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Archiv Der Pharmazie May 2024Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized...
Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (K of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Ks in the low nanomolar range of 20.5-176.6 nM and 6.0-127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with K of 20.5 nM and S of 200.1, and K of 6.0 nM and S of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Ks = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Ks = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II.
PubMed: 38713910
DOI: 10.1002/ardp.202400157 -
ChemMedChem May 2024Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes....
Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes. They show a wide diversity in tissue distribution and their subcellular localization. Twenty-two novel phthalazine derivatives were designed, synthesized, and evaluated against four human isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds appeared to be very active mostly against hCA IX (7) and hCA I (6) isoforms being more potent than reference drug acetazolamide (AAZ). Some compounds appeared to be very selective with a selectivity index up to 13.8. Furthermore, docking was performed for some of these compounds on all isoforms to understand the possible interactions with the active site. Additionally, the most active compounds against hCA IX were subjected to cell viability assay. The anticancer activity of the compounds (3 a-d, 5 d, 5 i, and 5 m) was investigated using two human breast cancer cell lines, i. e. MCF-7 and MDA-MB-231 cells, and the normal counterpart, namely MCF10-A cells.
PubMed: 38713763
DOI: 10.1002/cmdc.202400147 -
European Journal of Ophthalmology May 2024To study the outcomes of diode laser transscleral cyclophotocoagulation (TSCPC) with trans-corneal transillumination using a novel low-cost torchlight method in...
PURPOSE
To study the outcomes of diode laser transscleral cyclophotocoagulation (TSCPC) with trans-corneal transillumination using a novel low-cost torchlight method in refractory glaucoma.
METHODS AND ANALYSIS
This prospective interventional study included patients with refractory glaucoma who underwent TSCPC with trans-corneal transillumination (TSCPC-TI) using a novel low-cost torchlight method. Patients completing a minimum 6-month follow-up were analyzed. They were compared to a historical control group of patients who underwent TSCPC without transillumination (TSCPC-No TI) at 6-month follow-up period. We analyzed the mean laser energy delivered, post-laser intraocular pressure (IOP) reduction, number of antiglaucoma medications (AGM), the requirement of retreatment and complications of the procedure in both groups.
RESULTS
32 eyes of 29 patients comprised the TSCPC-TI group and were compared with 39 eyes of 37 patients in the TSCPC-No TI group. The TSCPC-TI group required lower energy than the TSCPC-No TI group (46.15 ± 22.8 Vs 80.65 ± 56.1 J < 0.001). At 6-month follow-up, the TSCPC-TI group required lesser AGM for IOP control (2.33 ± 1.02 vs 3.02 ± 1.32 = 0.01). There was a significantly reduced dependence of oral acetazolamide in the TSCPC-TI group at 6 months follow-up (15.6% vs 41% = 0.03%). The success and response rates were 71.8% Vs 23.1%; < 0.0001 and 87.5% Vs 51.2%; = 0.001 significantly high in the TSCPC-TI group. The TSCPC-No TI group had a significantly high failure rate (12.5% Vs 48.2% = 0.001). Hypotony ( = 1) and phthisis ( = 2) were noted TSCPC-No TI group.
CONCLUSIONS
TSCPC with transillumination with a low-cost torchlight resulted in a more efficient and effective cycloablation than TSCPC without transillumination.
PubMed: 38710194
DOI: 10.1177/11206721241253305 -
Clinical Research in Cardiology :... May 2024To determine the prevalence and the impact on prognosis of metabolic alkalosis (MA) in patients admitted for acute heart failure (AHF).
AIMS
To determine the prevalence and the impact on prognosis of metabolic alkalosis (MA) in patients admitted for acute heart failure (AHF).
METHODS AND RESULTS
The ALCALOTIC is a multicenter, observational cohort study that prospectively included patients admitted for AHF. Patients were classified into four groups according to their acid-base status on admission: acidosis, MA, respiratory alkalosis, and normal pH (reference group for comparison). Primary endpoint was all-cause in-hospital mortality, and secondary endpoints included 30/90-day all-cause mortality, all-cause readmission, and readmission for HF. Associations between endpoints and acid-base alterations were estimated in a multivariate Cox regression model including sex, age, comorbidities, and Barthel index and expressed as hazard ratio (HR) with 95% confidence interval (95% CI). Six hundred sixty-five patients were included (84 years and 57% women), and 40% had acid-base alterations on admission: 188 (28%) acidosis and 78 (12%) alkalosis. The prevalence (95% CI) of MA was 9% (6.8-11.2%). Patients with MA were more women; had fewer comorbidities, better renal function, and higher left ventricle ejection fraction values; and received more treatment with oral acetazolamide during hospitalization and at discharge. MA was not associated with a higher risk of in-hospital mortality and 30/90-day all-cause mortality or readmissions but was associated with a significant increase in readmissions for HF at 30 and 90 days (adjusted HR [95% CI] 3.294 [1.397-7.767], p = 0.006 and 2.314 [1.075-4.978], p = 0.032).
CONCLUSION
The prevalence of MA in patients admitted for AHF was 9%, and its presence was associated with more readmissions for HF but not with all-cause mortality.
PubMed: 38709335
DOI: 10.1007/s00392-024-02452-z -
Neurology India Mar 2024Acute glaucoma following carotid artery recanalization is a rare but severe complication of underlying ocular ischemic syndrome. We present a case of a 71-year-old woman...
Acute glaucoma following carotid artery recanalization is a rare but severe complication of underlying ocular ischemic syndrome. We present a case of a 71-year-old woman with ocular ischemic syndrome and severe stenosis of the right internal and external carotid artery undergoing carotid artery stenting. Immediate postprocedural angiography showed pronounced reperfusion of the ophthalmic artery. Subsequently, the patient developed vision-threatening acute glaucoma despite treatment with acetazolamide. Monitoring of intraocular pressure is important in patients who are at risk of developing ocular ischemic syndrome because of internal carotid artery stenosis. Interventionalists should also assess the degree of vascular collateralization from the external carotid artery.
Topics: Humans; Female; Aged; Carotid Stenosis; Stents; Glaucoma; Carotid Artery, Internal; Ischemia
PubMed: 38691486
DOI: 10.4103/neuroindia.NI_1800_20 -
Neurosurgery May 2024The role of bypass surgery in intracranial atherosclerotic steno-occlusive diseases (ICADs) remains controversial. We aimed to analyze the surgical outcomes of bypass...
BACKGROUND AND OBJECTIVES
The role of bypass surgery in intracranial atherosclerotic steno-occlusive diseases (ICADs) remains controversial. We aimed to analyze the surgical outcomes of bypass surgery in patients with the ICADs in a single tertiary institution.
METHODS
Among 1018 cases of low-flow bypass surgery between 2003 and 2022, 215 patients with the ICAD refractory to medical treatment were finally enrolled in this study. Clinical and radiological outcomes were retrospectively evaluated, with survival analyses.
RESULTS
All strokes, cerebral infarctions, and intracranial hemorrhages occurred in 12.1% (n = 26), 9.8% (n = 21), and 2.3% (n = 5), respectively, during the clinical follow-up of 54.6 ± 47.6 months (range, 0.6-237.8 months). Among all stroke events, 84.6% (n = 22) occurred within 30 postoperative days. The 2-year and 5-year cumulative risks of all strokes were 12.1% each. The mean modified Rankin Scale scores were 1.6 ± 1.1 (range, 0-5) preoperatively and 0.8 ± 1.2 (range, 0-6) at last (P < .01). The patency of direct bypass was 99.1% (n = 213) just before discharge and 96.3% (n = 184 of 191 patients with available tests) at the last angiographic follow-up of 27.0 ± 27.3 months (range, 2.3-97.3 months). All the patients with available data (n = 190) showed hemodynamic improvement on acetazolamide-challenged single-photon emission computed tomography with 99mTc-hexamethylpropyleneamine oxime during the follow-up of 38.6 ± 36.7 months (range, 2.3-158.6 months).
CONCLUSION
Low-flow bypass surgery showed acceptable treatment outcomes in the prevention of recurrent stroke.
PubMed: 38690884
DOI: 10.1227/neu.0000000000002972 -
American Journal of Physiology.... Jun 2024Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CB) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, < 0.05) and decreased end-tidal CO (ETCO; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CB compared with control (-22.5% vs. -8.7%, < 0.005). To mitigate the orthostatic CB reduction, we administered supplemental CO, phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CB. We evaluated cognitive function before and after CO, acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.
Topics: Humans; Cerebrovascular Circulation; Phenylephrine; Female; Male; Orthostatic Intolerance; Adult; Young Adult; Blood Flow Velocity; Blood Pressure; Fatigue Syndrome, Chronic; Tilt-Table Test; Cognition; Homeostasis; Case-Control Studies; Heart Rate; Arterial Pressure; Postural Orthostatic Tachycardia Syndrome
PubMed: 38682242
DOI: 10.1152/ajpregu.00071.2024 -
Ophthalmology. Glaucoma Apr 2024To identify and quantify medications causing angle-closure glaucoma through the FDA Adverse Event Reporting System (FAERS).
OBJECTIVE
To identify and quantify medications causing angle-closure glaucoma through the FDA Adverse Event Reporting System (FAERS).
DESIGN
National retrospective database analysis.
SUBJECTS
There were 11 737 133 total adverse event reports from the FDA Federal Adverse Event Reporting System (FAERS) database 2004 to third quarter of 2023 (2023Q3), which included 1629 reports of angle-closure glaucoma.
METHODS
Drugs associated with reports of angle-closure glaucoma were identified in FAERS through disproportionality analysis MAIN OUTCOME MEASURES: To ascertain if these reports yielded statistically significant signals, we used the proportional reporting ratio (PRR), reporting odds ratio (ROR), empirical Bayes geometric mean (EBGM), and information component (IC). We considered a signal to be detected when all 4 disproportionality analysis metrics were positive.
RESULTS
We identified a total of 1629 adverse event reports linked to 611 suspected drugs over the course of 20 years (2004-2023Q3). Frequently reported drugs included topiramate (520 reports) and citalopram (69 reports), amongst many others. Eighteen medications yielded a positive signal, including lesser-known medications like olanzapine, phentermine, and ranibizumab. Tropicamide exhibited the most robust statistical significance (n = 18; PRR: 164.263; ROR [95% confidence interval {CI}]: 167.95 [104.994-268.655]; EBGM [EBGM05]: 162.421 [109.5]; IC [IC05]: 7.344 [4.591]), while acetazolamide was the second strongest (n = 51; PRR: 113.088; ROR 95% CI: 114.782 [86.665-152.021]; EBGM [EBGM05]: 109.506 [86.501]; IC [IC05]: 6.775 [5.115]).
CONCLUSIONS
Drug-induced glaucoma included both well-known medications such as topiramate as well as lesser-known medications such as olanzapine, phentermine, and ranibizumab. Clinician awareness of these findings is important.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38679326
DOI: 10.1016/j.ogla.2024.04.006 -
Biomolecules Apr 2024Andersen-Tawil syndrome (ATS) is a multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, prolonged QT interval, and facial dysmorphisms...
Andersen-Tawil syndrome (ATS) is a multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, prolonged QT interval, and facial dysmorphisms occurring in the first/second decade of life. High phenotypic variability and incomplete penetrance of the genes causing the disease make its diagnosis still a challenge. We describe a three-generation family with six living individuals affected by ATS. The proband is a 37-year-old woman presenting since age 16, with episodes of muscle weakness and cramps in the pre-menstrual period. The father, two brothers, one paternal uncle and one cousin also complained of cramps, muscle stiffness, and weakness. Despite normal serum potassium concentration, treatment with potassium, magnesium, and acetazolamide alleviated paralysis attacks suggesting a dyskalemic syndrome. Dysmorphic features were noted in the proband, only later. On the ECG, all but one had normal QT intervals. The affected males developed metabolic syndrome or obesity. The father had two myocardial infarctions and was implanted with an intracardiac cardioverter defibrillator (ICD). A genetic investigation by WES analysis detected the heterozygous pathogenic variant (NM_000891.2: c.652C>T, p. Arg218Trp) in the gene related to ATS, confirmed by segregation studies in all affected members. Furthermore, we performed a review of cases with the same mutation in the literature, looking for similarities and divergences with our family case.
Topics: Adult; Female; Humans; Male; Alleles; Andersen Syndrome; Mutation; Pedigree; Phenotype; Potassium Channels, Inwardly Rectifying
PubMed: 38672523
DOI: 10.3390/biom14040507 -
Antioxidants (Basel, Switzerland) Apr 2024Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) signaling pathway. Notably, its active site...
Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) signaling pathway. Notably, its active site contains a cysteine residue that is susceptible to oxidation by hydrogen peroxide (HO). This oxidation inhibits the phosphatase function of PTEN, critically contributing to the activation of the PI3K/AKT pathway. Upon the stimulation of cell surface receptors, the activity of NADPH oxidase (NOX) generates a transient amount of HO, serving as a mediator in this pathway by oxidizing PTEN. The mechanism underlying this oxidation, occurring despite the presence of highly efficient and abundant cellular oxidant-protecting and reducing systems, continues to pose a perplexing conundrum. Here, we demonstrate that the presence of bicarbonate (HCO) promoted the rate of HO-mediated PTEN oxidation, probably through the formation of peroxymonocarbonate (HCO), and consequently potentiated the phosphorylation of AKT. Acetazolamide (ATZ), a carbonic anhydrase (CA) inhibitor, was shown to diminish the oxidation of PTEN. Thus, CA can also be considered as a modulator in this context. In essence, our findings consolidate the crucial role of HCO in the redox regulation of PTEN by HO, leading to the presumption that HCO is a signaling molecule during cellular physiological processes.
PubMed: 38671920
DOI: 10.3390/antiox13040473