance. Clinical trials have shown that DRZ nanoparticle eye drops and nanoliposome formulations offer efficacy comparable to conventional therapies, with the potential for better tolerability. Overall, this review highlights significant progress in DRZ delivery systems, suggesting their potential to transform glaucoma treatment by addressing current limitations and improving therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and efficacy of sublingual methazolamide in patients with open-angle glaucoma (OAG) and inform future trial design. Methods: Fourteen participants (28 eyes) aged 50 to 90 years with bilateral OAG and intraocular pressure (IOP) between 18 and 35 mmHg after medication washout were included. Participants were randomized to receive either 25 mg or 50 mg of sublingual methazolamide once daily for one week, followed by twice-daily administration during the second week. The primary outcome was change in IOP from baseline to days 7 and 14. Secondary outcomes included changes in serum methazolamide levels, serum electrolytes, urine pH and electrolytes, and side effects. Results: After randomization, exclusion, and two dropouts, four patients in the 25 mg group and ten in the 50 mg group completed the study in full. Both doses of sublingual methazolamide resulted in significant reductions in IOP from the post-washout baseline at all follow-up points (all p < 0.05). Lowest mean IOPs were recorded 8 hours post-dose; after a week of daily dosing, the 25 mg and 50 mg groups achieved reductions of 6.6 mmHg (− 26.5%) and 4.2 mmHg (− 19.3%), respectively (both p < 0.001). Twice-daily dosing resulted in significantly lower morning IOPs compared to once-daily in each group (p = 0.05 for 25 mg; p = 0.003 for 50 mg). Serum methazolamide levels correlated with dose amount and frequency. Serum electrolyte levels were stable throughout, while urinary pH and urinary electrolytes fluctuated based on time since last dose. Side effects of mild headaches and/or fatigue were reported by 3 out of 14 (21.4%) participants, with no serious adverse events. Conclusion: Sublingual methazolamide demonstrated effective IOP reduction with a favorable safety profile. Twice-daily dosing may offer more sustained IOP control. These findings support further investigation into sublingual methazolamide as an alternative glaucoma treatment. [ABSTRACT FROM AUTHOR]

Central sleep apnea (CSA) is a significant concern in children with neurodevelopmental disorders and genetic syndromes, where conventional treatments such as bilevel positive airway pressure (BiLevelPAP) therapy may be poorly tolerated. Acetazolamide, a carbonic anhydrase inhibitor, is an alternative treatment that induces a metabolic acidosis, which may help stabilize respiratory disturbances by enhancing ventilatory drive. However, evidence regarding its use in pediatric populations remains limited. We report the case of a 12-year-old male with an FBXO28 gene-related disorders with significant CSA. Due to intolerance to BiLevelPAP therapy, a trial of acetazolamide was initiated. The dose was adjusted to maintain a mild metabolic acidosis, with regular blood work and clinical monitoring to assess for potential side effects. Follow-up polysomnography (PSG) demonstrated significant improvements in the central apnea-hypopnea index (CAHI) and periodic breathing. No significant adverse effects were reported, and the family noted a substantial improvement in quality of life. This case highlights that maintaining a mild metabolic acidosis with acetazolamide is sufficient to stimulate respiratory drive and stabilize breathing in pediatric CSA, while minimizing risks of electrolyte imbalances and long-term renal consequences. Our findings align with existing literature, which indicates that acetazolamide may be effective for CSA without hypoventilation in children, particularly those with genetic syndromes. Further research is necessary to establish standardized treatment protocols, optimal dosing, and long-term safety. • Acetazolamide may serve as a safe and effective alternative for managing central sleep apnea in pediatric children. • Maintaining a mild metabolic acidosis is sufficient to stabilize breathing while minimizing electrolyte imbalances. • Further research is necessary to establish standardized treatment protocols. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) continues to be the most prevalent type of liver cancer worldwide. Diethylnitrosamine (DEN)‐induced HCC is an extensively used hepatic cancer model in experimental animals. Acetazolamide (AZA) is a carbonic anhydrase enzyme inhibitor. This study aimed to assess the therapeutic mechanism of AZA against DEN‐induced HCC. Thirty male Wistar albino rats were divided equally into three groups. Group I (C): control group, Group II (HCC): DEN‐induced HCC, and Group III (HCC/AZA): AZA‐treated HCC. Verification of the HCC induced by DEN was confirmed by elevated liver enzymes' activities, and increased α‐fetoprotein (AFP) levels, as well as distinct liver architecture changes. On the other hand, the AZA‐treated HCC group experienced decreases in the activities of serum liver enzymes and AFP levels, as well as, regulated liver architecture. Additionally, it downregulated p‐p38 MAPK/p‐JNK1/JNK2/p‐C‐Jun/p‐NF‐κB p65 protein expressions. Moreover, it ameliorated autophagy by controlling the expression of the p‐AMPK/p‐mTOR1/LC3 I/II proteins. Furthermore, it downregulated the relative gene expressions of carbonic anhydrase‐IX (CAIX) and hexokinase‐II (HKII). Histopathological examination of AZA‐treated HCC liver tissues supported these findings. Conclusion: AZA provides a new dimension in ameliorating experimentally induced HCC through regulation of hepatic biomarkers, antioxidant status, inflammatory markers, and autophagy, mediated by amelioration of CAIX and HKII gene expressions. [ABSTRACT FROM AUTHOR]

Acute mountain sickness (AMS) occurs due to rapid altitude ascents and/or insufficient acclimatization. Acetazolamide (AZ) is commonly prescribed for AMS prophylaxis but inhibits exercise performance. Methazolamide (MZ), an analogous drug, has similar prophylactic benefits but does not impair isolated muscle mass exercise performance in normoxia. We sought to compare whole body exercise performance in acute hypoxia (fraction of inspired oxygen, F I O 2 = 0.15) between AZ, MZ, and placebo (PLA). Fifteen healthy participants completed five testing visits: day 1 for maximal exercise test, day 2 for familiarization, and days 3–5 were the experimental visits. Each experimental visit involved a 5-km hypoxic cycling time trial (TT) performed after a 2-day dosing protocol of either AZ (250 mg three times a day), MZ (100 mg twice a day), or PLA (three times a day); the order was randomized and double-blinded. Before exercise, capillary blood samples were taken, and maximal voluntary contractions of quadriceps were performed. AZ and MZ resulted in a partially compensated metabolic acidosis at rest compared with PLA [capillary hydrogen ions (H+) 47 ± 3, 43 ± 2, and 39 ± 2 nmol for AZ, MZ, and PLA respectively, P < 0.01]. Time to complete 5 km with PLA (562 ± 32 s, P < 0.01) was significantly faster than AZ and MZ (577 ± 38 vs. 581 ± 37 s, respectively), with no differences between AZ and MZ (P = 0.96). There were no differences in average ventilation (124 ± 27, 127 ± 24, 127 ± 19 L/min) and oxyhemoglobin saturation (87 ± 2, 88 ± 2, 88 ± 3%) between AZ, MZ, and PLA, respectively (P > 0.05). Overall, both AZ and MZ impair whole body exercise performance in acute normobaric hypoxia. NEW & NOTEWORTHY: Administration of acetazolamide (AZ) and methazolamide (MZ) both resulted in a significantly slower 5-km time trial in acute normobaric hypoxia compared with a placebo. Both drugs lead to a partially compensated metabolic acidosis, but ventilation and oxyhemoglobin saturation were not different across the conditions. Overall, acetazolamide and methazolamide both impaired whole body exercise performance in acute normobaric hypoxia but potentially have different mechanisms of action. [ABSTRACT FROM AUTHOR]

Background: The choroid plexus (CP) plays a crucial role in cerebrospinal fluid (CSF) production and brain homeostasis. However, non-invasive imaging techniques to assess its function remain limited. This study was conducted to develop a novel, contrast-agent-free MRI technique, termed relaxation-exchange magnetic resonance imaging (REXI), for evaluating CP-CSF water transport, a potential biomarker of CP function. Methods: REXI utilizes the inherent and large difference in magnetic resonance transverse relaxation times (T2s) between CP tissue (e.g., blood vessels and epithelial cells) and CSF. It uses a filter block to remove most CP tissue magnetization (shorter T2), a mixing block for CP-CSF water exchange with mixing time tm, and a detection block with multi-echo acquisition to determine the CP/CSF component fraction after exchange. The REXI pulse sequence was implemented on a 9.4 T preclinical MRI scanner. For validation of REXI's ability to measure exchange, we conducted preliminary tests on urea-water proton-exchange phantoms with various pH levels. We measured the steady-state water efflux rate from CP to CSF in rats and tested the sensitivity of REXI in detecting CP dysfunction induced by the carbonic anhydrase inhibitor acetazolamide. Results: REXI pulse sequence successfully captured changes in the proton exchange rate (from short-T2 component to long-T2 component [i.e., ksl]) of urea-water phantoms at varying pH, demonstrating its sensitivity to exchange processes. In rat CP, REXI significantly suppressed the CP tissue signal, reducing the short-T2 fraction (fshort) from 0.44 to 0.23 (p < 0.0001), with significant recovery to 0.28 after a mixing time of 400 ms (p = 0.014). The changes in fshort at various mixing times can be accurately described by a two-site exchange model, yielding a steady-state water efflux rate from CP to CSF (i.e., kbc) of 0.49 s−1. A scan-rescan experiment demonstrated that REXI had excellent reproducibility in measuring kbc (intraclass correlation coefficient = 0.90). Notably, acetazolamide-induced CSF reduction resulted in a 66% decrease in kbc within rat CP. Conclusions: This proof-of-concept study demonstrates the feasibility of REXI for measuring trans-barrier water exchange in the CP, offering a promising biomarker for future assessments of CP function. [ABSTRACT FROM AUTHOR]

ABSTRACT Herein, two deep red phosphorescent responsive emissive cyclometalated iridium (III) complexes with CAIX inhibition moiety was designed and synthesized; they can penetrate into living cells quickly and mainly located in the lysosome. They showed a strong binding affinity towards CAIX in vitro and effectively reduced cellular expression of CAIX. Moreover, the tethered CAIX‐inhibition moiety of benzene sulfonamide can decrease the inherent cytotoxicity of Ir(III) complex towards normal cells and improve killing selectivity towards cancer cells in dark; Ir3 and Ir4 exhibit approximately five to eight times higher killing selectivity than that of cisplatin; they exhibit satisfied photodynamic therapy effect under irradiation of 425 nm, ultimately resulting in apoptosis of cancer cell, which is accompanied with weakening of extracellular acidification, increased inhibition of cellular CAIX expression, significant loss of mitochondrial membrane potential, and elevated level of reactive oxygen. Herein, our work may demonstrate that combination of inhibition CAIX and metal photosensitizer may provide a promising strategy for constructing a novel theranostic platform. [ABSTRACT FROM AUTHOR]

Objective: Patients with chronic idiopathic intracranial hypertension (IIH) commonly experience a high level of disability and low satisfaction with medical treatment. We aim to evaluate long-term functional improvement and patient satisfaction in IIH patients with similar symptoms by comparing venous sinus stenting (VSS) to standard medical therapy. Methods: We conducted a cross-sectional questionnaire study of 111 IIH patients, comparing 37 adult female patients who underwent venous sinus stenting with 74 patients treated medically. Propensity score matching was used to balance age and presence of papilledema at presentation between groups. Headache-related disability was evaluated using the Migraine Disability Assessment Scale (MIDAS), while general function and treatment satisfaction were assessed using custom questionnaires. Electronic medical records and the results of imaging upon diagnosis were reviewed retrospectively. Results: The stented group reported significantly better outcomes in physical well-being (median 4.0 vs. 1.0, p < 0.001), task completion (4.0 vs. 1.0, p < 0.001), work/school persistence (5.0 vs. 1.0, p < 0.001), and mental well-being (4.0 vs. 1.0, p < 0.001). Additionally, the stented group had a lower proportion of patients with severe MIDAS (MIDAS > 4, 24.3% vs. 47.9%, p = 0.017). Logistic regression suggested venous stenting as a protective factor against severe MIDAS scores (OR = 0.174, p = 0.004). Conclusion: Cerebral venous stenting in patients with IIH is associated with lower disability and higher patient satisfaction from medical treatment compared to those treated with medications only. These findings suggest that venous sinus stenting may be a valuable treatment option for selected IIH patients. However, larger prospective studies are needed to further validate our results. [ABSTRACT FROM AUTHOR]

The efficacy of 34 pyrazoline derivatives as carbonic anhydrase inhibitors was studied in silico. The quantum descriptors were calculated by the DFT/B3LYP method using the 6-31G(d) basis; the dataset was randomly divided into training and testing. By altering the compounds in the sets, four models were created, and they were then used to determine the predicted pIC50 values for the six chemicals in the test set. According to the OECD guidelines for QSAR model validation and the Golbraikh and Tropsha's criteria for model approval, each created model was independently validated both internally and externally, along with YRandomization. Model 3 is chosen because it has higher R2, R2test, and Q2cv values (R2 = 0.79, R2test = 0.95, Q2cv = 0.64). Only one descriptor has a proportional influence on pIC50 activity, but the other four descriptors have an inverse influence on pIC50 because of the negative contribution coefficient. Given the descriptors of the model, we could propose new molecules with remarkable inhibitory activity. [ABSTRACT FROM AUTHOR]

Dibenzocycloheptene antidepressants are tricyclic antidepressants (TCAs) that contain the dibenzocycloheptene moiety in their chemical structures. They are used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Herein, we report the synthesis of a pure tricyclic antidepressant containing dibenzocycloheptene moiety named N-(5H-dibenzo[a,d][7]annulen-5-ylidene)-2-methylpropane-2-sulfinamide (3) in high chemical yield through condensing (R)-tert-butanesulfinamide with a dibenzosuberon ketone. Its structure is elucidated by employing the X-ray technique, NMR spectroscopy characterization, and DFT calculations at the B3LYP/6-31++G(d,p) level of theory. The geometrical parameters are relatively well reproduced, and the optimized and X-ray geometries are relatively well superimposed. The interconnects in the crystalline form of 3 were identified through the analysis of its Hirshfeld surface (HS) and fingerprint plots. The highest interatomic contacts were found between H...H of 58.2% and C.H of 30.6%. Further, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) pharmacokinetics, and physicochemical properties of 3 were determined, which showed that 3 may act as a carbonic Anhydrase I inhibitor. The binding affinity of 3 into the binding site of carbonic Anhydrase I is investigated using a molecular docking study. It forms a stable complex into the binding site of CA I with a binding energy of −7.12 kcal/mol. [ABSTRACT FROM AUTHOR]

Purpose: To present a rare occurrence of bilateral macular hole secondary to vitrectomy that was successfully treated with topical carbonic anhydrase inhibitors and to review the literature for this phenomenon. Methods: Monthly clinical examination and optical coherence tomography was conducted before and after eight weeks of topical 2% dorzolamide administered twice a day. Results: A 62-year-old man who had bilateral giant retinal tears which were repaired with vitrectomy subsequently presented with bilateral small macular holes of size 74 and 78 mm. The patient was trialed on 2% topical dorzolamide twice a day and reviewed monthly with optical coherence tomography scans. Macular hole closure was identified after four weeks of topical treatment. Conclusion: Clinical improvement with conservative measures suggests a potential firstline approach to the treatment of macular holes avoiding surgery and its risk profile. We also present a review of the literature regarding macular holes treated with topical carbonic anhydrase inhibitors and its mechanism of action in treating macular holes. [ABSTRACT FROM AUTHOR]

We showcase the successful combination of photochemistry and kinetic target‐guided synthesis (KTGS) for rapidly pinpointing enzyme inhibitors. KTGS is a fragment‐based drug discovery (FBDD) methodology in which the biological target (BT) orchestrates the construction of its own ligand from fragments featuring complementary reactive functionalities. Notably, fragments interacting with the protein binding sites leverage their spatial proximity, facilitating a preferential reaction. Consequently, the resulting bivalent ligand exhibits heightened affinity. Within the realm of KTGS strategies, in situ click chemistry stands out as the most widely used to identify potent protein binders. This approach requires significant protein contributions, such as binding interactions and appropriate orientations of fragments, to overcome high activation barriers. This leads to prolonged incubation times and the potential for generating false negatives, thereby limiting this strategy to proteins that are stable enough in buffer. We herein unveil the possibility to integrate photochemistry into the realm of KTGS, accelerating the ligation reaction between fragments to a time scale of minutes. This approach should significantly expand the narrow reactivity window of traditional KTGS reactions, paving the way for the exploration and development of novel photo‐KTGS reactions. [ABSTRACT FROM AUTHOR]

Purpose: Glaucoma medication may accelerate the progression of presbyopia. The aim of this study was to compare presbyopia between controls and patients with glaucoma in their 40s. Methods: This was a cross-sectional study of bilateral phakic participants aged between 40 and 49, which included controls (n = 114, mean age 46.1 ± 2.7 y) and patients with primary open-angle glaucoma (n = 105, 46.4 ± 2.7 y) who had been using FP receptor agonists, beta blockers, and carbonic anhydrase inhibitors for at least six months. We compared the near add power between the two groups. Results: The mean near add power and the prevalence of symptomatic presbyopia (near add power ≥ 1.50 D) were 1.16 ± 0.74 D and 42.1% for controls and 1.77 ± 0.71 D (p < 0.01) and 79.0% (p < 0.01) for glaucoma patients, respectively. The odds ratio (OR) and confidence interval for symptomatic presbyopia were associated with age (1.36, 1.21–1.52), ganglion cell complex thickness (0.96, 0.94–0.99), presence of glaucoma (6.19, 3.13–12.23), and number of glaucoma medications (4.26, 2.42–7.43). Among medications, only FP receptor agonists (5.79, 2.68–12.32) produced significant results. Survival analysis showed that glaucoma patients reached the threshold of a near add power of +1.50 D significantly sooner than controls (p < 0.05; log-rank test). Conclusions: Glaucoma patients, especially those using FP receptor agonists, had higher near add power than controls. [ABSTRACT FROM AUTHOR]

1,3-Dithiocyanatoacetone was prepared by reaction of 1,3-dichloroacetone with potassium thiocyanate in ethanol in almost quantitative yield. In contrast to the NMR spectra recorded in acetone-d6, NMR spectra of 1,3-dithiocyanatoacetone in DMSO-d6 solution revealed the presence of the enol form. The keto-enol tautomerism is discussed and the structure of main conformers and tautomers of dithiocyanatoacetone and its acid hydrolysis product, S-[(2-oxo-2,3-dihydro- 1,3-thiazol-4-yl)methyl]thiocarbamate, was investigated by quantum chemical methods. The vibrational spectra were calculated and found to be in a good agreement with the experimental FT-IR spectra. The structure of 1,3-dithiocyanatoacetone and S-[(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)methyl]thiocarbamate was studied by X-ray diffraction analysis. Molecular docking and bioavailability parameters calculations showed the potential of the compounds as carbonic anhydrase inhibitors. [ABSTRACT FROM AUTHOR]

Human Carbonic Anhydrases (hCA) are enzymes that contribute to cancer's development and progression. Isoforms IX and XII have been identified as potential anticancer targets, and, more specifically, hCA IX is overexpressed in hypoxic tumor cells, where it plays an important role in reprogramming the metabolism. With the aim to find new inhibitors towards IX and XII isoforms, the hybridization of the privileged scaffolds isatin, dihydrothiazole, and benzenesulfonamide was investigated in order to explore how it may affect the activity and selectivity of the hCA isoforms. In this respect, a series of isatin thiazolidinone hybrids have been designed and synthesized and their biological activity and selectivity on hCA I, hCA II, hCA IX, and hCA XII explored. The new compounds exhibited promising inhibitory activity results on isoforms IX and XII in the nanomolar range, which has highlighted the importance of substituents in the isatin ring and in position 3 and 5 of thiazolidinone. In particular, compound 5g was the most active toward hCA IX, while 5f was the most potent inhibitor of hCA XII within the series. When both potency and selectivity were considered, compound 5f appeared as one of the most promising. Additionally, our investigations were supported by molecular docking experiments, which have highlighted the putative binding poses of the most promising compound. [ABSTRACT FROM AUTHOR]

Enzymes are molecules that play a crucial role in maintaining homeostasis and balance in all living organisms by catalyzing metabolic and cellular processes. If an enzyme's mechanism of action is inhibited, the progression of certain diseases can be slowed or halted, making enzymes a key therapeutic target. Therefore, identifying or developing enzyme inhibitors is essential for treating significant diseases and ensuring plant defense against pathogens. This review aims to compile information on various types of enzyme inhibitors, particularly those that are well studied and beneficial in both human and plant contexts, by analyzing their mechanisms of action and the resulting benefits. Specifically, this review focuses on three different types of enzyme inhibitors that are most studied, recognized, and cited, each with distinct areas of action and potential benefits. For instance, serine enzyme inhibitors in plants help defend against pathogens, while the other two classes—alpha-glucosidase inhibitors and carbonic anhydrase inhibitors—have significant effects on human health. Furthermore, this review is also intended to assist other researchers by providing valuable insights into the biological effects of specific natural or synthetic inhibitors. Based on the current understanding of these enzyme inhibitors, which are among the most extensively studied in the scientific community, future research could explore their use in additional applications or the development of synthetic inhibitors derived from natural ones. Such inhibitors could aid in defending against pathogenic organisms, preventing the onset of diseases in humans, or even slowing the growth of certain pathogenic microorganisms. Notably, carbonic anhydrase inhibitors have shown promising results in potentially replacing antibiotics, thereby addressing the growing issue of antibiotic resistance. [ABSTRACT FROM AUTHOR]

This study proposes a novel therapeutic strategy for cancer management by combining the antitumor effects of hydrogen sulfide (H2S) and inhibition of carbonic anhydrases (CAs; EC 4.2.1.1), specifically isoforms IV, IX, and XII. H2S has demonstrated cytotoxicity against various cancers at high concentrations. The inhibition of tumor-associated CAs leads to lethal intracellular alkalinization and acidification of the extracellular tumor microenvironment and restores tumor responsiveness to the immune system, chemotherapy, and radiotherapy. The study proposes H2S donor–CA inhibitor (CAI) hybrids for tumor management. These compounds effectively inhibit the target CAs, release H2S consistently, and exhibit potent antitumor effects against MDA-MB-231, HCT-116, and A549 cancer cell lines. Notably, some compounds display high cytotoxicity across all investigated cell lines. Derivative 30 shows a 2-fold increase in cytotoxicity (0.93 ± 0.02 µM) under chemically induced hypoxia in HCT-116 cells. These compounds also disturb the cell cycle, leading to a reduction in cell populations in G0/G1 and S phases, with a notable increase in G2/M and Sub-G1. This disruption is correlated with induced apoptosis, with fold increases of 37.2, 24.5, and 32.9 against HCT-116 cells and 14.2, 13.1, and 19.9 against A549 cells compared to untreated cells. These findings suggest the potential of H2S releaser–CAI hybrids as effective and versatile tools in cancer treatment. [ABSTRACT FROM AUTHOR]

Macular holes (MH) are full-thickness retinal defects affecting central vision. While vitrectomy with inner limiting membrane (ILM) peel is the conventional MH treatment, non-surgical alternatives are gaining interest to mitigate surgical risks. This study conducted a comprehensive literature review and analysis of nonsurgical MH management. A systematic literature search was conducted on PubMed, Embase, Scopus, and the Cochrane Library from January 1, 1973, to September 13, 2023. Treatments included laser therapy, carbonic anhydrase inhibitors (CAIs), nonsteroidal antiinflammatory drugs (NSAIDs), steroids (topical, subtenons, peribulbar, intravitreal), intravitreal gas, anti-vascular endothelial growth factors and ocriplasmin injections. Data extraction covered study details, patient characteristics, MH features, treatment outcomes, and recurrence rates. The initial search yielded 3352 articles, refined to 83 articles that met inclusion criteria following screening. Overall reported anatomical closure rates were 36% with laser photocoagulation, 37% with intravitreal ocriplasmin, 55% with intravitreal gas. Closures were more frequently observed with topical NSAIDs (79%), steroids (84%) and CAIs (73%). Closures were more often observed in patients with smaller MH and in the presence of cystic macular oedema. Although non-surgical MH management approaches show potential for conservative therapy, evidence is limited to support routine use. Stage 1 and traumatic MH may benefit from a short period of observation, but the gold standard approach for full-thickness MH remains to be vitrectomy with ILM peel. • Idiopathic macular holes are thought to develop due to vitreomacular traction and retinal hydration. • Macular holes have conventionally required surgical intervention but closures using topical anti-inflammatories, carbonic anhydrase inhibitors, steroids, ocular injections as laser therapy have been reported. • There is lack of evidence to support the use of non-surgical therapy in the management of macular holes. • Development of conservative treatment options may allow patients to avoid the risk profiles associated with surgery. [ABSTRACT FROM AUTHOR]

Volume overload represents a hallmark clinical feature linked to the development and progression of heart failure (HF). Alleviating signs and symptoms of volume overload represents a foundational HF treatment target that is achieved using loop diuretics in the acute and chronic setting. Recent work has provided evidence to support guideline-directed medical therapies, such as sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor (MR) antagonists, as important adjunct diuretics that may act synergistically when used with background loop diuretics in people with chronic HF. Furthermore, there is growing interest in understanding the role of SGLT2 inhibitors, carbonic anhydrase inhibitors, thiazide diuretics, and MR antagonists in treating volume overload in patients hospitalized for acute HF, particularly in the setting of loop diuretic resistance. Thus, the current review demonstrates that: (i) SGLT2 inhibitors and MR antagonists confer long-term cardioprotection in chronic HF patients but it is unclear whether natriuresis or diuresis represents the primary mechanisms for this benefit, (ii) SGLT2 inhibitors, carbonic anhydrase inhibitors, and thiazide diuretics increase natriuresis in the acute HF setting, but implications on long-term outcomes remain unclear and warrants further investigation, and (iii) a multi-nephron segment approach, using agents that act on distinct segments of the nephron, potentiate diuresis to alleviate signs and symptoms of volume overload in acute HF. [ABSTRACT FROM AUTHOR]

Research into novel anti-Helicobacter pylori agents represents an important approach for the identification of new treatments for chronic gastritis and peptic ulcers, which are associated with a high risk of developing gastric carcinoma. In this respect, two series of azobenzenesulfonamides were designed, synthesized, and tested against a large panel of human and bacterial CAs to evaluate their inhibitory activity. In addition, computational studies of the novel primary benzenesulfonamides (4a–j) were performed to predict the putative binding mode to both HpCAs. Then, the antimicrobial activity versus H. pylori of the two series was also studied. The best-in-class compounds were found to be 4c and 4e among the primary azobenzenesulfonamides and 5c and 5f belonging to the secondary azobenzenesulfonamides series, showing themselves to exert a promising anti-H. pylori activity, with MIC values of 4–8 μg/mL and MBCs between 4 and 16 μg/mL. Moreover, the evaluation of their toxicity on a G. mellonella larva in vivo model indicated a safe profile for 4c,e and 5c,f. The collected results warrant considering these azobenzenesulfonamides as an interesting starting point for the development of a new class of anti-H. pylori agents. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the long-term efficacy and safety of ripasudil-brimonidine fixed-dose combination (RBFC), a new intraocular pressure (IOP)-lowering medication for glaucoma and ocular hypertension (OHT). Methods: This prospective, multicentre (23 sites in Japan), open-label study enrolled patients with primary open-angle glaucoma (POAG), OHT or exfoliative glaucoma and assigned them to one of four combination therapy cohorts, based on previous treatment(s) received: prostaglandin (PG) analogue (Cohort 1); PG analogue and beta-adrenoceptor blocker (β-blocker) (Cohort 2); PG analogue, β-blocker and carbonic anhydrase inhibitor (Cohort 3); or other/no treatment (Cohort 4). After a ≥ 4-week screening period, eligible patients received twice-daily RBFC for 52 weeks in addition to the treatments they were already receiving. Efficacy was assessed by change in IOP from baseline through week 52. Adverse events and adverse drug reactions (ADRs) were monitored throughout. Results: In total, 179 patients from Cohort 1 (n = 48), Cohort 2 (n = 44), Cohort 3 (n = 41) and Cohort 4 (n = 46) entered the RBFC treatment period. For all cohorts, mean IOP was significantly reduced at 11:00 (2 h after instillation of RBFC) through week 52 with the changes from baseline at week 52 of − 2.7 to − 4.1 mmHg across cohorts; all p < 0.001. Common ADRs were conjunctival hyperaemia (58%), allergic conjunctivitis (18%) and blepharitis (17%), most of which were mild in severity. Conclusion: These data demonstrated the long-term efficacy and safety of RBFC, both alone and in combination with other anti-glaucoma agents. RBFC may offer a new treatment option for the long-term management of glaucoma and OHT. Trial registration: Japan Registry of Clinical Trials Identifier: jRCT2080225063. Date of registration: 17 February 2020. [ABSTRACT FROM AUTHOR]

To describe a patient with hypertensive herpetic uveitis complicated by arterial retinal occlusions and a decompression retinopathy revealing a sickle cell trait. Case report. A 24-year-old African man presented with a hypertensive herpetic keratouveitis. A brutal lowering of the intraocular pressure (IOP) by systemic acetazolamide resulted in a ocular decompression retinopathy and multiple arterial occlusions involving the macular and the mid-periphery retina. A hemoglobin electrophoresis revealed a sickle cell trait. Under rare circumstances, vaso occlusive events can occur in patients with a sickle cell trait. We identified high IOP and acetazolamide to be responsible of an increased blood viscosity and a reduction of the vessels' caliber, resulting in sickling and arterial retinal occlusions. We recommend a thorough anamnesis and a sickle cell screening for patients of African or Mediterranean descent with acute elevated IOP, especially if they have to be treated with carbonic anhydrase inhibitors. Abbreviations: HbA: Hemoglobin A; HbS: Hemoglobin S; HSV1: Herpes Simplex Virus – 1; IOP: IntraOcular Pressure; OCT-A: OCT-Angiography; SD-OCT: Spectral Domain Optical Coherence Tomography [ABSTRACT FROM AUTHOR]

PurposeTo compare the efficacy of intravitreal antivascular endothelial growth factor (anti-VEGF) agents with oral carbonic anhydrase inhibitors (CAIs) in treating cystoid macular edema (CME) secondary to retinitis pigmentosa (RP).MethodsThis retrospective study analyzed 98 patients (98 eyes) with RP-CME: 47 (48.0%) received intravitreal anti-VEGF agents (Ranibizumab or Bevacizumab) and 51 (52.0%) were treated with oral CAIs (methazolamide 50 mg/day or acetazolamide 500 mg/day). Medical records were reviewed to assess best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) at baseline and at 1, 3, 6, and 12 months post-treatment using Generalized Estimation Equations (GEE). Adverse events and risk factors influencing visual prognosis were also evaluated.ResultsBoth groups showed significant improvement in BCVA and reduction in CMT at 1 and 3 months post-treatment compared to baseline (all p < 0.001). In the oral CAIs group, these improvements persisted until 6 months. However, by 12 months, neither group exhibited significant improvements in BCVA or CMT compared to baseline (all p > 0.05). Intragroup comparisons revealed that the oral CAIs group had significantly better BCVA and CMT improvements at 3 and 6 months than intravitreal anti-VEGF group (p < 0.001 for BCVA at 3 months, p = 0.003 for BCVA at 6 months; all p < 0.001 for CMT at both 3 and 6 months). No significant differences were found between the two groups in BCVA and CMT at 12 months or in IOP at any time point (all p > 0.05). Subgroup analysis indicated that oral acetazolamide was more effective than methazolamide in reducing CMT and improving BCVA at 3 and 6 months (p = 0.005 for BCVA at 3 months, p = 0.015 for BCVA at 6 months; p = 0.037 for CMT at 3 months, p < 0.001 for CMT at 6 months). There were no significant differences in outcomes between intravitreal Ranibizumab and Bevacizumab (all p > 0.05). Correlation analysis showed that worse BCVA at 12 months was associated with older age (r = 0.202, p = 0.046), higher baseline CMT (r = 0.353, p < 0.001), poorer baseline BCVA (r = 0.579, p < 0.001), but showed no correlation with genotype. Adverse effects from oral CAIs included tingling sensation (3.9%), altered taste (9.8%), and gastrointestinal upset (7.8%). The Ranibizumab group required an average of 3.7 ± 0.8 treatments, and the Bevacizumab group required an average of 3.8 ± 0.5 treatments over the course of 1 year without experiencing severe adverse effects.ConclusionBoth intravitreal anti-VEGF agents and oral CAIs effectively improved CMT and BCVA in RP-CME patients within the first 3 months of treatment. However, oral CAIs demonstrated superior anatomic and functional improvements at 6 months. Poorer BCVA prognosis was associated with older age, higher baseline CMT, poorer baseline visual acuity. Larger, randomized clinical trials with extended follow-up periods are needed to confirm these findings.

The editorial discusses substance-based medical devices (SBMDs) and the challenges of demonstrating their efficacy, safety, and sustainability under the European Medical Device Regulation. It emphasizes the importance of well-designed clinical trials and postmarketing surveillance to ensure the therapeutic claims of SBMDs are supported by evidence. The article highlights the opportunities for innovation in healthcare and research presented by the new regulatory framework, particularly in addressing common medical needs where SBMDs can be safely and effectively used. Additionally, it explores the complexities of classifying products like citicoline in glaucoma and the need for collaboration among pharmacologists, clinicians, and regulators to maximize the potential benefits of SBMDs. [Extracted from the article]

The text discusses the importance, incidence, causes, and risk factors of acute intraocular pressure (IOP) elevation after cataract surgery, particularly in high-risk patients with preexisting optic nerve damage. It highlights the biphasic nature of IOP elevations post-surgery and the potential complications, such as post-cataract surgery optic neuropathy. The document also provides recommendations for prophylaxis and treatment, including the use of topical and systemic medications, as well as surgical interventions like microinvasive glaucoma surgeries (MIGS) for patients with sustained IOP elevation. Surgeons are advised to consider individual patient factors and history when making decisions regarding prophylaxis and treatment. [Extracted from the article]

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated. [ABSTRACT FROM AUTHOR]

Purpose: Investigating long-term trends in glaucoma medication. Methods: All patients diagnosed with glaucoma and prescribed glaucoma eye drops between 2007 and 2020 in Korea's Health Insurance Review and Assessment Service database participated in this study. A weight was assigned to each prescription using the reciprocal of the total number of prescriptions received by the individual in that year. The number of patients who received each type of glaucoma eye drop prescription was calculated by summing the weights for each year. Results: During the study period, prostaglandin analog eye drop monotherapy was the most frequently given type of glaucoma eye drop prescription. Until 2008, the second most frequently given type of glaucoma eye drop prescription was beta blocker eye drop monotherapy; thereafter, it changed to carbonic anhydrase inhibitor/beta blocker fixed-combination eye drop monotherapy. The prescription proportion of single-ingredient glaucoma eye drops decreased (-1.290%/year, P < 0.001), whereas that of fixed-combination glaucoma eye drops increased (1.291%/year, P < 0.001). The number of glaucoma eye drops prescribed per patient remained constant (-0.00030/year, P = 0.167) with an average of 1.302, while the number of active ingredients prescribed per patient increased (0.01737/year, P < 0.001) from 1.659 in 2007 to 1.896 in 2020. Conclusion: Over 14 years, there was no change in the number of glaucoma eye drops prescribed to individual patients in Korea. However, the number of active ingredients prescribed increased owing to the increased prescription of fixed-combination eye drops. The current trends in glaucoma medication are expected to help establish future treatment strategies. [ABSTRACT FROM AUTHOR]

Inhibiting the enzymes carbonic anhydrase I (CA I) and carbonic anhydrase II (CA II) presents a potential avenue for addressing nervous system ailments such as glaucoma and Alzheimer's disease. Our study explored harnessing explainable artificial intelligence (XAI) to unveil the molecular traits inherent in CA I and CA II inhibitors. The PubChem molecular fingerprints of these inhibitors, sourced from the ChEMBL database, were subjected to detailed XAI analysis. The study encompassed training 10 regression models using IC50 values, and their efficacy was gauged using metrics including R2, RMSE, and time taken. The Decision Tree Regressor algorithm emerged as the optimal performer (R2: 0.93, RMSE: 0.43, time‐taken: 0.07). Furthermore, the PFI method unveiled key molecular features for CA I inhibitors, notably PubChemFP432 (C(O)N) and PubChemFP6978 (C(O)O). The SHAP analysis highlighted the significance of attributes like PubChemFP539 (C(O)NCC), PubChemFP601 (C(O)OCC), and PubChemFP432 (C(O)N) in CA I inhibitiotable n. Likewise, features for CA II inhibitors encompassed PubChemFP528(C(O)OCCN), PubChemFP791 (C(O)OCCC), PubChemFP696 (C(O)OCCCC), PubChemFP335 (C(O)NCCN), PubChemFP580 (C(O)NCCCN), and PubChemFP180 (C(O)NCCC), identified through SHAP analysis. The sulfonamide group (S), aromatic ring (A), and hydrogen bonding group (H) exert a substantial impact on CA I and CA II enzyme activities and IC50 values through the XAI approach. These insights into the CA I and CA II inhibitors are poised to guide future drug discovery efforts, serving as a beacon for innovative therapeutic interventions. [ABSTRACT FROM AUTHOR]

Acute decompensated heart failure (HF) is the most common form of acute HF (AHF) and presents with systemic congestion due to left ventricular dysfunction with sodium and water retention. Diuretics are the mainstay of treatment for AHF, with loop diuretics being the first-line therapy. However, in some studies, patients who were given high doses of loop diuretics were discharged from the hospital with residual signs of volume overload. Combining acetazolamide, a carbonic anhydrase inhibitor, with loop diuretics has been shown to be beneficial as it increases the efficacy of loop diuretics and reduces the signs and symptoms of congestion. Further, it can be used for the prevention or treatment of diuretic resistance (DR). Sequential nephron blockade with acetazolamide has emerged as a novel strategy for the treatment of AHF to enhance the efficacy of loop diuretics and prevent DR. This review highlights the combination of acetazolamide with loop diuretics as an alternative and possibly more effective decongestive strategy option in AHF patients. Nevertheless, there is limited evidence to support this combination therapy, and further research is necessary to substantiate its use in AHF patients. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of topical carbonic anhydrase inhibitor (brinzolamide) versus placebo on visual function and waveforms in infantile nystagmus syndrome (INS). Design: Prospective, placebo‑controlled, double‑blind, cross‑over study. Methods: Setting‑ A tertiary eye care center. Patients‑ Cases of idiopathic INS with and without abnormal head posture aged ≥10 years who had not received previous treatment for nystagmus. Intervention‑ Patients were randomized into two groups. Group 1 was given placebo for 3 months, and after a washout period of 7 days started on topical brinzolamide for the next 3 months. In group 2, the order was reversed. The drops were administered topically three times (every 8 hours) in both eyes. Outcome measure‑ Binocular best corrected visual acuity (BCVA) using the ETDRS chart, eXpanded nystagmus acuity function (NAFX) score and INS waveforms obtained from eye movement recordings, intraocular pressure (IOP) by Goldmann applanation tonometer, near stereopsis by TNO stereo test, and change in abnormal head posture before and after intervention in the null position. Results: A total of 29 cases completed the study (23 with abnormal head posture; 6 without abnormal head posture). A significant improvement was noted in INS waveform characteristics, mean NAFX score (P < 0.001), and mean binocular visual acuity (P < 0.001) with topical brinzolamide in comparison to baseline as well as placebo. No significant change in head position and stereopsis was noted. No side effects were reported with 3 months of brinzolamide therapy. Conclusions: While brinzolamide shows improvement in visual acuity and NAFX score in idiopathic INS, its clinical significance needs further evidence. [ABSTRACT FROM AUTHOR]

Objectives: This real-life study aimed to evaluate the safety of acetazolamide (ACZ), a carbonic anhydrase inhibitor with diuretic effects. ACZ has recently been proven to improve decongestion in the context of patients hospitalized for acute heart failure (HF). However, data in terms of safety are lacking. Methods: We conducted a monocentric observational prospective study from November 2023 to February 2024 in a 12-bed cardiology department, recording adverse events (hypotension, severe metabolic acidosis, severe hypokalemia and renal events) during in-hospital HF treatment. All patients hospitalized for acute HF during the study period treated with ACZ (500 mg IV daily for 3 days) on top of IV furosemide (n = 28, 48.3%) were compared with patients who have been treated with IV furosemide alone (n = 30, 51.7%). Results: The patients treated with ACZ were younger than those without (median age 78 (range 67–86) vs. 85 (79–90) years, respectively, p = 0.01) and had less frequent chronic kidney disease (median estimated glomerular fraction rate (60 (35–65) vs. 38 (26–63) mL/min, p = 0.02). As concerned adverse events during HF treatment, there were no differences in the occurrences of hypotension (three patients [10.7%] in the ACZ group vs. four [13.3%], p = 0.8), renal events (four patients [14.3%] in the ACZ group vs. five [16.7%], p = 1) and severe hypokalemia (two [7.1%] in the ACZ group vs. three [10%], p = 1). No severe metabolic acidosis occurred in either group. Conclusions: Although the clinical characteristics differed at baseline, with younger age and better renal function in patients receiving ACZ, the tolerance profile did not significantly differ from patients receiving furosemide alone. Additional observational data are needed to further assess the safety of ACZ–furosemide combination in the in-hospital management of HF, especially in older, frail populations. [ABSTRACT FROM AUTHOR]

Objectives Animals Procedures Results Conclusions In equine glaucoma, topical treatment with carbonic anhydrase inhibitors (CAIs) is recommended. Oral acetazolamide, a systemic CAI, is used in horses with hyperkalemic periodic paralysis. Information regarding its effect on equine intraocular pressure (IOP) is scarce. The aim of the study was to determine the effect of oral acetazolamide treatment on IOP in horses, in a case–control study.Ten healthy horses.Horses were treated with oral acetazolamide (4.4 mg/kg) BID for 1 week. Serum acetazolamide concentrations were determined by liquid chromatography/tandem mass spectrometry, and IOP were measured before treatment, daily during treatment, and at 48 and 72 h after treatment.Acetazolamide serum levels reached steady state at 72 h after the first oral dose. In a mixed effect model logistic regression, there was a significant decrease in IOP on the third treatment day, of 2.4 mmHg (p = .012) and 2.7 mmHg (p = .006) in the left (OS) and right eye (OD), respectively. On the seventh day, there was a decrease in 2.5 mmHg (p = .008) and 2.7 mmHg (p = .007) OS and OD, respectively. A significant increase occurred 48 h following treatment discontinuation (3.6 mmHg, p < .001 and 3.5 mmHg, p < .001 OS and OD, respectively). The area under the concentration versus time curve (AUC(0–10h)) was 1.1 ± 0.5 μg/mL*h, mean residence time 6.7 ± 4.3 h, peak plasma concentration (Cmax) 0.4 ± 0.4 μg/mL and time to reach Cmax 1.8 h. There was a significant increase in serum concentrations 1, 2, 48, 72, and 156 h following the first drug administration (p < .05).Further studies are required to determine whether acetazolamide is a potential treatment for equine glaucoma. [ABSTRACT FROM AUTHOR]

Glaucoma is a chronic neurodegenerative disease that poses a significant threat of irreversible blindness worldwide. Current treatments for glaucoma focus on reducing intraocular pressure (IOP), which is the only modifiable risk factor. Traditional anti-glaucomatous agents, including carbonic anhydrase inhibitors, beta-blockers, alpha-2 agonists, and prostaglandin analogs, work by either improving uveoscleral outflow or reducing aqueous humor production. Rho kinase (ROCK) inhibitors represent a novel class of anti-glaucomatous drugs that have emerged from bench to bedside in the past decade, offering multifunctional characteristics. Unlike conventional medications, ROCK inhibitors directly target the trabecular meshwork outflow pathway. This review aims to discuss the mechanism of ROCK inhibitors in reducing IOP, providing neuroprotection, and preventing fibrosis. We also highlight recent studies and clinical trials evaluating the efficacy and safety of ROCK inhibitors, compare them with other clinical anti-glaucomatous medications, and outline future prospects for ROCK inhibitors in glaucoma treatment. [ABSTRACT FROM AUTHOR]

In medicinal chemistry, the precise configuration of molecules is a crucial determinant of their pharmacological properties. Hence, the introduction of a new chiral center during the synthetic pathway involves the assignment of configuration. Herein we assign, by means of molecular modeling 1H and 2D Nuclear Overhauser Effect NMR techniques, the configuration of the two diastereomers 2S-(1R-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine and 2S-(1S-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine, which are useful to synthetize analogs of the potent and highly selective dipeptidyl peptidase IV and carbonic anhydrase inhibitor recently published. [ABSTRACT FROM AUTHOR]

Two series, "a" and "b", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABAA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D1–3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABAA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABAA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a–9a and 1b–9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "b" series, particularly for compound 8b. [ABSTRACT FROM AUTHOR]

Pilomotor seizures are strongly associated with autoimmune encephalitis (AE), particularly anti‐LGI1 encephalitis. The carbonic anhydrase inhibitor acetazolamide may have special efficacy for treating AE‐associated pilomotor seizures. Six patients with AE (five anti‐LGI1, one seronegative) and temporal lobe pilomotor seizures (five with seizures inducible by hyperventilation) were treated with acetazolamide, administered in a cycling (2‐days‐ON, 4‐days‐OFF) regimen to offset tolerance. Seizures were assessed during epilepsy monitoring unit (EMU) recordings in four inpatients (one of whom also maintained an outpatient seizure diary chronicling 1203 seizures over 1079 days); two outpatients self‐reported seizure frequencies. The extended diary revealed an inverse correlation between acetazolamide and proportion of seizures/day: 6%, 2% (days 1, 2 ON); 3%, 13%, 31%, 45% (days 1, 2, 3, 4 OFF). This patient later developed focal status epilepticus upon wean of antiseizure medications during a seropositive AE relapse that was remarkably aborted with acetazolamide monotherapy. The other three EMU patients averaged.56 seizures/day ON, and 3.81 seizures/day OFF (p =.004). The two outpatients reported seizure reductions from 3–5/day to 2/week, and 15–20/day to none, respectively, after initiation of cycling acetazolamide. Likely related to cerebral CO2/pH sensitivity, acetazolamide can be unusually effective in controlling pilomotor seizures in AE, chronically or in acute settings. [ABSTRACT FROM AUTHOR]

Human carbonic anhydrase isoforms IX and XII play a key role in maintaining acid-base balance in solid tumors, creating a favorable microenvironment for the growth, invasion and metastasis of tumor cells. In the last few years, a number of scientific groups have published results that inhibition of isoforms IX and XII significantly increases the effectiveness of classical chemotherapy, makes it possible to suppress the resistance of tumor cells to chemotherapy and increase their sensitivity to the used drugs (including reducing the dose of cytostatics). In the review, we analyzed the scientific literature on the role of carbonic anhydrase isoforms IX and XII in carcinogenesis and on the combined effect of carbonic anhydrase inhibitors with antitumor drugs.

New substituted heterocyclic compounds 2a–2c were synthesized from N-(6-hydrazinyl-6-oxo-hexanoyl)phthalimide, and their structure was confirmed by FT-IR, 1H NMR, and 13C NMR spectra. In silico studies were performed to explore their chemical properties and predict biological activities. 2-[5-(1,3,4-Oxa-diazol-2-yl)pentanoyl]-1H-isoindole-1,3(2H)-dione (2a) and 2-(5-{4-[(2-hydroxy-4-nitrophenyl)diazenyl]-5-sulfanyl-4H-1,2,4-triazol-3-yl}pentanoyl)-1H-isoindole-1,3(2H)-dione (2b) showed good drug-like properties. Furthermore, molecular docking study showed that compounds 2a and 2b could be active as carbonic anhydrase I inhibitors. [ABSTRACT FROM AUTHOR]

Discoidin domain receptor 1 (DDR1) kinase has emerged as a promising target for cancer therapy, and selective DDR1 inhibitors have shown promise as effective therapeutic candidates. Herein, we have identified the first coumarin-based selective DDR1 inhibitors via repurposing of a recent series of carbonic anhydrase inhibitors. Among these, ureidocoumarins 3a, 3i, and 3q showed the best DDR1 inhibitory activities. The m-trifluoromethoxy phenyl member 3q potently inhibited DDR1 with an IC50 of 191 nM, while it showed less inhibitory activity against DDR2 (IC50 = 5080 nM). 3q also exhibited favorable selectivity in a screening platform with 23 common off-target kinases, including BCR-ABL. In the cellular context, 3q showed moderate antiproliferative effects, while 3i, with the third rank in DDR1 inhibition, exerted the best anticancer activity with sub-micromolar GI50 values over certain DDR1-dependent cell lines. Molecular docking and MD simulations disclosed the putative binding mode of this coumarin chemotype and provided insights for further optimization of this scaffold. The present findings collectively supported the potential improvement of ureidocoumarins 3i and 3q for cancer treatment. [ABSTRACT FROM AUTHOR]

Diuretics are widely used to treat pathologies of various genesis. However, the development of side effects during their long-term use remains a problem of traditional treatment regimens. The search for diuretics that would be aimed at inhibiting a key target molecule that is involved in the regulation of salt or water balance in the kidney, and certainly have a low level of toxicity and side effects, is an urgent task for researchers. Our preliminary screening of substituted quinones using in silico and in vitro methodology identified a number of effective compounds that outperform or compete with diuretics. The compounds are not "classic" carbonic anhydrase II inhibitors, but the pronounced diuretic effect of a number of compounds requires additional explanation. Therefore, the aim of the work was to study the effect of substituted quinones on the excretory function of rat kidneys to assess the prospects of their further structural modification and use as potential diuretics. Considering the experimental data, it should be noted that compounds AVD-6, AVD-7, AVD-8 and AVD-9 have pronounced diuretic activity. Thus, according to indicators of excretory indices of electrolytes, it is possible to note the predominant influence of compounds AVD-6, AVD-7, AVD-8 and AVD-9 on excretion of sodium, potassium and chlorine from the body. Compounds AVD-6, AVD-7, AVD-8 and AVD-9, in contrast to Hydrochlorothiazide, which blocks carbonic anhydrase in the proximal part of the convoluted tubules and accelerates the excretion of potassium with from the urine, have a much lower excretory index as for these ions. Thus, our conducted research made it possible to identify a new, little-known class of hybrid molecular structures, namely (N'-(4-[(aroyloxy)imino]cyclohexa-2,5-dien-1-ylidene) aroylhydrazides (AVD-6, AVD-7, AVD-8 and AVD-9), which, in addition to affecting the excretory function of the kidneys, have significant diuretic activity and are potential diuretics. [ABSTRACT FROM AUTHOR]