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Sample records for acetazolamide methazolamide ethoxzolamide

  1. Acetazolamide Oral

    MedlinePlus

    Acetazolamide is used to treat glaucoma, a condition in which increased pressure in the eye can lead to gradual loss of vision. Acetazolamide decreases the pressure in the eye. Acetazolamide is also used to reduce the severity and duration of symptoms (upset stomach, ...

  2. Methazolamide Is a New Hepatic Insulin Sensitizer That Lowers Blood Glucose In Vivo

    PubMed Central

    Konstantopoulos, Nicky; Molero, Juan C.; McGee, Sean L.; Spolding, Briana; Connor, Tim; de Vries, Melissa; Wanyonyi, Stephen; Fahey, Richard; Morrison, Shona; Swinton, Courtney; Jones, Sharon; Cooper, Adrian; Garcia-Guerra, Lucia; Foletta, Victoria C.; Krippner, Guy; Andrikopoulos, Sofianos; Walder, Ken R.

    2012-01-01

    We previously used Gene Expression Signature technology to identify methazolamide (MTZ) and related compounds with insulin sensitizing activity in vitro. The effects of these compounds were investigated in diabetic db/db mice, insulin-resistant diet-induced obese (DIO) mice, and rats with streptozotocin (STZ)-induced diabetes. MTZ reduced fasting blood glucose and HbA1c levels in db/db mice, improved glucose tolerance in DIO mice, and enhanced the glucose-lowering effects of exogenous insulin administration in rats with STZ-induced diabetes. Hyperinsulinemic-euglycemic clamps in DIO mice revealed that MTZ increased glucose infusion rate and suppressed endogenous glucose production. Whole-body or cellular oxygen consumption rate was not altered, suggesting MTZ may inhibit glucose production by different mechanism(s) to metformin. In support of this, MTZ enhanced the glucose-lowering effects of metformin in db/db mice. MTZ is known to be a carbonic anhydrase inhibitor (CAI); however, CAIs acetazolamide, ethoxyzolamide, dichlorphenamide, chlorthalidone, and furosemide were not effective in vivo. Our results demonstrate that MTZ acts as an insulin sensitizer that suppresses hepatic glucose production in vivo. The antidiabetic effect of MTZ does not appear to be a function of its known activity as a CAI. The additive glucose-lowering effect of MTZ together with metformin highlights the potential utility for the management of type 2 diabetes. PMID:22586591

  3. Methazolamide Plus Aminophylline Abrogates Hypoxia-Mediated Endurance Exercise Impairment.

    PubMed

    Scalzo, Rebecca L; Binns, Scott E; Klochak, Anna L; Giordano, Gregory R; Paris, Hunter L R; Sevits, Kyle J; Beals, Joseph W; Biela, Laurie M; Larson, Dennis G; Luckasen, Gary J; Irwin, David; Schroeder, Thies; Hamilton, Karyn L; Bell, Christopher

    2015-12-01

    In hypoxia, endurance exercise performance is diminished; pharmacotherapy may abrogate this performance deficit. Based on positive outcomes in preclinical trials, we hypothesized that oral administration of methazolamide, a carbonic anhydrase inhibitor, aminophylline, a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor, and/or methazolamide combined with aminophylline would attenuate hypoxia-mediated decrements in endurance exercise performance in humans. Fifteen healthy males (26 ± 5 years, body-mass index: 24.9 ± 1.6 kg/m(2); mean ± SD) were randomly assigned to one of four treatments: placebo (n = 9), methazolamide (250 mg; n = 10), aminophylline (400 mg; n = 9), or methazolamide (250 mg) with aminophylline (400 mg; n = 8). On two separate occasions, the first in normoxia (FIO2 = 0.21) and the second in hypoxia (FIO2 = 0.15), participants sat for 4.5 hours before completing a standardized exercise bout (30 minutes, stationary cycling, 100 W), followed by a 12.5-km time trial. The magnitude of time trial performance decrement in hypoxia versus normoxia did not differ between placebo (+3.0 ± 2.7 minutes), methazolamide (+1.4 ± 1.7 minutes), and aminophylline (+1.8 ± 1.2 minutes), all with p > 0.09; however, the performance decrement in hypoxia versus normoxia with methazolamide combined with aminophylline was less than placebo (+0.6 ± 1.5 minutes; p = 0.01). This improvement may have been partially mediated by increased SpO2 in hypoxia with methazolamide combined with aminophylline compared with placebo (73% ± 3% vs. 79% ± 6%; p < 0.02). In conclusion, coadministration of methazolamide and aminophylline may promote endurance exercise performance during a sojourn at high altitude.

  4. Methazolamide improves neurological behavior by inhibition of neuron apoptosis in subarachnoid hemorrhage mice

    PubMed Central

    Li, Mingchang; Wang, Wei; Mai, Haojian; Zhang, Xinmu; Wang, Jian; Gao, Yufeng; Wang, Yuefei; Deng, Gang; Gao, Ling; Zhou, Shuanhu; Chen, Qianxue; Wang, Xin

    2016-01-01

    Subarachnoid hemorrhage (SAH) results in significant nerve dysfunction, such as hemiplegia, mood disorders, cognitive and memory impairment. Currently, no clear measures can reduce brain nerve damage. The study of brain nerve protection after SAH is of great significance. We aim to evaluate the protective effects and the possible mechanism of methazolamide in C57BL/6J SAH animal model in vivo and in blood-induced primary cortical neuron (PCNs) cellular model of SAH in vitro. We demonstrate that methazolamide accelerates the recovery of neurological damage, effectively relieves cerebral edema, and improves cognitive function in SAH mice as well as offers neuroprotection in blood- or hemoglobin-treated PCNs and partially restores normal neuronal morphology. In addition, western blot analyses show obviously decreased expression of active caspase-3 in methazolamide-treated SAH mice comparing with vehicle-treated SAH animals. Furthermore, methazolamide effectively inhibits ROS production in PCNs induced by blood exposure or hemoglobin insult. However, methazolamide has no protective effects in morality, fluctuation of cerebral blood flow, SAH grade, and cerebral vasospasm of SAH mice. Given methazolamide, a potent carbonic anhydrase inhibitor, can penetrate the blood–brain barrier and has been used in clinic in the treatment of ocular conditions, it provides potential as a novel therapy for SAH. PMID:27731352

  5. 21 CFR 520.44 - Acetazolamide sodium soluble powder.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Acetazolamide sodium soluble powder. 520.44... Acetazolamide sodium soluble powder. (a) Specifications. The drug is in a powder form containing acetazolamide sodium, USP equivalent to 25 percent acetazolamide activity. (b) Sponsor. See No. 053501 in §...

  6. 21 CFR 522.44 - Sterile sodium acetazolamide.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Sterile sodium acetazolamide. 522.44 Section 522....44 Sterile sodium acetazolamide. (a) Specifications. Sterile sodium acetazolamide contains acetazolamide sodium complying with United States Pharmacopeia as a sterile powder with directions...

  7. 21 CFR 520.44 - Acetazolamide sodium soluble powder.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Acetazolamide sodium soluble powder. 520.44... Acetazolamide sodium soluble powder. (a) Specifications. The drug is in a powder form containing acetazolamide sodium, USP equivalent to 25 percent acetazolamide activity. (b) Sponsor. See No. 053501 in §...

  8. Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug

    DOE PAGES

    Aggarwal, Mayank; Kovalevsky, Andrey Y.; Velazquez, Hector; Fisher, S. Zoë; Smith, Jeremy C.; McKenna, Robert

    2016-07-22

    Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO 2 and HCO 3 − , and their inhibitors have long been used as diuretics and as a therapeutic treatment for many disorders such as glaucoma and epilepsy. Acetazolamide (AZM) and methazolamide (MZM, a methyl derivative of AZM) are two of the classical CA inhibitory drugs that have been used clinically for decades. The jointly refined X-ray/neutron structure of MZM in complex with human CA isoform II (hCA II) has been determined to a resolution of 2.2 Å with an R cryst of ∼16.0%. Presented in this article, along withmore » only the second neutron structure of a clinical drug-bound hCA, is an in-depth structural comparison and analyses of differences in hydrogen-bonding network, water-molecule orientation and solvent displacement that take place upon the binding of AZM and MZM in the active site of hCA II. Even though MZM is slightly more hydrophobic and displaces more waters than AZM, the overall binding affinity ( K i ) for both of the drugs against hCA II is similar (∼10 n M ). The plausible reasons behind this finding have also been discussed using molecular dynamics and X-ray crystal structures of hCA II–MZM determined at cryotemperature and room temperature. This study not only allows a direct comparison of the hydrogen bonding, protonation states and solvent orientation/displacement of AZM and MZM, but also shows the significant effect that the methyl derivative has on the solvent organization in the hCA II active site.« less

  9. 21 CFR 520.44 - Acetazolamide sodium soluble powder.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Acetazolamide sodium soluble powder. 520.44 Section 520.44 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Acetazolamide sodium soluble powder. (a) Specifications. The drug is in a powder form containing...

  10. 21 CFR 520.44 - Acetazolamide sodium soluble powder.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Acetazolamide sodium soluble powder. 520.44 Section 520.44 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Acetazolamide sodium soluble powder. (a) Specifications. The drug is in a powder form containing...

  11. 21 CFR 522.44 - Sterile sodium acetazolamide.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Sterile sodium acetazolamide. 522.44 Section 522.44 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... milligrams acetazolamide activity per milliliter. (b) Sponsor. See No. 010042 in § 510.600(c) of this...

  12. Acetazolamide inhibits osmotic water permeability by interaction with aquaporin-1.

    PubMed

    Gao, Junwei; Wang, Xiaohua; Chang, Yongjie; Zhang, Jianzhao; Song, Qianliu; Yu, Heming; Li, Xuejun

    2006-03-15

    Water channel proteins, known as aquaporins, are transmembrane proteins that mediate osmotic water permeability. In a previous study, we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin-1 (AQP1). The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 (HEK293) cells transfected with pEGFP/AQP1 and to investigate the interaction between acetazolamide and AQP1. The fluorescence intensity of HEK293 cells transfected with pEGFP/AQP1, which corresponds to the cell volume when the cells swell in a hyposmotic solution, was recorded under confocal laser fluorescence microscopy. The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area. Acetazolamide, at concentrations of 1 and 10muM, inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP/AQP1. The direct binding between acetazolamide and AQP1 was detected by surface plasmon resonance. AQP1 was prepared from rat red blood cells and immobilized on a CM5 chip. The binding assay showed that acetazolamide could directly interact with AQP1. This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with AQP1. PMID:16480680

  13. Acetazolamide and chronic hypoxia: effects on haemorheology and pulmonary haemodynamics.

    PubMed

    Pichon, Aurélien; Connes, Philippe; Quidu, Patricia; Marchant, Dominique; Brunet, Julien; Levy, Bernard I; Vilar, José; Safeukui, Innocent; Cymbalista, Florence; Maignan, Maxime; Richalet, Jean-Paul; Favret, Fabrice

    2012-12-01

    We tested the effect of acetazolamide on blood mechanical properties and pulmonary vascular resistance (PVR) during chronic hypoxia. Six groups of rats were either treated or not treated with acetazolamide (curative: treated after 10 days of hypoxic exposure; preventive: treated before hypoxic exposure with 40 mg · kg(-1) · day(-1)) and either exposed or not exposed to 3 weeks of hypoxia (at altitude >5,500 m). They were then used to assess the role of acetazolamide on pulmonary artery pressure, cardiac output, blood volume, haematological and haemorheological parameters. Chronic hypoxia increased haematocrit, blood viscosity and PVR, and decreased cardiac output. Acetazolamide treatment in hypoxic rats decreased haematocrit (curative by -10% and preventive by -11%), PVR (curative by -36% and preventive by -49%) and right ventricular hypertrophy (preventive -20%), and increased cardiac output (curative by +60% and preventive by +115%). Blood viscosity was significantly decreased after curative acetazolamide treatment (-16%) and was correlated with PVR (r=0.87, p<0.05), suggesting that blood viscosity could influence pulmonary haemodynamics. The fall in pulmonary vascular hindrance (curative by -27% and preventive by -45%) after treatment suggests that acetazolamide could decrease pulmonary vessels remodelling under chronic hypoxia. The effect of acetazolamide is multifactorial by acting on erythropoiesis, pulmonary circulation, haemorheological properties and cardiac output, and could represent a pertinent treatment of chronic mountain sickness. PMID:22523353

  14. HLA-B*59:01: a marker for Stevens-Johnson syndrome/toxic epidermal necrolysis caused by methazolamide in Han Chinese.

    PubMed

    Yang, F; Xuan, J; Chen, J; Zhong, H; Luo, H; Zhou, P; Sun, X; He, L; Chen, S; Cao, Z; Luo, X; Xing, Q

    2016-02-01

    Methazolamide is an intraocular pressure-lowering drug that is used in the treatment of glaucoma and other ophthalmologic abnormalities. The use of methazolamide has been shown to cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients of Asian ancestry. Methazolamide-induced SJS/TEN is associated with the presence of HLA-B59 serotype/HLA-B*59:01 in Korean and Japanese populations. To better understand the genetic risk factors for these adverse reactions in the Han Chinese population, we characterized the HLA class I genotypes of eight Chinese patients with methazolamide-induced SJS/TEN from 2008 to 2014. The frequency of HLA-B*59:01 was 87.5% (7/8) in the case patients, which was significantly different from 0% (0/30) in the methazolamide-tolerant patients (odds ratio (OR)=305.0; P=6.3 × 10(-7)) and 0.35% (1/283) in healthy subjects from the human major histocompatibility complex database (OR=1974.0; P=2.0 × 10(-12)). HLA-C*01:02, which is closely linked to HLA-B*59:01, had a weaker but notable association with methazolamide-induced SJS/TEN compared with the tolerant controls (OR=12.1; P=0.016) and general population (OR=15.5; P=2.0 × 10(-3)). The distribution of the HLA-B*59:01-C*01:02 haplotype was also significantly different in cases and controls. This study demonstrated a strong association between HLA-B*59:01 and methazolamide-induced SJS/TEN in the Han Chinese population for the first time. Pretherapy screening for HLA-B*59:01 would be useful to reduce the risk of methazolamide-induced SJS/TEN. PMID:25918017

  15. Acetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus.

    PubMed

    de Groot, Theun; Sinke, Anne P; Kortenoeven, Marleen L A; Alsady, Mohammad; Baumgarten, Ruben; Devuyst, Olivier; Loffing, Johannes; Wetzels, Jack F; Deen, Peter M T

    2016-07-01

    To reduce lithium-induced nephrogenic diabetes insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.

  16. Preformulation study of methazolamide for topical ophthalmic delivery: physicochemical properties and degradation kinetics in aqueous solutions.

    PubMed

    Jiang, Sunmin; Wang, Fengzhen; Zhu, Shuning; Zhang, Xiumei; Guo, Zhigang; Li, Rui; Xu, Qunwei

    2013-05-20

    Methazolamide (MTZ) is an anti-glaucoma drug. The present paper aims to characterize the physicochemical properties and degradation kinetics of MTZ to provide a basis for topical ophthalmic delivery. With the increase in pH (pH 5.5-8.0) of aqueous solution, the solubility of the compound increased while the partition coefficient (Ko/w) which was estimated in the system n-octanol/aqueous solution decreased. The degradation of MTZ in aqueous solution followed pseudo-first-order kinetic. The degradation rate kpH is the rate in the absence of buffer catalysis. Plotting the natural logarithm of kpH versus the corresponding pH value gave a V-shaped pH-rate profile with a maximum stability at pH 5.0. The degradation rate constants as a function of the temperature obeyed the Arrhenius equation (R(2)=0.9995 at pH 7.0 and R(2)=0.9955 at pH 9.0, respectively). A decrease in ionic strength and buffer concentration displayed a stabilizing effect on MTZ. Buffer species also influenced the MTZ hydrolysis. Phosphate buffer system was more catalytic than tris and borate buffer systems. In brief, it is important to consider the physicochemical properties and the stability of MTZ during formulation.

  17. Acetazolamide alters temperature regulation during submaximal exercise.

    PubMed

    Brechue, W F; Stager, J M

    1990-10-01

    Acetazolamide (ACZ), a potent carbonic anhydrase inhibitor, is known to decrease submaximal exercise tolerance under normoxic and hypoxic conditions. These decrements in performance occur despite the maintenance of O2 consumption and CO2 removal. Because ACZ is a diuretic, it induces a moderate hypohydration that may have a role in reducing the ability to sustain exercise through cardiovascular and thermoregulatory impairment. To investigate this potential impairment, seven healthy males between 21 and 35 yr of age were studied in a double-blind crossover design (placebo vs. ACZ). ACZ was administered in three 250-mg oral doses 14, 8, and 2 h before exercise. Subjects exercised at 70% peak O2 uptake for 30 min on a cycle ergometer in a normoxic thermoneutral environment (25 degrees C, 40% relative humidity). Results indicate that exercise minute ventilation was greater but O2 uptake, CO2 output, and respiratory exchange ratio did not differ with ACZ. ACZ led to lower mean skin (0.7 degrees C), higher rectal (0.6 degrees C), and higher mean body temperatures (0.4 degrees C) after 30 min of exercise. Whole-body sweat loss was reduced 23%, and heat storage during the exercise bout was increased 55%. Stroke volume decreased 25%, and arteriovenous O2 difference increased 15%. A significant inverse relationship (r = -0.63) between heart rate and stroke volume was observed. It is concluded that previously reported decreases in the ability to sustain submaximal exercise with ACZ may be related to hypohydration-induced impairment of the cardiovascular and thermoregulatory systems. PMID:2262461

  18. 21 CFR 520.28 - Acetazolamide sodium soluble powder.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Acetazolamide sodium soluble powder. 520.28 Section 520.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... congestive heart failure and for rapid reduction of intraocular pressure.1 1 These conditions are...

  19. Optimization of methazolamide-loaded solid lipid nanoparticles for ophthalmic delivery using Box-Behnken design.

    PubMed

    Wang, Fengzhen; Chen, Li; Jiang, Sunmin; He, Jun; Zhang, Xiumei; Peng, Jin; Xu, Qunwei; Li, Rui

    2014-09-01

    The purpose of the present study was to optimize methazolamide (MTZ)-loaded solid lipid nanoparticles (SLNs) which were used as topical eye drops by evaluating the relationship between design factors and experimental data. A three factor, three-level Box-Behnken design (BBD) was used for the optimization procedure, choosing the amount of GMS, the amount of phospholipid, the concentration of surfactant as the independent variables. The chosen dependent variables were entrapment efficiency, dosage loading, and particle size. The generated polynomial equations and response surface plots were used to relate the dependent and independent variables. The optimal nanoparticles were formulated with 100 mg GMS, 150 mg phospholipid, and 1% Tween80 and PEG 400 (1:1, w/v). A new formulation was prepared according to these levels. The observed responses were close to the predicted values of the optimized formulation. The particle size was 197.8 ± 4.9 nm. The polydispersity index of particle size was 0.239 ± 0.01 and the zeta potential was 32.7 ± 2.6 mV. The entrapment efficiency and dosage loading were about 68.39% and 2.49%, respectively. Fourier transform infrared spectroscopy (FT-IR) study indicated that the drug was entrapped in nanoparticles. The optimized formulation showed a sustained release followed the Peppas model. MTZ-SLNs showed significant prolonged decreasing intraocular pressure effect comparing with MTZ solution in vivo pharmacodynamics studies. The results of acute eye irritation study indicated that MTZ-SLNs and AZOPT both had no eye irritation. Furthermore, the MTZ-SLNs were suitable to be stored at low temperature (4 °C).

  20. Development and validation of an UPLC-MS/MS method for the quantification of ethoxzolamide in plasma and bioequivalent buffers: Applications to absorption, brain distribution, and pharmacokinetic studies

    PubMed Central

    Gao, Song; Zhao, Jing; Yin, Taijun; Ma, Yong; Xu, Beibei; Moore, Anthony N.; Dash, Pramod K.; Hu, Ming

    2015-01-01

    The purpose of this study is to develop and validate an UPLC-MS/MS method to quantify ethoxzolamide in plasma (EZ) and apply the method to absorption, brain distribution, as well as pharmacokinetic studies. A C18 column was used with 0.1% of formic acid in acetonitrile and 0.1% of formic acid in water as the mobile phases to resolve EZ. The mass analysis was performed in a triple quadrupole mass spectrometer using multiple reaction monitoring (MRM) with positive scan mode. The results show that the linear range of EZ is 4.88–10,000.00 nM. The intra-day variance is less than 12.43 % and the accuracy is between 88.88–08.00 %. The inter-day variance is less than 12.87 % and accuracy is between 89.27–115.89 %. Protein precipitation was performed using methanol to extract EZ from plasma and brain tissues. Only 40 µL of plasma is needed for analysis due to the high sensitivity of this method, which could be completed in less than three minutes. This method was used to study the pharmacokinetics of EZ in SD rats, and the transport of EZ in Caco-2 and MDCK-MDR1 overexpressing cell culture models. Our data show that EZ is not a substrate for p-glycoprotein (P-gp) and its entry into the brain may not limited by the blood-brain barrier. PMID:25706567

  1. Effect of acetazolamide on cerebral blood flow in subacute and chronic cerebrovascular disease

    SciTech Connect

    Hojer-Pedersen, E.

    1987-09-01

    Acetazolamide increases cerebral blood flow. The generalized and regional changes in blood flow after administration of acetazolamide were evaluated by the xenon-133 inhalation technique in a series of patients with subacute or chronic focal cerebral ischemia. Acetazolamide augmented interhemispheric asymmetry of cerebral blood flow in patients with unilateral occlusion of major cerebral arteries, whereas no significant side-to-side asymmetry was evident in patients with minor arterial lesions. Low flow areas in relation to computed tomography-verified infarcts tended to be larger after administration of acetazolamide. Hyperfrontality was present at rest and during stimulation with acetazolamide. A decline of cerebral blood flow with advancing age was greater in patients than in normal controls. The vasodilator response to acetazolamide did not change with age.

  2. Acetazolamide for cystoid macular oedema in Bietti crystalline retinal dystrophy.

    PubMed

    Broadhead, Geoffrey K; Chang, Andrew A

    2014-04-01

    Bietti crystalline retinal dystrophy is a rare, inherited disorder whose hallmark is the presence of retinal crystal deposits associated with later chorioretinal degeneration. This condition may rarely be complicated by the development of cystoid macular oedema leading to rapid visual decline. Currently, treatment options for this complication of Bietti dystrophy are limited and the visual prognosis is poor. Here, we present a case of cystoid macular oedema associated with Bietti dystrophy that was successfully diagnosed using multimodal imaging techniques including optical coherence tomography and fluorescein angiography. These modalities confirmed the diagnosis of macular oedema and excluded other possible causes of oedema such as choroidal neovascularisation. In this patient, cystoid macular oedema was resolved with oral acetazolamide therapy, a treatment that has not been previously reported in this context. Acetazolamide treatment resulted in oedema resolution and improvement in visual function, and can be considered a therapeutic option for other patients with Bietti dystrophy who develop cystoid macular oedema.

  3. In vitro study on sustained release capsule formulation of acetazolamide.

    PubMed

    Pandey, V P; Kannan, K; Manavalan, R; Desai, N

    2003-10-01

    In the present study formulation of sustained release capsule of acetazolamide 250 mg was tried using nonpareil seeds. Nonpareil seeds were coated with drug, polyvinylpyrrolidone, glyceryl monostearate, microcrystalline wax, and glyceryl distearate either individually or in combination to achieve sustained release capsule 250 mg. In successful formulation 20% drug coated pellets and 80% wax coated pellets were taken. Wax coated pellets for successful formulation contained coating of microcrystalline wax and glyceryl distearate on drug coated pellets of the same concentration of 1.6% w/w. Successful formulated sustained release capsule 250 mg of acetazolamide was compared in in vitro study with theoretical sustained release formulation suggested by wagner and one marketed sustained release capsule 250 mg. Formulated capsule showed result superior to or on par with marketed capsule. For successful formulation pellets were filled in '1' size hard gelatin capsule and stability study was carried out in hot air over at room temperature and 45 degrees C for 5 weeks. The formulation was found stable in respect of drug content and release rate.

  4. Acetazolamide-induced cilio-choroidal effusion after cataract surgery: unusual posterior involvement

    PubMed Central

    Malagola, Romualdo; Arrico, Loredana; Giannotti, Rossella; Pattavina, Luigi

    2013-01-01

    Idiosyncratic reactions to a large number of drugs have been reported to cause choroidal detachment and secondary angle-closure glaucoma (ACG). We report a case of bilateral acute ACG and peculiar choroidal effusion following administration of oral acetazolamide immediately after cataract surgery. Few cases of acute secondary ACG with choroidal effusion and anterior shift of the lens-iris diaphragm have been associated with acetazolamide compared with other sulfonamides. As far as we are aware, posterior involvement with retinal folds and papillary edema due to acetazolamide has not been described before. PMID:23378740

  5. Sulfonamide inhibition studies of the β-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.

    PubMed

    Del Prete, Sonia; Vullo, Daniela; De Luca, Viviana; Carginale, Vincenzo; Ferraroni, Marta; Osman, Sameh M; AlOthman, Zeid; Supuran, Claudiu T; Capasso, Clemente

    2016-03-01

    The genome of the pathogenic bacterium Vibrio cholerae encodes for three carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β- and γ-classes. VchCA, the α-CA from this species was investigated earlier, whereas the β-class enzyme, VchCAβ was recently cloned, characterized kinetically and its X-ray crystal structure reported by this group. Here we report an inhibition study with sulfonamides and one sulfamate of this enzyme. The best VchCAβ inhibitors were deacetylated acetazolamide and methazolamide and hydrochlorothiazide, which showed inhibition constants of 68.2-87.0nM. Other compounds, with medium potency against VchCAβ, (KIs in the range of 275-463nM), were sulfanilamide, metanilamide, sulthiame and saccharin whereas the clinically used agents such as acetazolamide, methazolamide, ethoxzolamide, dorzolamide, zonisamide and celecoxib were micromolar inhibitors (KIs in the range of 4.51-8.57μM). Identification of potent and possibly selective inhibitors of VchCA and VchCAβ over the human CA isoforms, may lead to pharmacological tools useful for understanding the physiological role(s) of this under-investigated enzymes.

  6. Low-Dose Acetazolamide in the Treatment of Premenstrual Dysphoric Disorder: A Case Series

    PubMed Central

    Kotzalidis, Georgios D.; Panaccione, Isabella; Simonetti, Alessio; De Chiara, Lavinia; Del Casale, Antonio; Ambrosi, Elisa; Napoletano, Flavia; Janiri, Delfina; Danese, Emanuela; Girardi, Nicoletta; Rapinesi, Chiara; Serata, Daniele; Manfredi, Giovanni; Koukopoulos, Alexia E.; Angeletti, Gloria; Nicoletti, Ferdinando; Girardi, Paolo

    2014-01-01

    The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms. PMID:24605130

  7. Acetazolamide and exercise in sojourners to 6,300 meters--a preliminary study.

    PubMed

    Hackett, P H; Schoene, R B; Winslow, R M; Peters, R M; West, J B

    1985-10-01

    To examine the effect of acetazolamide on resting acid-base balance and on exercise performance at extreme altitude, we studied four members of the American Medical Research Expedition to Mount Everest at an altitude of 6,300 meters. After an initial progressive exercise test to exhaustion on a bicycle ergometer, subjects were re-studied after taking acetazolamide 250 mg every 8 h for three doses. We measured venous blood during rest for determination of hemoglobin, hematocrit, 2,3-diphosphoglycerate (DPG), bicarbonate, pH, P50, and arterial oxygen saturation by ear oximeter. The results showed that pH, bicarbonate, and DPG:hemoglobin ratio were lower on acetazolamide, whereas P50 at in vivo conditions was unchanged. Exercise ventilation and oxygen consumption for the same workload were slightly higher after acetazolamide, whereas VCO2/VO2 respiratory exchange ratio (R) was lower, and oxygen saturation was unchanged. Two of four subjects had decreased time at maximum workload on acetazolamide; none had an increased performance. The results of this study show that partial carbonic anhydrase inhibition in individuals sojourning to very high altitude produces a further base deficit and a metabolic acidosis, stimulates ventilation, and may impair maximum exercise performance. Although acetazolamide effectively prevents acute mountain sickness, it does not improve performance, and may even impair exercise performance at extreme altitude. PMID:4068966

  8. Novel Polymeric Nanoparticles Intended for Ophthalmic Administration of Acetazolamide.

    PubMed

    Quinteros, Daniela A; Ferreira, Luana M; Schaffazick, Scheila Rezende; Palma, Santiago D; Allemandi, Daniel A; Cruz, Letícia

    2016-10-01

    Glaucoma is characterized by increased intraocular pressure (IOP) that results in blindness if it remains untreated. Acetazolamide (AZM) is a carbonic anhydrase inhibitor, mainly used to reduce IOP in the treatment of glaucoma. However, the potential of topical treatment is limited, due to its low permeability across the ocular epithelium. An alternative to overcome this limitation is the incorporation of AZM in nanoparticulate systems, such as polymeric nanocapsules (NCs). In this way, the aim of this work was to prepare and characterize NC formulations containing AZM, using ethylcellulose (EC) and Eudragit(®) RS100 (EUD) as encapsulating polymers. The formulations showed high encapsulation efficiency. Particle size measurements showed that NCs are in the nanometric range. Comparing both groups of formulations, the NCEC proved to be smaller than those prepared with EUD. The formulations prepared with EC showed negative zeta potentials, while NCs of EUD were positively charged. For both groups of formulations, no more than 30% of drug was released in 120 min. Ex vivo and in vivo studies evidenced that the NCEC formulations were the most efficient, because an increased amount of permeated drug was observed, along with a greater IOP decrease and longer duration of the effect in normotensive rabbits.

  9. Novel Polymeric Nanoparticles Intended for Ophthalmic Administration of Acetazolamide.

    PubMed

    Quinteros, Daniela A; Ferreira, Luana M; Schaffazick, Scheila Rezende; Palma, Santiago D; Allemandi, Daniel A; Cruz, Letícia

    2016-10-01

    Glaucoma is characterized by increased intraocular pressure (IOP) that results in blindness if it remains untreated. Acetazolamide (AZM) is a carbonic anhydrase inhibitor, mainly used to reduce IOP in the treatment of glaucoma. However, the potential of topical treatment is limited, due to its low permeability across the ocular epithelium. An alternative to overcome this limitation is the incorporation of AZM in nanoparticulate systems, such as polymeric nanocapsules (NCs). In this way, the aim of this work was to prepare and characterize NC formulations containing AZM, using ethylcellulose (EC) and Eudragit(®) RS100 (EUD) as encapsulating polymers. The formulations showed high encapsulation efficiency. Particle size measurements showed that NCs are in the nanometric range. Comparing both groups of formulations, the NCEC proved to be smaller than those prepared with EUD. The formulations prepared with EC showed negative zeta potentials, while NCs of EUD were positively charged. For both groups of formulations, no more than 30% of drug was released in 120 min. Ex vivo and in vivo studies evidenced that the NCEC formulations were the most efficient, because an increased amount of permeated drug was observed, along with a greater IOP decrease and longer duration of the effect in normotensive rabbits. PMID:27519647

  10. Acetazolamide for electrical status epilepticus in slow-wave sleep.

    PubMed

    Fine, Anthony L; Wirrell, Elaine C; Wong-Kisiel, Lily C; Nickels, Katherine C

    2015-09-01

    Electrical status epilepticus in slow-wave sleep (ESES) is characterized by nearly continuous spike-wave discharges during non-rapid eye movement (REM) sleep. ESES is present in Landau-Kleffner syndrome (LKS) and continuous spike and wave in slow-wave sleep (CSWS). Sulthiame has demonstrated reduction in spike-wave index (SWI) in ESES, but is not available in the United States. Acetazolamide (AZM) is readily available and has similar pharmacologic properties. Our aims were to assess the effect of AZM on SWI and clinical response in children with LKS and CSWS. Children with LKS or CSWS treated with AZM at our institution were identified retrospectively. Pre- and posttherapy electroencephalography (EEG) studies were evaluated for SWI. Parental and teacher report of clinical improvement was recorded. Six children met criteria for inclusion. Three children (50%) demonstrated complete resolution or SWI <5% after AZM. All children had improvement in clinical seizures and subjective improvement in communication skills and school performance. Five of six children had subjective improvement in hyperactivity and attention. AZM is a potentially effective therapy for children with LKS and CSWS. This study lends to the knowledge of potential therapies that can be used for these disorders, which can be challenging for families and providers.

  11. Acetazolamide challenge for three-dimensional time-of-flight MR angiography of the brain

    SciTech Connect

    Mandai, Kenji; Sueyoshi, Kenji; Fukunaga, Ryuzo; Nukada, Masaru; Ohtani, Fumio; Araki, Yutaka; Tsukaguchi, Isao; Abe, Hiroshi )

    1994-04-01

    We compared three-dimensional time-of-flight MR angiograms obtained before and after acetazolamide administration to evaluate whether use of this drug could improve visualization of small peripheral intracranial arteries and atherosclerotic stenosis. For evaluation of small peripheral arteries, 10 patients with clinical diagnosis of ischemic cerebrovascular disease and 10 healthy volunteers were investigated, and for evaluation of stenosis, another 6 patients were investigated. Vascular images were obtained by three-dimensional time-of-flight MR angiography. After a baseline scan, 17 mg/kg acetazolamide was injected intravenously and the second scan was performed 20 minutes later. Several small peripheral arteries that had not been seen on the baseline images were visible on the acetazolamide images without any augmentation of the background signals. Stenotic lesions in the main trunks of the major cerebral arteries were detected more clearly on acetazolamide images. Acetazolamide improves visualization of small peripheral intracranial arteries and sensitivity in detecting atherosclerotic stenosis in the main trunk of major cerebral artery by three-dimensional time-of-flight MR angiography without changing MR apparatus and software. 15 refs., 5 figs., 2 tabs.

  12. Possible association between acetazolamide administration during pregnancy and multiple congenital malformations.

    PubMed

    Al-Saleem, Afnan I; Al-Jobair, Asma M

    2016-01-01

    Congenital malformations might occur because of environmental or genetic factors, and sometimes occur because of unknown causes. Acetazolamide is a carbonic anhydrase inhibitor that is used to treat idiopathic intracranial hypertension, glaucoma, and epilepsy. The use of acetazolamide has not been recommended for pregnant women because of reported teratogenic risks. Congenital malformations, such as ectrodactyly, syndactyly, cleft lip/palate, and retarded incisor teeth development, have been reported in experimental animals. However, tooth agenesis due to the use of acetazolamide has not been reported yet. Oligodontia is a severe type of tooth agenesis involving six or more congenitally missing teeth. The causes of oligodontia are attributed to environmental factors, such as irradiation, drugs, trauma, tumors, infection, genetic factors, or a combination. There is no credible evidence of undesirable effects of acetazolamide use in human pregnancy. However, we report a case of a 12-year-old Saudi boy who was exposed to maternal acetazolamide (1,000 mg/day) for treatment of idiopathic intracranial hypertension before pregnancy, during the first trimester, and throughout the pregnancy. This treatment might have resulted in some congenital malformations, such as ectrodactyly, syndactyly, and oligodontia. PMID:27143854

  13. Impaired cerebral vasoreactivity after embolization of arteriovenous malformations: assessment with serial acetazolamide challenge xenon CT

    SciTech Connect

    Tarr, R.W.; Johnson, D.W.; Horton, J.A.; Yonas, H.; Pentheny, S.; Durham, S.; Jungreis, C.A.; Hecht, S.T. )

    1991-05-01

    Embolization of a portion of the nidus of an arteriovenous malformation not only may alter hemodynamics within the nidus, but also may change blood flow dynamics in adjacent normal vessels. Sequential acetazolamide-challenge xenon CT cerebral blood flow studies were performed in eight patients before and after embolization of arteriovenous malformations to assess the hemodynamic effects on the major vascular territories supplying the malformation. Acetazolamide is a potent cerebral vasodilator, and its administration combined with cerebral blood flow studies allows assessment of cerebral vasoreactivity. In seven of the eight patients, one or more parenchymal areas exhibited a normal cerebral blood flow augmentation response to acetazolamide before embolization, but diminished acetazolamide flow augmentation was seen after embolization, indicating abnormal vasoreactivity. We found that the decrease in vasoreactivity peaked 6-10 days after embolization. In one of the eight patients, a temporary delayed neurologic deficit developed during a period of impaired cerebral vasoreactivity following embolization. Our results suggest that embolization of an arteriovenous malformation can induce vasoreactivity changes in adjacent normal vessels. Because these changes appear to be somewhat time-dependent, an appropriate interval should be observed between embolization stages or before surgical resection of an arteriovenous malformation following embolization to allow hemodynamic equilibration to occur. Acetazolamide challenge combined with serial cerebral blood flow studies following embolization enables determination of this hemodynamic equilibration.

  14. Role of carbonic anhydrase in bone - Plasma acetazolamide concentrations associated with inhibition of bone loss

    NASA Technical Reports Server (NTRS)

    Kenny, A. D.

    1985-01-01

    The effects of acetazolamide and benzolamide on bone formation are examined. Solutions of acetazolamide and benzolamide with 1 M THAM/tris(hydromethyl)aminoethane/ or without 1 M THAM were injected subcutaneous with a minipump and into the food of Sprague-Dawley rats. The data reveal that for 8-day and 12-day infusions only acetazolamide combined with 1 M THAM caused any reduction in bone loss and there were no changes in body weights, food consumption and plasma calcium and phosphorus values. Following 8 days of infusion of acetazolamide with 1 M THAM at infusion rates of 0.5, 5.0, and 50 micrograms/hr, no reduction was detected at 0.5 microgram/hr, a 30 percent reduction occurred at 5.0 micrograms/hr and a 49 percent decrease at 50 micrograms/hr. In the benzolamide experiment it was observed that 0.5 percent of the solution in the food caused no reduction in bone loss; however, infusions with benzolamide plus 1 M THAM resulted in a bone loss reduction of 30 percent at 5.0 micrograms/hr, and a 49 percent decrease at 50 micrograms/hr. Acetazolamide levels in the plasma at 50 micrograms/hr doses are calculated as ranging from 99 ng/ml-223 ng/ml and as 46 ng/ml at 5 micrograms/hr doses.

  15. Possible association between acetazolamide administration during pregnancy and multiple congenital malformations

    PubMed Central

    Al-Saleem, Afnan I; Al-Jobair, Asma M

    2016-01-01

    Congenital malformations might occur because of environmental or genetic factors, and sometimes occur because of unknown causes. Acetazolamide is a carbonic anhydrase inhibitor that is used to treat idiopathic intracranial hypertension, glaucoma, and epilepsy. The use of acetazolamide has not been recommended for pregnant women because of reported teratogenic risks. Congenital malformations, such as ectrodactyly, syndactyly, cleft lip/palate, and retarded incisor teeth development, have been reported in experimental animals. However, tooth agenesis due to the use of acetazolamide has not been reported yet. Oligodontia is a severe type of tooth agenesis involving six or more congenitally missing teeth. The causes of oligodontia are attributed to environmental factors, such as irradiation, drugs, trauma, tumors, infection, genetic factors, or a combination. There is no credible evidence of undesirable effects of acetazolamide use in human pregnancy. However, we report a case of a 12-year-old Saudi boy who was exposed to maternal acetazolamide (1,000 mg/day) for treatment of idiopathic intracranial hypertension before pregnancy, during the first trimester, and throughout the pregnancy. This treatment might have resulted in some congenital malformations, such as ectrodactyly, syndactyly, and oligodontia. PMID:27143854

  16. Effect of Acetazolamide on Visual Function in Patients With Idiopathic Intracranial Hypertension and Mild Visual Loss

    PubMed Central

    2015-01-01

    IMPORTANCE Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use. OBJECTIVE To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between −2 dB and −7 dB. The mean age was 29 years and all but 4 participants were women. INTERVENTIONS Low-sodium weight-reduction diet plus the maximally tolerated dosage or acetazolamide (up to 4 g/d) or matching placebo for 6 months. MAIN OUTCOMES AND MEASURES The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to −32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6. RESULTS The mean improvement in PMD was greater with acetazolamide (1.43 dB, from −3.53 dB at baseline to −2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from −3.53 dB to −2.82 dB;n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P= .050). Mean improvements in papilledema grade (acetazolamide: −1

  17. Biocompatibility of acetazolamide pastes in the subcutaneous tissue of rats.

    PubMed

    Mori, Graziela Garrido; Moraes, Ivaldo Gomes de; Nunes, Daniele Clapes; Castilho, Lithiene Ribeiro; Poi, Wilson Roberto

    2009-01-01

    This aim of this study was to investigate the biocompatibility of two experimental acetazolamide (AZ)-based pastes in the subcutaneous tissue of rats. Both pastes contained AZ as the main component in similar concentration. The vehicle in experimental paste 1 was saline, while experimental paste 2 was prepared with propylene glycol. Sixty polyethylene tubes were sealed at one end with gutta-percha (GP), which served as a control. Half of the tubes were filled with paste 1 and half with paste 2. The tubes were implanted in the subcutaneous tissue of 15 rats, being 4 tubes for each animal. The animals were killed 7, 15 and 45 days after surgery and the specimens were processed in laboratory. The histological sections were stained with hematoxylin and eosin and were analyzed by light microscopy. Scores were assigned to level of inflammatory process: 1- none; 2- mild; 3- moderate; 4- severe. The data were analyzed statistically by the Kruskal-Wallis test (p< or =0.05). Paste 1 produced an inflammatory process at 7 days. However, the intensity of this inflammation decreased with time and was nearly absent at 45 days. No statistically significant difference (p>0.05) was observed between the control (GP) and paste 1. However, paste 2 produced inflammatory response at all study periods and differed significantly (p<0.05) from the control. In conclusion, in the present study, the experimental AZ-based paste 1 was considered as biocompatible as the control matrial (GP), while experimental paste 2 was irritating to rat subcutaneous tissue.

  18. Ventilatory oscillations at exercise: effects of hyperoxia, hypercapnia, and acetazolamide

    PubMed Central

    Hermand, Eric; Lhuissier, François J; Larribaut, Julie; Pichon, Aurélien; Richalet, Jean-Paul

    2015-01-01

    Periodic breathing has been found in patients with heart failure and sleep apneas, and in healthy subjects in hypoxia, during sleep and wakefulness, at rest and, recently, at exercise. To unravel the cardiorespiratory parameters liable to modulate the amplitude and period of ventilatory oscillations, 26 healthy subjects were tested under physiological (exercise) and environmental (hypoxia, hyperoxia, hyperoxic hypercapnia) stresses, and under acetazolamide (ACZ) treatment. A fast Fourier transform spectral analysis of breath-by-breath ventilation evidenced an increase in peak power under hypercapnia (vs. normoxia and hyperoxia, P < 0.001) and a decrease under ACZ (vs. placebo, P < 0.001), whereas it was not modified in hyperoxia. period was shortened by exercise in all conditions (vs. rest, P < 0.01) and by hypercapnia (vs. normoxia, P < 0.05) but remained unchanged under ACZ (vs. placebo). peak power was positively related to cardiac output () and in hyperoxia (P < 0.01), in hypercapnia (P < 0.001) and under ACZ (P < 0.001). period was negatively related to and in hyperoxia (P < 0.01 and P < 0.001, respectively), in hypercapnia (P < 0.05 and P < 0.01, respectively) and under ACZ (P < 0.05 and P < 0.01, respectively). Total respiratory cycle time was the main factor responsible for changes in period. In conclusion, exercise, hypoxia, and hypercapnia increase ventilatory oscillations by increasing and , whereas ACZ decreases ventilatory instability in part by a contrasting action on O2 and CO2 sensing. An intrinsic oscillator might modulate ventilation through a complex system where peripheral chemoreflex would play a key role. PMID:26109194

  19. Carbonic anhydrase inhibitors. Inhibition studies of a coral secretory isoform by sulfonamides.

    PubMed

    Bertucci, Anthony; Innocenti, Alessio; Zoccola, Didier; Scozzafava, Andrea; Tambutté, Sylvie; Supuran, Claudiu T

    2009-07-15

    The inhibition of a newly cloned coral carbonic anhydrase (CA, EC 4.2.1.1) has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and sulpiride, or indisulam, a compound in clinical development as antitumor drug), as well as the sulfamate antiepileptic topiramate. Some simple amino-/hydrazine-/hydroxy-substituted aromatic/heterocyclic sulfonamides have also been included in the study. All types of activity have been detected, with low potency inhibitors (K(I)s in the range of 163-770nM), or with medium potency inhibitors (K(I)s in the range of 75.1-105nM), whereas ethoxzolamide, several clinically used sulfonamides and heterocyclic compounds showed stronger potency, with K(I)s in the range of 16-48.2nM. These inhibitors may be useful to better understand the physiological role of the Stylophora pistillata CA (STPCA) in corals and its involvement in biomineralisation in this era of global warming.

  20. Acetazolamide: a second wind for a respiratory stimulant in the intensive care unit?

    PubMed Central

    2012-01-01

    Patients with chronic obstructive pulmonary disease (COPD) are affected by episodes of respiratory exacerbations, some of which can be severe and may necessitate respiratory support. Prolonged invasive mechanical ventilation is associated with increased mortality rates. Persistent failure to discontinue invasive mechanical ventilation is a major issue in patients with COPD. Pure or mixed metabolic alkalosis is a common finding in the intensive care unit (ICU) and is associated with a worse outcome. In patients with COPD, the condition is called post-hypercapnic alkalosis and is a complication of mechanical ventilation. Reversal of metabolic alkalosis may facilitate weaning from mechanical ventilation of patients with COPD. Acetazolamide, a non-specific carbonic anhydrase inhibitor, is one of the drugs employed in the ICU to reverse metabolic alkalosis. The drug is relatively safe, undesirable effects being rare. The compartmentalization of the different isoforms of the carbonic anhydrase enzyme may, in part, explain the lack of evidence of the efficacy of acetazolamide as a respiratory stimulant. Recent findings suggest that the usually employed doses of acetazolamide in the ICU may be insufficient to significantly improve respiratory parameters in mechanically ventilated patients with COPD. Randomized controlled trials using adequate doses of acetazolamide are required to address this issue. PMID:22866939

  1. Role of carbonic anhydrase in bone - Partial inhibition of disuse atrophy of bone by parenteral acetazolamide

    NASA Technical Reports Server (NTRS)

    Kenny, A. D.

    1985-01-01

    The effectiveness of orally and subcutaneously administered acetazolamide sodium in preventing denervation-induced bone loss in rats is examined. Male Sprague-Dawley rats were treated with acetazolamide either orally by incorporation of 0.2, 0.5, or 1.5 percent concentrations in their diet for 15 days, or subcutaneously by either injection of 0.5 ml/rat of a solution containing either 20 or 100 mg/ml of the drug twice daily for 15 days or by continuous infusion of 5, 50, 500, or 1000 mg/ml of acetazolamide sodium for 8 days using an osmotic minipump. The effects of acetazolamide on body weight, food consumption, and plasma calcium content are evaluated. It is observed that parenteral administration is equally effective as oral administration in partially preventing denervation-induced bone mass changes. The data reveal that approximately 50 percent protection occurs with daily doses of 1094, 129, and 8 mg/kg body weight for the oral, subcutaneous injection, and subcutaneous infusion methods, respectively.

  2. Acetazolamide attenuates transvascular fluid flux in equine lungs during intense exercise.

    PubMed

    Vengust, Modest; Staempfli, Henry; Viel, Laurent; Swenson, Erik R; Heigenhauser, George

    2013-09-15

      During intense exercise in horses the transvascular fluid flux in the pulmonary circulation (Jv-a) represents 4% of cardiac output (Q). This fluid flux has been attributed to an increase in pulmonary transmural hydrostatic forces, increases in perfused microvascular surface area, and reversible alterations in capillary permeability under conditions of high flow and pressure. Erythrocyte fluid efflux, however, accounts for a significant fraction of Jv-a. In the lung the Jacobs-Stewart cycle occurs with diffusion of CO2 into alveolar space with possible accompanying chloride (Cl-) and water movement from the erythrocyte directly into the pulmonary interstitium. We hypothesised that inhibition of carbonic anhydrase in erythrocytes inhibits the Jacobs-Stewart cycle and attenuates Jv-a. Five horses were exercised on a treadmill until fatigue without (control) and with acetazolamide treatment (30 mg kg(-1) 30 min before exercise). Erythrocyte fluid efflux, plasma fluid flux across the lung and Jv-a were calculated using haemoglobin, haematocrit, plasma protein and Q. Fluid fluxes were used to calculate erythrocyte, plasma and whole blood Cl- fluxes across the lung. Cardiac output was not different between control and acetazolamide treatment. During exercise erythrocyte fluid efflux and Jv-a increased in control (9.3±3.3 and 11.0±4.4 l min(-1), respectively) and was higher than after acetazolamide treatment (3.8±1.6 and 1.2±1.2 l min(-1), respectively) (P<0.05). Plasma fluid flux did not change from rest in control and decreased after acetazolamide treatment (-4.5±1.5 l min(-1)) (P<0.05). Erythrocyte Cl- flux increased during exercise in control and after acetazolamide treatment (P<0.05). During exercise plasma Cl- flux across the lung did not change in control; however, it increased with acetazolamide treatment (P=0.0001). During exercise whole blood Cl- flux increased across the lung in control (P<0.05) but not after acetazolamide treatment. The results

  3. High pseudotumor cerebri incidence in tretinoin and arsenic treated acute promyelocytic leukemia and the role of topiramate after acetazolamide failure

    PubMed Central

    Smith, Morgan B.; Griffiths, Elizabeth A.; Thompson, James E.; Wang, Eunice S.; Wetzler, Meir; Freyer, Craig W.

    2014-01-01

    Dual differentiation therapy with arsenic trioxide and tretinoin (all-trans-retinoic acid; ATRA) for the management of low and intermediate risk acute promyelocytic leukemia has recently been recommended by the National Comprehensive Cancer Network. Some less common toxicities of the combination may have yet to be fully realized. Of ten patients we have treated thus far, five (50%) have developed pseudotumor cerebri. In one patient, temporary discontinuation of ATRA and initiation of acetazolamide controlled symptoms. In four patients, topiramate was substituted for acetazolamide to relieve symptoms and allow ATRA dose re-escalation. We conclude that providers should monitor for pseudotumor cerebri and consider topiramate if acetazolamide fails. PMID:25180154

  4. Equivalence of conventional and sustained release oral dosage formulations of acetazolamide in primary open angle glaucoma.

    PubMed

    Joyce, P W; Mills, K B; Richardson, T; Mawer, G E

    1989-05-01

    1. Outpatients with primary open angle glaucoma uncontrolled on single topical therapy with either pilocarpine or timolol were recruited for a stratified double dummy cross over trial. Once or twice daily sustained release acetazolamide (SRA) was compared with an identical regimen of conventional tablets (CA). 2. During the run in period the patients received 500 mg SRA once or twice daily as needed to control intraocular pressure (IOP). The dose was thereafter kept constant and patients were allocated randomly to 4 weeks treatment with CA followed by 4 weeks SRA or vice versa. IOP and venous plasma concentrations of acetazolamide were measured at weekly intervals. At the end of each 4 week course, patients were admitted for a 24 h profile of IOP and drug concentration measurements. 3. Thirty-five patients were recruited, but eleven were withdrawn during the run in period largely because of adverse effects; these became less troublesome when it was decided to give the once daily dose at 22.00 h. Four were withdrawn during the cross over, two because of inadequate IOP control. Twenty completed the trial. 4. The morning plasma concentration of acetazolamide measured each week showed no tendency to accumulation during the study. The mean swing (maximum minus minimum) in plasma acetazolamide concentration during the 24 h profile was less (P less than 0.005) with the SR formulation (11.6 +/- 4.9; mg l-1) +/- s.d.) than with the conventional (15.5 +/- 4.7) but the mean concentrations over the 24 h profile were indistinguishable (P greater than 0.05; 9.7 +/- 3.8 and 8.6 +/- 2.8 respectively). 5. Satisfactory control of IOP (no more than one reading above 22 mmHg) was maintained despite the changes in formulation in all but two of the patients who entered the cross over study. No close relationship between IOP and plasma concentration of acetazolamide was found. The 24 h IOP profiles whilst receiving each of the formulations were indistinguishable; thus the smoothing of

  5. Binary and ternary cocrystals of sulfa drug acetazolamide with pyridine carboxamides and cyclic amides

    PubMed Central

    Bolla, Geetha; Nangia, Ashwini

    2016-01-01

    A novel design strategy for cocrystals of a sulfonamide drug with pyridine carboxamides and cyclic amides is developed based on synthon identification as well as size and shape match of coformers. Binary adducts of acetazolamide (ACZ) with lactams (valerolactam and caprolactam, VLM, CPR), cyclic amides (2-pyridone, labeled as 2HP and its derivatives MeHP, OMeHP) and pyridine amides (nicotinamide and picolinamide, NAM, PAM) were obtained by manual grinding, and their single crystals by solution crystallization. The heterosynthons in the binary cocrystals of ACZ with these coformers suggested a ternary combination for ACZ with pyridone and nicotinamide. Novel supramolecular synthons of ACZ with lactams and pyridine carboxamides are reported together with binary and ternary cocrystals for a sulfonamide drug. This crystal engineering study resulted in the first ternary cocrystal of acetazolamide with amide coformers, ACZ–NAM–2HP (1:1:1). PMID:27006778

  6. Binary and ternary cocrystals of sulfa drug acetazolamide with pyridine carboxamides and cyclic amides.

    PubMed

    Bolla, Geetha; Nangia, Ashwini

    2016-03-01

    A novel design strategy for cocrystals of a sulfonamide drug with pyridine carboxamides and cyclic amides is developed based on synthon identification as well as size and shape match of coformers. Binary adducts of acetazolamide (ACZ) with lactams (valerolactam and caprolactam, VLM, CPR), cyclic amides (2-pyridone, labeled as 2HP and its derivatives MeHP, OMeHP) and pyridine amides (nicotinamide and picolinamide, NAM, PAM) were obtained by manual grinding, and their single crystals by solution crystallization. The heterosynthons in the binary cocrystals of ACZ with these coformers suggested a ternary combination for ACZ with pyridone and nicotinamide. Novel supramolecular synthons of ACZ with lactams and pyridine carboxamides are reported together with binary and ternary cocrystals for a sulfonamide drug. This crystal engineering study resulted in the first ternary cocrystal of acetazolamide with amide coformers, ACZ-NAM-2HP (1:1:1).

  7. The spray drying of acetazolamide as method to modify crystal properties and to improve compression behaviour.

    PubMed

    Di Martino, P; Scoppa, M; Joiris, E; Palmieri, G F; Andres, C; Pourcelot, Y; Martelli, S

    2001-02-01

    Acetazolamide shows a very poor compression ability and tablets must usually be produced through a wet granulation process. However, the possibility to obtain pure acetazolamide for direct compression could be interesting for industrial application. With the scope to obtain a material for direct compression, three different crystallisation methods were chosen, with respect to acetazolamide solvent solubility. (a) Acetazolamide was dissolved in an ammonia solution and then spray dried. It was possible to characterise the spherical particles as a mixture of two polymorphic forms, I and II by Powder X-ray diffraction study. (b) Pure form I was obtained by slowly cooling to room temperature a boiling water solution. (c) Pure form II, the marketed form, was obtained by neutralisation of an ammonia solution. Their compression behaviour was investigated firstly by a rotary press. Whilst pure polymorphic forms I and II could not be compressed, the spray dried particles showed very good compression properties. In fact, tablets were obtained only by spray dried particles, which show very good properties under compression and the absence of capping tendency. On the other hand, it was impossible to obtain tablets from polymorphic forms I and II, whatever compression pressures were used. In order to explain their densification mechanism, a single-punch tablet machine, equipped for the measurement of the upper punch displacement in the die, was used. From calculated Heckel's parameters, it was demonstrated that the spray dried material shows a greater particle rearrangement in the initial stage of compression due to its spherical habit and minor wrinkledness of particle surface. The crystalline structure due to the presence of polymorphic forms I and II concur to lowering the intrinsic elasticity of the material. This fact avoids the risk of the rupturing the interpaticulate bonds, which are formed during the compression, concurring to the consolidation of the tablet. PMID

  8. Impact of bicarbonate, ammonium chloride, and acetazolamide on hepatic and renal SLC26A4 expression.

    PubMed

    Alesutan, Ioana; Daryadel, Arezoo; Mohebbi, Nilufar; Pelzl, Lisann; Leibrock, Christina; Voelkl, Jakob; Bourgeois, Soline; Dossena, Silvia; Nofziger, Charity; Paulmichl, Markus; Wagner, Carsten A; Lang, Florian

    2011-01-01

    SLC26A4 encodes pendrin, a transporter exchanging anions such as chloride, bicarbonate, and iodide. Loss of function mutations of SLC26A4 cause Pendred syndrome characterized by hearing loss and enlarged vestibular aqueducts as well as variable hypothyroidism and goiter. In the kidney, pendrin is expressed in the distal nephron and accomplishes HCO(3)(-) secretion and Cl(-) reabsorption. Renal pendrin expression is regulated by acid-base balance. The liver contributes to acid-base regulation by producing or consuming glutamine, which is utilized by the kidney for generation and excretion of NH(4)(+), paralleled by HCO(3)(-) formation. Little is known about the regulation of pendrin in liver. The present study thus examined the expression of Slc26a4 in liver and kidney of mice drinking tap water without or with NaHCO(3) (150 mM), NH(4)Cl (280 mM) or acetazolamide (3.6 mM) for seven days. As compared to Gapdh transcript levels, Slc26a4 transcript levels were moderately lower in liver than in renal tissue. Slc26a4 transcript levels were not significantly affected by NaHCO(3) in liver, but significantly increased by NaHCO(3) in kidney. Pendrin protein expression was significantly enhanced in kidney and reduced in liver by NaHCO(3). Slc26a4 transcript levels were significantly increased by NH(4)Cl and acetazolamide in liver, and significantly decreased by NH(4)Cl and by acetazolamide in kidney. NH(4)Cl and acetazolamide reduced pendrin protein expression significantly in kidney, but did not significantly modify pendrin protein expression in liver. The observations point to expression of pendrin in the liver and to opposite effects of acidosis on pendrin transcription in liver and kidney. PMID:22116370

  9. Fluconazole and acetazolamide in the treatment of ectopic Cushing's syndrome with severe metabolic alkalosis

    PubMed Central

    Aberer, Felix; Stiegler, Claudia; R Pieber, Thomas; Obermayer-Pietsch, Barbara; Pilz, Stefan

    2015-01-01

    Summary Cushing's syndrome (CS) due to ectopic ACTH production accounts for about 10% of all types of CS and is frequently associated with metabolic alkalosis. Treatment of CS involves surgical resection and/or medical therapy to control hypercortisolism. We present the case of an 80-year-old woman affected by CS due to an unknown cause. The patient had severe metabolic alkalosis with refractory hypokalemia. To treat the underlying CS, fluconazole was initiated due to unavailability of ketoconazole. In spite of markedly decreasing cortisol levels, metabolic alkalosis persisted. Treatment of metabolic alkalosis with acetazolamide was thus initiated and pH levels successfully lowered. This case report shows that hypercortisolism can be effectively treated with fluconazole in cases where ketoconazole is unavailable or not tolerated and that persistent severe metabolic alkalosis caused by glucocorticoid excess can be safely and successfully treated with acetazolamide. Learning points Hypercortisolism can be effectively treated with fluconazole where ketoconazole is unavailable or not tolerated.Glucocorticoid excess can cause severe metabolic alkalosis.Persistent severe metabolic alkalosis can be safely and successfully treated with acetazolamide. PMID:26380091

  10. Effect of edetate disodium and reduced glutathione on absorption of acetazolamide from GI tract of rats.

    PubMed

    Schoenwald, R D; Ward, R L

    1976-05-01

    The absorption of acetazolamide suspensions from in situ rat gastric and intestinal loop segments was studied. In 1 hr, 66.2 and 64.3% remained unabsorbed from the rat stomach and intestine, respectively. Although 1% (w/v) reduced glutathione and 1% (w/v) (24 mM) edetate disodium had no effect on gastric absorption, drug absorption from the rat intestine (1 hr) was increased 1.5 and 2 times, respectively. It was hypothesized that the relatively poor intestinal absorption was due primarily to the formation of a pH-dependent (pH 4.5-10), nonabsorbable complex between acetazolamide and carbonic anhydrase present in the gut and that reduced glutathione acted as an inhibitor to promote intestinal absorption. Equilibrium dialysis studies showed that reduced glutathion could reduce the fraction of drug bound to human carbonic anhydrase B by one-half when present in a molar ratio 10 times that of acetazolamide; edetate disodium had no effect on the in vitro binding. It was, therefore, assumed that edetate disodium promoted an increase in intestinal absorption by altering the permeability of intestinal epithelium. Based upon present experimentation, however, the alteration of intestinal epithelium by reduced glutathione cannot be ruled out. PMID:6773

  11. Acute Mountain Sickness Symptom Severity at the South Pole: The Influence of Self-Selected Prophylaxis with Acetazolamide

    PubMed Central

    Johnson, Jacob B.; Richert, Maile; Miller, Andrew D.

    2016-01-01

    Introduction Acetazolamide, a carbonic anhydrase inhibitor, remains the only FDA approved pharmaceutical prophylaxis for acute mountain sickness (AMS) though its effectiveness after rapid transport in real world conditions is less clear. Methods Over 2 years, 248 healthy adults traveled by airplane from sea level (SL) to the South Pole (ALT, ~3200m) and 226 participants provided Lake Louise Symptom Scores (LLSS) on a daily basis for 1 week; vital signs, blood samples, and urine samples were collected at SL and at ALT. Acetazolamide was available to any participant desiring prophylaxis. Comparisons were made between the acetazolamide with AMS (ACZ/AMS) (n = 42), acetazolamide without AMS (ACZ/No AMS)(n = 49), no acetazolamide with AMS (No ACZ/AMS) (n = 56), and the no acetazolamide without AMS (No ACZ/No AMS) (n = 79) groups. Statistical analysis included Chi-squared and one-way ANOVA with Bonferroni post-hoc tests. Significance was p≤0.05. Results No significant differences were found for between-group characteristics or incidence of AMS between ACZ and No ACZ groups. ACZ/AMS reported greater LLSS, BMI, and red cell distribution width. ACZ/No AMS had the highest oxygen saturation (O2Sat) at ALT. No significant differences were found in serum electrolyte concentrations or PFT results. Discussion Acetazolamide during rapid ascent provided no apparent protection from AMS based on LLSS. However, it is unclear if this lack of effect was directly associated with the drug or if perhaps there was some selection bias with individuals taking ACZ more likely to have symptoms or if there may have been more of perceptual phenomenon related to a constellation of side effects. PMID:26848757

  12. Two-dimensional crystal structure of aquaporin-4 bound to the inhibitor acetazolamide.

    PubMed

    Kamegawa, Akiko; Hiroaki, Yoko; Tani, Kazutoshi; Fujiyoshi, Yoshinori

    2016-04-01

    Acetazolamide (AZA) reduces the water permeability of aquaporin-4, the predominant water channel in the brain. We determined the structure of aquaporin-4 in the presence of AZA using electron crystallography. Most of the features of the 5-Å density map were consistent with those of the previously determined atomic model. The map showed a protruding density from near the extracellular pore entrance, which most likely represents the bound AZA. Molecular docking simulations supported the location of the protrusion as the likely AZA-binding site. These findings suggest that AZA reduces water conduction by obstructing the pathway at the extracellular entrance without inducing a large conformational change in the protein. PMID:26908838

  13. Two-dimensional crystal structure of aquaporin-4 bound to the inhibitor acetazolamide

    PubMed Central

    Kamegawa, Akiko; Hiroaki, Yoko; Tani, Kazutoshi; Fujiyoshi, Yoshinori

    2016-01-01

    Acetazolamide (AZA) reduces the water permeability of aquaporin-4, the predominant water channel in the brain. We determined the structure of aquaporin-4 in the presence of AZA using electron crystallography. Most of the features of the 5-Å density map were consistent with those of the previously determined atomic model. The map showed a protruding density from near the extracellular pore entrance, which most likely represents the bound AZA. Molecular docking simulations supported the location of the protrusion as the likely AZA-binding site. These findings suggest that AZA reduces water conduction by obstructing the pathway at the extracellular entrance without inducing a large conformational change in the protein. PMID:26908838

  14. Methazolamide-loaded solid lipid nanoparticles modified with low-molecular weight chitosan for the treatment of glaucoma: vitro and vivo study.

    PubMed

    Wang, Fengzhen; Chen, Li; Zhang, Dongsheng; Jiang, Sunmin; Shi, Kun; Huang, Yuan; Li, Rui; Xu, Qunwei

    2014-11-01

    The aims of this study were to design and characterize methazolamide (MTZ)-loaded solid lipid nanoparticles (SLN) with and without modification of low molecular weight chitosan (CS) and compare their potentials for ocular drug delivery. Low molecular weight CS was obtained via a modified chemical oxidative degradation method. SLN with CS (CS-SLN-MTZ) and without CS (SLN-MTZ) were prepared according to a modified emulsion-solvent evaporation method. SLN-MTZ and CS-SLN-MTZ were 199.4 ± 2.8 nm and 252.8 ± 4.0 nm in particle size, -21.3 ± 1.9 mV and +31.3 ± 1.7 mV in zeta potential, respectively. Physical stability studies demonstrated that CS-SLN-MTZ remained stable for at least 4 months at 4 °C, while SLN-MTZ no more than 2 months. A prolonged in vitro release profile of MTZ from CS-SLN-MTZ was obtained compared with SLN-MTZ. Furthermore, CS-SLN-MTZ presented a better permeation property in excised rabbit cornea. In vivo studies indicated that the intraocular pressure lowering effect of CS-SLN-MTZ (245.75 ± 18.31 mmHg × h) was significantly better than both SLN-MTZ (126.74 ± 17.73 mmHg × h) and commercial product Brinzolamide Eye Drops AZOPT® (171.17 ± 16.45 mmHg × h). The maximum percentage decrease in IOP of CS-SLN-MTZ (42.78 ± 7.71%) was higher than SLN-MTZ (27.82 ± 4.15%) and was comparable to AZOPT (38.06 ± 1.25%). CS-SLN-MTZ showed no sign of ocular irritancy according to the Draize method and the histological examination.

  15. Correlation between cerebral oxygen metabolism and cerebral blood flow simultaneously measured before and after acetazolamide administration

    NASA Astrophysics Data System (ADS)

    Yamaguchi, Hiroichiro; Yamauchi, Hideto; Hazama, Shiro; Hamamoto, Hirotsugu; Inoue, Nobuhiro

    1999-10-01

    The cerebral circulation and metabolism of ten preoperative cardiac surgery patients were assessed. Alterations in regional cerebral blood flow (rCBF), measured by 123I-N- isopropyl-p-iodo-amphetamine single-photon emission computed tomography, and in cerebral oxygen metabolism, simultaneously detected by near-infrared spectroscopy (NIRS) before and after acetazolamide administration, were investigated. The rCBF (ml/min/100 g) increased significantly from 40.21 +/- 7.65 to 56.24 +/- 13.69 (p equals 0.001), and a significant increase in oxyhemoglobin (Oxy-Hb) of 13.9% (p equals 0.0022) and total hemoglobin (Total-Hb) of 5.7% (0.0047) along with a significant decrease in deoxyhemoglobin (Deoxy-Hb) of 8.9% (p equals 0.0414) were observed concomitantly. Thus, the Oxy-Hb/Total- Hb ratio (%Oxy-Hb) rose significantly from 67.26 +/- 9.82% to 72.98 +/- 8.09% (p equals 0.0022). Examination of the relationships between individual parameters showed that the percentage changes in rCBF and Oxy-Hb were significantly correlated (r equals 0.758, p equals 0.011). The percentage changes in rCBF and %Oxy-Hb were also correlated significantly (r equals 0.740, p equals 0.014). In conclusion, this evidence suggested that NIRS is able to detect relative changes in cerebral hemodynamics and reflect luxury perfusion induced by acetazolamide.

  16. Acetazolamide does not disrupt limb regenerate morphogenesis in the salamander, Plethodon cinereus.

    PubMed

    Dinsmore, C E; Maren, T H

    1986-02-01

    Acetazolamide, a potent and highly specific inhibitor of carbonic anhydrase, is teratogenic in mammalian embryos and when administered during early limb development causes unique limb defects in a time- and dose-dependent manner. The regenerating urodele limb is often considered to be a good experimental analog of limb development and, if it employs the same mechanisms of tissue interactions during pattern formation, should be susceptible to teratogens which selectively disrupt developmental limb patterning. This study demonstrates that while carbonic anhydrase inhibition is toxic to the red-backed salamander, Plethodon cinereus, it does not have the same teratogenic effect on limb regeneration as seen in mammalian limb development. Several points are considered as to why the regenerating limb, at least in this salamander species, may not be suitable for studying this class of teratogen.

  17. Differential effects of flurbiprofen and aspirin on acetazolamide disposition in humans.

    PubMed Central

    Sweeney, K R; Chapron, D J; Antal, E J; Kramer, P A

    1989-01-01

    The plasma concentration-time profile of acetazolamide (AZ) following an intravenous bolus dose (5 mg kg-1) was determined during control, aspirin and flurbiprofen (FLU) treatment periods. The unbound fraction of AZ in plasma increased three-fold in the presence of salicylate (SA) while, in contrast, FLU produced consistent, but statistically insignificant, increases in binding. SA caused a two-fold decrease in both unbound AZ renal clearance and apparent volume of distribution at steady-state, while FLU produced a small, but significant, increase only in the latter. The area under the concentration-time curve for AZ in erythrocytes was increased by about 40% during SA treatment while FLU had no effect. Our results suggest that on a pharmacokinetic basis FLU may be a safer nonsteroidal anti-inflammatory drug (NSAID) to co-administer with AZ. PMID:2757898

  18. Benzolamide improves oxygenation and reduces acute mountain sickness during a high-altitude trek and has fewer side effects than acetazolamide at sea level.

    PubMed

    Collier, David J; Wolff, Chris B; Hedges, Anne-Marie; Nathan, John; Flower, Rod J; Milledge, James S; Swenson, Erik R

    2016-06-01

    Acetazolamide is the standard carbonic anhydrase (CA) inhibitor used for acute mountain sickness (AMS), however some of its undesirable effects are related to intracellular penetrance into many tissues, including across the blood-brain barrier. Benzolamide is a much more hydrophilic inhibitor, which nonetheless retains a strong renal action to engender a metabolic acidosis and ventilatory stimulus that improves oxygenation at high altitude and reduces AMS. We tested the effectiveness of benzolamide versus placebo in a first field study of the drug as prophylaxis for AMS during an ascent to the Everest Base Camp (5340 m). In two other studies performed at sea level to test side effect differences between acetazolamide and benzolamide, we assessed physiological actions and psychomotor side effects of two doses of acetazolamide (250 and 1000 mg) in one group of healthy subjects and in another group compared acetazolamide (500 mg), benzolamide (200 mg) and lorazepam (2 mg) as an active comparator for central nervous system (CNS) effects. At high altitude, benzolamide-treated subjects maintained better arterial oxygenation at all altitudes (3-6% higher at all altitudes above 4200 m) than placebo-treated subjects and reduced AMS severity by roughly 50%. We found benzolamide had fewer side effects, some of which are symptoms of AMS, than any of the acetazolamide doses in Studies 1 and 2, but equal physiological effects on renal function. The psychomotor side effects of acetazolamide were dose dependent. We conclude that benzolamide is very effective for AMS prophylaxis. With its lesser CNS effects, benzolamide may be superior to acetazolamide, in part, because some of the side effects of acetazolamide may contribute to and be mistaken for AMS. PMID:27433337

  19. Benzolamide improves oxygenation and reduces acute mountain sickness during a high-altitude trek and has fewer side effects than acetazolamide at sea level.

    PubMed

    Collier, David J; Wolff, Chris B; Hedges, Anne-Marie; Nathan, John; Flower, Rod J; Milledge, James S; Swenson, Erik R

    2016-06-01

    Acetazolamide is the standard carbonic anhydrase (CA) inhibitor used for acute mountain sickness (AMS), however some of its undesirable effects are related to intracellular penetrance into many tissues, including across the blood-brain barrier. Benzolamide is a much more hydrophilic inhibitor, which nonetheless retains a strong renal action to engender a metabolic acidosis and ventilatory stimulus that improves oxygenation at high altitude and reduces AMS. We tested the effectiveness of benzolamide versus placebo in a first field study of the drug as prophylaxis for AMS during an ascent to the Everest Base Camp (5340 m). In two other studies performed at sea level to test side effect differences between acetazolamide and benzolamide, we assessed physiological actions and psychomotor side effects of two doses of acetazolamide (250 and 1000 mg) in one group of healthy subjects and in another group compared acetazolamide (500 mg), benzolamide (200 mg) and lorazepam (2 mg) as an active comparator for central nervous system (CNS) effects. At high altitude, benzolamide-treated subjects maintained better arterial oxygenation at all altitudes (3-6% higher at all altitudes above 4200 m) than placebo-treated subjects and reduced AMS severity by roughly 50%. We found benzolamide had fewer side effects, some of which are symptoms of AMS, than any of the acetazolamide doses in Studies 1 and 2, but equal physiological effects on renal function. The psychomotor side effects of acetazolamide were dose dependent. We conclude that benzolamide is very effective for AMS prophylaxis. With its lesser CNS effects, benzolamide may be superior to acetazolamide, in part, because some of the side effects of acetazolamide may contribute to and be mistaken for AMS.

  20. Acetazolamide on the ventral medulla of the cat increases phrenic output and delays the ventilatory response to CO2.

    PubMed Central

    Coates, E L; Li, A H; Nattie, E E

    1991-01-01

    1. Acetazolamide (0.1 mM) applied to the surface of the rostral ventrolateral medulla or microinjected beneath the medullary surface in chloralose-urethane-anaesthetized, vagotomized, carotid-denervated, paralysed, servo-ventilated cats produced a long-lasting increase in integrated phrenic nerve activity. 2. Extracellular pH measured beneath the rostral ventrolateral medulla exhibited a long-lasting decrease after surface acetazolamide but was not a good predictor, in each individual animal, of changes in phrenic activity. 3. Medullary carbonic anhydrase inhibition reduced the slope and the half-time of the phrenic response to rapid step CO2 increases. Conversely, acetazolamide did not affect the phrenic response to steady-state CO2 increases. 4. These data indicate that localized inhibition of medullary carbonic anhydrase causes a centrally mediated increase in ventilation that we attribute to medullary tissue hypercapnia and acidosis. In addition, these data indicate that medullary carbonic anhydrase may play a role in central CO2 chemotransduction. Images Fig. 8 PMID:1816381

  1. Anuric Acute Kidney Injury Induced by Acute Mountain Sickness Prophylaxis With Acetazolamide

    PubMed Central

    Castle Alvarez-Maza, James; Novak, James E.

    2014-01-01

    Acetazolamide (ACZ) is a sulfonamide derivative that inhibits carbonic anhydrase and is the mainstay for prevention and treatment of acute mountain sickness (AMS). Acute kidney injury (AKI) is not well recognized as a complication of ACZ ingestion, especially when low doses are used for short periods of time. We report a case of a healthy, middle-aged man who developed severe AKI after the ingestion of ACZ for AMS prophylaxis. The patient presented with bilateral flank pain and anuric AKI without radiographic signs of obstructive uropathy. All blood and urine testing to determine the cause of AKI were negative or normal. The patient required 2 sessions of hemodialysis due to worsening metabolic derangements, which included severe anion gap metabolic acidosis and hyperphosphatemia. Renal function returned to baseline after 96 hours of supportive care. The pathogenesis of AKI in our patient was attributed to ACZ-induced sulfonamide crystalluria causing intratubular obstruction and retrograde urine flow, but not intraureteric precipitation or obstructive uropathy. This classic presentation of anuric AKI and renal colic has been previously described with higher doses of ACZ for prolonged periods of time but never with low doses for AMS prophylaxis such as in our patient (total dose of 1250 mg within 48 hours). Our case highlights the risk of adverse renal outcomes following ACZ ingestion, even in previously healthy individuals, and suggests that increased fluid intake may be advisable for travelers taking ACZ prophylaxis. PMID:25264540

  2. Preparation and evaluation of sustained release calcium alginate beads and matrix tablets of acetazolamide.

    PubMed

    Barzegar-Jalali, M; Hanaee, J; Omidi, Y; Ghanbarzadeh, S; Ziaee, S; Bairami-Atashgah, R; Adibkia, K

    2013-02-01

    The aim of this study was to develop sustained release dosage forms of acetazolamide (ACZ) preparing its calcium alginate beads and matrix tablets. ACZ was incorporated into calcium alginate beads using microencapsulation method. Two methods were applied to prolong ACZ release rate. In the first method, the drug was incorporated into calcium alginate beads either alone or with various polymers in internal phase. The second method involved the preparation of matrix tablet from the beads benefiting direct compression method with or without various polymers in external phase. The release rate of these prepared formulations and an innovator's sustained-release capsule (Diamox®) were assessed. In-vitro dissolution studies revealed that the matrix tablets prepared by the second method containing NaCMC could sustain ACZ release properly and the drug released until 9 h. It was also found that several parameters such as concentration of sodium alginate, calcium chloride and ACZ; type and concentration of polymers; syringe needle size as well as distance between needle tip and surface of the calcium chloride could affect the properties of beads, matrix tablets and subsequently release profile. Preparation of polymer free beads, incorporation of polymers in internal phase of the beads and direct compression of the beads did not give sustained release property. Whereas, incorporation of NaCMC in the external phase of the beads in matrix tablets or in combination with alginate powder in directly compressed conventional tablets could produce dosage form with sustained release property similar to reference formulation. PMID:23447074

  3. [Quantitative evaluation of response at acetazolamide test using 99mTc-ECD SPECT; a trial of production of the response map].

    PubMed

    Oyama, T; Sutoh, H; Kawamura, H; Teraoka, S; Midorikawa, H

    1997-06-01

    In the method by Matsuda and Takeuchi et al. for easy regional cerebral blood flow (rCBF) measurements at pre- and post-acetazolamide tests using 99mTc-ECD, a study was done for producing the increase rate of rCBF as a response map after acetazolamide administration. To prepare the response map calculated from the arithmetic operation of [(rCBF image at administration--rCBF image at rest)/rCBF image at rest x 100], the images were preprocessed by combination of matrix size conversion and smoothing techniques and then areas outside the brain were masked to remove amplified noises. The response map seemed helpful for visual evaluation of the response after acetazolamide administration, and also for understanding the disease conditions and clinical courses.

  4. Aquaporin-1 Translocation and Degradation Mediates the Water Transportation Mechanism of Acetazolamide

    PubMed Central

    Gao, Junwei; Han, Jing; Pan, Xueyang; Pan, Yan; Tie, Lu; Li, Xuejun

    2012-01-01

    Background Diuretic agents are widely used on the treatment of water retention related diseases, among which acetazolamide (AZA) acts originally as a carbonic anhydrase (CA) inhibitor. Aquaporin-1 (AQP1) being located in renal proximal tubules is required for urine concentration. Previously our lab has reported AZA putatively modulated AQP1. Aim of this study is to testify our hypothesis that regulating AQP1 may mediate diuretic effect of AZA. Methodology/Principal Findings For in vivo study, we utilized Sprague Dawley rats, as well as AQP1 knock-out (AQP1−/−) mice to examine urine volume, and human kidney-2 (HK-2) cell line was used for in vitro mechanism study. In our present study we found that AZA decreased CAs activity initially but the activity gradually recovered. Contrarily, diuretic effect was consistently significant. AQP1 protein expression was significantly decreased on day 7 and 14. By utilizing AQP1−/− mice, we found diuretic effect of AZA was cancelled on day 14, while urine volume continuously increased in wild-type mice. Surface plasmon resonance (SPR) results indicated AQP1 was physiologically bound by myosin heavy chain (MHC), immunoprecipitation and immunofluorescence results confirmed this protein interaction. In vitro study results proved AZA facilitated AQP1 translocation onto cell membrane by promoting interaction with MHC, dependent on ERK/ myosin light chain kinase (MLCK) pathway activation. MHC inhibitor BDM and ERK inhibitor U0126 both abolished above effect of AZA. Eventually AZA induced AQP1 ubiquitination, while proteasome inhibitor MG132 reversed AZA's down-regulating effect upon AQP1. Conclusions/Significance Our results identified AZA exerted diuretic effect through an innovative mechanism by regulating AQP1 and verified its inhibitory mechanism was via promoting MHC-dependent translocation onto cell membrane and then ubiquitin mediated degradation, implicating a novel mechanism and target for diuretic agent discovering

  5. Myopic Changes in a Climber after Taking Acetazolamide and the Use of Corrective Lenses to Temporize Symptoms: A Case Report from Mount Kilimanjaro.

    PubMed

    Hill, Adam D

    2016-09-01

    When performing detailed tasks related to climbing or hiking, accurate vision is important for safety. Acetazolamide is a medication commonly used to prevent acute mountain sickness, but it has an uncommon side effect of transient myopia. Reports of this side effect are mainly associated with its use in obstetrics, where it is often prescribed in higher doses than used in acute mountain sickness prophylaxis. We describe the case of a climber taking low-dose acetazolamide who developed transient myopia. We further describe potential mechanisms of this rare side effect as well as a novel approach of field management utilizing possible materials at hand. PMID:27397528

  6. Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets.

    PubMed

    Supuran, Claudiu T

    2016-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO₂ hydration, with kcat values in the range of (3.4-8.3) × 10⁵ s(-1) and kcat/KM values of (4.7-8.5) × 10⁷ M(-1)·s(-1). In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide (KIs in the range of 40.3-90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide, and dichlorophenamide (KIs in the range of 25.2-88.5 nM). Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets. PMID:27322334

  7. Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets

    PubMed Central

    Supuran, Claudiu T.

    2016-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO2 hydration, with kcat values in the range of (3.4–8.3) × 105 s−1 and kcat/KM values of (4.7–8.5) × 107 M−1·s−1. In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide (KIs in the range of 40.3–90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide, and dichlorophenamide (KIs in the range of 25.2–88.5 nM). Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets. PMID:27322334

  8. Effects of cryoprotectants on the structure and thermostability of the human carbonic anhydrase II–acetazolamide complex

    SciTech Connect

    Aggarwal, Mayank; Boone, Christopher D.; Kondeti, Bhargav; Tu, Chingkuang; Silverman, David N.; McKenna, Robert

    2013-05-01

    Here, a case study of the effects of cryoprotectants on the kinetics of carbonic anhydrase II (CA II) and its inhibition by the clinically used inhibitor acetazolamide (AZM) is presented. Protein X-ray crystallography has seen a progressive shift from data collection at cool/room temperature (277–298 K) to data collection at cryotemperature (100 K) because of its ease of crystal preparation and the lessening of the detrimental effects of radiation-induced crystal damage, with 20–25%(v/v) glycerol (GOL) being the preferred choice of cryoprotectant. Here, a case study of the effects of cryoprotectants on the kinetics of carbonic anhydrase II (CA II) and its inhibition by the clinically used inhibitor acetazolamide (AZM) is presented. Comparative studies of crystal structure, kinetics, inhibition and thermostability were performed on CA II and its complex with AZM in the presence of either GOL or sucrose. These results suggest that even though the cryoprotectant GOL was previously shown to be directly bound in the active site and to interact with AZM, it affects neither the thermostability of CA II nor the binding of AZM in the crystal structure or in solution. However, addition of GOL does affect the kinetics of CA II, presumably as it displaces the water proton-transfer network in the active site.

  9. Washout rate in rat brain irradiated by a 11C beam after acetazolamide loading using a small single-ring OpenPET prototype

    NASA Astrophysics Data System (ADS)

    Hirano, Yoshiyuki; Takuwa, Hiroyuki; Yoshida, Eiji; Nishikido, Fumihiko; Nakajima, Yasunori; Wakizaka, Hidekatsu; Yamaya, Taiga

    2016-03-01

    In dose verification techniques of particle therapies based on in-beam positron emission tomography (PET), the causes of washout of positron emitters by physiological effects should be clarified to correct washout for accurate verification. As well, the quantitative washout rate has a potential usefulness as a diagnostic index which should be explored. Therefore, we measured washout rates of rat brain after vasodilator acetazolamide loading to investigate the possible effects of blood flow on washout. Six rat brains were irradiated by a radioisotope 11C beam and time activity curves on the whole brains were obtained with a small single-ring OpenPET prototype. Then, washout rates were calculated with the Mizuno model, where two washout rates (k 2m and k 2s ) were assumed, and a two-compartment model including efflux from tissue to blood (k 2) and influx (k 3) and efflux (k 4) between the two tissue compartments. Before the irradiations, we used laser-Doppler flowmetry to confirm that acetazolamide increased cerebral blood flow (CBF) of a rat. We compared means of k 2m , k 2s and k 2, k 3 and k 4 without acetazolamide loading (Rest) and with acetazolamide loading (ACZ). For all k values, ACZ values were lower than Rest values. In other words, though CBF increased, washout rates were decreased. This may be attributed to the implanted 11C reacting to form 11CO2. Because acetazolamide increased the concentration of CO2 in brain, suppressed diffusion of 11CO2 and decomposition of 11CO2 into ions were prevented.

  10. Sildenafil, nifedipine and acetazolamide do not allow for blood flow through intrapulmonary arteriovenous anastomoses during exercise while breathing 100% oxygen.

    PubMed

    Elliott, Jonathan E; Friedman, Jonathan M; Futral, Joel E; Goodman, Randall D; Lovering, Andrew T

    2014-12-01

    Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) is known to increase in healthy humans during exercise while breathing room air, but is prevented or significantly reduced during exercise while breathing 100% O2, potentially due to vasoconstriction of IPAVAs. Thus, pharmacological interventions that target known pathways regulating the cardiopulmonary circulation may be able to prevent the hyperoxia-induced reduction in IPAVA blood flow (Q̇ IPAVA ) during exercise. In nine healthy human subjects, we investigated the effects of sildenafil (100 mg p.o.), nifedipine (20 mg p.o.) and acetazolamide (250 mg p.o. three times a day for 3 days) on Q̇ IPAVA at rest and during cycle ergometer exercise at 50, 100, 150, 200 and 250 W, while breathing room air (normoxia) and 100% O2 (hyperoxia). Transthoracic saline contrast echocardiography and a 0-5 bubble scoring system were used to detect and assess Q̇ IPAVA qualitatively; ultrasound was used to assess the blood flow velocity oftricuspid regurgitation and the left ventricular outflow tract blood flow to calculate pulmonary artery systolic pressure (PASP) and cardiac output, respectively. Without drugs, bubble scores increased significantly to ≥2 at 150 W in normoxia and to ≤2 at 200 W in hyperoxia. Only nifedipine consistently increased cardiac output at rest and during low-intensity exercise in normoxia and hyperoxia. However, there was no detectable effect of any drug on Q̇ IPAVA ; specifically, bubble scores were the same during exercise in either normoxia or hyperoxia. Accordingly, the reduction in Q̇ IPAVA during exercise while breathing 100% O2 is likely not to be due to the independent pharmacological mechanisms of action associated with sildenafil, nifedipine or acetazolamide.

  11. Neuronal activation induced BOLD and CBF responses upon acetazolamide administration in patients with steno-occlusive artery disease.

    PubMed

    Siero, Jeroen C W; Hartkamp, Nolan S; Donahue, Manus J; Harteveld, Anita A; Compter, Annette; Petersen, Esben T; Hendrikse, Jeroen

    2015-01-15

    Blood-oxygenation-level-dependent (BOLD) MRI is widely used for inferring neuronal activation and is becoming increasingly popular for assessing cerebrovascular reactivity (CVR) when combined with a vasoactive stimulus. The BOLD signal contains changes in cerebral blood flow (CBF) and thus information regarding neurovascular coupling and CVR. The BOLD signal, however, is also modulated by changes in cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2), as well as changes in the physiological baseline state. Here, we measured BOLD and CBF responses upon neuronal (visual) activation, before and after a vasodilatory challenge (acetazolamide, ACZ) in patients with vertebrobasilar steno-occlusive disease. After ACZ, the neuronal activation induced BOLD response was reduced or even negative (3 out of 8 subjects), whereas the CBF response remained similar. We show that BOLD alone cannot correctly assess the neuronal activation and underlying neurovascular coupling. The generally assumed positive relationship between BOLD and CBF responses may be severely compromised under changes in the physiological baseline state. Accompanying CBF measurements contain crucial information, and simulations suggest an altered flow-metabolism coupling in these patients.

  12. Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines

    PubMed Central

    2013-01-01

    Background Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14-25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids. Methods In vitro studies were used for the dose–response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase). Results Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0–80 μM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content. Conclusions The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids. PMID:23927827

  13. Structural Studies of β-Carbonic Anhydrase from the Green Alga Coccomyxa: Inhibitor Complexes with Anions and Acetazolamide

    PubMed Central

    Huang, Shenghua; Hainzl, Tobias; Grundström, Christin; Forsman, Cecilia; Samuelsson, Göran; Sauer-Eriksson, A. Elisabeth

    2011-01-01

    The β-class carbonic anhydrases (β-CAs) are widely distributed among lower eukaryotes, prokaryotes, archaea, and plants. Like all CAs, the β-enzymes catalyze an important physiological reaction, namely the interconversion between carbon dioxide and bicarbonate. In plants the enzyme plays an important role in carbon fixation and metabolism. To further explore the structure-function relationship of β-CA, we have determined the crystal structures of the photoautotroph unicellular green alga Coccomyxa β-CA in complex with five different inhibitors: acetazolamide, thiocyanate, azide, iodide, and phosphate ions. The tetrameric Coccomyxa β-CA structure is similar to other β-CAs but it has a 15 amino acid extension in the C-terminal end, which stabilizes the tetramer by strengthening the interface. Four of the five inhibitors bind in a manner similar to what is found in complexes with α-type CAs. Iodide ions, however, make contact to the zinc ion via a zinc-bound water molecule or hydroxide ion — a type of binding mode not previously observed in any CA. Binding of inhibitors to Coccomyxa β-CA is mediated by side-chain movements of the conserved residue Tyr-88, extending the width of the active site cavity with 1.5-1.8 Å. Structural analysis and comparisons with other α- and β-class members suggest a catalytic mechanism in which the movements of Tyr-88 are important for the CO2-HCO3- interconversion, whereas a structurally conserved water molecule that bridges residues Tyr-88 and Gln-38, seems important for proton transfer, linking water molecules from the zinc-bound water to His-92 and buffer molecules. PMID:22162771

  14. A validated stability-indicating LC method for acetazolamide in the presence of degradation products and its process-related impurities.

    PubMed

    Srinivasu, Prabha; Subbarao, Devarakonda V; Vegesna, Raju V K; Sudhakar Babu, K

    2010-05-01

    The objective of the current study was to develop a validated, specific and stability-indicating reverse phase liquid chromatographic method for the quantitative determination of acetazolamide and its related substances. The determination was done for an active pharmaceutical ingredient, its pharmaceutical dosage form in the presence of degradation products, and its process-related impurities. The drug was subjected to stress conditions of hydrolysis (acid and base), oxidation, photolysis and thermal degradation as per International Conference on Harmonization (ICH) prescribed stress conditions to show the stability-indicating power of the method. Significant degradation was observed during acid and base hydrolysis, and the major degradant was identified by LC-MS, FTIR and (1)H/(13)C NMR spectral analysis. The chromatographic conditions were optimized using an impurity-spiked solution and the generated samples were used for forced degradation studies. In the developed HPLC method, the resolution between acetazolamide and, its process-related impurities (namely imp-1, imp-2, imp-3, imp-4 and its degradation products) was found to be greater than 2. The chromatographic separation was achieved on a C18, 250mmx4.6mm, 5microm column. The LC method employed a linear gradient elution, and the detection wavelength was set at 254nm. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.6%. The developed RP-LC method was validated with respect to linearity, accuracy, precision and robustness.

  15. Analytical development of a binuclear oxo-manganese complex bio-inspired on oxidase enzyme for doping control analysis of acetazolamide.

    PubMed

    Machini, Wesley B S; Teixeira, Marcos F S

    2016-05-15

    A bio-inspired electrochemical sensor using a binuclear oxo-manganese complex was evaluated and applied in the detection of a substance associated with doping in sports: acetazolamide (ACTZ). Investigation was made of the influence of different experimental variables on the electrocatalytic oxidation of ACTZ by the bio-inspired sensor, such as pH and interfering species. The bio-inspired sensor showed the best response in the range from 5.00×10(-9) to 7.00×10(-8) mol L(-1) ACTZ, with a linear range from 5.00×10(-9) to 2.50×10(-8) mol L(-1) and a detection limit of 4.76×10(-9) mol L(-1). The sensor exhibited characteristics similar to the Michaelis-Menten model of an enzymatic electrode, due to the use of a multinucleated complex of manganese with μ-oxo units, which was able to mimic the properties of enzymes with manganese as a cofactor in their composition, such as Mn-containing oxidase. The determination of ACTZ with the bio-inspired sensor was evaluated using three different synthetic biological fluids (plasma, saliva, and urine), demonstrating its viability for use with real samples. The analysis of ACTZ in real urine samples using the bio-inspired sensor, simulating the method adopted by the World Anti-Doping Agency, which revealed viable, suggesting a new and promising platform to be used in these analysis.

  16. S···O chalcogen bonding in sulfa drugs: insights from multipole charge density and X-ray wavefunction of acetazolamide.

    PubMed

    Thomas, Sajesh P; Jayatilaka, Dylan; Guru Row, T N

    2015-10-14

    Experimental charge density analysis combined with the quantum crystallographic technique of X-ray wavefunction refinement (XWR) provides quantitative insights into the intra- and intermolecular interactions formed by acetazolamide, a diuretic drug. Firstly, the analysis of charge density topology at the intermolecular level shows the presence of exceptionally strong interaction motifs such as a DDAA-AADD (D-donor, A-acceptor) type quadruple hydrogen bond motif and a sulfonamide dimer synthon. The nature and strength of intra-molecular S···O chalcogen bonding have been characterized using descriptors from the multipole model (MM) and XWR. Although pure geometrical criteria suggest the possibility of two intra-molecular S···O chalcogen bonded ring motifs, only one of them satisfies the "orbital geometry" so as to exhibit an interaction in terms of an electron density bond path and a bond critical point. The presence of 'σ-holes' on the sulfur atom leading to the S···O chalcogen bond has been visualized on the electrostatic potential surface and Laplacian isosurfaces close to the 'reactive surface'. The electron localizability indicator (ELI) and Roby bond orders derived from the 'experimental wave function' provide insights into the nature of S···O chalcogen bonding.

  17. Does Preoperative Measurement of Cerebral Blood Flow with Acetazolamide Challenge in Addition to Preoperative Measurement of Cerebral Blood Flow at the Resting State Increase the Predictive Accuracy of Development of Cerebral Hyperperfusion after Carotid Endarterectomy? Results from 500 Cases with Brain Perfusion Single-photon Emission Computed Tomography Study

    PubMed Central

    OSHIDA, Sotaro; OGASAWARA, Kuniaki; SAURA, Hiroaki; YOSHIDA, Koji; FUJIWARA, Shunro; KOJIMA, Daigo; KOBAYASHI, Masakazu; YOSHIDA, Kenji; KUBO, Yoshitaka; OGAWA, Akira

    2015-01-01

    The purpose of the present study was to determine whether preoperative measurement of cerebral blood flow (CBF) with acetazolamide in addition to preoperative measurement of CBF at the resting state increases the predictive accuracy of development of cerebral hyperperfusion after carotid endarterectomy (CEA). CBF at the resting state and cerebrovascular reactivity (CVR) to acetazolamide were quantitatively assessed using N-isopropyl-p-[123I]-iodoamphetamine (IMP)-autoradiography method with single-photon emission computed tomography (SPECT) before CEA in 500 patients with ipsilateral internal carotid artery stenosis (≥ 70%). CBF measurement using 123I-IMP SPECT was also performed immediately and 3 days after CEA. A region of interest (ROI) was automatically placed in the middle cerebral artery territory in the affected cerebral hemisphere using a three-dimensional stereotactic ROI template. Preoperative decreases in CBF at the resting state [95% confidence intervals (CIs), 0.855 to 0.967; P = 0.0023] and preoperative decreases in CVR to acetazolamide (95% CIs, 0.844 to 0.912; P < 0.0001) were significant independent predictors of post-CEA hyperperfusion. The area under the receiver operating characteristic curve for prediction of the development of post-CEA hyperperfusion was significantly greater for CVR to acetazolamide than for CBF at the resting state (difference between areas, 0.173; P < 0.0001). Sensitivity, specificity, and positive- and negative-predictive values for the prediction of the development of post-CEA hyperperfusion were significantly greater for CVR to acetazolamide than for CBF at the resting state (P < 0.05, respectively). The present study demonstrated that preoperative measurement of CBF with acetazolamide in addition to preoperative measurement of CBF at the resting state increases the predictive accuracy of the development of post-CEA hyperperfusion. PMID:25746308

  18. Emerging role of calcium-activated potassium channel in the regulation of cell viability following potassium ions challenge in HEK293 cells and pharmacological modulation.

    PubMed

    Tricarico, Domenico; Mele, Antonietta; Calzolaro, Sara; Cannone, Gianluigi; Camerino, Giulia Maria; Dinardo, Maria Maddalena; Latorre, Ramon; Conte Camerino, Diana

    2013-01-01

    Emerging evidences suggest that Ca(2+)activated-K(+)-(BK) channel is involved in the regulation of cell viability. The changes of the cell viability observed under hyperkalemia (15 mEq/L) or hypokalemia (0.55 mEq/L) conditions were investigated in HEK293 cells expressing the hslo subunit (hslo-HEK293) in the presence or absence of BK channel modulators. The BK channel openers(10(-11)-10(-3)M) were: acetazolamide(ACTZ), Dichlorphenamide(DCP), methazolamide(MTZ), bendroflumethiazide(BFT), ethoxzolamide(ETX), hydrochlorthiazide(HCT), quercetin(QUERC), resveratrol(RESV) and NS1619; and the BK channel blockers(2 x 10(-7)M-5 x 10(-3)M) were: tetraethylammonium(TEA), iberiotoxin(IbTx) and charybdotoxin(ChTX). Experiments on cell viability and channel currents were performed using cell counting kit-8 and patch-clamp techniques, respectively. Hslo whole-cell current was potentiated by BK channel openers with different potency and efficacy in hslo-HEK293. The efficacy ranking of the openers at -60 mV(Vm) was BFT> ACTZ >DCP ≥RESV≥ ETX> NS1619> MTZ≥ QUERC; HCT was not effective. Cell viability after 24 h of incubation under hyperkalemia was enhanced by 82+6% and 33+7% in hslo-HEK293 cells and HEK293 cells, respectively. IbTx, ChTX and TEA enhanced cell viability in hslo-HEK293. BK openers prevented the enhancement of the cell viability induced by hyperkalemia or IbTx in hslo-HEK293 showing an efficacy which was comparable with that observed as BK openers. BK channel modulators failed to affect cell currents and viability under hyperkalemia conditions in the absence of hslo subunit. In contrast, under hypokalemia cell viability was reduced by -22+4% and -23+6% in hslo-HEK293 and HEK293 cells, respectively; the BK channel modulators failed to affect this parameter in these cells. In conclusion, BK channel regulates cell viability under hyperkalemia but not hypokalemia conditions. BFT and ACTZ were the most potent drugs either in activating the BK current and in preventing

  19. Development of a mechanism and an accurate and simple mathematical model for the description of drug release: Application to a relevant example of acetazolamide-controlled release from a bio-inspired elastin-based hydrogel.

    PubMed

    Fernández-Colino, A; Bermudez, J M; Arias, F J; Quinteros, D; Gonzo, E

    2016-04-01

    Transversality between mathematical modeling, pharmacology, and materials science is essential in order to achieve controlled-release systems with advanced properties. In this regard, the area of biomaterials provides a platform for the development of depots that are able to achieve controlled release of a drug, whereas pharmacology strives to find new therapeutic molecules and mathematical models have a connecting function, providing a rational understanding by modeling the parameters that influence the release observed. Herein we present a mechanism which, based on reasonable assumptions, explains the experimental data obtained very well. In addition, we have developed a simple and accurate “lumped” kinetics model to correctly fit the experimentally observed drug-release behavior. This lumped model allows us to have simple analytic solutions for the mass and rate of drug release as a function of time without limitations of time or mass of drug released, which represents an important step-forward in the area of in vitro drug delivery when compared to the current state of the art in mathematical modeling. As an example, we applied the mechanism and model to the release data for acetazolamide from a recombinant polymer. Both materials were selected because of a need to develop a suitable ophthalmic formulation for the treatment of glaucoma. The in vitro release model proposed herein provides a valuable predictive tool for ensuring product performance and batch-to-batch reproducibility, thus paving the way for the development of further pharmaceutical devices.

  20. Development of a mechanism and an accurate and simple mathematical model for the description of drug release: Application to a relevant example of acetazolamide-controlled release from a bio-inspired elastin-based hydrogel.

    PubMed

    Fernández-Colino, A; Bermudez, J M; Arias, F J; Quinteros, D; Gonzo, E

    2016-04-01

    Transversality between mathematical modeling, pharmacology, and materials science is essential in order to achieve controlled-release systems with advanced properties. In this regard, the area of biomaterials provides a platform for the development of depots that are able to achieve controlled release of a drug, whereas pharmacology strives to find new therapeutic molecules and mathematical models have a connecting function, providing a rational understanding by modeling the parameters that influence the release observed. Herein we present a mechanism which, based on reasonable assumptions, explains the experimental data obtained very well. In addition, we have developed a simple and accurate “lumped” kinetics model to correctly fit the experimentally observed drug-release behavior. This lumped model allows us to have simple analytic solutions for the mass and rate of drug release as a function of time without limitations of time or mass of drug released, which represents an important step-forward in the area of in vitro drug delivery when compared to the current state of the art in mathematical modeling. As an example, we applied the mechanism and model to the release data for acetazolamide from a recombinant polymer. Both materials were selected because of a need to develop a suitable ophthalmic formulation for the treatment of glaucoma. The in vitro release model proposed herein provides a valuable predictive tool for ensuring product performance and batch-to-batch reproducibility, thus paving the way for the development of further pharmaceutical devices. PMID:26838852

  1. Label-free determination of protein-ligand binding constants using mass spectrometry and validation using surface plasmon resonance and isothermal titration calorimetry.

    PubMed

    Jecklin, Matthias C; Schauer, Stefan; Dumelin, Christoph E; Zenobi, Renato

    2009-01-01

    We performed a systematic comparison of three label-free methods for quantitative assessment of binding strengths of proteins interacting with small molecule ligands. The performance of (1) nanoelectrospray ionization mass spectrometry (nESI-MS), (2) surface plasmon resonance (SPR), and (3) isothermal titration calorimetry (ITC) was compared for the determination of dissociation constants (K(D)). The model system studied for this purpose was the human carbonic anhydrase I (hCAI) with eight known and well characterized sulfonamide inhibitors (Krishnamurthy et al., Chem. Rev. 2008, 108: 946-1051). The binding affinities of the inhibitors chosen vary by more than four orders of magnitude e.g., the K(D) value determined for ethoxzolamide by nESI-MS was 5 +/- 1 nM and the K(D) value for sulfanilamide was 145.7 +/- 10.0 microM. The agreement of the determined K(D) values by the three methods investigated was excellent for ethoxzolamide and benzenesulfonamide (variation with experimental error), good for acetazolamide and 4-carboxybenzenesulfonamide (variation by approximately one order of magnitude), but poor for others e.g., sulpiride. The accuracies of the K(D) values are determined, and advantages and drawbacks of the individual methods are discussed. Moreover, we critically evaluate the three examined methods in terms of ease of the measurement, sample consumption, time requirement, and discuss their limitations. PMID:19373858

  2. The effect of carbonic anhydrase inhibitors on secretion by the parotid and mandibular glands of red kangaroos Macropus rufus.

    PubMed

    Beal, A M

    1991-01-01

    The effects of carbonic anhydrase inhibitors on secretion by macropodine parotid and mandibular glands were investigated using anaesthetized red kangaroos. In the parotid gland, acetazolamide (500 mumol.l-1) reduced a stable acetylcholine-evoked, half-maximal flow rate of 2.02 +/- 0.034 to 0.27 +/- 0.023 ml.min-1 (87% reduction). Concurrently, salivary bicarbonate concentration and secretion fell (129.4 +/- 1.46 to 80.9 +/- 1.63 mmol.l-1 and 264.8 +/- 7.96 to 22.3 +/- 2.30 mumol.min-1, respectively), phosphate and chloride concentrations rose (14.0 +/- 0.79 to 27.6 +/- 0.85 mmol.l-1 and 5.6 +/- 0.25 to 27.5 +/- 1.32 mmol.l-1, respectively), sodium concentration and osmolality were unaltered, and potassium concentration fell (8.8 +/- 0.33 to 6.4 +/- 0.29 mmol.l-1). High-rate cholinergic stimulation during acetazolamide blockade was unable to increase salivary flow beyond 11 +/- 0.9% of that for equivalent unblocked control stimulation. However, superimposition of isoprenaline infusion on the acetylcholine stimulation caused a three-fold increase in the blocked flow rate. These treatments were accompanied by small increases in salivary phosphate and chloride concentrations but not bicarbonate concentration. Methazolamide infusion caused similar changes in parotid secretion. In the mandibular gland, acetazolamide infusion had no effect on salivary flow rate during either low- or high-level acetylcholine stimulation. Acetazolamide caused no alterations in salivary electrolyte secretion at low flow rates, but curtailed the rise in bicarbonate concentration associated with high-level acetylcholine stimulation. Acetazolamide administration did not affect the increase in salivary flow rate associated with isoprenaline infusion, but did block the concomitant increase in bicarbonate concentration and secretion substantially.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Acetazolamide Mitigates Astrocyte Cellular Edema Following Mild Traumatic Brain Injury

    NASA Astrophysics Data System (ADS)

    Sturdivant, Nasya M.; Smith, Sean G.; Ali, Syed F.; Wolchok, Jeffrey C.; Balachandran, Kartik

    2016-09-01

    Non-penetrating or mild traumatic brain injury (mTBI) is commonly experienced in accidents, the battlefield and in full-contact sports. Astrocyte cellular edema is one of the major factors that leads to high morbidity post-mTBI. Various studies have reported an upregulation of aquaporin-4 (AQP4), a water channel protein, following brain injury. AZA is an antiepileptic drug that has been shown to inhibit AQP4 expression and in this study we investigate the drug as a therapeutic to mitigate the extent of mTBI induced cellular edema. We hypothesized that mTBI-mediated astrocyte dysfunction, initiated by increased intracellular volume, could be reduced when treated with AZA. We tested our hypothesis in a three-dimensional in vitro astrocyte model of mTBI. Samples were subject to no stretch (control) or one high-speed stretch (mTBI) injury. AQP4 expression was significantly increased 24 hours after mTBI. mTBI resulted in a significant increase in the cell swelling within 30 min of mTBI, which was significantly reduced in the presence of AZA. Cell death and expression of S100B was significantly reduced when AZA was added shortly before mTBI stretch. Overall, our data point to occurrence of astrocyte swelling immediately following mTBI, and AZA as a promising treatment to mitigate downstream cellular mortality.

  4. Acetazolamide Mitigates Astrocyte Cellular Edema Following Mild Traumatic Brain Injury

    PubMed Central

    Sturdivant, Nasya M.; Smith, Sean G.; Ali, Syed F.; Wolchok, Jeffrey C.; Balachandran, Kartik

    2016-01-01

    Non-penetrating or mild traumatic brain injury (mTBI) is commonly experienced in accidents, the battlefield and in full-contact sports. Astrocyte cellular edema is one of the major factors that leads to high morbidity post-mTBI. Various studies have reported an upregulation of aquaporin-4 (AQP4), a water channel protein, following brain injury. AZA is an antiepileptic drug that has been shown to inhibit AQP4 expression and in this study we investigate the drug as a therapeutic to mitigate the extent of mTBI induced cellular edema. We hypothesized that mTBI-mediated astrocyte dysfunction, initiated by increased intracellular volume, could be reduced when treated with AZA. We tested our hypothesis in a three-dimensional in vitro astrocyte model of mTBI. Samples were subject to no stretch (control) or one high-speed stretch (mTBI) injury. AQP4 expression was significantly increased 24 hours after mTBI. mTBI resulted in a significant increase in the cell swelling within 30 min of mTBI, which was significantly reduced in the presence of AZA. Cell death and expression of S100B was significantly reduced when AZA was added shortly before mTBI stretch. Overall, our data point to occurrence of astrocyte swelling immediately following mTBI, and AZA as a promising treatment to mitigate downstream cellular mortality. PMID:27623738

  5. Acetazolamide Mitigates Astrocyte Cellular Edema Following Mild Traumatic Brain Injury.

    PubMed

    Sturdivant, Nasya M; Smith, Sean G; Ali, Syed F; Wolchok, Jeffrey C; Balachandran, Kartik

    2016-01-01

    Non-penetrating or mild traumatic brain injury (mTBI) is commonly experienced in accidents, the battlefield and in full-contact sports. Astrocyte cellular edema is one of the major factors that leads to high morbidity post-mTBI. Various studies have reported an upregulation of aquaporin-4 (AQP4), a water channel protein, following brain injury. AZA is an antiepileptic drug that has been shown to inhibit AQP4 expression and in this study we investigate the drug as a therapeutic to mitigate the extent of mTBI induced cellular edema. We hypothesized that mTBI-mediated astrocyte dysfunction, initiated by increased intracellular volume, could be reduced when treated with AZA. We tested our hypothesis in a three-dimensional in vitro astrocyte model of mTBI. Samples were subject to no stretch (control) or one high-speed stretch (mTBI) injury. AQP4 expression was significantly increased 24 hours after mTBI. mTBI resulted in a significant increase in the cell swelling within 30 min of mTBI, which was significantly reduced in the presence of AZA. Cell death and expression of S100B was significantly reduced when AZA was added shortly before mTBI stretch. Overall, our data point to occurrence of astrocyte swelling immediately following mTBI, and AZA as a promising treatment to mitigate downstream cellular mortality. PMID:27623738

  6. 21 CFR 522.44 - Sterile sodium acetazolamide.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....44 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED.... (c) Conditions of use. (1) It is used as an aid in the treatment of dogs with mild congestive heart... intramuscularly or intraperitoneally to dogs at a level of 5 to 15 milligrams per pound of body weight...

  7. 21 CFR 522.44 - Sterile sodium acetazolamide.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....44 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED.... (c) Conditions of use. (1) It is used as an aid in the treatment of dogs with mild congestive heart... intramuscularly or intraperitoneally to dogs at a level of 5 to 15 milligrams per pound of body weight...

  8. Sulfonamide inhibition study of the β-class carbonic anhydrase from the caries producing pathogen Streptococcus mutans.

    PubMed

    Dedeoglu, Nurcan; DeLuca, Viviana; Isik, Semra; Yildirim, Hatice; Kockar, Feray; Capasso, Clemente; Supuran, Claudiu T

    2015-06-01

    Streptococcus mutans, the oral pathogenic bacterium provoking dental caries formation, encodes for a β-class carbonic anhydrase (CA, EC 4.2.1.1), SmuCA. This enzyme was cloned, characterized and investigated for its inhibition profile with the major class of CA inhibitors, the primary sulfonamides. SmuCA has a good catalytic activity for the CO2 hydration reaction, with a kcat of 4.2×10(5) s(-1) and kcat/Km of 5.8×10(7) M(-1)×s(-1), and is efficiently inhibited by most sulfonamides (KIs of 246 nM-13.5 μM). The best SmuCA inhibitors were bromosulfanilamide, deacetylated acetazolamide, 4-hydroxymethylbenzenesulfonamide, a pyrimidine-substituted sulfanilamide derivative, aminobenzolamide and compounds structurally similar to it, as well as acetazolamide, methazolamide, indisulam and valdecoxib. These compounds showed inhibition constants ranging between 246 and 468 nM. Identification of effective inhibitors of this enzyme may lead to pharmacological tools useful for understanding the role of S. mutans CAs in dental caries formation, and eventually the development of pharmacological agents with a new mechanism of antibacterial action. PMID:25913199

  9. Sulfonamide inhibition study of the carbonic anhydrases from the bacterial pathogen Porphyromonas gingivalis: the β-class (PgiCAb) versus the γ-class (PgiCA) enzymes.

    PubMed

    Prete, Sonia Del; Vullo, Daniela; Osman, Sameh M; Scozzafava, Andrea; AlOthman, Zeid; Capasso, Clemente; Supuran, Claudiu T

    2014-09-01

    The oral pathogenic bacterium Porphyromonas gingivalis, encodes for two carbonic anhydrases (CAs, EC 4.2.1.1) one belonging to the γ-class (PgiCA) and another one to the β-class (PgiCAb). This last enzyme has been cloned and characterized here for its inhibition profile with the main class of CA inhibitors, the sulfonamides. Many of the clinically used sulfonamides as well as simple aromatic/heterocyclic sulfonamides were ineffective as PgiCAb inhibitors whereas better inhibition was observed with simple derivatives such as sulfanilamide, metanilamide, 4-aminoalkylbenzenesulfonamides (KIs of 364-475nM). The halogenosulfanilamides incorporating heavy halogens, 4-hydroxy- and 4-hydroxyalkyl-benzenesulfonamides, were also micromolar, ineffective PgiCAb inhibitors. The best inhibitors of the β-class enzyme were acetazolamide and ethoxzolamide, with KIs of 214-280nM. Interestingly, the γ-class enzyme was much more sensitive to sulfonamide inhibitors compared to the β-class one, PgiCAb. Identification of potent and possibly selective inhibitors of PgiCAb/PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of these enzymes, since this bacterium is the main causative agent of periodontitis and few treatment options are presently available. PMID:25129169

  10. Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c.

    PubMed

    Carta, Fabrizio; Maresca, Alfonso; Covarrubias, Adrian Suarez; Mowbray, Sherry L; Jones, T Alwyn; Supuran, Claudiu T

    2009-12-01

    The Rv3588c gene product of Mycobacterium tuberculosis, a beta-carbonic anhydrase (CA, EC 4.2.1.1) denominated here mtCA 2, shows the highest catalytic activity for CO(2) hydration (k(cat) of 9.8 x 10(5)s(-1), and k(cat)/K(m) of 9.3 x 10(7)M(-1)s(-1)) among the three beta-CAs encoded in the genome of this pathogen. A series of sulfonamides/sulfamates was assayed for their interaction with mtCA 2, and some diazenylbenzenesulfonamides were synthesized from sulfanilamide/metanilamide by diazotization followed by coupling with amines or phenols. Several low nanomolar mtCA 2 inhibitors have been detected among which acetazolamide, ethoxzolamide and some 4-diazenylbenzenesulfonamides (K(I)s of 9-59 nM). As the Rv3588c gene was shown to be essential to the growth of M. tuberculosis, inhibition of this enzyme may be relevant for the design of antituberculosis drugs possessing a novel mechanism of action. PMID:19846301

  11. [Reduction of omalgia in laparoscopic cholecystectomy: clinical randomized trial ketorolac vs ketorolac and acetazolamide].

    PubMed

    Figueroa-Balderas, Lorena; Franco-López, Francisco; Flores-Álvarez, Efrén; López-Rodríguez, Jorge Luis; Vázquez-García, José Antonio; Barba-Valadez, Claudia Teresa

    2013-01-01

    Antecedentes: la colecistectomía laparoscópica es el patrón de referencia del tratamiento de la colelitiasis sintomática. El 63% de los pacientes operados sufre dolor postquirúrgico referido al hombro (omalgia), circunstancia que limita el tratamiento ambulatorio. Objetivo: evaluar la utilidad de la acetazolamida asociada con ketorolaco para disminuir la omalgia consecutiva al tratamiento de mínima invasión. Material y métodos: ensayo clínico, aleatorizado, doble ciego realizado en pacientes a quienes se efectuó colecistectomía laparoscópica para evaluar la reducción de la omalgia postoperatoria y comparar el efecto de ketorolaco y ketorolaco más acetazolamida. En cada grupo se estudiaron 31 pacientes. El grupo de estudio recibió 250 mg de acetazolamida antes de la inducción anestésica, y 30 mg de ketorolaco en el postoperatorio inmediato. El grupo control recibió una tableta de placebo antes de la inducción anestésica, y 30 mg de ketorolaco en el postoperatorio inmediato. La omalgia se evaluó con la escala visual análoga. Las variables estudiadas incluyeron: edad, sexo, flujo de dióxido de carbono, presión intrabdominal, tiempo quirúrgico, cirugía electiva o urgente, omalgia, intensidad del dolor evaluada con la escala visual análoga y analgesia de rescate. Resultados: los grupos estudiados fueron homogéneos, el análisis estadístico no mostró diferencias en las variables estudiadas. En el grupo de estudio la omalgia coexistió en 9.67% de los pacientes y en el grupo control en 58.06% (p < 0.001). Conclusión: la administración por vía oral de 250 mg de acetazolamida y 30 mg de ketorolaco redujo significativamente la omalgia en los pacientes a quienes se realizó colecistectomía laparoscópica.

  12. Cloning, expression, purification and sulfonamide inhibition profile of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum.

    PubMed

    Del Prete, Sonia; Vullo, Daniela; De Luca, Viviana; Carginale, Vincenzo; Osman, Sameh M; AlOthman, Zeid; Supuran, Claudiu T; Capasso, Clemente

    2016-09-01

    We report the cloning, purification and characterization of the full domain of carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, which incorporates 358 amino acid residues (from 181 to 538, in the sequence of this 600 amino acid long protein), called PfCAdom. The enzyme, which belongs to the η-CA class showed the following kinetic parameters: kcat of 3.8×10(5)s(-1) and kcat/Km of 7.2×10(7)M(-1)×s(-1), being 13.3 times more effective as a catalyst compared to the truncated form PfCA. PfCAdom is more effective than the human (h) isoform hCA I, being around 50% less effective compared to hCA II, one of the most catalytically efficient enzymes known so far. Intriguingly, the sulfonamides CA inhibitors generally showed much weaker inhibitory activity against PfCAdom compared to PfCA, prompting us to hypothesize that the 69 amino acid residues insertion present in the active site of this η-CA is crucial for the active site architecture. The best sulfonamide inhibitors for PfCAdom were acetazolamide, methazolamide, metanilamide and sulfanilamide, with KIs in the range of 366-808nM. PMID:27485387

  13. Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Colwellia psychrerythraea.

    PubMed

    Vullo, Daniela; De Luca, Viviana; Del Prete, Sonia; Carginale, Vincenzo; Scozzafava, Andrea; Osman, Sameh M; AlOthman, Zeid; Capasso, Clemente; Supuran, Claudiu T

    2016-02-15

    The Antarctic bacterium Colwellia psychrerythraea encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (CpsCAγ) has a moderate catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) 6.0×10(5) s(-1) and a k(cat)/K(m) of 4.7×10(6) M(-1) s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. The best inhibitor was metanilamide (K(I) of 83.5 nM) followed by indisulam, valdecoxib, celecoxib, sulthiame and hydrochlorothiazide (K(I)s ranging between 343 and 491 nM). Acetazolamide, methazolamide as well as other aromatic/heterocyclic derivatives showed inhibition constants between 502 and 7660 nM. The present study may shed some more light regarding the role that γ-CAs play in the life cycle of psychrophilic bacteria as the Antarctic one investigated here, by allowing the identification of inhibitors which may be useful as pharmacologic tools. PMID:26832216

  14. Glaucoma and the applications of carbonic anhydrase inhibitors.

    PubMed

    Scozzafava, Andrea; Supuran, Claudiu T

    2014-01-01

    Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the treatment of glaucoma, a disease affecting a large number of people and characterized by an elevated intraocular pressure (IOP). At least three isoforms, CA II, IV and XII are targeted by the sulfonamide inhibitors, some of which are clinically used drugs. Acetazolamide, methazolamide and dichlorophenamide are first generation CA inhibitors (CAIs) still used as systemic drugs for the management of this disease. Dorzolamide and brinzolamide represent the second generation inhibitors, being used topically, as eye drops, with less side effects compared to the first generation drugs. Third generation inhibitors have been developed by using the tail approach, but they did not reach the clinics yet. The most promising such derivatives are the sulfonamides incorporating either tails with nitric oxide releasing moieties or hybrid drugs possessing prostaglandin (PG) F agonist moieties in their molecules. Recently, the dithiocarbamates have also been described as CAIs possessing IOP lowering effects in animal models of glaucoma. CAIs are used alone or in combination with other drugs such as adrenergic agonist/antagonists, or PG analogs, being an important component of the antiglaucoma drugs armamentarium. PMID:24146387

  15. Anion and sulfonamide inhibition studies of an α-carbonic anhydrase from the Antarctic hemoglobinless fish Chionodraco hamatus.

    PubMed

    Cincinelli, Alessandra; Martellini, Tania; Vullo, Daniela; Supuran, Claudiu T

    2015-12-01

    An α-carbonic anhydrase (CA, EC 4.2.1.1) has been purified from the Antarctic hemoglobinless fish Chionodraco hamatus (icefish). The new enzyme, denominated ChaCA, has a good catalytic activity for the physiologic CO2 hydration to bicarbonate reaction, similar to that of the low activity human isoform hCA I, with a kcat of 5.3×10(5) s(-1), and a kcat/Km of 3.7×10(7) M(-1) s(-1). The enzyme was inhibited in the submillimolar range by most inorganic anions (cyanate, thiocyanate, cyanide, bicarbonate, halides), whereas sulfamide, sulfamate, phenylboronic/phenylarsonic acids were micromolar inhibitors, with KIs in the range of 9-77 μM. Many clinically used drugs, such as acetazolamide, methazolamide, dorzolamide, brinzolamide, topiramate and benzolamide were low nanomolar inhibitors, with KIs in the range of 39.1-77.6 nM. As the physiology of CO2/bicarbonate transport or the Root effect in this Antarctic fish are poorly understood at this moment, such inhibition data may give a more detailed insight in the role that CAs play in these phenomena, by the use of inhibitors described here as physiologic tools.

  16. Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Colwellia psychrerythraea.

    PubMed

    Vullo, Daniela; De Luca, Viviana; Del Prete, Sonia; Carginale, Vincenzo; Scozzafava, Andrea; Osman, Sameh M; AlOthman, Zeid; Capasso, Clemente; Supuran, Claudiu T

    2016-02-15

    The Antarctic bacterium Colwellia psychrerythraea encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (CpsCAγ) has a moderate catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) 6.0×10(5) s(-1) and a k(cat)/K(m) of 4.7×10(6) M(-1) s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. The best inhibitor was metanilamide (K(I) of 83.5 nM) followed by indisulam, valdecoxib, celecoxib, sulthiame and hydrochlorothiazide (K(I)s ranging between 343 and 491 nM). Acetazolamide, methazolamide as well as other aromatic/heterocyclic derivatives showed inhibition constants between 502 and 7660 nM. The present study may shed some more light regarding the role that γ-CAs play in the life cycle of psychrophilic bacteria as the Antarctic one investigated here, by allowing the identification of inhibitors which may be useful as pharmacologic tools.

  17. Salts of 5-amino-2-sulfonamide-1,3,4-thiadiazole, a structural and analog of acetazolamide, show interesting carbonic anhydrase inhibitory properties, diuretic, and anticonvulsant action.

    PubMed

    Diaz, Jorge R A; Camí, Gerardo Enrique; Liu-González, Malva; Vega, Daniel R; Vullo, Daniela; Juárez, Américo; Pedregosa, José C; Supuran, Claudiu T

    2016-12-01

    Three salts of 5-amino-2-sulfonamide-1,3,4-thiadiazole (Hats) were prepared and characterized by physico-chemical methods. The p-toluensulfonate, the methylsulfonate, and the chlorhydrate monohydrate salts of Hats were evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) and as anticonvulsants and diuretics, since many CAIs are clinically used as pharmacological agents. The three Hats salts exhibited diuretic and anticonvulsant activities with little neurotoxicity. The human (h) isoforms hCA I, II, IV, VII, IX, and XII were inhibited in their micromolar range by these salts, whereas pathogenic beta and gamma CAs showed similar, weak inhibitory profiles.

  18. The effect of acetzolamide on Ion transport across isolated sheep rumen epithelium.

    PubMed

    Emanović, D; Harrison, F A; Keynes, R D; Rankin, J C

    1976-01-01

    1. The net fluxes of sodium and chloride from the lumen to the blood side of isolated sheep rumen epithelium were reduced by treatment of both sides of the epithelium with acetazolamide. 2. The changes in the net fluxes of sodium and chloride were significantly correlated and showed recovery after removal of acetazolamide. 3. The net flux of potassium from blood to lumen side of the epithelim was not affected by treatment with acetazolamide. 4. It is suggested that acetazolamide blocks coupled sodium and chloride transport which may be mediated through 'low-activity' carbonic anhydrase enzymes.

  19. Hypophosphatemia

    MedlinePlus

    The following may cause hypophosphatemia: Alcoholism Antacids Certain medicines, including acetazolamide, foscarnet, imatinib, pentamidine, and sorafenib Fanconi syndrome Starvation Too little vitamin D Overactive parathyroid gland (hyperparathyroidism)

  20. Effect of carbonic anhydrase inhibition on superficial and deep nephron bicarbonate reabsorption in the rat.

    PubMed Central

    DuBose, T D; Lucci, M S

    1983-01-01

    The nephron segment responsible for the acetazolamide-insensitive fraction of renal bicarbonate reabsorption has not been clearly delineated. This study compares superficial and deep nephron bicarbonate reabsorption before and after acetazolamide at two dose levels (20 and 50 mg/kg per h) in mutant Munich-Wistar rats employing both cortical and papillary micropuncture and microcalorimetry. Systemic acid-base balance and right whole kidney glomerular filtration rate were similar in all groups examined. The effects of the two doses of acetazolamide were indistinguishable and resulted in a significant increase in whole kidney bicarbonate excretion that compared favorably with the fraction delivered out of the left papillary tip. Acetazolamide inhibited superficial proximal bicarbonate reabsorption by 80.0%, whereas reabsorption up to the deep loop of Henle was decreased by only 52% (P less than 0.001). Bicarbonate reabsorption that was insensitive to acetazolamide occurred in the superficial and deep loop of Henle and between the distal tubule and base collecting duct. Because water reabsorption in these segments could serve to generate transepithelial bicarbonate concentration gradients favorable for reabsorption, we attempted to minimize water abstraction by combined administration of mannitol and acetazolamide. During this condition a significant increase in bicarbonate delivery up to the deep loop of Henle was noted (52 vs. 65%), whereas superficial nephron reabsorption was not altered. Furthermore, an outwardly directed bicarbonate concentration gradient from the deep loop of Henle to vasa recta was demonstrated during acetazolamide (delta tCO2 = 20.9 +/- 3.3 mM), but was abolished during combined mannitol and acetazolamide administration (delta tCO2 = 3.5 +/- 0.9 mM). It is concluded that carbonic anhydrase inhibition results in a disparate effect on nephron bicarbonate reabsorption when juxtamedullary and superficial nephron segments are compared. Our findings

  1. Pendrin, an anion exchanger on lung epithelial cells, could be a novel target for lipopolysaccharide-induced acute lung injury mice

    PubMed Central

    Jia, Chun-E; Jiang, Dingyuan; Dai, Huaping; Xiao, Fei; Wang, Chen

    2016-01-01

    Objective: The aim of this study is to evaluate the role of pendrin in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and to explore whether pendrin expression existing on alveolar cells. Methods: ALI C57BL/6 mice model induced by lipopolysaccharide (LPS) was established. The expression of pendrin in lung was analyzed by RT-PCR and western blotting methods, the changes of lung inflammatory parameters and pathology were observed, the cellular distribution of pendrin in the lung was determined using immunofluorescence. Statistical comparisons between groups were made by two-tailed Student’s t-test. Results: Enhanced expression of the slc26a4 gene and production of pendrin in lungs of LPS-induced ALI mice were confirmed. In comparison with vehicle-control mice, methazolamide treatment mitigated lung inflammatory parameters and pathology. IL-6 and MCP-1 in lung tissues and BALF in methazolamide-treated mice were statistically decreased. Methazolamide treatment had significant effect on the total protein concentration in the BALF and the ratio of lung wet/dry weight. The percentage of macrophages in the BALF was increased. There was a low expression of pendrin in ATII. Conclusions: Pendrin may be involved in pathological process of LPS-induced ALI. Inhibition of the pendrin function could be used to treat ALI. Airway epithelial cell may be a valuable therapeutic target for discovering and developing new drugs and/or new therapeutic strategies for the treatment of ALI/ARDS. PMID:27158384

  2. A randomised controlled trial of treatment for idiopathic intracranial hypertension.

    PubMed

    Ball, Alexandra K; Howman, Andrew; Wheatley, Keith; Burdon, Michael A; Matthews, Timothy; Jacks, Andrew S; Lawden, Mark; Sivaguru, Arul; Furmston, Alexandra; Howell, Steven; Sharrack, Basil; Davies, M Brendan; Sinclair, Alexandra J; Clarke, Carl E

    2011-05-01

    The cause of idiopathic intracranial hypertension (IIH) remains unknown, and no consensus exists on how patients should be monitored and treated. Acetazolamide is a common treatment but has never been examined in a randomised controlled trial. The objectives of this pilot trial are to prospectively evaluate the use of acetazolamide, to explore various outcome measures and to inform the design of a definitive trial in IIH. Fifty patients were recruited from six centres over 23 months and randomised to receive acetazolamide (n = 25) or no acetazolamide (n = 25). Symptoms, body weight, visual function and health-related quality-of-life measures were recorded over a 12-month period. Recruited patients had typical features of mild IIH and most showed improvement, with 44% judged to have IIH in remission at the end of the trial. Difficulties with recruitment were highlighted as well as poor compliance with acetazolamide therapy (12 patients). A composite measure of IIH status was tested, and the strongest concordance with final disease status was seen with perimetry (Somers' D = 0.66) and optic disc appearance (D = 0.59). Based on the study data, a sample size of 320 would be required to demonstrate a 20% treatment effect in a substantive trial. Clinical trials in IIH require pragmatic design to involve sufficiently large numbers of patients. Future studies should incorporate weighted composite scores to reflect the relative importance of common outcome measures in IIH.

  3. Diuretics and the renal adenylate cyclase system

    PubMed Central

    Dawborn, J.K.; Macneil, S.; Martin, T.J.

    1977-01-01

    1 The relationship between the diuretic effectiveness and the effect on the renal adenylate cyclase of three diuretics, acetazolamide, frusemide and ethacrynic acid, was examined. The hypothesis that acetazolamide and parathyroid hormone (PTH), inhibit renal carbonic anhydrase by a cyclic adenosine 3′,5′-monophosphate (cyclic AMP)-dependent mechanism was also tested. 2 In vitro, acetazolamide, frusemide and ethacrynic acid at high concentrations (10-3M) all produced some inhibition of basal and stimulated rat kidney plasma membrane adenylate cyclase. The effect of acetazolamide was much less than that of frusemide and ethacrynic acid. These plasma membrane effects were reproduced in studies of cyclic AMP formation in isolated kidney tubules of rats. 3 Intravenous injections of acetazolamide did not change the total cyclic AMP content of the kidneys of rats killed by microwave irradiation. 4 Acetazolamide produced a diuresis in the rat and a slight inhibition of the antidiuretic effect of Pitressin. Frusemide produced a diuresis and greatly reduced the antidiuretic response to Pitressin. Ethacrynic acid was ineffective as a diuretic in the rat and actually enhanced the antidiuretic response to Pitressin. 5 In investigating the possible influence of diuretics and PTH on the activity and state of phosphorylation of carbonic anhydrase it was found that: there was no correlation between the ability of diuretics to inhibit carbonic anhydrase activity and to inhibit carbonic anhydrase phosphorylation; neither PTH nor cyclic AMP (in the presence of adenosine triphosphate, Mg2+, K+ and incubation at 37°C) inhibited rat cortex homogenate carbonic anhydrase activity. 6 It seems unlikely that any of the tested diuretics exerts its pharmacological effect by means of changes in kidney cyclic AMP metabolism. PMID:202362

  4. H+ transport from CNS in hypercapnia and regulation of CSF [HCO3-].

    PubMed

    Kazemi, H; Choma, L

    1977-05-01

    CSF HCO3- increases more than plasma HCO3- in hypercapnia, and there are at least two sources for the CSF HCO3- increase--one derived from the simultaneous increase in plasma HCO3-, and the other, HCO3-formed from hydration of CO2 in the choroid plexus and glia and susceptible to inhibition by acetazolamide (J. Appl. Physiol. 38: 504-512, 1975). It was proposed that the H+ formed in the CNS in CO2 hydration is actively exchanged for plasma Na+ utilizing the Na-K ATPase pump. H+ transport from the CNS was therefore studied in four groups of dogs breathing 5% CO2 at constant VA for 4 h with repeated injections of saline, acetazolamide 5 mg/ml, ouabain 0.1 mg/ml, and acetazolamide and ouabain together into lateral cerebral ventricles. Arterial HCO3-increased 2.5 meq/l at 4 h of hypercapnia in all groups. CSF HCO3-increased 5.8 meq/l in the saline-injected animals, but it increased only about 2 meq/l and equaled plasma HCO3- rise in the other three groups. Therefore CNS HCO3- formation in hypercapnia can be blocked by inhibiting the CO2 hydration reaction with acetazolamide or by blocking H+ removal by inhibiting Na-K ATPase with ouabain. The data support the thesis of active H+ removal from the CNS in exchange for plasma Na+ in hypercapnia.

  5. Visual Field Outcomes for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT)

    PubMed Central

    Wall, Michael; Johnson, Chris A.; Cello, Kimberly E.; Zamba, K. D.; McDermott, Michael P.; Keltner, John L.

    2016-01-01

    Purpose The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) showed that acetazolamide provided a modest, significant improvement in mean deviation (MD). Here, we further analyze visual field changes over the 6-month study period. Methods Of 165 subjects with mild visual loss in the IIHTT, 125 had perimetry at baseline and 6 months. We evaluated pointwise linear regression of visual sensitivity versus time to classify test locations in the worst MD (study) eye as improving or not; pointwise changes from baseline to month 6 in decibels; and clinical consensus of change from baseline to 6 months. Results The average study eye had 36 of 52 test locations with improving sensitivity over 6 months using pointwise linear regression, but differences between the acetazolamide and placebo groups were not significant. Pointwise results mostly improved in both treatment groups with the magnitude of the mean change within groups greatest and statistically significant around the blind spot and the nasal area, especially in the acetazolamide group. The consensus classification of visual field change from baseline to 6 months in the study eye yielded percentages (acetazolamide, placebo) of 7.2% and 17.5% worse, 35.1% and 31.7% with no change, and 56.1% and 50.8% improved; group differences were not statistically significant. Conclusions In the IIHTT, compared to the placebo group, the acetazolamide group had a significant pointwise improvement in visual field function, particularly in the nasal and pericecal areas; the latter is likely due to reduction in blind spot size related to improvement in papilledema. (ClinicalTrials.gov number, NCT01003639.) PMID:26934136

  6. Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis.

    PubMed

    Vullo, Daniela; De Luca, Viviana; Del Prete, Sonia; Carginale, Vincenzo; Scozzafava, Andrea; Capasso, Clemente; Supuran, Claudiu T

    2015-09-01

    The Antarctic bacterium Pseudoalteromonas haloplanktis encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (PhaCAγ) has a good catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) of 1.4×10(5) s(-1) and a k(cat)/K(m) of 1.9×10(6) M(-1)×s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. Methazolamide and indisulam showed the best inhibitory properties (K(I)s of 86.7-94.7 nM). This contribution shed new light on γ-CAs inhibition profiles with a relevant class of pharmacologic agents.

  7. Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis.

    PubMed

    Vullo, Daniela; De Luca, Viviana; Del Prete, Sonia; Carginale, Vincenzo; Scozzafava, Andrea; Capasso, Clemente; Supuran, Claudiu T

    2015-09-01

    The Antarctic bacterium Pseudoalteromonas haloplanktis encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (PhaCAγ) has a good catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) of 1.4×10(5) s(-1) and a k(cat)/K(m) of 1.9×10(6) M(-1)×s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. Methazolamide and indisulam showed the best inhibitory properties (K(I)s of 86.7-94.7 nM). This contribution shed new light on γ-CAs inhibition profiles with a relevant class of pharmacologic agents. PMID:26174556

  8. Effects of carbonic anhydrase inhibition on ventilation-perfusion matching in the dog lung.

    PubMed Central

    Swenson, E R; Robertson, H T; Hlastala, M P

    1993-01-01

    Lung carbonic anhydrase (CA) permits rapid pH responses when changes in regional ventilation or perfusion alter airway and alveolar PCO2. These pH changes affect airway and vascular resistances and lung compliance to optimize the balance of regional ventilation (VA) and perfusion (Q) in the lung. To test the hypothesis that these or other CA-dependent mechanisms contribute to VA/Q matching, we administered acetazolamide (25 mg/kg intravenously) to six anesthetized and paralyzed dogs and measured VA/Q relationships before and after CA inhibition by the multiple inert gas elimination technique. Four other groups of dogs were studied to control for possible confounding effects of time under anesthesia and nonselective CA inhibition by acetazolamide: (a) saline placebo as a control for duration of anesthesia, (b) 4% CO2 inhalation to mimic systemic CO2 retention, (c) 1 mg/kg benzolamide (a selective renal CA inhibitor) or 0.5 meq/kg HCl to mimic systemic metabolic acidosis, and (d) 500 mg/kg 4,4'-dinitrostilbene-2,2'-disulfonate (an inhibitor of red cell band 3 protein) to mimic the respiratory acidosis arising from an intracapillary block to rapid mobilization of plasma HCO3- in CO2 exchange. Acetazolamide increased VA/Q mismatch and reduced arterial PO2 measured at equilibrium but these did not occur in the control group. There was no deterioration in VA/Q matching when systemic respiratory acidosis produced either by CO2 inhalation or 4,4'-dinitrostilbene-2,2'-disulfonate or metabolic acidosis (benzolamide or HCl) were imposed to mimic the effects of acetazolamide apart from its inhibition of lung CA. These results support the concept that lung CA subserves VA/Q matching in the normal lung. Images PMID:8349809

  9. Intracellular pH: Its role in normal development and teratogenesis

    SciTech Connect

    Duggan, C.A.

    1989-01-01

    Reduction of intracellular pH (pH{sub i}) leading to reduced cell proliferation has been proposed as a mechanism by which acetazolamide induces its teratogenic postaxial limb reduction defect in rodents. In vivo studies measured pH{sub i} using a weak acid and found that pH{sub i} decreased with increasing gestational age during the period of organogenesis in C57 mouse embryos. This decreasing pH{sub i} had a high correlation with the simultaneously occurring decrease in the rate of proliferation determined by {sup 3}H-thymidine incorporation. pH{sub i} or pH was measured for the embryo, embryonic plasma, and extraembryonic fluids following a teratogenic dose of acetazolamide in sensitive C57 and resistant SWV mice. Reduced embryonic pH{sub i} was seen only in the sensitive strain while both strains showed decreased pH values for embryo plasma and extraembryonic fluids, with larger reductions found in the C57 strain. The plasma membrane Na{sup +}/H{sup +} antiporter is known to regulate intracellular pH. Treatment with acetazolamide plus amiloride, and inhibitor of the Na{sup +}/H{sup +} antiporter, resulted in a dramatically increased teratogenic response in C57 embryos and several incidences of the specific limb defect in the resistant SWV embryos. The pH{sub i} and pH effects following the combined drug treatment resulted in larger reductions, the magnitude and duration being greatest in the sensitive strain. The presence of a functional Na{sup +}/H{sup +} antiporter in primary cultures of limb bud mesenchymal cells was documented for both strains of mice using a pH sensitive fluorescent dye. Quantitative studies were done to look for functional differences in the Na{sup +}/H{sup +} antiporter of limb cells from acetazolamide sensitive and resistant embryos.

  10. Acute mountain sickness: controversies and advances.

    PubMed

    Bartsch, Peter; Bailey, Damian M; Berger, Marc M; Knauth, Michael; Baumgartner, Ralf W

    2004-01-01

    This review discusses the impact of recent publications on pathophysiologic concepts and on practical aspects of acute mountain sickness (AMS). Magnetic resonance imaging studies do not provide evidence of total brain volume increase nor edema within the first 6 to 10 h of exposure to hypoxia despite symptoms of AMS. After 16 to 32 h at about 4500 m, brain volume increases by 0.8% to 2.7%, but morphological changes do not clearly correlate with symptoms of AMS, and lumbar cerebrospinal fluid pressure was unchanged from normoxic values in individuals with AMS. These data do not support the prevailing hypothesis that AMS is caused by cerebral edema and increased intracranial pressure. Direct measurement of increased oxygen radicals in hypoxia and a first study reducing AMS when lowering oxygen radicals by antioxidants suggest that oxidative stress is involved in the pathophysiology of AMS. Placebo-controlled trials demonstrate that theophylline significantly attenuates periodic breathing without improving arterial oxygen saturation during sleep. Its effects on AMS are marginal and clearly inferior to acetazolamide. A most recent large trial with Ginkgo biloba clearly showed that this drug does not prevent AMS in a low-risk setting in which acetazolamide in a low dose of 2 x 125 mg was effective. Therefore, acetazolamide remains the drug of choice for prevention and the recommended dose remains 2 x 250 mg daily until a lower dose has been tested in a high-risk setting and larger clinical trials with antioxidants have been performed.

  11. Comparative analyses of a small molecule/enzyme interaction by multiple users of Biacore technology.

    PubMed

    Cannon, Michelle J; Papalia, Giuseppe A; Navratilova, Iva; Fisher, Robert J; Roberts, Lindsey R; Worthy, Karen M; Stephen, Andrew G; Marchesini, Gerardo R; Collins, Edward J; Casper, Dave; Qiu, Huawei; Satpaev, Daulet; Liparoto, Stefano F; Rice, Dax A; Gorshkova, Inna I; Darling, Ryan J; Bennett, Donald B; Sekar, Michael; Hommema, Eric; Liang, Amy M; Day, Eric S; Inman, Jean; Karlicek, Shannon M; Ullrich, Stephen J; Hodges, Dianne; Chu, Teresa; Sullivan, Eric; Simpson, Jack; Rafique, Ashique; Luginbühl, Béatrice; Westin, Susanne Nyholm; Bynum, Magdalena; Cachia, Paul; Li, Yue-Jin; Kao, Daniel; Neurauter, Amy; Wong, Melanie; Swanson, Michael; Myszka, David G

    2004-07-01

    To gauge the experimental variability associated with Biacore analysis, 36 different investigators analyzed a small molecule/enzyme interaction under similar conditions. Acetazolamide (222 g/mol) binding to carbonic anhydrase II (CAII; 30000 Da) was chosen as a model system. Both reagents were stable and their interaction posed a challenge to measure because of the low molecular weight of the analyte and the fast association rate constant. Each investigator created three different density surfaces of CAII and analyzed an identical dilution series of acetazolamide (ranging from 4.1 to 1000 nM). The greatest variability in the results was observed during the enzyme immobilization step since each investigator provided their own surface activating reagents. Variability in the quality of the acetazolamide binding responses was likely a product of how well the investigators' instruments had been maintained. To determine the reaction kinetics, the responses from the different density surfaces were fit globally to a 1:1 interaction model that included a term for mass transport. The averaged association and dissociation rate constants were 3.1+/-1.6 x 10(6)M(-1)s(-1) and 6.7+/-2.5 x 10(-2)s(-1), respectively, which corresponded to an average equilibrium dissociation constant (K(D) of 2.6+/-1.4 x 10(-8)M. The results provide a benchmark of variability in interpreting binding constants from the biosensor and highlight keys areas that should be considered when analyzing small molecule interactions.

  12. Freeze-dried amorphous dispersions for solubility enhancement of thermosensitive API having low molecular lipophilicity.

    PubMed

    Kulthe, V V; Chaudhari, P D; Aboul-Enein, H Y

    2014-09-01

    The present study focuses on the development of an alternative 'thermally gentle' strategy such as freeze-drying to obtain not only solubility enhanced but also physically stabilised amorphous solid dispersions of acetazolamide, which melt with decomposition (M.P.~260°C). The solid dispersions were prepared by freeze-drying an aqueous dispersion of acetazolamide containing a lyoprotectant as sugar alcohol (mannitol) in 1:0.5, 1:1 and 1:2 proportions by weight. All the proportions of solid dispersions reported a marked increase in solubility characteristics compared to those of pure drug; with outstanding performance by 1:1 ratio of about 6 folds rise in saturation solubility and 90% drug release in about initial 30 minutes. This could be attributed to the formation amorphous molecular dispersions, cosolvent effect of mannitol on dispersed acetazolamide as well as its local solubilisation effect at the diffusion layer. During stability study also, 1:1 ratio of solid dispersions reported an insignificant change in solubility characteristics subjected to an unchanged amorphous nature. Such physical stability could be attributed to decreased molecular mobility of the drug molecules in amorphous carrier because of weaker drug-carrier interactions. Thus, it was demonstrated that freeze-drying is an effective method of forming dissolution-enhanced, amorphous solid dispersions of thermally degradable APIs.

  13. Diabetic ketoacidosis and acute mountain sickness: case report and review of treatment options in type 1 diabetes mellitus.

    PubMed

    Miller, Steven C M

    2015-06-01

    A 30-year-old man with a 20-year history of well-controlled type 1 diabetes mellitus and no microvascular complications traveled from near sea level to an altitude of 3000 m within 6 hours. At altitude, his blood glucose levels began to rise, necessitating increased insulin delivery. Typical symptoms of acute mountain sickness (AMS) developed, and he became increasingly hyperglycemic and unwell. Upon presentation to an emergency clinic, diabetic ketoacidosis (DKA) was diagnosed and was managed with insulin, intravenous fluids with potassium, and acetazolamide orally. No other potential causes for diabetic ketoacidosis were identified. Hyperglycemia, ketosis, and acidosis resolved with treatment as expected, but an increased insulin requirement was noted for the next 48 hours, until returning to expected levels when acetazolamide was discontinued. This case describes an episode of mild diabetic ketoacidosis potentially precipitated by moderate to severe acute mountain sickness, and an apparent hyperglycemic effect of acetazolamide. Individuals with type 1 diabetes traveling to altitude and their physicians should be vigilant for this complication and should be aware of the effects of conventional first-line therapies for acute mountain sickness on insulin requirement, glycemic control, and preexisting microvascular diabetes complications.

  14. Near-Infrared Transillumination Back Scattering Sounding—New Method to Assess Brain Microcirculation in Patients with Chronic Carotid Artery Stenosis

    PubMed Central

    Frydrychowski, Andrzej F.; Winklewski, Pawel J.; Szarmach, Arkadiusz; Halena, Grzegorz; Bandurski, Tomasz

    2013-01-01

    Purpose The purpose of the study was to assess the responses of pial artery pulsation (cc-TQ) and subarachnoid width (sas-TQ) to acetazolamide challenge in patients with chronic carotid artery stenosis and relate these responses to changes in peak systolic velocity (PSV), cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and time to peak response (TTP). Methods Fifteen patients with carotid artery stenosis ≥90% on the ipsilateral side and <50% on the contralateral side were enrolled into the study. PSV was assessed using colour-coded duplex sonography, CBF, CBV, MTT and TTP with perfusion computed tomography, cc-TQ and sas-TQ with near-infrared transillumination/backscattering sounding (NIR-T/BSS). Results Based on the ipsilateral/contralateral cc-TQ ratio after acetazolamide challenge two groups of patients were distinguished: the first group with a ratio ≥1 and the second with a ratio <1. In the second group increases in CBF and CBV after the acetazolamide test were significantly higher in both hemispheres (ipsilateral: +33.0%±8.1% vs. +15.3%±4.4% and +26.3%±6.6% vs. +14.3%±5.1%; contralateral: +26.8%±7.0% vs. +17.6%±5.6% and +20.0%±7.3% vs. +10.0%±3.7%, respectively), cc-TQ was significantly higher only on the ipsilateral side (+37.3%±9.3% vs. +26.6%±8.6%) and the decrease in sas-TQ was less pronounced on the ipsilateral side (−0.7%±1.5% vs. −10.2%±1.5%), in comparison with the first group. The changes in sas-TQ following the acetazolamide test were consistent with the changes in TTP. Conclusions The ipsilateral/contralateral cc-TQ ratio following acetazolamide challenge may be used to distinguish patient groups characterized by different haemodynamic parameters. Further research on a larger group of patients is warranted. PMID:23613977

  15. A class of sulfonamide carbonic anhydrase inhibitors with neuropathic pain modulating effects.

    PubMed

    Carta, Fabrizio; Di Cesare Mannelli, Lorenzo; Pinard, Melissa; Ghelardini, Carla; Scozzafava, Andrea; McKenna, Robert; Supuran, Claudiu T

    2015-04-15

    A series of benzene sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors which incorporate lipophilic 4-alkoxy- and 4-aryloxy moieties, together with several derivatives of ethoxzolamide and sulfanilamide are reported. These derivatives were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) of which multiple isoforms are known, and some appear to be involved in pain. These sulfonamides showed modest inhibition against the cytosolic isoform CA I, but were generally effective, low nanomolar CA II, VII, IX and XII inhibitors. X-ray crystallographic data for the adduct of several such sulfonamides with CA II allowed us to rationalize the good inhibition data. In a mice model of neuropathic pain induced by oxaliplatin, one of the strong CA II/VII inhibitors reported here induced a long lasting pain relieving effect, a fact never observed earlier. This is the first report of rationally designed sulfonamide CA inhibitors with pain effective modulating effects. PMID:25766630

  16. Mechanisms of fluid and ion secretion by the parotid gland of the kangaroo, Macropus rufus, assessed by administration of transport-inhibiting drugs.

    PubMed

    Beal, A M

    1995-01-01

    Possible mechanisms of primary fluid formation by macropodine parotid glands were investigated in anaesthetized red kangaroos using ion transport inhibitors. Carotid plasma amiloride concentrations of 0.05-0.5 mmol.l-1 progressively reduced a stable acetylcholine-evoked half-maximal flow rate of 2.0 +/- 0.04 to 0.22 +/- 0.024 ml.min-1 (mean +/- SEM). Concurrently, saliva bicarbonate concentration and secretion fell (135 +/- 1.6 to 67 +/- 1.7 mmol.l-1 and 272 +/- 7.6 to 15 +/- 2.6 mumol.min-1, respectively); [phosphate], [chloride] and [sodium] rose and [potassium] and osmolality were unaltered. High-rate cholinergic stimulation did not increase saliva flow beyond 11 +/- 1.0% of that for equivalent pre-amiloride stimulation. Equipotent levels of amiloride and methazolamide given concurrently were no more effective at blocking flow and bicarbonate secretion than when given separately. Furosemide (up to 2 mmol.l-1), bumetanide (up to 0.2 mmol.l-1) and ethacrynate (1 mmol.l-1) in carotid plasma had no effect on salivary flow or ion concentrations. During methazolamide blockade, furosemide did not curtail the concurrent increase in salivary [chloride]. Chlorothiazide at 0.25-1.0 mmol.l-1 caused progressive depression of saliva flow and [bicarbonate], and elevation of [chloride]. 4-acetamido-4'-isothiocyanatostilbene-2,2'disulphonic acid at 0.1 mmol.l-1 was without effect, whereas at 0.5 mmol.l-1 it stimulated fluid secretion and increased saliva [protein], [sodium], [potassium], [bicarbonate] and osmolality. Concurrently, mean arterial blood pressure and pulse pressure fell and heart rate, haematocrit and carotid artery plasma flow rose. These responses were absent if saliva flow was kept constant by reduction in cholinergic stimulation during 4-acetamido-4-isothiocyanatostilbene-2,2'disulphonic acid administration. It is concluded that secretion of primary fluid by the kangaroo parotid is initiated mainly (> 90%) by secretion of bicarbonate which is formed in the

  17. The effect of transport-blocking drugs on secretion of fluid and electrolytes by the mandibular gland of red kangaroos, Macropus rufus.

    PubMed

    Beal, A M

    1997-01-01

    Mechanisms of primary fluid formation by macropodine mandibular glands were investigated in anaesthetized red kangaroos using ion-transport and carbonic anhydrase inhibitors. Bumetanide at carotid plasma concentrations of 0.005-0.1 mmol/l progressively reduced a stable, acetylcholine-evoked flow rate of 1.02 +/- 0.024 ml/min to 0.16 +/- 0.016 ml/min (mean +/- SEM). Concurrently, saliva [Na], [Cl] and osmolality decreased, [K] and [HCO3] increased and HCO3 excretion was unaffected. High-rate cholinergic stimulation was unable to increase salivary flow above 12 +/- 1.5% of that for equivalent pre-bumetanide stimulation. Furosemide (1.0 mmol/l) and ethacrynate (0.5 mmol/l) caused depression of salivary flow and qualitatively similar effects on ion concentrations to those of bumetanide. Amiloride (up to 0.5 mmol/l) caused no reduction in salivary flow rates or [Na] but decreased [K] and [Cl] and increased [HCO3]. When compared with bumetanide alone, amiloride combined with bumetanide further augmented [K] and [HCO3] and lowered [Cl], but had no additional effects on Na or flow. At the higher level, 4-acetamido-4'- isothiocyanatostilbene-2,2'disulphonic acid (SITS) (0.05 and 0.5 mmol/l) stimulated fluid output, increased [HCO3] and [protein], and depressed [Na], [K] and [Cl]. Relative to bumetanide alone, SITS given with bumetanide had no additional effects on salivary flow or electrolytes. Methazolamide (0.5 mmol/l) in combination with bumetanide curtailed the decrease in [Cl] and the increases in [K] and [HCO3] associated with bumetanide. The residual methazolamide-resistant HCO3 excretion was sufficient to support 2-6% of primary fluid secretion. It was concluded that secretion of primary fluid by the kangaroo mandibular gland is initiated mainly (> 90%) by Cl transport resulting from Na-K-2Cl symport activity. A small proportion of the fluid secretion (up to 6%) appears to be supported by HCO3 secretion. No evidence was found for fluid secretion being dependent on

  18. Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro.

    PubMed

    Jackson, Stewart J; Varley, James; Sellers, Claudia; Josephs, Katherine; Codrington, Lucy; Duke, Georgina; Njelekela, Marina A; Drummond, Gordon; Sutherland, Andrew I; Thompson, A A Roger; Baillie, J Kenneth

    2010-01-01

    We investigated the incidence of AMS amongst a general population of trekkers on Mount Kilimanjaro, using the Lake Louise consensus scoring system (LLS). Additionally we examined the effect of prophylactic acetazolamide and different ascent profiles. Climbers on 3 different ascent itineraries were recruited. At 2743 m we recruited 177 participants (mean age 31, range [18-71]) who completed LLS together with an epidemiological questionnaire. At 4730 m participants (n=189, male=108, female=68, mean age 33, range [1871]) completed LLS, 136 of whom had been followed up from 2730 m. At 2743 m, 3% (5/177) of climbers were AMS positive, and 47% (89/189) of climbers from all itineraries were AMS positive at 4730 m. Of climbers attempting the Marangu itineraries, 33% (45/136) were taking acetazolamide. This group had a similar rate of AMS and no statistical difference in severity of LLS when compared with those not taking prophylactic drugs. We also did not demonstrate a difference between the incidence of AMS in climbers who did or did not take a rest day at 3700  m. However, there was a significant reduction in the incidence of AMS amongst pre-acclimatized subjects. Consistent with previous work, we found that the rate of AMS on Mount Kilimanjaro is high. Furthermore, at these fast ascent rates, there was no evidence of a protective effect of acetazolamide or a single rest day. There is a need to increase public awareness of the risks of altitude sickness and we advocate a pragmatic "golden rules" approach (http://www.altitude.org/altitude_sickness.php). PMID:20919888

  19. Carbonic anhydrase II plays a major role in osteoclast differentiation and bone resorption by effecting the steady state intracellular pH and Ca2+.

    PubMed

    Lehenkari, P; Hentunen, T A; Laitala-Leinonen, T; Tuukkanen, J; Väänänen, H K

    1998-07-10

    Carbonic anhydrase II (CA II) expression in characteristic for the early stage of osteoclast differentiation. To study how CA II, which is crucial in proton generation in mature osteoclasts, influences the osteoclast differentiation process we performed rat bone marrow cultures. In this model, acetazolamide, a specific CA inhibitor, decreased the 1,25 (OH)2D3-induced formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells, in a dose-dependent manner. We then performed intracellular pH (pHi) and Ca2+ (Cai2+) measurements for cultured osteoclasts and noticed that addition of acetazolamide caused a rapid, transient increase of both parameters. The increase in pHi was dependent neither on the culture substrate nor on the extracellular pH (pHe) but the increase could be diminished by DIDS or by bicarbonate removal. Membrane-impermeable CA inhibitors (benzolamide and pd5000) did not have this effect. Addition of CA II antisense oligonucleotides into the cultures reduced the pHi increase significantly. CA II inhibition was also found to neutralize the intracellular vesicles at extracellular pH (pHe) of 7.4, but at less extent at pHe 7.0. In mouse calvaria cultures, bone resorption was inhibited dose dependently by acetazolamide at pHe 7.4 while inhibition was smaller at pHe 7.0. We conclude that CA II is essential not only in bone resorption but also in osteoclast differentiation. In both processes, however, the crucial role of CA II is at least partially due to the effect on the osteoclast pHi regulation.

  20. Carbonic anhydrase inhibition by 1-aroyl-3-(4-aminosulfonylphenyl)thioureas.

    PubMed

    Saeed, Aamer; Al-Rashida, Mariya; Hamayoun, Mehwish; Mumtaz, Amara; Iqbal, Jamshed

    2014-12-01

    A series of 1-aroyl-3-(4-aminosulfonylphenyl)thioureas containing free sulfonamide group has been evaluated for their ability to inhibit bovine carbonic anhydrase II (bCA, EC 4.2.1.1). All compounds in the series were able to inhibit bCA II, the most active inhibitor had IC50 value of 0.26 ± 0.01 µM. Molecular docking studies and detailed structure-activity relationship studies were carried out. The absorption, distribution, metabolism, excretion (ADME) properties, as a predictor of oral absorption, were computationally calculated and compared with the clinically used drug acetazolamide. PMID:24666305

  1. Bulk and surface sensitivity of a resonant waveguide grating imager

    NASA Astrophysics Data System (ADS)

    Orgovan, Norbert; Kovacs, Boglarka; Farkas, Eniko; Szabó, Bálint; Zaytseva, Natalya; Fang, Ye; Horvath, Robert

    2014-02-01

    We report the assessment of the sensitivity of a microplate-compatible resonant waveguide grating imager. The sensitivity to bulk refractive index changes was determined using a serial dilution of glycerol solution with the help of a refractometer. The surface sensitivity was examined using layer-by-layer polyelectrolyte films in conjunction with optical waveguide lightmode spectroscopy and characterized by the binding of acetazolamide to immobilized carbonic anhydrase under microfluidics. The results suggest that the imager has a limit of detection down to 2.2 × 10-6 for refractive index change and 0.078 ng/cm2 for the adsorbed mass.

  2. Acute pulmonary oedema on the Ruwenzori mountain range.

    PubMed Central

    Naeije, R; Mélot, C

    1990-01-01

    A 40 year old man had an episode of severe pulmonary oedema at 4000-5000 m during the ascent of the Margherita peak (5109 m) of Mount Stanley on the Ruwenzori. He had taken acetazolamide and high dose dexamethasone to treat symptoms of acute mountain sickness. Six years before he had been studied by right heart catheterisation as a healthy volunteer during hypoxic breathing at sea level. His pulmonary vascular reactivity had been within the normal range for 32 healthy subjects. This man had high altitude pulmonary oedema despite currently recommended treatments for acute mountain sickness and normal pulmonary vascular reactivity to hypoxia at sea level. PMID:2271350

  3. Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays.

    PubMed

    Sarang, Satinder S; Yoshida, Takumi; Cadet, Rodolphe; Valeras, Andrew S; Jensen, Roderick V; Gullans, Steven R

    2002-10-29

    Oxidative injury and the resulting death of neurons is a major pathological factor involved in numerous neurodegenerative diseases. However, the development of drugs that target this mechanism remains limited. The goal of this study was to test a compound library of approved Food and Drug Administration drugs against a hydrogen peroxide-induced oxidant injury model in neuroblastoma cells. We identified 26 neuroprotective compounds, of which megestrol, meclizine, verapamil, methazolamide, sulindac, and retinol were examined in greater detail. Using large-scale oligonucleotide microarray analysis, we identified genes modulated by these drugs that might underlie the cytoprotection. Five key genes were either uniformly upregulated or downregulated by all six drug treatments, namely, tissue inhibitor of matrix metalloproteinase (TIMP1), ret-proto-oncogene, clusterin, galanin, and growth associated protein (GAP43). Exogenous addition of the neuropeptide galanin alone conferred survival to oxidant-stressed cells, comparable to that seen with the drugs. Our approach, which we term "interventional profiling," represents a general and powerful strategy for identifying new bioactive agents for any biological process, as well as identifying key downstream genes and pathways that are involved. PMID:12388792

  4. Comparison of the sulfonamide inhibition profiles of the α-, β- and γ-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae.

    PubMed

    Del Prete, Sonia; Vullo, Daniela; De Luca, Viviana; Carginale, Vincenzo; Osman, Sameh M; AlOthman, Zeid; Supuran, Claudiu T; Capasso, Clemente

    2016-04-15

    Carbonic anhydrases (CA, EC 4.2.1.1) are ubiquitous metalloenzymes, which catalyze the conversion of carbon dioxide (CO2) to bicarbonate (HCO3(-)) and protons (H(+)). In prokaryotes, the existence of genes encoding for α-, β- and γ-classes suggests that these enzymes play an important role in the prokaryotic physiology. It has been demonstrated, in fact, that their inhibition in vivo leads to growth impairment or growth defects of the microorganism. Ultimately, we started to investigate the biochemical properties and the inhibitory profiles of the α- and β-CAs identified in the genome of Vibrio cholerae, which is the causative agent of cholera. The genome of this pathogen encodes for CAs belonging to α, β and γ classes. Here, we report a sulfonamide inhibition study of the γ-CA (named VchCAγ) comparing it with data obtained for the α- and β-CA enzymes. VchCAγ activity (kcat=7.39 × 10(5)s(-1)) was significantly higher than the other γ-CAs. The inhibition study with a panel of sulfonamides and one sulfamate led to the detection of a large number of nanomolar VchCAγ inhibitors, including simple aromatic/heterocyclic sulfonamides (compounds 2-9, 11, 13-15, 24) as well as EZA, DZA, BRZ, BZA, TPM, ZNS, SLP, IND (KIs in the range of 66.2-95.3 nM). As it was proven that bicarbonate is a virulence factor of this bacterium and since ethoxzolamide was shown to inhibit this virulence in vivo, we propose that VchCA, VchCAβ and VchCAγ may be a target for antibiotic development, exploiting a mechanism of action rarely considered up until now, i.e., interference with bicarbonate supply as a virulence factor. PMID:26972117

  5. Characterization of Na+ uptake in the endangered desert pupfish, Cyprinodon macularius (Baird and Girard)

    PubMed Central

    Brix, Kevin V.; Grosell, Martin

    2013-01-01

    This study provided an initial characterization of Na+ uptake in saline freshwater by the endangered pupfish, Cyprinodon macularius. This species occurs only in several saline water systems in the southwestern USA and northern Mexico, where salinity is largely controlled by water-management practices. Consequently, understanding the osmoregulatory capacity of this species is important for their conservation. The lower acclimation limit of C. macularius in freshwater was found to be 2 mM Na+. Fish acclimated to 2 or 7 mM Na+ displayed similar Na+ uptake kinetics, with Km values of 4321 and 3672 μM and Vmax values of 4771 and 3602 nmol g−1 h−1, respectively. A series of experiments using pharmacological inhibitors indicated that Na+ uptake in C. macularius was not sensitive to bumetanide, metolazone, or phenamil. These results indicate the Na+–K+–2Cl− cotransporter, Na+–Cl− cotransporter, and the Na+ channel–H+-ATPase system are likely not to be involved in Na+ uptake at the apical membrane of fish gill ionocytes in fish acclimated to 2 or 7 mM Na+. However, Na+ uptake was sensitive to 1 × 10−3 M amiloride (not 1 × 10−4 or 1 × 10−5 M), 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), and ethoxzolamide. These data suggest that C. macularius relies on a low-affinity Na+–H+ exchanger for apical Na+ uptake and that H+ ions generated via carbonic anhydrase-mediated CO2 hydration are important for the function of this protein. PMID:27293589

  6. Patients with Obstructive Sleep Apnea at Altitude.

    PubMed

    Bloch, Konrad E; Latshang, Tsogyal D; Ulrich, Silvia

    2015-06-01

    Bloch, Konrad E., Tsogyal D. Latshang, and Silvia Ulrich. Patients with obstructive sleep apnea at altitude. High Alt Med Biol 16:110-116, 2015.--Obstructive sleep apnea (OSA) is highly prevalent in the general population, in particular in men and women of older age. In OSA patients sleeping near sea level, the apneas/hypopneas associated with intermittent hypoxemia are predominantly due to upper airway collapse. When OSA patients stay at altitudes above 1600 m, corresponding to that of many tourist destinations, hypobaric hypoxia promotes frequent central apneas in addition to obstructive events, resulting in combined intermittent and sustained hypoxia. This induces strong sympathetic activation with elevated heart rate, cardiac arrhythmia, and systemic hypertension. There are concerns that these changes expose susceptible OSA patients, in particular those with advanced age and co-morbidities, to an excessive risk of cardiovascular and other adverse events during a stay at altitude. Based on data from randomized trials, it seems advisable for OSA patients to use continuous positive airway pressure treatment with computer controlled mask pressure adjustment (autoCPAP) in combination with acetazolamide during an altitude sojourn. If CPAP therapy is not feasible, acetazolamide alone is better than no treatment at all, as it improves oxygenation and sleep apnea and prevents excessive blood pressure rises of OSA patients at altitude.

  7. Stimulatory effect of Coca-Cola on gastroduodenal HCO3- secretion in rats.

    PubMed

    Sasaki, Y; Aihara, E; Ise, F; Kita, K; Takeuchi, K

    2007-10-01

    We examined the effect of various carbonated beverages, especially Coca-Cola, on the HCO3- secretion in the rat stomach and duodenum. Under urethane anaesthesia, a chambered stomach or a proximal duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. The amount of CO2 contained in these beverages was about 4-7 g/mL. Coca-Cola topically applied to the mucosa for 10 min significantly increased the HCO3- secretion in both the stomach and the duodenum. The HCO3- response in the duodenum was totally abolished by indomethacin and also partially inhibited by acetazolamide, an inhibitor of carbonic anhydrase. Likewise, the response in the stomach was also markedly inhibited by either acetazolamide or indomethacin. The mucosal application of Coca-Cola increased the PGE2 contents in both the stomach and the duodenum. Other carbonated beverages, such as sparkling water, Fanta Grape or cider, also increased the HCO3- secretion in these tissues. These results suggest that Coca-Cola induces HCO3- secretion in both the stomach and the duodenum, and these responses may be attributable to both the intracellular supply of HCO3- generated via carbonic anhydrase, and endogenous PGs, probably related to the acidic pH of the solution.

  8. The effect of diuretics on the water excretion of protein deficient rats.

    PubMed

    BLACKMORE, K E; SCHNIEDEN, H

    1957-09-01

    Adult rats kept for eleven weeks on a diet deficient in protein lost weight and some developed scrotal oedema. The retention of bromsulphthalein was increased, but the thymol turbidity test was unaffected; the apparent plasma volume was increased.Water diuresis in the protein deficient animals was impaired. There was no apparent delay in the mean rate of water absorption from the whole gastro-intestinal tract although a delayed absorption of water from the intestine was found in some animals. The concentrations of total plasma proteins and plasma albumin were low as compared with normal animals, but the plasma sodium levels were within normal limits. The inulin clearance (glomerular filtration rate) of the animals on the protein-deficient diet was significantly lower than that of the controls.In normal rats, aminophylline and acetazolamide were diuretic. Caffeine and sodium benzoate did not increase the urine output and mersalyl was antidiuretic. In the protein deficient rats, cortisone acetate increased the water diuresis. Caffeine and sodium benzoate, aminophylline and acetazolamide did not significantly increase this response, mersalyl had an antidiuretic effect. Cortisone acetate increased the food and water intake of the protein deficient rats; it also increased the glomerular filtration rate. PMID:13460231

  9. Role of intracellular carbonic anhydrase in inorganic-carbon assimilation by Porphyridium purpureum.

    PubMed

    Dixon, G K; Patel, B N; Merrett, M J

    1987-12-01

    Air-grown cells of Porphyridium purpurem contain appreciable carbonic-anhydrase activity, comparable to that in air-grown Chlamydomonas reinhardtii, but activity is repressed in CO2-grown cells. Assay of carbonic-anhydrase activity in intact cells and cell extracts shows all activity to be intracellular in Porphyridium. Measurement of inorganic-carbon-dependent photosynthetic O2 evolution shows that sodium ions increase the affinity of Porphyridium cells for HCO 3 (-) . Acetazolamide and ethoxyzolamide were potent inhibitors of carbonic anhydrase in cell extracts but at pH 5.0 both acetazolamide and ethoxyzolamide had little effect upon the concentration of inorganic carbon required for the half-maximal rate of photosynthetic O2 evolution (K0.5[CO2]). At pH 8.0, where HCO 3 (-) is the predominant species of inorganic carbon, the K0.5 (CO2) was increased from 50 μM to 950 μM in the presence of ethoxyzolamide. It is concluded that in air-grown cells of Porphyridium. HCO 3 (-) is transported across the plasmalemma and intracellular carbonic anhydrase increases the steady-state flux of CO2 from inside the plasmalemma to ribulose-1,5-bisphosphate carboxylase-oxygenase by catalysing the interconversion of HCO 3 (-) and CO2 within the cell.

  10. Metabolic Effect of Estrogen Receptor Agonists on Breast Cancer Cells in the Presence or Absence of Carbonic Anhydrase Inhibitors

    PubMed Central

    Belkaid, Anissa; Čuperlović-Culf, Miroslava; Touaibia, Mohamed; Ouellette, Rodney J.; Surette, Marc E.

    2016-01-01

    Metabolic shift is one of the major hallmarks of cancer development. Estrogen receptor (ER) activity has a profound effect on breast cancer cell growth through a number of metabolic changes driven by its effect on transcription of several enzymes, including carbonic anhydrases, Stearoyl-CoA desaturase-1, and oncogenes including HER2. Thus, estrogen receptor activators can be expected to lead to the modulation of cell metabolism in estrogen receptor positive cells. In this work we have investigated the effect of 17β-estradiol, an ER activator, and ferulic acid, a carbonic anhydrase inhibitor, as well as ER activator, in the absence and in the presence of the carbonic anhydrase inhibitor acetazolamide on the metabolism of MCF7 cells and MCF7 cells, stably transfected to express HER2 (MCF7HER2). Metabolic profiles were studied using 1D and 2D metabolomic Nuclear Magnetic Resonance (NMR) experiments, combined with the identification and quantification of metabolites, and the annotation of the results in the context of biochemical pathways. Overall changes in hydrophilic metabolites were largest following treatment of MCF7 and MC7HER2 cells with 17β-estradiol. However, the carbonic anhydrase inhibitor acetazolamide had the largest effect on the profile of lipophilic metabolites. PMID:27240414

  11. Role of carbonic anhydrase in bone resorption induced by prostaglandin E2 in vitro

    NASA Technical Reports Server (NTRS)

    Hall, G. E.; Kenny, A. D.

    1985-01-01

    The possible role of carbonic anhydrase in bone resorption induced by prostaglandin E2 (PGE2) was studied using an in vitro neonatal mouse calvarial culture system. PGE2 (10 to the -6th M) was effective in stimulating resorption, as assessed by calcium release into culture media. This enhanced resorption was accompanied by significant increases in calvarial carbonic anhydrase activity over control values at 48 and 96 h. At 48 h, bones treated with PGE2 had 20 percent more carbonic anhydrase activity than controls. By 96 h, treated bones contained 79 percent more carbonic anhydrase activity than controls. PGE2-induced bone resorption was inhibited by the carbonic anhydrase inhibitor acetazolamide in a dose-dependent fashion from 10 to the -5th to 10 to the -4th M with 77 percent inhibition observed at 10 to the -4th M. The acetazolamide analogue CL 13,850 (N-t-butylacetazolamide), which does not inhibit carbonic anhydrase, failed to inhibit PGE2-induced resorption. These results are consistent with the hypothesis that carbonic anhydrase is a necessary component of the osteoclastic bone resorptive mechanism.

  12. Effects of drug solubility, state and loading on controlled release in bicomponent electrospun fibers.

    PubMed

    Natu, Mădălina V; de Sousa, Hermínio C; Gil, M H

    2010-09-15

    Bicomponent fibers of two semi-crystalline (co)polymers, poly(varepsilon-caprolactone), and poly(oxyethylene-b-oxypropylene-b-oxyethylene), were obtained by electrospinning. Acetazolamide and timolol maleate were loaded in the fibers in different concentrations (below and above the drug solubility limit in polymer) in order to determine the effect of drug solubility in polymer, drug state, drug loading and fiber composition on fiber morphology, drug distribution and release kinetics. The high loadings fibers (with drug in crystalline form) showed higher burst and faster release than low drug content fibers, indicating the release was more sustained when the drug was encapsulated inside the fibers, in amorphous form. Moreover, timolol maleate was released faster than acetazolamide, indicating that drug solubility in polymer influences the partition of drug between polymer and elution medium, while fiber composition also controlled drug release. At low loadings, total release was not achieved (cumulative release percentages smaller than 100%), suggesting that drug remained trapped in the fibers. The modeling of release data implied a three stage release mechanism: a dissolution stage, a desorption and subsequent diffusion through water-filled pores, followed by polymer degradation control.

  13. High-Altitude Illnesses: Physiology, Risk Factors, Prevention, and Treatment

    PubMed Central

    Taylor, Andrew T.

    2011-01-01

    High-altitude illnesses encompass the pulmonary and cerebral syndromes that occur in non-acclimatized individuals after rapid ascent to high altitude. The most common syndrome is acute mountain sickness (AMS) which usually begins within a few hours of ascent and typically consists of headache variably accompanied by loss of appetite, nausea, vomiting, disturbed sleep, fatigue, and dizziness. With millions of travelers journeying to high altitudes every year and sleeping above 2,500 m, acute mountain sickness is a wide-spread clinical condition. Risk factors include home elevation, maximum altitude, sleeping altitude, rate of ascent, latitude, age, gender, physical condition, intensity of exercise, pre-acclimatization, genetic make-up, and pre-existing diseases. At higher altitudes, sleep disturbances may become more profound, mental performance is impaired, and weight loss may occur. If ascent is rapid, acetazolamide can reduce the risk of developing AMS, although a number of high-altitude travelers taking acetazolamide will still develop symptoms. Ibuprofen can be effective for headache. Symptoms can be rapidly relieved by descent, and descent is mandatory, if at all possible, for the management of the potentially fatal syndromes of high-altitude pulmonary and cerebral edema. The purpose of this review is to combine a discussion of specific risk factors, prevention, and treatment options with a summary of the basic physiologic responses to the hypoxia of altitude to provide a context for managing high-altitude illnesses and advising the non-acclimatized high-altitude traveler. PMID:23908794

  14. Patients with Obstructive Sleep Apnea at Altitude.

    PubMed

    Bloch, Konrad E; Latshang, Tsogyal D; Ulrich, Silvia

    2015-06-01

    Bloch, Konrad E., Tsogyal D. Latshang, and Silvia Ulrich. Patients with obstructive sleep apnea at altitude. High Alt Med Biol 16:110-116, 2015.--Obstructive sleep apnea (OSA) is highly prevalent in the general population, in particular in men and women of older age. In OSA patients sleeping near sea level, the apneas/hypopneas associated with intermittent hypoxemia are predominantly due to upper airway collapse. When OSA patients stay at altitudes above 1600 m, corresponding to that of many tourist destinations, hypobaric hypoxia promotes frequent central apneas in addition to obstructive events, resulting in combined intermittent and sustained hypoxia. This induces strong sympathetic activation with elevated heart rate, cardiac arrhythmia, and systemic hypertension. There are concerns that these changes expose susceptible OSA patients, in particular those with advanced age and co-morbidities, to an excessive risk of cardiovascular and other adverse events during a stay at altitude. Based on data from randomized trials, it seems advisable for OSA patients to use continuous positive airway pressure treatment with computer controlled mask pressure adjustment (autoCPAP) in combination with acetazolamide during an altitude sojourn. If CPAP therapy is not feasible, acetazolamide alone is better than no treatment at all, as it improves oxygenation and sleep apnea and prevents excessive blood pressure rises of OSA patients at altitude. PMID:25973669

  15. Relationship between the flow pattern and vasomotor reactivity in the ophthalmic artery, siphon and vessels within the circle of Willis in the unilateral internal carotid artery occlusion.

    PubMed

    Zbornikova, V; Lassvik, C

    1996-12-01

    The aim was to study a relationship between the flow pattern in the ophthalmic artery (OA), the siphon and vessels within the circle of Willis. 27 patients, 22 males and 5 females, mean age 63 +/- 15 years (SD) with unilateral occlusion of the internal carotid artery (ICA) were examined by 3-dimensional Transcranial Doppler scanner. Flow signals from the OA, the siphon and intracranial vessels were registered before and after i.v. injection of 1 g acetazolamide. Pathological flow pattern was found in 18 patients in the OA on the occluded side consisting of 12 retrograde and 6 isoelectric flow directions. After acetazolamide injection retrograde systolic velocities (SV) increased significantly (p < 0.01), but anterograde velocities remained unchanged as did 3 isoelectric flow patterns, 2 turned to retrograde and one to anterograde flow direction. In the siphon lower resting anterograde mean velocities (MV) were found on both sides (p < 0.05) compared to normal subjects. Six patients had the same retrograde flow as in the OA. After acetazolamide MV in the siphon increased (p < 0.01) only on the nonoccluded side. Baseline retrograde ophthalmic SV and MV in the siphon correlated (p < 0.01 and p < 0.05 respectively) with MV in the middle cerebral artery (MCA) according to linear regression analysis (r = 0.78 and 0.59 respectively). All patients, having impaired vasomotor reactivity (VMR) < or = 11% in the anterior cerebral artery (ACA) on the occluded side, had pathological flow pattern in the OA. Patients with greatest difference (delta) between MV in the ACA on the nonoccluded and occluded side had a tendency to anterograde flow (r = 0.56, p < 0.05). Pulsative index (PI) in the ACA on the occluded side was lowest in the category with retrograde flow in the OA (0.67 +/- 0.14) and differed (p < 0.05) from normals and from the category with isoelectric and anterograde flow. Correlation of retrograde flow direction in the OA and baseline MV in the MCA and low PI in the

  16. Observation on therapeutic efficacy of rt-PA intravenous thrombolysis combined with compound anisodine injection on central retinal artery occlusion

    PubMed Central

    Wu, Xiao-Jun; Gao, Feng; Liu, Xu; Zhao, Qing

    2016-01-01

    The aim of the present study was to observe the clinical efficacy and safety of recombinant tissue plasminogen activator (rt-PA) combined with compound anisodine in treating central retinal artery occlusion (CRAO). Forty-eight patients diagnosed with CRAO were randomly divided into a treatment group (24 cases) and a control group (24 cases). For the control group, nitroglycerin, 654-2, methazolamide, puerarin and compound anisodine were used for the treatment, along with oxygen, massage and other conventional treatments. Besides conventional therapy, the treatment group was also given intravenous rt-PA thrombolysis. Visual acuity, fundus oculi, visual field changes were taken as indicators for efficacy evaluation. It was found that the total effective rate of the control group was 70.83%, while that for the treatment group was 91.67%, and the comparative difference between the two groups was of statistical significance (p<0.05). The visual field defect of the control group after treatment was approximately 74.26±12.91%, and the visual field defect of the treatment group after treatment approximately 35.08±16.33%; thus, the comparative difference was statistically significant (p<0.01). The comparative difference of the original contents of fibrous protein in blood in the treatment group before and after treatment was statistically significant (p<0.01). In conclusion, the result show that intravenous thrombolysis with rt-PA combined with compound anisodine is safe and effective in treating CRAO, which can significantly improve the prognosis of patients. PMID:27698763

  17. Observation on therapeutic efficacy of rt-PA intravenous thrombolysis combined with compound anisodine injection on central retinal artery occlusion

    PubMed Central

    Wu, Xiao-Jun; Gao, Feng; Liu, Xu; Zhao, Qing

    2016-01-01

    The aim of the present study was to observe the clinical efficacy and safety of recombinant tissue plasminogen activator (rt-PA) combined with compound anisodine in treating central retinal artery occlusion (CRAO). Forty-eight patients diagnosed with CRAO were randomly divided into a treatment group (24 cases) and a control group (24 cases). For the control group, nitroglycerin, 654-2, methazolamide, puerarin and compound anisodine were used for the treatment, along with oxygen, massage and other conventional treatments. Besides conventional therapy, the treatment group was also given intravenous rt-PA thrombolysis. Visual acuity, fundus oculi, visual field changes were taken as indicators for efficacy evaluation. It was found that the total effective rate of the control group was 70.83%, while that for the treatment group was 91.67%, and the comparative difference between the two groups was of statistical significance (p<0.05). The visual field defect of the control group after treatment was approximately 74.26±12.91%, and the visual field defect of the treatment group after treatment approximately 35.08±16.33%; thus, the comparative difference was statistically significant (p<0.01). The comparative difference of the original contents of fibrous protein in blood in the treatment group before and after treatment was statistically significant (p<0.01). In conclusion, the result show that intravenous thrombolysis with rt-PA combined with compound anisodine is safe and effective in treating CRAO, which can significantly improve the prognosis of patients.

  18. Carbonic anhydrase inhibition prevents and reverts cardiomyocyte hypertrophy

    PubMed Central

    Alvarez, Bernardo V; Johnson, Danielle E; Sowah, Daniel; Soliman, Daniel; Light, Peter E; Xia, Ying; Karmazyn, Morris; Casey, Joseph R

    2007-01-01

    Hypertrophic cardiomyocyte growth contributes substantially to the progression of heart failure. Activation of the plasma membrane Na+–H+ exchanger (NHE1) and Cl−–HCO3− exchanger (AE3) has emerged as a central point in the hypertrophic cascade. Both NHE1 and AE3 bind carbonic anhydrase (CA), which activates their transport flux, by providing H+ and HCO3−, their respective transport substrates. We examined the contribution of CA activity to the hypertrophic response of cultured neonatal and adult rodent cardiomyocytes. Phenylephrine (PE) increased cell size by 37 ± 2% and increased expression of the hypertrophic marker, atrial natriuretic factor mRNA, twofold in cultured neonatal rat cardiomyocytes. Cell size was also increased in adult cardiomyocytes subjected to angiotensin II or PE treatment. These effects were associated with increased expression of cytosolic CAII protein and the membrane-anchored isoform, CAIV. The membrane-permeant CA inhibitor, 6-ethoxyzolamide (ETZ), both prevented and reversed PE-induced hypertrophy in a concentration-dependent manner in neonate cardiomyocytes (IC50 = 18 μm). ETZ and the related CA inhibitor methazolamide prevented hypertrophy in adult cardiomyocytes. In addition, ETZ inhibited transport activity of NHE1 and the AE isoform, AE3, with respective EC50 values of 1.2 ± 0.3 μm and 2.7 ± 0.3 μm. PE significantly increased neonatal cardiomyocyte Ca2+ transient frequency from 0.33 ± 0.4 Hz to 0.77 ± 0.04 Hz following 24 h treatment; these Ca2+-handling abnormalities were completely prevented by ETZ (0.28 ± 0.07 Hz). Our study demonstrates a novel role for CA in mediating the hypertrophic response of cardiac myocytes to PE and suggests that CA inhibition represents an effective therapeutic approach towards mitigation of the hypertrophic phenotype. PMID:17124262

  19. Intracranial hypertension: was it really idiopathic?

    PubMed

    Williams, Manon Wyn; Vishwanath, Mandagere

    2011-01-01

    A healthy 44-year-old slim female presented with a constant, non-specific dull headache of subacute onset. The examination showed papilloedema but no other problem. On further questioning she revealed transient visual obscurations and pulsatile tinnitus. The CT scan of the brain was normal, the lumbar puncture showed increased pressure but normal cerebrospinal fluid, and the MR scan and MR venogram was reported showing a small area of developmental venous anomaly in the left parietal region but no venous thrombosis. Benign intracranial hypertension (BIH) was diagnosed but later in the course further tests were done as the patient was atypical for BIH, which revealed essential thrombocythaemia. A CT venogram was arranged which showed partly recanalised chronic sigmoid sinus thrombosis with dilation of collaterals. The patient was treated with acetazolamide, wafarin and hydroxycarbamide. The headache resolved quickly and the papilloedema reduced significantly over 6 months. PMID:22696634

  20. Carbonic Anhydrase Inhibitors: Design, Synthesis, and Biological Evaluation of Novel Sulfonyl Semicarbazide Derivatives

    PubMed Central

    2014-01-01

    A series of novel sulfonyl semicarbazides 5–13 was designed, synthesized, and evaluated for human carbonic anhydrase (hCA) inhibition. The new sulfonyl semicarbazides were tested against a panel of hCA isoforms I, II, IX, and XII, using acetazolamide (AZA, 1) as standard. All the sulfonyl semicarbazides showed subnanomolar affinity for hCA XII (pKi range 0.59–0.79 nM) and high selectivity over hCA I (58–114-fold) and hCA IX (26–114-fold) compared to hCA II (5–20-fold except 11, 121-fold). The importance of the nature of para-substitution on the sulfonyl substituted aromatic ring for potency and selectivity against one hCA isoform versus others is discussed. Overall, the research work led to the development of highly potent and selective hCA inhibitors. PMID:25050167

  1. Free-solution interaction assay of carbonic anhydrase to its inhibitors using back-scattering interferometry.

    PubMed

    Morcos, Ereny F; Kussrow, Amanda; Enders, Carolyn; Bornhop, Darryl

    2010-11-01

    Back-scattering interferometry (BSI) is a label-free, free-solution, small-volume technique used for characterizing binding interactions, which is also relevant to a growing number of biosensing applications including drug discovery. Here, we use BSI to characterize the interaction of carbonic anhydrase enzyme II with five well-known carbonic anhydrase enzyme II inhibitors (± sulpiride, sulfanilamide, benzene sulfonamide, dansylamide, and acetazolamide) in the presence of DMSO. Dissociation constants calculated for each interaction were consistent with literature values previously obtained using surface plasmon resonance and fluorescence-based competition assays. Results demonstrate the potential of BSI as a drug-screening tool which is fully compatible with DMSO and does not require immobilization or labeling, therefore allowing binding interactions to be characterized in the native state. BSI has the potential for reducing labor costs, sample consumption, and assay time while providing enhanced reliability over existing techniques. PMID:20972990

  2. Carbonic anhydrase inhibition for the management of cerebral ischemia: in vivo evaluation of sulfonamide and coumarin inhibitors.

    PubMed

    Di Cesare Mannelli, Lorenzo; Micheli, Laura; Carta, Fabrizio; Cozzi, Andrea; Ghelardini, Carla; Supuran, Claudiu T

    2016-12-01

    Ischemia of brain areas is a global health problem, causing death or long-term disability. Current pharmacological options have limited impact on ischemic damages. Recently, a relationship between hypoxia and carbonic anhydrase (CA) over-expression has been highlighted suggesting CA inhibition as a possible target. This study aimed to evaluate the pharmacological profile of sulfonamide and coumarin CA inhibitors in rats underwent permanent middle cerebral artery occlusion (pMCAO). The neurological score of pMCAO rats was dramatically reduced 24 h after occlusion. Repeated subcutaneous injections of the CA inhibitors 4 and 7 (1 mg kg(-1)) were able to increase the neurological score by 40%. Compound 7 showed the tendency to reduce the volume of hemisphere infarction. The standard CA inhibitor acetazolamide was ineffective. The properties of novel CA inhibitors to improve neurological functionalities after cerebral ischemic insult are shown. The CA involvement in cerebral hypoxic phenomena deserves deeper investigations.

  3. Sleep and Breathing at High Altitude.

    PubMed

    Wickramasinghe, Himanshu; Anholm, James D.

    1999-01-01

    Sleep at high altitude is characterized by poor subjective quality, increased awakenings, frequent brief arousals, marked nocturnal hypoxemia, and periodic breathing. A change in sleep architecture with an increase in light sleep and decreasing slow-wave and REM sleep have been demonstrated. Periodic breathing with central apnea is almost universally seen amongst sojourners to high altitude, although it is far less common in long-standing high altitude dwellers. Hypobaric hypoxia in concert with periodic breathing appears to be the principal cause of sleep disruption at altitude. Increased sleep fragmentation accounts for the poor sleep quality and may account for some of the worsened daytime performance at high altitude. Hypoxic sleep disruption contributes to the symptoms of acute mountain sickness. Hypoxemia at high altitude is most severe during sleep. Acetazolamide improves sleep, AMS symptoms, and hypoxemia at high altitude. Low doses of a short acting benzodiazepine (temazepam) may also be useful in improving sleep in high altitude. PMID:11898114

  4. PET evaluation of cerebral blood flow reactivity in symptomatic and asymptomatic carotid artery stenosis

    SciTech Connect

    Dey, H.M.; Brass, L.; Rich, D.

    1994-05-01

    The purpose of this study was to use acetazolamide (AZ) enhanced O-15 water PET to evaluate cerebral perfusion reserve in symptomatic and asymptomatic carotid artery stenosis. We hypothesized that impaired vasoreactivity would be associated with symptomatic disease and a higher likelihood of future ischemic events. Twenty-two patients with significant (>75%) carotid artery occlusion underwent cerebral blood flow imaging at baseline and following AZ infusion. Paired O-15 data sets were coregistered and globally normalized. Regions of interest were drawn on baseline blood flow images and superimposed upon (AZ - baseline) difference images to derive a % change in regional blood flow after AZ administration. The results showed a significant difference in cerebral perfusion reserve between symptomatic (n=19) and asymptomatic (n=3) carotid artery disease.

  5. Woman with Sickle Cell Disease with Current Sigmoid Sinus Thrombosis and History of Inadequate Warfarin Use during a Past Thrombotic Event

    PubMed Central

    Çelikbilek, Asuman; Çelikbilek, Mehmet; Bozkurt, Alper; Karakurum Göksel, Başak; Tan, Meliha; Özdoğu, Hakan

    2009-01-01

    We report a 20-year-old woman with sickle cell disease (SCD) who presented with a severe pulsating headache, nausea, and vomiting. Her history was significant for a past thrombotic event during which she had not used anticoagulation therapy as prescribed. Her mental status was mildly confused. On funduscopic examination, papilledema and retinal hemorrhages were found. Results of a computed tomogram were normal. A lumbar puncture demonstrated increased intracranial pressure (60 cm H2O). Magnetic resonance venography demonstrated a right sigmoid sinus thrombosis. Although SCD has been reported as a cause of thrombotic dural venous sinus events, this case increases the knowledge about neurological complications of SCD. The patient was treated with low molecular weight heparin, blood transfusions, acetazolamide, and methylprednisolone, and her symptoms and signs resolved. PMID:20847926

  6. Effects of angiotensin, vasopressin and atrial natriuretic peptide on intraocular pressure in anesthetized rats

    NASA Technical Reports Server (NTRS)

    Palm, D. E.; Shue, S. G.; Keil, L. C.; Balaban, C. D.; Severs, W. B.

    1995-01-01

    The effects of atrial natriuretic peptide (ANP), vasopressin (AVP) and angiotensin (ANG) on blood and intraocular pressures of pentobarbital anesthetized rats were evaluated following intravenous, intracerebroventricular or anterior chamber routes of administration. Central injections did not affect intraocular pressure. Equipressor intravenous infusions of ANG raised, whereas AVP decreased, intraocular pressure. Direct infusions of a balanced salt solution (0.175 microliter/min) raised intraocular pressure between 30 and 60 min. Adding ANG or ANP slightly reduced this solvent effect but AVP was markedly inhibitory. An AVP-V1 receptor antagonist reversed the blunting of the solvent-induced rise by the peptide, indicating receptor specificity. Acetazolamide pretreatment lowered intraocular pressure, but the solvent-induced rise in intraocular pressure and inhibition by AVP still occurred without altering the temporal pattern. Thus, these effects appear unrelated to aqueous humor synthesis rate. The data support the possibility of intraocular pressure regulation by peptides acting from the blood and aqueous humor.

  7. Central retinal artery occlusion following orbital tumor resection: Is rapid intervention effective?

    PubMed

    Rajabi, Mohammad Taher; Naderan, Mohammad; Mohammadi, Seyed Ziaeddin Tabatabaei; Rajabi, Mohammad Bagher

    2015-08-01

    A 52-year-old male patient presented at our hospital with unilateral proptosis and vision loss in his left eye. Imaging evaluations showed orbital tumor, so the patient underwent surgery. About an hour later after tumor removal, patient developed sudden vision loss and became no light perception. Fundus evaluation revealed central retinal artery occlusion (CRAO). The patient was treated immediately with ocular massage and anterior chamber paracentesis as well as systemic therapy with mannitol and intravenous administration of acetazolamide. After thirty minutes, he recovered perception to light and then hand motion and 2 h later, it was improved to 1 m counting finger. CRAO following orbital tumor has not been reported before. We recommend ocular examination in all patients that undergo orbital surgery immediately to 2-3 h after surgery. PMID:26576528

  8. Flecainide-Responsive Myotonia Permanens With SNEL Onset: A New Case and Literature Review.

    PubMed

    Portaro, Simona; Rodolico, Carmelo; Sinicropi, Stefano; Musumeci, Olimpia; Valenzise, Mariella; Toscano, Antonio

    2016-04-01

    Sodium channel myotonias are inherited muscle diseases linked to mutations in the voltage-gated sodium channel. These diseases may also affect newborns with variable symptoms. More recently, severe neonatal episodic laryngospasm (SNEL) has been described in a small number of patients. A timely diagnosis of SNEL is crucial because a specific treatment is now available that will likely reduced laryngospasm and improve vital and cerebral outcomes. We report here on an 8-year-old girl who had presented, at birth, with SNEL who subsequently developed myotonia permanens starting at age 3 years. Results of molecular analysis revealed a de novo SCN4A G1306E mutation. The girl was treated with carbamazepine, acetazolamide, and mexiletine, with little improvement; after switching her treatment to flecainide, she experienced a dramatic reduction in muscle stiffness and myotonic symptoms as well as an improvement in behavior. PMID:26944947

  9. A Gain-of-Function Mutation in NALCN in a Child with Intellectual Disability, Ataxia, and Arthrogryposis.

    PubMed

    Aoyagi, Kyota; Rossignol, Elsa; Hamdan, Fadi F; Mulcahy, Ben; Xie, Lin; Nagamatsu, Shinya; Rouleau, Guy A; Zhen, Mei; Michaud, Jacques L

    2015-08-01

    NALCN and its homologues code for the ion channel responsible for half of background Na(+) -leak conductance in vertebrate and invertebrate neurons. Recessive mutations in human NALCN cause intellectual disability (ID) with hypotonia. Here, we report a de novo heterozygous mutation in NALCN affecting a conserved residue (p.R1181Q) in a girl with ID, episodic and persistent ataxia, and arthrogryposis. Interestingly, her episodes of ataxia were abolished by the administration of acetazolamide, similar to the response observed in episodic ataxia associated with other ion channels. Introducing the analogous mutation in the Caenorhabditis elegans homologue nca-1 induced a coiling locomotion phenotype, identical to that obtained with previously characterized C. elegans gain-of-function nca alleles, suggesting that p.R1181Q confers the same property to NALCN. This observation thus suggests that dominant mutations in NALCN can cause a neurodevelopmental phenotype that overlaps with, while being mostly distinct from that associated with recessive mutations in the same gene.

  10. [Alternating hemiplegia in childhood. Clinical report and single photon emission computed tomography study].

    PubMed

    Siemes, H; Casaer, P

    1988-08-01

    From 6 months of age on this girl experienced frequent episodes of hemiplegia involving both sides of the body and lasting up to 8 days. The attacks were often precipitated by tonic deviation of the head and/or the eyes to one side and nystagmus. At this stage the girl used to cry. Squinting, tonic stiffening of body and extremities, and dystonic posturing also occurred. Autonomic dysfunctions such as paleness of the skin, sweating, respiratory embarrassment, tachycardia, and mydriasis were associated features of the attacks. Motor and mental development of the girl is delayed. Improvement concerning severity, duration and frequency of the attacks has been achieved by permanent treatment with flunarizine in combination with acetazolamide and acetylsalicylic acid. If the child falls asleep immediately after rectal application of chloral hydrate at the onset of an attack there is no hemiplegia after awakening. PMID:3265484

  11. Characterization, bioinformatic analysis and dithiocarbamate inhibition studies of two new α-carbonic anhydrases, CAH1 and CAH2, from the fruit fly Drosophila melanogaster.

    PubMed

    Syrjänen, Leo; Tolvanen, Martti E E; Hilvo, Mika; Vullo, Daniela; Carta, Fabrizio; Supuran, Claudiu T; Parkkila, Seppo

    2013-03-15

    Carbonic anhydrases (CAs) are essential and ubiquitous enzymes. Thus far, there are no articles on characterization of Drosophila melanogaster α-CAs. Data from invertebrate CA studies may provide opportunities for anti-parasitic drug development because α-CAs are found in many parasite or parasite vector invertebrates. We have expressed and purified D. melanogaster CAH1 and CAH2 as proteins of molecular weights 30kDa and 28kDa. CAH1 is cytoplasmic whereas CAH2 is a membrane-attached protein. Both are highly active enzymes for the CO2 hydration reaction, being efficiently inhibited by acetazolamide. CAH2 in the eye of D. melanogaster may provide a new animal model for CA-related eye diseases. A series of dithiocarbamates were also screened as inhibitors of these enzymes, with some representatives showing inhibition in the low nanomolar range. PMID:22989910

  12. Management of Root Resorption Using Chemical Agents: A Review

    PubMed Central

    Mohammadi, Zahed; C. Cehreli, Zafer; Shalavi, Sousan; Giardino, Luciano; Palazzi, Flavio; Asgary, Saeed

    2016-01-01

    Root resorption (RR) is defined as the loss of dental hard tissues because of clastic activity inside or outside of tooth the root. In the permanent dentition, RR is a pathologic event; if untreated, it might result in the premature loss of the affected tooth. Several hypotheses have been suggested as the mechanisms of root resorption such as absence of the remnants of Hertwig's epithelial root sheath (HERS) and the absence of some intrinsic factors in cementum and predentin such as amelogenin or osteoprotegerin (OPG). It seems that a barrier is formed by the less-calcified intermediate cementum or the cementodentin junction that prevents external RR. There are several chemical strategies to manage root resorption. The purpose of this paper was to review several chemical agents to manage RR such as tetracycline, sodium hypochlorite, acids (citric acid, phosphoric acid, ascorbic acid and hydrochloric acid), acetazolamide, calcitonin, alendronate, fluoride, Ledermix and Emdogain. PMID:26843869

  13. Pharmacologic Approaches to Electrolyte Abnormalities in Heart Failure.

    PubMed

    Grodin, Justin L

    2016-08-01

    Electrolyte abnormalities are common in heart failure and can arise from a variety of etiologies. Neurohormonal activation from ventricular dysfunction, renal dysfunction, and heart failure medications can perturb electrolyte homeostasis which impact both heart failure-related morbidity and mortality. These include disturbances in serum sodium, chloride, acid-base, and potassium homeostasis. Pharmacological treatments differ for each electrolyte abnormality and vary from older, established treatments like the vaptans or acetazolamide, to experimental or theoretical treatments like hypertonic saline or urea, or to newer, novel agents like the potassium binders: patiromer and zirconium cyclosilicate. Pharmacologic approaches range from limiting electrolyte intake or directly repleting the electrolyte, to blocking or promoting their resorption, and to neurohormonal antagonism. Because of the prevalence and clinical impact of electrolyte abnormalities, understanding both the older and newer therapeutic options is and will continue to be necessity for the management of heart failure. PMID:27278221

  14. Vertebrobasilar insufficiency revealed by xenon-133 inhalation SPECT

    SciTech Connect

    Delecluse, F.; Voordecker, P.; Raftopoulos, C.

    1989-07-01

    A study of cerebral and cerebellar blood flow reactivity to acetazolamide by xenon-133-inhalation single photon emission computed tomography (/sup 133/Xe SPECT) was carried out in a patient with bouts of transient basilar ischemia, whose neurological examination, computed tomographic scan, and auditory evoked potentials were normal. Though the patient was symptom-free at the time of the study, /sup 133/Xe SPECT demonstrated vertebrobasilar insufficiency by showing an impaired vasodilatory response in both the occipital lobes and the right cerebellar hemisphere. Three weeks later, the patient suffered an extensive stroke in these same areas. We therefore suggest that this method could be of great value in the assessment of vertebrobasilar insufficiency.

  15. A 17-year-old male with pseudotumor cerebri secondary to performance-enhancing steroids triggering venous thrombosis in the brain.

    PubMed

    DeSena, Allen D; Weimer, Stephen

    2009-03-01

    This article is a case report of a 17-year-old male who presented with a headache and blurry vision. He subsequently was noted to have papilledema on a fundoscopic examination and an initial normal magnetic resonance imaging and computed tomography of his head; his condition was, therefore, diagnosed as pseudotumor cerebri. A subsequent magnetic resonance venography of his head revealed venous thrombosis, and other investigations revealed an elevated factor VIII level as well as a mutation at the MTHFR locus, consistent with an elevated risk for hypercoagulability. In addition, he admitted to steroid usage for purposes of performance enhancement in baseball. The patient's condition eventually improved with acetazolamide and serial lumbar punctures. Steroids have been linked to predisposition to hypercoagulable states, but there are no reports identified by these authors that link performance-enhancing steroids with pseudotumor cerebri as a result of a coagulation dyscrasia.

  16. [Pseudotumor cerebri secondary to consumption of minocycline in a pediatric patient].

    PubMed

    González Gili, Lucas O; Buffone, Ignacio R; Carrara, Laura E; Coto, María B; Fortunatti, Eliana A; Dejtera, Mabel; García Elliot, María F; Giacone, Alejandra; Luncio, Anabella C; Masnicoff, Sebastián D; Oviedo Crosta, María B; Parroua, Marianela; Romano, Mariana

    2016-04-01

    Pseudotumor cerebri is a syndrome characterized by an elevated intracranial pressure greater than 20 cmH2O with ventricles and cerebrospinal fluid of normal characteristics. Consumption of minocycline have been described among the causes associated with this syndrome. We present a 13-year old female patient with a history of acne treated with minocycline who began with severe headache, diplopia and blurred vision. The diagnosis of pseudotumor cerebri was made, indicating the immediate antibiotic suspension and the beginning of the treatment with acetazolamide. Although the pathogenesis of pseudotumor cerebri is not fully known, an association with minocycline has been observed. This antibiotic is often used by health professionals for the management of acne, so it is important to consider its complications before being prescribed.

  17. [Central apnea in newborns].

    PubMed

    van Putten, M J; Bosman-Vermeeren, J M; Brouwer, O F

    1999-02-27

    Three neonates had diverse kinds of central apnoea. The first child, a girl aged 3 weeks, had an upper respiratory tract infection caused by the respiratory syncytial virus; she was intubated and needed ventilatory support for three days. The second patient, a boy of 17 days, had an Arnold-Chiari-malformation with apnoeas treated with a carbonic anhydrase inhibitor (acetazolamide). The third patient, a boy of 5 days, had central apnoeas of epileptic origin and was treated with phenobarbital. All three recovered well. If in an infant with apnoeas no paediatric explanation is found, and the child is neurologically at risk, it is advisable to make an EEG to determine if an epileptic substrate is present, even in the absence of motor phenomena. PMID:10221119

  18. Sulfamates of methyl triterpenoates are effective and competitive inhibitors of carbonic anhydrase II.

    PubMed

    Schwarz, Stefan; Sommerwerk, Sven; Lucas, Susana D; Heller, Lucie; Csuk, René

    2014-10-30

    Carbonic anhydrase II, belonging to one of the most important enzyme groups of the human body, is a well-studied isozyme from the family of the carbonic anhydrases. Since it is involved in several physiological processes, it has been a pharmaceutical target for many years. In this study we synthesized a number of sulfamates derived from pentacyclic methyl triterpenoates, and we demonstrate their potential as carbonic anhydrase II inhibitors using the well-established photometric 4-nitrophenyl acetate assay. Inhibition constants, as an indicator of their inhibition strength, were in the micromolar range; one compound (10, methyl (3β) 3-(aminosulfonyloxy)-oleanoate) showed a Ki value as low as 0.3 μM. This Ki value is comparable to that of acetazolamide which is a potent carbonic anhydrase inhibitor and a drug for the treatment of glaucoma.

  19. The blockade of GABA mediated responses in the frog spinal cord by ammonium ions and furosemide.

    PubMed Central

    Nicoll, R A

    1978-01-01

    1. A variety of compounds which are known to block chloride transport in a variety of systems have been examined for their effects on amino acid and synaptic responses in the frog spinal cord in vitro. 2. A number of monocarboxylic aromatic acids, copper sulphate, and acetazolamide had no effect on any of the responses. 3. Ammonium ions blocked the motoneurone hyperpolarizing responses to all the neutral amino acids. In addition it selectively blocked dorsal root potentials and the action of GABA and beta-alanine on primary afferents. 5. Intracellular recording from dorsal root ganglion cells demonstrated that furosemide had little effect on the reversal potential for the GABA response. These results suggest that furosemide acts primarily by blocking the conductance increase elicited by GABA. 6. The results with furosemide provide indirect evidence that chloride ions are involved in generating the GABA depolarizations of primary afferent terminals and dorsal root potentials. PMID:722571

  20. Chronic meningitis with intracranial hypertension and bilateral neuroretinitis following Mycoplasma pneumoniae infection.

    PubMed

    Karampatsas, Konstantinos; Patel, Himanshu; Basheer, Sheikh N; Prendergast, Andrew J

    2014-12-23

    A previously well 12-year-old boy presented with a 2-week history of headache, nausea, vomiting and left-sided weakness. He subsequently developed meningism, right abducens nerve palsy, persistent papilloedema and reduced visual acuity in association with a bilateral macular star, consistent with neuroretinitis. Cerebrospinal fluid (CSF) examination indicated chronic meningitis and serological testing confirmed recent Mycoplasma pneumoniae infection, although PCR in CSF was negative. He was treated for aseptic meningitis with ceftriaxone, aciclovir, azithromycin and acetazolamide for intracranial hypertension, with gradual improvement in clinical condition and visual acuity over several weeks. This is the first report of M. pneumoniae chronic meningitis further complicated with bilateral neuroretinitis and intracranial hypertension. Evidence of central nervous system inflammation in the absence of direct infection suggests an immune-mediated pathophysiology. Although the use of macrolides with antibiotic and immunomodulatory activity might be beneficial, it was not possible to ascertain whether it influenced clinical recovery in this case.

  1. Type I Chiari malformation presenting central sleep apnea.

    PubMed

    Kitamura, Takuro; Miyazaki, Soichiro; Kadotani, Hiroshi; Kanemura, Takashi; Okawa, Masako; Tanaka, Toshihiko; Komada, Ichiro; Hatano, Taketo; Suzuki, Hideaki

    2014-04-01

    Sleep apnea is a rare but a well-known clinical feature of type I Chiari malformation. It may be obstructive or central in nature. Sleep apnea in patients with type I Chiari malformation rarely presents without accompanying neurological signs or symptoms. We here report a case of a 10-year-old girl who presented with central sleep apnea without any other neurological signs but was ultimately diagnosed with type I Chiari malformation. The patient initially showed mild improvement in symptoms after administration of an acetazolamide. Finally, posterior fossa decompression dramatically improved her respiratory status during sleep, both clinically and on polysomnography. This case suggests that type I Chiari malformation should be considered in the differential diagnoses of central apneas in children, even if there are no other neurological signs and symptoms. Furthermore, sagittal craniocervical magnetic resonance imaging may be necessary for a definitive diagnosis.

  2. Drugs, food additives and natural products as promoters in rat urinary bladder carcinogenesis.

    PubMed

    Ito, N; Fukushima, S; Shirai, T; Hagiwara, A; Imaida, K

    1984-01-01

    The promoting effects of various chemicals on urinary bladder carcinogenesis in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were studied. Male Fischer 344 rats were given BBN at 0.01% or 0.05% in their drinking-water for four weeks. One of the following chemicals was then administered in the diet for 32 or 34 weeks: acetazolamide, allopurinol, phenobarbital, phenacetin, ortho-phenylphenol, sodium ortho-phenylphenate, diphenyl, sodium L-ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, sodium saccharin, aspartame, sodium cyclamate, stevioside, DL-tryptophan, quercetin, caffeine, nicotine and hippuric acid. Phenacetin, sodium ortho-phenylphenate, sodium L-ascorbate and butylated hydroxyanisole were significant promoters of urinary bladder neoplasia in rats initiated with BBN. Sodium saccharin, diphenyl, butylated hydroxytoluene, allopurinol, and DL-tryptophan caused moderate or slight promotion of neoplastic changes in the experimental animals. No change in tumour yield was observed after administration of the other chemicals.

  3. Neuro-Ophthalmological Manifestations after Intramuscular Medroxyprogesterone: A Forme Fruste of Idiopathic Intracranial Hypertension?

    PubMed Central

    Bahall, Mandreker; Reyes, Antonio Jose; Ramcharan, Kanterpersad; Hosein, Nadeem; Seegobin, Karan; Bahall, Krishni; Sharma, Hiranyadeva; Dhansingh, Stephanie; Mahabir, Amanda

    2016-01-01

    We report a case of a 22-year-old female student nurse who presented to hospital with an acute neuro-ophthalmological syndrome characterized by papilledema, ataxia, ophthalmoplegia and headache after a single first time use of 150 mg medroxyprogesterone intramuscular injection. Clinical, laboratory, radiological and ophthalmological investigations were in keeping with the diagnosis of idiopathic intracranial hypertension but lumbar puncture did not show a raised cerebrospinal fluid pressure suggesting a forme fruste of this entity. Her neuro-ophthalmological clinical features responded well to acetazolamide and diagnostic/therapeutic lumbar puncture. Full recovery was achieved three months after medroxyprogesterone usage. Health care providers must be aware of this adverse drug reaction. PMID:27761224

  4. A neurogenic basis for acute altitude illness.

    PubMed

    Krasney, J A

    1994-02-01

    Acute altitude illnesses include acute mountain sickness (AMS), a benign condition involving headache, nausea, vomiting, irritability, insomnia, dizziness, lethargy, and peripheral edema, and potentially lethal high-altitude cerebral edema and pulmonary edema (HAPE). Recent evidence is summarized that AMS is related to cerebral edema secondary at least in part to hypoxic cerebral vasodilation and elevated cerebral capillary hydrostatic pressure. This results in reduced brain compliance with compression of intracranial structures in the absence of altered global brain metabolism. It is postulated that these primary intracranial events elevate peripheral sympathetic activity that acts neurogenically in the lung possibly in concert with pulmonary capillary stress failure to cause HAPE and in the kidney to promote salt and water retention. The adrenergic responses are likely modulated by striking increases of aldosterone, vasopressin and atrial natriuretic peptide. The effects of exercise on altitude-induced illness and various therapeutic regimens (acetazolamide, CO2 breathing, dexamethasone, and alpha adrenergic inhibitors) are discussed in light of this hypothesis.

  5. Brain but not retinal glial cells have carbonic anhydrase activity in the honeybee drone.

    PubMed

    Walz, B

    1988-02-15

    Carbonic anhydrase (CA) activity was localized histochemically in the retina and brain of the honeybee drone. A positive reaction that could be inhibited with 10(-5) M acetazolamide was found only in brain glial cells such as those in the lamina and medulla of the optic lobes. In the retina, neither the photoreceptors nor the pigmented glial cells showed CA activity. Hence, there is a marked difference between retinal and brain glial cells with respect to those functions thought to be performed by CA. This study extends the range of tissues in which CA has been shown to be localized in glial cells, but the absence of CA from the retina will impose constraints on a general explanation of the role of CA in nervous tissue.

  6. The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932-2015).

    PubMed

    Buzás, György M; Supuran, Claudiu T

    2016-08-01

    Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) started to be used in the treatment of peptic ulcers in the 1970s, and for more than two decades, a group led by Ioan Puşcaş used them for this purpose, assuming that by inhibiting the gastric mucosa CA isoforms, hydrochloric acid secretion is decreased. Although acetazolamide and other sulfonamide CAIs are indeed effective in healing ulcers, the inhibition of CA isoforms in other organs than the stomach led to a number of serious side effects which made this treatment obsolete when the histamine H2 receptor antagonists and the proton pump inhibitors became available. Decades later, in 2002, it has been discovered that Helicobacter pylori, the bacterial pathogen responsible for gastric ulcers and cancers, encodes for two CAs, one belonging to the α-class and the other one to the β-class of these enzymes. These enzymes are crucial for the life cycle of the bacterium and its acclimation within the highly acidic environment of the stomach. Inhibition of the two bacterial CAs with sulfonamides such as acetazolamide, a low-nanomolar H. pylori CAI, is lethal for the pathogen, which explains why these compounds were clinically efficient as anti-ulcer drugs. Thus, the approach promoted by Ioan Puşcaş for treating this disease was a good one although the rationale behind it was wrong. In this review, we present a historical overview of the sulfonamide CAIs as anti-ulcer agents, in memoriam of the scientist who was in the first line of this research trend.

  7. CAUSES AND CONSEQUENCES OF ZINC DYSHOMEOSTASIS IN RATS WITH CHRONIC ALDOSTERONISM

    PubMed Central

    Gandhi, Malay S.; Deshmukh, Prajwal A.; Kamalov, German; Zhao, Tieqiang; Zhao, Wenyuan; Whaley, Jonathan T.; Tichy, Jill R.; Bhattacharya, Syamal K.; Ahokas, Robert A.; Sun, Yao; Gerling, Ivan C.; Weber, Karl T.

    2009-01-01

    Iterations in Ca2+ and Mg2+ balance accompany aldosteronism (inappropriate for dietary Na+ intake). Increased Zn excretion and Zn translocation to injured tissues, including the heart, also occurs. Several causes and consequences of Zn dyshomeostasis in rats receiving aldosterone/salt treatment (ALDOST) were examined: 1) the role of urinary acidification in promoting hyperzincuria, acetazolamide (75 mg/kg), a carbonic anhydrase inhibitor, was used as cotreatment to raise urinary HCO3− excretion; 2) assess Zn levels in the heart, including cardiomyocyte cytosolic free [Zn2+]i and mitochondrial Zn, the expression of metallothionein (MT-I), a Zn binding protein, and biomarkers of oxidative stress; and 3) monitor oxidative stress and cardiac pathology in response to ZnSO4 supplement (40 mg/day). Compared to controls, at 4 wks ALDOST we found: an acidification of urine and metabolic alkalosis associated with increased urinary Zn excretion and hypozincemia, each of which were prevented by acetazolamide; a rise in cardiac Zn including increased [Zn2+]i and mitochondrial Zn, associated with increased tissue MT-I, 8-isoprostane, malondialdehyde, and gp91phox, coupled with oxidative stress in plasma and urine; and ZnSO4 prevented hypozincemia, but not ionized hypocalcemia, and attenuated oxidative stress and microscopic scarring without preventing the vasculitis and perivascular fibrosis of intramural coronary arteries. Thus, the hyperzincuria seen with ALDOST is due to urinary acidification. The oxidative stress that appears in the heart is accompanied by increased tissue Zn serving as an antioxidant. Cotreatment with ZnSO4 attenuated cardiomyocyte necrosis, however, polynutrient supplement may be required to counteract the dyshomeostasis of all 3 cations that accompanies aldosteronism and contribute to cardiac pathology. PMID:18806605

  8. Evidence from simultaneous intracellular- and surface-pH transients that carbonic anhydrase IV enhances CO2 fluxes across Xenopus oocyte plasma membranes.

    PubMed

    Musa-Aziz, Raif; Occhipinti, Rossana; Boron, Walter F

    2014-11-01

    Human carbonic anhydrase IV (CA IV) is GPI-anchored to the outer membrane surface, catalyzing CO2/HCO3 (-) hydration-dehydration. We examined effects of heterologously expressed CA IV on intracellular-pH (pHi) and surface-pH (pHS) transients caused by exposing oocytes to CO2/HCO3 (-)/pH 7.50. CO2 influx causes a sustained pHi fall and a transient pHS rise; CO2 efflux does the opposite. Both during CO2 addition and removal, CA IV increases magnitudes of maximal rate of pHi change (dpHi/dt)max, and maximal pHS change (ΔpHS) and decreases time constants for pHi changes (τpHi ) and pHS relaxations (τpHS ). Decreases in time constants indicate that CA IV enhances CO2 fluxes. Extracellular acetazolamide blocks all CA IV effects, but not those of injected CA II. Injected acetazolamide partially reduces CA IV effects. Thus, extracellular CA is required for, and the equivalent of cytosol-accessible CA augments, the effects of CA IV. Increasing the concentration of the extracellular non-CO2/HCO3 (-) buffer (i.e., HEPES), in the presence of extracellular CA or at high [CO2], accelerates CO2 influx. Simultaneous measurements with two pHS electrodes, one on the oocyte meridian perpendicular to the axis of flow and one downstream from the direction of extracellular-solution flow, reveal that the downstream electrode has a larger (i.e., slower) τpHS , indicating [CO2] asymmetry over the oocyte surface. A reaction-diffusion mathematical model (third paper in series) accounts for the above general features, and supports the conclusion that extracellular CA, which replenishes entering CO2 or consumes exiting CO2 at the extracellular surface, enhances the gradient driving CO2 influx across the cell membrane.

  9. Drug Use on Mont Blanc: A Study Using Automated Urine Collection

    PubMed Central

    Robach, Paul; Trebes, Gilles; Lasne, Françoise; Buisson, Corinne; Méchin, Nathalie; Mazzarino, Monica; de la Torre, Xavier; Roustit, Matthieu; Kérivel, Patricia; Botré, Francesco; Bouzat, Pierre

    2016-01-01

    Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance. PMID:27253728

  10. Thermodynamics of binding of Zn2+ to carbonic anhydrase inhibitors

    NASA Astrophysics Data System (ADS)

    Remko, Milan; Garaj, Vladimír

    The Becke3LYP functional of DFT theory and the two-layered ONIOM (B3LYP/6-311+G(d,p): MNDO) method were used to characterize 46 gas-phase complexes of 34 neutral and anionic ligands (H2O, CH3OH, CH3COOH, CH3CONH2, HOSO2NH2, CO2, HSO2NH2, CH3SO2NH2, CH3C(=O)NHOH, imidazole, NH2SO2NH2, anions of 4-aminobenzenesulphonamide, saccharin, 1I9L, brinzolamide, dorzolamide, acetazolamide, further HO(-), CH3O(-), CH3COO(-), CH3CONH(-), N=N=N(-), S=C=N(-), CH3C(=O)NHO(-), HOCOO(-), imidazoleN(-), phenol-O(-), HOSO2NH(-), (-)OSO2NH(-), (-)OSO2NH2, H2NSO2NH(-), HSO2NH(-), CH3SO2NH(-), and CF3SO2NH(-), respectively) with Zn2+. Proton dissociation enthalpies and Gibbs energies of acidic inhibitors in the presence of zinc were computed. Their gas-phase acidity considerably increases upon chelation. Of the bases investigated, the weakest zinc affinity is exhibited by carbon dioxide (-313.5 kJ mol-1). Deprotonated inhibitors have higher affinities for zinc than the neutral ones. Compared to the other mono-deprotonated ligands the acetohydroxamic acid anion has the highest affinity for zinc (-1872.7 kJ mol-1). The zinc affinity of the acetazolamide anion computed using the hybrid ONIOM (B3LYP/6-311+G(d,p): MNDO) method is in very good agreement with the full DFT ones and this method can be adopted to model large complexes of inhibitors with the active site of carbonic anhydrase.

  11. Positron emission tomography/magnetic resonance hybrid scanner imaging of cerebral blood flow using 15O-water positron emission tomography and arterial spin labeling magnetic resonance imaging in newborn piglets

    PubMed Central

    Andersen, Julie B; Henning, William S; Lindberg, Ulrich; Ladefoged, Claes N; Højgaard, Liselotte; Greisen, Gorm; Law, Ian

    2015-01-01

    Abnormality in cerebral blood flow (CBF) distribution can lead to hypoxic–ischemic cerebral damage in newborn infants. The aim of the study was to investigate minimally invasive approaches to measure CBF by comparing simultaneous 15O-water positron emission tomography (PET) and single TI pulsed arterial spin labeling (ASL) magnetic resonance imaging (MR) on a hybrid PET/MR in seven newborn piglets. Positron emission tomography was performed with IV injections of 20 MBq and 100 MBq 15O-water to confirm CBF reliability at low activity. Cerebral blood flow was quantified using a one-tissue-compartment-model using two input functions: an arterial input function (AIF) or an image-derived input function (IDIF). The mean global CBF (95% CI) PET-AIF, PET-IDIF, and ASL at baseline were 27 (23; 32), 34 (31; 37), and 27 (22; 32) mL/100 g per minute, respectively. At acetazolamide stimulus, PET-AIF, PET-IDIF, and ASL were 64 (55; 74), 76 (70; 83) and 79 (67; 92) mL/100 g per minute, respectively. At baseline, differences between PET-AIF, PET-IDIF, and ASL were 22% (P<0.0001) and −0.7% (P=0.9). At acetazolamide, differences between PET-AIF, PET-IDIF, and ASL were 19% (P=0.001) and 24% (P=0.0003). In conclusion, PET-IDIF overestimated CBF. Injected activity of 20 MBq 15O-water had acceptable concordance with 100 MBq, without compromising image quality. Single TI ASL was questionable for regional CBF measurements. Global ASL CBF and PET CBF were congruent during baseline but not during hyperperfusion. PMID:26058699

  12. Drug Use on Mont Blanc: A Study Using Automated Urine Collection.

    PubMed

    Robach, Paul; Trebes, Gilles; Lasne, Françoise; Buisson, Corinne; Méchin, Nathalie; Mazzarino, Monica; de la Torre, Xavier; Roustit, Matthieu; Kérivel, Patricia; Botré, Francesco; Bouzat, Pierre

    2016-01-01

    Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance. PMID:27253728

  13. Ionic mechanisms of Ca(2+)-dependent electrolyte transport across equine sweat gland epithelium.

    PubMed Central

    Ko, W H; Chan, H C; Chew, S B; Wong, P Y

    1996-01-01

    1. The ionic mechanism involved in Ca(2+)-stimulated electrolyte transport in cultured equine sweat gland epithelial cells was studied using the short-circuit current (ISC) technique. 2. Microscopy revealed that the cultured cells grown on Millipore filters formed polarized monolayers with tight junctions. Monolayers exhibited a mean transepithelial resistance of 333.9 +/- 40.4 omega cm2. 3. Ca(2+)-mobilizing agents, A23187 (1 microM) or thapsigargin (0.01-1 microM), stimulated ISC while forskolin exerted little effect on the ISC. 4. Replacement of external Cl- by gluconate significantly reduced the ISC by 63% when stimulated by 0.1 microM thapsigargin. Residual ISC could be abolished (> 99%) by elimination of HCO3- from the bathing solution. 5. Basolateral addition of bumetanide (0.1 mM), ouabain (0.01 mM) and acetazolamide (45 microM) and apical addition of methyl isobutyl amiloride (MIA, 1-100 microM) all had inhibitory effects on the thapsigargin-stimulated ISC to various extents. 6. Substantial current inhibition could be obtained using 4, 4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and diphenylamine-2-carboxylate (DPC) in a concentration-dependent manner. 7. The K+ channel blocker barium (5 mM) was effective on both sides of the epithelium with a much larger effect on the basolateral side. 8. The inhibitory effects of acetazolamide, amiloride, MIA, DIDS and DPC on the thapsigargin-stimulated ISC were also observed when a Cl(-)-free solution was used. 9. The results provide evidence for Ca(2+)-stimulated HCO3- as well as Cl- secretion by equine sweat gland epithelium. Images Figure 1 PMID:8799908

  14. The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932-2015).

    PubMed

    Buzás, György M; Supuran, Claudiu T

    2016-08-01

    Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) started to be used in the treatment of peptic ulcers in the 1970s, and for more than two decades, a group led by Ioan Puşcaş used them for this purpose, assuming that by inhibiting the gastric mucosa CA isoforms, hydrochloric acid secretion is decreased. Although acetazolamide and other sulfonamide CAIs are indeed effective in healing ulcers, the inhibition of CA isoforms in other organs than the stomach led to a number of serious side effects which made this treatment obsolete when the histamine H2 receptor antagonists and the proton pump inhibitors became available. Decades later, in 2002, it has been discovered that Helicobacter pylori, the bacterial pathogen responsible for gastric ulcers and cancers, encodes for two CAs, one belonging to the α-class and the other one to the β-class of these enzymes. These enzymes are crucial for the life cycle of the bacterium and its acclimation within the highly acidic environment of the stomach. Inhibition of the two bacterial CAs with sulfonamides such as acetazolamide, a low-nanomolar H. pylori CAI, is lethal for the pathogen, which explains why these compounds were clinically efficient as anti-ulcer drugs. Thus, the approach promoted by Ioan Puşcaş for treating this disease was a good one although the rationale behind it was wrong. In this review, we present a historical overview of the sulfonamide CAIs as anti-ulcer agents, in memoriam of the scientist who was in the first line of this research trend. PMID:26108882

  15. Mechanisms of transepithelial ammonia excretion and luminal alkalinization in the gut of an intestinal air-breathing fish, Misgurnus anguilliacaudatus.

    PubMed

    Wilson, Jonathan M; Moreira-Silva, Joana; Delgado, Inês L S; Ebanks, Sue C; Vijayan, Mathilakath M; Coimbra, João; Grosell, Martin

    2013-02-15

    The weatherloach, Misgurnus angulliacaudatus, is an intestinal air-breathing, freshwater fish that has the unique ability to excrete ammonia through gut volatilization when branchial and cutaneous routes are compromised during high environmental ammonia or air exposure. We hypothesized that transepithelial gut NH(4)(+) transport is facilitated by an apical Na(+)/H(+) (NH(4)(+)) exchanger (NHE) and a basolateral Na(+)/K(+)(NH(4)(+))-ATPase, and that gut boundary layer alkalinization (NH(4)(+) → NH(3) + H(+)) is facilitated by apical HCO(3)(-) secretion through a Cl(-)/HCO(3)(-) anion exchanger. This was tested using a pharmacological approach with anterior (digestive) and posterior (respiratory) intestine preparations mounted in pH-stat-equipped Ussing chambers. The anterior intestine had a markedly higher conductance, increased short-circuit current, and greater net base (J(base)) and ammonia excretion rates (J(amm)) than the posterior intestine. In the anterior intestine, HCO(3)(-) accounted for 70% of J(base). In the presence of an imposed serosal-mucosal ammonia gradient, inhibitors of both NHE (EIPA, 0.1 mmol l(-1)) and Na(+)/K(+)-ATPase (ouabain, 0.1 mmol l(-1)) significantly inhibited J(amm) in the anterior intestine, although only EIPA had an effect in the posterior intestine. In addition, the anion exchange inhibitor DIDS significantly reduced J(base) in the anterior intestine although only at a high dose (1 mmol l(-1)). Carbonic anhydrase does not appear to be associated with gut alkalinization under these conditions as ethoxzolamide was without effect on J(base). Membrane fluidity of the posterior intestine was low, suggesting low permeability, which was also reflected in a lower mucosal-serosal J(amm) in the presence of an imposed gradient, in contrast to that in the anterior intestine. To conclude, although the posterior intestine is highly modified for gas exchange, it is the anterior intestine that is the likely site of ammonia excretion and

  16. Evidence from simultaneous intracellular- and surface-pH transients that carbonic anhydrase II enhances CO2 fluxes across Xenopus oocyte plasma membranes.

    PubMed

    Musa-Aziz, Raif; Occhipinti, Rossana; Boron, Walter F

    2014-11-01

    The α-carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the interconversion of CO2 and HCO3 (-). Here, we focus on human CA II (CA II), a ubiquitous cytoplasmic enzyme. In the second paper in this series, we examine CA IV at the extracellular surface. After microinjecting recombinant CA II in a Tris solution (or just Tris) into oocytes, we expose oocytes to 1.5% CO2/10 mM HCO3 (-)/pH 7.50 while using microelectrodes to monitor intracellular pH (pHi) and surface pH (pHS). CO2 influx causes the familiar sustained pHi fall as well as a transient pHS rise; CO2 efflux does the opposite. Both during CO2 addition and removal, CA II increases the magnitudes of the maximal rate of pHi change, (dpHi/dt)max, and the maximal change in pHS, ΔpHS. Preincubating oocytes with the inhibitor ethoxzolamide eliminates the effects of CA II. Compared with pHS, pHi begins to change only after a delay of ~9 s and its relaxation has a larger (i.e., slower) time constant (τpHi > τpHS ). Simultaneous measurements with two pHi electrodes, one superficial and one deep, suggest that impalement depth contributes to pHi delay and higher τpHi . Using higher CO2/HCO3 (-) levels, i.e., 5%/33 mM HCO3 (-) or 10%/66 mM HCO3 (-), increases (dpHi/dt)max and ΔpHS, though not in proportion to the increase in [CO2]. A reaction-diffusion mathematical model (described in the third paper in this series) accounts for the above general features and supports the conclusion that cytosolic CA-consuming entering CO2 or replenishing exiting CO2-increases CO2 fluxes across the cell membrane.

  17. Mechanisms of transepithelial ammonia excretion and luminal alkalinization in the gut of an intestinal air-breathing fish, Misgurnus anguilliacaudatus.

    PubMed

    Wilson, Jonathan M; Moreira-Silva, Joana; Delgado, Inês L S; Ebanks, Sue C; Vijayan, Mathilakath M; Coimbra, João; Grosell, Martin

    2013-02-15

    The weatherloach, Misgurnus angulliacaudatus, is an intestinal air-breathing, freshwater fish that has the unique ability to excrete ammonia through gut volatilization when branchial and cutaneous routes are compromised during high environmental ammonia or air exposure. We hypothesized that transepithelial gut NH(4)(+) transport is facilitated by an apical Na(+)/H(+) (NH(4)(+)) exchanger (NHE) and a basolateral Na(+)/K(+)(NH(4)(+))-ATPase, and that gut boundary layer alkalinization (NH(4)(+) → NH(3) + H(+)) is facilitated by apical HCO(3)(-) secretion through a Cl(-)/HCO(3)(-) anion exchanger. This was tested using a pharmacological approach with anterior (digestive) and posterior (respiratory) intestine preparations mounted in pH-stat-equipped Ussing chambers. The anterior intestine had a markedly higher conductance, increased short-circuit current, and greater net base (J(base)) and ammonia excretion rates (J(amm)) than the posterior intestine. In the anterior intestine, HCO(3)(-) accounted for 70% of J(base). In the presence of an imposed serosal-mucosal ammonia gradient, inhibitors of both NHE (EIPA, 0.1 mmol l(-1)) and Na(+)/K(+)-ATPase (ouabain, 0.1 mmol l(-1)) significantly inhibited J(amm) in the anterior intestine, although only EIPA had an effect in the posterior intestine. In addition, the anion exchange inhibitor DIDS significantly reduced J(base) in the anterior intestine although only at a high dose (1 mmol l(-1)). Carbonic anhydrase does not appear to be associated with gut alkalinization under these conditions as ethoxzolamide was without effect on J(base). Membrane fluidity of the posterior intestine was low, suggesting low permeability, which was also reflected in a lower mucosal-serosal J(amm) in the presence of an imposed gradient, in contrast to that in the anterior intestine. To conclude, although the posterior intestine is highly modified for gas exchange, it is the anterior intestine that is the likely site of ammonia excretion and

  18. The intraocular pressure-lowering properties of intravenous paracetamol

    PubMed Central

    van den Heever, Henning; Meyer, David

    2016-01-01

    Aim The aim of this paper was to investigate the intraocular pressure (IOP)-changing properties of a single standard dose of intravenous (IV) paracetamol and compare it to that of topical timolol, oral acetazolamide, and no treatment. Methods A prospective, randomized, investigator-blind, parallel-group study was conducted in 73 eyes of 52 subjects. Subjects received a single dose of IV paracetamol (1 g), oral acetazolamide (250 mg), topical timolol (0.5%, one drop), or no treatment. Baseline IOP was measured, and the measurement was repeated at 1, 2, 4, and 6 hours after treatment. Results Paracetamol reduced IOP from baseline by −10.8% (95% confidence interval [CI]: −4.9% to −16.8%, P=0.146) at 1 hour, −13.3% (95% CI: −8.3% to −18.4%, P=0.045) at 2 hours, −11.8% (95% CI: −5.5% to −18.4%, P=1.000) at 4 hours, and −23.9% (95% CI: −17.8% to −30.1%, P=0.006) at 6 hours after treatment. In the no-treatment group, the change was −2.9% (95% CI: +1.0% to −6.7%, P= referent) at 1 hour, −2.1% (95% CI: +2.9% to −7.2%, P= referent) at 2 hours, −7.6% (95% CI: −3.9% to −11.2%, P= referent) at 4 hours, and −6.9% (95% CI: −3.6% to −10.2%, P= referent) at 6 hours. Acetazolamide reduced IOP by −18.8% (95% CI: −12.7% to −24.8%, P=0.000) at 1 hour, −26.2% (95% CI: −18.2% to −34.2%, P=0.001) at 2 hours, −24.6% (95% CI: −16.9% to −32.3%, P=0.000) after 4 hours, and −26.9% (95% CI: −19.6% to −34.3%, P=0.000) 6 hours after treatment. Timolol reduced IOP by −31.2% (95% CI: −26.7% to −35.7%, P=0.000) at 1 hour, −27.7% (95% CI: −20.7% to −34.8%, P=0.000) at 2 hours, −28.7% (95% CI: −21.1% to −36.2%, P=0.000) at 4 hours, and −21.3% (95% CI: −13.4% to −30.0%, P=0.030) at 6 hours after treatment. The average change in IOP for the no-treatment group was −4.8% (95% CI: −2.6% to −6.9%, P= referent). It was −15.7% (95% CI: −9.3% to −22.1%, P=0.021) for paracetamol, −23.1% (95% CI: −16.4% to

  19. Epithelial carbonic anhydrases facilitate PCO2 and pH regulation in rat duodenal mucosa

    PubMed Central

    Mizumori, Misa; Meyerowitz, Justin; Takeuchi, Tetsu; Lim, Shu; Lee, Paul; Supuran, Claudiu T; Guth, Paul H; Engel, Eli; Kaunitz, Jonathan D; Akiba, Yasutada

    2006-01-01

    The duodenum is the site of mixing of massive amounts of gastric H+ with secreted HCO3−, generating CO2 and H2O accompanied by the neutralization of H+. We examined the role of membrane-bound and soluble carbonic anhydrases (CA) by which H+ is neutralized, CO2 is absorbed, and HCO3− is secreted. Rat duodena were perfused with solutions of different pH and PCO2 with or without a cell-permeant CA inhibitor methazolamide (MTZ) or impermeant CA inhibitors. Flow-through pH and PCO2 electrodes simultaneously measured perfusate and effluent pH and PCO2. High CO2 (34.7 kPa) perfusion increased net CO2 loss from the perfusate compared with controls (pH 6.4 saline, PCO2 ≈ 0) accompanied by portal venous (PV) acidification and PCO2 increase. Impermeant CA inhibitors abolished net perfusate CO2 loss and increased net HCO3− gain, whereas all CA inhibitors inhibited PV acidification and PCO2 increase. The changes in luminal and PV pH and [CO2] were also inhibited by the Na+–H+ exchanger-1 (NHE1) inhibitor dimethylamiloride, but not by the NHE3 inhibitor S3226. Luminal acid decreased total CO2 output and increased H+ loss with PV acidification and PCO2 increase, all inhibited by all CA inhibitors. During perfusion of a 30% CO2 buffer, loss of CO2 from the lumen was CA dependent as was transepithelial transport of perfused 13CO2. H+ and CO2 loss from the perfusate were accompanied by increases of PV H+ and tracer CO2, but unchanged PV total CO2, consistent with CA-dependent transmucosal H+ and CO2 movement. Inhibition of membrane-bound CAs augments the apparent rate of net basal HCO3− secretion. Luminal H+ traverses the apical membrane as CO2, is converted back to cytosolic H+, which is extruded via NHE1. Membrane-bound and cytosolic CAs cooperatively facilitate secretion of HCO3− into the lumen and CO2 diffusion into duodenal mucosa, serving as important acid–base regulators. PMID:16556652

  20. Carbonic anhydrase generates a pH gradient in Bombyx mori silk glands.

    PubMed

    Domigan, L J; Andersson, M; Alberti, K A; Chesler, M; Xu, Q; Johansson, J; Rising, A; Kaplan, D L

    2015-10-01

    Silk is a protein of interest to both biological and industrial sciences. The silkworm, Bombyx mori, forms this protein into strong threads starting from soluble silk proteins using a number of biochemical and physical cues to allow the transition from liquid to fibrous silk. A pH gradient has been measured along the gland, but the methodology employed was not able to precisely determine the pH at specific regions of interest in the silk gland. Furthermore, the physiological mechanisms responsible for the generation of this pH gradient are unknown. In this study, concentric ion selective microelectrodes were used to determine the luminal pH of B. mori silk glands. A gradient from pH 8.2 to 7.2 was measured in the posterior silk gland, with a pH 7 throughout the middle silk gland, and a gradient from pH 6.8 to 6.2 in the beginning of the anterior silk gland where silk processing into fibers occurs. The small diameter of the most anterior region of the anterior silk gland prevented microelectrode access in this region. Using a histochemical method, the presence of active carbonic anhydrase was identified in the funnel and anterior silk gland of fifth instar larvae. The observed pH gradient collapsed upon addition of the carbonic anhydrase inhibitor methazolamide, confirming an essential role for this enzyme in pH regulation in the B. mori silk gland. Plastic embedding of whole silk glands allowed clear visualization of the morphology, including the identification of four distinct epithelial cell types in the gland and allowed correlations between silk gland morphology and silk stages of assembly related to the pH gradient. B. mori silk glands have four different epithelial cell types, one of which produces carbonic anhydrase. Carbonic anhydrase is necessary for the mechanism that generates an intraluminal pH gradient, which likely regulates the assembly of silk proteins and then the formation of fibers from soluble silk proteins. These new insights into native silk

  1. Acute high-altitude exposure reduces lung diffusion: data from the HIGHCARE Alps project.

    PubMed

    Agostoni, Piergiuseppe; Swenson, Erik R; Fumagalli, Roberto; Salvioni, Elisabetta; Cattadori, Gaia; Farina, Stefania; Bussotti, Maurizio; Tamplenizza, Margherita; Lombardi, Carolina; Bonacina, Daniele; Brioschi, Maura; Caravita, Sergio; Modesti, Pietro; Revera, Miriam; Giuliano, Andrea; Meriggi, Paolo; Faini, Andrea; Bilo, Grzegorz; Banfi, Cristina; Parati, Gianfranco

    2013-08-15

    The causes and development of lung fluid, as well as the integrity of the alveolar-capillary membrane at high altitude, are undefined. This study was conceived to see whether fluid accumulates within the lung with acute high altitude exposure, and whether this is associated with alveolar capillary membrane damage. We studied lung carbon monoxide diffusion (DLCO), its components - membrane diffusion (DM) and capillary volume (VC) and alveolar volume (VA) measured in 43 healthy subjects in Milan (122 m) and after 1 and 3 days at Capanna Regina Margherita (4559 m). DLCO measurement was adjusted for hemoglobin and inspired oxygen. We also measured plasma surfactant derived protein B (SPB) and Receptor of Advanced Glycation End-products (RAGE) as markers of alveolar-capillary membrane damage, and ultrasound lung comets as a marker of extravascular lung water. 21 subjects received acetazolamide and 22 placebo. DLCO was lower at Capanna Regina Margherita (day 1: 24.3 ± 4.7 and day 3: 23.6 ± 5.4 mL/mmHg/min), than in Milan (25.8 ± 5.5; p<0.001 vs. day 1 and 3) due to DM reduction (Milan: 50.5 ± 14.6 mL/mmHg/min, Capanna Regina Margherita day 1: 45.1 ± 11.5 mL/mmHg/min, day 3: 43.2 ± 13.9 mL/mmHg/min; p<0.05 Milan vs. day 3) with a partially compensatory VC increase (Milan: 96 ± 37 mL, Capanna Regina Margherita day 1: 152 ± 66 mL, day 3: 153 ± 59 mL; p<0.001 Milan vs. day 1 and day 3). Acetazolamide did not prevent the fall in DLCO albeit, between day 1 and 3, such a trend was observed. Regardless of treatment lung comets increased from 0 to 7.2 ± 3.6 (p<0.0001). SPB and RAGE were unchanged. Lung fluid increased at high altitude without evidence from plasma measurements, supporting alveolar-capillary damage. PMID:23619193

  2. Study on the cerebrovascular reserve capacity by MR perfusion weighted imaging in SHR

    NASA Astrophysics Data System (ADS)

    Zhou, Quan; Dong, Yang; Chen, WenLi; Lin, Xueying; Xing, Da; Huang, Li

    2007-05-01

    Cerebrovascular disease is one of the leading causes of death, and approximately 50% of survivors have a residual neurologic deficit and greater than 25% require chronic care. Cerebrovascular reserve capacity (CVRC) describes how far cerebral perfusion can increase from a baseline value after stimulation. High blood pressure is the most important independent risk factor for stroke and other vascular diseases. The incidence of stroke in the hypertensive is six times higher than in the patient with normal blood pressure. CVRC in the hypertensive was even lower than in control patients. MR perfusion weighted imaging (MR PWI) with the well-established acetazolamide (ACZ) stimulation test has been used for assessing brain function. The aim of this work is to assess the cerebrovascular reserve capacity by MR PWI with "ACZ" tolerance test in spontaneous hypertensive rat (SHR) and to identify its value in evaluating the CVRC. Experimental animal including 3 groups: Wistar-Kyoto rats (WKY) (12-week-old) as control group, SHR (12-week-old and 20-week-old) as experimental group. MR PWI was performed respectively before and after acetazolamide administrated orally in 3 groups on a clinical 1.5 Tesla GE Signa MR fx/i whole-body MR system. The ROI was chosen in the bilateral frontal lobe to measure the value of rCBV, rCBF and MTT. The results showed that before ACZ-test, there was statistic differences between the WKY and SHR(12-week-old), and between SHR(12-week-old) and SHR(20-week-old) in the values of rCBV and rCBF (P>0.05), and after ACZ-test, there were statistic differences between WKY and SHR (20-week-old), and between SHR(12-week-old) and SHR(20-week-old) in the rCBV value (P<0.05). It is concluded that the method of MRI PWI combined with the "ACZ stress test" can provide more qualitative and half-quantitative information on the cerebral perfusion to evaluate the CVRC in SHR.

  3. Novel Water-Soluble Mucoadhesive Carbosilane Dendrimers for Ocular Administration.

    PubMed

    Bravo-Osuna, I; Vicario-de-la-Torre, M; Andrés-Guerrero, V; Sánchez-Nieves, J; Guzmán-Navarro, M; de la Mata, F J; Gómez, R; de Las Heras, B; Argüeso, P; Ponchel, G; Herrero-Vanrell, R; Molina-Martínez, I T

    2016-09-01

    The purpose of this research was to determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (generations 1-3) as mucoadhesive polymers in eyedrop formulations. Cationic carbosilane dendrimers decorated with ammonium -NH3(+) groups were prepared by hydrosylilation of Boc-protected allylamine and followed by deprotection with HCl. Anionic carbosilane dendrimers with terminal carboxylate groups were also employed in this study. In vitro and in vivo tolerance studies were performed in human ocular epithelial cell lines and rabbit eyes respectively. The interaction of dendrimers with transmembrane ocular mucins was evaluated with a surface biosensor. As proof of concept, the hypotensive effect of a carbosilane dendrimer eyedrop formulation containing acetazolamide (ACZ), a poorly water-soluble drug with limited ocular penetration, was tested after instillation in normotensive rabbits. The methodology used to synthesize cationic dendrimers avoids the difficulty of obtaining neutral -NH2 dendrimers that require harsher reaction conditions and also present high aggregation tendency. Tolerance studies demonstrated that both prototypes of water-soluble anionic and cationic carbosilane dendrimers were well tolerated in a range of concentrations between 5 and 10 μM. Permanent interactions between cationic carbosilane dendrimers and ocular mucins were observed using biosensor assays, predominantly for the generation-three (G3) dendrimer. An eyedrop formulation containing G3 cationic carbosilane dendrimers (5 μM) and ACZ (0.07%) (289.4 mOsm; 5.6 pH; 41.7 mN/m) induced a rapid (onset time 1 h) and extended (up to 7 h) hypotensive effect, and led to a significant increment in the efficacy determined by AUC0(8h) and maximal intraocular pressure reduction. This work takes advantage of the high-affinity interaction between cationic carbosilane dendrimers and ocular transmembrane mucins, as well as the tensioactive behavior observed for these

  4. Alkalinization by chloride/bicarbonate pathway in larval mosquito midgut

    PubMed Central

    Boudko, Dmitri Y.; Moroz, Leonid L.; Harvey, William R.; Linser, Paul J.

    2001-01-01

    The midgut of mosquito larvae maintains a specific lumen alkalinization profile with large longitudinal gradients (pH ≈ 3 units⋅mm−1) in which an extremely alkaline (pH ≈ 11) anterior midgut lies between near-neutral posterior midgut and gastric cecum (pH 7–8). A plasma membrane H+ V-ATPase energizes this alkalinization but the ion carriers involved are unknown. Capillary zone electrophoresis of body samples with outlet conductivity detection showed a specific transepithelial distribution of chloride and bicarbonate/carbonate ions, with high concentrations of both anions in the midgut tissue: 68.3 ± 5.64 and 50.8 ± 4.21 mM, respectively. Chloride was higher in the hemolymph, 57.6 ± 7.84, than in the lumen, 3.51 ± 2.58, whereas bicarbonate was higher in the lumen, 58.1 ± 7.34, than the hemolymph, 3.96 ± 2.89. Time-lapse video assays of pH profiles in vivo revealed that ingestion of the carbonic anhydrase inhibitor acetazolamide and the ion exchange inhibitor DIDS (4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid), at 10−4 M eliminates lumen alkalinization. Basal application of these inhibitors in situ also reduced gradients recorded with self-referencing pH-sensitive microelectrodes near the basal membrane by ≈65% and 85% respectively. Self-referencing chloride-selective microelectrodes revealed a specific spatial profile of transepithelial chloride transport with an efflux maximum in anterior midgut. Both acetazolamide and DIDS reduced chloride effluxes. These data suggest that an H+ V-ATPase-energized anion exchange occurs across the apical membrane of the epithelial cells and implicate an electrophoretic Cl−/HCO\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} \\begin{equation*}{\\mathrm{_{3}^{-}}}\\end{equation*}\\end{document} exchanger and carbonic anhydrase as

  5. The Treatment of Central Sleep Apnea Syndromes in Adults: Practice Parameters with an Evidence-Based Literature Review and Meta-Analyses

    PubMed Central

    Aurora, R. Nisha; Chowdhuri, Susmita; Ramar, Kannan; Bista, Sabin R.; Casey, Kenneth R.; Lamm, Carin I.; Kristo, David A.; Mallea, Jorge M.; Rowley, James A.; Zak, Rochelle S.; Tracy, Sharon L.

    2012-01-01

    The International Classification of Sleep Disorders, Second Edition (ICSD-2) distinguishes 5 subtypes of central sleep apnea syndromes (CSAS) in adults. Review of the literature suggests that there are two basic mechanisms that trigger central respiratory events: (1) post-hyperventilation central apnea, which may be triggered by a variety of clinical conditions, and (2) central apnea secondary to hypoventilation, which has been described with opioid use. The preponderance of evidence on the treatment of CSAS supports the use of continuous positive airway pressure (CPAP). Much of the evidence comes from investigations on CSAS related to congestive heart failure (CHF), but other subtypes of CSAS appear to respond to CPAP as well. Limited evidence is available to support alternative therapies in CSAS subtypes. The recommendations for treatment of CSAS are summarized as follows: CPAP therapy targeted to normalize the apnea-hypopnea index (AHI) is indicated for the initial treatment of CSAS related to CHF. (STANDARD)Nocturnal oxygen therapy is indicated for the treatment of CSAS related to CHF. (STANDARD)Adaptive Servo-Ventilation (ASV) targeted to normalize the apnea-hypopnea index (AHI) is indicated for the treatment of CSAS related to CHF. (STANDARD)BPAP therapy in a spontaneous timed (ST) mode targeted to normalize the apnea-hypopnea index (AHI) may be considered for the treatment of CSAS related to CHF only if there is no response to adequate trials of CPAP, ASV, and oxygen therapies. (OPTION)The following therapies have limited supporting evidence but may be considered for the treatment of CSAS related to CHF after optimization of standard medical therapy, if PAP therapy is not tolerated, and if accompanied by close clinical follow-up: acetazolamide and theophylline. (OPTION)Positive airway pressure therapy may be considered for the treatment of primary CSAS. (OPTION)Acetazolamide has limited supporting evidence but may be considered for the treatment of primary

  6. Altitude Stress During Participation of Medical Congress.

    PubMed

    Kim, Soon Bae; Kim, Jong Sung; Kim, Sang Jun; Cho, Su Hee; Suh, Dae Chul

    2016-09-01

    Medical congresses often held in highlands. We reviewed several medical issues associated with altitude stress especially while physicians have participated medical congress held in high altitude. Altitude stress, also known as an acute mountain sickness (AMS), is caused by acute exposure to low oxygen level at high altitude which is defined as elevations at or above 1,200 m and AMS commonly occurs above 2,500 m. Altitude stress with various symptoms including insomnia can also be experienced in airplane. AMS and drunken state share many common features in symptoms, neurologic manifestations and even show multiple microbleeds in corpus callosum and white matter on MRI. Children are more susceptible to altitude stress than adults. Gradual ascent is the best method for the prevention of altitude stress. Adequate nutrition (mainly carbohydrates) and hydration are recommended. Consumption of alcohol can exacerbate the altitude-induced impairments in judgment and the visual senses and promote psychomotor dysfunction. For prevention or treatment of altitude stress, acetazolamide, phosphodiesterase inhibitors, dexamethasone and erythropoietin are helpful. Altitude stress can be experienced relatively often during participation of medical congress. It is necessary to remind the harmful effect of AMS because it can cause serious permanent organ damage even though the symptoms are negligible in most cases.

  7. Varicella Zoster Aseptic Meningitis: Report of an Atypical Case and Literature Review

    PubMed Central

    Ibrahim, Walid; Elzouki, Abdel-Naser; Husain, Ahmed; Osman, Lubna

    2015-01-01

    Patient: Female, 15 Final Diagnosis: Varicella Zoster aseptic meningitis Symptoms: — Medication: — Clinical Procedure: Lumber punctur Specialty: Infectious Diseases Objective: Unusual clinical course Background: Neurologic complications can occur with varicella zoster virus (VZV) infection, usually after vesicular exanthem. A review of the literature revealed 3 cases of viral meningitis associated with 6th nerve palsy but without significantly increased intracranial pressure. Case Report: We report a case of a previously healthy 15-year-old girl with aseptic meningitis as a result of reactivated-VZV infection with symptoms of increased intracranial pressure and reversible 6th cranial nerve palsy but without exanthema. Diagnosis was made by detection of VZV-DNA in cerebrospinal fluid using polymerase chain reaction and documented high intracranial pressure. Full recovery was achieved after a course of acyclovir and acetazolamide. Conclusions: This case demonstrates that VZV may be considered in cases of aseptic meningitis in immunocompetent individuals, even without exanthema, and it may increase the intracranial pressure, leading to symptoms, and causing reversible neurological deficit. PMID:26342350

  8. Glaucoma Surgery in Pregnancy: A Case Series and Literature Review

    PubMed Central

    Razeghinejad, Mohammad Reza; Masoumpour, Masoumeh; Eghbal, Mohammad Hossein; Myers, Jonathan S.; Moster, Marlene R.

    2016-01-01

    Glaucoma management in pregnant patients is a real challenge, especially when the glaucoma is not controlled with medications. We report the results of 6 incisional glaucoma surgeries for the management of medically uncontrolled glaucoma patients during pregnancy. This retrospective, case series was conducted on the 6 eyes of 3pregnant patients with uncontrolled glaucoma using maximum tolerable medications. Details of the glaucoma surgical management of these patients as well as their postoperative care and pregnancy and clinical outcomes on longitudinal follow-up are discussed. All 3 patients had juvenile open-angle glaucoma and were on various anti-glaucoma medications, including oral acetazolamide. The first case described underwent trabeculectomy without antimetabolites in both eyes because of uncontrolled intraocular pressure with topical medications. The surgery was done with topical lidocaine jelly and subconjunctival lidocaine during the second and third trimesters. The second patient had an Ahmed valve implantation in both eyes during the second and third trimesters because of uncontrolled IOP with topical medications and no response to selective laser trabeculoplasty. Surgery was done with topical tetracaine and subconjunctival and sub-Tenon’s lidocaine. The third case had a Baerveldt valve implantation under general anesthesia in the second trimester. In selected pregnant glaucoma patients with medically uncontrolled intraocular pressure threatening vision, incisional surgery may lead to good outcomes for the patient with no risk for the fetus. PMID:27582594

  9. The antioxidative effect of a novel free radical scavenger 4'-hydroxyl-2-substituted phenylnitronyl nitroxide in acute high-altitude hypoxia mice.

    PubMed

    Fan, Peng-Cheng; Ma, Hui-Ping; Jing, Lin-lin; Li, Lin; Jia, Zheng-Ping

    2013-01-01

    Acute mountain sickness is caused by sub-acute hypoxia in healthy individuals going rapidly to altitude. Both tissue hypoxia in vitro and whole-body hypoxia in vivo have been found to promote the release of reactive oxygen species. Nitronyl nitroxide can trap free radicals such as ·NO or ·OH, and may therefore be efficient protective agents. This study assessed the ability of nitronyl nitroxide to against acute mountain sickness as a free radical scavenger in acute high-altitude hypoxia mice model. Normobaric hypoxia and hypobaric hypoxia model were used to estimate the protect effects of nitronyl nitroxide against acute mountain sickness. Low pressure oxygen compartment system was used to stimulate high-altitude hypobaric hypoxia environment. Mice in nitronyl nitroxide groups survived longer than acetazolamide group in normobaric hypoxia test. Hydrogen peroxide (H2O2) and malondialdehyde (MDA) increased in both cerebrum and myocardium in vehicle group. The results indicated more radicals were generated during high-altitude hypobaric hypoxia environment. In therapeutic groups H2O2 and MDA were significantly reduced while the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were similar to normal group. These results demonstrated that nitronyl nitroxide was an efficient tissue radical scavenger and a potential protective agent for acute mountain sickness.

  10. Cerebral Hyperperfusion after Revascularization Inhibits Development of Cerebral Ischemic Lesions Due to Artery-to-Artery Emboli during Carotid Exposure in Endarterectomy for Patients with Preoperative Cerebral Hemodynamic Insufficiency: Revisiting the “Impaired Clearance of Emboli” Concept

    PubMed Central

    Fujimoto, Kentaro; Matsumoto, Yoshiyasu; Oikawa, Kohki; Nomura, Jun-ichi; Shimada, Yasuyoshi; Fujiwara, Shunrou; Terasaki, Kazunori; Kobayashi, Masakazu; Yoshida, Kenji; Ogasawara, Kuniaki

    2016-01-01

    The purpose of the present study was to determine whether cerebral hyperperfusion after revascularization inhibits development of cerebral ischemic lesions due to artery-to-artery emboli during exposure of the carotid arteries in carotid endarterectomy (CEA). In patients undergoing CEA for internal carotid artery stenosis (≥70%), cerebral blood flow (CBF) was measured using single-photon emission computed tomography (SPECT) before and immediately after CEA. Microembolic signals (MES) were identified using transcranial Doppler during carotid exposure. Diffusion-weighted magnetic resonance imaging (DWI) was performed within 24 h after surgery. Of 32 patients with a combination of reduced cerebrovascular reactivity to acetazolamide on preoperative brain perfusion SPECT and MES during carotid exposure, 14 (44%) showed cerebral hyperperfusion (defined as postoperative CBF increase ≥100% compared with preoperative values), and 16 (50%) developed DWI-characterized postoperative cerebral ischemic lesions. Postoperative cerebral hyperperfusion was significantly associated with the absence of DWI-characterized postoperative cerebral ischemic lesions (95% confidence interval, 0.001–0.179; p = 0.0009). These data suggest that cerebral hyperperfusion after revascularization inhibits development of cerebral ischemic lesions due to artery-to-artery emboli during carotid exposure in CEA, supporting the “impaired clearance of emboli” concept. Blood pressure elevation following carotid declamping would be effective when embolism not accompanied by cerebral hyperperfusion occurs during CEA. PMID:27527146

  11. Bacterial pathogens of otitis media and sinusitis: detection in the nasopharynx with selective agar media.

    PubMed

    Dudley, S; Ashe, K; Winther, B; Hendley, J O

    2001-11-01

    Carriage rates for the bacterial pathogens associated with otitis media (Streptococcus pneumoniae [SP], Hemophilus influenzae [HI], and Moraxella catarrhalis [MC]) are of interest. Culture on three selective agars was compared with culture on two standard agars to determine the more accurate method for detection of these species in the nasopharynx of healthy children. Weekly samples were obtained in winter from 18 healthy children (ages 1 through 9 years) as part of a longitudinal study. A 0.1-mL sample of 116 nasopharyngeal aspirate/washes was inoculated onto each of five agars. Two were standard (sheep blood and chocolate), and three were selective (blood with gentamicin for SP; chocolate with vancomycin, bacitracin, and clindamycin for HI; blood with amphotericin B, vancomycin, trimethoprim, and acetazolamide for MC). One technician read the standard plates and another the selective; both were blinded to the results of the other. SP was found in 44% of samples with selective agar versus 25% with standard agar; HI was found in 31% with selective versus 9% with standard; MC was found in 56% with selective versus 37% with standard. Overall, 80% of samples had one or more pathogens detected with selective agars as compared with 58% with standard agars (P =.0004). Selective agars were more accurate than standard agars for detecting otitis pathogens in the nasopharynx, where they are a common part of normal flora in healthy children.

  12. The effects of some avermectins on bovine carbonic anhydrase enzyme.

    PubMed

    Kose, Leyla Polat; Gülçin, İlhami; Özdemir, Hasan; Atasever, Ali; Alwasel, Saleh H; Supuran, Claudiu T

    2016-10-01

    Avermectins are effective agricultural pesticides and antiparasitic agents that are widely employed in the agricultural, veterinary and medical fields. The aim of this study was to investigate the inhibitory effects of selected avermectins including abamectin, doramectin, emamectin, eprinomectin, ivermectin and moxidectin that are used as drugs against a wide variety of internal and external mammalian parasites, on the carbonic anhydrase enzyme (CA, EC 4.2.1.1.) purified from fresh bovine erythrocyte. CA catalyses the rapid interconversion of carbon dioxide (CO2) and water (H2O) to bicarbonate ([Formula: see text]) and protons (H(+)) and regulate the acidity of the local tissues. Bovine erythrocyte CA (bCA) enzyme was purified by Sepharose-4B affinity chromatography with a yield of 21.96% and 262.7-fold purification. The inhibition results obtained from this study showed Ki values of 9.73, 17.39, 20.43, 13.39, 16.44 and 17.73 nM for abamectin, doramectin, emamectin, eprinomectin, ivermectin and moxidectin, respectively. However, acetazolamide, well-known clinically established CA inhibitor, possessed a Ki value of 27.68 nM.

  13. Regulation of renal peripheral benzodiazepine receptors by anion transport inhibitors

    SciTech Connect

    Basile, A.S.; Lueddens, W.M.; Skolnick, P.

    1988-01-01

    The in vitro and in vivo regulation of (/sup 3/H)Ro 5-4864 binding to peripheral benzodiazepine receptors (PBR) by ion transport/exchange inhibitors was studied in the kidney. The potencies of 9-anthroic acid, furosemide, bumetanide, hydrochlorothiazide and SITS as inhibitors of (/sup 3/H)Ro 5-4864 binding to renal membranes were consistent with their actions as anion transport inhibitors (Ki approx. = 30 - 130 ..mu..M). In contrast, spironolactone, amiloride, acetazolamide, and ouabain were less potent (Ki=100-1000 ..mu..M). Administration of furosemide to rats for five days resulted in a profound diuresis accompanied by a significant increase in PBR density (43%) that was apparent by the fifth day of treatment. Administration of hydrochlorothiazide or Ro 5-4864 for five days also caused diuresis and increased renal PBR density. Both the diuresis and increased density of PBR produced by Ro 5-4864 were blocked by coadministration of PK 11195, which alone had no effect on either PBR density or urine volume. The equilibrium binding constants of (/sup 3/H)Ro 5-4864 to cardiac membranes were unaffected by administration of any of these drugs. These findings suggest that renal PBR may be selectively modulated in vivo and in vitro by administration of ion transport/exchange inhibitors. 36 references, 4 tables.

  14. Depression of vitamin B6 levels due to gentamicin.

    PubMed

    Weir, M R; Keniston, R C; Enriquez, J I; McNamee, G A

    1990-06-01

    The renal toxicity of gentamicin is altered by dietary protein modifications, bicarbonate and acetazolamide administration, magnesium supplementation, polyaspartic acid, piperacillin, hypercalcemia and calcium channel blockers. Renal tissue gentamicin levels have an undetermined role. Reduction of renal pyridoxal 5'-phosphate (PLP- by gentamicin has been shown, as has protection from nephrotoxicity by administration of vitamin B6. To explore an interaction between gentamicin and vitamin B6, gentamicin (5 mg/kg) was given to rabbits by ip injection, with either pyridoxine (10 mg) or isovolemic saline for 3 weeks. There was not a difference between gentamicin levels for animals given gentamicin and pyridoxine versus those given gentamicin and saline. Gentamicin administration led to a 47% fall (p = .0001) in plasma PLP levels. Three days after the last gentamicin administration, the animals maintained a 32% decrease from the pre-gentamicin baseline values (p = 0.02). When pyridoxine was administered concurrently with gentamicin, the PLP rise of 49% was significant (p = 0.001). The mean level after the study (6%) was not significantly lower than baseline (p = .6). We believe that gentamicin interfers with vitamin B6 metabolism, but that vitamin B6 status does not affect levels of gentamicin. A number of drugs affect B6 levels, creating the potential for hypovitaminosis B6 to be an important mechanism of drug-drug interaction in seriously ill patients, particularly in sick newborns or the elderly with lower average PLP levels.

  15. Bilateral acute closed angle glaucoma associated with the discontinuation of escitalopram: a case report.

    PubMed

    AlQuorain, Sara; Alfaraj, Sukayna; Alshahrani, Mohammed

    2016-01-01

    A 45-year-old woman presented to the Emergency Department complaining of severe headache for 3 hours duration associated with bilateral blurred vision, photophobia, and one attack of vomiting. Her clinical examination revealed normal vital signs and decrease in visual acuity with hazy cornea bilaterally. There were no signs of increased intracranial pressure and no neck rigidity or meningeal signs. The patient was diagnosed with bilateral acute closed angle glaucoma (AACG) with intraocular pressure of 60 mmHg in both eyes. She was using escitalopram for the treatment of depression, which was the only known risk factor for her condition. Standard treatment for AACG was provided. It included topical β-blocker, α agonists, and acetazolamide. This was followed by bilateral peripheral iridotomy. Follow-up intraocular pressure measurement revealed a value of 5 mmHg after 24 hours, indicating complete recovery. To the best of our knowledge, this is the first case to describe AACG after stopping the medication. It is highly important that clinicians be aware of this risk factor for AACG and have high index of suspicion in such patients with vision-threatening condition even after discontinuing the medication, because the risk persists for some time. PMID:27660499

  16. Carbonic anhydrase inhibitors: purification and inhibition studies of pigeon (Columba livia var. domestica) red blood cell carbonic anhydrase with sulfonamides.

    PubMed

    Ozensoy, Ozen; Arslan, Mikail; Supuran, Claudiu T

    2011-10-01

    A carbonic anhydrase (CA, EC 4.2.1.1) from red blood cells of pigeons (Columba livia var. domestica), clCA, was purified to homogeneity. Its kinetic parameters for the CO(2) hydration reaction were measured. With a k(cat)/K(m) of 1.1 × 10(8) M(-1) s(-1), and a k(cat) of 1.3 × 10(6) s(-1), clCA has a high activity, similar to that of the human isoform hCA II. A group of 25 aromatic/heterocyclic sulfonamides incorporating the sulfanilamide, homosulfanilamide, benzene-1,3-disulfonamide, and acetazolamide scaffolds showed variable inhibitory activity against the pigeon enzyme, with K(I)s in the range of 1.9-3460 nM. Red blood cells of pigeons, like those of ostriches, contain thus just one CA isoform, unlike the blood of mammals, which normally contain two isoforms, one of low (CA I-like) and one of very high activity (CA II-like). However, from the sulfonamide inhibition viewpoint, the pigeon enzyme was more similar to hCA II than to the ostrich enzyme. PMID:21476925

  17. Synthesis and characterization of novel dioxoacridine sulfonamide derivatives as new carbonic anhydrase inhibitors.

    PubMed

    Kaya, Muharrem; Basar, Erhan; Cakir, Emrah; Tunca, Ekrem; Bülbül, Metin

    2012-08-01

    Novel dioxoacridine sulfonamide compounds were synthesized from reaction of cyclic 1,3-diketones, sulfanilamide (4-amino benzene sulfonamide) and aromatic aldehydes. The structures of these compounds were confirmed by using spectral analysis (IR, H-NMR, (13)C-NMR, and mass). Human carbonic anhydrase isoenzymes (hCA I and hCA II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of sulfanilamide, acetazolamide (AAZ), and newly synthesized sulfonamides on hydratase and esterase activities of these isoenzymes have been studied in vitro. The IC(50) values of compounds for esterase activity are 0.71-0.11 µM for hCA I and 0.45-0.12 µM for hCA II, respectively. The K(i) values of these inhibitors were determined as 0,38-0,008 µM for hCA I and 0,19-0,001 µM for hCA II, respectively. PMID:21846203

  18. Characterization and inhibition studies of an α-carbonic anhydrase from the endangered sturgeon species Acipenser gueldenstaedti.

    PubMed

    Kolayli, Sevgi; Karahalil, Fatma; Sahin, Huseyin; Dincer, Barbaros; Supuran, Claudiu T

    2011-12-01

    An α-carbonic anhydrase (CA, EC 4.2.1.1) was purified and characterized kinetically from erythrocytes of the sturgeon Acipenser gueldenstaedti, an endangered species. The sturgeon enzyme (AgCA) showed kinetic parameters for the CO(2) hydration reaction comparable with those of the human erythrocytes enzyme hCA II, being a highly active enzyme, whereas its esterase activity with 4-nitrophenyl acetate as substrate was lower. Sulphonamide inhibitors (acetazolamide, sulphanilamide) strongly inhibited AgCA, whereas metal ions (Ag(+), Zn(2+), Cu(2+) and Co(2+)) were weak, millimolar inhibitors. Several widely used pesticides (2,4-dichlorophenol, dithiocarbamates, parathion and carbaryl) were also assayed as inhibitors of this enzyme. The dithiocarbamates were low micromolar AgCA inhibitors (IC(50) of 16-18 μM), whereas the other pesticides inhibited the enzyme with IC(50)s in the range of 102-398 μM. The wide use of dithiocarbamate pesticides may be one of the factors enhancing the vulnerability of this sturgeon species to pollutants. PMID:21381885

  19. Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune.

    PubMed

    Vullo, Daniela; De Luca, Viviana; Del Prete, Sonia; Carginale, Vincenzo; Scozzafava, Andrea; Capasso, Clemente; Supuran, Claudiu T

    2015-04-15

    A carbonic anhydrase (CA, EC 4.2.1.1) belonging to the γ-class has been cloned, purified and characterized from the Antarctic cyanobacterium Nostoc commune. The enzyme showed a good catalytic activity for the physiologic reaction (hydration of carbon dioxide to bicarbonate and a proton) with the following kinetic parameters, kcat of 9.5×10(5)s(-1) and kcat/KM of 8.3×10(7)M(-1)s(-1), being the γ-CA with the highest catalytic activity described so far. A range of aromatic/heterocyclic sulfonamides and one sulfamate were investigated as inhibitors of the new enzyme, denominated here NcoCA. The best NcoCA inhibitors were some sulfonylated sulfanilamide derivatives possessing elongated molecules, aminobenzolamide, acetazolamide, benzolamide, dorzolamide, brinzolamide and topiramate, which showed inhibition constants in the range of 40.3-92.3nM. As 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and γ-CAs are closely associated in carboxysomes of cyanobacteria for enhancing the affinity of RubisCO for CO2 and the efficiency of photosynthesis, investigation of this new enzyme and its affinity for modulators of its activity may bring new insights in these crucial processes. PMID:25773015

  20. Exercise oscillatory ventilation: Mechanisms and prognostic significance

    PubMed Central

    Dhakal, Bishnu P; Lewis, Gregory D

    2016-01-01

    Alteration in breathing patterns characterized by cyclic variation of ventilation during rest and during exercise has been recognized in patients with advanced heart failure (HF) for nearly two centuries. Periodic breathing (PB) during exercise is known as exercise oscillatory ventilation (EOV) and is characterized by the periods of hyperpnea and hypopnea without interposed apnea. EOV is a non-invasive parameter detected during submaximal cardiopulmonary exercise testing. Presence of EOV during exercise in HF patients indicates significant impairment in resting and exercise hemodynamic parameters. EOV is also an independent risk factor for poor prognosis in HF patients both with reduced and preserved ejection fraction irrespective of other gas exchange variables. Circulatory delay, increased chemosensitivity, pulmonary congestion and increased ergoreflex signaling have been proposed as the mechanisms underlying the generation of EOV in HF patients. There is no proven treatment of EOV but its reversal has been noted with phosphodiesterase inhibitors, exercise training and acetazolamide in relatively small studies. In this review, we discuss the mechanistic basis of PB during exercise and the clinical implications of recognizing PB patterns in patients with HF. PMID:27022457

  1. Altitude Stress During Participation of Medical Congress.

    PubMed

    Kim, Soon Bae; Kim, Jong Sung; Kim, Sang Jun; Cho, Su Hee; Suh, Dae Chul

    2016-09-01

    Medical congresses often held in highlands. We reviewed several medical issues associated with altitude stress especially while physicians have participated medical congress held in high altitude. Altitude stress, also known as an acute mountain sickness (AMS), is caused by acute exposure to low oxygen level at high altitude which is defined as elevations at or above 1,200 m and AMS commonly occurs above 2,500 m. Altitude stress with various symptoms including insomnia can also be experienced in airplane. AMS and drunken state share many common features in symptoms, neurologic manifestations and even show multiple microbleeds in corpus callosum and white matter on MRI. Children are more susceptible to altitude stress than adults. Gradual ascent is the best method for the prevention of altitude stress. Adequate nutrition (mainly carbohydrates) and hydration are recommended. Consumption of alcohol can exacerbate the altitude-induced impairments in judgment and the visual senses and promote psychomotor dysfunction. For prevention or treatment of altitude stress, acetazolamide, phosphodiesterase inhibitors, dexamethasone and erythropoietin are helpful. Altitude stress can be experienced relatively often during participation of medical congress. It is necessary to remind the harmful effect of AMS because it can cause serious permanent organ damage even though the symptoms are negligible in most cases. PMID:27621942

  2. Cl-HCO3 exchange in choroid plexus: analysis by the DMO method for cell pH

    SciTech Connect

    Johanson, C.E.; Parandoosh, Z.; Smith, Q.R.

    1985-10-01

    ( UC)DMO distribution was used to measure steady-state intracellular pH (pHi) and (HCO3)i in adult rat choroid plexus (CP) incubated in synthetic cerebrospinal fluid (CSF) for 30 min. In controls at 37 degrees C, mean pHi (6.95 at PCO2 = 30 mmHg) was close to corresponding in vivo values; and (HCO3)i/(HCO3)csf, i.e., rHCO3, was 0.37. At normal (HCO3)csf = 18 mM, cell HCO3 was accumulated threefold above electrochemical equilibrium. (HCO3)i decreased proportionally with (HCO3)csf, as the latter was altered from 47 to 9 mM; in severe extracellular acidosis (( HCO3)csf = 3.7 mM), (HCO3)i was not reduced further and so rHCO3 rose to 0.66. Except in low (HCO3)csf, acetazolamide and ouabain (10(-4) M) caused small depletion of cell HCO3. 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid lowered (HCO3)i by 60%, thus decreasing rHCO3 (0.16) and rCl (0.25) to values close to estimated equilibrium distribution (0.15). Augmented PCO2 associated with temperature reduction to 15 degrees C elevated (HCO3)i, thereby increasing rHCO3 (to 0.66) as well as rCl. Anion distribution ratios indicate heteroanion exchange in mammalian CP.

  3. Entry and exit pathways of CO2 in rat liver mitochondria respiring in a bicarbonate buffer system.

    PubMed

    Balboni, E; Lehninger, A L

    1986-03-15

    The dynamics and pathways of CO2 movements across the membranes of mitochondria respiring in vitro in a CO2/HCO-3 buffer at concentrations close to that in intact rat tissues were continuously monitored with a gas-permeable CO2-sensitive electrode. O2 uptake and pH changes were monitored simultaneously. Factors affecting CO2 entry were examined under conditions in which CO2 uptake was coupled to electrophoretic influx of K+ (in the presence of valinomycin) or Ca2+. The role of mitochondrial carbonic anhydrase (EC 4.2.1.1) in CO2 entry was evaluated by comparison of CO2 uptake by rat liver mitochondria, which possess carbonic anhydrase, versus rat heart mitochondria, which lack carbonic anhydrase. Such studies showed that matrix carbonic anhydrase activity is essential for rapid net uptake of CO2 with K+ or Ca2+. Studies with acetazolamide (Diamox), a potent inhibitor of carbonic anhydrase, confirmed the requirement of matrix carbonic anhydrase for net CO2 uptake. It was shown that at pH 7.2 the major species leaving respiring mitochondria is dissolved CO2, rather than HCO-3 or H2CO3 suggested by earlier reports. Efflux of endogenous CO2/HCO-3 is significantly inhibited by inhibitors of the dicarboxylate and tricarboxylate transport systems of the rat liver inner membrane. The possibility that these anion carriers mediate outward transport of HCO-3 is discussed.

  4. Carbonic anhydrase inhibitors with dual-tail moieties to match the hydrophobic and hydrophilic halves of the carbonic anhydrase active site.

    PubMed

    Tanpure, Rajendra P; Ren, Bin; Peat, Thomas S; Bornaghi, Laurent F; Vullo, Daniela; Supuran, Claudiu T; Poulsen, Sally-Ann

    2015-02-12

    We present a new approach to carbonic anhydrase II (CA II) inhibitor design that enables close interrogation of the regions of the CA active site where there is the greatest variability in amino acid residues among the different CA isozymes. By appending dual tail groups onto the par excellence CA inhibitor acetazolamide, compounds that may interact with the distinct hydrophobic and hydrophilic halves of the CA II active site were prepared. The dual-tail combinations selected included (i) two hydrophobic moieties, (ii) two hydrophilic moieties, and (iii) one hydrophobic and one hydrophilic moiety. The CA enzyme inhibition profile as well as the protein X-ray crystal structure of compound 3, comprising one hydrophobic and one hydrophilic tail moiety, in complex with CA II is described. This novel dual-tail approach has provided an enhanced opportunity to more fully exploit interactions with the CA active site by enabling these molecules to interact with the distinct halves of the active site. In addition to the dual-tail compounds, a corresponding set of single-tail derivatives was synthesized, enabling a comparative analysis of the single-tail versus dual-tail compound CA inhibition profile.

  5. Regulation of statoconia mineralization in Aplysia californica in vitro

    NASA Technical Reports Server (NTRS)

    Pedrozo, H. A.; Schwartz, Z.; Dean, D. D.; Wiederhold, M. L.; Boyan, B. D.

    1996-01-01

    Statoconia are calcium carbonate inclusions in the lumen of the gravity-sensing organ, the statocyst, of Aplysia californica. The aim of the present study was to examine the role of carbonic anhydrase and urease in statoconia mineralization in vitro. The experiments were performed using a previously described culture system (Pedrozo et al., J. Comp. Physiol. (A) 177:415-425). Inhibition of carbonic anhydrase by acetazolamide decreased statoconia production and volume, while inhibition of urease by acetohydroxamic acid reduced total statoconia number, but had no affect on statoconia volume. Inhibition of carbonic anhydrase initially increased and then decreased the statocyst pH, whereas inhibition of urease decreased statocyst pH at all times examined; simultaneous addition of both inhibitors also decreased pH. These effects were dose and time dependent. The results show that carbonic anhydrase and urease are required for statoconia formation and homeostasis, and for regulation of statocyst pH. This suggests that these two enzymes regulate mineralization at least partially through regulation of statocyst pH.

  6. Idiopathic intracranial hypertension and oxaliplatin: a causal association?

    PubMed

    Painhas, Teresa; Amorim, Manuela; Soares, Raquel; Duarte, Lilianne; Salgado-Borges, José

    2015-01-01

    We report a case of a 54-year-old woman presented at the emergency service with complaints of transitory visual obscurations for four days, and headache, nausea and occasional vomiting in the last two months. She had been diagnosed of colorectal cancer one year ago and she was on treatment with oxaliplatin on a FOLFOX schedule. On ophthalmic examination, the vision was of 20/20 in both eyes and bilateral disc swelling was noted. The neurologic examination was normal. Magnetic resonance revealed no changes. A diagnostic lumbar puncture demonstrated an elevated opening pressure of 290 mm H2O with normal compounds. Due to the suspicion of ocular toxicity, oxaliplatin treatment was stopped. Treatment with oral acetazolamide was started and maintained for one month. In three weeks ocular and systemic symptoms totally disappeared and disc swelling gradually improved in the following months. Ocular toxicity has been reported as an infrequent adverse effect of oxaliplatin, but intracranial idiopathic pressure has not yet been described. Findings in this case suggest that oxaliplatin could be the cause for these symptoms. As the use of oxaliplatin is increasing as first-line treatment in colorectal cancer, we have to be alert to its potential toxicity.

  7. High Altitude Medical Problems

    PubMed Central

    Hultgren, Herbert N.

    1979-01-01

    Increased travel to high altitude areas by mountaineers and nonclimbing tourists has emphasized the clinical problems associated with rapid ascent. Acute mountain sickness affects most sojourners at elevations above 10,000 feet. Symptoms are usually worse on the second or third day after arrival. Gradual ascent, spending one to three days at an intermediate altitude, and the use of acetazolamide (Diamox) will prevent or ameliorate symptoms in most instances. Serious and potentially fatal problems, such as high altitude pulmonary edema or cerebral edema, occur in approximately 0.5 percent to 1.0 percent of visitors to elevations above 10,000 feet—especially with heavy physical exertion on arrival, such as climbing or skiing. Early recognition, high flow oxygen therapy and prompt descent are crucially important in management. Our knowledge of the causes of these and other high altitude problems, such as retinal hemorrhage, systemic edema and pulmonary hypertension, is still incomplete. Even less is known of the effect of high altitudes on medical conditions common at sea level or on the action of commonly used drugs. ImagesFigure 2. PMID:483805

  8. Acute hypervitaminosis A in a young lady.

    PubMed

    Khasru, M R; Yasmin, R; Salek, A K; Khan, K H; Nath, S D; Selim, S

    2010-04-01

    Acute vitamin A toxicity from a large dose has been reported to cause pseudotumour cerebri. Usually it is common in children. Herein we present the case of a young lady of 18 years old with the complaints of headache, vomiting, back pain and diplopia after ingestion of high dose (about 10 million international units) vitamin A capsule intentionally at a time due to some family problems. She gave no history of fever, convulsion, unconsciousness, pain in eyes, difficulties in walking and jaundice or any urinary problem during this illness. On query she gave no history of taking any other drugs including oral contraceptive and tetracycline & steroids. She also gave no history of sleep disorder. There was bilateral papilloedema, pupils were a bit dilated symmetrically but reacting to light, visual acuity 6/60 on left eye and 6/18 on right eye and bilateral 6th cranial nerve palsy more marked on left side. MRI of brain and orbits showed normal study. Patient improved after giving acetazolamide. PMID:20395929

  9. Mechansims and components of renal tubular acidification.

    PubMed Central

    Cassola, A C; Giebisch, G; Malnic, G

    1977-01-01

    1. Renal cortical tubules of control and acetazolamide infused rats were perfused with 100 mM phosphate buffer at pH 5-5. The rate of alkalinization was measured by means of antimony micro-electrodes and was used to compute passive H ion fluxes from lumen to blood across the proximal and distal tubular epithelium. 2. The importance of other ionic movements that might contribute to pH changes of luminal buffers (chloride inflow into the lumen and bicarbonate diffusion across the epithelium) was assessed but found to be minor. H ion movements accounted for the majority of the observed pH changes. 3. H ion permeability of the tubular wall was calculated from the measured H fluxes and transepithelial concentration differences. It was 1-10 cm/sec, several orders of magnitude larger than those for other ions. However, such values are compatible with the mobility of protons in a medium of structure water within the limiting membrane. 4. A kinetic analysis of the mechanism of movement of H ions across the renal tubule is presented on the basis of experiments in which acidification and alkalinization of luminal buffers was followed in stationary microperfusions. The data are compatible with a pump-leak system in the proximal tubule, and with a model with low H ion permeability and a gradient dependent pump in the distal tubule. PMID:17737

  10. Mechanism of delayed intracranial hypertension after cerebroventricular infusions in conscious rats

    NASA Technical Reports Server (NTRS)

    Morrow, B. A.; Holt, M. R.; Starcevic, V. P.; Keil, L. C.; Severs, W. B.

    1992-01-01

    Prior studies showed that cerebroventricular infusions of artificial cerebrospinal fluid, 8 microliter/min for 10 min, followed by a 10 min rest and a 24 h infusion of 0.5 microliters/min, raised cerebrospinal fluid pressure (CSFp) of conscious, unrestrained rats after about 2 h. Here, we report that the 10 min infusion alone evoked a delayed, prolonged rise in CSFp. Pressure during the infusion itself rose and recovered quickly, as is usually reported. Pressure/volume tests, used to calculate resistance to outflow (Ro) and compliance (C), revealed that infusions increased Ro and decreased C, after a delay (P less than 0.05). The rise in CSFp after infusion was blocked by pretreatment with acetazolamide + ouabain (P less than 0.05), but the delayed changes in Ro and C were unaffected. We suggest that the 10 min infusion of a sterile, balanced salt solution has a primary effect that increases Ro; as CSF synthesis continues, C is exhausted and the delayed rise in CSFp ensues. This non-traumatic method of raising CSFp may be a useful method to study intracranial fluid dynamics.

  11. Bilateral acute closed angle glaucoma associated with the discontinuation of escitalopram: a case report

    PubMed Central

    AlQuorain, Sara; Alfaraj, Sukayna; Alshahrani, Mohammed

    2016-01-01

    A 45-year-old woman presented to the Emergency Department complaining of severe headache for 3 hours duration associated with bilateral blurred vision, photophobia, and one attack of vomiting. Her clinical examination revealed normal vital signs and decrease in visual acuity with hazy cornea bilaterally. There were no signs of increased intracranial pressure and no neck rigidity or meningeal signs. The patient was diagnosed with bilateral acute closed angle glaucoma (AACG) with intraocular pressure of 60 mmHg in both eyes. She was using escitalopram for the treatment of depression, which was the only known risk factor for her condition. Standard treatment for AACG was provided. It included topical β-blocker, α agonists, and acetazolamide. This was followed by bilateral peripheral iridotomy. Follow-up intraocular pressure measurement revealed a value of 5 mmHg after 24 hours, indicating complete recovery. To the best of our knowledge, this is the first case to describe AACG after stopping the medication. It is highly important that clinicians be aware of this risk factor for AACG and have high index of suspicion in such patients with vision-threatening condition even after discontinuing the medication, because the risk persists for some time.

  12. Wilderness medicine at high altitude: recent developments in the field.

    PubMed

    Shah, Neeraj M; Hussain, Sidra; Cooke, Mark; O'Hara, John P; Mellor, Adrian

    2015-01-01

    Travel to high altitude is increasingly popular. With this comes an increased incidence of high-altitude illness and therefore an increased need to improve our strategies to prevent and accurately diagnose these. In this review, we provide a summary of recent advances of relevance to practitioners who may be advising travelers to altitude. Although the Lake Louise Score is now widely used as a diagnostic tool for acute mountain sickness (AMS), increasing evidence questions the validity of doing so, and of considering AMS as a single condition. Biomarkers, such as brain natriuretic peptide, are likely correlating with pulmonary artery systolic pressure, thus potential markers of the development of altitude illness. Established drug treatments include acetazolamide, nifedipine, and dexamethasone. Drugs with a potential to reduce the risk of developing AMS include nitrate supplements, propagators of nitric oxide, and supplemental iron. The role of exercise in the development of altitude illness remains hotly debated, and it appears that the intensity of exercise is more important than the exercise itself. Finally, despite copious studies demonstrating the value of preacclimatization in reducing the risk of altitude illness and improving performance, an optimal protocol to preacclimatize an individual remains elusive. PMID:26445563

  13. Refractory nausea and vomiting in the setting of well-controlled idiopathic intracranial hypertension.

    PubMed

    Barnett, Dennis L; Rosenbaum, Rachel A; Diaz, Jonathan R

    2014-06-03

    Summary A 27-year-old woman with a history of recurrent nausea and vomiting in the setting of idiopathic intracranial hypertension (IIH) was admitted for control of unremitting nausea and vomiting. Initial antiemetic therapy included optimisation of IIH therapy by titrating acetazolamide, in addition to using ondansetron and metoclopramide as needed, with minimal relief. She was ultimately treated with palonosetron with complete resolution of her acute nausea. Nausea, often treated with 5-hydroxytryptamine (5-HT3) receptor antagonists, approved for perioperative and chemotherapy-induced nausea, are used off-label to treat nausea and vomiting outside of those settings. The efficacy of different regimens has been compared in the literature and continues to remain controversial. When choosing from different 5-HT3 antagonists there are other considerations, in addition to efficacy to consider: dosing schedule, half-life, time of onset, duration and cost-to-benefit ratio, and although one 5-HT3 antagonist may not have been effective, another one may be. In our case palonosetron, with a significantly longer half-life than other 5-HT3 antagonists, was effective in resolving nausea when compared with the more commonly used ondansetron.

  14. Sleep apnoea in patients with heart failure: part II: therapy.

    PubMed

    Bordier, Philippe

    2009-10-01

    Nasal continuous positive airway pressure (CPAP) is generally recommended for the treatment of obstructive sleep apnoea. CPAP lowers the cardiovascular morbidity and mortality associated with severe obstructive sleep apnoea. At least 50% of patients presenting with chronic heart failure (HF) have sleep apnoea; a subset of these patients may have obstructive sleep apnoea and may derive a survival benefit from CPAP. However, this population is also prone to developing central sleep apnoea, Cheyne-Stokes respiration or both (CSA/CSR), for which CPAP lowers the apnoea-hypopnoea index only partially and for which the overall effect of CPAP on survival remains to be determined, particularly as it has been observed to increase the mortality rate in subsets of patients. Other treatments may prove effective in patients with chronic HF and CSA/CSR, although none, thus far, has been found to confer a survival benefit. New ventilatory modes include bi-level positive airway pressure and automated adaptive servoventilation, the latter being most effective against CSA/CSR. Measures that can alleviate CSA/CSR indirectly include beta-adrenergic blockers and renin-angiotensin-aldosterone system inhibitors, nocturnal supplemental oxygen and cardiac resynchronization therapy (CRT). The effects of theophylline, acetazolamide and nocturnal CO(2) have also been studied. The second part of this review describes the applications and effects of therapies that are available for sleep apnoea in patients with chronic HF.

  15. Posterior Ciliary Artery Occlusion Caused by Hyaluronic Acid Injections Into the Forehead: A Case Report.

    PubMed

    Hu, Xiu Zhuo; Hu, Jun Yan; Wu, Peng Sen; Yu, Sheng Bo; Kikkawa, Don O; Lu, Wei

    2016-03-01

    Although cosmetic facial soft tissue fillers are generally safe and effective, improper injections can lead to devastating and irreversible consequences. We represent the first known case of posterior ciliary artery occlusion caused by hyaluronic acid. A 41-year-old female presented with right visual loss 7 hours after receiving cosmetic hyaluronic acid injections into her forehead. Examination revealed no light perception in the right eye and multiple dark ischemic area of injection over the forehead and nose. The right fundus revealed a pink retina with optic nerve edema. Fluorescein angiogram showed several filling defects in the choroidal circulation and late hyperfluorescence in the choroid. A right posterior ciliary artery occlusion and embolic occlusion of facial artery braches was diagnosed. With hyaluronidase injection, hyperbaric oxygen therapy, oral aspirin, oral acetazolamide and dexamethasone venotransfuse treatment, the patient's forehead and nasal skin improved and vision recovered to hand movements. With proper technique, vascular occlusion is rare following facial filler injection. Vision consequences can be severe if filler emboli enter the ocular circulation. Physicians should be aware of this potential side effect, recognize its presentation, and be knowledgeable of effective management. PMID:26986163

  16. The effects of some avermectins on bovine carbonic anhydrase enzyme.

    PubMed

    Kose, Leyla Polat; Gülçin, İlhami; Özdemir, Hasan; Atasever, Ali; Alwasel, Saleh H; Supuran, Claudiu T

    2016-10-01

    Avermectins are effective agricultural pesticides and antiparasitic agents that are widely employed in the agricultural, veterinary and medical fields. The aim of this study was to investigate the inhibitory effects of selected avermectins including abamectin, doramectin, emamectin, eprinomectin, ivermectin and moxidectin that are used as drugs against a wide variety of internal and external mammalian parasites, on the carbonic anhydrase enzyme (CA, EC 4.2.1.1.) purified from fresh bovine erythrocyte. CA catalyses the rapid interconversion of carbon dioxide (CO2) and water (H2O) to bicarbonate ([Formula: see text]) and protons (H(+)) and regulate the acidity of the local tissues. Bovine erythrocyte CA (bCA) enzyme was purified by Sepharose-4B affinity chromatography with a yield of 21.96% and 262.7-fold purification. The inhibition results obtained from this study showed Ki values of 9.73, 17.39, 20.43, 13.39, 16.44 and 17.73 nM for abamectin, doramectin, emamectin, eprinomectin, ivermectin and moxidectin, respectively. However, acetazolamide, well-known clinically established CA inhibitor, possessed a Ki value of 27.68 nM. PMID:26207514

  17. Novel frameshift mutation in the CACNA1A gene causing a mixed phenotype of episodic ataxia and familiar hemiplegic migraine.

    PubMed

    Kinder, S; Ossig, C; Wienecke, M; Beyer, A; von der Hagen, M; Storch, A; Smitka, M

    2015-01-01

    Episodic ataxia type 2 (EA2, MIM#108500) is the most common form of EA and an autosomal-dominant inherited disorder characterized by paroxysmal episodes of ataxia. The disease causative gene CACNA1A encodes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel. We report on a family with a novel mutation in the CACNA1A gene. The clinical symptoms within the family varied from the typical clinical presentation of EA2 with dysarthria, gait ataxia and oculomotor symptoms to migraine and dystonia. A novel nonsense mutation of the CACNA1A gene was identified in all affected family members and is most likely the disease causing molecular defect. The pharmacological treatment with acetazolamide (AAA) was successful in three family members so far. Treatment with AAA led to a reduction of migraine attacks and an improvement of the dystonia. This relationship confirmed the hypothesis that this novel mutation results in a heterogeneous phenotype and confutes the coincidence with common migraine. Dystonia is potentially included as a further part of the phenotype spectrum of CACNA1A gene mutations.

  18. Altitude Stress During Participation of Medical Congress

    PubMed Central

    Kim, Soon Bae; Kim, Jong Sung; Kim, Sang Jun; Cho, Su Hee

    2016-01-01

    Medical congresses often held in highlands. We reviewed several medical issues associated with altitude stress especially while physicians have participated medical congress held in high altitude. Altitude stress, also known as an acute mountain sickness (AMS), is caused by acute exposure to low oxygen level at high altitude which is defined as elevations at or above 1,200 m and AMS commonly occurs above 2,500 m. Altitude stress with various symptoms including insomnia can also be experienced in airplane. AMS and drunken state share many common features in symptoms, neurologic manifestations and even show multiple microbleeds in corpus callosum and white matter on MRI. Children are more susceptible to altitude stress than adults. Gradual ascent is the best method for the prevention of altitude stress. Adequate nutrition (mainly carbohydrates) and hydration are recommended. Consumption of alcohol can exacerbate the altitude-induced impairments in judgment and the visual senses and promote psychomotor dysfunction. For prevention or treatment of altitude stress, acetazolamide, phosphodiesterase inhibitors, dexamethasone and erythropoietin are helpful. Altitude stress can be experienced relatively often during participation of medical congress. It is necessary to remind the harmful effect of AMS because it can cause serious permanent organ damage even though the symptoms are negligible in most cases.

  19. Consensus Paper: Management of Degenerative Cerebellar Disorders

    PubMed Central

    Ilg, W.; Bastian, A. J.; Boesch, S.; Burciu, R. G.; Celnik, P.; Claaßen, J.; Feil, K.; Kalla, R.; Miyai, I.; Nachbauer, W.; Schöls, L.; Strupp, M.; Synofzik, M.; Teufel, J.

    2015-01-01

    Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation. PMID:24222635

  20. An Unusual Transudative Pleural Effusion Succeeded by Pulmonary and Brain Edema and Death

    PubMed Central

    Mortazavimoghaddam, Sayyed Gholam Reza; Riasi, H. R.

    2012-01-01

    Here we report a 22-year old woman with massive and bilateral transudative effusion succeeded by pulmonary edema and brain edema and death. Investigations for systemic disorders were negative. Exacerbation of dyspnea after intravenous fluid infusion was a main problem. As effusion was refractory to medical treatment, the patient was referred for surgical pleurodesis and bilateral surgical pleurodesis were done separately. Postsurgically, dyspnea exacerbation occurred after each common cold infection. Vertigo and high intracranial pressure were also a problem postsurgically. CSF pressure was 225 mm/H2O. Therapeutic lumbar puncture was done in two sequential weeks, and the patient was on acetazolamide 250 mg/trivise a day. Despite the medical treatment, progressive dyspnea, headache, and high intracranial pressure followed by death nine months after pleurodesis. As there is a gradient of pressure between pleura and CSF, after pleurodesis brain edema must be a consequence of inversing this gradient. In conclusion, when there are any abnormalities about fluid volume or pressure in any of these cavities, we have to study other cavities. PMID:22934227

  1. Idiopathic intracranial hypertension: ongoing clinical challenges and future prospects

    PubMed Central

    Julayanont, Parunyou; Karukote, Amputch; Ruthirago, Doungporn; Panikkath, Deepa; Panikkath, Ragesh

    2016-01-01

    Idiopathic intracranial hypertension (IIH) is an uncommon disorder characterized by increased intracranial pressure without radiological or laboratory evidence of intracranial pathology except empty sella turcica, optic nerve sheath with filled out cerebrospinal fluid spaces, and smooth-walled nonflow-related venous sinus stenosis or collapse. This condition typically affects obese women. The incidence of IIH is increasing with the rising prevalence of obesity. Persistent headache is the most common symptom. Visual impairment is a serious complication that may not be recognized by the patients. This paper reviews clinical manifestations, diagnostic challenges, and current treatments of IIH in adults. Various imaging modalities have been studied on their validity for detection of IIH and papilledema. This review also includes new studies on medical, surgical, and interventional management of this condition. Acetazolamide and topiramate are the only two medications that have been studied in randomized controlled trials about their efficacy in treatment of IIH. In patients who have severe visual impairment or progressive visual deterioration despite medical management, surgical or interventional treatment may be considered. The efficacy and complications of cerebrospinal fluid diversion, optic nerve sheath fenestration, and endovascular venous stenting reported in the last 3 decades have been summarized in this review. Finally, the prospective aspects of biomarkers and treatments are proposed for future research. PMID:26929666

  2. In vitro measurement of rate of fluid secretion in rat isolated seminiferous tubules: effects of metabolic inhibitors and ions.

    PubMed Central

    Cheung, Y M; Hwang, J C; Wong, P Y

    1977-01-01

    1. An in vitro technique for measuring secretory rate in rat isolated seminiferous tubules is described. 2. The basal rate of fluid secretion was 0-44+/-0-06 nl. cm-1 min-1 (S.E.) (n=21). The rate was found to be inhibited by cooling, addition of metabolic inhibitor 2,4-dinitrophenol (2-5 x 10(-4) M) and removal of glucose from the incubating solution. This indicates that fluid secretion in isolated rat seminiferous tubules is an energy dependent process. 3. Removal of K+ from the incubating medium inhibited the secretory rate in the isolated seminiferous tubules, whereas a fivefold increase in [K+]0 to 23-5 mM had no effect. The secretory rate was also unaffected by the absence of Cl- in the peritubular fluid. 4. Removal of Ca2+ from the peritubular medium caused a rise in the secretory rate. 5. Ouabain (10(-3) M) and acetazolamide (4 x 10(-5) M) caused a fall in the rate of fluid secretion in isolated seminiferous tubules. 6. These results are discussed in relation to the nature of the ionic secretion produced in the tubules. PMID:894530

  3. Idiopathic intracranial hypertension as an initial presentation of systemic lupus erythematosus

    PubMed Central

    Maloney, Keisha

    2013-01-01

    A 14-year-old girl with no known illness presented with a several week history of headaches and vomiting. The patient also reported having joint pain and swelling to the wrists and knees. She had no prior history of headaches, use of hormonal contraception or other medications, recent weight changes or family history of autoimmune disease. Blood pressure temperature, height and weight were normal. She was alert, there was alopecia, cervical lympadenopathy, symmetrical synovitis to the wrists, bilateral papilloedema and cranial nerve VI palsy. Laboratory investigations revealed a normochromic normocytic anaemia, leucopenia and lymphopenia. Serum chemistries were normal. CT of the brain was normal. Lumbar puncture revealed an opening pressure of greater than 300 mm H2O; cerebrospinal fluid (CSF) analysis was normal. HIV antibodies were non-reactive. Despite treatment with acetazolamide she developed somnolence. Hence MR venography was performed which showed no evidence of cerebral vein thrombosis. Further investigations revealed a positive direct coombs test, positive antinuclear antibodies (ANA) positive antidouble-stranded DNA (dsDNA) and false positive VDRL. Complement levels were reduced. Anti-Smith, anticardiolipin antibodies and lupus anticoagulant were negative. PMID:23943808

  4. Reassessment of sup 14 CO sub 2 compartmentation and of ( sup 14 C)formate oxidation in rat liver

    SciTech Connect

    Marsolais, C.; Lafreniere, F.; David, F.; Dodgson, S.J.; Brunengraber, H. )

    1989-11-25

    Our previous report had concluded that a fraction of ({sup 14}C)formate oxidation in liver occurs in the mitochondrion. This conclusion was based on the labeling patterns of urea and acetoacetate labeled via {sup 14}CO{sub 2} generated from ({sup 14}C)formate and other ({sup 14}C)substrates. We reassessed our interpretation in experiments conducted in (i) perifused mitochondria and (ii) isolated livers perfused with buffer containing ({sup 14}C)formate, ({sup 14}C)gluconolactone, {sup 14}CO{sub 2}, or NaH{sup 13}CO{sub 3}, in the absence and presence of acetazolamide, an inhibitor of carbonic anhydrase. Our data show that the cytosolic pools of bicarbonate and CO{sub 2} are not in isotopic equilibrium when {sup 14}CO{sub 2} is generated in the cytosol or is supplied as NaH{sup 14}CO3. We retract our earlier suggestion of a mitochondrial site of ({sup 14}C)formate oxidation.

  5. Experience of Staged Angioplasty to Avoid Hyperperfusion Syndrome for Carotid Artery Stenosis.

    PubMed

    Uchida, Kazutaka; Yoshimura, Shinichi; Shirakawa, Manabu; Shindo, Seigo; Egashira, Yusuke; Iwama, Toru; Yamada, Kiyofumi

    2015-01-01

    Hyperperfusion syndrome (HPS) after carotid artery stenting (CAS) may cause hemorrhagic or ischemic events leading to serious sequelae. We previously reported the staged angioplasty (SAP) to prevent HPS. In the present study, we analyzed our treatment results of SAP to know its effectiveness and problems. The study included 43 patients scheduled for SAP in whom preoperative single photon emission computed tomography (SPECT) showed severely impaired cerebral blood flow (CBF). The analyzed subjects were 38 males and 4 females, mean age was 73 ± 8.5 years old. SAP was indicated for the patients whose CBF ratio in the affected/unaffected hemisphere (asymmetry index) was below 0.8, and cerebrovascular reactivity measured by acetazolamide challenge was below 10%. First, percutaneous transluminal angioplasty (PTA) was performed. If PTA was successful, CAS was performed 2 weeks later. If PTA was not successful due to inadequate dilatation or extensive dissection, a stent was placed. SPECT was performed immediately after PTA and CAS to confirm the presence or absence of hyperperfusion phenomenon (HPP) indicating radiologic hyperperfusion. In 39 of 43 patients (91%), SAP was successfully performed and HPP was not observed. On the other hand, in the other four patients (9%), immediate stent placement was added due to inadequate dilatations in three patients and vascular dissection in one. Among 43 candidates for SAP, 41 patients (95.4%) had favorable course, but one hemorrhagic and one ischemic complications were observed after PTA. SAP was a relatively simple procedure, and its clinical results seemed acceptable. PMID:26447098

  6. Glaucoma Surgery in Pregnancy: A Case Series and Literature Review.

    PubMed

    Razeghinejad, Mohammad Reza; Masoumpour, Masoumeh; Eghbal, Mohammad Hossein; Myers, Jonathan S; Moster, Marlene R

    2016-09-01

    Glaucoma management in pregnant patients is a real challenge, especially when the glaucoma is not controlled with medications. We report the results of 6 incisional glaucoma surgeries for the management of medically uncontrolled glaucoma patients during pregnancy. This retrospective, case series was conducted on the 6 eyes of 3pregnant patients with uncontrolled glaucoma using maximum tolerable medications. Details of the glaucoma surgical management of these patients as well as their postoperative care and pregnancy and clinical outcomes on longitudinal follow-up are discussed. All 3 patients had juvenile open-angle glaucoma and were on various anti-glaucoma medications, including oral acetazolamide. The first case described underwent trabeculectomy without antimetabolites in both eyes because of uncontrolled intraocular pressure with topical medications. The surgery was done with topical lidocaine jelly and subconjunctival lidocaine during the second and third trimesters. The second patient had an Ahmed valve implantation in both eyes during the second and third trimesters because of uncontrolled IOP with topical medications and no response to selective laser trabeculoplasty. Surgery was done with topical tetracaine and subconjunctival and sub-Tenon's lidocaine. The third case had a Baerveldt valve implantation under general anesthesia in the second trimester. In selected pregnant glaucoma patients with medically uncontrolled intraocular pressure threatening vision, incisional surgery may lead to good outcomes for the patient with no risk for the fetus. PMID:27582594

  7. Therapeutic Options for Controlling Fluids in the Visual System

    NASA Technical Reports Server (NTRS)

    Curry, Kristina M.; Wotring, Virginia E.

    2014-01-01

    Visual Impairment/Intracranial Pressure (VIIP) is a newly recognized risk at NASA. The VIIP project examines the effect of long-term exposure to microgravity on vision of crewmembers before and after they return to Earth. Diamox (acetazolamide) is a medication which is used to decrease intraocular pressure; however, it carries a 3% risk of kidney stones. Astronauts are at a higher risk of kidney stones during spaceflight and the use Diamox would only increase the risk; therefore alternative therapies were investigated. Histamine 2 (H2) antagonist acid blockers such as cimetidine, ranitidine, famotidine and nizatidine are typically used to relieve the symptoms of gastroesophageal reflux disease (GERD). H2 receptors have been found in the human visual system, which has led to research on the use of H2 antagonist blockers to control fluid production in the human eye. Another potential therapeutic strategy is targeted at aquaporins, which are water channels that help maintain fluid homeostasis. Aquaporin antagonists are also known to affect intracranial pressure which can in turn alter intraocular pressure. Studies on aquaporin antagonists suggest high potential for effective treatment. The primary objective of this investigation is to review existing research on alternate medications or therapy to significantly reduce intracranial and intraocular pressure. A literature review was conducted. Even though we do not have all the answers quite yet, a considerable amount of information was discovered, and findings were narrowed, which should allow for more conclusive answers to be found in the near future.

  8. Wilderness medicine at high altitude: recent developments in the field

    PubMed Central

    Shah, Neeraj M; Hussain, Sidra; Cooke, Mark; O’Hara, John P; Mellor, Adrian

    2015-01-01

    Travel to high altitude is increasingly popular. With this comes an increased incidence of high-altitude illness and therefore an increased need to improve our strategies to prevent and accurately diagnose these. In this review, we provide a summary of recent advances of relevance to practitioners who may be advising travelers to altitude. Although the Lake Louise Score is now widely used as a diagnostic tool for acute mountain sickness (AMS), increasing evidence questions the validity of doing so, and of considering AMS as a single condition. Biomarkers, such as brain natriuretic peptide, are likely correlating with pulmonary artery systolic pressure, thus potential markers of the development of altitude illness. Established drug treatments include acetazolamide, nifedipine, and dexamethasone. Drugs with a potential to reduce the risk of developing AMS include nitrate supplements, propagators of nitric oxide, and supplemental iron. The role of exercise in the development of altitude illness remains hotly debated, and it appears that the intensity of exercise is more important than the exercise itself. Finally, despite copious studies demonstrating the value of preacclimatization in reducing the risk of altitude illness and improving performance, an optimal protocol to preacclimatize an individual remains elusive. PMID:26445563

  9. Pharmacology of acute mountain sickness: old drugs and newer thinking.

    PubMed

    Swenson, Erik R

    2016-01-15

    Pharmacotherapy in acute mountain sickness (AMS) for the past half century has largely rested on the use of carbonic anhydrase (CA) inhibitors, such as acetazolamide, and corticosteroids, such as dexamethasone. The benefits of CA inhibitors are thought to arise from their known ventilatory stimulation and resultant greater arterial oxygenation from inhibition of renal CA and generation of a mild metabolic acidosis. The benefits of corticosteroids include their broad-based anti-inflammatory and anti-edemagenic effects. What has emerged from more recent work is the strong likelihood that drugs in both classes act on other pathways and signaling beyond their classical actions to prevent and treat AMS. For the CA inhibitors, these include reduction in aquaporin-mediated transmembrane water transport, anti-oxidant actions, vasodilation, and anti-inflammatory effects. In the case of corticosteroids, these include protection against increases in vascular endothelial and blood-brain barrier permeability, suppression of inflammatory cytokines and reactive oxygen species production, and sympatholysis. The loci of action of both classes of drug include the brain, but may also involve the lung as revealed by benefits that arise with selective administration to the lungs by inhalation. Greater understanding of their pluripotent actions and sites of action in AMS may help guide development of better drugs with more selective action and fewer side effects. PMID:26294748

  10. High Altitude Illnesses in Hawai‘i

    PubMed Central

    2014-01-01

    High Altitude Headache (HAH), Acute Mountain Sickness (AMS), and High Altitude Cerebral Edema (HACE) are all high altitude related illnesses in order of severity from the mildly symptomatic to the potentially life-threatening. High altitude illnesses occur when travelers ascend to high altitudes too rapidly, which does not allow enough time for the body to adjust. Slow graded ascent to the desired altitude and termination of ascent if AMS symptoms present are keys to illness prevention. Early recognition and rapid intervention of AMS can halt progression to HACE. Pharmacologic prophylaxis with acetazolamide is a proven method of prevention and treatment of high altitude illness. If prevention fails then treatment modalities include supplemental oxygen, supportive therapy, hyperbaric treatment, and dexamethasone. Given the multitude of visitors to the mountains of Hawai‘i, high altitude illness will continue to persist as a prevalent local condition. This paper will emphasize the prevention and early diagnosis of AMS so that the illness does not progress to HACE. PMID:25478293

  11. Carbonic Anhydrase is Required for Statoconia Homeostasis in Organ Cultures of Statocysts from Aplysia californica

    NASA Technical Reports Server (NTRS)

    Pedrozo, H. A.; Schwartz, Z.; Nakaya, H.; Harrison, J. L.; Dean, D. D.; Wiederhold, M. L.; Boyan, B. D.

    1995-01-01

    A novel organ culture system has been developed to study the regulation of statoconia production in the gravity sensing organ in Aplysia californica. Statocysts were cultured in Leibovitz (LI5) medium supplemented with salts and Aplysia haemolymph for four days at 17 C. The viability of the system was evaluated by examining four parameters: statocyst morphology, the activity of the mechanosensory cilia in the statocyst, production of new statoconia during culture and change in statoconia volume after culture. There were no morphological differences in statocysts before and after culture when ciliary beating was maintained. There was a 29% increase in the number of statoconia after four days in culture. Mean statocyst, statolith and statoconia volumes were not affected by culture conditions. The presence of carbonic anhydrase in the statocysts was shown using immunohistochemistry. When statocysts were cultured in the presence of 4.0 x 10(exp -4) M acetazolamide to inhibit the enzyme activity, there was a decrease in statoconia production and statoconia volume, indicating a role for this enzyme in statoconia homeostasis, potentially, via pH regulation. These studies are the first to report a novel system for the culture of statocysts and show that carbonic anhydrase is involved in the regulation of statoconia volume and production.

  12. Synthesis and in vivo diuretic activity of some new benzothiazole sulfonamides containing quinoxaline ring system.

    PubMed

    Husain, Asif; Madhesia, Diwakar; Rashid, Mohd; Ahmad, Aftab; Khan, Shah Alam

    2016-12-01

    A series of new 6-substituted-N-[3-{2-(substituted phenyl)-ethenyl} quinoxaline-2(1H)-ylidene]-1,3-benzothiazole-2-amine (4a-f) were designed and synthesized by condensing 2-amino-benzothiazole-6-sulfonic acid amide (1) with chalcones of quinoxaline-2-one (3a-f) in a hope to obtain promising and a new class of diuretic agents. Structures of all the newly synthesized compounds were characterized by spectral data and elemental analysis. The pharmacological studies in experimental rats indicates that compound 4c possesses excellent in vivo diuretic activity of 1.13 and appears to be a better diuretic agent than the reference drugs, acetazolamide (1.0) and urea (0.88). Insight of the binding mode of the synthesized compounds (ligand) into the binding sites of carbonic anhydrase enzyme (PDF code: 4KUV) was provided by docking studies, performed with the help of Maestro 9.0 docking software. Further pharmacokinetic and toxicological studies are needed to confirm the safety of compound 4c which emerged as a lead diuretic compound.

  13. Bilateral acute closed angle glaucoma associated with the discontinuation of escitalopram: a case report

    PubMed Central

    AlQuorain, Sara; Alfaraj, Sukayna; Alshahrani, Mohammed

    2016-01-01

    A 45-year-old woman presented to the Emergency Department complaining of severe headache for 3 hours duration associated with bilateral blurred vision, photophobia, and one attack of vomiting. Her clinical examination revealed normal vital signs and decrease in visual acuity with hazy cornea bilaterally. There were no signs of increased intracranial pressure and no neck rigidity or meningeal signs. The patient was diagnosed with bilateral acute closed angle glaucoma (AACG) with intraocular pressure of 60 mmHg in both eyes. She was using escitalopram for the treatment of depression, which was the only known risk factor for her condition. Standard treatment for AACG was provided. It included topical β-blocker, α agonists, and acetazolamide. This was followed by bilateral peripheral iridotomy. Follow-up intraocular pressure measurement revealed a value of 5 mmHg after 24 hours, indicating complete recovery. To the best of our knowledge, this is the first case to describe AACG after stopping the medication. It is highly important that clinicians be aware of this risk factor for AACG and have high index of suspicion in such patients with vision-threatening condition even after discontinuing the medication, because the risk persists for some time. PMID:27660499

  14. Coupling between chloride absorption and base excretion in isolated skin of Rana esculenta.

    PubMed

    Ehrenfeld, J; Garcia-Romeu, F

    1978-07-01

    The net excretory fluxes of base (HCO3- or OH-) and the unidirectional fluxes of chloride were measured and their relationship examined in isolated frog skin maintained in open- or short-circuit (OC and SC) conditions. When the mucosal solution was a 2 mM choline chloride solution and the serosal solution a Ringer solution buffered with a HCO3-/CO2 mixture, the rate of base excretion was -105 +/- 10 in OC and -60 +/- 7 neq h-1 cm-2 in SC. A highly significant correlation was observed between the influx of chloride and the excretion of base. As a function of external chloride both these parameters followed saturation kinetics, Vmax being obtained for a chloride concentration below 2 mM. The removal of chloride in the external solution was followed by a 70 or 100% inhibition of base excretion in OC and SC conditions, respectively. Chloride transport is dependent on the presence of a HCO3-/CO2 mixture in the internal or the external medium. This transport, as well as base excretion, is inhibited to a considerable extent by removal of HCO3-/CO2 or by acetazolamide (10(-3) M). This investigation characterizes a saturable transport system in which chloride absorption and base excretion are coupled. PMID:307916

  15. Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A.

    PubMed

    García Segarra, Nuria; Gautschi, Ivan; Mittaz-Crettol, Laureane; Kallay Zetchi, Christine; Al-Qusairi, Lama; Van Bemmelen, Miguel Xavier; Maeder, Philippe; Bonafé, Luisa; Schild, Laurent; Roulet-Perez, Eliane

    2014-07-15

    Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel Ca(V)2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant Ca(V)2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.

  16. RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2.

    PubMed

    Salvi, Julie; Bertaso, Federica; Mausset-Bonnefont, Anne-Laure; Metz, Alexandra; Lemmers, Céline; Ango, Fabrice; Fagni, Laurent; Lory, Philippe; Mezghrani, Alexandre

    2014-08-01

    Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while β-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress-induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease.

  17. Cloning, expression and biochemical characterization of a β-carbonic anhydrase from the soil bacterium Enterobacter sp. B13.

    PubMed

    Eminoğlu, Ayşenur; Vullo, Daniela; Aşık, Aycan; Çolak, Dilşat Nigar; Supuran, Claudiu T; Çanakçı, Sabriye; Osman Beldüz, Ali

    2016-12-01

    A recombinant carbonic anhydrase (CA, EC 4.2.1.1) from the soil-dwelling bacterium Enterobacter sp. B13 was cloned and purified by Co(2+) affinity chromatography. Bioinformatic analysis showed that the new enzyme (denominated here B13-CA) belongs to the β-class CAs and to possess 95% homology with the ortholog enzyme from Escherichia coli encoded by the can gene, whereas its sequence homology with the other such enzyme from E. coli (encoded by the cynT gene) was of 33%. B13-CA was characterized kinetically as a catalyst for carbon dioxide hydration to bicarbonate and protons. The enzyme shows a significant catalytic activity, with the following kinetic parameters at 20 °C and pH of 8.3: kcat of 4.8 × 10(5) s(-1) and kcat/Km of 5.6 × 10(7) M(-1) × s(-1). This activity was potently inhibited by acetazolamide which showed a KI of 78.9 nM. Although only this compound was investigated for the moment as B13-CA inhibitor, further studies may reveal new classes of inhibitors/activators of this enzyme which may show biomedical or environmental applications, considering the posssible role of this enzyme in CaCO3 biomineralization processes. PMID:26497870

  18. Aerobic and anaerobic metabolism of bovine ciliary process: effects of metabolic and transport inhibitors.

    PubMed

    Braunagel, S C; Yorio, T

    1987-01-01

    In the present study we have measured the oxygen consumption and lactic acid production, under aerobic and anaerobic conditions, in the bovine ciliary process epithelium (CPE) in the presence and absence of transport modifiers. Basal oxygen consumption was 8-15 microliters O2 consumed/mg protein/hr and decreased by 35% when sodium was removed or ouabain was added to the media. Anaerobic metabolism as measured by lactate production was also attenuated by sodium-free or ouabain treatment. When O2 consumption was severely limited by cyanide, lactic acid production increased significantly ("Pasteur effect"), whereas 2-deoxyglucose reduced lactate formation. Both chloride-free and acetazolamide treated CPE increased their dependency on aerobic glycolysis, and this response was also observed under anaerobic conditions, suggesting the presence of an anion transport mechanism. A net lactate production was also found to occur across the aqueous epithelium under aerobic and anaerobic conditions. These results are consistent with the presence of a bicarbonate-sensitive anion transport system located in the ciliary process epithelium.

  19. Immobilization of carbonic anhydrase enzyme purified from Bacillus subtilis VSG-4 and its application as CO(2) sequesterer.

    PubMed

    Oviya, M; Giri, Sib Sankar; Sukumaran, V; Natarajan, P

    2012-01-01

    The purification, immobilization, and characterization of carbonic anhydrase (CA) secreted by Bacillus subtilis VSG-4 isolated from tropical soil have been investigated in this work. Carbonic anhydrase was purified using ammonium sulfate precipitation, Sephadex-G-75 column chromatography, and DEAE-cellulose chromatography, achieving a 24.6-fold purification. The apparent molecular mass of purified CA obtained by SDS-PAGE was found to be 37 kD. The purified CA was entrapped within a chitosan-alginate polyelectrolyte complex (C-A PEC) hydrogel for potential use as an immobilized enzyme. The optimum pH and temperature for both free and immobilized enzymes were 8.2 and 37°C, respectively. The immobilized enzyme had a much higher storage stability than the free enzyme. Certain metal ions, namely, Co(2+), Cu(2+), and Fe(3+), increased the enzyme activity, whereas CA activity was inhibited by Pb(2+), Hg(2+), ethylenediamine tetraacetic acid (EDTA), 5,5'-dithiobis-(2-nitrobenzoic acid (DTNB), and acetazolamide. Free and immobilized CAs were tested further for the targeted application of the carbonation reaction to convert CO(2) to CaCO(3). The maximum CO(2) sequestration potential was achieved with immobilized CA (480 mg CaCO(3)/mg protein). These properties suggest that immobilized VSG-4 carbonic anhydrase has the potential to be used for biomimetic CO(2) sequestration. PMID:22897768

  20. Cloning, characterization and anion inhibition studies of a γ-carbonic anhydrase from the Antarctic bacterium Colwellia psychrerythraea.

    PubMed

    De Luca, Viviana; Vullo, Daniela; Del Prete, Sonia; Carginale, Vincenzo; Osman, Sameh M; AlOthman, Zeid; Supuran, Claudiu T; Capasso, Clemente

    2016-02-15

    We have cloned, purified and characterized the γ-carbonic anhydrase (CA, EC 4.2.1.1) present in the genome of the Antarctic bacterium Colwellia psychrerythraea, which is an obligate psychrophile. The enzyme shows a significant catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with the following kinetic parameters: kcat of 6.0×10(5)s(-1) and a kcat/Km of 4.7×10(6)M(-1)×s(-1). This activity was inhibited by the sulfonamide CA inhibitor (CAI) acetazolamide, with a KI of 502nM. A range of anions was also investigated for their inhibitory action against the new enzyme CpsCA. Perchlorate, tetrafluoroborate, fluoride and bromide were not inhibitory, whereas cyanate, thiocyanate, cyanide, hydrogensulfide, carbonate and bicarbonate showed KIs in the range of 1.4-4.4mM. Diethyldithiocarbamate was a better inhibitor (KI of 0.58mM) whereas sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid were the most effective inhibitors detected, with KIs ranging between 8 and 38μM. The present study may shed some more light regarding the role that γ-CAs play in the life cycle of psychrophilic bacteria as the Antarctic one investigated here.

  1. Major contribution of the type II beta carbonic anhydrase CanB (Cj0237) to the capnophilic growth phenotype of Campylobacter jejuni.

    PubMed

    Al-Haideri, Halah; White, Michael A; Kelly, David J

    2016-02-01

    Campylobacter jejuni, the leading cause of human bacterial gastroenteritis, requires low environmental oxygen and high carbon dioxide for optimum growth, but the molecular basis for the carbon dioxide requirement is unclear. One factor may be inefficient conversion of gaseous CO2 to bicarbonate, the required substrate of various carboxylases. Two putative carbonic anhydrases (CAs) are encoded in the genome of C. jejuni strain NCTC 11168 (Cj0229 and Cj0237). Here, we show that the deletion of the cj0237 (canB) gene alone prevents growth in complex media at low (1% v/v) CO2 and significantly reduces the growth rate at high (5% v/v) CO2. In minimal media incubated under high CO2, the canB mutant grew on L-aspartate but not on the key C3 compounds L-serine, pyruvate and L-lactate, showing that CanB is crucial in bicarbonate provision for pyruvate carboxylase-mediated oxaloacetate synthesis. Nevertheless, purified CanB (a dimeric, anion and acetazolamide sensitive, zinc-containing type II beta-class enzyme) hydrates CO2 actively only above pH 8 and with a high Km (∼ 34 mM). At typical cytoplasmic pH values and low CO2, these kinetic properties might limit intracellular bicarbonate availability. Taken together, our data suggest CanB is a major contributor to the capnophilic growth phenotype of C. jejuni. PMID:26470757

  2. Central Sleep Apnea at High Altitude.

    PubMed

    Burgess, Keith R; Ainslie, Philip N

    2016-01-01

    The discovery of central sleep apnea (CSA) at high altitude is usually attributed to Angelo Mosso who published in 1898. It can occur in susceptible individuals at altitude above 2000 m, but at very high altitude, say above 5000 m, it will occur in most subjects. Severity is correlated with ventilatory responsiveness, particularly to hypoxia. Theoretically, it should spontaneously improve with time and acclimatization. Although the time course of resolution is not well described, it appears to persist for more than a month at 5000 m.It occurs due to the interaction of hypocapnia with stages 1 and 2 NREM sleep, in the presence of increased loop-gain. The hypocapnia is secondary to hypoxic ventilatory drive. With acclimatization, one might expect that the increase in PaO2 and cerebral blood flow (CBF) would mitigate the CSA. However, over time, both the hypoxic and hypercapnic ventilatory responses increase, causing an increase in loop gain which is a counteracting force.The severity of the CSA can be reduced by descent, supplemental oxygen therapy, oral or intravenous acetazolamide. Recent studies suggest that acute further increases in cerebral blood flow will substantially, but temporarily, reduce central sleep apnea, without altering acid based balance. Very recently, bi-level noninvasive ventilation has also been shown to help (mechanism unknown). Sleep quality can be improved independent of the presence of CSA by the use of benzodiazepine sedation. PMID:27343103

  3. sup 14 C fixation by leaves and leaf cell protoplasts of the submerged aquatic angiosperm Potamogeton lucens: Carbon dioxide or bicarbonate

    SciTech Connect

    Staal, M.; Elzenga, J.T.M.; Prins, H.B.A. )

    1989-07-01

    Protoplasts were isolated from leaves of the aquatic angiosperm Potamogeton lucens L. The leaves utilize bicarbonate as a carbon source for photosynthesis, and show polarity; that is acidification of the periplasmic space of the lower, and alkalinization of the space near the upper leaf side. At present there are two models under consideration for this photosynthetic bicarbonate utilization process: conversion of bicarbonate into free carbon dioxide as a result of acidification and, second, a bicarbonate-proton symport across the plasma membrane. Carbon fixation of protoplasts was studied at different pH values and compared with that in leaf strips. Using the isotopic disequilibrium technique, it was established that carbon dioxide and not bicarbonate was the form in which DIC actually crossed the plasma membrane. It is concluded that there is probably no true bicarbonate transport system at the plasma membrane of these cells and that bicarbonate utilization in this species apparently rests on the conversion of bicarbonate into carbon dioxide. Experiments with acetazolamide, an inhibitor of periplasmic carbonic anhydrase, and direct measurements of carbonic anhydrase activity in intact leaves indicate that in this species the role of this enzyme for periplasmic conversion of bicarbonate into carbon dioxide is insignificant.

  4. Acetate transport across the intestinal epithelium of an herbivorous teleost. [Oreochromis mossambicus

    SciTech Connect

    Titus, E.; Ahearn, G.A. )

    1990-02-26

    {sup 3}H-acetate transport across the upper intestine of the tilapia, Oreochromis mossabicus, using brush border and basolateral membrane vesicles, and intestinal sheets mounted in modified Ussing chambers was investigated. Brush border and basolateral vesicles demonstrated qualitatively similar anion antiport activity where, in the presence of a full profile of organic and inorganic anions, volatile fatty acids (VFA; acetate, propionate, butyrate) and bicarbonate showed reciprocal trans-stimulation and cis-inhibition of {sup 3}H-acetate influx, suggesting both membranes had the same VFA/bicarbonate exchange mechanism. Kinetic analysis of {sup 3}H-acetate influx into brush border and basolateral vesicles revealed different half-saturation constants (Km) as a function of external acetate concentrations (6.43 mM and 11.91 mM, respectively) and as a function of internal bicarbonate (5.89 mM and 0.41 mM, respectively). Intestinal sheets supported net absorptive fluxes when serosal acetate concentrations were held steady at 1.0 mM and mucosal acetate was varied from 1.60 to 10.0 mM. Unidirectional fluxes were significantly diminished by the addition of acetazolamide. This study postulates a transcellular transport pathway for VFA whereby qualitatively similar antiporters in series lead to a downhill flow of luminal acetate to the blood, which is driven by intracellular carbonic anhydrase and a transmural VFA concentration gradient.

  5. Respiratory control in residents at high altitude: physiology and pathophysiology.

    PubMed

    León-Velarde, Fabiola; Richalet, Jean-Paul

    2006-01-01

    Highland population (HA) from the Andes, living above 3000 m, have a blunted ventilatory response to increasing hypoxia, breathe less compared to acclimatized newcomers, but more, compared to sea-level natives at sea level. Subjects with chronic mountain sickness (CMS) breathe like sea-level natives and have excessive erythrocytosis (EE). The respiratory stimulation that arises through the peripheral chemoreflex is modestly less in the CMS group when compared with the HA group at the same P(ET(O2)). With regard to CO(2) sensitivity, CMS subjects seem to have reset their central CO(2) chemoreceptors to operate around the sea-level resting P(ET(CO2)). Acetazolamide, an acidifying drug that increases the chemosensitivity of regions in the brain stem that contain CO(2)/H(+) sensitive neurons, partially reverses this phenomenon, thus, providing CMS subjects with the possibility to have high CO(2) changes, despite small changes in ventilation. However, the same type of adjustments of the breathing pattern established for Andeans has not been found necessarily in Asian humans and/or domestic animals nor in the various high altitude species studied. The differing time frames of exposure to hypoxia among the populations, as well as the reversibility of the different components of the respiratory process at sea level, provide key concepts concerning the importance of time at high altitude in the evolution of an appropriate breathing pattern.

  6. Evidence for the involvement of carbonic anhydrase and urease in calcium carbonate formation in the gravity-sensing organ of Aplysia californica

    NASA Technical Reports Server (NTRS)

    Pedrozo, H. A.; Schwartz, Z.; Dean, D. D.; Harrison, J. L.; Campbell, J. W.; Wiederhold, M. L.; Boyan, B. D.

    1997-01-01

    To better understand the mechanisms that could modulate the formation of otoconia, calcium carbonate granules in the inner ear of vertebrate species, we examined statoconia formation in the gravity-sensing organ, the statocyst, of the gastropod mollusk Aplysia californica using an in vitro organ culture model. We determined the type of calcium carbonate present in the statoconia and investigated the role of carbonic anhydrase (CA) and urease in regulating statocyst pH as well as the role of protein synthesis and urease in statoconia production and homeostasis in vitro. The type of mineral present in statoconia was found to be aragonitic calcium carbonate. When the CA inhibitor, acetazolamide (AZ), was added to cultures of statocysts, the pH initially (30 min) increased and then decreased. The urease inhibitor, acetohydroxamic acid (AHA), decreased statocyst pH. Simultaneous addition of AZ and AHA caused a decrease in pH. Inhibition of urease activity also reduced total statoconia number, but had no effect on statoconia volume. Inhibition of protein synthesis reduced statoconia production and increased statoconia volume. In a previous study, inhibition of CA was shown to decrease statoconia production. Taken together, these data show that urease and CA play a role in regulating statocyst pH and the formation and maintenance of statoconia. CA produces carbonate ion for calcium carbonate formation and urease neutralizes the acid formed due to CA action, by production of ammonia.

  7. Carbonic anhydrase, a respiratory enzyme in the gills of the shore crab Carcinus maenas

    NASA Astrophysics Data System (ADS)

    Böttcher, K.; Siebers, D.; Sender, S.

    1995-03-01

    This paper summarizes investigations on the enzyme carbonic anhydrase (CA) in the gills of the osmoregulating shore crab Carcinus maenas. Carbonic anhydrase, an enzyme catalyzing the reversible hydration of CO2 to HCO3 - and H+, is localized with highest activities in the posterior salt-transporting gills of the shore crab- and here CA activity is strongly dependent on salinity. Contrary to the earlier hypothesis established for the blue crab Callinectes sapidus that cytoplasmic branchial CA provides the counter ions HCO3 - and H+ for apical exchange against Na+ and Cl-, the involvement of CA in NaCl uptake mechanisms can be excluded in Carcinus. Differential and density gradient centrifugations indicate that branchial CA is a predominantly membrane-associated protein. Branchial CA was greatly inhibited by the sulfonamide acetazolamide (AZ) Ki=2.4·10-8 mol/l). Using the preparation of the isolated perfused gill, application of 10-4 mol/l AZ resulted in an 80% decrease of CO2/HCO3 - excretion. Thus we conclude that CA is localized in plasma membranes, maintaining the CO2 gradient by accelerating adjustment of the pH-dependent CO2/HCO3 - equilibrium.

  8. CARBONIC ANHYDRASE ACTIVITY OF INTEGRAL-FUNCTIONAL COMPLEXES OF THYLAKOID MEMBRANES OF SPINACH CHLOROPLASTS.

    PubMed

    Semenihin, A V; Zolotareva, O K

    2015-01-01

    Isolated thylakoid membranes were disrupted by treatment with nonionic detergents digitonin or dodecyl maltoside. Solubilized polypeptide complexes were separated by native gel charge shift electrophoresis. The position of ATP-synthase complex and its isolated catalytic part (CF1) within gel was determined using the color reaction for ATPase activity. Due to the presence of cytochromes, the red band in unstained gels corresponded to the cytochrome b6f complex. Localization of the cytochrome b6f complex, ATP synthase and coupling CF1 in the native gel was confirmed by their subunit composition determined after SDS-electrophoretic analysis. Carbonic anhydrase (CA) activity in polypeptide zones of PS II, cytochrome b6f complex, and ATP-synthase CF1 was identified in native gels using indicator bromothymol blue. CA activity of isolated CF1 in solution was determined by infrared gas analysis as the rate of bicarbonate dehydration. The water-soluble acetazolamide, an inhibitor of CA, unlike lipophilic ethoxyzolamide inhibited CA activity of CF1 Thus, it was shown for the first time that ATP-synthase has a component which is capable of catalyzing the interconversion of forms of carbonic acid associated with proton exchange. The data obtained suggest the presence of multiple forms of carbonic anhydrase in the thylakoid membranes of spinach chloroplasts and confirm their involvement in the proton transfer to the ATP synthase. PMID:26502699

  9. Reduced Gut Acidity Induces an Obese-Like Phenotype in Drosophila melanogaster and in Mice

    PubMed Central

    Yen, Jui-Hung; Kuo, Ping-Chang; Yeh, Sheng-Rong; Lin, Hung-Yu; Fu, Tsai-Feng; Wu, Ming-Shiang; Wang, Horng-Dar; Wang, Pei-Yu

    2015-01-01

    In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H+-ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients. PMID:26436771

  10. Epileptic encephalopathy with continuous spikes and waves in the occipito-temporal region during slow-wave sleep in two patients with acquired Kanji dysgraphia.

    PubMed

    Kuki, Ichiro; Kawawaki, Hisashi; Okazaki, Shin; Ikeda, Hiroko; Tomiwa, Kiyotaka

    2014-12-01

    We encountered two patients with acquired Kanji dysgraphia in whom continuous spikes and waves, dominant in the occipito-temporal region, were recorded during slow-wave sleep. Electrical status epileptics during sleep (ESES) was demonstrated on overnight electroencephalography, and dipoles clustered in and around the posterior inferior temporal cortex on magnetoencephalography. Functional neuroimaging suggested dysfunction in the left posterior temporal lobe, including the posterior inferior temporal cortex. The patients had normal intelligence with no problems in reading and writing Kana, as well as copying, reading aloud, and identifying Kanjis, but showed Kanji dysgraphia (morphological, phonemic, and semantic error) accompanied by impaired visual processing. ESES was resolved by sodium valproate, clonazepam, and acetazolamide in Patient 1, and by adrenocorticotropic hormone, sodium valproate, and clorazepate in Patient 2. The present cases had the unique cognitive dysfunction of Kanji dysgraphia, which is distinct from that of Landau-Kleffner syndrome and continuous spikes and waves during slow-wave sleep. However, the present cases also share common features with these two encephalopathies in terms of the clinical course, pathophysiology, neuroimaging, and response to steroids and antiepileptic drugs. In the context of the Japanese language, acquired Kanji dysgraphia may occur due to electrical dysfunction of left posterior inferior temporal cortex in patients with ESES. PMID:25333864

  11. Review of tumoral calcinosis: A rare clinico-pathological entity

    PubMed Central

    Fathi, Ibrahim; Sakr, Mahmoud

    2014-01-01

    Tumoral calcinosis (TC) has long been a controversial clinico-pathological entity. Its pathogenesis and genetic background have been gradually unravelled since its first description in 1943. According to the presence or absence of an underlying calcifying disease process, TC has been divided into primary and secondary varieties. Two subtypes of the primary variety exist; a hyper-phosphatemic type with familial basis represented by mutations in GalNAc transferase 3 gene (GALNT3), KLOTHO or Fibroblast growth factor 23 (FGF23) genes, and a normo-phosphatemic type with growing evidence of underlying familial base represented by mutation in SAMD9 gene. The secondary variety is mainly associated with chronic renal failure and the resulting secondary or tertiary hyperparathyroidism. Diagnosis of TC relies on typical radiographic features (on plain radiographs and computed tomography) and the biochemical profile. Magnetic resonance imaging can be done in difficult cases, and scintigraphy reflects the disease activity. Treatment is mainly surgical for the primary variety; however, a stage-oriented conservative approach using phosphate binders, phosphate restricted diets and acetazolamide should be considered before the surgical approach is pursued due to the high rate of recurrences and complications after surgical intervention. Medical treatment is the mainstay for treatment of the secondary variety, with failure warranting subtotal or total parathyroidectomy. Surgical intervention in these patients should be kept as a last resort. PMID:25232542

  12. Changes in body fluid compartments on re-induction to high altitude and effect of diuretics

    NASA Astrophysics Data System (ADS)

    Singh, M. V.; Rawal, S. B.; Tyagi, A. K.; Bhagat, Maj J. K.; Parshad, R.; Divekar, H. M.

    1988-03-01

    Studies were carried out in 29 healthy young adults in the Indian Army stationed in the plains and posted at an elevation of 3500 m for more than 6 months. After exposure to a low elevation in Delhi (260 m) for 3 weeks they were reinduced to a height of 3500 m. The subjects were divided into three groups, each of which was treated with either placebo or acetazolamide or spironolactone. The drug treatment was started immediately after their landing at high altitude and continued for 2 days only. Total body water, extracellular fluid, intracellular fluid, plasma volume, blood pH, PaO2, PaCO2 and blood viscosity were determined on exposure at Delhi and on re-induction to high altitude. Plasma volume was increased after the descent from high altitude and remained high for up to 21 day's study. This increased plasma volume may have some significance in the pathogenesis of pulmonary oedema. Total body water and intracellular fluid content were increased at 260 m elevation, while extracellular fluid decreased. On re-induction there was a decrease in total body water with no change in the extracellular fluid content.

  13. Diagnostic applications of simultaneously acquired dual-isotope single-photon emission CT scans

    SciTech Connect

    Mathews, D.; Walker, B.S.; Allen, B.C.; Batjer, H.; Purdy, P.D. )

    1994-01-01

    To report the development and validation of a technique of dual tracer single-photon emission CT brain imaging using technetium-99m hexamethyl-propyleneamine oxime and iodine-123 iodoamphetamine agents and the application of this technique in patients with a variety of diagnoses. Contamination between the two isotopes' energy windows was calculated by opening both energy windows while scanning a group of patients using a single isotope. To compare uniformity of I-123 down-scatter. Tc-99m studies were performed both before and after the administration of I-123 in five of 24 dual studies. The 24 patients studied with the dual-isotope technique were evaluated during acetazolamide testing, trial balloon occlusion, or embolization of an arteriovenous malformation. In a dual acquisition, average count contamination of an I-123 study by Tc-99m was less than 1% of the total I-123 counts, and contamination of a Tc-99m study by I-123 was approximately 12% of the total Tc-99m counts. Tc-99m studies performed both before and after the administration of I-123 demonstrated that contaminating counts do not adversely affect scan interpretation. Dual-tracer scans were completed in all 24 patients, 10 of whom showed changes after intervention. Dual-tracer single-photon emission CT brain scans of adequate diagnostic quality are possible using Tc-99m and I-123. 18 refs., 5 figs., 3 tabs.

  14. Characterization and inhibition studies of carbonic anhydrase from gill of Russian Sturgeon Fish (Acipenser gueldenstaedtii).

    PubMed

    Dinçer, Barbaros; Ekinci, Arife Pınar; Akyüz, Gülay; Kurtoğlu, İlker Zeki

    2016-12-01

    An α-carbonic anhydrase (CA, EC 4.2.1.1) was purified and characterized kinetically from gill of Acipenser gueldenstaedtii as an endangered sturgeon species. The carbonic anhydrase was purified 66-folds with yield 20.7% by Sepharose-4B-l-tyrosine-sulfanilamide affinity column and the specific activity was determined as 222.2 EU/mg protein. Km and Vmax kinetic values for gill carbonic anhydrase were calculated by a Lineweaver-Burk graph using p-nitrophenol acetate (p-NPA) as a substrate, and was defined as 2.5 mM and 5 × 10(6 )μM/min, respectively. It was observed that CA from the sturgeon gill in the presence of the sulfanilamide and acetazolamide as an inhibitor had very low IC50 values such as 13.0 and 0.1 μM, respectively. In addition, it was determined that the enzyme was inhibited by Fe(2+,) Co(2+,) Ni(2+), and Zn(2+)-Ba(2+) with the IC50 values of 0.2, 1.7, 1.2, and 1.1 mM, respectively.

  15. [Acute mountain sickness : How can it be treated and how can it be avoided?].

    PubMed

    Fischer, R

    2014-03-01

    Due to the decreasing partial pressure of oxygen, high altitude sickness can occur at heights over 2,500 m. This can be best avoided by slow adaptation to the altitude (acclimatization). In this way the organism adapts to the chronic hyperventilation and in the further process the oxygen content is normalized by an increase in erythrocytes. The commonest form of high altitude sickness is acute mountain sickness which is characterized by the leading symptom of headache. When additional signs of ataxia occur there is an acute danger of edema which is associated with a high mortality. Stress dyspnea, coughing and rasping breathing noises also occur by the potentially fatal high altitude pulmonary edema. All forms of high altitude sickness can be countered by a rapid descent to a height of at least 500 m. In acute mountain sickness acetazolamide can be administered (2 × 250 mg), for high altitude cerebral edema dexamethasone (3 × 4-8 mg) and for high altitude pulmonary edema nifedipine (initially 10 mg then 20 mg retard).

  16. Chemical and enzymological characterization of an Indonesian variant of human erythrocyte carbonic anhydrase II, CAII Jogjakarta (17 Lys leads to Glu).

    PubMed

    Jones, G L; Sofro, A S; Shaw, D C

    1982-10-01

    A new variant of human erythrocyte carbonic anhydrase II (CAII) was discovered in a single heterozygous individual during routine screening of blood samples from the island of Java in Indonesia. The normal and variant components of the heterozygous CAII mixture were resolved by isoelectric focusing following purification by a specific affinity matrix. Specific esterase activities and Michaelis-Menten constants were identical. Only very small differences were noted with respect to inhibition by acetazolamide and chloride. Double diffusion analysis showed the immunological identify of the normal and variant enzymes. The variant CAII was considerably less heat stable than the normal enzyme. The variant was slightly more stable than the normal enzyme upon dialysis against the zinc chelator dipicolinic acid (PDCA), indicating a tighter binding of zinc than the normal enzyme. Analysis of tryptic peptides from the normal and variant enzymes indicated that, in the variant, lysine at position 17 from the N terminus had changed to glutamic acid. The differences in physiochemical properties observed for the normal and variant enzyme are discussed in relation to the possible effects of this substitution on the structure of the CAII molecule. PMID:6817747

  17. Cl- uptake mechanism in freshwater-adapted tilapia (Oreochromis mossambicus).

    PubMed

    Chang, I-Chi; Hwang, Pung-Pung

    2004-01-01

    In this study, the correlation between Cl(-) influx in freshwater tilapia and various transporters or enzymes, the Cl(-)/HCO(3)(-) exchanger, Na(+),K(+)-ATPase, V-type H(+)-ATPase, and carbonic anhydrase were examined. The inhibitors 2x10(-4) M ouabain (a Na(+),K(+)-ATPase inhibitor), 10(-5) M NEM (a V-type H(+)-ATPase inhibitor), 10(-2) M ACTZ (acetazolamide, a carbonic anhydrase inhibitor), and 6x10(-4) M DIDS (a Cl(-)/HCO(3)(-) exchanger inhibitor) caused 40%, 60%-80%, 40%-60%, and 40%-60% reduction in Cl(-) influx of freshwater tilapia, respectively. The inhibitor 2x10(-4) M ouabain also caused 50%-65% inhibition in gill Na(+),K(+)-ATPase activity. Western blot results showed that protein levels of gill Na(+),K(+)-ATPase, V-type H(+)-ATPase, and carbonic anhydrase in tilapia acclimated in low-Cl(-) freshwater were significantly higher than those acclimated to high-Cl(-) freshwater. Based on these data, we conclude that Na(+),K(+)-ATPase, V-H(+)-ATPase, the Cl(-)/HCO(3)(-) exchanger, and carbonic anhydrase may be involved in the active Cl(-) uptake mechanism in gills of freshwater-adapted tilapia. PMID:15286914

  18. A polymorphic variant of human erythrocyte carbonic anhydrase I with a widespread distribution in Australian aborigines, CAI Australia-9 (8 Asp leads to Gly): purification, properties, amino acid substitution, and possible physiological significance of the variant enzyme.

    PubMed

    Jones, G L; Shaw, D C

    1982-10-01

    Carbonic anhydrase I (EC 4.2.1.1) purified from the pooled packed red blood cells of 100 individuals typed as heterozygous for the common Australian Aboriginal carbonic anhydrase I variant CAI Australia-9 had a slightly higher specific CO2 hydratase or esterase (toward p-nitrophenyl acetate) activity than the normal component and a higher Km and Vmax using the esterase substrate. The variant enzyme was slightly more resistant to heat inactivation. The extent of inhibition of both enzymes by the specific inhibitor acetazolamide was identical, as was their immunological behavior and the lability of the active-site zinc ion. The variant enzyme was more resistant to chloride inhibition. The physiological importance of this observation is discussed in the context of a proposed adaptive advantage of the variant gene in the arid western and central regions of Australia. The amino acid substitution in the Aboriginal variant of a glycine for an aspartic acid residue has been located at residue 8 from the N terminus (i.e., 8 Asp leads to Gly), by proteolytic and partial acid hydrolyses. The possible effects of this substitution on the structure and function of the molecule are discussed. PMID:6817746

  19. The effects of temperature and inhibitors on HCO3-stimulated swelling and ion uptake of monkey cerebral cortex.

    PubMed

    Bourke, R S; Kimelberg, H K; Nelson, L R

    1976-03-26

    In the presence of high concentrations of K+, additions of HCO3- as low as 0.35 mM caused a 23% increase in swelling, and concomitant increases in the chloride content of incubating monkey cerebrocortical slices. The uptake of chloride was accompanied by increased uptake of sodium and was highly temperature dependent, showing a marked activation at approximately 30 degrees C. A similar temperature activation was also found for a Mg2+-dependent, HCO3-stimulated ATPase activity in monkey cerebral cortex, consistent with a possible role for this enzyme in the K+ and HCO3-dependent swelling process and its associated ion movements. K+-dependent, HCO3-stimulated cerebrocortical tissue swelling with uptake of Na+ and Cl- was inhibited by acetazolamide indicating that carbonic anhydrase was also involved. The addition of ouabain also inhibited swelling and K+ and Cl- uptake at low concentrations, but led to increased swelling at higher concentrations ( greater than 10 mum). A similar biphasic effect on swelling was also seen following addition of ethacrynic acid. PMID:130962

  20. Altitude Stress During Participation of Medical Congress

    PubMed Central

    Kim, Soon Bae; Kim, Jong Sung; Kim, Sang Jun; Cho, Su Hee

    2016-01-01

    Medical congresses often held in highlands. We reviewed several medical issues associated with altitude stress especially while physicians have participated medical congress held in high altitude. Altitude stress, also known as an acute mountain sickness (AMS), is caused by acute exposure to low oxygen level at high altitude which is defined as elevations at or above 1,200 m and AMS commonly occurs above 2,500 m. Altitude stress with various symptoms including insomnia can also be experienced in airplane. AMS and drunken state share many common features in symptoms, neurologic manifestations and even show multiple microbleeds in corpus callosum and white matter on MRI. Children are more susceptible to altitude stress than adults. Gradual ascent is the best method for the prevention of altitude stress. Adequate nutrition (mainly carbohydrates) and hydration are recommended. Consumption of alcohol can exacerbate the altitude-induced impairments in judgment and the visual senses and promote psychomotor dysfunction. For prevention or treatment of altitude stress, acetazolamide, phosphodiesterase inhibitors, dexamethasone and erythropoietin are helpful. Altitude stress can be experienced relatively often during participation of medical congress. It is necessary to remind the harmful effect of AMS because it can cause serious permanent organ damage even though the symptoms are negligible in most cases. PMID:27621942

  1. Diffusion of water-soluble sorptive drugs in HEMA/MAA hydrogels.

    PubMed

    Liu, D E; Dursch, T J; Taylor, N O; Chan, S Y; Bregante, D T; Radke, C J

    2016-10-10

    We measure and, for the first time, theoretically predict four prototypical aqueous-drug diffusion coefficients in five soft-contact-lens material hydrogels where solute-specific adsorption is pronounced. Two-photon fluorescence confocal microscopy and UV/Vis-absorption spectrophotometry assess transient solute concentration profiles and concentration histories, respectively. Diffusion coefficients are obtained for acetazolamide, riboflavin, sodium fluorescein, and theophylline in 2-hydroxyethyl methacrylate/methacrylic acid (HEMA/MAA) copolymer hydrogels as functions of composition, equilibrium water content (30-90%), and aqueous pH (2 and 7.4). At pH2, MAA chains are nonionic, whereas at pH7.4, MAA chains are anionic (pKa≈5.2). All studied prototypical drugs specifically interact with HEMA and nonionic MAA (at pH2) moieties. Conversely, none of the prototypical drugs adsorb specifically to anionic MAA (at pH7.4) chains. As expected, diffusivities of adsorbing solutes are significantly diminished by specific interactions with hydrogel strands. Despite similar solute size, relative diffusion coefficients in the hydrogels span several orders of magnitude because of varying degrees of solute interactions with hydrogel-polymer chains. To provide a theoretical framework for the new diffusion data, we apply an effective-medium model extended for solute-specific interactions with hydrogel copolymer strands. Sorptive-diffusion kinetics is successfully described by local equilibrium and Henry's law. All necessary parameters are determined independently. Predicted diffusivities are in good agreement with experiment. PMID:27565214

  2. Major contribution of the type II beta carbonic anhydrase CanB (Cj0237) to the capnophilic growth phenotype of Campylobacter jejuni.

    PubMed

    Al-Haideri, Halah; White, Michael A; Kelly, David J

    2016-02-01

    Campylobacter jejuni, the leading cause of human bacterial gastroenteritis, requires low environmental oxygen and high carbon dioxide for optimum growth, but the molecular basis for the carbon dioxide requirement is unclear. One factor may be inefficient conversion of gaseous CO2 to bicarbonate, the required substrate of various carboxylases. Two putative carbonic anhydrases (CAs) are encoded in the genome of C. jejuni strain NCTC 11168 (Cj0229 and Cj0237). Here, we show that the deletion of the cj0237 (canB) gene alone prevents growth in complex media at low (1% v/v) CO2 and significantly reduces the growth rate at high (5% v/v) CO2. In minimal media incubated under high CO2, the canB mutant grew on L-aspartate but not on the key C3 compounds L-serine, pyruvate and L-lactate, showing that CanB is crucial in bicarbonate provision for pyruvate carboxylase-mediated oxaloacetate synthesis. Nevertheless, purified CanB (a dimeric, anion and acetazolamide sensitive, zinc-containing type II beta-class enzyme) hydrates CO2 actively only above pH 8 and with a high Km (∼ 34 mM). At typical cytoplasmic pH values and low CO2, these kinetic properties might limit intracellular bicarbonate availability. Taken together, our data suggest CanB is a major contributor to the capnophilic growth phenotype of C. jejuni.

  3. In vivo and in vitro effects of a pulsed electromagnetic field on net calcium flux in rat calvarial bone.

    PubMed

    Spadaro, J A; Bergstrom, W H

    2002-06-01

    Although PEMF's have been found to promote fracture healing and to modulate the activity of bone cells in vitro, effects on bone metabolism are largely unexplored. A bioassay using neonatal rat calvarial bone was used to determine the early effects of a pulsing electromagnetic field (PEMF) exposure in vivo and in vitro on bone metabolic calcium exchange. Bone discs taken from whole body exposed animals (0-4 hours) show a log exposure time-dependent average increase in net Ca uptake in the 0-50% range (r2 = 0.83). This increase could be detected immediately after exposure and also after 24 hours, but not 48 hours later. Animals given whole body PEMF exposure also showed a decrease in serum calcium and did not elevate serum Ca after administration of exogenous parathyroid hormone (PTH). Bone discs from untreated rats, exposed to PEMF for 15 minutes in vitro and then assayed, showed net Ca uptake increases of a similar magnitude and also were refractory to the Ca-releasing effect of PTH. Unexposed discs responded normally to PTH by decreasing net Ca uptake. Treatment of calvarial discs with calcitonin or acetazolamide, both of which inactivate osteoclasts, made the bone refractory to further increases in Ca uptake by PEMF. These results suggest that PEMF exposure produces PTH-refractory osteoclastics and has a relatively rapid effect on increasing net bone Ca uptake, putatively due to a decrease in PTH/paracrine-mediated bone resorption. PMID:11976773

  4. Mechanisms of Na+ uptake, ammonia excretion, and their potential linkage in native Rio Negro tetras (Paracheirodon axelrodi, Hemigrammus rhodostomus, and Moenkhausia diktyota).

    PubMed

    Wood, Chris M; Robertson, Lisa M; Johannsson, Ora E; Val, Adalberto Luis

    2014-10-01

    Mechanisms of Na(+) uptake, ammonia excretion, and their potential linkage were investigated in three characids (cardinal, hemigrammus, moenkhausia tetras), using radiotracer flux techniques to study the unidirectional influx (J in), efflux (J out), and net flux rates (J net) of Na(+) and Cl(-), and the net excretion rate of ammonia (J Amm). The fish were collected directly from the Rio Negro, and studied in their native "blackwater" which is acidic (pH 4.5), ion-poor (Na(+), Cl(-) ~20 µM), and rich in dissolved organic matter (DOM 11.5 mg C l(-1)). J in (Na) , J in (Cl) , and J Amm were higher than in previous reports on tetras obtained from the North America aquarium trade and/or studied in low DOM water. In all three species, J in (Na) was unaffected by amiloride (10(-4) M, NHE and Na(+) channel blocker), but both J in (Na) and J in (Cl) were virtually eliminated (85-99 % blockade) by AgNO3 (10(-7) M). A time course study on cardinal tetras demonstrated that J in (Na) blockade by AgNO3 was very rapid (<5 min), suggesting inhibition of branchial carbonic anhydrase (CA), and exposure to the CA-blocker acetazolamide (10(-4) M) caused a 50 % reduction in J in (Na) .. Additionally, J in (Na) was unaffected by phenamil (10(-5) M, Na(+) channel blocker), bumetanide (10(-4) M, NKCC blocker), hydrochlorothiazide (5 × 10(-3) M, NCC blocker), and exposure to an acute 3 unit increase in water pH. None of these treatments, including partial or complete elimination of J in (Na) (by acetazolamide and AgNO3 respectively), had any inhibitory effect on J Amm. Therefore, Na(+) uptake in Rio Negro tetras depends on an internal supply of H(+) from CA, but does not fit any of the currently accepted H(+)-dependent models (NHE, Na(+) channel/V-type H(+)-ATPase), or co-transport schemes (NCC, NKCC), and ammonia excretion does not fit the current "Na(+)/NH4 (+) exchange metabolon" paradigm. Na(+), K(+)-ATPase and V-type H(+)-ATPase activities were present at similar

  5. Absence of carbonic anhydrase on the surface of red cells suspended in an elutriator

    SciTech Connect

    Dodek, P.; Effros, R.M.

    1986-03-01

    Studies of the carbonic anhydrase activity of intact red cells are complicated by hemolysis, which markedly accelerates catalytic conversion between HCO/sub 2//sup -/ and CO/sub 2/. The authors have reduced this effect to negligible levels by studying red cells suspended with an elutriator. 1.Oml of packed rabbit red cells were introduced in an elutriator chamber which was spun in a centrifuge with a force of 2900G. An isotonic, pH 7.4, 6/sup 0/C, HCO/sub 3//sup -/ Ringer's lactate solution was pumped centripetally through the chamber to keep the cells in suspension. 0.1 ml of the perfusion solution containing /sup 22/Na/sup +/, /sup 36/Cl-, H/sup 14/CO/sub 3//sup -///sup 14/CO/sub 2/ (equilibrated), and /sup 3/H/sub 2/O were injected into the elutriator inflow and 22 samples were collected with a computerized anaerobic collector. Outflow concentrations of each radionuclide were divided by the amounts injected to yield fractional concentrations and upslope areas of indicators were divided by that of /sup 22/Na/sup +/ to yield an index of red cell exchange, R. Under control conditions, R(/sup 14/C) averaged .80 +/- .01 (S.E.). After anion exchange had been blocked with 0.1..mu..M DIDS, R(/sup 14/C) increased to .86 +/- .01. When 100 mg/1 bovine carbonic anhydrase was added R(/sup 1/$C) fell to .78 +/- .01. Subsequent addition of acetazolamide (10/sup -5/) increased R(/sup 14/C) to .86 +/- .01. R(/sup 36/Cl/sup -/) was increased from .91 +/- .02 to .96 +/- .01 after DIDS. These data indicate no detectable carbonic anhydrase activity on red cell surface.

  6. Transport of butyrate across the isolated bovine rumen epithelium--interaction with sodium, chloride and bicarbonate.

    PubMed

    Sehested, J; Diernaes, L; Møller, P D; Skadhauge, E

    1999-08-01

    The Ussing chamber technique was used for studying unidirectional fluxes of 14C-butyrate across the bovine rumen epithelium in vitro. Significant amounts of butyrate were absorbed across the bovine rumen epithelium in vitro, without any external driving force. The paracellular pathway was quantitatively insignificant. The transcellular pathway was predominately voltage-insensitive. The serosal to mucosal (SM) pathway was regulated by mass action, whereas the mucosal to serosal (MS) pathway further includes a saturable process, which accounted for 30 to 55% of the MS flux. The studied transport process for 14C-butyrate across the epithelium could include metabolic processes and transport of 14C-labelled butyrate metabolites. The transport of butyrate interacted with Na+, Cl- and HCO3-, and there was a linear relationship between butyrate and sodium net transport. Lowering the sodium concentration from 140 to 10 mmol l-1 decreased the butyrate MS flux significantly. Amiloride (1 mmol l-1) did, however, not reduce the butyrate flux significantly. Chloride concentration in itself did not seem to influence the transport of butyrate, but chloride-free conditions tended to increase the MS and SM flux of butyrate by a DIDS-sensitive pathway. DIDS (bilateral 0.5 mmol l-1) did further decrease the butyrate SM flux significantly at all chloride concentrations. Removing bicarbonate from the experimental solutions decreased the MS and increased the SM flux of butyrate significantly, and abolished net butyrate flux. There were no significant effects of the carbonic anhydrase inhibitor Acetazolamide (bilateral 1.0 mmol l-1). The results can be explained by a model where butyrate and butyrate metabolites are transported both by passive diffusion and by an electroneutral anion-exchange with bicarbonate. The model couples sodium and butyrate via CO2 from metabolism of butyrate, and intracellular pH.

  7. Characterization of the first beta-class carbonic anhydrase from an arthropod (Drosophila melanogaster) and phylogenetic analysis of beta-class carbonic anhydrases in invertebrates

    PubMed Central

    2010-01-01

    Background The β-carbonic anhydrase (CA, EC 4.2.1.1) enzymes have been reported in a variety of organisms, but their existence in animals has been unclear. The purpose of the present study was to perform extensive sequence analysis to show that the β-CAs are present in invertebrates and to clone and characterize a member of this enzyme family from a representative model organism of the animal kingdom, e.g., Drosophila melanogaster. Results The novel β-CA gene, here named DmBCA, was identified from FlyBase, and its orthologs were searched and reconstructed from sequence databases, confirming the presence of β-CA sequences in 55 metazoan species. The corresponding recombinant enzyme was produced in Sf9 insect cells, purified, kinetically characterized, and its inhibition was investigated with a series of simple, inorganic anions. Holoenzyme molecular mass was defined by dynamic light scattering analysis and gel filtration, and the results suggested that the holoenzyme is a dimer. Double immunostaining confirmed predictions based on sequence analysis and localized DmBCA protein to mitochondria. The enzyme showed high CO2 hydratase activity, with a kcat of 9.5 × 105 s-1 and a kcat/KM of 1.1 × 108 M-1s-1. DmBCA was appreciably inhibited by the clinically-used sulfonamide acetazolamide, with an inhibition constant of 49 nM. It was moderately inhibited by halides, pseudohalides, hydrogen sulfide, bisulfite and sulfate (KI values of 0.67 - 1.36 mM) and more potently by sulfamide (KI of 0.15 mM). Bicarbonate, nitrate, nitrite and phenylarsonic/boronic acids were much weaker inhibitors (KIs of 26.9 - 43.7 mM). Conclusions The Drosophila β-CA represents a highly active mitochondrial enzyme that is a potential model enzyme for anti-parasitic drug development. PMID:20659325

  8. Variations of gastric transmucosal potential difference and lesion formation during hemorrhagic shock in the rat.

    PubMed

    Takeuchi, K; Ohno, T; Okabe, S

    1986-11-01

    We measured transmucosal potential difference (PD) of the stomach in anesthetized rats before, during, and after hemorrhagic shock, and investigated the effects of various drugs on the PD and gastric lesion during this period. After hemorrhagic shock, there was a decrease of PD and an increase of luminal pH in the saline-perfused stomach, the degree of these changes being dependent on a fall in the arterial blood pressure. The graded reduction of PD in response to hemorrhagic shock was similarly observed in the acid-perfused stomach as in the saline-perfused one. However, gastric lesions developed only in the former, and a significant correlation was found between the lesion index and the fall in blood pressure, the reduction in PD, or the concentration of HCl as the perfusate. Subcutaneously administered propantheline bromide (30 mg/kg) or cimetidine (100 mg/kg) had no effect on gastric lesion and PD reduction caused by hemorrhagic shock. These lesions were significantly inhibited by 16,16-dimethyl prostaglandin E2 (10 micrograms/kg) or sulindac (100 mg/kg), a scavenger of OH., and aggravated by indomethacin (1 mg/kg), with less effect on the PD reduction. Intravenous infusion of NaHCO3 (0.5 M) also significantly prevented the lesion with a concomitant suppression of the PD reduction in response to hemorrhagic shock, but these effects were significantly reversed by pretreatment of the animals with acetazolamide (50 mg/kg). These results indicate that during hemorrhagic shock the PD may largely reflect the impairment of mucosal blood flow and may be used as an indicator of mucosal vulnerability to acid, gastric lesions develop only in the presence of exogenous acid, and production of prostaglandins and superoxide radicals may be involved in the pathogenesis of gastric lesions. PMID:3019817

  9. Selective pharmacological modulation of renal peripheral-type benzodiazepine binding by treatment with diuretic drugs

    SciTech Connect

    Lukeman, D.S.; Vaughn, D.A.; Fanestil, D.D.

    1988-01-01

    The authors have assessed the effects of in vivo administration of different classes of diuretic drugs on the expression of the peripheral-type benzodiazepine binding site (PBBS) in crude membranes derived from the cortex and outer medulla of rat kidney by saturation analysis with the PBBS-selective ligands (/sup 3/H)RO5-4864 and (/sup 3/H)PH 11195 in cortex and (/sup 3/H)RO5-4864 in outer medulla. Administration for 14-15 days of furosemide, a drug that blocks NaCl-KCl coupled transport in the thick ascending limb of the loop of Henle, produced a significant doubling in the PBBS density (B/sub max/) in outer medulla, a region of the kidney rich in thick ascending limbs, and produced a lesser but significant increase in PBBS density in the cortex. Conversely, administration for 14-15 days of the carbonic anhydrase inhibitor acetazolamide, which acts predominantly in the proximal tubule, and hydrochlorothiazide, which acts predominantly in the early distal tubule, elicited statistically significant increases in PBBS density in renal cortex but not in renal outer medulla. Furthermore, all drug treatments were without effect on the equilibrium dissociation constants (K/sub d/s) of (/sup 3/H)RO5-4864 and (/sup 3/H)PK 11195 binding to cortical and outer medullary membrane preparations. These findings demonstrate that the PBBS can be selectively up-regulated in different regions of the kidney by diuretic drugs with different modes/sites of action. 50 references, 1 table.

  10. Risk factors for poor visual outcome in patients with idiopathic intracranial hypertension

    PubMed Central

    Falardeau, Julie; Fletcher, William A.; Granadier, Robert J.; Lam, Byron L.; Longmuir, Reid A.; Patel, Anil D.; Bruce, Beau B.; He, Hua; McDermott, Michael P.

    2015-01-01

    Objectives: Determine potential risk factors for progressive visual field loss in the Idiopathic Intracranial Hypertension Treatment Trial, a randomized placebo-controlled trial of acetazolamide in patients with idiopathic intracranial hypertension and mild visual loss concurrently receiving a low sodium, weight reduction diet. Methods: Logistic regression and classification tree analyses were used to evaluate potential risk factors for protocol-defined treatment failure (>2 dB perimetric mean deviation [PMD] change in patients with baseline PMD −2 to −3.5 dB or >3 dB PMD change with baseline PMD −3.5 to −7 dB). Results: Seven participants (6 on diet plus placebo) met criteria for treatment failure. The odds ratio for patients with grades III to V papilledema vs those with grades I and II was 8.66 (95% confidence interval [CI] 1.65–∞, p = 0.025). A 1-unit decrease in the number of letters correct on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at baseline was associated with an increase in the odds of treatment failure by a factor of 1.16 (95% CI 1.04–1.30, p = 0.005). Compared with female participants, the odds ratio for male participants was 26.21 (95% CI 1.61–433.00, p = 0.02). The odds of treatment failure were 10.59 times higher (95% CI 1.63–116.83, p = 0.010) for patients with >30 transient visual obscurations per month vs those with ≤30 per month. Conclusions: Male patients, those with high-grade papilledema, and those with decreased visual acuity at baseline were more likely to experience treatment failure. All but one of these patients were treated with diet alone. These patients should be monitored closely and be considered for aggressive treatment of their idiopathic intracranial hypertension. PMID:26245929

  11. Dynamic volume changes in astrocytes are an intrinsic phenomenon mediated by bicarbonate ion flux.

    PubMed

    Florence, Clare M; Baillie, Landon D; Mulligan, Sean J

    2012-01-01

    Astrocytes, the major type of non-neuronal cells in the brain, play an important functional role in extracellular potassium ([K(+)](o)) and pH homeostasis. Pathological brain states that result in [K(+)](o) and pH dysregulation have been shown to cause astrocyte swelling. However, whether astrocyte volume changes occur under physiological conditions is not known. In this study we used two-photon imaging to visualize real-time astrocyte volume changes in the stratum radiatum of the hippocampus CA1 region. Astrocytes were observed to swell by 19.0±0.9% in response to a small physiological increase in the concentration of [K(+)](o) (3 mM). Astrocyte swelling was mediated by the influx of bicarbonate (HCO(3-)) ions as swelling was significantly decreased when the influx of HCO(3-) was reduced. We found: 1) in HCO(3-) free extracellular solution astrocytes swelled by 5.4±0.7%, 2) when the activity of the sodium-bicarbonate cotransporter (NBC) was blocked the astrocytes swelled by 8.3±0.7%, and 3) in the presence of an extracellular carbonic anhydrase (CA) inhibitor astrocytes swelled by 11.4±0.6%. Because a significant HCO(3-) efflux is known to occur through the γ-amino-butyric acid (GABA) channel, we performed a series of experiments to determine if astrocytes were capable of HCO(3-) mediated volume shrinkage with GABA channel activation. Astrocytes were found to shrink -7.7±0.5% of control in response to the GABA(A) channel agonist muscimol. Astrocyte shrinkage from GABA(A) channel activation was significantly decreased to -5.0±0.6% of control in the presence of the membrane-permeant CA inhibitor acetazolamide (ACTZ). These dynamic astrocyte volume changes may represent a previously unappreciated yet fundamental mechanism by which astrocytes regulate physiological brain functioning. PMID:23226475

  12. Light Levels Affect Carbon Utilisation in Tropical Seagrass under Ocean Acidification

    PubMed Central

    2016-01-01

    Under future ocean acidification (OA), increased availability of dissolved inorganic carbon (DIC) in seawater may enhance seagrass productivity. However, the ability to utilise additional DIC could be regulated by light availability, often reduced through land runoff. To test this, two tropical seagrass species, Cymodocea serrulata and Halodule uninervis were exposed to two DIC concentrations (447 μatm and 1077 μatm pCO2), and three light treatments (35, 100, 380 μmol m-2 s-1) for two weeks. DIC uptake mechanisms were separately examined by measuring net photosynthetic rates while subjecting C. serrulata and H. uninervis to changes in light and addition of bicarbonate (HCO3-) use inhibitors (carbonic anhydrase inhibitor, acetazolamide) and TRIS buffer (pH 8.0). We observed a strong dependence on energy driven H+-HCO3- co-transport (TRIS, which disrupts H+ extrusion) in C. serrulata under all light levels, indicating greater CO2 dependence in low light. This was confirmed when, after two weeks exposure, DIC enrichment stimulated maximum photosynthetic rates (Pmax) and efficiency (α) more in C. serrulata grown under lower light levels (36–60% increase) than for those in high light (4% increase). However, C. serrulata growth increased with both DIC enrichment and light levels. Growth, NPP and photosynthetic responses in H. uninervis increased with higher light treatments and were independent of DIC availability. Furthermore, H. uninervis was found to be more flexible in HCO3- uptake pathways. Here, light availability influenced productivity responses to DIC enrichment, via both carbon fixation and acquisition processes, highlighting the role of water quality in future responses to OA. PMID:26938454

  13. Microsensor studies on Padina from a natural CO2 seep: implications of morphology on acclimation to low pH.

    PubMed

    Hofmann, Laurie C; Fink, Artur; Bischof, Kai; de Beer, Dirk

    2015-12-01

    Low seawater pH can be harmful to many calcifying marine organisms, but the calcifying macroalgae Padina spp. flourish at natural submarine carbon dioxide seeps where seawater pH is low. We show that the microenvironment created by the rolled thallus margin of Padina australis facilitates supersaturation of CaCO3 and calcifi-cation via photosynthesis-induced elevated pH. Using microsensors to investigate oxygen and pH dynamics in the microenvironment of P. australis at a shallow CO2 seep, we found that, under saturating light, the pH inside the microenvironment (pHME ) was higher than the external seawater (pHSW ) at all pHSW levels investigated, and the difference (i.e., pHME - pHSW ) increased with decreasing pHSW (0.9 units at pHSW 7.0). Gross photosynthesis (Pg ) inside the microenvironment increased with decreasing pHSW , but algae from the control site reached a threshold at pH 6.5. Seep algae showed no pH threshold with respect to Pg within the pHSW range investigated. The external carbonic anhydrase (CA) inhibitor, acetazolamide, strongly inhibited Pg of P. australis at pHSW 8.2, but the effect was diminished under low pHSW (6.4-7.5), suggesting a greater dependence on membrane-bound CA for the dehydration of HCO3 (-) ions during dissolved inorganic carbon uptake at the higher pHSW . In comparison, a calcifying green alga, Halimeda cuneata f. digitata, was not inhibited by AZ, suggesting efficient bicarbonate transport. The ability of P. australis to elevate pHME at the site of calcification and its strong dependence on CA may explain why it can thrive at low pHSW . PMID:26987005

  14. Fit for high altitude: are hypoxic challenge tests useful?

    PubMed

    Matthys, Heinrich

    2011-01-01

    Altitude travel results in acute variations of barometric pressure, which induce different degrees of hypoxia, changing the gas contents in body tissues and cavities. Non ventilated air containing cavities may induce barotraumas of the lung (pneumothorax), sinuses and middle ear, with pain, vertigo and hearing loss. Commercial air planes keep their cabin pressure at an equivalent altitude of about 2,500 m. This leads to an increased respiratory drive which may also result in symptoms of emotional hyperventilation. In patients with preexisting respiratory pathology due to lung, cardiovascular, pleural, thoracic neuromuscular or obesity-related diseases (i.e. obstructive sleep apnea) an additional hypoxic stress may induce respiratory pump and/or heart failure. Clinical pre-altitude assessment must be disease-specific and it includes spirometry, pulsoximetry, ECG, pulmonary and systemic hypertension assessment. In patients with abnormal values we need, in addition, measurements of hemoglobin, pH, base excess, PaO2, and PaCO2 to evaluate whether O2- and CO2-transport is sufficient.Instead of the hypoxia altitude simulation test (HAST), which is not without danger for patients with respiratory insufficiency, we prefer primarily a hyperoxic challenge. The supplementation of normobaric O2 gives us information on the acute reversibility of the arterial hypoxemia and the reduction of ventilation and pulmonary hypertension, as well as about the efficiency of the additional O2-flow needed during altitude exposure. For difficult judgements the performance of the test in a hypobaric chamber with and without supplemental O2-breathing remains the gold standard. The increasing numbers of drugs to treat acute pulmonary hypertension due to altitude exposure (acetazolamide, dexamethasone, nifedipine, sildenafil) or to other etiologies (anticoagulants, prostanoids, phosphodiesterase-5-inhibitors, endothelin receptor antagonists) including mechanical aids to reduce periodical or

  15. Bicarbonate absorption stimulates active calcium absorption in the rat proximal tubule.

    PubMed Central

    Bomsztyk, K; Calalb, M B

    1988-01-01

    To evaluate the effect of luminal bicarbonate on calcium reabsorption, rat proximal tubules were perfused in vivo. Perfusion solution contained mannitol to reduce water flux to zero. Total Ca concentration was measured by atomic absorption spectrometry, Ca ion concentration in the tubule lumen (CaL2+) and the peritubular capillary (CaP2+), and luminal pH (pHL) with ion-selective microelectrodes and transepithelial voltage (VTE) with conventional microelectrodes. When tubules were perfused with buffer-free Cl-containing solution, net Ca absorption (JCa) averaged 3.33 pmol/min. Even though VTE was 1.64 mV lumen-positive, CaL2+, 1.05 mM, did not fall below the concentration in the capillary blood, 1.07 mM. When 27 mM of Cl was replaced with HCO3, there was luminal fluid acidification. Despite a decrease in VTE and CaL2+, JCa increased to 7.13 pmol/min, indicating that the enhanced JCa could not be accounted for by the reduced electrochemical gradient, delta CCa. When acetazolamide or an analogue of amiloride was added to the HCO3 solution, JCa was not different from the buffer-free solution, suggesting that HCO3-stimulated JCa may be linked to acidification. To further test this hypothesis, we used 27 mM Hepes as the luminal buffer. With Hepes there was luminal fluid acidification and JCa was not different from the buffer-free solution but delta CCa was significantly reduced, indicating enhanced active calcium transport. We conclude from the results of the present study that HCO3 stimulates active Ca absorption, a process that may be linked to acidification-mediated HCO3 absorption. PMID:3366902

  16. Microsensor studies on Padina from a natural CO2 seep: implications of morphology on acclimation to low pH.

    PubMed

    Hofmann, Laurie C; Fink, Artur; Bischof, Kai; de Beer, Dirk

    2015-12-01

    Low seawater pH can be harmful to many calcifying marine organisms, but the calcifying macroalgae Padina spp. flourish at natural submarine carbon dioxide seeps where seawater pH is low. We show that the microenvironment created by the rolled thallus margin of Padina australis facilitates supersaturation of CaCO3 and calcifi-cation via photosynthesis-induced elevated pH. Using microsensors to investigate oxygen and pH dynamics in the microenvironment of P. australis at a shallow CO2 seep, we found that, under saturating light, the pH inside the microenvironment (pHME ) was higher than the external seawater (pHSW ) at all pHSW levels investigated, and the difference (i.e., pHME - pHSW ) increased with decreasing pHSW (0.9 units at pHSW 7.0). Gross photosynthesis (Pg ) inside the microenvironment increased with decreasing pHSW , but algae from the control site reached a threshold at pH 6.5. Seep algae showed no pH threshold with respect to Pg within the pHSW range investigated. The external carbonic anhydrase (CA) inhibitor, acetazolamide, strongly inhibited Pg of P. australis at pHSW 8.2, but the effect was diminished under low pHSW (6.4-7.5), suggesting a greater dependence on membrane-bound CA for the dehydration of HCO3 (-) ions during dissolved inorganic carbon uptake at the higher pHSW . In comparison, a calcifying green alga, Halimeda cuneata f. digitata, was not inhibited by AZ, suggesting efficient bicarbonate transport. The ability of P. australis to elevate pHME at the site of calcification and its strong dependence on CA may explain why it can thrive at low pHSW .

  17. Contemporary reliance on bicarbonate acquisition predicts increased growth of seagrass Amphibolis antarctica in a high-CO2 world

    PubMed Central

    Burnell, Owen W.; Connell, Sean D.; Irving, Andrew D.; Watling, Jennifer R.; Russell, Bayden D.

    2014-01-01

    Rising atmospheric CO2 is increasing the availability of dissolved CO2 in the ocean relative to HCO3−. Currently, many marine primary producers use HCO3− for photosynthesis, but this is energetically costly. Increasing passive CO2 uptake relative to HCO3− pathways could provide energy savings, leading to increased productivity and growth of marine plants. Inorganic carbon-uptake mechanisms in the seagrass Amphibolis antarctica were determined using the carbonic anhydrase inhibitor acetazolamide (AZ) and the buffer tris(hydroxymethyl)aminomethane (TRIS). Amphibolis antarctica seedlings were also maintained in current and forecasted CO2 concentrations to measure their physiology and growth. Photosynthesis of A. antarctica was significantly reduced by AZ and TRIS, indicating utilization of HCO3−-uptake mechanisms. When acclimated plants were switched between CO2 treatments, the photosynthetic rate was dependent on measurement conditions but not growth conditions, indicating a dynamic response to changes in dissolved CO2 concentration, rather than lasting effects of acclimation. At forecast CO2 concentrations, seedlings had a greater maximum electron transport rate (1.4-fold), photosynthesis (2.1-fold), below-ground biomass (1.7-fold) and increase in leaf number (2-fold) relative to plants in the current CO2 concentration. The greater increase in photosynthesis (measured as O2 production) compared with the electron transport rate at forecasted CO2 concentration suggests that photosynthetic efficiency increased, possibly due to a decrease in photorespiration. Thus, it appears that the photosynthesis and growth of seagrasses reliant on energetically costly HCO3− acquisition, such as A. antarctica, might increase at forecasted CO2 concentrations. Greater growth might enhance the future prosperity and rehabilitation of these important habitat-forming plants, which have experienced declines of global significance. PMID:27293673

  18. Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation.

    PubMed

    Beyer, Jochen; Bierl, Anabelle; Peters, Frank T; Maurer, Hans H

    2005-08-01

    A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the detection of diuretics, uricosurics, and/or their metabolites in human urine after extractive methylation. Phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by GC and identified by MS in the full-scan mode. The possible presence of the following drugs and/or their metabolites could be indicated using mass chromatography with the given ions: m/z 267, 352, 353, 355, 386, and 392 for thiazide diuretics bemetizide, bendroflumethiazide, butizide, chlorothiazide, cyclopenthiazide, cyclothiazide, hydrochlorothiazide, metolazone, polythiazide, and for canrenoic acid and spironolactone; m/z 77, 81, 181, 261, 270, 295, 406, and 438 for loop diuretics bumetanide, ethacrynic acid, furosemide, piretanide, torasemide, as well as the uricosurics benzbromarone, probenecid, and sulfinpyrazone; m/z 84, 85, 111, 112, 135, 161, 249, 253, 289, and 363 for the other diuretics acetazolamide, carzenide, chlorthalidone, clopamide, diclofenamide, etozoline, indapamide, mefruside, tienilic acid, and xipamide. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with reference spectra. This method allowed the detection of the abovementioned drugs and/or their metabolites in human urine samples, except torasemide. The limits of detection ranged from 0.001 to 5 mg/L in the full-scan mode. Recoveries of selected diuretics and uricosurics, representing the different chemical classes, ranged from 46% to 99% with coefficients of variation of less than 21%. After ingestion of the lowest therapeutic doses, furosemide was detectable in urine samples for 67 hours, hydrochlorothiazide for 48 hours, and spironolactone for 52 hours (via its target analyte canrenone). The procedure described here is part of a systematic toxicological analysis

  19. Chloride dysregulation and inhibitory receptor blockade yield equivalent disinhibition of spinal neurons yet are differentially reversed by carbonic anhydrase blockade.

    PubMed

    Lee, Kwan Yeop; Prescott, Steven A

    2015-12-01

    Synaptic inhibition plays a key role in processing somatosensory information. Blocking inhibition at the spinal level is sufficient to produce mechanical allodynia, and many neuropathic pain conditions are associated with reduced inhibition. Disinhibition of spinal neurons can arise through decreased GABAA/glycine receptor activation or through dysregulation of intracellular chloride. We hypothesized that these distinct disinhibitory mechanisms, despite all causing allodynia, are differentially susceptible to therapeutic intervention. Specifically, we predicted that reducing bicarbonate efflux by blocking carbonic anhydrase with acetazolamide (ACTZ) would counteract disinhibition caused by chloride dysregulation without affecting normal inhibition or disinhibition caused by GABAA/glycine receptor blockade. To test this, responses to innocuous tactile stimulation were recorded in vivo from rat superficial dorsal horn neurons before and after different forms of pharmacological disinhibition and again after application of ACTZ. Blocking GABAA or glycine receptors caused hyperresponsiveness equivalent to that caused by blocking the potassium chloride cotransporter KCC2, but, consistent with our predictions, only disinhibition caused by KCC2 blockade was counteracted by ACTZ. ACTZ did not alter responses of neurons with intact inhibition. As pathological downregulation of KCC2 is triggered by brain-derived neurotrophic factor, we also confirmed that ACTZ was effective against brain-derived neurotrophic factor-induced hyperresponsiveness. Our results argue that intrathecal ACTZ has antiallodynic effects only if allodynia arises through chloride dysregulation; therefore, behavioral evidence that ACTZ is antiallodynic in nerve-injured animals affirms the contribution of chloride dysregulation as a key pathological mechanism. Although different disinhibitory mechanisms are not mutually exclusive, these results demonstrate that their relative contribution dictates which

  20. [A Case of Aplastic or Twig-Like Middle Cerebral Artery Presenting with an Intracranial Hemorrhage Two Years after a Transient Ischemic Attack].

    PubMed

    Uchiyama, Taku; Okamoto, Hiroaki; Koguchi, Motofumi; Tajima, Yutaka; Suzuyama, Kenji

    2016-02-01

    Aplastic or twig-like middle cerebral artery (Ap/T-MCA) is a rare anatomical anomaly, which can be associated with intracranial hemorrhage and cerebral ischemia. A 52-year-old woman who presented with sudden headache was admitted to our hospital. Computed tomography (CT) and magnetic resonance imaging showed no abnormality; however, magnetic resonance angiogram revealed an occlusion or severe stenosis in the left middle cerebral artery. Three-dimensional CT angiography demonstrated severe stenosis in the left middle cerebral artery. The patient was discharged without any neurological deficit; however, she subsequently complained of temporary weakness in the right hand. It was possibly due to a transient ischemic attack; therefore, cilostazol 200 mg/day was administered for prevention of cerebral ischemia. Single photon emission computed tomography(with or without administration of acetazolamide)showed neither significant decrease in the cerebral blood flow nor cerebrovascular reactivity; hence, surgical revascularization was not performed. However, two years after the initial admission, she was urgently admitted to our hospital with sudden headache and nausea followed by aphasia and weakness of the right extremities. CT images showed diffuse subarachnoid hemorrhage and intracerebral hemorrhage in the left temporo-parietal lobe. Cerebral angiography revealed that the left middle cerebral artery was Ap/T-MCA without cerebral aneurysms. The patient was treated conservatively, and she eventually recovered without any neurological deficit except mild aphasia. Since Ap/T-MCA is associated with both hemorrhagic and ischemic stroke, antiplatelet therapy should be administered carefully. Moreover, it is necessary to consider extracranial-intracranial bypass to reduce hemodynamic stress on the abnormal vessels.

  1. The relevance of hemodynamic factors to perioperative ischemic complications in childhood moyamoya disease.

    PubMed

    Iwama, T; Hashimoto, N; Yonekawa, Y

    1996-06-01

    Of 124 children younger than 15 years who underwent surgery for moyamoya disease, 21 (16.9%) experienced perioperative ischemic complications that could not be unequivocally attributed to the surgery. Eleven of the 21 patients experienced infarctions, and 10 experienced reversible ischemic neurological deficits without new lesions, as revealed by computed tomographic scans. An examination of the patients' perioperative clinical and laboratory data revealed that the mean values of intra- and postoperative minimum arterial carbon dioxide pressure, maximum arterial carbon dioxide pressure, and mean arterial pressure were similar in patients with and without ischemic complications. However, in patients with perioperative complications, the incidence of preoperative transient ischemic attacks (TIAs) and intra- and postoperative hypercapnia (maximum arterial carbon dioxide pressure > 45 mm Hg) was significantly higher. In addition, 7 of the 11 perioperative infarctions occurred in patients with frequent preoperative TIAs and intra- and postoperative hypercapnia. Cerebral blood flow studies with preoperative acetazolamide loading showed that the new infarctions were located in areas in which the cerebral blood flow had been compromised. Our results suggest that the occurrence of frequent preoperative TIA is an important indicator of the instability of the cerebral hemodynamics and of the risk of perioperative ischemic complications. To prevent these complications, preoperative management aimed at stabilizing the hemodynamic status is very important. Children who have moyamoya disease and who experience frequent preoperative TIAs are at risk for ischemic brain damage caused by hypercapnia as well as hypocapnia and hypotension. The establishment and maintenance of normocapnia with normotension are highly desirable for the perioperative management of moyamoya disease in children.

  2. Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

    PubMed Central

    Klotz, Jenna; Porter, Brenda E; Colas, Claire; Schlessinger, Avner; Pajor, Ana M

    2016-01-01

    Mutations in the SLC13A5 gene that codes for the Na+/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In this study, we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and the treatment strategies. Currently, there are no effective treatments, but some antiepileptic drugs targeting the γ-aminobutyric acid system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical antiseizure medication, decreases seizures in four patients. In contrast to previous reports, the ketogenic diet and fasting resulted in worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improved transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, this study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na+/citrate transporters. PMID:27261973

  3. Bicarbonate-dependent chloride transport drives fluid secretion by the human airway epithelial cell line Calu-3

    PubMed Central

    Shan, Jiajie; Liao, Jie; Huang, Junwei; Robert, Renaud; Palmer, Melissa L; Fahrenkrug, Scott C; O'Grady, Scott M; Hanrahan, John W

    2012-01-01

    Anion and fluid secretion are both defective in cystic fibrosis (CF); however, the transport mechanisms are not well understood. In this study, Cl− and HCO3− secretion was measured using genetically matched CF transmembrane conductance regulator (CFTR)-deficient and CFTR-expressing cell lines derived from the human airway epithelial cell line Calu-3. Forskolin stimulated the short-circuit current (Isc) across voltage-clamped monolayers, and also increased the equivalent short-circuit current (Ieq) calculated under open-circuit conditions. Isc was equivalent to the HCO3− net flux measured using the pH-stat technique, whereas Ieq was the sum of the Cl− and HCO3− net fluxes. Ieq and HCO3− fluxes were increased by bafilomycin and ZnCl2, suggesting that some secreted HCO3− is neutralized by parallel electrogenic H+ secretion. Ieq and fluid secretion were dependent on the presence of both Na+ and HCO3−. The carbonic anhydrase inhibitor acetazolamide abolished forskolin stimulation of Ieq and HCO3− secretion, suggesting that HCO3− transport under these conditions requires catalysed synthesis of carbonic acid. Cl− was the predominant anion in secretions under all conditions studied and thus drives most of the fluid transport. Nevertheless, 50–70% of Cl− and fluid transport was bumetanide-insensitive, suggesting basolateral Cl− loading by a sodium–potassium–chloride cotransporter 1 (NKCC1)-independent mechanism. Imposing a transepithelial HCO3− gradient across basolaterally permeabilized Calu-3 cells sustained a forskolin-stimulated current, which was sensitive to CFTR inhibitors and drastically reduced in CFTR-deficient cells. Net HCO3− secretion was increased by bilateral Cl− removal and therefore did not require apical Cl−/HCO3− exchange. The results suggest a model in which most HCO3− is recycled basolaterally by exchange with Cl−, and the resulting HCO3−-dependent Cl− transport provides an osmotic driving force for

  4. Carbonic anhydrase II binds to and increases the activity of the epithelial sodium-proton exchanger, NHE3.

    PubMed

    Krishnan, Devishree; Liu, Lei; Wiebe, Shane A; Casey, Joseph R; Cordat, Emmanuelle; Alexander, R Todd

    2015-08-15

    Two-thirds of sodium filtered by the renal glomerulus is reabsorbed from the proximal tubule via a sodium/proton exchanger isoform 3 (NHE3)-dependent mechanism. Since sodium and bicarbonate reabsorption are coupled, we postulated that the molecules involved in their reabsorption [NHE3 and carbonic anhydrase II (CAII)] might physically and functionally interact. Consistent with this, CAII and NHE3 were closely associated in a renal proximal tubular cell culture model as revealed by a proximity ligation assay. Direct physical interaction was confirmed in solid-phase binding assays with immobilized CAII and C-terminal NHE3 glutathione-S-transferase fusion constructs. To assess the effect of CAII on NHE3 function, we expressed NHE3 in a proximal tubule cell line and measured NHE3 activity as the rate of intracellular pH recovery, following an acid load. NHE3-expressing cells had a significantly greater rate of intracellular pH recovery than controls. Inhibition of endogenous CAII activity with acetazolamide significantly decreased NHE3 activity, indicating that CAII activates NHE3. To ascertain whether CAII binding per se activates NHE3, we expressed NHE3 with wild-type CAII, a catalytically inactive CAII mutant (CAII-V143Y), or a mutant unable to bind other transporters (CAII-HEX). NHE3 activity increased upon wild-type CAII coexpression, but not in the presence of the CAII V143Y or HEX mutant. Together these studies support an association between CAII and NHE3 that alters the transporter's activity.

  5. Unusual Case of Angle Closure Glaucoma in a Patient with Neurofibromatosis Type 1

    PubMed Central

    Mantelli, Flavio; Abdolrahimzadeh, Solmaz; Mannino, Giuseppe; Lambiase, Alessandro

    2014-01-01

    We report the case of a 29-year-old female patient who presented with an acute onset of anisocoria, blurred vision, nausea and severe left-sided headache. There was no history of trauma, drug abuse, or instillation of topical mydriatic compounds. The ocular history was negative for similar events. On presentation, her visual acuity was 0.2 in the left and 1.0 in the right eye with a +2.5 dpt sph. correction. Slit-lamp examination demonstrated a shallow anterior chamber as well as the presence of iris nodules in both eyes. These nodules were identified as Lisch nodules as the patient referred to the previous diagnosis as being neurofibromatosis type 1. A third nerve palsy was considered, but a brain MRI showed normal results. Her ocular motility was normal, but the left pupil was mydriatic and poorly reacting to light, with an associated raised intraocular pressure (IOP) of 38 mm Hg. An examination of the fellow eye was normal, with the IOP measuring 18 mm Hg. Gonioscopy of the right eye showed a narrow angle. On further anamnestic investigation, the patient revealed that the pain and the blurred vision begun in the morning while she was helping her mother in the garden. Finally, after showing the patient a picture of Datura flowers, which she recognized immediately, we made the unusual diagnosis of angle closure glaucoma by Datura, a well-known toxic plant with mydriatic properties. The patient was successfully treated with systemic acetazolamide and topical pilocarpine. PMID:25762928

  6. Fluid absorption in the isolated midgut of adult female yellow fever mosquitoes (Aedes aegypti).

    PubMed

    Onken, Horst; Moffett, David F

    2015-07-01

    The transepithelial voltage (Vte) and the volume of isolated posterior midguts of adult female yellow fever mosquitoes (Aedes aegypti) were monitored. In all experiments, the initial Vte after filling the midgut was lumen negative, but subsequently became lumen positive at a rate of approximately 1 mV min(-1). Simultaneously, the midgut volume decreased, indicating spontaneous fluid absorption. When the midguts were filled and bathed with mosquito saline, the average rate of fluid absorption was 36.5±3.0 nl min(-1) (N=4, ±s.e.m.). In the presence of theophylline (10 mmol l(-1)), Vte reached significantly higher lumen-positive values, but the rate of fluid absorption was not affected (N=6). In the presence of NaCN (5 mmol l(-1)), Vte remained close to 0 mV (N=4) and fluid absorption was reduced (14.4±1.3 nl min(-1), N=3, ±s.e.m.). When midguts were filled with buffered NaCl (154 mmol l(-1) plus 1 mmol l(-1) HEPES) and bathed in mosquito saline with theophylline, fluid absorption was augmented (50.0±5.8 nl min(-1), N=12, ±s.e.m.). Concanamycin A (10 µmol l(-1)), ouabain (1 mmol l(-1)), and acetazolamide (1 mmol l(-1)) affected Vte in different ways, but all reduced fluid absorption by 60-70% of the value before addition of the drugs.

  7. 1,3-propanediol binds deep inside the channel to inhibit water permeation through aquaporins.

    PubMed

    Yu, Lili; Rodriguez, Roberto A; Chen, L Laurie; Chen, Liao Y; Perry, George; McHardy, Stanton F; Yeh, Chih-Ko

    2016-02-01

    Aquaporins and aquaglyceroporins (AQPs) are membrane channel proteins responsible for transport of water and for transport of glycerol in addition to water across the cell membrane, respectively. They are expressed throughout the human body and also in other forms of life. Inhibitors of human AQPs have been sought for therapeutic treatment for various medical conditions including hypertension, refractory edema, neurotoxic brain edema, and so forth. Conducting all-atom molecular dynamics simulations, we computed the binding affinity of acetazolamide to human AQP4 that agrees closely with in vitro experiments. Using this validated computational method, we found that 1,3-propanediol (PDO) binds deep inside the AQP4 channel to inhibit that particular aquaporin efficaciously. Furthermore, we used the same method to compute the affinities of PDO binding to four other AQPs and one aquaglyceroporin whose atomic coordinates are available from the protein data bank (PDB). For bovine AQP1, human AQP2, AQP4, AQP5, and Plasmodium falciparum PfAQP whose structures were resolved with high resolution, we obtained definitive predictions on the PDO dissociation constant. For human AQP1 whose PDB coordinates are less accurate, we estimated the dissociation constant with a rather large error bar. Taking into account the fact that PDO is generally recognized as safe by the US FDA, we predict that PDO can be an effective diuretic which directly modulates water flow through the protein channels. It should be free from the serious side effects associated with other diuretics that change the hydro-homeostasis indirectly by altering the osmotic gradients.

  8. Transport of H(+), Na(+) and K(+) across the posterior midgut of blood-fed mosquitoes (Aedes aegypti).

    PubMed

    Pacey, Evan K; O'Donnell, Michael J

    2014-02-01

    Following ingestion of a blood meal, the adult female mosquito undergoes a massive diuresis during which Na(+), Cl(-) and water are secreted at high rates by the Malpighian tubules. In the hours following completion of diuresis, digestion of the K(+)-rich blood cells provides a source of energy as well as amino acids for proteins in the developing eggs. Although the transport of inorganic ions by the Malpighian tubules of blood-fed mosquitoes has been extensively characterized, relatively little is known of the epithelial transport mechanisms responsible for movement of Na(+), H(+), and K(+) across the posterior midgut. In this paper we have used the Scanning Ion-selective Electrode Technique (SIET) to measure the basal (unstimulated) rates of transport of K(+), Na(+) and H(+) across the isolated posterior midgut at intervals after the blood meal. We have also measured luminal concentrations of Na(+) and K(+) and the transepithelial electrical potential at the same time points and have calculated the electrochemical potentials for Na(+), K(+) and H(+) across the midgut. SIET measurements reveal absorption (lumen to bath) of Na(+) and H(+) and secretion of K(+) for the first 2h after blood-feeding. By 24h after the meal, absorption of Na(+) and H(+) remains active while there is an electrochemical gradient favouring absorption of K(+). Inhibition by ouabain and Ba(2+) suggest a role for the Na(+)/K(+)-ATPase and K(+) channels in absorption of Na(+) and K(+), respectively. Inhibition of H(+) absorption by acetazolamide implicates carbonic anhydrase in transepithelial H(+) transport.

  9. Tumoral Calcinosis as an Initial Complaint of Juvenile-Onset Amyopathic Dermatomyositis

    PubMed Central

    Doh, Eun Jin; Moon, Jungyoon; Shin, Sue; Seo, Soo Hyun; Park, Hyun Sun; Yoon, Hyun-Sun

    2016-01-01

    Calcinosis is rarely observed in juvenile-onset amyopathic dermatomyositis in contrast to juvenile-onset dermatomyositis. A 6-year-old female presented with several 0.5 to 2 cm-sized painless grouped masses on both knees for 3 years. The patient also presented with multiple erythematous scaly patches and plaques on both elbows, knuckles, buttock, ankles and cheeks. Her mother had similar skin lesions which were erythematous scaly patches on the knuckles and elbows, since her childhood. When skin biopsy was performed from a left knee nodule, liquid chalky discharge was observed. The biopsy results were consistent with calcinosis cutis. Other biopsies from erythematous patch of the patient and erythematous patch of her mother showed vacuolization of basal cell layer with inflammatory cell infiltrations. Laboratory findings showed normal range of serum phosphorus (4.5 mg/dl), calcium (9.3 mg/dl), 1,25-dihydroxy-vitamin D (10.8 ng/ml) and parathyroid hormone levels (11 pg/ml). Both patient and her mother had no history of muscle weakness and showed normal levels of muscle-specific enzyme. Both patients were diagnosed with juvenile-onset amyopathic dermatomyositis based on histopathology and cutaneous manifestations with no evidence of muscle weakness and no serum muscle enzyme abnormalities. Tumoral calcium deposits observed in daughter was diagnosed as dystrophic calcinosis which can be rarely seen in juvenile-onset amyopathic dermatomyositis. The patient is being treated with oral acetazolamide (40 mg/kg/d) for calcinosis. PMID:27274638

  10. Bicarbonate-dependent chloride transport drives fluid secretion by the human airway epithelial cell line Calu-3.

    PubMed

    Shan, Jiajie; Liao, Jie; Huang, Junwei; Robert, Renaud; Palmer, Melissa L; Fahrenkrug, Scott C; O'Grady, Scott M; Hanrahan, John W

    2012-11-01

    Anion and fluid secretion are both defective in cystic fibrosis (CF); however, the transport mechanisms are not well understood. In this study, Cl(-) and HCO(3)(-) secretion was measured using genetically matched CF transmembrane conductance regulator (CFTR)-deficient and CFTR-expressing cell lines derived from the human airway epithelial cell line Calu-3. Forskolin stimulated the short-circuit current (I(sc)) across voltage-clamped monolayers, and also increased the equivalent short-circuit current (I(eq)) calculated under open-circuit conditions. I(sc) was equivalent to the HCO(3)(-) net flux measured using the pH-stat technique, whereas I(eq) was the sum of the Cl(-) and HCO(3)(-) net fluxes. I(eq) and HCO(3)(-) fluxes were increased by bafilomycin and ZnCl(2), suggesting that some secreted HCO(3)(-) is neutralized by parallel electrogenic H(+) secretion. I(eq) and fluid secretion were dependent on the presence of both Na(+) and HCO(3)(-). The carbonic anhydrase inhibitor acetazolamide abolished forskolin stimulation of I(eq) and HCO(3)(-) secretion, suggesting that HCO(3)(-) transport under these conditions requires catalysed synthesis of carbonic acid. Cl(-) was the predominant anion in secretions under all conditions studied and thus drives most of the fluid transport. Nevertheless, 50-70% of Cl(-) and fluid transport was bumetanide-insensitive, suggesting basolateral Cl(-) loading by a sodium-potassium-chloride cotransporter 1 (NKCC1)-independent mechanism. Imposing a transepithelial HCO(3)(-) gradient across basolaterally permeabilized Calu-3 cells sustained a forskolin-stimulated current, which was sensitive to CFTR inhibitors and drastically reduced in CFTR-deficient cells. Net HCO(3)(-) secretion was increased by bilateral Cl(-) removal and therefore did not require apical Cl(-)/HCO(3)(-) exchange. The results suggest a model in which most HCO(3)(-) is recycled basolaterally by exchange with Cl(-), and the resulting HCO(3)(-)-dependent Cl(-) transport

  11. Treatment of Retinitis Pigmentosa-Associated Cystoid Macular Oedema Using Intravitreal Aflibercept (Eylea) despite Minimal Response to Ranibizumab (Lucentis): A Case Report

    PubMed Central

    Strong, Stacey A.; Gurbaxani, Avinash; Michaelides, Michel

    2016-01-01

    Background We present an interesting case of bilateral retinitis pigmentosa (RP)-associated cystoid macular oedema that responded on two separate occasions to intravitreal injections of aflibercept, despite previously demonstrating only minimal response to intravitreal ranibizumab. This unique case would support a trial of intravitreal aflibercept for the treatment of RP-associated cystoid macular oedema. Case Presentation A 38-year-old man from Dubai, United Arab Emirates, presented to the UK with a 3-year history of bilateral RP-associated cystoid macular oedema. Previous treatment with topical dorzolamide, oral acetazolamide, and intravitreal ranibizumab had demonstrated only minimal reduction of cystoid macular oedema. Following re-confirmation of the diagnosis by clinical examination and optical coherence tomography imaging, bilateral loading doses of intravitreal aflibercept were given. Central macular thickness reduced and the patient returned to Dubai. After 6 months, the patient was treated with intravitreal ranibizumab due to re-accumulation of fluid and the unavailability of aflibercept in Dubai. Only minimal reduction of central macular thickness was observed. Once available in Dubai, intravitreal aflibercept was administered bilaterally with further reduction of central macular thickness observed. Visual acuity remained stable throughout. Conclusions This is the first case report to demonstrate a reduction of RP-associated CMO following intravitreal aflibercept, despite inadequate response to ranibizumab on two separate occasions. Aflibercept may provide superior action to other anti-VEGF medications due to its intermediate size (115 kDa) and higher binding affinity. This is worthy of further investigation in a large prospective cohort over an extended time to determine the safety and efficacy of intravitreal aflibercept for use in this condition. PMID:27721789

  12. Physiological and Molecular Biological Characterization of Intracellular Carbonic Anhydrase from the Marine Diatom Phaeodactylum tricornutum1

    PubMed Central

    Satoh, Dan; Hiraoka, Yasutaka; Colman, Brian; Matsuda, Yusuke

    2001-01-01

    A single intracellular carbonic anhydrase (CA) was detected in air-grown and, at reduced levels, in high CO2-grown cells of the marine diatom Phaeodactylum tricornutum (UTEX 642). No external CA activity was detected irrespective of growth CO2 conditions. Ethoxyzolamide (0.4 mm), a CA-specific inhibitor, severely inhibited high-affinity photosynthesis at low concentrations of dissolved inorganic carbon, whereas 2 mm acetazolamide had little effect on the affinity for dissolved inorganic carbon, suggesting that internal CA is crucial for the operation of a carbon concentrating mechanism in P. tricornutum. Internal CA was purified 36.7-fold of that of cell homogenates by ammonium sulfate precipitation, and two-step column chromatography on diethylaminoethyl-sephacel and p-aminomethylbenzene sulfone amide agarose. The purified CA was shown, by SDS-PAGE, to comprise an electrophoretically single polypeptide of 28 kD under both reduced and nonreduced conditions. The entire sequence of the cDNA of this CA was obtained by the rapid amplification of cDNA ends method and indicated that the cDNA encodes 282 amino acids. Comparison of this putative precursor sequence with the N-terminal amino acid sequence of the purified CA indicated that it included a possible signal sequence of up to 46 amino acids at the N terminus. The mature CA was found to consist of 236 amino acids and the sequence was homologous to β-type CAs. Even though the zinc-ligand amino acid residues were shown to be completely conserved, the amino acid residues that may constitute a CO2-binding site appeared to be unique among the β-CAs so far reported. PMID:11500545

  13. Extracellular H+ induces Ca2+ signals in respiratory chemoreceptors of zebrafish.

    PubMed

    Abdallah, Sara J; Jonz, Michael G; Perry, Steve F

    2015-02-01

    Neuroepithelial cells (NECs) of the fish gill are respiratory chemoreceptors that detect changes in O2 and CO2/H(+) and are homologous to type I cells of the mammalian carotid body. In zebrafish (Danio rerio), stimulation of NECs by hypoxia or hypercapnia initiates inhibition of K(+) channels and subsequent membrane depolarisation. The goal of the present study was to further elucidate, in zebrafish NECs, the signalling pathways that underlie CO2/H(+) sensing and generate intracellular Ca(2+) ([Ca(2+)]i) signals. Breathing frequency was elevated maximally in fish exposed to 5 % CO2 (~37.5 mmHg). Measurement of [Ca(2+)]i in isolated NECs using Fura-2 imaging indicated that [Ca(2+)]i increased in response to acidic hypercapnia (5 % CO2, pH 6.6) and isocapnic acidosis (normocapnia, pH 6.6), but not to isohydric hypercapnia (5 % CO2, pH 7.6). Measurement of intracellular pH (pHi) using BCECF demonstrated a rapid decrease in pHi in response to acidic and isohydric hypercapnia, while isocapnic acidosis produced a smaller change in pHi. Intracellular acidification was reduced by the carbonic anhydrase inhibitor, acetazolamide, without affecting [Ca(2+)]i responses. Moreover, intracellular acidification using acetate (at constant extracellular pH) was without effect on [Ca(2+)]i. The acid-induced increase in [Ca(2+)]i persisted in the absence of extracellular Ca(2+) and was unaffected by Ca(2+) channel blockers (Cd(2+), Ni(2+) or nifedipine). The results of this study demonstrate that, unlike type I cells, extracellular H(+) is critical to the hypercapnia-induced increase in [Ca(2+)]i in NECs. The increase in [Ca(2+)]i occurs independently of pHi and appears to originate primarily from Ca(2+) derived from intracellular stores.

  14. Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis.

    PubMed

    Basting, Tyler M; Burke, Peter G R; Kanbar, Roy; Viar, Kenneth E; Stornetta, Daniel S; Stornetta, Ruth L; Guyenet, Patrice G

    2015-01-14

    In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (Δf(R)) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔV(T)) followed the same trend. The effect of hypoxia on Δf(R) was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). Δf(R) was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN.

  15. Light Levels Affect Carbon Utilisation in Tropical Seagrass under Ocean Acidification.

    PubMed

    Ow, Yan X; Uthicke, Sven; Collier, Catherine J

    2016-01-01

    Under future ocean acidification (OA), increased availability of dissolved inorganic carbon (DIC) in seawater may enhance seagrass productivity. However, the ability to utilise additional DIC could be regulated by light availability, often reduced through land runoff. To test this, two tropical seagrass species, Cymodocea serrulata and Halodule uninervis were exposed to two DIC concentrations (447 μatm and 1077 μatm pCO2), and three light treatments (35, 100, 380 μmol m(-2) s(-1)) for two weeks. DIC uptake mechanisms were separately examined by measuring net photosynthetic rates while subjecting C. serrulata and H. uninervis to changes in light and addition of bicarbonate (HCO3-) use inhibitors (carbonic anhydrase inhibitor, acetazolamide) and TRIS buffer (pH 8.0). We observed a strong dependence on energy driven H+-HCO3- co-transport (TRIS, which disrupts H+ extrusion) in C. serrulata under all light levels, indicating greater CO2 dependence in low light. This was confirmed when, after two weeks exposure, DIC enrichment stimulated maximum photosynthetic rates (Pmax) and efficiency (α) more in C. serrulata grown under lower light levels (36-60% increase) than for those in high light (4% increase). However, C. serrulata growth increased with both DIC enrichment and light levels. Growth, NPP and photosynthetic responses in H. uninervis increased with higher light treatments and were independent of DIC availability. Furthermore, H. uninervis was found to be more flexible in HCO3- uptake pathways. Here, light availability influenced productivity responses to DIC enrichment, via both carbon fixation and acquisition processes, highlighting the role of water quality in future responses to OA. PMID:26938454

  16. POST-EXERCISE LACTATE PRODUCTION AND METABOLISM IN THREE SPECIES OF AQUATIC AND TERRESTRIAL DECAPOD CRUSTACEANS

    PubMed

    Walsh

    1994-01-01

    Aquatic and terrestrial crustaceans are dependent on both aerobic and anaerobic metabolism for energy production during exercise. Anaerobic energy production is marked by an accumulation of lactate in both muscle tissue and haemolymph, but the metabolic fate of lactate is not clear. Lactate recycling via gluconeogenesis and the potential role of carbonic anhydrase (CA) in supplying bicarbonate for the carboxylation of pyruvate were investigated in three species of decapod crustaceans: Callinectes sapidus (aquatic), Cardisoma guanhumi (semi-terrestrial) and Gecarcinus lateralis (terrestrial). CA activity was found in mitochondria and cytoplasmic fractions of gill, hepatopancreas and muscle of all three species. Significant activities of key enzymes of gluconeogenesis (e.g. pyruvate carboxylase, phosphoenolpyruvate carboxykinase and fructose bisphosphatase), however, could not be detected. Exercise to exhaustion produced a species-specific pattern of accumulation and clearance of lactate in tissue and haemolymph, indicating a differential degree of reliance on anaerobic energy production. Treatment with acetazolamide, a CA inhibitor, did not significantly alter the pattern of lactate dynamics in animals given repeated bouts of exhaustive exercise interspersed with periods of recovery. Injection of [U-14C]lactate resulted in the appearance of label in both muscle glycogen and excreted carbon dioxide, suggesting multiple metabolic fates for lactate. Lactate turnover rates for G. lateralis were similar to those reported for fish. In these animals, gluconeogenesis possibly proceeds via the reversal of pyruvate kinase, or via the typical Cori cycle but so slowly that the uncatalysed supply of bicarbonate is sufficient to keep pace with the low activities of pyruvate carboxylase and the subsequent low rates of pyruvate carboxylation.

  17. Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation.

    PubMed

    Aamand, Rasmus; Dalsgaard, Thomas; Jensen, Frank B; Simonsen, Ulf; Roepstorff, Andreas; Fago, Angela

    2009-12-01

    In catalyzing the reversible hydration of CO2 to bicarbonate and protons, the ubiquitous enzyme carbonic anhydrase (CA) plays a crucial role in CO2 transport, in acid-base balance, and in linking local acidosis to O2 unloading from hemoglobin. Considering the structural similarity between bicarbonate and nitrite, we hypothesized that CA uses nitrite as a substrate to produce the potent vasodilator nitric oxide (NO) to increase local blood flow to metabolically active tissues. Here we show that CA readily reacts with nitrite to generate NO, particularly at low pH, and that the NO produced in the reaction induces vasodilation in aortic rings. This reaction occurs under normoxic and hypoxic conditions and in various tissues at physiological levels of CA and nitrite. Furthermore, two specific inhibitors of the CO2 hydration, dorzolamide and acetazolamide, increase the CA-catalyzed production of vasoactive NO from nitrite. This enhancing effect may explain the known vasodilating effects of these drugs and indicates that CO2 and nitrite bind differently to the enzyme active site. Kinetic analyses show a higher reaction rate at high pH, suggesting that anionic nitrite participates more effectively in catalysis. Taken together, our results reveal a novel nitrous anhydrase enzymatic activity of CA that would function to link the in vivo main end products of energy metabolism (CO2/H+) to the generation of vasoactive NO. The CA-mediated NO production may be important to the correlation between blood flow and metabolic activity in tissues, as occurring for instance in active areas of the brain. PMID:19820197

  18. Fit for high altitude: are hypoxic challenge tests useful?

    PubMed Central

    2011-01-01

    Altitude travel results in acute variations of barometric pressure, which induce different degrees of hypoxia, changing the gas contents in body tissues and cavities. Non ventilated air containing cavities may induce barotraumas of the lung (pneumothorax), sinuses and middle ear, with pain, vertigo and hearing loss. Commercial air planes keep their cabin pressure at an equivalent altitude of about 2,500 m. This leads to an increased respiratory drive which may also result in symptoms of emotional hyperventilation. In patients with preexisting respiratory pathology due to lung, cardiovascular, pleural, thoracic neuromuscular or obesity-related diseases (i.e. obstructive sleep apnea) an additional hypoxic stress may induce respiratory pump and/or heart failure. Clinical pre-altitude assessment must be disease-specific and it includes spirometry, pulsoximetry, ECG, pulmonary and systemic hypertension assessment. In patients with abnormal values we need, in addition, measurements of hemoglobin, pH, base excess, PaO2, and PaCO2 to evaluate whether O2- and CO2-transport is sufficient. Instead of the hypoxia altitude simulation test (HAST), which is not without danger for patients with respiratory insufficiency, we prefer primarily a hyperoxic challenge. The supplementation of normobaric O2 gives us information on the acute reversibility of the arterial hypoxemia and the reduction of ventilation and pulmonary hypertension, as well as about the efficiency of the additional O2-flow needed during altitude exposure. For difficult judgements the performance of the test in a hypobaric chamber with and without supplemental O2-breathing remains the gold standard. The increasing numbers of drugs to treat acute pulmonary hypertension due to altitude exposure (acetazolamide, dexamethasone, nifedipine, sildenafil) or to other etiologies (anticoagulants, prostanoids, phosphodiesterase-5-inhibitors, endothelin receptor antagonists) including mechanical aids to reduce periodical or

  19. Topiramate modulates pH of hippocampal CA3 neurons by combined effects on carbonic anhydrase and Cl−/HCO3− exchange

    PubMed Central

    Leniger, Tobias; Thöne, Jan; Wiemann, Martin

    2004-01-01

    Topiramate (TPM) is an anticonvulsant whose impact on firing activity and intracellular pH (pHi) regulation of CA3 neurons was investigated. Using the 4-aminopyridine-treated hippocampal slice model bathed in bicarbonate-buffered solution, TPM (25–50 μM) reduced the frequency of epileptiform bursts and action potentials without affecting membrane potential or input resistance. Inhibitory effects of TPM were reversed by trimethylamine-induced alkalinization. TPM also lowered the steady-state pHi of BCECF-AM-loaded neuronal somata by 0.18±0.07 pH units in CO2/HCO3−-buffered solution. Subsequent to an ammonium prepulse, TPM reduced the acidotic peak but clearly slowed pHi recovery. These complex changes were mimicked by the protein phosphatase inhibitor okadaic acid. Alkalosis upon withdrawal of extracellular Cl− was augmented by TPM. Furthermore, at decreased pHi due to the absence of extracellular Na+, TPM reversibly increased pHi. These findings demonstrate that TPM modulates Na+-independent Cl−/HCO3− exchange. In the nominal absence of extracellular CO2/HCO3− buffer, both steady-state pHi and firing of epileptiform bursts remained unchanged upon adding TPM. However, pHi recovery subsequent to an ammonium prepulse was slightly increased, as was the case in the presence of the carbonic anhydrase (CA) inhibitor acetazolamide. Thus, a slight reduction of intracellular buffer capacity by TPM may be due to an inhibitory effect on intracellular CA. Together, these findings show that TPM lowers neuronal pHi most likely due to a combined effect on Na+-independent Cl−/HCO3− exchange and CA. The apparent decrease of steady-state pHi may contribute to the anticonvulsive property of TPM. PMID:15197104

  20. Cotransport of sodium and chloride by the adult mammalian choroid plexus

    SciTech Connect

    Johanson, C.E.; Sweeney, S.M.; Parmelee, J.T.; Epstein, M.H. )

    1990-02-01

    Cerebrospinal fluid formation stems primarily from the transport of Na and Cl in choroid plexus (CP). To characterize properties and modulation of choroidal transporters, we tested diuretics and other agents for ability to alter ion transport in vitro. Adult Sprague-Dawley rats were the source of CPs preincubated with drug for 20 min and then transferred to cerebrospinal fluid (CSF) medium containing 22Na or 36Cl with (3H)mannitol (extracellular correction). Complete base-line curves were established for cellular uptake of Na and Cl at 37 degrees C. The half-maximal uptake occurred at 12 s, so it was used to assess drug effects on rate of transport (nmol Na or Cl/mg CP). Bumetanide (10(-5) and 10(-4) M) decreased uptake of Na and Cl with maximal inhibition (up to 45%) at 10(-5) M. Another cotransport inhibitor, furosemide (10(-4) M), reduced transport of Na by 25% and Cl by 33%. However, acetazolamide (10(-4) M) and atriopeptin III (10(-7) M) significantly lowered uptake of Na (but not Cl), suggesting effect(s) other than on cotransport. The disulfonic stilbene 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; 10(-4) M), known to inhibit Cl-HCO3 exchange, substantially reduced the transport of 36Cl. Bumetanide plus DIDS (both 10(-4) M) caused additive inhibition of 90% of Cl uptake, which provides strong evidence for the existence of both cotransport and antiport Cl carriers. Overall, this in vitro analysis, uncomplicated by variables of blood flow and neural tone, indicates the presence in rat CP of the cotransport of Na and Cl in addition to the established Na-H and Cl-HCO3 exchangers.

  1. Evidence against luminal one-for-one Cl -HCO3 exchange in urodele small intestine

    SciTech Connect

    White, J.F.

    1986-08-01

    The ratio of Cl absorbed to HCO3 secreted by the in vitro small intestine of Amphiuma was measured using TWCl and titration. The aim was to estimate the stoichiometry and thereby elucidate the underlying transport mechanisms. For every mole of HCO3 secreted 1.8 mol of Cl underwent net absorption. Indirect measures of net Cl absorption and HCO3 secretion were validated. Several known and putative Cl transport inhibitors were examined for their ability to inhibit the anion transport events. Disulfonic stilbenes (DIDS) and the diuretics piretanide and furosemide inhibited the Cl absorptive flux (J/sub m s/sup Cl/) and simultaneously the HCO3 secretory flux (J/sup HCO3 /). The diuretics acetazolamide and bumetanide also reduced J/sup HCO3 and J/sub m s/sup Cl/, although the latter effect was not statistically significant. The ratio of inhibition, J/sub m s/sup Cl// J/sup HCO3 /, varied from 1.2 to 1.8 for the different inhibitors. The presence of Cl -HCO3 exchange at the serosal membrane was deduced from 1) the reduction of J/sub m s/sup Cl/ and J/sup HCO3 / by serosally added stilbenes, 2) the reduction of Cl absorption when serosal Cl was replaced, 3) inhibition of the secretory-to-mucosal Cl flux by serosal stilbenes, and 4) enhancement of J/sup HCO3 when serosal medium HCO3 was elevated. The observations are not consistent with one-for-one exchange of Cl for HCO3 at the mucosal membrane. The observed coupling ratio is compatible with a one-for-one exchange of Cl for HCO3 at the serosal membrane.

  2. Tumoral Calcinosis as an Initial Complaint of Juvenile-Onset Amyopathic Dermatomyositis.

    PubMed

    Doh, Eun Jin; Moon, Jungyoon; Shin, Sue; Seo, Soo Hyun; Park, Hyun Sun; Yoon, Hyun-Sun; Cho, Soyun

    2016-06-01

    Calcinosis is rarely observed in juvenile-onset amyopathic dermatomyositis in contrast to juvenile-onset dermatomyositis. A 6-year-old female presented with several 0.5 to 2 cm-sized painless grouped masses on both knees for 3 years. The patient also presented with multiple erythematous scaly patches and plaques on both elbows, knuckles, buttock, ankles and cheeks. Her mother had similar skin lesions which were erythematous scaly patches on the knuckles and elbows, since her childhood. When skin biopsy was performed from a left knee nodule, liquid chalky discharge was observed. The biopsy results were consistent with calcinosis cutis. Other biopsies from erythematous patch of the patient and erythematous patch of her mother showed vacuolization of basal cell layer with inflammatory cell infiltrations. Laboratory findings showed normal range of serum phosphorus (4.5 mg/dl), calcium (9.3 mg/dl), 1,25-dihydroxy-vitamin D (10.8 ng/ml) and parathyroid hormone levels (11 pg/ml). Both patient and her mother had no history of muscle weakness and showed normal levels of muscle-specific enzyme. Both patients were diagnosed with juvenile-onset amyopathic dermatomyositis based on histopathology and cutaneous manifestations with no evidence of muscle weakness and no serum muscle enzyme abnormalities. Tumoral calcium deposits observed in daughter was diagnosed as dystrophic calcinosis which can be rarely seen in juvenile-onset amyopathic dermatomyositis. The patient is being treated with oral acetazolamide (40 mg/kg/d) for calcinosis. PMID:27274638

  3. A distinctive electrophysiological signature from the Peyer's patches of rabbit intestine.

    PubMed Central

    Brayden, D J; Baird, A W

    1994-01-01

    1. Rabbit small intestinal segments containing Peyer's patches (PP) were examined in Ussing chambers using short-circuit current (Isc) recording. By comparison with control small intestinal mucosal segments, rabbit PP-containing epithelia exhibited decreased basal Isc, increased transepithelial resistance (TER) and unchanged potential difference (PD). 2. Carbachol caused a decrease in Isc in rabbit PP epithelia. Forskolin, dibutyryl cyclic GMP, histamine and the calcium ionophore, A23187, were without effect. In contrast, control epithelial segments of rabbit intestine responded to carbachol and forskolin with an increased Isc, indicative of electrogenic chloride secretion. The EC50 for carbachol was approximately 2 microM in both types of epithelia. Methacholine also caused an outward current in rabbit PP epithelia which had similar properties to that of carbachol. The effect of the cholinomimetics on rabbit PP was basolateral-sided, reversible, and sensitive to low concentrations of the general muscarinic cholinoceptor blockers, atropine, scopolamine and also to the M1 cholinoceptor blocker, pirenzepine. 3. The Isc response to cholinomimetics in rabbit PP was insensitive to bumetanide, amiloride, TEA, barium, acetazolamide, piroxicam and omeprazole, but was attenuated in the presence of ouabain. Using bilaterally-substituted solutions, the carbachol effect on rabbit PP Isc was abolished in chloride/bicarbonate-free, but not in chloride-free solutions, suggestive of stimulation of electrogenic bicarbonate absorption by the agent. Substitution for sodium abolished both the basal current and the Isc response to carbachol. Part of the effect of carbachol on PP Isc appeared to be mediated by submucosal neurones because addition of tetrodotoxin reduced the effect by 60%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7530575

  4. High-altitude Pulmonary Hypertension: an Update on Disease Pathogenesis and Management

    PubMed Central

    Mirrakhimov, Aibek E.; Strohl, Kingman P.

    2016-01-01

    High-altitude pulmonary hypertension (HAPH) affects individuals residing at altitudes of 2,500 meters and higher. Numerous pathogenic variables play a role in disease inception and progression and include low oxygen concentration in inspired air, vasculopathy, and metabolic abnormalities. Since HAPH affects only some people living at high altitude genetic factors play a significant role in its pathogenesis. The clinical presentation of HAPH is nonspecific and includes fatigue, shortness of breath, cognitive deficits, cough, and in advanced cases hepatosplenomegaly and overt right-sided heart failure. A thorough history is important and should include a search for additional risk factors for lung disease and pulmonary hypertension (PH) such as smoking, indoor air pollution, left-sided cardiac disease and sleep disordered breathing. Twelve-lead electrocardiogram, chest X-ray and echocardiography can be used as screening tools. A definitive diagnosis should be made with right-sided heart catheterization using a modified mean pulmonary artery pressure of at least 30 mm Hg, differing from the 25 mm Hg used for other types of PH. Treatment of HAPH includes descent to a lower altitude whenever possible, oxygen therapy and the use of medications such as endothelin receptor antagonists, phosphodiesterase 5 blockers, fasudil and acetazolamide. Some recent evidence suggests that iron supplementation may also be beneficial. However, it is important to note that the scientific literature lacks long-term randomized controlled data on the pharmacologic treatment of HAPH. Thus, an individualized approach to treatment and informing the patients regarding the benefits and risks of the selected treatment regimen are essential. PMID:27014374

  5. Light Levels Affect Carbon Utilisation in Tropical Seagrass under Ocean Acidification.

    PubMed

    Ow, Yan X; Uthicke, Sven; Collier, Catherine J

    2016-01-01

    Under future ocean acidification (OA), increased availability of dissolved inorganic carbon (DIC) in seawater may enhance seagrass productivity. However, the ability to utilise additional DIC could be regulated by light availability, often reduced through land runoff. To test this, two tropical seagrass species, Cymodocea serrulata and Halodule uninervis were exposed to two DIC concentrations (447 μatm and 1077 μatm pCO2), and three light treatments (35, 100, 380 μmol m(-2) s(-1)) for two weeks. DIC uptake mechanisms were separately examined by measuring net photosynthetic rates while subjecting C. serrulata and H. uninervis to changes in light and addition of bicarbonate (HCO3-) use inhibitors (carbonic anhydrase inhibitor, acetazolamide) and TRIS buffer (pH 8.0). We observed a strong dependence on energy driven H+-HCO3- co-transport (TRIS, which disrupts H+ extrusion) in C. serrulata under all light levels, indicating greater CO2 dependence in low light. This was confirmed when, after two weeks exposure, DIC enrichment stimulated maximum photosynthetic rates (Pmax) and efficiency (α) more in C. serrulata grown under lower light levels (36-60% increase) than for those in high light (4% increase). However, C. serrulata growth increased with both DIC enrichment and light levels. Growth, NPP and photosynthetic responses in H. uninervis increased with higher light treatments and were independent of DIC availability. Furthermore, H. uninervis was found to be more flexible in HCO3- uptake pathways. Here, light availability influenced productivity responses to DIC enrichment, via both carbon fixation and acquisition processes, highlighting the role of water quality in future responses to OA.

  6. Mechanisms of pH regulation in lamprey (Lampetra fluviatilis) red blood cells.

    PubMed

    Nikinmaa, M; Kunnamo-Ojala, T; Railo, E

    1986-05-01

    Mechanisms regulating the red cell pH in lamprey (Lampetra fluviatilis) were studied using the ammonium chloride prepulse technique. The cells were initially incubated in a physiological saline containing 20 mmol l-1 ammonium chloride, and intracellular pH measured with the DMO technique. Ammonium chloride was then rapidly removed by centrifugation, and the changes in the intracellular pH followed. The intraerythrocytic pH is primarily regulated by an amiloride-sensitive sodium/proton exchange. When sodium is present in the incubation medium, the intracellular pH rapidly recovers from the acidification associated with the removal of ammonium chloride from the incubation. When sodium is removed from the incubation medium, intracellular pH does not recover, and when the cells are treated with 10(-3) mol l-1 amiloride in the presence of sodium, carbon dioxide and bicarbonate, the intracellular pH recovery is drastically reduced. The movements of carbon dioxide, its consecutive catalysed hydration and dissociation to protons and bicarbonate and, possibly, movements of bicarbonate out of the cell acidify the cell contents. This is shown by the observation that the steady-state intracellular pH is higher in a HEPES-buffered medium than in a CO2/HCO3(-)-buffered medium at the same extracellular pH. The acidification is dependent on cellular carbonic anhydrase activity, present in lamprey red cells, which speeds up the hydration reaction. When the action of carbonic anhydrase is inhibited by acetazolamide, removal of ammonium chloride from the incubation medium does not cause intracellular acidification. PMID:3088194

  7. Fit for high altitude: are hypoxic challenge tests useful?

    PubMed

    Matthys, Heinrich

    2011-01-01

    Altitude travel results in acute variations of barometric pressure, which induce different degrees of hypoxia, changing the gas contents in body tissues and cavities. Non ventilated air containing cavities may induce barotraumas of the lung (pneumothorax), sinuses and middle ear, with pain, vertigo and hearing loss. Commercial air planes keep their cabin pressure at an equivalent altitude of about 2,500 m. This leads to an increased respiratory drive which may also result in symptoms of emotional hyperventilation. In patients with preexisting respiratory pathology due to lung, cardiovascular, pleural, thoracic neuromuscular or obesity-related diseases (i.e. obstructive sleep apnea) an additional hypoxic stress may induce respiratory pump and/or heart failure. Clinical pre-altitude assessment must be disease-specific and it includes spirometry, pulsoximetry, ECG, pulmonary and systemic hypertension assessment. In patients with abnormal values we need, in addition, measurements of hemoglobin, pH, base excess, PaO2, and PaCO2 to evaluate whether O2- and CO2-transport is sufficient.Instead of the hypoxia altitude simulation test (HAST), which is not without danger for patients with respiratory insufficiency, we prefer primarily a hyperoxic challenge. The supplementation of normobaric O2 gives us information on the acute reversibility of the arterial hypoxemia and the reduction of ventilation and pulmonary hypertension, as well as about the efficiency of the additional O2-flow needed during altitude exposure. For difficult judgements the performance of the test in a hypobaric chamber with and without supplemental O2-breathing remains the gold standard. The increasing numbers of drugs to treat acute pulmonary hypertension due to altitude exposure (acetazolamide, dexamethasone, nifedipine, sildenafil) or to other etiologies (anticoagulants, prostanoids, phosphodiesterase-5-inhibitors, endothelin receptor antagonists) including mechanical aids to reduce periodical or

  8. Determinations of renal cortical and medullary oxygenation using BOLD Magnetic Resonance Imaging and selective diuretics

    PubMed Central

    Warner, Lizette; Glockner, James F.; Woollard, John; Textor, Stephen C.; Romero, Juan C.; Lerman, Lilach O.

    2010-01-01

    Objective This study was undertaken to test the hypothesis that blood O2 level dependent magnetic resonance imaging (BOLD MRI) can detect changes in cortical proximal tubule (PT) and medullary thick ascending limb of Henle (TAL) oxygenation consequent to successive administration of furosemide and acetazolamide (Az). Assessment of PT and TAL function could be useful to monitor renal disease states in vivo. Therefore, the adjunct use of diuretics that inhibit Na+ reabsorption selectively in PT and TAL, Az and furosemide, respectively, may help discern tubular function by using BOLD MRI to detect changes in tissue oxygenation. Material and Methods BOLD MRI signal R2* (inversely related to oxygenation) and tissue oxygenation with intrarenal O2 probes were measured in pigs that received either furosemide (0.5mg/kg) or Az (15mg/kg) alone, Az sequentially after furosemide (n=6 each, 15-minute intervals), or only saline vehicle (n=3). Results R2* decreased in the cortex of Az-treated and medulla of furosemide-treated kidneys, corresponding to an increase in their tissue O2 assessed with probes. However, BOLD MRI also showed decreased cortical R2* following furosemide that was additive to the Az-induced decrease. Az administration, both alone and after furosemide, also decreased renal blood flow (−26±3.5 and −29.2±3%, respectively, p<0.01). Conclusion These results suggest that an increase in medullary and cortical tissue O2 elicited by selective diuretics is detectable by BOLD MRI, but may be complicated by hemodynamic effects of the drugs. Therefore, the BOLD MRI signal may reflect functional changes additional to oxygenation, and needs to be interpreted cautiously. PMID:20856128

  9. Ocean acidification alleviates low-temperature effects on growth and photosynthesis of the red alga Neosiphonia harveyi (Rhodophyta).

    PubMed

    Olischläger, Mark; Wiencke, Christian

    2013-12-01

    This study aimed to examine interactive effects between ocean acidification and temperature on the photosynthetic and growth performance of Neosiphonia harveyi. N. harveyi was cultivated at 10 and 17.5 °C at present (~380 µatm), expected future (~800 µatm), and high (~1500 µatm) pCO2. Chlorophyll a fluorescence, net photosynthesis, and growth were measured. The state of the carbon-concentrating mechanism (CCM) was examined by pH-drift experiments (with algae cultivated at 10 °C only) using ethoxyzolamide, an inhibitor of external and internal carbonic anhydrases (exCA and intCA, respectively). Furthermore, the inhibitory effect of acetazolamide (an inhibitor of exCA) and Tris (an inhibitor of the acidification of the diffusive boundary layer) on net photosynthesis was measured at both temperatures. Temperature affected photosynthesis (in terms of photosynthetic efficiency, light saturation point, and net photosynthesis) and growth at present pCO2, but these effects decreased with increasing pCO2. The relevance of the CCM decreased at 10 °C. A pCO2 effect on the CCM could only be shown if intCA and exCA were inhibited. The experiments demonstrate for the first time interactions between ocean acidification and temperature on the performance of a non-calcifying macroalga and show that the effects of low temperature on photosynthesis can be alleviated by increasing pCO2. The findings indicate that the carbon acquisition mediated by exCA and acidification of the diffusive boundary layer decrease at low temperatures but are not affected by the cultivation level of pCO2, whereas the activity of intCA is affected by pCO2. Ecologically, the findings suggest that ocean acidification might affect the biogeographical distribution of N. harveyi.

  10. Crystal structure and functional characterization of photosystem II-associated carbonic anhydrase CAH3 in Chlamydomonas reinhardtii.

    PubMed

    Benlloch, Reyes; Shevela, Dmitriy; Hainzl, Tobias; Grundström, Christin; Shutova, Tatyana; Messinger, Johannes; Samuelsson, Göran; Sauer-Eriksson, A Elisabeth

    2015-03-01

    In oxygenic photosynthesis, light energy is stored in the form of chemical energy by converting CO2 and water into carbohydrates. The light-driven oxidation of water that provides the electrons and protons for the subsequent CO2 fixation takes place in photosystem II (PSII). Recent studies show that in higher plants, HCO3 (-) increases PSII activity by acting as a mobile acceptor of the protons produced by PSII. In the green alga Chlamydomonas reinhardtii, a luminal carbonic anhydrase, CrCAH3, was suggested to improve proton removal from PSII, possibly by rapid reformation of HCO3 (-) from CO2. In this study, we investigated the interplay between PSII and CrCAH3 by membrane inlet mass spectrometry and x-ray crystallography. Membrane inlet mass spectrometry measurements showed that CrCAH3 was most active at the slightly acidic pH values prevalent in the thylakoid lumen under illumination. Two crystal structures of CrCAH3 in complex with either acetazolamide or phosphate ions were determined at 2.6- and 2.7-Å resolution, respectively. CrCAH3 is a dimer at pH 4.1 that is stabilized by swapping of the N-terminal arms, a feature not previously observed in α-type carbonic anhydrases. The structure contains a disulfide bond, and redox titration of CrCAH3 function with dithiothreitol suggested a possible redox regulation of the enzyme. The stimulating effect of CrCAH3 and CO2/HCO3 (-) on PSII activity was demonstrated by comparing the flash-induced oxygen evolution pattern of wild-type and CrCAH3-less PSII preparations. We showed that CrCAH3 has unique structural features that allow this enzyme to maximize PSII activity at low pH and CO2 concentration. PMID:25617045

  11. High-altitude Pulmonary Hypertension: an Update on Disease Pathogenesis and Management.

    PubMed

    Mirrakhimov, Aibek E; Strohl, Kingman P

    2016-01-01

    High-altitude pulmonary hypertension (HAPH) affects individuals residing at altitudes of 2,500 meters and higher. Numerous pathogenic variables play a role in disease inception and progression and include low oxygen concentration in inspired air, vasculopathy, and metabolic abnormalities. Since HAPH affects only some people living at high altitude genetic factors play a significant role in its pathogenesis. The clinical presentation of HAPH is nonspecific and includes fatigue, shortness of breath, cognitive deficits, cough, and in advanced cases hepatosplenomegaly and overt right-sided heart failure. A thorough history is important and should include a search for additional risk factors for lung disease and pulmonary hypertension (PH) such as smoking, indoor air pollution, left-sided cardiac disease and sleep disordered breathing. Twelve-lead electrocardiogram, chest X-ray and echocardiography can be used as screening tools. A definitive diagnosis should be made with right-sided heart catheterization using a modified mean pulmonary artery pressure of at least 30 mm Hg, differing from the 25 mm Hg used for other types of PH. Treatment of HAPH includes descent to a lower altitude whenever possible, oxygen therapy and the use of medications such as endothelin receptor antagonists, phosphodiesterase 5 blockers, fasudil and acetazolamide. Some recent evidence suggests that iron supplementation may also be beneficial. However, it is important to note that the scientific literature lacks long-term randomized controlled data on the pharmacologic treatment of HAPH. Thus, an individualized approach to treatment and informing the patients regarding the benefits and risks of the selected treatment regimen are essential. PMID:27014374

  12. The radiopacity of ingested medications.

    PubMed

    Savitt, D L; Hawkins, H H; Roberts, J R

    1987-03-01

    We investigated prospectively the radiopacity of 312 pills found on a university hospital formulary by first radiographing them through 15 and 25 cm of water to duplicate the radiodensity of the human body. The pills that were radiodense through water were studied in a human cadaver model, and their densities were quantified by computed tomography (CT). Thirty-five of 312 pills were radiopaque in 15 cm or more of water, and 23 of these pills were radiopaque on a plain radiograph when placed in the stomach of a cadaver. Common mnemonics used to identify radiopaque pills were found to be incomplete and inadequate. Chloral hydrate, iron-containing preparations, calcium carbonate, iodinated compounds, acetazolamide, busulfan, and potassium preparations were consistently radiopaque. Antihistamines, phenothiazines, and tricyclic antidepressants demonstrated varying radiopacity. There was varying radiopacity among the same medications made by different manufacturers. The presence of an enteric coating did not assure that the pill would be radiopaque. Merely radiographing a pill that has been placed on a standard radiograph cassette will make pills that are actually radiolucent in the body appear radiopaque. This test cannot be used to predict radiopacity in vivo. Visibility when radiographed through 15 cm or more of water and a CT radiodensity of more than 1,300 Hounsfield units are predictors of the radiopacity of a pill in the stomach of a cadaver model on a standard KUB radiograph. Variables, such as the size of the patient, the arrangement of pills in the stomach, air contrasting a pill, and the specific composition of the enteric coating or the pillmatrix, affect the radiodensity of pills.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. A distinct carbonic anhydrase in the mucus of the colon of humans and other mammals.

    PubMed

    Kleinke, Tanja; Wagner, Siegfried; John, Harald; Hewett-Emmett, David; Parkkila, Seppo; Forssmann, Wolf-Georg; Gros, Gerolf

    2005-02-01

    We have collected gastrointestinal, mainly colonic, mucus from humans, guinea pigs, rats, and normal and carbonic anhydrase II (CAII)-deficient mice. In the mucus of all species, substantial CA activity was present. Using antibodies against human CA isoforms we found that the human mucus CA differs from cytosolic CAI and CAII, membrane-bound CAIV, and the secreted CAVI of saliva. The high sensitivity of mucus CA to acetazolamide rules out its identity with cytosolic CAIII. Partial sequences obtained from the purified human mucus CA show similarity, but not identity, with human CAI, and clear differences from the other known CAs. Additional evidence concerning the CA isoform present in mucus was obtained for the mucus CA of other species and was derived from: (1) the mucus of CAII-deficient mice, whose high CA activity confirms that it is not CAII that is responsible; (2) the inhibitory effect of iodide, which shows that mucus CA from mice, guinea pig and humans does not have the high anion sensitivity of CAI; (3) the inactivating effect of 0.2% SDS on guinea pig, mouse and human mucus CA, ruling out the SDS-resistant CAIV; and (4) the partitioning of guinea-pig mucus CA into the water phase in Triton X114 phase separation experiments, which also argues against its identity with membrane-bound CAs, such as CAIV. A comparison of colonic mucus CA activity in normal and germ-free rats indicates that the mucus CA is not of bacterial origin but is produced by the gastrointestinal tissues. We conclude (from its immunoreactivity, from iodide inhibition and from partial amino acid sequences) that mucus CA of human origin probably represents an isozyme, which is specific for mucus and is not identical with the known CA isozymes. The results obtained for mucus CA of other species collectively point in the same direction. PMID:15671337

  14. Asymmetric subcellular mRNA distribution correlates with carbonic anhydrase activity in Acetabularia acetabulum.

    PubMed

    Serikawa, K A; Porterfield, D M; Mandoli, D F

    2001-02-01

    The unicellular green macroalga Acetabularia acetabulum L. Silva is an excellent system for studying regional differentiation within a single cell. In late adults, physiologically mediated extracellular alkalinity varies along the long axis of the alga with extracellular pH more alkaline along the apical and middle regions of the stalk than at and near the rhizoid. Respiration also varies with greater respiration at and near the rhizoid than along the stalk. We hypothesized that the apical and middle regions of the stalk require greater carbonic anhydrase (CA) activity to facilitate inorganic carbon uptake for photosynthesis. Treatment of algae with the CA inhibitors acetazolamide and ethoxyzolamide decreased photosynthetic oxygen evolution along the stalk but not at the rhizoid, indicating that CA facilitates inorganic carbon uptake in the apical portions of the alga. To examine the distribution of enzymatic activity within the alga, individuals were dissected into apical, middle, and basal tissue pools and assayed for both total and external CA activity. CA activity was greatest in the apical portions. We cloned two CA genes (AaCA1 and AaCA2). Northern analysis demonstrated that both genes are expressed throughout much of the life cycle of A. acetabulum. AaCA1 mRNA first appears in early adults. AaCA2 mRNA appears in juveniles. The AaCA1 and AaCA2 mRNAs are distributed asymmetrically in late adults with highest levels of each in the apical portion of the alga. mRNA localization and enzyme activity patterns correlate for AaCA1 and AaCA2, indicating that mRNA localization is one mechanism underlying regional differentiation in A. acetabulum.

  15. Color-coded digital subtraction angiography in the management of a rare case of middle cerebral artery pure arterial malformation. A technical and case report.

    PubMed

    Feliciano, Caleb E; Pamias-Portalatin, Eva; Mendoza-Torres, Jorge; Effio, Euclides; Moran, Yadira; Rodriguez-Mercado, Rafael

    2014-12-01

    The advent of flow dynamics and the recent availability of perfusion analysis software have provided new diagnostic tools and management possibilities for cerebrovascular patients. To this end, we provide an example of the use of color-coded angiography and its application in a rare case of a patient with a pure middle cerebral artery (MCA) malformation. A 42-year-old male chronic smoker was evaluated in the emergency room due to sudden onset of severe headache, nausea, vomiting and left-sided weakness. Head computed tomography revealed a right basal ganglia hemorrhage. Cerebral digital subtraction angiography (DSA) showed a right middle cerebral artery malformation consisting of convoluted and ectatic collateral vessels supplying the distal middle cerebral artery territory-M1 proximally occluded. An associated medial lenticulostriate artery aneurysm was found. Brain single-photon emission computed tomography with and without acetazolamide failed to show problems in vascular reserve that would indicate the need for flow augmentation. Twelve months after discharge, the patient recovered from the left-sided weakness and did not present any similar events. A follow-up DSA and perfusion study using color-coded perfusion analysis showed perforator aneurysm resolution and adequate, albeit delayed perfusion in the involved vascular territory. We propose a combined congenital and acquired mechanism involving M1 occlusion with secondary dysplastic changes in collateral supply to the distal MCA territory. Angiographic and cerebral perfusion work-up was used to exclude the need for flow augmentation. Nevertheless, the natural course of this lesion remains unclear and long-term follow-up is warranted.

  16. Color-Coded Digital Subtraction Angiography in the Management of a Rare Case of Middle Cerebral Artery Pure Arterial Malformation

    PubMed Central

    Feliciano, Caleb E; Pamias-Portalatin, Eva; Mendoza-Torres, Jorge; Effio, Euclides; Moran, Yadira; Rodriguez-Mercado, Rafael

    2014-01-01

    Summary The advent of flow dynamics and the recent availability of perfusion analysis software have provided new diagnostic tools and management possibilities for cerebrovascular patients. To this end, we provide an example of the use of color-coded angiography and its application in a rare case of a patient with a pure middle cerebral artery (MCA) malformation. A 42-year-old male chronic smoker was evaluated in the emergency room due to sudden onset of severe headache, nausea, vomiting and left-sided weakness. Head computed tomography revealed a right basal ganglia hemorrhage. Cerebral digital subtraction angiography (DSA) showed a right middle cerebral artery malformation consisting of convoluted and ectatic collateral vessels supplying the distal middle cerebral artery territory-M1 proximally occluded. An associated medial lenticulostriate artery aneurysm was found. Brain single-photon emission computed tomography with and without acetazolamide failed to show problems in vascular reserve that would indicate the need for flow augmentation. Twelve months after discharge, the patient recovered from the left-sided weakness and did not present any similar events. A follow-up DSA and perfusion study using color-coded perfusion analysis showed perforator aneurysm resolution and adequate, albeit delayed perfusion in the involved vascular territory. We propose a combined congenital and acquired mechanism involving M1 occlusion with secondary dysplastic changes in collateral supply to the distal MCA territory. Angiographic and cerebral perfusion work-up was used to exclude the need for flow augmentation. Nevertheless, the natural course of this lesion remains unclear and long-term follow-up is warranted. PMID:25496681

  17. Pelczaria aurantia gen. nov., sp. nov., a newly described orange-colored bacterium.

    PubMed

    Poston, J M

    1993-01-01

    An organism from a goldfish aquarium, isolated on barbital medium, was found to be a Gram-positive coccus which divided in alternating planes, often appearing as a doublet or as a tetrad with adjacent sides flattened. It grew well, although slowly, on rich solid medium (LB agar) and in liquid brain-heart infusion at room temperature (ca. 22 degrees C); growth was slower and less extensive at 30 degrees C or 37 degrees C. No growth was seen at 4-5 degrees C or at 42 degrees C. It withstands brief exposure to ultraviolet radiation. Its growth was inhibited by low levels (0.1 unit/ml) of penicillin but was unaffected by levels of acetazolamide in excess of 1 mg/ml, indicating that it lacks carbonic anhydrase. Acid was not produced from glucose, maltose, mannose, lactose, or sucrose and only weakly, if at all, from fructose. Its DNA has a G + C mol percent of 59 measured chromatographically and neither the DNA nor rRNA from the organism hybridized with DNA from any organism that seemed related on morphological or other bases. Thin-layer chromatography of chloroform:methanol extracts of the organism show that it contains phosphatidyl choline, phosphatidyl ethanolamine, and phosphatidyl glycerol. Cell-wall preparations contain glutamic acid, serine, histidine, lysine, and alanine in the ratio of 1:1:1:1:8. Colonies were red-orange in color due, in larger measure, to a carotenoid tentatively identified as rhodopin. The organism was named Pelczaria aurantia. PMID:8379810

  18. High-altitude Pulmonary Hypertension: an Update on Disease Pathogenesis and Management.

    PubMed

    Mirrakhimov, Aibek E; Strohl, Kingman P

    2016-01-01

    High-altitude pulmonary hypertension (HAPH) affects individuals residing at altitudes of 2,500 meters and higher. Numerous pathogenic variables play a role in disease inception and progression and include low oxygen concentration in inspired air, vasculopathy, and metabolic abnormalities. Since HAPH affects only some people living at high altitude genetic factors play a significant role in its pathogenesis. The clinical presentation of HAPH is nonspecific and includes fatigue, shortness of breath, cognitive deficits, cough, and in advanced cases hepatosplenomegaly and overt right-sided heart failure. A thorough history is important and should include a search for additional risk factors for lung disease and pulmonary hypertension (PH) such as smoking, indoor air pollution, left-sided cardiac disease and sleep disordered breathing. Twelve-lead electrocardiogram, chest X-ray and echocardiography can be used as screening tools. A definitive diagnosis should be made with right-sided heart catheterization using a modified mean pulmonary artery pressure of at least 30 mm Hg, differing from the 25 mm Hg used for other types of PH. Treatment of HAPH includes descent to a lower altitude whenever possible, oxygen therapy and the use of medications such as endothelin receptor antagonists, phosphodiesterase 5 blockers, fasudil and acetazolamide. Some recent evidence suggests that iron supplementation may also be beneficial. However, it is important to note that the scientific literature lacks long-term randomized controlled data on the pharmacologic treatment of HAPH. Thus, an individualized approach to treatment and informing the patients regarding the benefits and risks of the selected treatment regimen are essential.

  19. In vivo support for the new concept of pulmonary blood flow-mediated CO2 gas excretion in the lungs.

    PubMed

    Kawai, Yoshiko; Ajima, Kumiko; Kaidoh, Maki; Sakaguchi, Masao; Tanaka, Satoshi; Kawamata, Mikito; Kimura, Hiroko; Ohhashi, Toshio

    2015-06-15

    To further examine the validity of the proposed concept of pulmonary blood flow-dependent CO2 gas excretion in the lungs, we investigated the effects of intramediastinal balloon catheterization-, pulmonary artery catheterization-, or isoprenaline (ISP)-induced changes in pulmonary blood flow on the end-expiratory CO2 gas pressure (PeCO2 ), the maximal velocity of the pulmonary artery (Max Vp), systemic arterial pressure, and heart rate of anesthetized rabbits. We also evaluated the changes in the PeCO2 in clinical models of anemia or pulmonary embolism. An almost linear relationship was detected between the PeCO2 and Max Vp. In an experiment in which small pulmonary arteries were subjected to stenosis, the PeCO2 fell rapidly, and the speed of the reduction was dependent on the degree of stenosis. ISP produced significant increases in the PeCO2 of the anesthetized rabbits. Conversely, treatment with piceatannol or acetazolamide induced significant reductions in the PeCO2 . Treatment with a cell surface F1/FO ATP synthase antibody caused significant reductions in the PeCO2 itself and the ISP-induced increase in the PeCO2 . Neither the PeCO2 nor SAP was significantly influenced by marked anemia [%hematocrit (Ht), 70 ∼ 47%]. On the other hand, in the presence of less severe anemia (%Ht: 100 ∼ 70%) both the PeCO2 and SAP fell significantly when the rabbits' blood viscosity was decreased. The rabbits in which pulmonary embolisms were induced demonstrated significantly reduced PeCO2 values, which was compatible with the lowering of their Max Vp. In conclusion, we reaffirm the validity of the proposed concept of CO2 gas exchange in the lungs.

  20. Contemporary reliance on bicarbonate acquisition predicts increased growth of seagrass Amphibolis antarctica in a high-CO2 world.

    PubMed

    Burnell, Owen W; Connell, Sean D; Irving, Andrew D; Watling, Jennifer R; Russell, Bayden D

    2014-01-01

    Rising atmospheric CO2 is increasing the availability of dissolved CO2 in the ocean relative to HCO3 (-). Currently, many marine primary producers use HCO3 (-) for photosynthesis, but this is energetically costly. Increasing passive CO2 uptake relative to HCO3 (-) pathways could provide energy savings, leading to increased productivity and growth of marine plants. Inorganic carbon-uptake mechanisms in the seagrass Amphibolis antarctica were determined using the carbonic anhydrase inhibitor acetazolamide (AZ) and the buffer tris(hydroxymethyl)aminomethane (TRIS). Amphibolis antarctica seedlings were also maintained in current and forecasted CO2 concentrations to measure their physiology and growth. Photosynthesis of A. antarctica was significantly reduced by AZ and TRIS, indicating utilization of HCO3 (-)-uptake mechanisms. When acclimated plants were switched between CO2 treatments, the photosynthetic rate was dependent on measurement conditions but not growth conditions, indicating a dynamic response to changes in dissolved CO2 concentration, rather than lasting effects of acclimation. At forecast CO2 concentrations, seedlings had a greater maximum electron transport rate (1.4-fold), photosynthesis (2.1-fold), below-ground biomass (1.7-fold) and increase in leaf number (2-fold) relative to plants in the current CO2 concentration. The greater increase in photosynthesis (measured as O2 production) compared with the electron transport rate at forecasted CO2 concentration suggests that photosynthetic efficiency increased, possibly due to a decrease in photorespiration. Thus, it appears that the photosynthesis and growth of seagrasses reliant on energetically costly HCO3 (-) acquisition, such as A. antarctica, might increase at forecasted CO2 concentrations. Greater growth might enhance the future prosperity and rehabilitation of these important habitat-forming plants, which have experienced declines of global significance.

  1. Effect of oral coadministration of drugs on the disposition of (/sup 14/C)-celiprolol HCl in rats

    SciTech Connect

    Town, C.; Knipe, J.; Taft, C.; Tantillo, N.; Klunk, L.; Grebow, P.

    1986-03-01

    Celiprolol HCL (C) is a cardioselective ..beta..-blocker undergoing clinical trials as an antihypertensive agent. Studies with rats indicated that the oral coadministration of 2.5 mg/kg of chlorthalidone (CT) caused a 40% decrease in the urinary excretion of radioactivity from a 40 mg/kg dose of (/sup 14/C)-C(C). In order to further understand the nature of this interaction, groups of 6 rats were given 40 mg/kg of (C) alone and, one week later,/sub R.(C) pluse the drug to be tested. The vehicle was 0.5% Methocel. After each dosing, urine was collected for 96 hours from each rat and the amount of total radioactivity excreted was compared between treatments. The results showed that oral coadministration of 2.5 mg/kg hydrochlorothiazide, 2.5 mg/kg furosemide, 2.5 mg/kg indapamide, 5.0 mg/kg cimetidine, 10.0 mg/kg theophylline, and 1.0 mg/kg digoxin were without effect on the disposition of orally administered (C). Conversely, 2.5 mg/kg CT, 2.5 mg/kg acetazolamide (AZ) and 5.0 mg/kg hydralazine (H) caused a significant (p < 0.05) decrease in the urinary excretio of orally administered (C). CT and AZ are both potent inhibitors of carbonic anhydrase and their action on this enzyme may cause the effect on the disposition of (C). The action of H may be due to its pharmacologic action and warrants further study.

  2. Carbonic anhydrase in the sarcoplasmic reticulum of rabbit skeletal muscle.

    PubMed Central

    Bruns, W; Dermietzel, R; Gros, G

    1986-01-01

    Sarcoplasmic reticulum vesicles and mitochondria were prepared from red and white skeletal muscles of the rabbit. The preparations were characterized in terms of their specific activities of citrate synthase, basal (Mg2+-dependent) and Ca2+-dependent ATPase (the latter two in the presence of NaN3 and ouabain), and their specific carbonic anhydrase activities were determined. Skeletal muscle mitochondria had high specific activities of citrate synthase (700-1200 mu. mg protein-1) and low carbonic anhydrase activities (0.1-0.4 u. ml mg protein-1). The latter are likely to be due to a contamination of the preparations with sarcoplasmic reticulum (s.r.) Preparations of s.r. vesicles showed negligible activities of citrate synthase and the expected differing patterns of basal and Ca2+-dependent ATPase in red and white muscles. Specific carbonic anhydrase activities in s.r. from both muscle types were high (2-4 u. ml mg protein-1). The highest carbonic anhydrase activity, 11 u. ml mg protein-1, was found in s.r. from rabbit m. masseter. The inhibition constant of s.r. carbonic anhydrase towards acetazolamide was 4-6 X 10(-8) M and similar but not identical to that of cytosolic carbonic anhydrase II. It appears possible that the carbonic anhydrase II-like enzyme previously found by us in muscle homogenates (Siffert & Gros, 1982) originates from the s.r. Histochemical studies using the dansylsuphonamide method described previously (Dermietzel, Leibstein, Siffert, Zamboglou & Gros, 1985) showed an intracellular pattern of carbonic anhydrase staining compatible with the presence of the enzyme in s.r.: spots homogeneously distributed across the fibre cross-sections in transversely sectioned fibres and thin, longitudinally oriented, bands in longitudinally sectioned fibres. It is estimated that s.r. carbonic anhydrase accelerates CO2 hydration within the s.r. approximately 1000-fold. Thus, CO2 and HCO3- react fast enough to provide a rapid source and sink for protons leaving

  3. Immunosuppressive agents versus steroids in the treatment of IgA nephropathy-induced proteinuria: A meta-analysis

    PubMed Central

    LIU, YANLI; XIAO, JUN; SHI, XINTIAN; HAO, GUOJUN; CHEN, QINKAI; ZHOU, JING; WEI, XIN

    2016-01-01

    Immunoglobulin A nephropathy (IgAN) is one of the most common types of primary glomerular disease. Immunosuppressive treatment for patients with IgAN remains controversial. The present meta-analysis aimed to assess the efficacy and safety of various immunosuppressive agents compared with steroids in patients with IgAN and moderate to severe proteinuria. PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, Weipu, Chinese Biomedical Literature Database and Qinghuatongfang were searched for relevant randomized controlled trials (RCTs) published between 1990 and September 2013. All eligible studies (biopsy proven IgA nephropathy, use of immunosuppressive agents) measured urinary protein excretion and proteinuria remission. Data were analyzed with the random effects model using Review Manager. A total of 29 RCTs were included, involving 1,466 patients. Compared with steroids, immunosuppressive agents, including acetazolamide (AZA) [complete response (CR)/partial response (PR); relative risk (RR), 3.43; 95% confidence interval (CI) 1.92–6.12; P<0.0001], mycophenolate mofetil (MMF) (CR/PR; RR, 2.19; 95% CI, 1.25–3.85; P=0.006) and leflunomide (LET) (CR/PR; RR, 2.64; 95% CI, 1.80–3.86; P<0.00001) resulted in increased partial or complete proteinuria remission. Cyclophosphamide (CTX) resulted in a higher reduction of urinary protein excretion than steroids (SMD, 0.91; 95% CI, 0.41–1.41; P=0.0004)). Compared to CTX, LET showed higher effectiveness (CR/PR; RR, 2.01; 95% CI, 1.08–3.75; P=0.03) with a lower incidence of adverse events. The present meta-analysis, which is based on IgAN patients, suggested that AZA, MMF, LET and CTX are effective in reducing proteinuria levels, with acceptable side effects. Therefore, immunosuppressive agents may be considered promising therapeutic agents for the treatment of IgAN and should be investigated further in large sample size, high-quality studies. PMID:26889216

  4. Mechanisms for vasopressin effects on intraocular pressure in anesthetized rats

    NASA Technical Reports Server (NTRS)

    Balaban, C. D.; Palm, D. E.; Shikher, V.; Searles, R. V.; Keil, L. C.; Severs, W. B.

    1997-01-01

    Continuous intracameral infusions of a balanced salt solution (0.175 microliter min-1) have been reported to raise intraocular pressure (IOP) in anesthetized rats. Palm et al. (1995) previously reported that this effect was attenuated significantly by inclusion of arginine-vasopressin (AVP, 10 ng 0.175 microliter-1) in the infusate. This study used experimental and computer simulation methods to investigate factors underlying these changes in IOP. First, constant intracameral infusions of artificial cerebrospinal fluid (aCSF) at different fixed rates (0.049-0.35 microliter min-1) were used to estimate the outflow resistance. Secondly, IOP responses were measured during an 2 hr intracameral infusion of either aCSF or AVP that was the sum of a small constant component (0.05 microliter min-1) and a larger periodic component (0.25 microliter min-1, cycling for 4 min on, then 4 min off); the mean infusion rate was 0.175 microliter min-1. As shown previously for 0.175 microliter min-1 constant infusions, the periodic aCSF infusion induced a significant rise in IOP that was attenuated by AVP administration. Complex demodulation analysis and the estimated gain parameter of a second order transfer function fit to the periodic responses indicated that outflow resistance increased significantly during the infusions in both aCSF and AVP groups, but that the indices of resistance did not differ significantly between aCSF and AVP infused eyes. This finding implies that changes in outflow resistance do not explain the difference in IOP responses to intracameral aCSF and AVP. The two responses differed significantly, though, in damping factors, such that the aCSF responses were considerably more underdamped than the AVP responses. It is hypothesized that aCSF-induced increase in IOP reflects both (1) a small component reflecting increased outflow resistance and (2) a larger non-resistive component. Since the non-resistive component is insensitive to pretreatment with acetazolamide

  5. High-speed gas chromatography in doping control: fast-GC and fast-GC/MS determination of beta-adrenoceptor ligands and diuretics.

    PubMed

    Brunelli, Claudio; Bicchi, Carlo; Di Stilo, Antonella; Salomone, Alberto; Vincenti, Marco

    2006-12-01

    In official doping controls, about 300 drugs and metabolites have to be screened for each sample. Moreover, the number of determinations to be routinely processed increases continuously as the number of both samples and potential illicit drugs keeps growing. As a consequence, increasingly specific, sensitive, and, above all, fast methods for doping controls are needed. The present study presents an efficient fast-GC/MS approach to the routine screening of two different classes of doping agents, namely beta-adrenoceptor ligands and diuretics (belonging to the S3, P2, and S5 groups of the WADA list of prohibited substances). Narrow bore columns (100 mm id) of different lengths and coated with apolar stationary phases were successfully used to separate the derivatized analytes; preliminary experiments (results not shown) showed better performances with OV-1701 for the separation of beta-adrenoceptor ligands. On the same stationary phase some diuretics required too high a temperature or a long isothermal time for elution, in which case a DB1-MS column was preferred. Two methods of sample preparation, derivatization, and analysis were used on aqueous standard mixtures of, respectively, (i) eight beta-adrenoceptor ligands, including five beta-antagonists (acebutolol, alprenolol, atenolol, metoprolol, pindolol) and three beta2-agonists (salbutamol, clenbuterol, terbutaline) and (ii) seventeen diuretic drugs (acetazolamide, althiazide, bendroflumethiazide, bumethanide, canrenone, chlorothiazide, chlortalidone, clopamide, ethacrinic acid, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, indomethacine, spironolactone, triamterene, trichloromethiazide) and one masking agent (probenecid). The mixture of beta-adrenoceptor ligand derivatives was efficiently separated in about 5.6 min, while the one of 18 diuretics and masking agents required less than 5 min for analysis. Limits of detection were from 1 microg/L for pindolol, ethacrinic acid, furosemide

  6. Risk assessment of physiological effects of atmospheric composition and pressure in Constellation vehicles

    NASA Astrophysics Data System (ADS)

    Scheuring, Richard; Conkin, Johnny; Jones, Jeffrey A.; Gernhardt, Michael L.

    CEV, and use a gradual or staged reduction in cabin pressure during lunar outbound; (2) train crews for symptoms of hypoxia, to allow early recognition and consider pre-adaptation of crews to a hypoxic environment prior to launch; (3) consider prophylactic acetazolamide for acute pressure changes and be prepared to treat any AMS associated symptoms early with both carbonic anhydrase inhibitors and supplemental oxygen.

  7. Biotic Control of Surface pH and Evidence of Light-Induced H+ Pumping and Ca2+-H+ Exchange in a Tropical Crustose Coralline Alga

    PubMed Central

    Hofmann, Laurie C.; Koch, Marguerite; de Beer, Dirk

    2016-01-01

    Presently, an incomplete mechanistic understanding of tropical reef macroalgae photosynthesis and calcification restricts predictions of how these important autotrophs will respond to global change. Therefore, we investigated the mechanistic link between inorganic carbon uptake pathways, photosynthesis and calcification in a tropical crustose coralline alga (CCA) using microsensors. We measured pH, oxygen (O2), and calcium (Ca2+) dynamics and fluxes at the thallus surface under ambient (8.1) and low (7.8) seawater pH (pHSW) and across a range of irradiances. Acetazolamide (AZ) was used to inhibit extracellular carbonic anhydrase (CAext), which mediates hydrolysis of HCO3-, and 4,4′ diisothiocyanatostilbene-2,2′-disulphonate (DIDS) that blocks direct HCO3- uptake by anion exchange transport. Both inhibited photosynthesis, suggesting both diffusive uptake of CO2 via HCO3- hydrolysis to CO2 and direct HCO3- ion transport are important in this CCA. Surface pH was raised approximately 0.3 units at saturating irradiance, but less when CAext was inhibited. Surface pH was lower at pHSW 7.8 than pHSW 8.1 in the dark, but not in the light. The Ca2+ fluxes were large, complex and temporally variable, but revealed net Ca2+ uptake under all conditions. The temporal variability in Ca2+ dynamics was potentially related to localized dissolution during epithallial cell sloughing, a strategy of CCA to remove epiphytes. Simultaneous Ca2+ and pH dynamics suggest the presence of Ca2+/H+ exchange. Rapid light-induced H+ surface dynamics that continued after inhibition of photosynthesis revealed the presence of a light-mediated, but photosynthesis-independent, proton pump. Thus, the study indicates metabolic control of surface pH can occur in CCA through photosynthesis and light-inducible H+ pumps. Our results suggest that complex light-induced ion pumps play an important role in biological processes related to inorganic carbon uptake and calcification in CCA. PMID:27459463

  8. XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement.

    PubMed

    Borbulevych, Oleg; Martin, Roger I; Tickle, Ian J; Westerhoff, Lance M

    2016-04-01

    Gaining an understanding of the protein-ligand complex structure along with the proper protonation and explicit solvent effects can be important in obtaining meaningful results in structure-guided drug discovery and structure-based drug discovery. Unfortunately, protonation and tautomerism are difficult to establish with conventional methods because of difficulties in the experimental detection of H atoms owing to the well known limitations of X-ray crystallography. In the present work, it is demonstrated that semiempirical, quantum-mechanics-based macromolecular crystallographic refinement is sensitive to the choice of a protonation-state/tautomer form of ligands and residues, and can therefore be used to explore potential states. A novel scoring method, called XModeScore, is described which enumerates the possible protomeric/tautomeric modes, refines each mode against X-ray diffraction data with the semiempirical quantum-mechanics (PM6) Hamiltonian and scores each mode using a combination of energetic strain (or ligand strain) and rigorous statistical analysis of the difference electron-density distribution. It is shown that using XModeScore it is possible to consistently distinguish the correct bound protomeric/tautomeric modes based on routine X-ray data, even at lower resolutions of around 3 Å. These X-ray results are compared with the results obtained from much more expensive and laborious neutron diffraction studies for three different examples: tautomerism in the acetazolamide ligand of human carbonic anhydrase II (PDB entries 3hs4 and 4k0s), tautomerism in the 8HX ligand of urate oxidase (PDB entries 4n9s and 4n9m) and the protonation states of the catalytic aspartic acid found within the active site of an aspartic protease (PDB entry 2jjj). In each case, XModeScore applied to the X-ray diffraction data is able to determine the correct protonation state as defined by the neutron diffraction data. The impact of QM-based refinement versus conventional

  9. XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement

    PubMed Central

    Borbulevych, Oleg; Martin, Roger I.; Tickle, Ian J.; Westerhoff, Lance M.

    2016-01-01

    Gaining an understanding of the protein–ligand complex structure along with the proper protonation and explicit solvent effects can be important in obtaining meaningful results in structure-guided drug discovery and structure-based drug discovery. Unfortunately, protonation and tautomerism are difficult to establish with conventional methods because of difficulties in the experimental detection of H atoms owing to the well known limitations of X-ray crystallography. In the present work, it is demonstrated that semiempirical, quantum-mechanics-based macromolecular crystallographic refinement is sensitive to the choice of a protonation-state/tautomer form of ligands and residues, and can therefore be used to explore potential states. A novel scoring method, called XModeScore, is described which enumerates the possible protomeric/tautomeric modes, refines each mode against X-ray diffraction data with the semiempirical quantum-mechanics (PM6) Hamiltonian and scores each mode using a combination of energetic strain (or ligand strain) and rigorous statistical analysis of the difference electron-density distribution. It is shown that using XModeScore it is possible to consistently distinguish the correct bound protomeric/tautomeric modes based on routine X-ray data, even at lower resolutions of around 3 Å. These X-ray results are compared with the results obtained from much more expensive and laborious neutron diffraction studies for three different examples: tautomerism in the acetazolamide ligand of human carbonic anhydrase II (PDB entries 3hs4 and 4k0s), tautomerism in the 8HX ligand of urate oxidase (PDB entries 4n9s and 4n9m) and the protonation states of the catalytic aspartic acid found within the active site of an aspartic protease (PDB entry 2jjj). In each case, XModeScore applied to the X-ray diffraction data is able to determine the correct protonation state as defined by the neutron diffraction data. The impact of QM-based refinement versus conventional

  10. Biotic Control of Surface pH and Evidence of Light-Induced H+ Pumping and Ca2+-H+ Exchange in a Tropical Crustose Coralline Alga.

    PubMed

    Hofmann, Laurie C; Koch, Marguerite; de Beer, Dirk

    2016-01-01

    Presently, an incomplete mechanistic understanding of tropical reef macroalgae photosynthesis and calcification restricts predictions of how these important autotrophs will respond to global change. Therefore, we investigated the mechanistic link between inorganic carbon uptake pathways, photosynthesis and calcification in a tropical crustose coralline alga (CCA) using microsensors. We measured pH, oxygen (O2), and calcium (Ca2+) dynamics and fluxes at the thallus surface under ambient (8.1) and low (7.8) seawater pH (pHSW) and across a range of irradiances. Acetazolamide (AZ) was used to inhibit extracellular carbonic anhydrase (CAext), which mediates hydrolysis of HCO3-, and 4,4' diisothiocyanatostilbene-2,2'-disulphonate (DIDS) that blocks direct HCO3- uptake by anion exchange transport. Both inhibited photosynthesis, suggesting both diffusive uptake of CO2 via HCO3- hydrolysis to CO2 and direct HCO3- ion transport are important in this CCA. Surface pH was raised approximately 0.3 units at saturating irradiance, but less when CAext was inhibited. Surface pH was lower at pHSW 7.8 than pHSW 8.1 in the dark, but not in the light. The Ca2+ fluxes were large, complex and temporally variable, but revealed net Ca2+ uptake under all conditions. The temporal variability in Ca2+ dynamics was potentially related to localized dissolution during epithallial cell sloughing, a strategy of CCA to remove epiphytes. Simultaneous Ca2+ and pH dynamics suggest the presence of Ca2+/H+ exchange. Rapid light-induced H+ surface dynamics that continued after inhibition of photosynthesis revealed the presence of a light-mediated, but photosynthesis-independent, proton pump. Thus, the study indicates metabolic control of surface pH can occur in CCA through photosynthesis and light-inducible H+ pumps. Our results suggest that complex light-induced ion pumps play an important role in biological processes related to inorganic carbon uptake and calcification in CCA. PMID:27459463

  11. Mechanism of exaggerated natriuresis in hypertensive man: impaired sodium transport in the loop of henle

    PubMed Central

    Buckalew, Vardaman M.; Puschett, Jules B.; Kintzel, James E.; Goldberg, Martin

    1969-01-01

    To evaluate the effects of saline loading on distal sodium reabsorption in hypertensive man, studies were performed during both water deprivation and water diuresis in eight hypertensive subjects, and the results were compared to data obtained from similar studies in normal subjects. All hypertensive patients exhibited an enhanced excretion of filtered sodium (CNa/CIn) at any level of distal delivery of sodium compared to normal controls. Free water reabsorption (TcH2O) during hypertonic saline loading was quantitatively abnormal in the hypertensives at high levels of osmolar clearance (COsm), and also the curve of TcH2O vs. COsm leveled off above a COsm of 18 ml/min per 1.73 m2 in the hypertensive group in contrast to the normal controls in whom TcH2O showed no evidence of achieving an upper limit. Sodium depletion exaggerated the abnormality in TcH2O in hypertensives, and resulted in a positive free water clearance (CH2O) during hydropenia. During hypotonic saline loading in water diuresis, changes in free water clearance per 100 ml of glomerular filtrate (CH2O/CIn) were less at any given increment in urine flow per 100 ml of glomerular filtrate (V/CIn) in the hypertensives compared to normal controls (P < 0.001). This abnormality in CH2O/CIn in the hypertensives in conjunction with the defect in TcH2O observed during hydropenia indicates that sodium reabsorption in the loop of Henle was abnormal at any given rate of distal delivery of sodium in hypertension. Furthermore, these abnormalities in TcH2O and CH2O coincided temporally with the development of the exaggerated natriuresis. Although the distal defect in sodium transport, in large part, accounted for the augmented natriuresis in hypertension, evidence was present also for enhanced rejection of sodium in the proximal tubule during saline loading in the hypertensives. Additional studies utilizing acetazolamide which increases distal delivery of sodium without extracellular fluid volume expansion showed only

  12. S0859, an N-cyanosulphonamide inhibitor of sodium-bicarbonate cotransport in the heart

    PubMed Central

    Ch'En, F F-T; Villafuerte, F C; Swietach, P; Cobden, P M; Vaughan-Jones, R D

    2008-01-01

    Background and purpose: Intracellular pH (pHi) in heart is regulated by sarcolemmal H+-equivalent transporters such as Na+-H+ exchange (NHE) and Na+-HCO3 − cotransport (NBC). Inhibition of NBC influences pHi and can be cardioprotective in animal models of post-ischaemic reperfusion. Apart from a rabbit polyclonal NBC-antibody, a selective NBC inhibitor compound has not been studied. Compound S0859 (C29H24ClN3O3S) is a putative NBC inhibitor. Here, we provide the drug's chemical structure, test its potency and selectivity in ventricular cells and assess its suitability for experiments on cardiac contraction. Experimental approach: pHi recovery from intracellular acidosis was monitored using pH-epifluorescence (SNARF-fluorophore) in guinea pig, rat and rabbit isolated ventricular myocytes. Electrically evoked cell shortening (contraction) was measured optically. With CO2/HCO3 −-buffered superfusates containing 30 μM cariporide (to inhibit NHE), pHi recovery is mediated by NBC. Key results: S0859, an N-cyanosulphonamide compound, reversibly inhibited NBC-mediated pHi recovery (K i=1.7 μM, full inhibition at ∼30 μM). In HEPES-buffered superfusates, NHE-mediated pHi recovery was unaffected by 30 μM S0859. With CO2/HCO3 − buffer, pHi recovery from intracellular alkalosis (mediated by Cl−/HCO3 − and Cl−/OH− exchange) was also unaffected. Selective NBC-inhibition was not due to action on carbonic anhydrase (CA) enzymes, as 100 μM acetazolamide (a membrane-permeant CA-inhibitor) had no significant effect on NBC activity. pHi recovery from acidosis was associated with increased contractile-amplitude. The time course of recovery of pHi and contraction was slowed by S0859, confirming that NBC is a significant controller of contractility during acidosis. Conclusions and implications: Compound S0859 is a selective, high-affinity generic NBC inhibitor, potentially important for probing the transporter's functional role in heart and other tissues

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

    PubMed

    Ferraroni, Marta; Del Prete, Sonia; Vullo, Daniela; Capasso, Clemente; Supuran, Claudiu T

    2015-12-01

    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.

  14. Characterization of H+ and HCO3- transporters in CFPAC-1 human pancreatic duct cells

    PubMed Central

    Jr, Zoltán Rakonczay; Fearn, Amy; Hegyi, Péter; Boros, Imre; Gray, Michael A; Argent, Barry E

    2006-01-01

    AIM: To characterize H+ and HCO3- transporters in polarized CFPAC-1 human pancreatic duct cells, which were derived from a cystic fibrosis patient with the ΔF508 CFTR mutation. METHODS: CFPAC-1 cells were seeded at high density onto permeable supports and grown to confluence. The cells were loaded with the pH-sensitive fluorescent dye BCECF, and mounted into a perfusion chamber, which allowed the simultaneous perfusion of the basolateral and apical membranes. Transmembrane base flux was calculated from the changes in intracellular pH and the buffering capacity of the cells. RESULTS: Our results showed differential permeability to HCO3-/CO2 at the apical and basolateral membranes of CFPAC-1 cells. Na+/HCO3- co-transporters (NBCs) and Cl-/HCO3- exchangers (AEs) were present on the basolateral membrane, and Na+/H+ exchangers (NHEs) on both the apical and basolateral membranes of the cells. Basolateral HCO3- uptake was sensitive to variations of extracellular K+ concentration, the membrane permeable carbonic anhydrase (CA) inhibitors acetazolamide (100 µmol/L) and ethoxyzolamide (100 µmol/L), and was partially inhibited by H2-DIDS (600 µmol/L). The membrane-impermeable CA inhibitor 1-N-(4-sulfamoylphenylethyl)-2,4,6-trimethylpyridine perchlorate did not have any effect on HCO3- uptake. The basolateral AE had a much higher activity than that in the apical membrane, whereas there was no such difference with the NHE under resting conditions. Also, 10 µmol/L forskolin did not significantly influence Cl-/HCO3- exchange on the apical and basolateral membranes. The administration of 250 µmol/L H2-DIDS significantly inhibited the basolateral AE. Amiloride (300 µmol/L) completely inhibited NHEs on both membranes of the cells. RT-PCR revealed the expression of pNBC1, AE2, and NHE1 mRNA. CONCLUSION: These data suggest that apart from the lack of CFTR and apical Cl-/HCO3- exchanger activity, CFPAC-1 cells express similar H+ and HCO3- transporters to those observed in native

  15. Water and salt intake of wild rabbits (Oryctolagus cuniculus (L)) following dipsogenic stimuli.

    PubMed Central

    Denton, D A; Nelson, J F; Tarjan, E

    1985-01-01

    Wild rabbits trapped in their natural habitat and adapted to laboratory conditions were studied. Food, water and electrolyte (0.5 M-NaCl, 0.5 M-KCl, 0.25 M-MgCl2 and 0.25 M-CaCl2) consumption, urinary volume and sodium losses were monitored daily following stimuli which were found dipsogenic in other species. Water drinking was observed immediately after the intravenous injection of 1 M-NaCl (3 ml/kg), and following withdrawal of a mean of 13.9% of calculated blood volume. Daily intake of water decreased during intracerebroventricular (I.C.V.) infusion of 0.3 M-NaCl in artificial cerebrospinal fluid (c.s.f.), during I.C.V. infusion of 0.9 M-mannitol c.s.f., both at a rate of 17 microliters/h, following peritoneal dialysis with 5% (w/v) glucose solution, and during food restriction. Water intake was not affected following intravenous administration of acetazolamide (10 mg/kg). Daily intake of 0.5 M-NaCl solution was increased following peritoneal dialysis with 5% (w/v) glucose solution, which caused hyponatraemia, but not after haemorrhage which caused about the same sodium deficit as peritoneal dialysis, but as an isosmotic loss. Administration of two different angiotensin II analogues, systemically or I.C.V., failed to induce water drinking. However, urinary sodium excretion and intake of 0.5 M-NaCl were increased during the 5 days of I.C.V. infusion of angiotensin II (10 pmol/h). Infusion for 1 day of angiotensin II (500 pmol/h) led to increased urinary sodium excretion which was followed by increased intake. The intake of other electrolyte solutions was not significantly affected by any of the treatments detailed above. The mechanisms participating in initiation of thirst in wild rabbits are very sensitive to decrease in blood volume, in contrast to other species studied in laboratories. Angiotensin II at the doses and routes administered was not dipsogenic in wild rabbits. The increased intake of 0.5 M-NaCl solution observed during and after the long

  16. Effect of genistein on basal jejunal chloride secretion in R117H CF mice is sex and route specific.

    PubMed

    Rayyan, Esa; Polito, Sarah; Leung, Lana; Bhakta, Ashesh; Kang, Jonathan; Willey, Justin; Mansour, Wasim; Drumm, Mitchell L; Al-Nakkash, Layla

    2015-01-01

    Cystic fibrosis (CF) results from the loss or reduction in function of the CFTR (cystic fibrosis transmembrane conductance regulatory protein) chloride channel. The third most common CFTR mutation seen clinically is R117H. Genistein, a naturally occurring phytoestrogen, is known to stimulate CFTR function in vitro. We aimed to determine whether route of administration of genistein could mediate differential effects in R117H male and female CF mice. Mice were fed (4 weeks) or injected subcutaneously (1 week) with the following: genistein 600 mg/kg diet (600Gd); genistein-free diet (0Gd); genistein injection 600 mg/kg body weight (600Gi); dimethyl sulfoxide control (0Gi). In male R117H mice fed 600Gd, basal short circuit current (Isc) was unchanged. In 600Gd-fed female mice, there was a subgroup that demonstrated a significant increase in basal Isc (53.14±7.92 μA/cm(2), n=6, P<0.05) and a subgroup of nonresponders (12.05±6.59 μA/cm(2), n=4), compared to 0Gd controls (29.3±6.5 μA/cm(2), n=7). In R117H mice injected with 600Gi, basal Isc was unchanged in both male and female mice compared to 0Gi controls. Isc was measured in response to the following: the adenylate cyclase activator forskolin (10 μM, bilateral), bumetanide (100 μM, basolateral) to indicate the Cl(-) secretory component, and acetazolamide (100 μM, bilateral) to indicate the HCO3 (-) secretory component; however, there was no effect of genistein (diet or injection) on any of these parameters. Jejunal morphology (ie, villi length, number of goblet cells per villus, crypt depth, and number of goblet cells per crypt) in R117H mice suggested no genistein-mediated difference among the groups. Serum levels of genistein were significantly elevated, compared to respective controls, by either 600Gd (equally elevated in males and females) or 600Gi (elevated more in females versus males). These data suggest a sex-dependent increase in basal Isc of R117H mice and that the increase is also specific for route

  17. Evidence for Bicarbonate Secretion by Ameloblasts in a Novel Cellular Model.

    PubMed

    Bori, E; Guo, J; Rácz, R; Burghardt, B; Földes, A; Kerémi, B; Harada, H; Steward, M C; Den Besten, P; Bronckers, A L J J; Varga, G

    2016-05-01

    Formation and growth of hydroxyapatite crystals during amelogenesis generate a large number of protons that must be neutralized, presumably by HCO3 (-)ions transported from ameloblasts into the developing enamel matrix. Ameloblasts express a number of transporters and channels known to be involved in HCO3 (-)transport in other epithelia. However, to date, there is no functional evidence for HCO3 (-)transport in these cells. To address questions related to HCO3 (-)export from ameloblasts, we have developed a polarized 2-dimensional culture system for HAT-7 cells, a rat cell line of ameloblast origin. HAT-7 cells were seeded onto Transwell permeable filters. Transepithelial resistance was measured as a function of time, and the expression of transporters and tight junction proteins was investigated by conventional and quantitative reverse transcription polymerase chain reaction. Intracellular pH regulation and HCO3 (-)transport were assessed by microfluorometry. HAT-7 cells formed epithelial layers with measureable transepithelial resistance on Transwell permeable supports and expressed claudin-1, claudin-4, and claudin-8-key proteins for tight junction formation. Transport proteins previously described in maturation ameloblasts were also present in HAT-7 cells. Microfluorometry showed that the HAT-7 cells were polarized with a high apical membrane CO2 permeability and vigorous basolateral HCO3 (-)uptake, which was sensitive to Na(+)withdrawal, to the carbonic anhydrase inhibitor acetazolamide and to H2DIDS inhibition. Measurements of transepithelial HCO3 (-)transport showed a marked increase in response to Ca(2+)- and cAMP-mobilizing stimuli. Collectively, 2-dimensional HAT-7 cell cultures on permeable supports 1) form tight junctions, 2) express typical tight junction proteins and electrolyte transporters, 3) are functionally polarized, and 4) can accumulate HCO3 (-)ions from the basolateral side and secrete them at the apical membrane. These studies provide

  18. Influence of volume expansion on NaC1 reabsorption in the diluting segments of the nephron: a study using clearance methods.

    PubMed

    Danovitch, G M; Bricker, N S

    1976-09-01

    Whether volume expansion influences NaC1 reabsorption by the diluting segment of the nephron remains a matter of controversy. In the present studies this question has been examined in normal unanesthetized dogs, undergoing maximal water diuresis. Free water clearance (CH2O/GFR) has been used as the index of NaC1 reabsorption in the diluting segment. Three expressions have been employed for "distal delivery" of NaC1: a) V/GFR, designated as the "volume term"; b) (CNa/GFR + CH2O/GFR), the "sodium term;" and c) (CC1/GFR + CH2O/GFR), the "chloride term". The validity of these terms is discussed. Three techniques were used to increase distal delivery: 1) the administration of acetazolamide to dogs in which extracellular fluid (ECF) volume was not expanded (grop 1); 2) "moderate" volume expansion (group 2); and 3) "marked" volume expansion (group 3). CH2O/GFR increased progressively with rising values for "distal delivery" regardless of which term was used to calculate the latter. With all three delivery terms, differences in distal NaC1 reabsorption emerged between the two volume-expanded groups, though only with the "chloride" term did substantial differences also emerge between the nonexpanded group 1 dogs and both volume-expanded groups. In group 1, values for CH2O/GFR increased in close to a linear fashion up to distal delivery values equal to 24% of the volume of glomerular filtrate. However, at high rates of distal delivery the rate of rise of CH2O/GFR was less in group 2 than in group 1 and the depression of values was even greater in group 3. Within the limits of the techniques used, the data suggest that volume expansion inhibits fractional NaC1 reabsorption in the diluting segment of the nephron in a dose-related fashion. The "chloride" term was found to be superior to the "volume" and "sodium" terms in revealing these changes.

  19. The regulation of intracellular pH studied by 31P- and 1H-NMR spectroscopy in superfused guinea-pig cerebral cortex slices.

    PubMed

    Brooks, K J; Bachelard, H S

    1992-10-01

    (1) The intracellular pH (pHi) of superfused slices of guinea-pig cerebral cortex was measured in 31P-NMR spectra using the chemical shifts of intracellular inorganic phosphate (Pi) and of 2-deoxyglucose 6-phosphate (DOG6P). The pHi was found to be 7.30 +/- 0.04 (SD, n = 15) in bicarbonate-buffered medium and 7.20 +/- 0.05 (n = 10, P < 0.001) in bicarbonate-free HEPES buffer of the same pH (7.4). (2) Decreases in pHe below 7.05 resulted in pHi falling to similar values, with a decrease in the energy state. There was no change in intracellular lactate as assessed by 1H-NMR. (3) The tissues showed an ability to buffer higher pH: increasing pHe to 8.0 had no effect on pHi, PCr or lactate. (4) In order to characterize possible mechanisms of pH regulation in the tissue, the recovery from acid insult was investigated under various conditions. Initially pHi was decreased to 6.44 +/- 0.15 (n = 15) by exposure to media containing 6 mM bicarbonate gassed with O2/CO2, 80:20 (pHe 6.4). When this medium was replaced by normal bicarbonate buffer (pH 7.4) there was full recovery of pHi to 7.31 +/- 0.05 (n = 15), whereas replacing the buffer with HEPES resulted in incomplete recovery of pHi to 6.88 +/- 0.15 (n = 15, P < 0.001). (5) In the presence of the carbonic anhydrase inhibitor, acetazolamide (1 mM), or the sodium/proton exchange inhibitor, amiloride (1 mM), there was an incomplete return of pHi to the control value (pHi 6.90 +/- 0.20, n = 5, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1303163

  20. Bicarbonate effects, electromotive forces and potassium effluxes in rabbit and guinea-pig gall-bladder.

    PubMed

    Cremaschi, D; Meyer, G; Rossetti, C

    1983-02-01

    The stimulating effect of external HCO3- on Na+ salt transport has been examined in rabbit and guinea-pig gall-bladder by electrophysiological methods, as a sequel to a previous study carried out by radiochemical techniques. At steady state, cell K+ activity was found to be significantly reduced in the presence of HCO3-, whereas cell Na+ activity significantly increased; in parallel the apical membrane p.d. was depolarized; K+ equilibrium potential was higher than membrane p.d. in every case. The apical p.d. dependence on K+ was unaffected by HCO3-, but in the guinea-pig it was affected by Cl-. Rapid increases in HCO3- concentration on the luminal side caused a depolarization of the apical p.d. of the guinea-pig within about 30 sec, an effect that did not occur if the tissue was pre-treated with 10(-4) M-acetazolamide; the epithelial resistance and apical/basolateral resistance ratio were unchanged in all cases. The primary action of HCO3- is confirmed to be on the apical membrane; an HCO3- conductance does not seem to be present at this level, either in the rabbit or guinea-pig, nor does HCO3- affect Na+ influx through the apical conductive pathway, so that all the stimulating effects of the anion are confirmed to be on the neutral transports of Na+ salts; in spite of this, the apical electromotive force is modified due to the changed cell K+ activity. The rapid depolarization caused by the anion in the guinea-pig is in agreement with an HCO3- electrogenic secretion and/or a basolateral conductance for the anion. Polyelectrolyte dissociation from protons increases in the absence of external HCO3-: the negative charges are mainly counterbalanced by bound Na+ in the rabbit and by free K+ in the guinea-pig. K+ leakage from the cell into the lumen is calculated to be minimal in the rabbit and all K+ lost could be reabsorbed through the paracellular pathways; K+ efflux to the subepithelial layer via conductive routes is insufficient to account for the over-all K

  1. Synthesis, characterization and antiglaucoma activity of a novel proton transfer compound and a mixed-ligand Zn(II) complex.

    PubMed

    Yenikaya, Cengiz; Sari, Musa; Bülbül, Metin; Ilkimen, Halil; Celik, Hülya; Büyükgüngör, Orhan

    2010-01-15

    A novel proton transfer compound, pyridin-2-ylmethanaminium 2,4-dichloro-5-sulfamoylbenzoate (1), and a mixed-ligand Zn(II) complex, bis(2,4-dichloro-5-sulfamoylbenzoate)(2-aminomethylpyridine)aquazinc(II) monohydrate (2), have been synthesized from the same free ligands, which are 2,4-dichloro-5-sulfamoylbenzoic acid (Hsba) and 2-aminomethylpyridine (amp). They have been characterized by elemental, spectral ((1)H NMR, IR and UV-vis.) and thermal analyses. Additionally, magnetic measurement and single crystal X-ray diffraction technique were applied to compound 2. In the complex, Zn(II) ion exhibits a distorted octahedral configuration coordinated by O1 and O1(i) atoms of two mono dentante sba anions and N1, N2, N2(i) atoms of bidentante amp anion and a water molecule (O1w). The free ligands Hsba and amp, and the products 1 and 2, and acetazolamide (AAZ) as the control compound, were also evaluated for their in vitro inhibitor effects on human Carbonic Anhydrase isoenzymes (hCA I and hCA II) purified from erythrocyte cell by affinity chromatography for their hydratase and esterase activities. The IC(50) values of products 1 and 2 for hydratase activity are 0.26 and 0.13microM for hCA I and 0.30 and 0.15microM for hCA II, respectively. The IC(50) values of the same inhibitors for esterase activity are 0.32 and 0.045microM for hCA I and 0.29 and 0.23microM for hCA II, respectively. In relation to esterase activities, the inhibition equilibrium constants (K(i)) were also determined and found 0.25 and 0.058microM on hCA I and 0.22 and 0.24microM on hCA II for 1 and 2, respectively. The comparison of the inhibition studies of newly synthesized compounds 1 and 2 to parent compounds Hsba and amp and to AAZ indicated that 1 and 2 have effective inhibitory activity on hCA I and II, and might be used potential inhibitors. PMID:20006931

  2. Evidence for Bicarbonate Secretion by Ameloblasts in a Novel Cellular Model.

    PubMed

    Bori, E; Guo, J; Rácz, R; Burghardt, B; Földes, A; Kerémi, B; Harada, H; Steward, M C; Den Besten, P; Bronckers, A L J J; Varga, G

    2016-05-01

    Formation and growth of hydroxyapatite crystals during amelogenesis generate a large number of protons that must be neutralized, presumably by HCO3 (-)ions transported from ameloblasts into the developing enamel matrix. Ameloblasts express a number of transporters and channels known to be involved in HCO3 (-)transport in other epithelia. However, to date, there is no functional evidence for HCO3 (-)transport in these cells. To address questions related to HCO3 (-)export from ameloblasts, we have developed a polarized 2-dimensional culture system for HAT-7 cells, a rat cell line of ameloblast origin. HAT-7 cells were seeded onto Transwell permeable filters. Transepithelial resistance was measured as a function of time, and the expression of transporters and tight junction proteins was investigated by conventional and quantitative reverse transcription polymerase chain reaction. Intracellular pH regulation and HCO3 (-)transport were assessed by microfluorometry. HAT-7 cells formed epithelial layers with measureable transepithelial resistance on Transwell permeable supports and expressed claudin-1, claudin-4, and claudin-8-key proteins for tight junction formation. Transport proteins previously described in maturation ameloblasts were also present in HAT-7 cells. Microfluorometry showed that the HAT-7 cells were polarized with a high apical membrane CO2 permeability and vigorous basolateral HCO3 (-)uptake, which was sensitive to Na(+)withdrawal, to the carbonic anhydrase inhibitor acetazolamide and to H2DIDS inhibition. Measurements of transepithelial HCO3 (-)transport showed a marked increase in response to Ca(2+)- and cAMP-mobilizing stimuli. Collectively, 2-dimensional HAT-7 cell cultures on permeable supports 1) form tight junctions, 2) express typical tight junction proteins and electrolyte transporters, 3) are functionally polarized, and 4) can accumulate HCO3 (-)ions from the basolateral side and secrete them at the apical membrane. These studies provide

  3. Transport of sodium across the isolated bovine rumen epithelium: interaction with short-chain fatty acids, chloride and bicarbonate.

    PubMed

    Sehested, J; Diernaes, L; Moller, P D; Skadhauge, E

    1996-01-01

    -1). There was no effect of the Cl(-)-HCO3- exchange inhibitor DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid; 0.5 mmol l-1) on sodium transport. HCO3- (13 mmol l-1) and CO2 (5%) themselves had only a small and non-significant stimulating effect on sodium fluxes, however, in the presence, but not the absence of HCO3- and CO2 in the experimental solutions acetazolamide (1 mmol l-1) significantly reduced active sodium transport. It is concluded that SCFAs could stimulate the active sodium and chloride transport as a result of their metabolism. The CO2 produced could stimulate apical Na(+)-H+ and Cl(-)-HCO3- exchangers running in parallel via increased H+ and HCO3- gradients.

  4. Intracellular pH and its regulation in isolated type I carotid body cells of the neonatal rat.

    PubMed Central

    Buckler, K J; Vaughan-Jones, R D; Peers, C; Nye, P C

    1991-01-01

    1. The dual-emission pH-sensitive fluoroprobe carboxy-SNARF-1 (carboxy-seminaptharhodofluor) was used to measure pHi in type I cells enzymically dispersed from the neonatal rat carotid body. 2. Steady-state pHi in cells bathed in a HEPES-buffered Tyrode solution (pH 7.4) was found to be remarkably alkaline (pHi = 7.77) whereas cells bathed in a CO2-HCO3(-)-buffered Tyrode solution (pH 7.4) had a more 'normal' pHi (pHi = 7.28). These observations were further substantiated by using an independent nullpoint test method to determine pHi. 3. Intracellular intrinsic buffering (beta, determined by acidifying the cell using an NH4Cl pre-pulse) was in the range 7-20 mM per pH unit and appeared to be dependent upon pHi with beta increasing as pHi decreased. 4. In cells bathed in a HEPES-buffered Tyrode solution, pHi recovery from an induced intracellular acid load (10 mM-NH4Cl pre-pulse) was inhibited by the Na(+)-H+ exchange inhibitor ethyl isopropyl amiloride (EIPA; 150 microM) or substitution of Nao+ with N-methyl-D-glucamine (NMG). Both EIPA and Nao+ removal also caused a rapid intracellular acidification, which in the case of Nao+ removal, was readily reversible. The rate of this acidification was similar for both Nao+ removal and EIPA addition. 5. Transferring cells from a HEPES-buffered Tyrode solution to one buffered with 5% CO2-HCO3- resulted in an intracellular acidification which was partially, or wholly, sustained. The rate of acidification upon transfer to CO2-HCO3- was considerably slowed by the membrane permeant carbonic anhydrase inhibitor, acetazolamide, thus indicating the presence of the enzyme in these cells. 6. In CO2-HCO3(-)-buffered Tyrode solution, pHi recovery from an intracellular acidosis (NH4+ pre-pulse) was only partially inhibited by EIPA or amiloride whereas Nao+ removal completely inhibited the recovery. The stilbene DIDS (4,4-diisothiocyanatostilbenedisulphonic acid, 200 microM) also partially inhibited pHi recovery following an induced

  5. Quantification of the response of rat medullary raphe neurones to independent changes in pH(o) and P(CO2).

    PubMed

    Wang, Wengang; Bradley, Stefania Risso; Richerson, George B

    2002-05-01

    and type IV (CA II and CA IV). However, CA immunoreactivity was also common in neurones of the hypoglossal motor nucleus, inferior olive, hippocampus and cerebellum, indicating that its presence is not uniquely associated with chemosensitive neurones. In addition, under the conditions used here, acetazolamide (100 microM) did not have a significant effect on the response to hypercapnic acidosis. We conclude that chemosensitivity of raphe neurones can occur independently of changes in pH(o), P(CO2) or bicarbonate. The results suggest that a change in intracellular pH (pH(i)) may be the primary stimulus for chemosensitivity in these putative central respiratory chemoreceptor neurones.

  6. Risk Assessment of Physiological Effects of Atmospheric Composition and Pressure in Constellation Vehicles

    NASA Technical Reports Server (NTRS)

    Scheuring, Richard A.; Conkin, Johnny; Jones, J. A.; Gernhardt, M.

    2007-01-01

    = 77 mmHg). So the following may be employed for operational risk reduction: 1) develop procedures to increase PB as needed in the CEV, and use a gradual or staged reduction in cabin pressure during lunar outbound; 2) train crews for symptoms of hypoxia, to allow early recognition and consider pre-adaptation of crews to a hypoxic environment prior to launch, 3) consider prophylactic acetazolamide for acute pressure changes and be prepared to treat any AMS associated symptoms early with both carbonic anhydrase inhibitors and supplemental oxygen.

  7. Role of cations, anions and carbonic anhydrase in fluid transport across rabbit corneal endothelium

    PubMed Central

    Fischbarg, J.; Lim, J. J.

    1974-01-01

    1. A small electrical potential difference (541 ± 48 μV, aqueous side negative) across rabbit corneal endothelium has been recently found. Its dependence on ambient [Na+], [K+], [H+] and metabolic and specific inhibitors was examined. 2. Changes in concentration of the ions above either were known or were presently shown to affect the rate of fluid transport across this preparation (normal value: 5·2 ± 0·4 μl./hr.cm2). Ionic concentration changes were also found here to influence potential difference in the same way as fluid transport. In the cases tested, the effects on both fluid transport and potential difference were reversible. 3. Fluid transport and potential difference were both decreased or abolished in absence of Na+, K+ and HCO3-, and when [H+] was decreased. Fluid transport and potential difference were saturable functions of [HCO3-] and half-saturation occurred in both cases at about 13 mM-HCO3-. The potential difference was also a saturable function of [Na+] (half-saturation around 15 mM). There was a pH optimum for potential difference in the range 7·4-7·6. Lower pH values decreases the potential difference and the fluid transport, and a small (-100 μV) reversed potential was observed in the range of 5·3-5·5. 4. Total replacement of Cl- by HCO3- or SO42- produced no impairment on either fluid transport or potential difference. 5. Carbonic anhydrase inhibitors (ethoxyzolamide 10-5 or 10-4 M and benzolamide 10-3 M) produced a 40-60% decrease in the rate of fluid pumping. In contrast, ethoxyzolamide 10-4 M or acetazolamide 10-3 M did not produce any change in the potential difference. NaCN and Na iodoacetate (both 2 mM) eliminated the potential difference in 1-1·5 hr while in controls it lasted for 5-6 hr. 6. Ouabain (10-5 M) abolished the potential difference in less than 10 sec when added to the aqueous side, which suggests the existence of an electrogenic pump. This extremely fast time transient can be accounted for by the accessibility

  8. Risk Assessment of Physiological Effects of Atmospheric Composition and Pressure in Constellation Vehicles

    NASA Technical Reports Server (NTRS)

    Scheuring, Richard A.; Conkin, Johnny; Jones, Jeffrey A.; Gernhardt, Michael L.

    2007-01-01

    environment. Conclusions: We feel that the slightly elevated risk of AMS with the recommended exploration atmospheric parameters is offset by the DCS risk reduction and improved operational efficiency offered by the hypobaric lunar surface vehicular pressure. We believe the risk of mild AMS is greater given a (P(sub A)O2) of 77 mmHg at 4,876 m altitude while breathing 32% O2 than at 1,828 m altitude while breathing 21% O2. Only susceptible astronauts would develop mild and transient AMS with prolonged exposure to 414 mmHg (4,876 m) while breathing 32% O2 (acute (P(sub A)O2) = 77 mmHg). So the following may be employed for operational risk reduction: 1) develop procedures to increase P(sub B) as needed in the CEV, and use a gradual or staged reduction in cabin pressure during lunar outbound; 2) train crews for symptoms of hypoxia, to allow early recognition and consider pre-adaptation of crews to a hypoxic environment prior to launch, 3) consider prophylactic acetazolamide for acute pressure changes and be prepared to treat any AMS associated symptoms early with both carbonic anhydrase inhibitors and supplemental oxygen.

  9. Quantification of the response of rat medullary raphe neurones to independent changes in pHo and PCO2

    PubMed Central

    Wang, Wengang; Bradley, Stefania Risso; Richerson, George B

    2002-01-01

    IV). However, CA immunoreactivity was also common in neurones of the hypoglossal motor nucleus, inferior olive, hippocampus and cerebellum, indicating that its presence is not uniquely associated with chemosensitive neurones. In addition, under the conditions used here, acetazolamide (100 μm) did not have a significant effect on the response to hypercapnic acidosis. We conclude that chemosensitivity of raphe neurones can occur independently of changes in pHo, PCO2 or bicarbonate. The results suggest that a change in intracellular pH (pHi) may be the primary stimulus for chemosensitivity in these putative central respiratory chemoreceptor neurones. PMID:11986382

  10. Improvement of signal-to-noise ratio using iterative reconstruction in a 99m Tc-ECD split-dose injection protocol.

    PubMed

    Yokoi, Takashi; Shinohara, Hiroyuki; Takaki, Akihiro

    2003-08-01

    Split-dose injection using technetium-99m ethyl cysteinate dimer ((99m)Tc-ECD) and consecutive SPET measurements performed before and after acetazolamide (ACZ) loading was used to estimate the cerebral perfusion reserve. The disadvantage of the split-dose method is that the signal-to-noise ratio (S/N) of ACZ-loaded images is decreased by subtraction of the 1st SPET data (rest) from the 2nd SPET data (ACZ loaded). To improve the S/N of reconstructed images, we implemented an iterative reconstruction algorithm including the term of remaining radioactivity in the brain from the 1st injection. It was expected that this method (the "addition method") would improve the S/N of rest and ACZ images compared with the conventional subtraction method owing to exclusion of the subtraction process. To evaluate the effect of statistical noise, we estimated the percentage coefficient of variation (%COV) as a function of total photon counts (from 1.35 to 86.5 Mcounts/slice) by Monte Carlo simulation with equal-volume split-dose injection. The %COV of the 2nd SPET study was higher than that of the 1st (e.g. 50.3% for the 1st and 80.5% for the 2nd at a total count of 2.70 Mcounts/slice) when using the conventional subtraction method. By contrast, the %COV of the 1st and 2nd SPET studies was almost equivalent (e.g. 43.1% for the 1st and 41.4% for the 2nd at a total count of 2.70 Mcounts/slice) when using the addition method. We also determined the optimal injection dose ratio of the 2nd to the 1st SPET study, which provides the equivalent %COV value between the 1st and 2nd images. With the subtraction method, the optimal injection dose ratio of the 2nd to the 1st SPET study was approximately 2.0, while with the addition method it was approximately 1.0. The absolute value of %COV at the optimal injection dose was about 54% and 43% with the subtraction method and the addition method, respectively. The addition method gave a lower %COV value than the subtraction method even at the

  11. Respiratory medicine at McMaster University, Hamilton, Ontario: 1968 to 2013

    PubMed Central

    Jones, Norman L; O’Byrne, Paul M

    2014-01-01

    disorders. EXERCISE CAPACITY: Norman Jones and Moran Campbell developed a system for noninvasive cardiopulmonary exercise testing using an incremental exercise test, and more complex studies with measurement of mixed venous PCO2 by rebreathing. The 6 min walk test was validated by Gordon Guyatt. Kieran Killian and Norman Jones introduced routine muscle strength measurements in clinical testing and symptom assessment in exercise testing. Muscle strength training improved exercise capacity in older subjects and patients with chronic obstructive pulmonary disease. METABOLISM AND ACID-BASE CONTROL IN EXERCISE: After showing that imposed acidosis reduced, and alkalosis improved performance, Norman Jones, John Sutton and George Heigenhauser investigated the interactions between acid-base status and metabolism in exercise. HIGH-ALTITUDE MEDICINE: John Sutton and Peter Powles participated in high-altitude research on Mount Logan (Yukon), demonstrating sleep hypoxemia in acute mountain sickness and its reversal by acetazol-amide, and participated in Operation Everest II. EPIDEMIOLOGY: David Pengelly and Tony Kerrigan followed children living in areas with differing air quality to show that lung development was adversely affected by pollution and maternal smoking. Malcolm Sears and Neil Johnstone showed that the ‘return to school’ asthma exacerbation epidemic was due mainly to rhinoviruses. David Muir investigated the effects of silica exposure in hard-rock miners, and mortality in the nickel industry. SUMMARY: The Respirology Division has grown to more than 50 physicians and PhD scientists, and currently provides the busiest outpatient clinic in Hamilton, and has successful training and research programs.