Use Of Carbonic Anhydrase Inhibitors Research Articles

New N-(1,3,4-thiadiazole-2-yl)acetamide derivatives as human carbonic anhydrase I and II and acetylcholinesterase inhibitors

Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by 1H NMR,13C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure–activity relationship. Communicated by Ramaswamy H. Sarma

Acetazolamide for acute kidney injury in patients undergoing high dose methotrexate therapy: a systematic review and meta-analysis.

Urine alkalization is one of the standard treatments to prevent acute kidney injury in patients receiving high-dose methotrexate. Carbonic anhydrase inhibitors are promising adjuvants/substitutes with advantages such as faster urine alkalization time and prevention of fluid overload. However, there is limited and contradictoryevidence on its efficacy and safety. We aimed to compare the efficacy and safety of carbonic anhydrase inhibitors to standard treatments in adult patients receiving high-dose methotrexate. The protocol was registered at PROSPERO (CRD42022352802) in August 2021. We evaluated the use of carbonic anhydrase inhibitors in combination with standard treatment compared to standard treatment alone. We excluded articles irrelevant to the efficacy and safety of acetazolamide in patients receiving high dose methotrexate and/or did not provide sufficient data regarding doses, recruitment criteria, and follow-up period. Two authors performed the data extraction independently. Among 198 articles retrieved, six observational studies met all eligibility criteria. Four studies with five datasets (totaling 558 patients/cycles) had enough data to be included in the meta-analysis. We independently report the results from the two remaining studies. The results did not show a significant difference between acetazolamide versus standard treatment in acute kidney injury (AKI) rate (OR = 0.79, 95% CI 0.48-1.29, P = 0.34, I2 = 0%). Regarding the time to urine pH goal, there was no significant time difference between the two groups (Mean Difference = 0.07, 95% CI - 1.9 to 2.04, P = 0.95, I2 = 25%). Furthermore, our meta-analysis showed that acetazolamide did not reduce length of stay (Mean Difference = 0.75, 95% CI -0.8 to 2.31, P = 0.34, I2 = 0%). In one study, the only reported side effect of acetazolamide was hypokalemia (nearly 50% in the acetazolamide group). This systematic review showed no significant difference between acetazolamide and standard care treatment regarding urine alkalinization time and AKI rate in adult patients receiving high dose methotrexate. We suggest performing a large blinded, randomized, controlled trial to evaluate the potential benefits of this low-cost medication.

Recent Trends in Treatment and Associated Costs of Primary Angle-Closure Glaucoma: A Retrospective Cohort Study

To describe recent trends in the treatment for primary angle-closure glaucoma (PACG) and its associated costs in a clinical setting. A retrospective cohort study. We included patients with PACG from 2011 to 2020 using a large-scale administrative claims database in Japan. We calculated the frequencies and costs of antiglaucoma drugs, ophthalmic examinations, and glaucoma-related surgeries, stratified by fiscal years and age groups. Frequencies and costs of antiglaucoma drugs, ophthalmic examinations, and glaucoma-related surgeries. We identified 5654 patients with PACG (15 338 patient-years). Prostanoid FP receptor agonist, nonselective β-blocker, and topical carbonic anhydrase inhibitor use decreased, whereas prostanoid EP2 receptor agonist, α-2 adrenergic agonist, Rho-associated protein kinase inhibitor, and fixed-combination eyedrops use increased. The total amount of drug per patient-year significantly decreased. In recent years, the frequency of cataract surgery increased, whereas that of laser peripheral iridotomy decreased. Visual field testing, slit-lamp examination, intraocular pressure measurement, and funduscopy were performed 0.83, 6.65, 5.15, and 4.61 times/patient-year, respectively. The total cost of drugs, examinations, and surgeries was 60 338 yen per patient-year. Patients with PACG spent more than twice the money on surgeries and examinations than they did on antiglaucoma drugs. The amount of antiglaucoma drugs dispensed decreased, and the proportion of fixed-combination and newly introduced eyedrops increased. Frequency of cataract surgery increased whereas that of laser peripheral iridotomy decreased in recent years. Surgeries and examinations were the major cost drivers for PACG treatment. The current results would be valuable information for future economic analyses and policy making. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Idiopathic Intracranial Hypertension: Current Neuroophthalmologic Points

Idiopathic intracranial hypertension (ICH) is a neuroophophthalmologic syndrome, the main ophthalmologic symptoms of which are vision loss and bilateral swelling of optic nerve disks (OD). The article provides a review covering various aspects of ICH. Epidemiology: ICH occurs mainly in women aged 20–45 years with body overweight. In this group of patients world incidence is 12–20 per 100 000 of population per year. In the total population it represents 0.5–2 cases per 100 000 of population per year. The eightfold gender predominance of women with ICH is observed. Etiology is not fully known until present time. The reliable connection between obesity in childbearing age women and menstrual cycle disorders as evidences of hormonal changes has been established. The probable mechanisms of increase of ICP are supposed: hyperproduction of and disturbances of its absorption, CSF mechanical pressure on the optic nerve sheath; restriction of venous outflow from the brain due to the pathology of venous sinuses; stimulating effect of abundant vitamin A in diet resulting in the fat tissue formation with the development of obesity; expression of the protein aquaporin, involved in the regulation of body mass and water metabolism in the subarachnoid space. Clinical manifestations. Ophthalmologic symptoms of ICH: transient visual impairment, sustained loss of visual acuity, photopsy, retrobulbar pain, diplopia. Non-ophthalmologic symptoms: headache, throbbing tinnitus, hearing loss, dizziness. Diagnostics. The valuable diagnostic data can be obtained by visual field investigation, ophthalmoscopic examination with revealing of bilateral OD-edema, OD and retinal optical coherent tomography, orbital ultrasound examination, brain MRI with venography. Treatment. Non-drug therapy: weight loss, lowcalorie diet with limited water and salt intake. Drug therapy: long-term oral use of carbonic anhydrase inhibitors (acetazolamide, topiramate). High doses of steroids (methylprednisone) are used for short-term treatment of patients with fulminant disease type before surgery. Surgery: bypass surgery, cerebral venous sinus stenting and fenestrations of the optic nerve sheath: bariatric surgery with reducing of stomach volume.

Развитие хориоидальной эффузии на фоне применения ингибиторов карбоангидразы

Relevance. Choroidal effusion is a complication accompanying both surgical interventions and ophthalmopathies of predominantly inflammatory etiology. The release of proteins from choriocapillaries lumen and decrease of intraocular pressure relative to the pressure in the episcleral veins lead to the choroid detachment. Purpose. To analyze the causal link between choroidal effusion and topical application of carbonic anhydrase inhibitors using a clinical example. Material and methods. The paper describes a clinical case of the development of unilateral recurrent choroidal effusion 13 years after sinus trabeculectomy associated with the use of carbonic anhydrase inhibitors. The first episode of choroidal effusion was induced by a fixed combination of brinzolamide with timolol, while the use of dorzolamide caused the repeated episode. The clinical picture was accompanied by significant decrease in visual acuity related to acute hypotension and severe folds of the descemet's membrane. Ultrasonic B-scanning revealed the choroid detachment. The dechallenge of carbonic anhydrase inhibitors, the use of anti-inflammatory and cycloplegic drugs contributed to achieve the choroid adherence. Results. This clinical case clearly demonstrates a causal link between choroidal effusion and topical application of carbonic anhydrase inhibitors. The timely drug therapy made it possible to avoid surgical intervention. Intraocular pressure increased later. Brimonidine was prescribed to reduce it, the intraocular pressure was normalized, and the clinical picture stabilized. Conclusion. Ciliochoroidal effusion may occur in the eyes with primary angle-closure glaucoma even several years after surgical treatment in the setting of the use of this group of hypotensive drugs. It is necessary to take a balanced approach to the use of carbonic anhydrase inhibitors in each particular case, including in primary angle-closure glaucoma. Key words: choroidal effusion, glaucoma, carbonic anhydrase inhibitors, fixed combinations, brimonidine, ophthalmic hypotension.

Utilization of the common functional groups in bioactive molecules: Exploring dual inhibitory potential and computational analysis of keto esters against α-glucosidase and carbonic anhydrase-II enzymes

Diabetes mellitus, a progressive chronic disease, characterized by the abnormal carbohydrate metabolism is associated with severe health complications including long term dysfunction or failure of several organs, cardiovascular and micro-angiopathic problems (neuropathy, nephropathy, retinopathy). Despite the existence of diverse chemical structural libraries of α-glucosidase inhibitors, the limited diabetic treatment due to the adverse side effects such as abdominal distention, flatulence, diarrhoea, and liver damage associated with these inhibitors encourage the medicinal research community to design and develop new and potent inhibitors of α-glucosidase with better pharmacokinetic properties. In this perspective, we demonstrate the successful integration of common functional groups (ketone & ester) in one combined pharmacophore which is favorable for the formation of hydrogen bonds and other weaker interactions with the target proteins. These keto ester derivatives were screened for their α-glucosidase inhibition potential and the in vitro results revealed compound 3c as the highly active inhibitor with an IC50 value of 12.4 ± 0.16 μM compared to acarbose (IC50 = 942 ± 0.74 μM). This inhibition potency was ~76-fold higher than acarbose. Other potent compounds were 3f (IC50 = 28.0 ± 0.28 μM), 3h (IC50 = 33.9 ± 0.09 μM), 3g (IC50 = 34.1 ± 0.04 μM), and 3d (IC50 = 76.5 ± 2.0 μM). In addition, the emerging use of carbonic anhydrase inhibitors for the treatment of diabetic retinopathy (a leading cause of vision loss) prompted us to screen the keto ester derivatives for the inhibition of carbonic anhydrase-II. Compound 3b was found significantly active against carbonic anhydrase-II with an IC50 of 16.5 ± 0.92 μM (acetazolamide; IC50 = 18.2 ± 1.23 μM). Compound 3a also exhibited comparable potency with an IC50 value of 18.9 ± 1.08 μM. Several structure-activity relationship analyses depicted the influence of the substitution pattern on both the aromatic rings. Molecular docking analysis revealed the formation of several H-bonding interactions through the ester carbonyl and the nitro oxygens of 3c with the side chains of His348, Arg212 and His279 in the active pocket of α-glucosidase whereas 3b interacted with His95, -OH of Thr197, Thr198 and WAT462 in the active site of carbonic anhydrase-II. Furthermore, evaluation of ADME properties suggests the safer pharmacological profile of the tested derivatives.

Comparative analysis of ocular redness score evaluated automatically in glaucoma patients under different topical medications.

To compare ocular redness score calculated automatically between glaucoma patients and healthy controls, and to assess the associations between this score and both demographical and clinical characteristics. Glaucoma patients under different topical medications and matched controls were enrolled in this observational cross-sectional study. The Keratograph 5M (Oculus Optikgeräte GmbH) was used to automatically measure 5 redness scores: global; nasal bulbar; temporal bulbar; nasal limbal; temporal limbal. The Student t and ANOVA tests were used to compare continuous variables between groups. A multiple linear regression analysis was performed to evaluate the associations between redness scores and the use of different active principles. One hundred two glaucoma patients and 32 controls were included. Ocular redness scores were significantly higher in glaucoma patients compared to controls (always p < 0.001). The number of active principles was significantly associated with all the redness scores (always p < 0.05). The use of carbonic anhydrase inhibitors (CAIs) was the strongest predictor of overall redness, followed by prostaglandin analogs (PAs) and alpha-adrenergic agonists (AAAs) (respectively, β = 0.400, p = 0.002; β = 0.330, p = 0.013; β = 0.311, p = 0.044). The post hoc analysis measuring the effect of different PAs on redness scores showed that overall redness and bulbar nasal redness scores were significantly lower in patients using tafluprost and latanoprost compared to those using travoprost and bimatoprost 0.01% (respectively, p = 0.025 and p = 0.024). Ocular redness was significantly higher in patients with glaucoma compared to control subjects. The number of active principles and the use of PAs, CAIs and AAAs were associated with higher redness scores.

High Correlation between Glaucoma Treatment with Topical Prostaglandin Analogs and BDNF Immunoreactivity in Human Retina

ABSTRACT Purpose To examine the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin-related kinase receptor-B (TrkB), in normal and glaucomatous human retinas. Methods Human retinas were collected from 8 donors who had been clinically diagnosed and treated for glaucoma, and from 9 control donors. Immunohistochemical analysis for BDNF and TrkB was performed. The percent of each retina expressing BDNF and TrkB was quantified for the total retinal thickness, and separately for the retinal ganglion cell (RGC) complex + retinal nerve fiber layer (RNFL). The expression of each protein was correlated with clinical outcomes obtained from the subject’s ocular histories. Results There was no significant difference in BDNF or TrkB expression when comparing glaucomatous and control retinas. Correlation analysis revealed a significant relationship between BDNF expression and the use of prostaglandin analogs. TrkB expression was highly correlated with the last-measured intraocular pressure (IOP), the use of carbonic anhydrase inhibitors, the use of beta blockers, and the total number of drugs used for the treatment of glaucoma. Conclusion Topical drugs used to treat glaucoma were associated with an increase in retinal BDNF and TrkB expression in human retina, independent of IOP, which may represent molecular evidence of neuroprotective pathway activation.

Crystal Structure of a Tetrameric Type II β-Carbonic Anhydrase from the Pathogenic Bacterium Burkholderia pseudomallei.

Carbonic anhydrase (CA) is a zinc enzyme that catalyzes the reversible conversion of carbon dioxide to bicarbonate and proton. Currently, CA inhibitors are widely used as antiglaucoma, anticancer, and anti-obesity drugs and for the treatment of neurological disorders. Recently, the potential use of CA inhibitors to fight infections caused by protozoa, fungi, and bacteria has emerged as a new research line. In this article, the X-ray crystal structure of β-CA from Burkholderia pseudomallei was reported. The X-ray crystal structure of this new enzyme was solved at 2.7 Å resolution, revealing a tetrameric type II β-CA with a “closed” active site in which the zinc is tetrahedrally coordinated to Cys46, Asp48, His102, and Cys105. B. pseudomallei is known to encode at least two CAs, a β-CA, and a γ-CA. These proteins, playing a pivotal role in its life cycle and pathogenicity, offer a novel therapeutic opportunity to obtain antibiotics with a different mechanism of action. Furthermore, the new structure can provide a clear view of the β-CA mechanism of action and the possibility to find selective inhibitors for this class of CAs.

Carbonic anhydrase inhibition and chemoreflex control of breathing: A litmus test for methazolamide as a viable alternative to acetazolamide.

Carbonic anhydrase inhibition and chemoreflex control of breathing: A litmus test for methazolamide as a viable alternative to acetazolamide.

3D-QSAR CoMFA Studies on Benzenesulfonamides with Benzimidazole Moieties as Inhibitors of Carbonic Anhydrases XII as Antitumor Agents

Introduction: In recent times, a new very significant research area has developed and obtained the potential use of Carbonic Anhydrase inhibitors as Antitumor agents. Methods: A series of sulfonamides and Benzenesulfonamides with benzimidazole moieties to inhibit CSXII was considered in this study. Results and Conclusion: The best model was obtained with a predictive r2 value of 0.678 and cross validated coefficient q2 value as 0.529 in tripos CoMFA region. The paper shows that the electrostatic and steric effects are important features in Carbonic Anhydrase XII inhibition for the investigated compounds. The effort has been undertaken to search for the structural aspects of bioactive molecules.

Carbonic anhydrase inhibitors in patients with respiratory failure and metabolic alkalosis: a systematic review and meta-analysis of randomized controlled trials

BackgroundMetabolic alkalosis is common in patients with respiratory failure and may delay weaning in mechanically ventilated patients. Carbonic anhydrase inhibitors block renal bicarbonate reabsorption, and thus reverse metabolic alkalosis. The objective of this systematic review is to assess the benefits and harms of carbonic anhydrase inhibitor therapy in patients with respiratory failure and metabolic alkalosis.MethodsWe searched the following electronic sources from inception to August 2017: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and SCOPUS. Randomized clinical trials were included if they assessed at least one of the following outcomes: mortality, duration of hospital stay, duration of mechanical ventilation, adverse events, and blood gas parameters. Teams of two review authors worked in an independent and duplicate manner to select eligible trials, extract data, and assess risk of bias of the included trials. We used meta-analysis to synthesize statistical data and then assessed the certainty of evidence using the GRADE methodology.ResultsSix eligible studies were identified with a total of 564 participants. The synthesized data did not exclude a reduction or an increase in mortality (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.57 to 1.56) or in duration of hospital stay (mean difference (MD) 0.42 days, 95% CI −4.82 to 5.66) with the use of carbonic anhydrase inhibitors. Carbonic anhydrase inhibitor therapy resulted in a decrease in the duration of mechanical ventilation of 27 h (95% CI −50 to −4). Also, it resulted in an increase in PaO2 (MD 11.37 mmHg, 95% CI 4.18 to 18.56) and a decrease in PaCO2 (MD −4.98 mmHg, 95% CI −9.66, −0.3), serum bicarbonate (MD −5.03 meq/L, 95% CI −6.52 to −3.54), and pH (MD −0.04, 95% CI −0.07 to −0.01). There was an increased risk of adverse events in the carbonic anhydrase inhibitor group (RR 1.71, 95% CI 0.98 to 2.99). Certainty of evidence was judged to be low for most outcomes.ConclusionIn patients with respiratory failure and metabolic alkalosis, carbonic anhydrase inhibitor therapy may have favorable effects on blood gas parameters. In mechanically ventilated patients, carbonic anhydrase inhibitor therapy may decrease the duration of mechanical ventilation. A major limitation of this finding was that only two trials assessed this clinically important outcome.

Microbial Carbonic Anhydrases in Biomimetic Carbon Sequestration for Mitigating Global Warming: Prospects and Perspectives.

All the leading cities in the world are slowly becoming inhospitable for human life with global warming playing havoc with the living conditions. Biomineralization of carbon dioxide using carbonic anhydrase (CA) is one of the most economical methods for mitigating global warming. The burning of fossil fuels results in the emission of large quantities of flue gas. The temperature of flue gas is quite high. Alkaline conditions are necessary for CaCO3 precipitation in the mineralization process. In order to use CAs for biomimetic carbon sequestration, thermo-alkali-stable CAs are, therefore, essential. CAs must be stable in the presence of various flue gas contaminants too. The extreme environments on earth harbor a variety of polyextremophilic microbes that are rich sources of thermo-alkali-stable CAs. CAs are the fastest among the known enzymes, which are of six basic types with no apparent sequence homology, thus represent an elegant example of convergent evolution. The current review focuses on the utility of thermo-alkali-stable CAs in biomineralization based strategies. A variety of roles that CAs play in various living organisms, the use of CA inhibitors as drug targets and strategies for overproduction of CAs to meet the demand are also briefly discussed.

Posttraumatic Pneumocephalus: The Spectrum in a Tertiary Neurosurgery Center

AbstractTraumatic head injuries are often encountered in the emergency triage, and usually these patients have open head injuries or traumatic pneumocephalus secondary to base of skull fractures. The first line of management involves conservative approaches that include the use of carbonic anhydrase inhibitors, loop diuretics, and, occasionally, lumbar CSF diversion techniques. Surgical intervention is considered once conservative management fails after 2 weeks of institution of conservative management. Here, we discuss the various clinical scenarios, clinical presentation, treatment dilemmas, and possible complications in patients with traumatic pneumocephalus.

Dexamethasone induced glaucoma as part of chemotherapy for lymphoblastic lymphoma and colorectal cancer

PurposeTo describe glaucoma in an 11‐year‐old girl and exacerbation of glaucoma in a 59 year old man after high dose oral corticosteroid chemotherapy.MethodsTopical steroids are well known to cause intraocular pressure (IOP) elevation, but oral steroids are less commonly associated. We report 2 cases of significant IOP elevation after high dose dexamethasone treatment as part of chemotherapy for lymphoblastic lymphoma in an eleven‐year old girl, and for metastatic colorectal cancer in a 59‐year old man.ResultsA week after induction with dexamethasone combination chemotherapy an 11‐year old girl presented with headaches, photophobia and blurring of vision. Intraocular pressures were 48 and 52 mmHg in the right and left eye respectively with bilateral arteriolar disc pulsation. Control of IOP was achieved through topical and systemic treatment but requiring renal support after systemic carbonic anhydrase inhibitor use. The second patient was an adult male with preexisting glaucoma controlled medically in the right eye and with an aqueous shunt in the left eye. During the course of chemotherapy with systemic dexamethasone for colorectal cancer he presented to casualty with reduced right vision from 6/12 to 6/60 associated with an IOP of 42 mmHg in the right eye, while the left was 21 mmHg. His right eye required cyclodiode laser for IOP control.ConclusionsThese cases illustrate that high dose systemic dexamethasone treatment for chemotherapy may cause a considerable rise in IOP potentially leading to significant visual loss from glaucoma. This possibility should be anticipated especially in children and in patients with pre existing glaucoma who are at higher risk of steroid responsiveness.

Crystal structure and kinetic studies of a tetrameric type II β-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.

Carbonic anhydrase (CA) is a zinc enzyme that catalyzes the reversible conversion of carbon dioxide to bicarbonate (hydrogen carbonate) and a proton. CAs have been extensively investigated owing to their involvement in numerous physiological and pathological processes. Currently, CA inhibitors are widely used as antiglaucoma, anticancer and anti-obesity drugs and for the treatment of neurological disorders. Recently, the potential use of CA inhibitors to fight infections caused by protozoa, fungi and bacteria has emerged as a new research direction. In this article, the cloning and kinetic characterization of the β-CA from Vibrio cholerae (VchCAβ) are reported. The X-ray crystal structure of this new enzyme was solved at 1.9 Å resolution from a crystal that was perfectly merohedrally twinned, revealing a tetrameric type II β-CA with a closed active site in which the zinc is tetrahedrally coordinated to Cys42, Asp44, His98 and Cys101. The substrate bicarbonate was found bound in a noncatalytic binding pocket close to the zinc ion, as reported for a few other β-CAs, such as those from Escherichia coli and Haemophilus influenzae. At pH 8.3, the enzyme showed a significant catalytic activity for the physiological reaction of the hydration of CO2 to bicarbonate and protons, with the following kinetic parameters: a kcat of 3.34 × 10(5) s(-1) and a kcat/Km of 4.1 × 10(7) M(-1) s(-1). The new enzyme, on the other hand, was poorly inhibited by acetazolamide (Ki of 4.5 µM). As this bacterial pathogen encodes at least three CAs, an α-CA, a β-CA and a γ-CA, these enzymes probably play an important role in the life cycle and pathogenicity of Vibrio, and it cannot be excluded that interference with their activity may be exploited therapeutically to obtain antibiotics with a different mechanism of action.

Dexamethasone induced glaucoma as part of chemotherapy for T cell lymphoblastic lymphoma

PurposeTo describe glaucoma after high dose corticosteroid chemotherapy in an 11‐year‐old girl.MethodsTopical steroids are well known to induce a rise in intraocular pressure, but responses to oral steroids are rare. We report a significant elevation in an 11‐year‐old girl following high dose dexamethasone treatment as part of her chemotherapy for T cell lymphoblastic lymphoma.ResultsSix days after initiation of her first cycle of chemotherapy including oral dexamethasone 4.5 mg bd she presented with headaches, photophobia and blurring of vision. Intraocular pressures IOP were 48 and 52 mm Hg in the right and left eye respectively. Control of IOP was achieved medically, although systemic carbonic anhydrase inhibitor use necessitated admission to intensive care for renal support.ConclusionsVision threatening IOP rise may be a complication of high dose oral dexamethasone treatment. Routine screening of children undergoing this type of chemotherapy may be indicated.

Carbonic Anhydrase Inhibitors in Corneal Endothelial Transport

Carbonic anhydrases play a central buffering role in current models of fluid transport in corneal endothelium, but in humans, clinical use of carbonic anhydrase inhibitors (CAIs) for the management of glaucoma does not cause corneal swelling. This study compares species differences in response to CAIs in human versus bovine corneal endothelial transport. Short-circuit current (Isc) measurements were performed on bovine and human corneal endothelium under identical conditions. The effects of four CAIs (acetazolamide, brinzolamide, dorzolamide, and ethoxzolamide) were measured. Endothelial expression of carbonic anhydrase II and IV was evaluated by immunofluorescence microscopy. Functional presence of carbonic anhydrase activity was determined using the Hansson's cobalt sulfide histochemical method. All four CAIs decreased bovine Isc (% change in Isc: acetazolamide, -21.0 ± 9.5, n = 8; brinzolamide, -35.5 ± 13.5, n = 9; dorzolamide, -33.6 ± 7.2, n = 8; ethoxzolamide, -35.3 ± 12.9, n = 8). That decrease was not present in humans (% change in Isc: acetazolamide, 16.2 ± 20.1, n = 3; brinzolamide, 6.7 ± 13.9, n = 3; dorzolamide, 8.0 ± 20.4, n = 3; ethoxzolamide, -4.8 ± 10.3, n = 2). Despite no functional effect of CAIs on Isc, both carbonic anhydrase II and IV were present in human corneal endothelium by immunofluorescence microscopy. Histochemical analysis of human corneal endothelium revealed functionally active carbonic anhydrase activity inhibited by brinzolamide. Carbonic anhydrase facilitates ion transport impacting the corneal endothelial Isc in bovine but not human corneal endothelium, despite its presence and functional activity in human tissue. This finding supports the clinical observation of no corneal swelling in humans administered CAIs and suggests that alternative ion transport mechanisms may be operational in corneal endothelium of different species.

Risk factors for hyperammonemia in pediatric patients with epilepsy

To identify risk factors for hyperammonemia in pediatric patients with epilepsy. A total of 2,944 pediatric patients (ages 0-15 years) were classified into the following three groups: a group without drug treatment (n = 445, group I), a group receiving antiepileptic drugs other than valproic acid (VPA) (n = 673, group II), and a VPA-treated group (n = 1,826, group III). Hyperammonemia was defined as a plasma ammonia level exceeding 100 μg/dl with reference to the standard range and previous reports. The mean ammonia level of groups I, II, and III was 36.0, 56.0, and 86.8 μg/dl, respectively, and the incidence of hyperammonemia was 1.6%, 7.7%, and 31.7%, respectively. In each group, the mean ammonia level of patients aged 3 years or younger was significantly higher than that of patients aged 4-15 years. In group II, concomitant use of topiramate and zonisamide were risk factors for hyperammonemia (adjusted odds ratio [OR] 3.9, 95% confidence interval [CI] 1.7-9.2, and OR 3.5, 95% CI 1.9-6.5, respectively). In group III, the ammonia level increased in a VPA dose-dependent manner. At a VPA dose of 30 mg/kg, there was 4.3-fold increase in the incidence of hyperammonemia. The other significant risk factors identified were female gender (OR 1.3, 95% CI 1.0-1.6), symptomatic generalized epilepsy (OR 1.4, 95% CI 1.1-1.8), and the concomitant use of phenytoin (OR 4.7, 95% CI 3.3-6.9), phenobarbital (OR 2.2. 95% CI 1.6-3.2), acetazolamide (OR 6.6, 95% CI 2.5-17.2), topiramate, or zonisamide. A young age and concomitant use of carbonic anhydrase inhibitors are associated with an increased risk of hyperammonemia regardless of whether the patient is taking VPA. In patients receiving VPA, concomitant use of phenytoin and/or phenobarbital enhances the risk of hyperammonemia. An increase in ammonia can be caused by multiple factors. Our results may help clinicians to avoid problems of hyperammonemia.

Nucleotide variations in genes encoding carbonic anhydrase 8 and 10 associated with femoral bone mineral density in Japanese female with osteoporosis

Osteoporosis is a multi-factorial common disease, which is caused by combination of genetic as well as environmental factors. Among several factors, osteoclast acidification pathways during bone resorption might play an important role. Carbonic anhydrases, consisting of a gene family, are essential for pH regulation by the osteoclast. Clinically, use of carbonic anhydrase inhibitors has been known to be associated with a bone-sparing effect as judged by spine bone mineral density (BMD). Here, we investigated single nucleotide polymorphisms (SNPs) in carbonic anhydrase genes that are expressed in bone tissues, i.e., CA8 and CA10, for possible association with femoral and lumbar BMD among 337 Japanese women with osteoporosis participated in BioBank Japan project. Significant correlation was observed between CA8 SNP, rs6984526, and femoral BMD (P = 0.00029); homozygous carriers of the major (C) allele (n = 166) had the highest BMD (0.754 +/- 0.006 g/cm(2), mean +/- SD), while heterozygous carriers (n = 135) were intermediate (0.741 +/- 0.07 g/cm(2)) and homozygous T-allele carriers (n = 31) had the lowest BMD (0.691 +/- 0.012 g/cm(2)). CA8 SNP as well displayed significant association with lumbar BMD in recessive model (P = 0.00017). In addition, CA10 SNP, rs2106329, also displayed strong association with femoral BMD (P = 0.00002). The results suggest that the variations of CA8 and CA10 loci may be important determinants of osteoporosis in Japanese women.