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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]

Introduction: Glaucoma is the second leading cause of blindness in the world. The only known modifiable risk factor for the onset and progression of glaucoma is Intraocular Pressure (IOP). There are a limited number of studies documenting the IOP-lowering effect of Selective Laser Trabeculoplasty (SLT) in Primary Open Angle Glaucoma (POAG) patients, especially within the North Indian population. Understanding the effect of SLT on IOP reduction in this population is crucial for the proper management of glaucoma patients. Aim: To study the IOP-lowering effect of SLT in North Indian POAG patients (who had not achieved target IOP on two or more antiglaucoma drugs) after a period of six months. Materials and Methods: A hospital-based, single-arm, prepost type of prospective analytical study was conducted at Lady Hardinge Medical College and associated hospitals in New Delhi, India, from January 2021 to June 2022. POAG patients aged 18 years or older, who had not achieved the target IOP while on two or more Antiglaucoma Medications (AGM), were given the option of treatment with SLT. A total of 33 eyes were considered for the study as per sample size calculations. Pre-SLT, IOP was recorded along with other baseline parameters. The SLT procedure was carried out according to the standard protocol. IOP was recorded during follow-ups at one week, one month, three months, and six months. The Friedman test was used to compare IOP values, with a significance level set at 0.05. Spearman correlation was employed to explore the correlation between baseline IOP and the change in IOP at six months. Results: A total of 33 eyes were included in the study. Of these, 28 (84.8%) eyes had advanced glaucoma, while 5 (15.2%) eyes had moderate glaucoma according to International Classification of Diseases, Tenth Revision (ICD-10) staging. Patients were on two or more commonly used AGMs, including prostaglandin analogues, beta blockers, alpha agonists, topical carbonic anhydrase inhibitors, and rho kinase inhibitors. The mean number of topical AGMs that patients were using was 3.03. The number and type of AGMs for each patient remained consistent pre and post-SLT throughout the study period. The mean IOP (baseline) was 16.39±2.73 mmHg, and after six months, the mean IOP was 13.86±1.99 mmHg. The mean IOP reduced by 2.53 mm Hg (15.44%). There was a strong negative correlation between baseline IOP and the change in IOP at six months, which was statistically significant (rho=-0.78, p-value<0.001). Conclusion: The present study indicates that SLT can be considered an adjunctive treatment for lowering IOP in North Indian POAG patients. A strong negative correlation was found between baseline IOP and IOP at six months post-SLT, suggesting that a higher reduction can be expected in patients with elevated baseline IOP. [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]

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]

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]

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]

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]

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.

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]

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]

This research delves into the examination of benzene sulphonamide derivatives featuring pyrazole rings as potential diuretics. Concentrating on their role as human carbonic anhydrase inhibitors (hCA), the investigation aims to unveil a groundbreaking diuretic drug. Six innovative benzenesulfonamide derivatives are synthesized utilizing a conventional heating process. Subsequently, employing AutoDock Vina 1.2.3, these compounds undergo molecular docking assessments and pharmacokinetic predictions at the active sites of hCA I and hCA II, while the SwissADME program is employed for pharmacokinetic forecasting. Notably, Compounds 17 and 19 exhibit robust binding affinities with hCA I and II, respectively, as evidenced by the docking study. ADME studies reveal favorable bioavailability and adherence to PAINS alerts, as well as Lipinski's rule of five requirements. Consequently, based on the findings, these compounds exhibit significant potential as diuretics in comparison to well-established acetazolamide medications. [ABSTRACT FROM AUTHOR]

Aim: To review the current state of knowledge on macular in retinitis pigmentosa, current treatment methods and management. Material and methods: Analysis of literature available on PubMed. Presentation of own treatment results. Results: Macular lesions occur in 11.5% to 59.7% of patients with pigmentary degeneration. The most commonly observed macular abnormalities include cystoid macular edema, epiretinal membranes, vitreomacular traction syndrome, and full-thickness macular holes. In conservative treatment, topical carbonic anhydrase inhibitors and steroids are the most effective. The best surgical treatment outcomes have been obtained for macular holes. Conservative and surgical treatment outcomes vary and depend on the stage of retinitis pigmentosa. Conclusions: Macular abnormalities are often observed in patients with retinitis pigmentosa. Carbonic anhydrase blockers and steroids can be effective in treating cystoid macular edema. Surgical treatment can improve macular morphology but improvement in visual function is limited due to long-term retinal dysfunction and progression of the underlying disease. [ABSTRACT FROM AUTHOR]

A series of novel pyrazole-dicarboxamides were synthesized from pyrazole-3,4-dicarboxylic acid chloride and various primary and secondary sulfonamides. The structures of the new compounds were confirmed by FT-IR, ¹H-NMR, 13C-NMR, and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.024-0.496 µM for hCA I and 0.006-5.441µM for hCA II. Compounds 7a and 7i showed nanomolar level of inhibition of hCA II, and these compounds exhibited high selectivity for this isoenzyme. Molecular docking studies were performed between the most active compounds 7a, 7b, 7i, and the reference inhibitor AAZ and the hCAI and hCAII to investigate the binding mechanisms between the compounds and the isozymes. These compounds showed better interactions than the AAZ. ADMET and drug-likeness analyses for the compounds have shown that the compounds can be used pharmacologically in living organisms. [ABSTRACT FROM AUTHOR]

In this study, we designed two series of novel anthraquinone-based benzenesulfonamide derivatives and their analogues as potential carbonic anhydrase inhibitors (CAIs) and evaluated their inhibitory activities against off-target human carbonic anhydrase II (hCA II) isoform and tumor-associated human carbonic anhydrase IX (hCA IX) isoform. Most of these compounds exhibited good inhibitory activities against hCA II and IX. The compounds that exhibited the best hCA inhibition were further studied against the MDA-MB-231, MCF-7, and HepG2 cell lines under hypoxic and normoxic conditions. Additionally, the compounds exhibiting the best antitumor activity were subjected to apoptosis and mitochondrial membrane potential assays, which revealed a significant increase in the percentage of apoptotic cells and a notable decrease in cell viability. Molecular docking studies were performed to demonstrate the presence of numerous hydrogen bonds and hydrophobic interactions between the compounds and the active site of hCA. Absorption, distribution, metabolism, excretion (ADME) predictions showed that all of the compounds had good pharmacokinetic and physicochemical properties. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) based on intracellular Fenton reaction to produce highly cytotoxic reactive oxygen species (ROS) has played an essential role in tumor therapy. However, this therapy still needs to be improved by weakly acidic pH and over-expression of glutathione (GSH) in tumor microenvironment (TEM), which hinders its future application. Herein, we reported a multifunctional bimetallic composite nanoparticle MnO2@GA-Fe@CAI based on a metal polyphenol network (MPN) structure, which could reduce intracellular pH and endogenous GSH by remodeling tumor microenvironment to improve Fenton activity. MnO2 nanoparticles were prepared first and MnO2@GA-Fe nanoparticles with Fe3+ as central ion and gallic acid (GA) as surface ligands were prepared by the chelation reaction. Then, carbonic anhydrase inhibitor (CAI) was coupled with GA to form MnO2@GA-Fe@CAI. The properties of the bimetallic composite nanoparticles were studied, and the results showed that CAI could reduce intracellular pH. At the same time, MnO2 could deplete intracellular GSH and produce Mn2+ via redox reactions, which re-established the TME with low pH and GSH. In addition, GA reduced Fe3+ to Fe2+. Mn2+ and Fe2+ catalyzed the endogenous H2O2 to produce high-lever ROS to kill tumor cells. Compared with MnO2, MnO2@GA-Fe@CAI could reduce the tumor weight and volume for the xenograft MDA-MB-231 tumor-bearing mice and the final tumor inhibition rate of 58.09 ± 5.77%, showing the improved therapeutic effect as well as the biological safety. Therefore, this study achieved the high-efficiency CDT effect catalyzed by bimetallic through reshaping the tumor microenvironment. [ABSTRACT FROM AUTHOR]

The present study investigates the potential of a new compound containing sulfonamide and 4(3H)-quinazolinone to inhibit the hCA-IIX enzyme using in silico methods. Density functional theory-based calculations of electronic properties have been addressed through the analysis of frontier molecular orbitals, molecule electrostatic potential, and IR and UV–vis spectroscopy data. A molecular electrostatic potential analysis predicts that the target protein will be most inhibited by the sulfonamide groups since it has the highest potential spots for electrophile and nucleophile attack. The investigated compound exhibited good ADMET properties and satisfied the Lipinski rule of drug likeness. The hCA-IIX protein binding affinity with the proposed compound was determined by molecular docking analysis, which revealed a stable conformation with more negative binding energy (−12.19 kcal/mol) than the standard AZA drug (−7.36 kcal/mol). Moreover, a molecular dynamics study confirmed the docking results through trajectory analysis. The RMSD and RMSF both showed convergence and no significant fluctuations during the simulation time, which revealed a stable interaction within the active domain of the target protein. According to these findings, the proposed compound has a good pharmacological nature and could potentially be an efficient drug against hCAIX enzymes. [ABSTRACT FROM AUTHOR]

Human carbonic anhydrase IX (hCA IX) is a zinc(II)-dependent metalloenzyme that plays a critical role in the conversion of carbon dioxide and water to protons and bicarbonate. It is a membrane-bound protein with an extracellular catalytic center that is predominantly overexpressed in solid hypoxic tumors. Sulfamates and sulfonamides, for example acetazolamide (AZA), have been used to inhibit hCA IX in order to improve the response to solid hypoxic tumors. In the present study, we propose a new drug targeting approach by attaching the natural cytotoxic substances betulin and betulinic acid (BA) via a linker to sulfonamides. The conjugate was designed with different spacer lengths to accumulate at the target site of hCA IX. Computational and cell biological studies suggest that the length of the linker may influence hCA IX inhibition. Cytotoxicity tests of the newly synthesized bifunctional conjugates 3, 5, and 9 show effective cytotoxicity in the range of 6.4 and 30.1 µM in 2D and 3D tumor models. The hCA IX inhibition constants of this conjugates, measured using an in vitro enzyme assay with p-nitrophenyl acetate, were determined in a low µM-range, and all compounds reveal a significant inhibition of hypoxia-induced CA activity in a cell-based assay using the Wilbur–Anderson method. In addition, the cells respond with G1 increase and apoptosis induction. Overall, the dual strategy to produce cytotoxic tumor therapeutics that inhibit tumor-associated hCA IX was successfully implemented. [ABSTRACT FROM AUTHOR]

The carbonic anhydrase inhibitor sulthiame reduces OSA severity, increases overnight oxygenation, and improves sleep quality. Insights into how sulthiame modulates OSA pathophysiologic features (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation. How does sulthiame treatment modify endotypic traits in OSA? Per-protocol tertiary analysis of a randomized controlled trial with the inclusion criteria as follow: BMI, ≥ 20 to ≤ 35 kg/m2; age, 18-75 years; apnea-hypopnea index (AHI) ≥ 15 events/h; Epworth sleepiness scale score, ≥ 6; as well as nonacceptance or nontolerance of positive airway pressure treatment. Patients were randomized to receive placebo (n = 22), sulthiame 200 mg (n = 12), or sulthiame 400 mg (n = 24) during 4 weeks of treatment. Polysomnography was applied twice at baseline and follow-up. Endotypic traits were determined from polysomnography tracings (PUPBeta). Sulthiame plasma concentration was analyzed. Differences from baseline to follow-up (Δs) were analyzed with the analysis of covariance or Kruskal-Wallis H test and Pearson (r) or Spearman correlations (r s). Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain (response to a 1-cycle/min disturbance, LG 1 ; mean, –0.16 [95% CI, –0.18 to –0.13]; P <.05) in addition to increased ventilation at lowest decile of ventilatory drive (V min ; median, +12 [95% CI, 4-20]; P <.05) and median ventilation at eupneic ventilatory drive (V passive ; median, +4 [95% CI, 0-5]; P <.05). ΔLG 1 correlated with ΔAHI percentage (200 mg: r = 0.65; P <.05). V min and V passive correlated with ΔAHI (all sulthiame: r s = –0.59 and r s = –0.65; P <.05 for all). The reduction of LG 1 was seen already in the lower sulthiame concentration range, whereas changes in V min peaked in the higher range. The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG 1) as well as upper airway collapsibility (V min and V passive). European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu [ABSTRACT FROM AUTHOR]

2H-Benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (BTD) based carbonic anhydrase (CA) inhibitors are here explored as new anti-mycobacterial agents. The chemical features of BTD derivatives meet the criteria for a potent inhibition of β-class CA isozymes. BTD derivatives show chemical features meeting the criteria for a potent inhibition of β-class CA isozymes. Specifically, three β-CAs (MtCA1, MtCA2, and MtCA3) were identified in Mycobacterium tuberculosis and their inhibition was shown to exert an antitubercular action. BTDs derivatives 2a-q effectively inhibited the mycobacterial CAs, especially MtCA2 and MtCA3, with Ki values up to a low nanomolar range (MtCA3, Ki = 15.1–2250 nM; MtCA2, Ki = 38.1–4480 nM) and with a significant selectivity ratio over the off-target human CAs I and II. A computational study was conducted to elucidate the compound structure-activity relationship. Importantly, the most potent MtCA inhibitors demonstrated efficacy in inhibiting the growth of M. tuberculosis strains resistant to both rifampicin and isoniazid—standard reference drugs for Tuberculosis treatment. [ABSTRACT FROM AUTHOR]

Purpose: Intraocular pressure (IOP) spikes (IOP > 30 mmHg or > 10 mmHg above baseline IOP) are a common and worrisome complication of gonioscopy-assisted transluminal trabeculotomy (GATT). The purpose of this study is to identify risk factors for IOP spikes and to describe their characteristics, management, and clinical course in a large cohort of patients. Methods: A retrospective, single-center study which included 217 consecutive eyes of patients that underwent GATT between December 2019 and April 2022 with follow-up of at least 90 days. Results: IOP spikes occurred in 52 of 217 (24%) eyes. Spikes occurred in 15.5% of patients in whom pre-operative IOP-lowering medications were continued after surgery (90 eyes), and in 29.9% in whom IOP-lowering medications were stopped after surgery (127 eyes). Spikes were diagnosed at a mean of 7.7 ± 6.5 days after surgery. All IOP spikes occurred within the first month of surgery. The mean duration of a spike was 4.9 ± 5.4 days. Management of IOP spikes included adding a mean of 3.13 ± 1.7 groups of glaucoma medications. Thirty-seven (72.5%) eyes were treated with oral carbonic anhydrase inhibitor, 11 (21.6%) were treated with IV mannitol, and anterior chamber paracentesis was performed in 16 (31.4%). Six (11.8%) eyes underwent additional glaucoma surgery to control IOP. Patients that continued their pre-operative IOP-lowering medications after surgery were 2.3 times less likely to develop a spike as compared to patients who discontinued their medications (P = 0.016). Spikes were found to be a risk factor for failure of GATT. Conclusions: IOP spikes are a common occurrence after GATT. They most commonly appear during the first two post-operative weeks and usually resolve with topical and systemic IOP-lowering treatment. The continuation of IOP-lowering medications after GATT is recommended to lower the risk of IOP spikes. [ABSTRACT FROM AUTHOR]

Glaucoma therapy aims at lowering intra-ocular pressure (IOP). Brinzolamide, a carbonic anhydrase inhibitor, is utilized as a second-line medication for treating ocular hypertension and primary open-angle glaucoma (POAG). The drug lowers the IOP making it a therapeutic agent against glaucoma, and due to its poor water solubility, is commercially available as Azopt®, a 1% ophthalmic suspension. Adverse effects such as blurred vision, ocular irritation, discomfort, and bitter taste are associated with the use of the marketed brinzolamide formulation. This study aims to test the feasibility of formulating and in vitro testing of brinzolamide-PLGA nanoparticles for improved toxicity profile. The nanoparticles were prepared by the oil-in-water (O/W) emulsion-solvent evaporation method. Particle size and zeta potential were determined by dynamic light scattering (DLS). The morphology of the nanoparticles was determined by scanning electron microscopy (SEM). Encapsulation of the drug was verified by high-performance liquid chromatography (HPLC) and the compatibility of the polymer and drug was verified by Fourier transform infrared (FTIR) spectroscopy. The in vitro drug release profile was assessed employing the dialysis method. Intracellular localization of the nanoparticles was assessed by confocal microscopy utilizing Rhodamine 123-loaded nanoparticles. Cytotoxicity of the formulation was assessed on Statens Seruminstitut Rabbit Cornea (SIRC) and transfected Human Corneal Epithelial (SV40 HCEC) cell lines. The particle size of the nanoparticle formulations ranged from 202.3 ± 2.9 nm to 483.1 ± 27.9 nm for blank nanoparticles, and 129.6 ± 1.5 nm to 350.9 ± 8.5 nm for drug-loaded nanoparticles. The polydispersity of the formulations ranged from 0.071 ± 0.032 to 0.247 ± 0.043 for blank nanoparticles, and 0.089 ± 0.028 to 0.158 ± 0.004 for drug-loaded nanoparticles. Drug loading and encapsulation efficiencies ranged from 7.42–15.84% and 38.93–74.18%, respectively. The in vitro drug release profile for the optimized formulation was biphasic, with a ~54% burst release for the initial 3 h, followed by a cumulative 85% and 99% released at 24 and 65 h, respectively. Uptake study showed nanoparticles(NPs) localization in the cytoplasm and around the nuclei of the cells. Brinzolamide-PLGA nanoparticles were successfully developed, characterized, and tested in vitro. Preliminary data show intracellular localization of the nanoparticles in the cytoplasm of SIRC and SV40 HCEC cells. The formulations appeared to be relatively non-cytotoxic to the cells. The research data from the study provided preliminary data for successful development and promising in vitro absorption efficacy for brinzolamide-loaded PLGA nanoparticle formulation. [ABSTRACT FROM AUTHOR]

Purpose To identify the pattern(s) in using antiglaucoma medications following glaucoma surgery in children and compare their efficacies. Methods Retrospective chart review of patients (≤12 years) receiving glaucoma surgery from January 2013 to December 2020. Partially responsive patients needing antiglaucoma medications to attain an Intraocular pressure (IOP) of at least 18 mmHg were divided into three groups: (A) received beta-blocker (β-Blockers); (B) received Prostaglandin analogues and (C) received fixed β-Blocker+ Carbonic anhydrase inhibitor (CAI) preparation. Data included demographics, clinical characteristics, IOP (before, after 1 month, and at last follow-up), and surgeries. Successful treatment attained IOP less than or equal to 18 mmHg on last follow-up. Side effects were recorded. Results Totally 200 eyes of 152 patients were included, (61%) presented within the first month of life, 54% were males, 31.6% had bilateral disease and (82.2%) had primary congenital glaucoma (PCG). Pre-treatment IOP was significantly higher in group C (P=0.009). The most common procedure performed was trabeculotomy (P=0.014). After a mean follow-up period of 20.12 months, all three groups showed a significant reduction in the IOP (P≤0.001), with the highest percent reduction attained in group C (43.7% vs. 33.4% and 33.1% in groups A and B, respectively) P=0.001. Final success rates were 41.2%, 83.3%, and 82.2% for groups A, B, and C, respectively. Dry eye was the most common side effect (32 eyes) mainly occurring in group A (21.6%). Conclusions The most frequently used antiglaucoma medications following partially successful surgery are CAI+β-Blocker combinations. They seem to have the most potent effect and are usually used as a first line the higher the initial IOP is.

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.

This study focused on the synthesis and evaluation of the biological activity of ten novel acetohydrazide hybrid derivatives, having furfuryloxy‐1,2,3‐triazole ring. All the target compounds were tested in vitro and in silico for their inhibitory potential against key enzymes: hAChE, hBChE, hCAI, and hCAII, all involved in significant physiological processes. Remarkably, two compounds, namely (E)‐2‐(4‐((furan‐2‐ylmethoxy)methyl)‐1H‐1,2,3‐triazol‐1‐yl)‐N′‐(4‐hydroxy‐3‐methoxybenzylidene)acetohydrazide (9) and (E)‐N′‐(4‐chlorobenzylidene)‐2‐(4‐((furan‐2‐ylmethoxy)methyl)‐1H‐1,2,3‐triazol‐1‐yl)acetohydrazide (11), exhibited strong inhibitory activity. Compound 9 emerged as the top‐performing inhibitor for both hAChE (IC50 of 0.23 μM) and hBChE (IC50 of 0.74 μM). Additionally, compounds 9 and 11 displayed potent inhibitory effects on hCAI and hCAII, with IC50 values of 0.18 μM and 0.15 μM, respectively. Furthermore, in silico studies provided valuable insights into the interaction mechanisms and stability of the ligand‐protein complexes. Compound 9 demonstrated strong binding scores of −12.063 kcal/mol for hAChE and −9.359 kcal/mol for hBChE, while Compound 11 exhibited substantial scores of −7.040 kcal/mol for hCAI and −8.216 kcal/mol for hCAII. In conclusion, they stand out as promising inhibitors of hAChE, hBChE, hCAI and hCAII enzymes. Their inhibitory activity, supported by low IC50 values, indicated their potential to inhibit enzymes associated with neurological and metabolic processes. [ABSTRACT FROM AUTHOR]

Glaucoma encompasses a group of optic neuropathies characterized by complex and often elusive etiopathology, involvihttng neurodegeneration of the optic nerve in conjunction with abnormal intraocular pressure (IOP). Currently, there is no cure for glaucoma, and treatment strategies primarily aim to halt disease progression by managing IOP. This review delves into the etiopathology, diagnostic methods, and treatment approaches for glaucoma, with a special focus on IOP management. We discuss a range of active pharmaceutical ingredients used in glaucoma therapy, emphasizing their chemical structure, pharmacological action, therapeutic effectiveness, and safety/tolerability profiles. Notably, most of these therapeutic agents are administered as topical formulations, a critical aspect considering patient compliance and drug delivery efficiency. The classes of glaucoma therapeutics covered in this review include prostaglandin analogs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and miotic (cholinergic) agents. This comprehensive overview highlights the importance of topical administration in glaucoma treatment, offering insights into the current state and future directions of pharmacological management in glaucoma. [ABSTRACT FROM AUTHOR]

The three‐components one‐pot Kabachnik‐Fields reaction of sulfapyridine, diethyl phosphite, and aldehyde under thermal catalysis reaction condition in the presence of bismuth (III) triflate as a catalyst afford the corresponding sulfonamide‐phosphonates (3a−3p) in good to excellent yields (78%−91%). The structures of the new synthesized compounds were elucidated and confirmed by variable spectroscopic studies. Single crystal X‐ray studies for 3a, 3d, and 3i verified the proposed structure. The newly developed sulfonamide‐phosphonates were evaluated for their inhibitory properties against four isoforms of human carbonic anhydrase (hCA I, II, IX, and XII). The results demonstrated that they exhibited greater potency in inhibiting hCA XII compared to hCA I, II, and IX, with Ki ranging from 5.1 to 51.1 nM. Compounds 3l and 3p displayed the highest potency, exhibiting selectivity ratios of I/XII >298.7 and 8.5, and II/XII ratios of 678.1 and 142.1, respectively. Molecular docking studies were conducted to explore their binding patterns within the binding pocket of CA XII. The results revealed that the sulfonamide NH group coordinated with the Zn2+ ion, and hydrogen bond interactions were observed with residue Thr200. Additionally, hydrophobic interactions were identified between the benzenesulfonamide phenyl ring and Leu198. Compounds 3p and 3l exhibited an additional hydrogen bonding interaction with other amino acid residues. These supplementary interactions may contribute to the enhanced potency and selectivity of these compounds toward the CA XII isoform. [ABSTRACT FROM AUTHOR]