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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]

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Introduction: Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies. Methods: Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration–approved against glaucoma and high‐altitude sickness. Results: Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro‐clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase‐VB (CA‐VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA‐VB silencing specifically reduces Aβ‐mediated endothelial apoptosis. Discussion: This work substantiates the potential application of CAIs in clinical trials for AD and CAA. [ABSTRACT FROM AUTHOR]

Introduction: Takotsubo syndrome is extremely rare and usually seen in postmenopausal women. It manifests as acute coronary syndromes (ACS), but coronaries are usually normal and the majority recover completely without residual myocardial damage. Methods: We are reporting one such case, which followed laser therapy for glaucoma under local anesthesia. She fulfilled all the revised Mayo Clinic criteria for diagnosis. Her preoperative cardiac evaluation and computerized tomography coronary angiograms were normal. Results: This report highlights the need for a wide index of suspicion in those presenting as ACS. Surgical procedures however minor they are, even under local anesthesia should not be considered no-risk ones. Conclusion: Takotsubo cardiomyopathy is reversible acute cardiomyopathy that can occur even after minor eye surgery under local anesthesia. Patients may need coronary angiogram and serial echocardiogram at follow-up. It can be prevented by avoiding trigger factors, addressing preexisting neuropsychiatric ailments, and institution of prophylactic beta-blocker therapy. [ABSTRACT FROM AUTHOR]

Two Shih-Tzu dogs with atopic dermatitis presented with delayed periocular dermatitis (PD) following the instillation of dorzolamide and dorzolamide/timolol combination eyedrops; the development of dermatologic signs took 94 and 104 d in cases 1 and 2, respectively. Hypersensitivity to anti-glaucoma eyedrops was highly suspected, and treatment was discontinued. Delayed PD was significantly relieved in cases 1 and 2, at days 155 and 64 after discontinuation, respectively. In this study, the clinical characteristics and progression of delayed PD were described to inform clinicians who may encounter this rare side effect. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) has aroused extensive attention as a potent therapeutic modality. However, its practical application is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within metastatic breast cancer. Herein, a copper-based single-site nanocatalyst functionalized with carbonic anhydrase inhibitor (CAI) was constructed for magnetic resonance/photoacoustic imaging (MRI/PA)-guided synergetic photothermal therapy (PTT) and CDT. Once reaching tumor sites, the nanocatalyst can be recognized by tumor cell membranes-overexpressed carbonic anhydrase IX (CA IX). Subsequently, the single-site CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant defense system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thereby continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst can generate local heat, which not only permits PTT but also enhances the nanocatalyst-mediated CDT. Moreover, the suppression of CA IX can hinder the tumor extracellular matrix degradation to prevent tumor metastasis. Overall, this work highlighted the great application prospect in enhancing CDT via tumor acidic/redox microenvironment remodeling, and provides an insightful paradigm for inhibiting breast cancer metastasis. The practical application of chemodynamic therapy (CDT) is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within cancer. Herein, we developed a carbonic anhydrase inhibitor (CAI)-functionalized Cu-based nanocatalyst. Once reaching tumor sites, the CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thus continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst not only permits PTT but also enhances the CDT. [Display omitted] [ABSTRACT FROM AUTHOR]

• Adulteration of diuretics in dietary supplements for weight-loss is increasing. • Using UHPLC-Q-Orbitrap (LC-HRMS), simultaneous analysis of diuretics is available. • The fragmentation pathways of diuretics were proposed using UHPLC-Q-Orbitrap (LC-HRMS). Diuretics are used to treat the edematous state in cases of renal insufficiency, nephrotic syndrome, liver cirrhosis, and heart failure. These compounds are used by athletes to lose weight and are included in the list of prohibited substances by the World Anti-Doping Agency. They are also used by obese and overweight people for losing weight, and there are a number of recent reports on the contamination of dietary supplements with diuretics. Due to the alluring online marketing and blogging, there is an extensive misuse of products that are illegally adulterated with diuretics, which has seriously increased health risks. Therefore, it is essential to develop an analytical method for the detection of adulterants in such substances. In this study, 23 diuretics, categorized into four groups, namely, thiazide diuretics (e.g., bendroflumethiazide), loop diuretics (e.g., bumetanide), potassium-sparing diuretics (e.g., amiloride), and carbonic anhydrase inhibitors (e.g., acetazolamide), were analyzed using ultrahigh-performance liquid chromatography-quadrupole orbitrap (UHPLC-Q-Orbitrap). Their fragmentation was elucidated based on the MS/MS data. The 124 products were screened by the UHPLC-Q-Orbitrap (LC-HRMS) method, and the confirmed compounds were quantitated by a previously established LC-MS/MS method. Approximately 5% of the samples were found to be illegally contaminated with diuretics at a concentration of 0.051–162 mg/g. The high selectivity and sensitivity of the UHPLC-Q-Orbitrap (LC-HRMS) method, in combination with the established fragmentation, offer a new approach for the rapid and accurate screening of diuretics in adulterated products, which would be ultimately beneficial for the public health. [ABSTRACT FROM AUTHOR]

Tumor imaging and fluorescence-guided surgical resection offers a promising therapeutic approach for the treatment of cancer with simple operation. Hypoxia, as a crucial feature in solid tumor, is closely related to the design of hypoxia-activated fluorescent probes to distinguish tumor and normal tissue. In present, many hypoxia-activated fluorescent probes have received widespread attention in various imaging applications. However, as far as we know, hypoxia-activated near-infrared fluorescent probe for tumor fluorescence-guided surgical resection is not currently reported. Therefore, a hypoxia-activated near-infrared fluorescent probes Fu-Cy was synthesized. It was able to produce near-infrared fluorescence (780 nm) in specific response to overexpressed nitroreductase in hypoxic tumors with rapid response. However, the uptake of the probe in the cell will affect the imaging ability of the probe. Therefore, acetazolamide (AZ), a well-known inhibitor of carbonic anhydrase IX (CAIX) , was coupled to Fu-Cy by clicking reaction to obtain the improved probe Az-Fu-Cy , which is more absorbed by cancer cells than Fu-Cy. Thus, Az-Fu-Cy can effectively distinguish between tumors and normal organs by spraying. Interestingly, it showed accurate guidance during surgical resection. [Display omitted] • The first hypoxic-activated NIR probe for fluorescence guided surgical resection was reported. • The cell uptake of probe in MDA-MB-231 cell was promoted by inhibiting CAIX. • The probe is good at distinguishing between normal tissue and tumors. [ABSTRACT FROM AUTHOR]

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Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay. We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms. Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them. Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment. • PTU associated with further symptoms such as developmental delay or ataxia seems to be more persistent. • PTU can be associated with genetic mutations in the CACNA1A gene but can also be of multifactorial genesis. • Treatment with carbonic anhydrase inhibitors should be considered in all children with persisting or severe forms of PTU. [ABSTRACT FROM AUTHOR]

Acetazolamide (molecular mass (MM), 222) belongs to the class of sulfonamides (R-SO 2 -NH 2) and is one of the strongest pharmacological inhibitors of carbonic anhydrase activity. Acetazolamide is excreted unchanged in the urine. Here, we report on the development, validation and biomedical application of a stable-isotope dilution GC-MS method for the reliable quantitative determination of acetazolamide in human urine. The method is based on evaporation to dryness of 50 μL urine aliquots, base-catalyzed derivatization of acetazolamide (d 0 -AZM) and its internal standard [ acetylo -2H 3 ]acetazolamide (d 3 -AZM) in 30 vol% pentafluorobenzyl (PFB) bromide in acetonitrile (60 min, 30 °C), reconstitution in toluene (200 μL) and injection of 1-μL aliquots. The negative-ion chemical ionization (NICI) mass spectra (methane) of the PFB derivatives contained several intense ions including [M]‒ at m/z 581 for d 0 -AZM and m/z 584 for d 3 -AZM, suggesting derivatization of their sulfonamide groups to form N,N -dipentafluorobenzyl derivatives (R-SO 2 -N(PFB) 2), i.e., d 0 -AZM-(PFB) 2 and d 3 -AZM-(PFB) 2 , respectively. Quantification was performed by selected-ion monitoring of m/z 581 and 83 for d 0 -AZM-(PFB) 2 and m/z 584 and 86 for d 3 -AZM-(PFB) 2. The limits of detection and quantitation of the method were determined to be 300 fmol (67 pg) and 1 μM of acetazolamide, respectively. Intra- and inter-assay precision and accuracy for acetazolamide in human urine samples in pharmacologically relevant concentration ranges were determined to be 0.3%–4.2% and 95.3%–109%, respectively. The method was applied to measure urinary acetazolamide excretion after ingestion of a 250 mg acetazolamide-containing tablet (Acemit®) by a healthy volunteer. Among other tested sulfonamide drugs, methazolamide (MM, 236) was also found to form a N,N -dipentafluorobenzyl derivative, whereas dorzolamide (MM, 324) was hardly detectable. No GC-MS peaks were obtained from the PFB bromide derivatization of hydrochlorothiazide (MM, 298), xipamide (MM, 355), indapamide and metholazone (MM, 366 each) or brinzolamide (MM, 384). We demonstrate for the first time that sulfonamide drugs can be derivatized with PFB bromide and quantitated by GC-MS. Sulfonamides with MM larger than 236 are likely to be derivatized by PFB bromide but to lack thermal stability. Image 1 • The sulfonamide group of acetazolamide was derivatized for the first time with pentafluorobenzyl bromide. • Other sulfonamides were also derivatized for the first time with pentafluorobenzyl bromide. • Pentafluorobenzyl derivatives of acetazolamide and other sulfonamides are useful for GC-MS. • The validated method was used to quantify pharmacological acetazolamide in human urine. [ABSTRACT FROM AUTHOR]

Inhalational anesthetics such as isoflurane, desflurane and halothane are the mainstay medications for surgical procedures; upon inhalation, they produce anesthesia described as reversible unconsciousness with the features of amnesia, sleep, immobility and analgesia. To date, how they produce anesthesia is unknown. This study proposes that carbonic anhydrase enzymes are likely targets mediating the actions of inhalational anesthetics. Carbonic anhydrase enzymes, commonly expressed in living organisms, utilize carbon dioxide (CO2) as a substrate and can generate H+ and HCO3- from CO2 with a great efficiency. There are remarkable lines of evidence for their likely roles in mediating anesthetic actions. Firstly, carbonic anhydrase enzymes are extensively expressed in the brain and spinal cord, and their importance in the brain activity, especially for the GABA and NMDA receptor signaling pathways, has been demonstrated in numerous studies. According to these studies, they provide HCO3- for GABA-A receptor activities and also buffer HCO3- excess resulting from NMDA receptor activation. Activation of GABA-A and inhibition of NMDA receptors are associated with the induction of anesthesia by the intravenous general anesthetics propofol and ketamine, respectively. Secondly, the carbonic anhydrase inhibitors topiramate and zonisamide are effectively used in the treatment of epilepsy for decades; their chronic use results in the requirement of increased levels of amobarbital in order to produce anesthesia in the epileptic patients during WADA test. In addition, given that CO2 is a substrate for these enzymes, their tertiary structure is likely has a hydrophobic pocket suitable for the anesthetic molecules to bind. Inhalational anesthetic molecules, which are lipophilic and inert in nature, have an ability to cross the membranes and inhibit carbonic anhydrases, which might not be accessible by topiramate and zonisamide. Unlike carbonic anhydrase inhibitors, they could bind to the hydrophobic pocket for CO2 molecules and produce a profound effect called anesthesia. Finally, there is a great deal of similarities between the physiological actions of inhalational anesthetics and carbonic anhydrase inhibitors; moreover well-known side effects of inhalational anesthetics could be associated with the inhibition of carbonic anhydrases. Therefore, this article presents a hypothesis that the anesthetic actions of inhalational anesthetics could be due to their inhibitory effects on the carbonic anhydrases. Investigating this hypothesis might lead to the development of new safer anesthetics, and more importantly it might reveal an endogenous anesthetic pathway, in which the carbonic anhydrase system is a component along with the GABA-A and NMDA receptor systems. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to measure sweat rate during exercise in the heat after directly inhibiting carbonic anhydrase (CA) in eccrine sweat glands via transdermal iontophoresis of acetazolamide. It was hypothesized that if CA was important for sweat production, local administration of acetazolamide, without the confounding systemic effects of dehydration typically associated with past studies, would have a significant effect on sweat rate during exercise. Methods: Ten healthy subjects volunteered to exercise in the heat following acetazolamide or distilled water iontophoresis on the forearm. Results: The distilled water iontophoresis site had a mean sweat rate during exercise in the heat of 0.59±0.31 μL/cm2/min, while the acetazolamide iontophoresis site had a mean sweat rate of 0.63±0.36 μL/cm2/min (p>0.05). Conclusions: The most important finding of the current study was that iontophoresis of acetazolamide did not significantly decrease sweat rate during exercise in the heat. Such results suggest that in past studies it was systemic dehydration, and not CA inhibition at the level of the sweat gland, that caused the reported decreased sweat rate. [ABSTRACT FROM AUTHOR]

New thiadiazole sulfonamide derivatives were designed as human carbonic anhydrase inhibitors (h CAIs) to develop robust and novel anticancer agents. Tail modification approach was considered in designing the target compounds which were synthesized following the two-step procedure starting from 5-acetyl-3- N -(4-sulfamoylphenyl)-2-imino-1,3,4-thiadiazoline. Cytotoxic evaluation revealed the potent diazene derivative 2 with IC 50 1.18 μM, 5.28 μM and 7.15 μM against MCF-7, Caco2 and HepG-2, respectively. Moreover, the dihydroxyphenyl triazene derivative 5 demonstrated IC 50 3.03 μM, 5.66 μM and 12.50 μM against Caco2, HepG-2 and MCF-7, respectively. Similarly, the carbohydrazide coumarin 18 showed IC 50 of 2.00 μM and 12.30 μM against Caco2 and HepG2, respectively. Molecular docking using h CAIX and h CAXII were adopted to explain the achieved cytotoxicity on molecular level with their in silico ADME evaluation. [ABSTRACT FROM AUTHOR]

Purpose Tumor targeted optical imaging using antibodies labeled with near infrared fluorophores is a sensitive imaging modality that might be used during surgery to assure complete removal of malignant tissue. We evaluated the feasibility of dual modality imaging and image guided surgery with the dual labeled anti-carbonic anhydrase IX antibody preparation 111 In-DTPA-G250-IRDye800CW in mice with intraperitoneal clear cell renal cell carcinoma. Materials and Methods BALB/c nu/nu mice with intraperitoneal SK-RC-52 lesions received 10 μg DTPA-G250-IRDye800CW labeled with 15 MBq 111 In or 10 μg of the dual labeled irrelevant control antibody NUH-82 (20 mice each). To evaluate when tumors could be detected, 4 mice per group were imaged weekly during 5 weeks with single photon emission computerized tomography/computerized tomography and the fluorescence imaging followed by ex vivo biodistribution studies. Results As early as 1 week after tumor cell inoculation single photon emission computerized tomography and fluorescence images showed clear delineation of intraperitoneal clear cell renal cell carcinoma with good concordance between single photon emission computerized tomography/computerized tomography and fluorescence images. The high and specific accumulation of the dual labeled antibody conjugate in tumors was confirmed in the biodistribution studies. Maximum tumor uptake was observed 1 week after inoculation (mean ± SD 58.5% ± 18.7% vs 5.6% ± 2.3% injected dose per gm for DTPA-G250-IRDye800CW vs NUH-82, respectively). High tumor uptake was also observed at other time points. Conclusions This study demonstrates the feasibility of dual modality imaging with dual labeled antibody 111 In-DTPA-G250-IRDye800CW in a clear cell renal cell carcinoma model. Results indicate that preoperative and intraoperative detection of carbonic anhydrase IX expressing tumors, positive resection margins and metastasis might be feasible with this approach. [ABSTRACT FROM AUTHOR]

Carbonic Anhydrase II (CAII) has role in pH regulation, water transport and hydration of CO 2 . In addition, CAII is also related to many diseases, including glaucoma, tumours, epilepsy, diabetes and osteopetrosis. Various inhibitors for CAII have been developed and commercialized as a drug. Recent development of CAII inhibitors drive the invention of novel inhibitors based on natural product structures and their derivatives. This research aim to screen potential inhibitors from phenolic and flavonoid groups by in silico approach. The screening of natural products compounds was performed by a molecular docking method. The best ligand derived from the molecular docking selection was further refined with a molecular dynamics simulation and the resulted structure was used to evaluate the stability of CAII-ligand complex. By using the upper mentioned procedures, fisetin (Fic) and 6-(3,4-dihydroxyphenyl)-5,6,7,8-tetrahydronaphthalene-1,3,7-triol (Afr3) were strongly suggested to be a potent inhibitor for CAII. [ABSTRACT FROM AUTHOR]

Copyright of Material Science & Applied Chemistry is the property of RTU Publishing House and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Density functional theory (DFT) using B3LYP and split-valance 6-31G* basis set have been employed to calculate the details of electronic structure and electronic energy of carbonic anhydrase enzyme active center (CA), six inhibitors of this enzyme including topiramate and its derivatives and its analogue, and complex between these inhibitors and active center of carbonic anhydrase. Also thermodynamic functions such as deprotonation enthalpy of inhibitors, standard enthalpies of formation , standard entropy of formation and standard Gibbs free energy of formation for six CA–inhibitor complexes are evaluated. The calculated results indicate that deprotonated inhibitors are coordinated to the Zn2+ ion and all the complexes have tetrahedral geometry. According to the calculated thermodynamic functions substitution of sulfonamide group with hydroxyl reduces the tendency of inhibitor to bind to the active center of carbonic anhydrase. In all calculations solvent effects have been considered in water using SCRF method. [Copyright &y& Elsevier]

Abstract: Topiramate, which is commonly prescribed for seizure disorders and migraine prophylaxis, sometimes causes metabolic acidosis and hypokalemia. Since the effects of topiramate on acid–base balance and potassium levels have not been well explored in children, acid–base balance, anion gap and potassium were assessed in 24 patients (8 females and 16 males) aged between 4.6 and 19 years on topiramate for more than 12 months and in an age-matched control group. Plasma bicarbonate (21.7 versus 23.4mmol/L; P <0.03), carbon dioxide pressure (39.7 versus 43.2mm Hg; P <0.05), and potassium (3.7 versus 4.0mmol/L; P <0.03) were on the average lower and chloride (109 versus 107mmol/L; P <0.03) higher in patients treated with topiramate than in controls. Blood pH, plasma sodium and the anion gap were similar in patients on topiramate and in controls. In patients on topiramate no significant correlation was observed between the dosage of this agent and plasma bicarbonate or potassium as well as between topiramate blood level and the mentioned electrolytes. In conclusion long-term topiramate treatment is associated with a mild, statistically significant tendency towards compensated normal anion gap metabolic acidosis and hypokalemia. [ABSTRACT FROM AUTHOR]

Purpose: To describe a rare case of recurring central serous chorioretinopathy associated with retinitis pigmentosa successfully treated with oral acetazolamide. Methods: A 17-year-old male with retinitis pigmentosa who developed four separate episodes of central serous chorioretinopathy over a 12-month period. Results: After the patient's fourth recurrence, he was treated with daily oral acetazolamide, which resulted in resolution of submacular fluid. He has had no subsequent recurrences while being maintained on alternating and then biweekly doses of oral acetazolamide. Conclusion: Recurrent central serous chorioretinopathy associated with retinitis pigmentosa is a rare occurrence. The presented case demonstrates that oral acetazolamide successfully treated and may have delayed recurrent episodes of central serous chorioretinopathy in the patient with retinitis pigmentosa. [ABSTRACT FROM AUTHOR]

Abstract: To test for environmental persistence in order to determine the potential of carbonic anhydrase inhibitors as larvicides, the decomposition and degradation of samples containing methazolamide (MTZ) and acetazolamide (ACZ) in aqueous solution were monitored under different conditions. Additionally, nontarget species impact was assessed in an acute toxicity test using sheepshead minnow (Cyprinodon variegatus). The fish were exposed for 120h to 10−3 and 10−4 M each compound in replicate seawater tanks. In the high-MTZ treatment, all fish died within 48h, while mortality in the low-MTZ treatment was 27% at 120h. In the high-ACZ treatment mortality reached 83% at 120h. We observed no mortality for the lowest dose of ACZ. Tissue samples were collected from the fish to investigate absorption of the compounds. In the gills, MTZ concentrations were around 40μgg−1 and ACZ reached concentrations up to 80μgg−1. Liver concentrations were low for MTZ probably due to metabolism. [Copyright &y& Elsevier]