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Cancers Oct 2023Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for...
Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES.
PubMed: 37958399
DOI: 10.3390/cancers15215225 -
The Lancet Regional Health. Europe Mar 2024The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs)...
BACKGROUND
The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs) affects fetal growth remains uncertain.
METHODS
This was a population-based cohort study of liveborn singleton children born in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2017. Prenatal exposure was defined as maternal filling of prescriptions for ASM during pregnancy registered in national prescription registries and primary outcomes were adjusted odds ratios (aORs) of microcephaly or being born small for gestational age.
FINDINGS
We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy. In the overall population, prenatal monotherapy exposure with carbamazepine (aOR: 1.25 (95% CI: 1.12-1.40)), pregabalin (aOR: 1.16 (95% CI: 1.02-1.31)), oxcarbazepine (aOR: 1.48 (95% CI: 1.28-1.71)), clonazepam (aOR: 1.27 (95% CI: 1.10-1.48)), and topiramate (aOR: 1.48 (95% CI: 1.18-1.85)) was associated with risk of being born small for gestational age, and carbamazepine was associated with microcephaly (aOR: 1.43 (95% CI: 1.17-1.75)). In children of mothers with epilepsy, prenatal exposure to carbamazepine (aOR: 1.27 (95% CI: 1.11-1.47)), oxcarbazepine (aOR: 1.42 (95% CI: 1.18-1.70)), clonazepam (aOR: 1.40 (95% CI: 1.03-1.89)), and topiramate (aOR: 1.86 (95% CI: 1.36-2.54)) was associated with being born small for gestational age; carbamazepine, with microcephaly (aOR: 1.51 (95% CI: 1.17-1.95)). No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide, but except for lamotrigine, valproate, gabapentin, and levetiracetam, numbers of exposed children were small.
INTERPRETATION
Prenatal exposure to carbamazepine, oxcarbazepine, clonazepam, and topiramate was associated with increased risk of being born small for gestational age in both the overall population and in children of women with epilepsy suggesting that prenatal exposure to these drugs is associated with fetal growth restriction.
FUNDING
The NordForsk Nordic Program on Health and Welfare (83539), the Independent Research Fund Denmark (1133-00026B), the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation (NNF16OC0019126 and NNF22OC0075033), and the Lundbeck Foundation (R400-2022-1205).
PubMed: 38476755
DOI: 10.1016/j.lanepe.2024.100849 -
Sports Medicine (Auckland, N.Z.) Apr 2024The (patho-)physiological responses to hypoxia are highly heterogeneous between individuals. In this review, we focused on the roles of sex differences, which emerge as... (Review)
Review
The (patho-)physiological responses to hypoxia are highly heterogeneous between individuals. In this review, we focused on the roles of sex differences, which emerge as important factors in the regulation of the body's reaction to hypoxia. Several aspects should be considered for future research on hypoxia-related sex differences, particularly altitude training and clinical applications of hypoxia, as these will affect the selection of the optimal dose regarding safety and efficiency. There are several implications, but there are no practical recommendations if/how women should behave differently from men to optimise the benefits or minimise the risks of these hypoxia-related practices. Here, we evaluate the scarce scientific evidence of distinct (patho)physiological responses and adaptations to high altitude/hypoxia, biomechanical/anatomical differences in uphill/downhill locomotion, which is highly relevant for exercising in mountainous environments, and potentially differential effects of altitude training in women. Based on these factors, we derive sex-specific recommendations for mountain sports and intermittent hypoxia conditioning: (1) Although higher vulnerabilities of women to acute mountain sickness have not been unambiguously shown, sex-dependent physiological reactions to hypoxia may contribute to an increased acute mountain sickness vulnerability in some women. Adequate acclimatisation, slow ascent speed and/or preventive medication (e.g. acetazolamide) are solutions. (2) Targeted training of the respiratory musculature could be a valuable preparation for altitude training in women. (3) Sex hormones influence hypoxia responses and hormonal-cycle and/or menstrual-cycle phases therefore may be factors in acclimatisation to altitude and efficiency of altitude training. As many of the recommendations or observations of the present work remain partly speculative, we join previous calls for further quality research on female athletes in sports to be extended to the field of altitude and hypoxia.
Topics: Humans; Hypoxia; Female; Altitude Sickness; Altitude; Acclimatization; Sex Factors; Mountaineering; Adaptation, Physiological; Physical Conditioning, Human; Male
PubMed: 38082199
DOI: 10.1007/s40279-023-01970-6 -
Graefe's Archive For Clinical and... Mar 2024To evaluate the efficacy of XEN-45 gel stent ab interno implantation for medically uncontrolled uveitic glaucoma.
PURPOSE
To evaluate the efficacy of XEN-45 gel stent ab interno implantation for medically uncontrolled uveitic glaucoma.
METHODS
Retrospective analysis of 25 eyes receiving XEN gel stent for medically uncontrolled uveitic glaucoma from February 2019 to February 2023 with recording of intraocular pressure (IOP) values, ocular hypotensive medication, requirement for revision or secondary surgery and complications. Prerequisites for XEN implantation were a clear cornea, an open iridocorneal angle and an unscarred, mobile conjunctiva at the implantation site. Minimum follow-up required for inclusion was 3 months. The primary outcome measure was IOP compared to baseline. Complete and qualified success were defined as final IOP of ≤ 18 mmHg without or with topical antiglaucomatous treatment, respectively. Failure was defined as IOP > 18 mmHg on two consecutive visits, IOP reduction < 20%, persisting complications from hypotony and open conjunctival bleb revision. Further glaucoma surgical intervention was defined as complete failure.
RESULTS
Mean preoperative IOP was 35.3 ± 10.9 mmHg on 2.9 ± 0.9 topical antiglaucomatous agents. 19 of 25 patients (76%) received additional oral acetazolamide. 19 eyes were pseudophakic, 5 eyes phakic and 1 aphakic. Early postoperatively, mean IOP reduced to 7.7 ± 3.0 mmHg (75.8% reduction). At final follow-up (mean 17.7 months) mean IOP was 12.0 ± 3.8 mmHg (62.5% reduction) on 0.2 ± 0.6 medications. Six eyes (24%) required bleb revision at mean 28 weeks and therefore were categorized as failure. One eye failed despite bleb revision and restart of topical ocular hypotensive medication. Three other eyes (12%) had IOP spikes with uveitis flare-ups. Transient hypotony complications occurred in 32%. At final follow-up, 18 eyes (72%) achieved complete success and one eye (4%) qualified success.
CONCLUSION
The XEN gel stent effectively reduced IOP in uncontrolled uveitic glaucoma, with 72% complete success. Bleb revision was required in 24%. IOP spikes occurred in 12% despite functioning blebs. Further follow-up is needed to determine long-term outcomes.
Topics: Humans; Retrospective Studies; Glaucoma; Intraocular Pressure; Tonometry, Ocular; Conjunctiva; Antihypertensive Agents
PubMed: 37855957
DOI: 10.1007/s00417-023-06254-3 -
Journal of the American Heart... Dec 2023
Topics: Humans; Acetazolamide; Tomography, X-Ray Computed; Positron-Emission Tomography; Cerebrovascular Disorders; Hemodynamics
PubMed: 38084748
DOI: 10.1161/JAHA.123.032657 -
Acta Neurochirurgica Aug 2023Moyamoya (MM) disease is characterized by progressive intracranial arterial stenosis. Patients commonly need revascularization surgery to optimize cerebral blood flow...
PURPOSE
Moyamoya (MM) disease is characterized by progressive intracranial arterial stenosis. Patients commonly need revascularization surgery to optimize cerebral blood flow (CBF). Estimation of CBF and cerebrovascular reserve (CVR) is therefore necessary before and after surgery. However, assessment of CBF before and after indirect revascularization surgery with the multiple burr hole (MBH) technique in MM has not been studied extensively. In this study, we describe our initial experience using arterial spin labeling magnetic resonance perfusion imaging (ASL-MRI) for CBF and CVR assessment before and after indirect MBH revascularization surgery in MM patients.
METHODS
Eleven MM patients (initial age 6-50 years, 1 male/10 female) with 19 affected hemispheres were included. A total of 35 ASL-MRI examinations were performed using a 3D-pCASL acquisition before and after i.v. acetazolamide challenge (1000 mg in adults and 10 mg/kg in children). Twelve MBH procedures were performed in seven patients. The first follow-up ASL-MRI was performed 7-21 (mean 12) months after surgery.
RESULTS
Before surgery, CBF was 46 ± 16 (mean ± SD) ml/100 g/min and CVR after acetazolamide challenge was 38.5 ± 9.9 (mean ± SD)% in the most affected territory (middle cerebral artery). In cases in which surgery was not performed, CVR was 56 ± 12 (mean ± SD)% in affected hemispheres. After MBH surgery, there was a relative change in CVR compared to baseline (preop) of + 23.5 ± 23.3% (mean ± SD). There were no new ischemic events.
CONCLUSION
Using ASL-MRI we followed changes in CBF and CVR in patients with MM. The technique was encouraging for assessments before and after revascularization surgery.
Topics: Adult; Child; Humans; Male; Female; Adolescent; Young Adult; Middle Aged; Moyamoya Disease; Acetazolamide; Magnetic Resonance Imaging; Middle Cerebral Artery; Cerebrovascular Circulation; Cerebral Revascularization
PubMed: 37326844
DOI: 10.1007/s00701-023-05641-3 -
Journal of Enzyme Inhibition and... Dec 2023The present investigation reports the design and synthesis of three series of benzoylthioureido derivatives bearing either benzenesulfonamide , benzoic acid or...
The present investigation reports the design and synthesis of three series of benzoylthioureido derivatives bearing either benzenesulfonamide , benzoic acid or ethylbenzoate moieties. The synthesised compounds were screened for their carbonic anhydrase inhibitory activity (CAI) against four isoforms hCA I, II, IX, and XII. Compounds , and exhibited a potent inhibitory activity towards hCAI (s = 58.20, 56.30, 33.00, and 43.00 nM), respectively compared to acetazolamide and SLC-0111 (s = 250.00 and 5080.00 nM). Compounds , and elicited selectivity over h CA II (s = 2.50, 2.10, 56.60,39.60 and 39.00 nM) respectively, relative to and SLC-0111(s = 12.10 and 960.00 nM). Also, compounds , and displayed selectivity against the tumour-associated isoform hCA IX (s = 31.20, 30.00 and 29.00 nM) respectively, compared to and SLC-0111 (s = 25.70 and 45.00 nM). Additionally, compounds and revealed a moderate to superior selectivity towards hCAXII (s = 17.00 and 11.00 nM) relative to and SLC-0111(s = 5.70 and 45.00 nM). Molecular docking and ADME prediction studies were performed on the most active compounds to shed light on their interaction with the hot spots of the active site of CA isoforms, in addition to prediction of their pharmacokinetic and physicochemical properties.
Topics: Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Molecular Docking Simulation; Structure-Activity Relationship; Molecular Structure; Acetazolamide; Protein Isoforms; Carbonic Anhydrase IX; Benzenesulfonamides
PubMed: 36305274
DOI: 10.1080/14756366.2022.2132485 -
Frontiers in Medicine 2023Carbonic anhydrase inhibitors (CAIs) reduce macular schisis in patients with X-linked retinoschisis (XLRS). The purpose of this study was to determine if CAIs reduce the...
PURPOSE
Carbonic anhydrase inhibitors (CAIs) reduce macular schisis in patients with X-linked retinoschisis (XLRS). The purpose of this study was to determine if CAIs reduce the incidence of complications from XLRS, including macular atrophy, retinal tears, and retinal detachment (RD), the most common causes of vision loss in patients with XLRS.
METHODS
For this retrospective interventional case series, a chart review of patients examined at Cincinnati Children's Hospital Medical Center [CCHMC] and Cincinnati Eye Institute [CEI] between 1/1/2015 and 1/16/2023 was performed. Male patients were included based on genetically-confirmed or typical clinical presentation with known family history of XLRS with at least two follow-up visits.
RESULTS
Twenty-eight patients (56 eyes) with XLRS were included. There were 10 variants among the 21 genotyped patients. Median age at clinical diagnosis was 10.4 years old (range: 0.4-55.7 years) with median follow-up time of 4.7 years (range: 0.2-38.3 years). Median presenting Snellen visual acuity was 20/60 (logMAR 0.48, range: 0.18-3). In 26 eyes of 15 patients treated with CAIs, median CST pre-treatment was 416 microns (range: 198-701 microns), and median percentage decrease in CST on treatment was 21.8% (range: 0-74.5%) from highest pre-treatment CST. Reduction in CST with CAI use was statistically significant ( = 0.02), but not logMAR VA ( = 0.64). There was no significant difference in CST between patients treated with topical vs. oral CAI ( = 0.95) or between patients with partial or complete CAI adherence ( = 0.60). Ten eyes of seven patients had an RD requiring surgical intervention. No treated eyes developed new macular atrophy, peripheral retinoschisis, retinal tears, or RD; two eyes on topical CAIs had spontaneous resolution of bullous peripheral retinoschisis.
CONCLUSION
During the follow-up period, patients taking CAIs reduced macular schisis and did not experience new complications of macular atrophy, retinal tears, or RD. This is a relatively large cohort with long-term follow-up periods for patients with XLRS. Reduced macular schisis may not require perfect adherence with CAIs. A large, prospective, randomized, controlled clinical trial is needed to determine the potential of CAIs to improve visual function, reduce retinoschisis, and prevent RD.
PubMed: 38020097
DOI: 10.3389/fmed.2023.1281068 -
Toxicology and Applied Pharmacology May 2024Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line...
BACKGROUND
Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues.
METHODS
Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA.
RESULTS
Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands.
CONCLUSION
These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.
Topics: Animals; Female; Topiramate; Rats, Sprague-Dawley; Acetazolamide; Endocrine Disruptors; Rats; Estrus; Luteinizing Hormone; Fructose; Pituitary Gland; Progesterone; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Estradiol; Ovary
PubMed: 38580201
DOI: 10.1016/j.taap.2024.116919 -
Journal of Clinical Medicine Jan 2024Most episodes of acute heart failure (AHF) are characterized by increasing signs and symptoms of congestion, manifested by edema, pleura effusion and/or ascites.... (Review)
Review
Most episodes of acute heart failure (AHF) are characterized by increasing signs and symptoms of congestion, manifested by edema, pleura effusion and/or ascites. Immediately and repeatedly administered intravenous (IV) loop diuretics currently represent the mainstay of initial therapy aiming to achieve adequate diuresis/natriuresis and euvolemia. Despite these efforts, a significant proportion of patients have residual congestion at discharge, which is associated with a poor prognosis. Therefore, a standardized approach is needed. The door to diuretic time should not exceed 60 min. As a general rule, the starting IV dose is 20-40 mg furosemide equivalents in loop diuretic naïve patients or double the preexisting oral home dose to be administered via IV. Monitoring responses within the following first hours are key issues. (1) After 2 h, spot urinary sodium should be ≥50-70 mmol/L. (2) After 6 h, the urine output should be ≥100-150 mL/hour. If these target measures are not reached, the guidelines currently recommend a doubling of the original dose to a maximum of 400-600 mg furosemide per day and in patients with severely impaired kidney function up to 1000 mg per day. Continuous infusion of loop diuretics offers no benefit over intermittent boluses (DOSE trial). Emerging evidence by recent randomized trials (ADVOR, CLOROTIC) supports the concept of an early combination diuretic therapy, by adding either acetazolamide (500 mg IV once daily) or hydrochlorothiazide. Acetazolamide is particularly useful in the presence of a baseline bicarbonate level of ≥27 mmol/L and remains effective in the presence of preexisting/worsening renal dysfunction but should be used only in the first three days to prevent severe metabolic disturbances. Patients should not leave the hospital when they are still congested and/or before optimized long-term guideline-directed medical therapy has been initiated. Special attention should be paid to AHF patients during the vulnerable post-discharge period, with an early follow-up visit focusing on up-titrate treatments of recommended doses within 2 weeks (STRONG-HF).
PubMed: 38256444
DOI: 10.3390/jcm13020311