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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 -
Acute Myopic Shift after a Single Dose of Acetazolamide: A Case Report and Review of the Literature.Klinische Monatsblatter Fur... Apr 2024We report the case of a 32-year-old male who presented with an acute myopic shift as a result of uveal effusion following a single administration of 250 mg... (Review)
Review
We report the case of a 32-year-old male who presented with an acute myopic shift as a result of uveal effusion following a single administration of 250 mg acetazolamide. The drug was discontinued and following cycloplegia and topical steroid therapy, we observed progressive deepening of the anterior chamber, reopening of the iridocorneal angle, and complete resolution of the myopic shift after 5 days. A literature review since 1956 identified 23 cases, including ours, which developed a myopic shift after a median time of 24 h (3 - 24) following a median dose of 500 mg (125 - 1000) acetazolamide, with about a third complicated by angle closure ocular hypertension. This presumed idiosyncratic reaction can occur without prior drug exposure and independent of the phakic status. Treatment options include systematic drug withdrawal associated with cycloplegia, anti-glaucomatous agents, and/or corticosteroids. Full recovery is achieved within about 5 days (2 - 14). Given the widespread use of acetazolamide, awareness of this idiosyncratic reaction is crucial to avoid complications of acute angle-closure glaucoma.
Topics: Humans; Acetazolamide; Male; Adult; Myopia; Carbonic Anhydrase Inhibitors; Acute Disease; Treatment Outcome
PubMed: 38653306
DOI: 10.1055/a-2244-6160 -
Cardiology Research Apr 2024Acetazolamide and thiazide diuretics have been combined with loop diuretics to overcome diuretic resistance in heart failure patients. However, recent studies have... (Review)
Review
Acetazolamide and thiazide diuretics have been combined with loop diuretics to overcome diuretic resistance in heart failure patients. However, recent studies have assessed the upfront combination of acetazolamide and hydrochlorothiazide with loop diuretics in hospitalized patients with acute decompensated heart failure without loop diuretic resistance. We reviewed two recent randomized controlled trials on the upfront use of acetazolamide and thiazide diuretics in acute decompensated heart failure, respectively. When the two trials on acetazolamide are considered together, adding oral or intravenous acetazolamide to loop diuretics in decompensated heart failure patients resulted in increased diuresis and natriuresis. However, the effects were significantly higher in patients with serum bicarbonate ≥ 27 mmol/L and those with higher baseline glomerular filtration rate (GFR). Similarly, when the two trials on thiazide diuretics are considered together, adding hydrochlorothiazide to loop diuretics in decompensated heart failure patients resulted in increased diuresis and weight loss. However, it increases the risk of impaired renal function. When all the trials are considered together, the upfront use of acetazolamide may be helpful in carefully selected patients, including patients with underlying elevated bicarbonate levels (≥ 27 mmol/L) and those with good renal function (GFR > 50). Conversely, though the upfront use of thiazide diuretic added to intravenous furosemide improved diuretic response in acute decompensated heart failure, it causes an increased risk of worsening renal function and lack of clear evidence of reducing hospital length of stay.
PubMed: 38645830
DOI: 10.14740/cr1627 -
Revue Neurologique May 2024Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset... (Review)
Review
Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.
Topics: Humans; Spinocerebellar Ataxias; Age of Onset; Cerebellar Ataxia; Fibroblast Growth Factors; Spinocerebellar Degenerations
PubMed: 38609751
DOI: 10.1016/j.neurol.2024.03.007 -
Cureus Mar 2024Acetazolamide is recommended for the prevention of acute mountain sickness (AMS); however, its use is limited in some areas because of side effects. Previous studies...
INTRODUCTION
Acetazolamide is recommended for the prevention of acute mountain sickness (AMS); however, its use is limited in some areas because of side effects. Previous studies report ibuprofen to be similar to or slightly inferior to acetazolamide. This randomized, triple-blinded, parallel-group, placebo-controlled trial was designed to compare ibuprofen with acetazolamide for the prevention of AMS.
METHODS
Four hundred forty-three healthy Asian Indian men with a mean age of 29 (range: 20-49) years were randomized into three groups A, B, and P at 350m (SL). Acetazolamide (A): 85 mg; ibuprofen (B): 600 mg; or placebo (P): calcium carbonate was administered thrice daily, starting one day prior and continuing for three days after arrival at 3500m (HA). Participants were evaluated for AMS using the Lake Louise Questionnaire and for pulse, BP, SpO, and respiratory rate twice daily for the first two days during rest and once a day for days three to six at HA.
RESULTS
Of the 443 participants recruited at SL, 139 could not be airlifted due to logistical limitations, and 304 were available for follow-up at HA. Among these, 254 had ascended as per protocol. By intent to treat (IT) (N = 304; A = 99, B = 102, P = 103), the incidence of AMS (LLQS>/=3) was 12%, 5%, and 13%, and the incidence of severe AMS was 1%, 2%, and 6%, in groups A, B, and P, respectively. Using per protocol analysis (PP) (N = 254; A = 83, B = 87, P = 84), the incidence of AMS was 12%, 6%, and 13% in groups A, B, and P, respectively. The relative risk for developing AMS vs. placebo was A-0.96 (CI:0.46-2.0, p=0.91), B-0.39 (CI:0.14-1.04, p=0.06), A-0.94 (CI:0.42-2.1, p=0.88), and B-0.45 (0.16-1.24, p=0.12) by IT and PP, respectively.
CONCLUSION
Ibuprofen is effective in males for the prevention of AMS with rapid ascent to 3500 m-rest for the first two days. Acetazolamide was superior to ibuprofen in the prevention of moderate-to-severe AMS.
PubMed: 38606209
DOI: 10.7759/cureus.55998 -
Journal of Medicine and Life Dec 2023This study aimed to design, synthesize, and evaluate the cytotoxic activity of novel thiazole-sulfanilamide derivatives, specifically compounds M3, M4, and M5, through...
In silico study, synthesis, and antineoplastic evaluation of thiazole-based sulfonamide derivatives and their silver complexes with expected carbonic anhydrase inhibitory activity.
This study aimed to design, synthesize, and evaluate the cytotoxic activity of novel thiazole-sulfanilamide derivatives, specifically compounds M3, M4, and M5, through molecular docking and biological assays. The synthesis utilized essential chemical compounds, including sulfanilamide, chloro-acetyl chloride, thiourea, derivatives of benzaldehyde, and silver nitrate. The docking study was carried out using Molecular Operating Environment (MOE) software, and cytotoxic activity was predicted by MTT assay. The synthesized compounds demonstrated a reduction in the viability of cancer cells. Compound M5 had an IC50 of 18.53 µg/ml against MCF-7 cells, comparable to the IC50 of cisplatin. Additionally, compounds M3 and M4 had higher S scores than acetazolamide, indicating greater binding affinity to the active pocket of the receptor. Incorporating the thiazole ring in the synthesized compound augmented their flexibility and affinity for binding to the receptor. The inclusion of the metal complex additionally heightened the compounds' capacity to impede cellular growth.
Topics: Humans; Molecular Docking Simulation; Thiazoles; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Sulfonamides; Antineoplastic Agents; Sulfanilamides
PubMed: 38585528
DOI: 10.25122/jml-2023-0180 -
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 -
Magnetic Resonance Imaging Jul 2024Paired cerebral blood flow (CBF) measurement is usually acquired before and after vasoactive stimulus to estimate cerebrovascular reserve (CVR). However, CVR may be...
BACKGROUND
Paired cerebral blood flow (CBF) measurement is usually acquired before and after vasoactive stimulus to estimate cerebrovascular reserve (CVR). However, CVR may be confounded because of variations in time-to-maximum CBF response (t) following acetazolamide injection. With a mathematical model, CVR can be calculated insensitive to variations in t, and a model offers the possibility to calculate additional model-derived parameters. A model that describes the temporal CBF response following a vasodilating acetazolamide injection is proposed and evaluated.
METHODS
A bi-exponential model was adopted and fitted to four CBF measurements acquired using arterial spin labelling before and initialised at 5, 15 and 25 min after acetazolamide injection in a total of fifteen patients with Moyamoya disease. Curve fitting was performed using a non-linear least squares method with a priori constraints based on simulations.
RESULTS
Goodness of fit (mean absolute error) varied between 0.30 and 0.62 ml·100 g·min. Model-derived CVR was significantly higher compared to static CVR measures. Maximum CBF increase occurred earlier in healthy- compared to diseased vascular regions.
CONCLUSIONS
The proposed mathematical model offers the possibility to calculate CVR insensitive to variations in time to maximum CBF response which gives a more detailed characterisation of CVR compared to static CVR measures. Although the mathematical model adapts generally well to this dataset of patients with MMD it should be considered as experimental; hence, further studies in healthy populations and other patient cohorts are warranted.
Topics: Humans; Moyamoya Disease; Acetazolamide; Cerebrovascular Circulation; Female; Male; Adult; Middle Aged; Models, Theoretical; Young Adult; Vasodilator Agents; Magnetic Resonance Imaging; Brain
PubMed: 38574981
DOI: 10.1016/j.mri.2024.03.044 -
Cureus Mar 2024Idiopathic intracranial hypertension (IIH) is a rare condition characterized by increased intracranial pressure, with an unknown cause. However, the pathophysiology of...
Idiopathic intracranial hypertension (IIH) is a rare condition characterized by increased intracranial pressure, with an unknown cause. However, the pathophysiology of antibiotic-induced IIH remains unclear. The clinical symptoms include headache, visual disturbances, and vomiting. The diagnosis is confirmed by an elevated intracranial pressure (ICP) with normal CSF study and cerebral imaging. Management includes discontinuing the offending antibiotic and reducing ICP with medications such as acetazolamide or diuretics. Therefore, surgical intervention may be necessary in severe cases. In this article, we report the case of a 19-year-old patient, admitted with symptoms of intracranial hypertension syndrome, occurring three days after receiving antibiotics (gentamicin, penicillin). Physical examination revealed bilateral optic disc edema. Cerebral magnetic resonance imaging (MRI) revealed indirect signs of intracranial hypertension. The CSF pressure measurement was approximately 290 mmHg, while CSF and other laboratory blood tests were normal. The patient received methylprednisolone bolus and topiramate (50 mg/day). A month later, the clinical outcome showed regression of headaches and regression of the papilledema.
PubMed: 38567240
DOI: 10.7759/cureus.55424 -
Scientific Reports Mar 2024The study presented here aims at assessing the effects of hypobaric hypoxia on RAAS pathway and its components along with mitigation of anomalies with quercetin...
The study presented here aims at assessing the effects of hypobaric hypoxia on RAAS pathway and its components along with mitigation of anomalies with quercetin prophylaxis. One hour prior to hypobaric hypoxia exposure, male SD rats were orally supplemented with quercetin (50 mg/kg BW) and acetazolamide (50 mg/kg BW) and exposed them to 25,000 ft. (7,620 m) in a simulated environmental chamber for 12 h at 25 ± 2 °C. Different biochemical parameters like renin activity, aldosterone, angiotensin I, ACE 2 were determined in plasma. As a conventional response to low oxygen conditions, oxidative stress parameters (ROS and MDA) were elevated along with suppressed antioxidant system (GPx and catalase) in plasma of rats. Quercetin prophylaxis significantly down regulated the hypoxia induced oxidative stress by reducing plasma ROS & MDA levels with efficient enhancement of antioxidants (GPx and Catalase). Further, hypoxia mediated regulation of renin and ACE 2 proves the outstanding efficacy of quercetin in repudiating altercations in RAAS cascade due to hypobaric hypoxia. Furthermore, differential protein expression of HIF-1α, NFκB, IL-18 and endothelin-1 analyzed by western blotting approves the biochemical outcomes and showed that quercetin significantly aids in the reduction of inflammation under hypoxia. Studies conducted with Surface Plasmon Resonance demonstrated a binding among quercetin and ACE 2 that indicates that this flavonoid might regulate RAAS pathway via ACE 2. Henceforth, the study promotes the prophylaxis of quercetin for the better adaptability under hypobaric hypoxic conditions via modulating the RAAS pathway.
Topics: Rats; Male; Animals; Quercetin; Renin; Catalase; Aldosterone; Rats, Sprague-Dawley; Reactive Oxygen Species; Hypoxia; Antioxidants; Oxidative Stress; Angiotensin I; Kidney
PubMed: 38556603
DOI: 10.1038/s41598-024-58134-3