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Cerebellum (London, England) Apr 2024Potassium channels (KCN) are transmembrane complexes that regulate the resting membrane potential and the duration of action potentials in cells. The opening of KCN... (Review)
Review
Potassium channels (KCN) are transmembrane complexes that regulate the resting membrane potential and the duration of action potentials in cells. The opening of KCN brings about an efflux of K ions that induces cell repolarization after depolarization, returns the transmembrane potential to its resting state, and enables for continuous spiking ability. The aim of this work was to assess the role of KCN dysfunction in the pathogenesis of hereditary ataxias and the mechanisms of action of KCN opening agents (KCO). In consequence, a review of the ad hoc medical literature was performed. Among hereditary KCN diseases causing ataxia, mutated Kv3.3, Kv4.3, and Kv1.1 channels provoke spinocerebellar ataxia (SCA) type 13, SCA19/22, and episodic ataxia type 1 (EA1), respectively. The K efflux was found to be reduced in experimental models of these diseases, resulting in abnormally prolonged depolarization and incomplete repolarization, thereby interfering with repetitive discharges in the cells. Hence, substances able to promote normal spiking activity in the cerebellum could provide symptomatic benefit. Although drugs used in clinical practice do not activate Kv3.3 or Kv4.3 directly, available KCO probably could ameliorate ataxic symptoms in SCA13 and SCA19/22, as verified with acetazolamide in EA1, and retigabine in a mouse model of hypokalemic periodic paralysis. To summarize, ataxia could possibly be improved by non-specific KCO in SCA13 and SCA19/22. The identification of new specific KCO agents will undoubtedly constitute a promising therapeutic strategy for these diseases.
Topics: Mice; Animals; Channelopathies; Ataxia; Spinocerebellar Degenerations; Cerebellar Ataxia; Mutation; Myokymia; Spinocerebellar Ataxias
PubMed: 37460907
DOI: 10.1007/s12311-023-01584-8 -
Kardiologiia Aug 2023Aim To determine the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on kidney function in acute decompensated heart failure (ADHF).Material and... (Randomized Controlled Trial)
Randomized Controlled Trial
Aim To determine the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on kidney function in acute decompensated heart failure (ADHF).Material and methods A controlled randomized study on the dapagliflozin treatment in ADHF was performed. Patients were randomized to a main group (standard therapy supplemented with dapagliflozin) or a control group (standard therapy for ADHF). The primary endpoint was the development of acute kidney injury (AKI). 200 patients were included (mean age, 74±12 years; 51% men). 31% of patients had type 2 diabetes mellitus (DM2). Mean left ventricular ejection fraction (LV EF) was 47±14 %; in 44.5% of patients, LV EF was less than 45%. Median concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) was 5225 [3120; 9743] pg / ml, glomerular filtration rate (GFR) was 51 [38; 64] ml / min / 1.73 m2.Results In-hospital mortality was 6.5%. Analysis of the dynamics of body weight loss showed significant differences (4200 [2925; 6300] g vs. 3000 [1113; 4850] g; p=0.011) in favor of the dapagliflozin group. The requirement for increasing the daily dose of furosemide and adding an another class diuretic (thiazide or acetazolamide) did not differ between the groups. However, median furosemide dose during the stay in the hospital was lower in the dapagliflozin group (80 [67; 120] mg vs. 102 [43; 120] mg; p=0.016). At 48 hours after randomization, GFR significantly decreased in the dapagliflozin group (-5.5 [-11; 3] ml/min/ 1.73 m2) compared to the control group (-0.3 [-4; 5] ml / min/1.73 m2, р=0.012). Despite this, GFR did not differ between the groups at discharge (51 [41; 66] ml/min/1.73 m2 and 49 [38; 67] ml/min/1.73 m2, respectively; p = 0.84). In the dapagliflozin group, frequency of AKI episodes was not increased compared to the control group (13 and 9.4%, respectively; p = 0.45).Conclusion The dapagliflozin treatment in ADHF is associated with more pronounced body weight loss and lower average doses of loop diuretics during the period of stay in the hospital, with no associated clinically significant impairment of renal function.
Topics: Male; Humans; Middle Aged; Aged; Aged, 80 and over; Female; Furosemide; Diabetes Mellitus, Type 2; Stroke Volume; Sodium-Glucose Transporter 2 Inhibitors; Ventricular Function, Left; Heart Failure; Acute Kidney Injury; Weight Loss
PubMed: 37691500
DOI: No ID Found -
The Annals of Pharmacotherapy Nov 2023Acetazolamide has been used for diuretic-induced metabolic alkalosis, but the preferred dose, route, and frequency of administration remain unknown.
BACKGROUND
Acetazolamide has been used for diuretic-induced metabolic alkalosis, but the preferred dose, route, and frequency of administration remain unknown.
OBJECTIVE
The purpose of this study was to characterize dosing strategies and determine the effectiveness of intravenous (IV) and oral (PO) acetazolamide for patients with heart failure (HF) with diuretic-induced metabolic alkalosis.
METHODS
This was a multicenter, retrospective cohort study comparing the use of IV versus PO acetazolamide in patients with HF receiving at least 120 mg of furosemide for the treatment of metabolic alkalosis (serum bicarbonate CO ≥32). The primary outcome was the change in CO on the first basic metabolic panel (BMP) within 24 hours of the first dose of acetazolamide. Secondary outcomes included laboratory outcomes, such as change in bicarbonate, chloride, and incidence of hyponatremia and hypokalemia. This study was approved by the local institutional review board.
RESULTS
IV acetazolamide was given in 35 patients and PO acetazolamide was given in 35 patients. Patients in both groups were given a median of 500 mg of acetazolamide in the first 24 hours. For the primary outcome, there was a significant decrease in CO on the first BMP within 24 hours after patients received the IV acetazolamide (-2 [interquartile range, IQR: -2, 0] vs 0 [IQR: -3, 1], = 0.047). There were no differences in secondary outcomes.
CONCLUSION AND RELEVANCE
IV acetazolamide resulted in significantly decreased bicarbonate within 24 hours of administration. IV acetazolamide may be preferred to treat diuretic-induced metabolic alkalosis in patients with HF.
Topics: Humans; Acetazolamide; Diuretics; Carbonic Anhydrase Inhibitors; Bicarbonates; Retrospective Studies; Carbon Dioxide; Alkalosis; Heart Failure
PubMed: 36803069
DOI: 10.1177/10600280231154603 -
Epilepsia May 2024Pilomotor seizures are strongly associated with autoimmune encephalitis (AE), particularly anti-LGI1 encephalitis. The carbonic anhydrase inhibitor acetazolamide may...
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 CO/pH sensitivity, acetazolamide can be unusually effective in controlling pilomotor seizures in AE, chronically or in acute settings.
Topics: Humans; Acetazolamide; Female; Male; Middle Aged; Encephalitis; Anticonvulsants; Aged; Adult; Hashimoto Disease; Carbonic Anhydrase Inhibitors; Treatment Outcome; Electroencephalography; Seizures
PubMed: 38536044
DOI: 10.1111/epi.17962 -
The Journal of Headache and Pain Jul 2023In idiopathic intracranial hypertension (IIH), sustained weight loss is the main pillar in modifying disease course, whereby glucagon-like peptide-1 receptor agonists...
BACKGROUND
In idiopathic intracranial hypertension (IIH), sustained weight loss is the main pillar in modifying disease course, whereby glucagon-like peptide-1 receptor agonists (GLP-1-RAs) could present an attractive treatment option.
METHODS
In this open-label, single-center, case-control pilot study, patients with IIH (pwIIH) and a body mass index (BMI) of ≥ 30 kg/m were offered to receive a GLP-1-RA (semaglutide, liraglutide) in addition to the usual care weight management (UCWM). Patients electing for UCWM only served as a control group matched for age-, sex- and BMI (1:2 ratio). The primary endpoint was the percentage weight loss at six months (M6) compared to baseline. Secondary endpoints included the rate of patients with a weight loss of ≥ 10%, monthly headache days (MHD), the rate of patients with a ≥ 30% and ≥ 50% reduction in MHD, visual outcome parameters, and adverse events (AEs).
RESULTS
We included 39 pwIIH (mean age 33.6 years [SD 8.0], 92.3% female, median BMI 36.3 kg/m [IQR 31.4-38.3]), with 13 patients being treated with GLP-1-RAs. At M6, mean weight loss was significantly higher in the GLP-1-RA group (-12.0% [3.3] vs. -2.8% [4.7]; p < 0.001). Accordingly, weight loss of ≥ 10% was more common in this group (69.2% vs. 4.0%; p < 0.001). Median reduction in MHD was significantly higher in the GLP-1-RA group (-4 [-10.5, 0.5] vs. 0 [-3, 1]; p = 0.02), and the 50% responder rate was 76.9% vs. 40.0% (p = 0.04). Visual outcome parameters did not change significantly from baseline to M6. Median reduction in acetazolamide dosage was significantly higher in the GLP-1-RA group (-16.5% [-50, 0] vs. 0% [-25, 50]; p = 0.04). AEs were mild or moderate and attributed to gastrointestinal symptoms in 9/13 patients. None of the AEs led to premature treatment discontinuation.
CONCLUSIONS
This open-label, single-center pilot study suggests that GLP-1-RAs are an effective and safe treatment option for achieving significant weight loss with a favorable effect on headache, leading to reduced acetazolamide dosage in pwIIH.
Topics: Humans; Female; Adult; Male; Pseudotumor Cerebri; Glucagon-Like Peptide-1 Receptor; Acetazolamide; Pilot Projects; Glucagon-Like Peptide 1; Headache; Weight Loss
PubMed: 37460968
DOI: 10.1186/s10194-023-01631-z -
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 -
Experimental Physiology May 2024It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the...
It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.
Topics: Animals; Furosemide; Acetazolamide; Amiloride; Diuretics; Sheep; Female; Kidney Cortex; Kidney Medulla; Oxygen; Hemodynamics; Oxygen Consumption
PubMed: 38551893
DOI: 10.1113/EP091479 -
Neurologia I Neurochirurgia Polska 2024Spontaneous CSF leak is a known complication of idiopathic intracranial hypertension (IIH). Patients with CSF rhinorrhea present a unique challenge within the IIH... (Review)
Review
INTRODUCTION
Spontaneous CSF leak is a known complication of idiopathic intracranial hypertension (IIH). Patients with CSF rhinorrhea present a unique challenge within the IIH population, as the occurrence of a leak can mask the typical IIH symptoms and signs, complicating the diagnosis. Treatment of leaks in this population can also be challenging, with the risk of rhinorrhea recurrence if intracranial hypertension is not adequately treated.
OBJECTIVE
The aim of this narrative review was to examine current literature on the association between spontaneous CSF rhinorrhea leaks and IIH, focusing on key clinical features, diagnostic approaches, management strategies, and outcomes.
MATERIAL AND METHODS
A literature search was executed using the PubMed and Scopus databases. The search was confined to articles published between January 1985 and August 2023; extracted data was then analysed to form the foundation of the narrative review.
RESULTS
This search yielded 26 articles, comprising 943 patients. Average age was 46.8 ± 6.5 years, and average body mass index was 35.8 ± 4.8. Most of the patients were female (74.33%). Presenting symptoms were rhinorrhea, headaches and meningitis. The most common imaging findings were empty sella and encephalocele. The standard treatment approach was endoscopic endonasal approach for correction of CSF rhinorrhea leak, and shunt placement was also performed in 128 (13%) patients. Recurrences were observed in 10% of cases.
CONCLUSIONS
The complex relationship between spontaneous CSF leaks and IIH is a challenge that benefits from multidisciplinary evaluation and management for successful treatment. Treatments such as endoscopic repair, acetazolamide, and VP/ /LP shunts reduce complications and recurrence. Personalised plans addressing elevated intracranial pressure are crucial for successful outcomes.
Topics: Humans; Female; Adult; Middle Aged; Male; Pseudotumor Cerebri; Cerebrospinal Fluid Rhinorrhea; Intracranial Hypertension; Acetazolamide; Endoscopy; Cerebrospinal Fluid Leak; Retrospective Studies
PubMed: 38393958
DOI: 10.5603/pjnns.98054 -
Journal of Cataract and Refractive... Jul 2023A 62-year-old woman with mild myopia presented to her local optometrist for a routine examination and was found to have intraocular pressure (IOP) of 30 mm Hg in both...
A 62-year-old woman with mild myopia presented to her local optometrist for a routine examination and was found to have intraocular pressure (IOP) of 30 mm Hg in both eyes and cupped nerves. She had a family history of glaucoma in her father. She was started on latanoprost in both eyes and was referred for a glaucoma evaluation. On initial evaluation, her IOP was 25 mm Hg in the right eye and 26 mm Hg in the left eye. Central corneal thickness measured 592 µm in the right eye and 581 µm in the left eye. Her angles were open to gonioscopy without any peripheral anterior synechia. She had 1+ nuclear sclerosis with a corrected distance visual acuity (CDVA) of 20/25 in the right eye and 20/30- in the left eye and uncorrected near visual acuity of J1+ in each eye. Her nerves were 0.85 mm in the right eye and 0.75 mm in the left eye. Optical coherence tomography (OCT) showed retinal nerve fiber layer thinning and a dense superior arcuate scotoma into fixation in her right eye, and superior and inferior arcuate scotomas in her left eye (Figures 1 and 2JOURNAL/jcrs/04.03/02158034-202307000-00019/figure1/v/2023-06-26T195222Z/r/image-tiffJOURNAL/jcrs/04.03/02158034-202307000-00019/figure2/v/2023-06-26T195222Z/r/image-tiff, Supplemental Figures 1 and 2, available at http://links.lww.com/JRS/A882 and http://links.lww.com/JRS/A883). She was successively trialed on fixed combination brimonidine-timolol, dorzolamide, and netarsudil, in addition to her latanoprost, but her IOP remained in the mid- to upper 20s in both eyes. The addition of acetazolamide lowered the pressure to 19 mm Hg in both eyes, but she tolerated it poorly. Methazolamide was also attempted with similar side effects. We elected to perform left eye cataract surgery combined with 360-degree viscocanaloplasty and insertion of a Hydrus microstent (Alcon Laboratories, Inc.). Surgery was uncomplicated with IOP of 16 mm Hg on postoperative day 1 with no glaucoma medications. However, by postoperative week 3, IOP returned to 27 mm Hg, and despite restarting latanoprost-netarsudil and finishing her steroid taper, IOP remained at 27 mm Hg by postoperative week 6. Brimonidine-timolol was added back to her left eye regimen and at postoperative week 8, IOP had elevated to 45 mm Hg. Maximizing her therapy with the addition of topical dorzolamide and oral methazolamide brought her IOP back down to 30 mm Hg. At that point, the decision was made to proceed with trabeculectomy of the left eye. The trabeculectomy was uneventful. However, postoperative attempts to augment filtration were rendered less successful by extremely thick Tenon layer. At her most recent follow-up the pressure in the left eye was mid-teens with brimonidine-timolol and dorzolamide. Her right eye IOP is in the upper 20s on maximum topical therapy. Knowing her postoperative course in the left eye, how would you manage the right eye? In addition to currently available options, would you consider a supraciliary shunt such as the MINIject (iSTAR) if such a device were U.S. Food and Drug Administration (FDA)-approved?
Topics: Humans; United States; Female; Adolescent; Middle Aged; Glaucoma, Open-Angle; Latanoprost; Methazolamide; Timolol; Glaucoma; Treatment Outcome
PubMed: 37390324
DOI: 10.1097/j.jcrs.0000000000001221 -
Expert Opinion on Therapeutic Patents Jun 2024is a common sexually transmitted disease connected with extensive drug resistance to many antibiotics. Presently, only expanded spectrum cephalosporins (ceftriaxone and... (Review)
Review
INTRODUCTION
is a common sexually transmitted disease connected with extensive drug resistance to many antibiotics. Presently, only expanded spectrum cephalosporins (ceftriaxone and cefixime) and azithromycin remain useful for its management.
AREAS COVERED
New chemotypes for the classical antibiotic drug target gyrase/topoisomerase IV afforded inhibitors with potent binding to these enzymes, with an inhibition mechanism distinct from that of fluoroquinolones, and thus less prone to mutations. The α-carbonic anhydrase from the genome of this bacterium (NgCAα) was also validated as an antibacterial target.
EXPERT OPINION
By exploiting different subunits from the gyrase/topoisomerase IV as well as new chemotypes, two new antibiotics reached Phase II/III clinical trials, zoliflodacin and gepotidacin. They possess a novel inhibition mechanism, binding in distinct parts of the enzyme compared to the fluoroquinolones. Other chemotypes with inhibitory activity in these enzymes were also reported. NgCAα inhibitors belonging to a variety of classes were obtained, with several sulfonamides showing MIC values in the range of 0.25-4 µg/mL and significant activity in animal models of this infection. Acetazolamide and similar CA inhibitors might thus be repurposed as antiinfectives. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2016 to 2024.
Topics: Neisseria gonorrhoeae; Anti-Bacterial Agents; Humans; Animals; Drug Repositioning; Patents as Topic; Gonorrhea; Drug Resistance, Bacterial; Topoisomerase II Inhibitors; Oxazolidinones; Microbial Sensitivity Tests; DNA Topoisomerase IV; DNA Gyrase; Morpholines; Isoxazoles; Spiro Compounds; Heterocyclic Compounds, 3-Ring; Barbiturates; Acenaphthenes
PubMed: 38856987
DOI: 10.1080/13543776.2024.2367005