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Sample records for acetazolamide methazolamide ethoxzolamide

  1. The noncarbonic anhydrase inhibiting acetazolamide analog N-methylacetazolamide reduces the hypercapnic, but not hypoxic, ventilatory response

    PubMed Central

    Teppema, Luc J; Swenson, Erik R

    2015-01-01

    Previous studies have shown that the carbonic anhydrase (CA) inhibitors acetazolamide (AZ) and methazolamide (MZ) have inhibiting actions on breathing. Classically these have been attributed to CA inhibition, but other effects unrelated to CA inhibition have been identified in other tissues. To explore this possibility in the control of ventilation by the central nervous system, we investigated whether an AZ-analog without CA inhibiting properties, by virtue of a single methylation on the sulfonamide moiety, N-methylacetazolamide (NMA), would still display similar actions to acetazolamide and methazolamide. NMA (20 mg kg−1) was given intravenously to anesthetized cats and we measured the responses to steady-state isocapnic hypoxia and stepwise changes in end-tidal pco2 before and after infusion of this AZ analog using the technique of end-tidal forcing. NMA caused a large decrease in the apneic threshold and CO2 sensitivity very similar to those previously observed with AZ and MZ, suggesting that these effects are mediated independently of CA inhibition. In contrast to acetazolamide, but similar to methazolamide, NMA did not affect the steady-state isocapnic hypoxic response. In conclusion, our data reveal complex effects of sulfonamides with very similar structure to AZ that reveal both CA-dependent and CA-independent effects, which need to be considered when using AZ as a probe for the role of CA in the control of ventilation. PMID:26290531

  2. 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. PMID:26680684

  3. The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence

    PubMed Central

    Johnson, Benjamin K.; Colvin, Christopher J.; Needle, David B.; Mba Medie, Felix; Champion, Patricia A. DiGiuseppe

    2015-01-01

    Mycobacterium tuberculosis must sense and adapt to host environmental cues to establish and maintain an infection. The two-component regulatory system PhoPR plays a central role in sensing and responding to acidic pH within the macrophage and is required for M. tuberculosis intracellular replication and growth in vivo. Therefore, the isolation of compounds that inhibit PhoPR-dependent adaptation may identify new antivirulence therapies to treat tuberculosis. Here, we report that the carbonic anhydrase inhibitor ethoxzolamide inhibits the PhoPR regulon and reduces pathogen virulence. We show that treatment of M. tuberculosis with ethoxzolamide recapitulates phoPR mutant phenotypes, including downregulation of the core PhoPR regulon, altered accumulation of virulence-associated lipids, and inhibition of Esx-1 protein secretion. Quantitative single-cell imaging of a PhoPR-dependent fluorescent reporter strain demonstrates that ethoxzolamide inhibits PhoPR-regulated genes in infected macrophages and mouse lungs. Moreover, ethoxzolamide reduces M. tuberculosis growth in both macrophages and infected mice. Ethoxzolamide inhibits M. tuberculosis carbonic anhydrase activity, supporting a previously unrecognized link between carbonic anhydrase activity and PhoPR signaling. We propose that ethoxzolamide may be pursued as a new class of antivirulence therapy that functions by modulating expression of the PhoPR regulon and Esx-1-dependent virulence. PMID:25987613

  4. The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence.

    PubMed

    Johnson, Benjamin K; Colvin, Christopher J; Needle, David B; Mba Medie, Felix; Champion, Patricia A DiGiuseppe; Abramovitch, Robert B

    2015-08-01

    Mycobacterium tuberculosis must sense and adapt to host environmental cues to establish and maintain an infection. The two-component regulatory system PhoPR plays a central role in sensing and responding to acidic pH within the macrophage and is required for M. tuberculosis intracellular replication and growth in vivo. Therefore, the isolation of compounds that inhibit PhoPR-dependent adaptation may identify new antivirulence therapies to treat tuberculosis. Here, we report that the carbonic anhydrase inhibitor ethoxzolamide inhibits the PhoPR regulon and reduces pathogen virulence. We show that treatment of M. tuberculosis with ethoxzolamide recapitulates phoPR mutant phenotypes, including downregulation of the core PhoPR regulon, altered accumulation of virulence-associated lipids, and inhibition of Esx-1 protein secretion. Quantitative single-cell imaging of a PhoPR-dependent fluorescent reporter strain demonstrates that ethoxzolamide inhibits PhoPR-regulated genes in infected macrophages and mouse lungs. Moreover, ethoxzolamide reduces M. tuberculosis growth in both macrophages and infected mice. Ethoxzolamide inhibits M. tuberculosis carbonic anhydrase activity, supporting a previously unrecognized link between carbonic anhydrase activity and PhoPR signaling. We propose that ethoxzolamide may be pursued as a new class of antivirulence therapy that functions by modulating expression of the PhoPR regulon and Esx-1-dependent virulence. PMID:25987613

  5. Acetazolamide attenuates chemical-stimulated but not thermal-stimulated acute pain in mice

    PubMed Central

    Sun, Ya-jie; Chen, Ying; Pang, Chong; Wu, Ning; Li, Jin

    2014-01-01

    Aim: Acetazolamide (AZA), a carbonic anhydrase (CA) inhibitor, has been found to alleviate inflammatory and neuropathic pain in rats. In the present study, we investigated the effects of AZA on thermal- and chemical-stimulated acute pain in mice and the possible mechanisms underlying the effects. Methods: Five acute pain models based on thermal and chemical stimuli were established to investigate the effects of AZA on different types of nociception in mice. The antinociceptive effects of methazolamide (another CA inhibitor) and diazepam (a positive allosteric modulator of GABAA receptor) were also examined. The drugs were administered either intraperitoneally (ip) or intrathecally. Results: AZA (50–200 mg/kg, ip) did not produce analgesia in two thermal-stimulated acute pain models, ie, mouse tail-flick and hot-plate tests. In contrast, AZA (50–200 mg/kg, ip) dose-dependently reduced paw licking time in both capsaicin and formalin tests in mice. A similar result was observed in a mouse acetic acid-induced writhing test. However, AZA (10 nmol/mouse, intrathecally) did not produce significant analgesia in the 3 chemical-stimulated acute pain models. In addition, methazolamide (50–200 mg/kg, ip) and diazepam (0.25–1.0 mg/kg, ip) did not produce significant analgesia in either thermal- or chemical-stimulated acute pain. Conclusion: AZA produces analgesia in chemical-stimulated, but not thermal-stimulated acute pain in mice. The attenuation of chemical-stimulated acute pain by AZA may not be due to enhancement of GABAA receptor-mediated inhibition via inhibiting CA activity but rather a peripheral ion channel-related mechanism. PMID:24335844

  6. 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 §...

  7. 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... 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. Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs

    PubMed Central

    Francis, Roland C.; Höhne, Claudia; Neubert, Friederike; Telalbasic, Stella; Boemke, Willehad; Swenson, Erik R.

    2014-01-01

    Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg·kg−1·h−1); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg·kg−1·h−1); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg·kg−1·h−1). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn·s·cm−5 with hypoxia (P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn·s·cm−5 during hypoxia. With MTZ and NMA, the MPAP rise (4 ± 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 ± 77 and 68 ± 82 dyn·s·cm−5 with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV. PMID:24481964

  9. 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

  10. Poly-(cyclo)dextrins as ethoxzolamide carriers in ophthalmic solutions and in contact lenses.

    PubMed

    García-Fernández, M J; Tabary, N; Martel, B; Cazaux, F; Oliva, A; Taboada, P; Concheiro, A; Alvarez-Lorenzo, C

    2013-11-01

    Efficient ophthalmic therapy requires the development of strategies that can provide sufficiently high drug levels in the ocular structures for a prolonged time. This work focuses on the suitability of poly-(cyclo)dextrins as carriers able to solubilize the carbonic anhydrase inhibitor (CAI) ethoxzolamide (ETOX), which is so far used for oral treatment of glaucoma. Topical ocular treatment should notably enhance the efficiency/safety profile of the drug. Natural α-, β- and γ-cyclodextrins and a maltodextrin were separately polymerized using citric acid as cross-linker agent under mild conditions. The resultant hydrophilic polymers exhibited larger capability to solubilize ETOX than the pristine (cyclo)dextrins. Moreover, they provided sustained drug diffusion in artificial lachrymal fluid. Interestingly the poly-(cyclo)dextrins solutions facilitate the loading of remarkably high doses of ETOX in poly(2-hydroxyethyl methacrylate)-based contact lenses. Exploiting ionic interactions between functional groups in the contact lenses and remnant free carboxylic acids in the citric acid linkers of poly-(cyclo)dextrins led to the retention of the drug-loaded poly-(cyclo)dextrins and, in turn, to sustained release for several weeks. PMID:24053812

  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. 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 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...

  13. 21 CFR 522.44 - Sterile sodium acetazolamide.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 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...

  14. 21 CFR 522.44 - Sterile sodium acetazolamide.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 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...

  15. 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 (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.28 Acetazolamide sodium soluble powder. (a)...

  16. 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 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...

  17. 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...

  18. 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

  19. 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

  20. 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. PMID:26574046

  1. 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). PMID:24611687

  2. Design of cationic nanostructured heterolipid matrices for ocular delivery of methazolamide

    PubMed Central

    Youshia, John; Kamel, Amany O; El Shamy, Abdelhameed; Mansour, Samar

    2012-01-01

    Solid lipid nanoparticles (SLNs) formulated from one type of lipid (homolipid) suffer from low drug encapsulation and drug bursting due to crystallization of the lipid into the more ordered β modification, which leads to decreased drug entrapment and faster drug release. This study assessed the feasibility of using nanostructured lipid matrices (NLMs) for ocular delivery of methazolamide-(MZA) adopting heterolipids composed of novel mixtures of Compritol ® and cetostearyl alcohol (CSA), and stabilized by Tween 80®. The systems were prepared using the modified high shear homogenization followed by ultrasonication method, which avoids the use of organic solvents. A 32 full factorial design was constructed to study the influence of two independent variables, namely the ratio of CSA:Compritol and the concentration of Tween 80, each in three levels. The dependent variables were the entrapment efficiency percentages (EE%), mean particle size (PS), polydispersity index (PDI), and zeta potential (ZP). In vivo intraocular pressure (IOP) lowering activity for the selected formulae was compared to that of MZA solution. The results showed that increasing the ratio of CSA to Compritol increased the EE% and PS, while increasing the concentration of Tween 80, decreased PS with no significant effect on EE%. The ZP values of all formulae were positive, and greater than 30 mV. The best formula, composed of 4% CSA, 2% Compritol, 0.15% stearylamine, and 2% Tween 80, with EE% of 25.62%, PS of 207.1 nm, PDI of 0.243, and ZP of 41.50 mV, showed in vitro sustained release properties for 8 hours and lowered the intraocular pressure by 8.3 mmHg within 3 hours, with this drop in pressure lasting for 12 hours. PMID:22679362

  3. DNA cloning, characterization, and inhibition studies of an α-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.

    PubMed

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

    2012-12-13

    We have cloned, purified, and characterized an α-carbonic anhydrase (CA, EC 4.2.1.1) from the human pathogenic bacterium Vibrio cholerae, VchCA. The new enzyme has significant catalytic activity, and an inhibition study with sulfonamides and sulfamates led to the detection of a large number of low nanomolar inhibitors, among which are methazolamide, acetazolamide, ethoxzolamide, dorzolamide, brinzolamide, benzolamide, and indisulam (KI values in the range 0.69-8.1 nM). As bicarbonate is a virulence factor of this bacterium and since ethoxzolamide was shown to inhibit the in vivo virulence, we propose that VchCA may be a target for antibiotic development, exploiting a mechanism of action rarely considered until now. PMID:23181552

  4. Genetic diagnosis and acetazolamide treatment of familial hemiplegic migraine.

    PubMed

    Omata, Taku; Takanashi, Jun-ichi; Wada, Takahito; Arai, Hidee; Tanabe, Yuzo

    2011-04-01

    A female patient presented with horizontal gaze nystagmus, mild cerebellar ataxia, recurrent headache and hemiplegia since childhood with cerebellar atrophy on magnetic resonance imaging. Genetic analysis revealed a CACNA1A gene mutation, leading to a diagnosis of familial hemiplegic migraine (FHM1). FHM is very rare, but should be considered as a differential diagnosis for childhood cerebellar symptoms and/or cerebellar atrophy. To avoid missing FHM1, a detailed clinical history including headache or hemiplegia is essential. Oral acetazolamide during the aura phase, comprising mild headache and abnormal leg sensation, relieved these symptoms in this patient, suggesting that acetazolamide could represent a first line of treatment. PMID:20542393

  5. 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.

  6. Effects of acetazolamide in patients with the sleep apnoea syndrome.

    PubMed

    Tojima, H; Kunitomo, F; Kimura, H; Tatsumi, K; Kuriyama, T; Honda, Y

    1988-02-01

    There is as yet no convincing evidence that acetazolamide, a carbonic anhydrase inhibitor, is effective in obstructive sleep apnoea. A study was therefore designed to examine the effect of acetazolamide (250 mg/day) on sleep events and ventilatory control during wakefulness in nine patients with the sleep apnoea syndrome. In eight of the nine patients the apnoea index and the total duration of apnoea were reduced by acetazolamide, and the mean (SEM) apnoea index of all patients changed from 25.0 (6.7) to 18.1 (5.8) episodes an hour. Furthermore, the total time of arterial oxygen desaturation (SaO2)--more than 4% depression in SaO2 from the baseline sleeping level--divided by total sleep time was also significantly decreased and its mean (SEM) value improved from 24.1 (7.9) to 13.6 (4.8)% of total sleep time. Five of the seven patients with varying degrees of daytime hypersomnolence had their symptoms obviously improved. There was no patient whose predominant type of apnoea was converted from the obstructive to the central type, or vice versa. In the studies of wakefulness, metabolic acidosis, an increase of arterial oxygen tension (PaO2) and a decrease of arterial carbon dioxide tension (PaCO2) were observed. The slopes of the occlusion pressure response and the ventilatory response to carbon dioxide increased, and the carbon dioxide ventilatory response line shifted to the left. It is suggested that acetazolamide cannot remove apnoea completely but has a beneficial effect in mild cases of obstructive sleep apnoea through an augmentation of central (CO2, H+) drive and a stabilising effect on ventilatory control. PMID:3127912

  7. Population Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients

    PubMed Central

    Heming, Nicholas; Urien, Saïk; Fulda, Virginie; Meziani, Ferhat; Gacouin, Arnaud; Clavel, Marc; Planquette, Benjamin; Faisy, Christophe

    2014-01-01

    Background Chronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis. Methods 619 time-respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time-PaCO2 observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug. Results The effect of acetazolamide on minute ventilation and PaCO2 levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO2 levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation (P<.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min−1 in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day. Conclusions Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide. PMID:24466018

  8. 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. PMID:26850377

  9. Effect of acetazolamide on respiratory muscle fatigue in humans.

    PubMed

    Gonzales, Joaquin U; Scheuermann, Barry W

    2013-01-15

    Previous studies have demonstrated that carbonic anhydrase inhibition with acetazolamide reduces exercise capacity. The mechanism responsible for this early fatigue is unclear, but may be partly mediated by impaired respiratory muscle function. Inspiratory muscle strength and endurance were assessed in seven healthy men (age 28 ± 5 yrs, ±SD) by measuring maximal inspiratory pressure (MIP) and time to task failure during a constant-load breathing test (CLBT), respectively, under control (CON) and acetazolamide (ACZ; 500 mg/8 h po for 3 days) conditions that were separated by two weeks and randomized between subjects. In addition, MIP was measured before and after moderate-intensity cycling exercise to fatigue while pulmonary gas exchange, plasma pH, and ventilation were measured during exercise. ACZ did not alter pulmonary function (FVC, FEV1, MVV) or MIP measured at rest (CON, -157 ± 47 vs. ACZ, -154 ± 45 cmH(2)O, p>0.05), but decreased time to task failure during the CLBT (CON, 1340 ± 820 vs. ACZ, 698 ± 434 s; p=0.01). Exercise duration during cycling exercise was reduced (p=0.003) with ACZ (1090 ± 254 s) compared to CON (1944 ± 532 s) in the presence of a significantly lower plasma pH and higher ventilation compared to control (p<0.05). Compared to resting values, MIP was reduced (p=0.03) in ACZ but not CON at exhaustion. In conclusion, carbonic anhydrase inhibition with ACZ is associated with impaired respiratory muscle function at rest and following constant load cycling which may contribute to reduced exercise tolerance with carbonic anhydrase inhibition. PMID:23017330

  10. The extremo-α-carbonic anhydrase from the thermophilic bacterium Sulfurihydrogenibium azorense is highly inhibited by sulfonamides.

    PubMed

    Vullo, Daniela; De Luca, Viviana; Scozzafava, Andrea; Carginale, Vincenzo; Rossi, Mosè; Supuran, Claudiu T; Capasso, Clemente

    2013-08-01

    The α-carbonic anhydrase (CA, EC 4.2.1.1) from the newly discovered extremophilic bacterium Sulfurihydrogenibium azorense (SazCA) is the most effective CA known to date. Here we investigated the inhibition profile of this enzyme with a series of aromatic and heterocyclic sulfonamides, and one sulfamate. Many clinically used sulfonamides, such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, celecoxib and sulpiride were low nanomolar/subnanomolar SazCA inhibitors (KIs in the range of 0.9-10.8 nM) whereas simple aromatic derivatives were less effective as SazCA inhibitors. The inhibition profile of SazCA is slightly different from that of the related enzyme from S. yellostonense (SspCA), investigated earlier by our groups. PMID:23777827

  11. Heterocyclic compounds as carbonic anhydrase inhibitor.

    PubMed

    Husain, Asif; Madhesia, Diwakar

    2012-12-01

    The carbonic anhydrases (CAs, EC 4.2.1.1) constitute interesting targets for the design of pharmacological agents useful in the treatment or prevention of a variety of disorders such as, glaucoma, acid-base disequilibria, epilepsy, and other neuromuscular diseases, altitude sickness, edema, and obesity. A quite new and unexpected application of the CA inhibitors (CAIs) is with regard to their potential use in the management (imaging and treatment) of hypoxic tumors. A series of sulfonamides, including some clinically used derivatives like 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 drug topiramate have been reported to inhibit various human carbonic anhydrase isozyme. Various heterocyclic sulfonamides have been reported in this review with their potency to inhibit different carbonic anhydrases isozymes. PMID:21981003

  12. Carbonic Anhydrase Inhibitors. Part 91. Metal Complexes of Heterocyclic Sulfonamides as Potential Pharmacological Agents in the Treatment of Gastric Acid Secretion Imbalances

    PubMed Central

    Ilies, Marc A.; Scozzafava, Andrea

    2000-01-01

    Zinc, magnesium, aluminum and copper complexes of several potent, clinically used carbonic anhydrase (CA) sulfonamide inhibitors, such as acetazolamide, methazolamide, ethoxzolamide and benzolamide were tested for their possible applications as antacids, in experimental animals. Gastric acid secretion parameters 3 days after treatment with these CA inhibitors (2 × 500 mg, twice a day), in dogs with chronic gastric fistulas, led to the observation that the gastric acid parameters BAO (the basal acid output), and MAO (the maximal acid output after stimulation with histamine) were drastically reduced, as compared to the same parameters in animals that did not receive these enzyme inhibitors. These are promising results for the possible use of metal complexes of heterocyclic sulfonamides as treatment alternatives (alone or in combination with other drugs) for gastric acid secretion imbalances. PMID:18475926

  13. Effect of Acetazolamide on Obesity-Induced Glomerular Hyperfiltration: A Randomized Controlled Trial

    PubMed Central

    Erman, Arie; Bar Sheshet Itach, Sarit; Ori, Yaacov; Rozen-Zvi, Benaya; Gafter, Uzi; Chagnac, Avry

    2015-01-01

    Aims Obesity is an important risk factor for the development of chronic kidney disease. One of the major factors involved in the pathogenesis of obesity-associated kidney disease is glomerular hyperfiltration. Increasing salt-delivery to the macula densa is expected to decrease glomerular filtration rate (GFR) by activating tubuloglomerular feedback. Acetazolamide, a carbonic anhydrase inhibitor which inhibits salt reabsorption in the proximal tubule, increases distal salt delivery. Its effects on obesity-related glomerular hyperfiltration have not previously been studied. The aim of this investigation was to evaluate whether administration of acetazolamide to obese non diabetic subjects reduces glomerular hyperfiltration. Materials and Methods The study was performed using a randomized double-blind crossover design. Obese non-diabetic men with glomerular hyperfiltration were randomized to receive intravenously either acetazolamide or furosemide at equipotent doses. Twelve subjects received the allocated medications. Two weeks later, the same subjects received the drug which they had not received during the first study. Inulin clearance, p-aminohippuric acid clearance and fractional lithium excretion were measured before and after medications administration. The primary end point was a decrease in GFR, measured as inulin clearance. Results GFR decreased by 21% following acetazolamide and did not decrease following furosemide. Renal vascular resistance increased by 12% following acetazolamide, while it remained unchanged following furosemide administration. Natriuresis increased similarly following acetazolamide and furosemide administration. Sodium balance was similar in both groups. Conclusions Intravenous acetazolamide decreased GFR in obese non-diabetic men with glomerular hyperfiltration. Furosemide, administered at equipotent dose, did not affect GFR, suggesting that acetazolamide reduced glomerular hyperfiltration by activating tubuloglomerular feedback

  14. Acetazolamide during acute hypoxia improves tissue oxygenation in the human brain.

    PubMed

    Wang, Kang; Smith, Zachary M; Buxton, Richard B; Swenson, Erik R; Dubowitz, David J

    2015-12-15

    Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2 ) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2 ) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2 , or PtiO2 . During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml(-1)·min(-1) (hypoxia), P < 0.05] and CMRO2 [1.54 (0.19) to 1.79 (0.25) μmol·ml(-1)·min(-1), P < 0.05] and a dramatic decline in PtiO2 [25.0 to 11.4 (2.7) mmHg, P < 0.05]. Acetazolamide prophylaxis mitigated these rises in CBF [53.7 (20.7) ml·100 ml(-1)·min(-1) (hypoxia + acetazolamide)] and CMRO2 [1.41 (0.09) μmol·ml(-1)·min(-1) (hypoxia + acetazolamide)] associated with acute hypoxia but also reduced O2 delivery [6.92 (1.45) (hypoxia) to 5.60 (1.14) mmol/min (hypoxia + acetazolamide), P < 0.05]. The net effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P < 0.05]. In addition to its renal effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia. PMID:26472861

  15. 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. PMID:26230617

  16. Electrosprayed 4-carboxybenzenesulfonamide-chitosan microspheres for acetazolamide delivery.

    PubMed

    Suvannasara, Phruetchika; Siralertmukul, Krisana; Muangsin, Nongnuj

    2014-03-01

    4-Carboxybenzensulfonamide-chitosan (4-CBS-chitosan) microspheres were prepared by electrospraying with acetazolamide (ACZ) as a model drug. The obtained 4-CBS-chitosan microspheres with or without ACZ-loading were characterized by Fourier transform infrared spectroscopy, differential scanning colorimetry, scanning electron microscopy and particle size analyses. The crystalline form and the stability of ACZ in a basic solution was determined using X-ray single crystal analysis. 4-CBS-chitosan had 90% encapsulation efficiency for ACZ compared to 47% of encapsulation efficiency (EE) obtained from native chitosan, forming 3.1 μm diameter microspheres with a low polydispersity index (0.4). After an initial burst release (58% in 5 min), ACZ-loaded 4-CBS-chitosan gave a sustained release of ACZ (∼ 100% over 3h) in simulated gastric fluid (0.1N HCl; pH 1.2), which was better than that seen for the release from ACZ-loaded chitosan (44% over 1.5h). Thus, 4-CBS-chitosan microspheres are a possible drug carrier in acidic conditions, such as at the gastric mucosal wall. PMID:24360896

  17. 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.

  18. 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

  19. 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.

  20. Impact of Acetazolamide and CPAP on Cortical Activity in Obstructive Sleep Apnea Patients

    PubMed Central

    Stadelmann, Katrin; Latshang, Tsogyal D.; Nussbaumer-Ochsner, Yvonne; Tarokh, Leila; Ulrich, Silvia; Kohler, Malcolm; Bloch, Konrad E.; Achermann, Peter

    2014-01-01

    Study Objectives 1) To investigate the impact of acetazolamide, a drug commonly prescribed for altitude sickness, on cortical oscillations in patients with obstructive sleep apnea syndrome (OSAS). 2) To examine alterations in the sleep EEG after short-term discontinuation of continuous positive airway pressure (CPAP) therapy. Design Data from two double-blind, placebo-controlled randomized cross-over design studies were analyzed. Setting Polysomnographic recordings in sleep laboratory at 490 m and at moderate altitudes in the Swiss Alps: 1630 or 1860 m and 2590 m. Patients Study 1: 39 OSAS patients. Study 2: 41 OSAS patients. Interventions Study 1: OSAS patients withdrawn from treatment with CPAP. Study 2: OSAS patients treated with autoCPAP. Treatment with acetazolamide (500–750 mg) or placebo at moderate altitudes. Measurements and Results An evening dose of 500 mg acetazolamide reduced slow-wave activity (SWA; approximately 10%) and increased spindle activity (approximately 10%) during non-REM sleep. In addition, alpha activity during wake after lights out was increased. An evening dose of 250 mg did not affect these cortical oscillations. Discontinuation of CPAP therapy revealed a reduction in SWA (5–10%) and increase in beta activity (approximately 25%). Conclusions The higher evening dose of 500 mg acetazolamide showed the “spectral fingerprint” of Benzodiazepines, while 250 mg acetazolamide had no impact on cortical oscillations. However, both doses had beneficial effects on oxygen saturation and sleep quality. PMID:24710341

  1. 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.

  2. 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

  3. 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

  4. 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

  5. Acetazolamide pre-treatment before ascending to high altitudes: when to start?

    PubMed

    Burtscher, Martin; Gatterer, Hannes; Faulhaber, Martin; Burtscher, Johannes

    2014-01-01

    Hypoxia is the main responsible factor initiating the symptoms of acute mountain sickness (AMS) in susceptible individuals. Measures that improve oxygenation and/or hasten acclimatization like pre-treatment with acetazolamide will prevent the development of AMS. We hypothesized that pre-treatment with acetazolamide the day before arrival at high altitude would elicit improved oxygenation compared to placebo not until the second day of high-altitude exposure. Fifteen study participants were randomly assigned in a double blind fashion to receive placebo or acetazolamide (2 × 125 mg) before (10 hours and 1 hour) exposure to high altitude (Monte Rosa plateau, 3480 m). Beside AMS scoring, heart rate, minute ventilation, and blood gas analyses were performed during rest and submaximal exercise at low altitude and on day 1, 2 and 3 at high altitude. From low altitude to day 1 at high altitude changes of pH (7.41 ± 0.01 vs. 7.48 ± 0.04) and HCO3 (24.0 ± 0.46 vs. 24.6 ± 2.6 mmol/L) within the placebo group differed significantly from those within the acetazolamide group (7.41 ± 0.01 vs. 7.41 ± 0.02; 23.6 ± 0.38 vs. 20.7 ± 1.8 mmol/L) (P < 0.05). AMS incidence tended to be lower with acetazolamide (P < 0.1). From low altitude to day 2 at high altitude changes of paO2 within the placebo group (75.3 ± 5.4 vs. 40.5 ± 3.4 mmHg) differed significantly from those within the acetazolamide group (76.5 ± 4.5 vs. 48.2 ± 4.9 mmHg) (P < 0.05). In conclusion, pre-treatment with low-dose acetazolamide on the day before ascending to high altitude tended to reduce AMS incidence on the first day at high altitude but improved oxygen availability to tissues not until the second day of exposure. Therefore, it is suggested that the beginning of pre-treatment with low-dose acetazolamide at least two days before arrival at high altitude, in contrast to usual recommendations, would be of greater beneficial effect on AMS development. PMID:25550957

  6. Acute pulmonary oedema due to single dose acetazolamide taken after cataract surgery.

    PubMed

    Guven Yilmaz, Suzan; Palamar, Melis; Gurgun, Cemil

    2016-01-01

    An increase in intraocular pressure following cataract surgery is very common. The main reason for this condition is viscoelastic agent remaining in the eye, which leads to mechanical obstruction of the trabecular meshwork. Prophylaxis with oral acetazolamide is frequently practised to prevent this early rise in intraocular pressure in the preoperative and postoperative periods. We report a case of an 81-year-old man with acute pulmonary oedema due to prophylactic acetazolamide intake after cataract surgery. The case is presented in order to draw attention to this serious complication. PMID:27170607

  7. Amelioration of acute mountain sickness: Comparative study of acetazolamide and spironolactone

    NASA Astrophysics Data System (ADS)

    Jain, S. C.; Singh, M. V.; Sharma, V. M.; Rawal, S. B.; Tyagi, A. K.

    1986-12-01

    Acetazolamide and spironolactone were evaluated for their ameliorating effects on acute mountain sickness (AMS). Studies were conducted in 29 healthy male subjects in lowland and at a height of 3,500 m after their airlift. A modified General High Altitude Questionnaire (GHAQ) was used to evaluate the effectiveness of these drugs for reducing the intensity of AMS symptoms. Both the drugs were found to be helpful in minimising the occurrence as well as severity of most of the symptoms. Spironolactone seems to be a superior prophylactic agent than acetazolamide.

  8. 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

  9. SPECT study of cerebral blood flow reactivity after acetazolamide in patients with transient ischemic attacks

    SciTech Connect

    Chollet, F.; Celsis, P.; Clanet, M.; Guiraud-Chaumeil, B.; Rascol, A.; Marc-Vergnes, J.P.

    1989-04-01

    We investigated 15 patients with one or more transient ischemic attacks (TIAs) in the internal carotid artery territory within the month following the most recent TIA. Cerebral blood flow (CBF) was measured by single-photon emission computed tomography, using intravenous xenon-133 before and after injection of 1 g acetazolamide. Six patients had severe carotid stenosis or occlusion; the other nine patients had no significant carotid lesions. Twenty age-matched volunteers free of neurologic symptoms or history were used as controls. Mean CBF in the sylvian region was not significantly different between patients and controls. Seven patients exhibited a focal hypoperfusion at rest in the symptomatic hemisphere, and their hypoperfused areas were hyporeactive after administration of acetazolamide. Seven other patients exhibited hyporeactive areas after acetazolamide administration while their CBF tomograms at rest were normal. Thus, CBF abnormalities were detected in 14 of the 15 patients. Our findings suggest that CBF measured early after acetazolamide administration could be useful to confirm the clinical diagnosis of TIA. In the nine patients with no significant lesion of the internal carotid artery, the areas of hypoperfusion were small and were probably related to the focal ischemic event. In the six patients with severe lesions of the internal carotid artery, abnormalities were of variable size and intensity but were often large and pronounced. The discrepancy between these two subgroups of patients could be ascribed to the hemodynamic influence of the internal carotid artery lesions. Moreover, our findings may provide some insight into the pathophysiology of TIAs.

  10. 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.

  11. 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

  12. 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

  13. Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier.

    PubMed Central

    Ellsworth, A. J.; Meyer, E. F.; Larson, E. B.

    1991-01-01

    Eighteen climbers actively ascended Mount Rainier (elevation 4,392 m) twice during a randomized, double-blind, concurrent, placebo-controlled, crossover trial comparing the use of acetazolamide, 250 mg, dexamethasone, 4 mg, and placebo every 8 hours as prophylaxis for acute mountain sickness. Each subject was randomly assigned to receive placebo during one ascent and one of the active medications during the other ascent. Assessment of acute mountain sickness was performed using the Environmental Symptoms Questionnaire and a clinical interview. At the summit or high point attained above base camp, the use of dexamethasone significantly reduced the incidence of acute mountain sickness and the severity of symptoms. Cerebral and respiratory symptom severity scores for subjects receiving dexamethasone (0.26 +/- 0.16 and 0.20 +/- 0.19, respectively) were significantly lower than similar scores for both acetazolamide (0.80 +/- 0.80 and 1.20 +/- 1.05; P = 0.25) and placebo (1.11 +/- 1.02 and 1.45 +/- 1.27; P = .025). Neither the use of dexamethasone nor that of acetazolamide measurably affected other physical or mental aspects. Compared with placebo, dexamethasone appears to be effective for prophylaxis of symptoms associated with acute mountain sickness accompanying rapid ascent. The precise role of dexamethasone for the prophylaxis of acute mountain sickness is not known, but it can be considered for persons without contraindications who are intolerant of acetazolamide, for whom acetazolamide is ineffective, or who must make forced, rapid ascent to high altitude for a short period of time with a guaranteed retreat route. PMID:2028586

  14. Sulfonamide inhibition studies of the β-carbonic anhydrase from the newly discovered bacterium Enterobacter sp. B13.

    PubMed

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

    2016-04-01

    The genome of the newly identified bacterium Enterobacter sp. B13 encodes for a β-class carbonic anhydrases (CAs, EC 4.2.1.1), EspCA. This enzyme was recently cloned, and characterized kinetically by this group (J. Enzyme Inhib. Med. Chem. 2016, 31). Here we report an inhibition study with sulfonamides and sulfamates of this enzyme. The best EspCA inhibitors were some sulfanylated sulfonamides with elongated molecules, metanilamide, 4-aminoalkyl-benzenesulfonamides, acetazolamide, and deacetylated methazolamide (KIs in the range of 58.7-96.5nM). Clinically used agents such as methazolamide, ethoxzolamide, dorzolamide, brinzolamide, benzolamide, zonisamide, sulthiame, sulpiride, topiramate and valdecoxib were slightly less effective inhibitors (KIs in the range of 103-138nM). Saccharin, celecoxib, dichlorophenamide and many simple benzenesulfonamides were even less effective as EspCA inhibitors, with KIs in the range of 384-938nM. Identification of effective inhibitors of this bacterial enzyme may lead to pharmacological tools useful for understanding the physiological role(s) of the β-class CAs in bacterial pathogenicity/virulence. PMID:26920803

  15. 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. PMID:25045926

  16. The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain.

    PubMed

    Fossati, Silvia; Giannoni, Patrizia; Solesio, Maria E; Cocklin, Sarah L; Cabrera, Erwin; Ghiso, Jorge; Rostagno, Agueda

    2016-02-01

    Mitochondrial dysfunction has been recognized as an early event in Alzheimer's disease (AD) pathology, preceding and inducing neurodegeneration and memory loss. The presence of cytochrome c (CytC) released from the mitochondria into the cytoplasm is often detected after acute or chronic neurodegenerative insults, including AD. The carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) was identified among a library of drugs as an inhibitor of CytC release and proved to be neuroprotective in Huntington's disease and stroke models. Here, using neuronal and glial cell cultures, in addition to an acute model of amyloid beta (Aβ) toxicity, which replicates by intra-hippocampal injection the consequences of interstitial and cellular accumulation of Aβ, we analyzed the effects of MTZ on neuronal and glial degeneration induced by the Alzheimer's amyloid. MTZ prevented DNA fragmentation, CytC release and activation of caspase 9 and caspase 3 induced by Aβ in neuronal and glial cells in culture through the inhibition of mitochondrial hydrogen peroxide production. Moreover, intraperitoneal administration of MTZ prevented neurodegeneration induced by intra-hippocampal Aβ injection in the mouse brain and was effective at reducing caspase 3 activation in neurons and microglia in the area surrounding the injection site. Our results, delineating the molecular mechanism of action of MTZ against Aβ-mediated mitochondrial dysfunction and caspase activation, and demonstrating its efficiency in a model of acute amyloid-mediated toxicity, provide the first combined in vitro and in vivo evidence supporting the potential of a new therapy employing FDA-approved CAIs in AD. PMID:26581638

  17. 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

  18. 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). PMID:27006778

  19. Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH

    PubMed Central

    Oliu, Carlos J.; Bagci, Ahmet M.; Lee, Sang H.; Kovanlikaya, Ilhami; Adams, David; Katzen, Heather; Ivkovic, Milos; Heier, Linda; Relkin, Norman

    2014-01-01

    Objective: To assess the effects of low-dose acetazolamide treatment on volumetric MRI markers and clinical outcome in idiopathic normal-pressure hydrocephalus (iNPH). Methods: We analyzed MRI and gait measures from 8 patients with iNPH with serial MRIs from an institutional review board–approved imaging protocol who had been treated off-label with low-dose acetazolamide (125–375 mg/day). MRI studies included fluid-attenuated inversion recovery and 3D T1-weighted high-resolution imaging. Automated analyses were employed to quantify each patient's ventricular, global white matter hyperintensities (WMH), and periventricular WMH (PVH) volumes prior to and throughout treatment. Clinical outcome was based on gait changes assessed quantitatively using the Boon scale. Results: Five of 8 patients responded positively to treatment, with median gait improvement of 4 points on the Boon scale. A significant decrease in PVH volume (−6.1 ± 1.9 mL, p = 0.002) was seen in these patients following treatment. One patient's gait was unchanged and 2 patients demonstrated worsened gait and were referred for shunt surgery. No reduction in PVH volume was detected in the latter 2 patients. Nonperiventricular WMH and lateral ventricle volumes remained largely unchanged in all patients. Conclusions: These preliminary findings provide new evidence that low-dose acetazolamide can reduce PVH and may improve gait in iNPH. PVH volume, reflecting transependymal CSF, is shown to be a potential MRI indicator of pharmacologic intervention effectiveness. Further studies of pharmacologic treatment of iNPH are needed and may be enhanced by incorporating quantitative MRI outcomes. Classification of evidence: This study provides Class IV evidence that low-dose acetazolamide reverses PVH volume and, in some cases, improves gait in iNPH. PMID:24634454

  20. The Effect of Acetazolamide on Cerebral Blood Flow and Oxygen Utilization in the Rhesus Monkey

    PubMed Central

    Laux, B. E.; Raichle, M. E.

    1978-01-01

    The brain is critically dependent for its moment to moment function and survival on an adequate supply of oxygen. The enzyme carbonic anhydrase (EC 4.2.1.1) may play an important role in oxygen delivery to brain tissue by facilitating the hydration of metabolically produced carbon dioxide in erythrocytes in brain capillaries, thus permitting the Bohr effect to occur. We examined the effect of 30 mg/kg i.v. acetazolamide, a potent inhibitor of carbonic anhydrase, upon cerebral blood flow and oxygen consumption in lightly anesthetized, passively ventilated rhesus monkeys. Cerebral blood flow and oxygen consumption were measured with oxygen-15-labeled water and oxygen-15-labeled oxyhemoglobin, respectively, injected into the internal carotid artery and monitored externally. Acetazolamide produced an immediate and significant increase in cerebral blood flow (from a mean of 64.7 to 83.8 ml/100 g per min), an increase in arterial carbon dioxide tension (from a mean of 40.7 to 47.5 torr), and a decrease in cerebral oxygen consumption (from a mean of 4.16 to 2.82 ml/100 g per min). Because the change in cerebral oxygen consumption occurred within minutes of the administration of acetazolamide, we believe that this effect probably was not due to a direct action on brain cells but was achieved by an interference with oxygen unloading in brain capillaries. A resultant tissue hypoxia might well explain part of the observed increase in cerebral blood flow. PMID:99455

  1. The protein profile of acetazolamide-treated sera in mice bearing Lewis neoplasm.

    PubMed

    Xiang, Yang; Ma, Bing; Yu, He-ming; Li, Xue-Jun

    2004-07-30

    The aim of the present research is to analyze the proteome of neoplasm serum before and after treated with acetazolamide (20, 40, 80 mg kg(-1) d(-1) for 3 days p.o.). The Lewis lung carcinoma mice were used and carried out a comprehensive proteomic analysis by using the technologies of high-resolution two-dimensional polyacrylamide gel electrophoresis (2D PAGE) and mass spectrometry (MS). The results showed that the acetazolamide could dramatically reduce the lung metastasis and primary tumor growth. Its most potent inhibition rate on lung metastases was reach to 77.7% at the dose of 80 mg kg(-1) d(-1). The two dimension electrophoresis and software analysis reveal 393 protein spots in control gel, 385 protein spots were detected in treated gel and matched 209 protein spots with control gel, indicating that intensive changes had occurred during the process of treatment. Two obviously different spots were cut off from gel and for the peptide mass fingerprinting. Data base searching showed the two proteins' peptide much more mach with Histone H2B fragment and Ubc-like protein CROC1 fragment. The results suggest that acetazolamide has a strong anti-tumor and anti-metastasis effect on Lewis-lung-carcinoma. The mechanism may be related to its regulation on plenty of proteins, in particular, on upregulation of H2B and CROC-1 expression of postreplicational DNA repair related protein in serum. PMID:15234186

  2. 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

  3. Sulfonamide inhibition studies of the α-carbonic anhydrase from the gammaproteobacterium Thiomicrospira crunogena XCL-2, TcruCA.

    PubMed

    Vullo, Daniela; Bhatt, Avni; Mahon, Brian P; McKenna, Robert; Supuran, Claudiu T

    2016-01-15

    We report a sulfonamide/sulfamate inhibition study of the α-carbonic anhydrase (CA, EC 4.2.1.1) present in the gammaproteobacterium Thiomicrospira crunogena XCL-2, a mesophilic hydrothermal vent-isolate organism, TcruCA. As Thiomicrospira crunogena is one of thousands of marine organisms that uses CA for metabolic regulation, the effect of sulfonamide inhibition has been considered. Sulfonamide-based drugs have been widely used in a variety of antibiotics, and bioelimination of these compounds results in exposure of these compounds to marine life. The enzyme was highly inhibited, with Ki values ranging from 2.5 to 40.7nM by a variety of sulfonamides including acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide and benzenesulfonamides incorporating 4-hydroxyalkyl moieties. Less effective inhibitors were topiramate, zonisamide, celecoxib, saccharin and hydrochlorothiazide as well as simple benzenesulfonamides incorporating amino, halogeno, alkyl, aminoalkyl and other moieties in the ortho- or para-positions of the aromatic ring (Kis of 202-933nM). The active site interactions between TcruCA and three clinically-used CA inhibitors, acetazolamide (Diamox®), dorzolamide (Trusopt®), and brinzolamide (Azopt®) are studied using molecular docking to provide insight into the reported Ki values. Comparison between various enzymes belonging to this family may also bring interesting hints in these fascinating phenomena. PMID:26691758

  4. Comparative study of acetazolamide and spironolactone on body fluid compartments on induction to high altitude

    NASA Astrophysics Data System (ADS)

    Singh, M. V.; Jain, S. C.; Rawal, S. B.; Divekar, H. M.; Parshad, Rajinder; Tyagi, A. K.; Sinha, K. C.

    1986-03-01

    Studies were conducted on 29 male healthy subjects having no previous experience of living at high altitude. These subjects were divided into three groups, i.e., subjects treated with placebo, acetazolamide and spironolactone. These subjects were first studied in Delhi. The drug schedule was started 24 hour prior to the airlift of these subjects to an altitude of 3,500 m and was continued for 48 hour after arrival at high altitude. Total body water, extra cellular water, plasma volume, blood electrolytes, pH, pO2, pCO2 and blood viscosity were determined on 3rd and 12th day of their stay at high altitude. Total body water, extra cellular water intracellular water and plasma volume decreased on high altitude exposure. There was a further slight decrease in these compartments with acetazolamide and spironolactone. It was also observed that spironolactone drives out more water from the extracellular compartment. Loss of plasma water was also confirmed by increased plasma osmolality. Increase in arterial blood pH was noticed on hypoxic exposure but the increase was found less in acetazolamide and spironolactone cases. This decrease in pH is expected to result in better oxygen delivery to the tissues at the low oxygen tension. It was also confirmed because blood pO2 increased in both the groups. No significant change in plasma electrolytes was observed in subjects of various groups. Blood viscosity slightly increased on exposure to high altitude. The degree of rise was found less in the group treated with spironolactone. This study suggests that both the drugs are likely to be beneficial in ameliorating/prevention of AMS syndrome.

  5. 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

  6. 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

  7. Stability of acetazolamide, allopurinol, azathioprine, clonazepam, and flucytosine in extemporaneously compounded oral liquids.

    PubMed

    Allen, L V; Erickson, M A

    1996-08-15

    The stability of drugs commonly prescribed for use in oral liquid dosage forms but not commercially available as such was studied. Acetazolamide 25 mg/mL, allopurinol 20 mg/mL, azathioprine 50 mg/mL, clonazepam 0.1 mg/mL, and flucytosine 10 mg/mL were prepared in 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus (Paddock Laboratories), and cherry syrup and placed in polyethylene terephthalate bottles. The sources of the drugs were capsules and tablets. Six bottles were prepared per liquid; three were stored at 5 degrees C and three at 25 degrees C, all in the dark. A sample was removed from each bottle initially and at intervals up to 60 days and analyzed for drug concentration by stability-indicating high-performance liquid chromatography. At least 94% of the initial drug concentration was retained in all the oral liquids for up to 60 days. There were no substantial changes in the appearance or odor of the liquids, or in the pH. Acetazolamide 25 mg/mL, allopurinol 20 mg/mL, azathioprine 50 mg/mL, clonazepam 0.1 mg/mL, and flucytosine 10 mg/mL were stable for up to 60 days at 5 and 25 degrees C in three extemporaneously compounded oral liquids. PMID:8862208

  8. Development and validation of an UPLC-MS/MS method for the quantification of ethoxzolamide in blood, brain tissue, and bioequivalent buffers: applications to absorption, brain distribution, and pharmacokinetic studies.

    PubMed

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

    2015-04-01

    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 and 108.00%. The inter-day variance is less than 12.87% and accuracy is between 89.27 and 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

  9. Acetazolamide Oral

    MedlinePlus

    ... the severity and duration of symptoms (upset stomach, headache, shortness of breath, dizziness, drowsiness, and fatigue) of ... numbness and tingling increased thirst and urination drowsiness headache confusion fever rash blood in urine painful urination ...

  10. Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT)

    PubMed Central

    Gertsch, Jeffrey H; Basnyat, Buddha; Johnson, E William; Onopa, Janet; Holck, Peter S

    2004-01-01

    Objective To evaluate the efficacy of ginkgo biloba, acetazolamide, and their combination as prophylaxis against acute mountain sickness. Design Prospective, double blind, randomised, placebo controlled trial. Setting Approach to Mount Everest base camp in the Nepal Himalayas at 4280 m or 4358 m and study end point at 4928 m during October and November 2002. Participants 614 healthy western trekkers (487 completed the trial) assigned to receive ginkgo, acetazolamide, combined acetazolamide and ginkgo, or placebo, initially taking at least three or four doses before continued ascent. Main outcome measures Incidence measured by Lake Louise acute mountain sickness score ≥ 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome (Lake Louise scores ≥ 5), incidence of headache, and severity of headache. Results Ginkgo was not significantly different from placebo for any outcome; however participants in the acetazolamide group showed significant levels of protection. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide (odds ratio 3.76, 95% confidence interval 1.91 to 7.39, number needed to treat 4), 35% for ginkgo (0.95, 0.56 to 1.62), and 14% for combined ginkgo and acetazolamide (3.04, 1.62 to 5.69). The proportion of patients with increased severity of acute mountain sickness was 18% for placebo, 3% for acetazoalmide (6.46, 2.15 to 19.40, number needed to treat 7), 18% for ginkgo (1, 0.52 to 1.90), and 7% for combined ginkgo and acetazolamide (2.95, 1.30 to 6.70). Conclusions When compared with placebo, ginkgo is not effective at preventing acute mountain sickness. Acetazolamide 250 mg twice daily afforded robust protection against symptoms of acute mountain sickness. PMID:15070635

  11. 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

  12. Effect of acetazolamide and gingko biloba on the human pulmonary vascular response to an acute altitude ascent.

    PubMed

    Ke, Tao; Wang, Jiye; Swenson, Erik R; Zhang, Xiangnan; Hu, Yunlong; Chen, Yaoming; Liu, Mingchao; Zhang, Wenbin; Zhao, Feng; Shen, Xuefeng; Yang, Qun; Chen, Jingyuan; Luo, Wenjing

    2013-06-01

    Acetazolamide and gingko biloba are the two most investigated drugs for the prevention of acute mountain sickness (AMS). Evidence suggests that they may also reduce pulmonary artery systolic pressure (PASP). To investigate whether these two drugs for AMS prevention also reduce PASP with rapid airlift ascent to high altitude, a randomized controlled trial was conducted on 28 healthy young men with acetazolamide (125 mg bid), gingko biloba (120 mg bid), or placebo for 3 days prior to airlift ascent (397 m) and for the first 3 days at high altitude (3658 m). PASP, AMS, arterial oxygen saturation (Sao2), mean arterial pressure (MAP), heart rate (HR), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF) were assessed both at 397 m and 3658 m. HR, PEF, and PASP increased with altitude exposure (p<0.05), and SaO2 decreased (p<0.05). PASP with acetazolamide (mean at 3658 m, 26.2 mm Hg; incremental change, 4.7 mm Hg, 95% CI., 2.6-6.9 mm Hg) was lower than that with ginkgo biloba (mean at 3658 m, 33.7 mm Hg, p=0.001; incremental change, 13.1 mm Hg, 95%CI., 9.6-16.5 mm Hg, p=0.002), and with placebo (mean at 3658 m, 34.7 mm Hg, p<0.001; 14.4 mm Hg, 95% CI., 8.8-20.0 mm Hg, p=0.001). The data show that a low prophylactic dosage of acetazolamide, but not gingko biloba, mitigates the early increase of PASP in a quick ascent profile. PMID:23795737

  13. The effects of acetazolamide and spironolactone on the body water distribution of rabbits during acute exposure to simulated altitude

    NASA Astrophysics Data System (ADS)

    Jain, S. C.; Singh, M. V.; Rawal, S. B.

    1984-06-01

    The role of body water metabolism on acute altitude exposure was studied. The studies were carried out in rabbits divided into four groups, namely, (i) control, (ii) exposed to acute hypoxia, (iii) exposed to acute hypoxia after treatment with 250 mg acetazolamide and (iv) exposed to acute hypoxia after treatment with 25 mg spironolactone. Total body water, extracellular water, intracellular water and blood volume decreased by an insignificant amount on exposure to hypoxia and plasma volume decreased by 5.7% (P<0.025). Treatment with either acetazolamide or spironolactone resulted in further marginal decrease in total body water. In the case of acetazolamide, the loss occurs from both intracellular and extracellular compartments, while treatment with spironolactone resulted in significant loss only from extracellular compartment. Treatment with both the drugs resulted in a small rise in pO2 and pCO2 with a slight decrease in pH. Our data suggested spironolactone to be a better prophylactic agent for use on acute high altitude induction.

  14. 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

  15. The effect of low-dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat.

    PubMed Central

    Wagenaar, M; Teppema, L; Berkenbosch, A; Olievier, C; Folgering, H

    1996-01-01

    1. The effect of 4 mg kg-1 acetazolamide (I.V.) on the slope (S) and intercept on the Pa,CO2 axis (B) of the ventilatory CO2 response curve of anaesthetized cats with intact or denervated carotid bodies was studied using the technique of dynamic end-tidal forcing. 2. This dose did not induce an arterial-to-end-tidal PCO2 (P(a-ET),CO2) gradient, indicating that erythrocytic carbonic anhydrase was not completely inhibited. Within the first 2 h after administration, this small dose caused only a slight decrease in mean standard bicarbonate of 1.8 and 1.7 mmol l-1 in intact (n = 7) and denervated animals (n = 7), respectively. Doses of acetazolamide larger than 4 mg kg-1 (up to 32 mg kg-1) caused a significant increase in the P(a-ET),CO2 gradient. 3. In carotid body-denervated cats, 4 mg kg-1 acetazolamide caused a decrease in the CO2 sensitivity of the central chemoreflex loop (Sc) from 1.52 +/- 0.42 to 0.96 +/- 0.32 l min-1 kPa-1 (mean +/- S.D.) while the intercept on the Pa,CO2 axis (B) decreased from 4.5 +/- 0.5 to 4.2 +/- 0.7 kPa. 4. In carotid body-intact animals, 4 mg kg-1 acetazolamide caused a decrease in the CO2 sensitivity of the peripheral chemoreflex loop (Sp) from 0.28 +/- 0.18 to 0.19 +/- 0.12 l min-1 kPa-1. Se and B decreased from 1.52 +/- 0.55 to 0.84 +/- 0.21 l min-1 kPa-1, and from 4.0 +/- 0.5 to 3.0 +/- 0.6 kPa, respectively, not significantly different from the changes encountered in the denervated animals. 5. It is argued that the effect of acetazolamide on the CO2 sensitivity of the peripheral chemoreflex loop in intact cats may be caused by a direct effect on the carotid bodies. Both in intact and in denervated animals the effects of the drug on Sc and B may not be due to a direct action on the central nervous system, but rather to an effect on cerebral vessels resulting in an altered relationship between brain blood flow and brain tissue PCO2. PMID:8866365

  16. Effect of acetazolamide on aquaporin-1 and fluid flow in cultured choroid plexus.

    PubMed

    Ameli, Pouya A; Madan, Meenu; Chigurupati, Srinivasulu; Yu, Amin; Chan, Sic L; Pattisapu, Jogi V

    2012-01-01

    Acetazolamide (AZA), used in treatment of early or infantile hydrocephalus, is effective in some cases, while its effect on the choroid plexus (CP) remains ill-defined. The drug reversibly inhibits aquaporin-4 (AQP4), the most ubiquitous "water pore" in the brain, and perhaps modulation of AQP1 (located apically on CP cells) by AZA may reduce cerebrospinal fluid (CSF) production. We sought to elucidate the effect of AZA on AQP1 and fluid flow in CP cell cultures.CP tissue culture from 10-day Sprague-Dawley rats and a TRCSF-B cell line were grown on Transwell permeable supports and treated with 100 μM AZA. Fluid assays to assess direction and extent of fluid flow, and AQP1 expression patterns by immunoblot, Immuncytochemistry (ICC), and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were performed.Immunoblots and ICC analyses showed a decrease in AQP1 protein shortly after AZA treatment (lowest at 12 h), with transient AQP1 reduction mediated by mRNA expression (lowest at 6 h). Transwell fluid assays indicated a fluid shift at 2 h, before significant changes in AQP1 mRNA or protein levels.Timing of AZA effect on AQP1 suggests the drug alters protein transcription, while affecting fluid flow by a concomitant method. It is plausible that other mechanisms account for these phenomena, as the processes may occur independently. PMID:22116425

  17. Acetazolamide-induced vasodilation does not inhibit the visually evoked flow response

    PubMed Central

    Yonai, Yaniv; Boms, Neta; Molnar, Sandor; Rosengarten, Bernhard; Bornstein, Natan M; Csiba, Laszlo; Olah, Laszlo

    2010-01-01

    Different methods are used to assess the vasodilator ability of cerebral blood vessels; however, the exact mechanism of cerebral vasodilation, induced by different stimuli, is not entirely known. Our aim was to investigate whether the potent vasodilator agent, acetazolamide (AZ), inhibits the neurovascular coupling, which also requires vasodilation. Therefore, visually evoked flow parameters were examined by transcranial Doppler in ten healthy subjects before and after AZ administration. Pulsatility index and peak systolic flow velocity changes, evoked by visual stimulus, were recorded in the posterior cerebral arteries before and after intravenous administration of 15 mg/kg AZ. Repeated-measures ANOVA did not show significant group main effect between the visually evoked relative flow velocity time courses before and after AZ provocation (P=0.43). Visual stimulation induced significant increase of relative flow velocity and decrease of pulsatility index not only before but also at the maximal effect of AZ. These results suggest that maximal cerebral vasodilation cannot be determined by the clinically accepted dose of AZ (15 mg/kg) and prove that neurovascular coupling remains preserved despite AZ-induced vasodilation. Our observation indicates independent regulation of vasodilation during neurovascular coupling, allowing the adaptation of cerebral blood flow according to neuronal activity even if other processes require significant vasodilation. PMID:19809468

  18. 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

  19. Sulfonamide inhibition studies of the η-class carbonic anhydrase from the malaria pathogen Plasmodium falciparum.

    PubMed

    Vullo, Daniela; Del Prete, Sonia; Fisher, Gillian M; Andrews, Katherine T; Poulsen, Sally-Ann; Capasso, Clemente; Supuran, Claudiu T

    2015-02-01

    The η-carbonic anhydrases (CAs, EC 4.2.1.1) were recently discovered as the sixth genetic class of this metalloenzyme superfamily, and are so far known only in protozoa, including various Plasmodium species, the causative agents of malaria. We report here an inhibition study of the η-CA from Plasmodium falciparum (PfCA) against a panel of sulfonamides and one sulfamate compound, some of which are clinically used. The strongest inhibitors identified were ethoxzolamide and sulthiame, with KIs of 131-132 nM, followed by acetazolamide, methazolamide and hydrochlorothiazide (KIs of 153-198 nM). Brinzolamide, topiramate, zonisamide, indisulam, valdecoxib and celecoxib also showed significant inhibitory action against PfCA, with KIs ranging from 217 to 308 nM. An interesting observation was that the more efficient PfCA inhibitors are representative of several scaffolds and chemical classes, including benzene sulfonamides, monocyclic/bicyclic heterocyclic sulfonamides and compounds with a more complex scaffold (i.e., the sugar sulfamate derivative, topiramate, and the coxibs, celecoxib and valdecoxib). A comprehensive inhibition study of small molecules for η-CAs is needed as a first step towards assessing PfCA as a druggable target. The present work identifies the first known η-CA inhibitors and provides a platform for the development of next generation novel PfCA inhibitors. PMID:25533402

  20. The alpha-carbonic anhydrase from the thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1 is highly susceptible to inhibition by sulfonamides.

    PubMed

    Vullo, Daniela; Luca, Viviana De; Scozzafava, Andrea; Carginale, Vincenzo; Rossi, Mosè; Supuran, Claudiu T; Capasso, Clemente

    2013-03-15

    The α-carbonic anhydrase (CA, EC 4.2.1.1) from the newly discovered thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1 (SspCA) was investigated for its inhibition with a large series of sulfonamides and a sulfamate, the classical inhibitors of these zinc enzymes. SspCA showed an inhibition profile with these compounds very similar to that of the predominant human cytosolic isoform hCA II, and not to that of the bacterial α-CA from Helicobacter pylori. Some clinically used drugs such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, celecoxib and sulthiame were low nanomolar SspCA/hCA II inhibitors (KIs in the range of 4.5-12.3nM) whereas simple aromatic/heterocyclic sulfonamides were less effective, micromolar inhibitors. As this highly catalytically active and thermostable enzyme may show biotechnological applications, its inhibition studies may be relevant for designing on/off systems to control its activity. PMID:22883029

  1. Acetazolamide for prevention of contrast-induced nephropathy: a new use for an old drug.

    PubMed

    Assadi, Farahnak

    2006-01-01

    Reactive oxygen species play a major role in the pathogenesis of contrast-induced nephropathy (CN). Hydration with sodium bicarbonate (HCO3-) can reduce the incidence of CN in high-risk patients, suggesting a direct causal relationship between low pH of tubular fluid and enhanced activity of generated reactive oxygen species to damage renal tubular cells. Whether acetazolamide (AZ), a carbonic anhydrase inhibitor, is more effective than HCO3- unknown. Ninety-six children with stable chronic renal insufficiency were randomly assigned to receive either a 154 mEq/L infusion of sodium bicarbonate (HCO3-) (n = 46) or 0.9% sodium chloride plus oral AZ (n = 50) at a rate of 3 ml/kg/hr for 1 hour before and 1 ml/kg/hr for 6 hours after the radiographic procedure. Serum creatinine concentration (Scr) was measured before and 48 hours after the procedure. The primary endpoint was an increase in the Scr concentration of > or = 25% 48 hours after the contrast administration. The baseline clinical and biochemical characteristics of the two groups were similar. The mean Scr concentration after contrast administration was significantly lower in the AZ group (p = 0.02) than in the HCO3- group (p = 0.27). The mean absolute decrease in Scr concentration at 48 hours was significantly greater in the AZ group (p < 0.01). Four of the 46 patients (8.7%) in the HCO3- group had an increase in the Scr concentration of > or = 25% compared with none of the 50 patients (0%) in the AZ group (p = 0.049). Thus, compared to HCO3-, AZ plus saline hydration was more effective for the prevention CN after radiographic procedure. PMID:16391986

  2. 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

  3. 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.

  4. 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

  5. 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

  6. Effect of acetazolamide on cytokines in rats exposed to high altitude.

    PubMed

    Wang, Chang; Wang, Rong; Xie, Hua; Sun, Yuhuan; Tao, Rui; Liu, Wenqing; Li, Wenbin; Lu, Hui; Jia, Zhengping

    2016-07-01

    Acute mountain sickness (AMS) is a dangerous hypoxic illness that can affect humans who rapidly reach a high altitude above 2500m. In the study, we investigated the changes of cytokines induced by plateau, and the acetazolamide (ACZ) influenced the cytokines in rats exposed to high altitude. Wistar rats were divided into low altitude (Control), high altitude (HA), and high altitude+ACZ (22.33mg/kg, Bid) (HA+ACZ) group. The rats were acute exposed to high altitude at 4300m for 3days. The HA+ACZ group were given ACZ by intragastric administration. The placebo was equal volume saline. The results showed that hypoxia caused the heart, liver and lung damage, compared with the control group. Supplementation with ACZ significantly alleviated hypoxia-caused damage to the main organs. Compared with the HA group, the biochemical and blood gas indicators of the HA+ACZ group showed no difference, while some cytokines have significantly changed, such as activin A, intercellular adhesion molecule-1 (ICAM-1, CD54), interleukin-1α,2 (IL-1α,2), l-selectin, monocyte chemotactic factor (MCP-1), CC chemokines (MIP-3α) and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). Then, the significant difference pro-inflammatory cytokines in protein array were chosen for further research. The protein and mRNA content of pro-inflammatory cytokines MCP-1, interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), interferon-γ (IFN-γ) in rat lung were detected. The results demonstrated that the high altitude affected the body's physiological and biochemical parameters, but, ACZ did not change those parameters of the hypoxia rats. This study found that ACZ could decrease the content of pro-inflammatory cytokines, such as MCP-1, IL-1β, TNF-α and IFN-γ in rat lungs, and, the lung injury in the HA+ACZ group reduced. The mechanism that ACZ protected hypoxia rats might be related to changes in cytokine content. The reducing of the pro-inflammatory cytokines in rat lung might be other

  7. Abnormal cerebral vasodilation in aneurysmal subarachnoid hemorrhage: use of serial 133Xe cerebral blood flow measurement plus acetazolamide to assess cerebral vasospasm.

    PubMed

    Tran Dinh, Y R; Lot, G; Benrabah, R; Baroudy, O; Cophignon, J; Seylaz, J

    1993-10-01

    A patient with cerebral vasospasm following subarachnoid hemorrhage (SAH) was investigated by serial measurement of cerebral blood flow (CBF) using the xenon-133 emission tomography method. The CBF was measured before and after acetazolamide injection. On Day 2 after SAH, there was early local hyperperfusion in the middle cerebral artery (MCA) territory, ipsilateral to the left posterior communicating artery aneurysm. The regional CBF of this arterial territory decreased slightly after acetazolamide injection, probably because of vasoplegia and the "steal" phenomenon, and thus surgery was delayed. A right hemiplegia with aphasia and disturbed consciousness occurred 4 days later (on Day 6 after SAH) due to arterial vasospasm, despite treatment with a calcium-channel blocker. The initial hyperemia of the left MCA territory was followed by ischemia. The vasodilation induced by acetazolamide administration was significantly subnormal until Day 13, at which time CBF and vasoreactivity amplitude returned to normal and the patient's clinical condition improved. Surgery on Day 14 and outcome were without complication. It is concluded that serial CBF measurements plus acetazolamide injection are useful for monitoring the development of cerebral vasospasm to determine the most appropriate time for aneurysm surgery. PMID:8410215

  8. 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.

  9. Effects of acetazolamide on the micro- and macro-vascular cerebral hemodynamics: a diffuse optical and transcranial doppler ultrasound study

    PubMed Central

    Zirak, Peyman; Delgado-Mederos, Raquel; Martí-Fàbregas, Joan; Durduran, Turgut

    2010-01-01

    Acetazolamide (ACZ) was used to stimulate the cerebral vasculature on ten healthy volunteers to assess the cerebral vasomotor reactivity (CVR). We have combined near infrared spectroscopy (NIRS), diffuse correlation spectroscopy (DCS) and transcranial Doppler (TCD) technologies to non-invasively assess CVR in real-time by measuring oxy- and deoxy-hemoglobin concentrations, using NIRS, local cerebral blood flow (CBF), using DCS, and blood flow velocity (CBFV) in the middle cerebral artery, using TCD. Robust and persistent increases in oxy-hemoglobin concentration, CBF and CBFV were observed. A significant agreement was found between macro-vascular (TCD) and micro-vascular (DCS) hemodynamics, between the NIRS and TCD data, and also within NIRS and DCS results. The relative cerebral metabolic rate of oxygen, rCMRO2, was also determined, and no significant change was observed. Our results showed that the combined diffuse optics-ultrasound technique is viable to follow (CVR) and rCMRO2 changes in adults, continuously, at the bed-side and in real time. PMID:21258561

  10. Structural studies of β-carbonic anhydrase from the green alga Coccomyxa: inhibitor complexes with anions and acetazolamide.

    PubMed

    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 CO(2)-HCO(3)(-) 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

  11. Microwave assisted synthesis of novel acridine-acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII.

    PubMed

    Ulus, Ramazan; Aday, Burak; Tanç, Muhammet; Supuran, Claudiu T; Kaya, Muharrem

    2016-08-15

    4-Amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide was condensed with cyclic-1,3-diketones (dimedone and cyclohexane-1,3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine-acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KIs in the range of 29.7-708.8nM (hCA IV), and of 1.3-90.7nM (hCA VII). For hCA I and II the KIs were in the range of 6.7-335.2nM (hCA I) and of 0.5-55.4nM (hCA II). The structure-activity relationships (SAR) for the inhibition of these isoforms with the acridine-acetazolamide conjugates reported here were delineated. PMID:27298005

  12. Molecular dynamics study of human carbonic anhydrase II in complex with Zn(2+) and acetazolamide on the basis of all-atom force field simulations.

    PubMed

    Wambo, Thierry O; Chen, Liao Y; McHardy, Stanton F; Tsin, Andrew T

    2016-01-01

    Human carbonic anhydrase II (hCAII) represents an ultimate example of the perfectly efficient metalloenzymes, which is capable of catalyzing the hydration of carbon dioxide with a rate approaching the diffusion controlled limit. Extensive experimental studies of this physiologically important metalloprotein have been done to elucidate the fundamentals of its enzymatic actions: what residues anchor the Zn(2+) (or another divalent cation) at the bottom of the binding pocket; how the relevant residues work concertedly with the divalent cation in the reversible conversions between CO2 and HCO3(-); what are the protonation states of the relevant residues and acetazolamide, an inhibitor complexed with hCAII, etc. In this article, we present a detailed computational study on the basis of the all-atom CHARMM force field where Zn(2+) is represented with a simple model of divalent cation using the transferrable parameters available from the current literature. We compute the hydration free energy of Zn(2+), the characteristics of hCAII-Zn(2+) complexation, and the absolute free energy of binding acetazolamide to the hCAII-Zn(2+) complex. In each of these three problems, our computed results agree with the experimental data within the known margin of error without making any case-by-case adjustments to the parameters. The quantitatively accurate insights we gain in this all-atom molecular dynamics study should be helpful in the search and design of more specific inhibitors of this and other carbonic anhydrases. PMID:27232456

  13. Short-term intraocular pressure trends following intravitreal ranibizumab injections for neovascular age-related macular degeneration—the role of oral acetazolamide in protecting glaucoma patients

    PubMed Central

    Murray, C D; Wood, D; Allgar, V; Walters, G; Gale, R P

    2014-01-01

    Purpose To determine the effect of oral acetazolamide on lowering the peak and duration of intraocular pressure (IOP) rise in glaucoma and glaucoma suspect patients, following intravitreal injection of ranibizumab for neovascular age-related macular degeneration. Methods The study was an open-label, parallel, randomised, controlled trial (EudraCT Number: 2010-023037-35). Twenty-four glaucoma or glaucoma suspect patients received either 500 mg acetazolamide or no treatment 60–90 min before 0.5 mg ranibizumab. The primary outcome measure was the difference in IOP immediately after injection (T0) and 5, 10, and 30 min following injection. ANCOVA was used to compare groups, adjusting for baseline IOP. The study was powered to detect a 9-mm Hg difference at T0. Results The IOP at T0 was 2.3 mm Hg higher in the non-treated group (mean 44.5 mm Hg, range (19–86 mm Hg)) compared with the treated group (mean 42.2 mm Hg, range (25–58 mm Hg)), but was not statistically significant after adjusting for baseline IOP (P=0.440). At 30 min, IOP was 4.9 mm Hg higher in the non-treated group (mean 20.6 mm Hg, range (11–46 mm Hg)) compared with the treated group (mean 15.7 mm Hg, range (8–21 mm Hg)). This was statistically significant after adjusting for baseline IOP (P=0.013). Conclusions Although the primary end points were not reached, 500 mg oral acetazolamide, 60–90 min before intravitreal injection, results in a statistically significant reduction in IOP at 3O min post injection. Prophylactic treatment may be considered as an option to minimise neuro-retinal rim damage in high-risk glaucoma patients who are most vulnerable to IOP spikes and undergoing repeated intravitreal injections of ranibizumab. PMID:25081290

  14. 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. PMID:26745790

  15. Evaluation of the cerebral vasodilatory capacity by the acetazolamide test before EC-IC bypass surgery in patients with occlusion of the internal carotid artery

    SciTech Connect

    Vorstrup, S.; Brun, B.; Lassen, N.A.

    1986-11-01

    Cerebral blood flow (CBF) was measured by xenon-133 inhalation tomography in 18 patients with cerebrovascular disease before and 4 months after extracranial-intracranial bypass surgery. Only patients who showed a reduced CBF in areas that were intact on the CT scan and relevant to the clinical and angiographical findings were operated. The majority of the patients had suffered a minor stroke with or without subsequent transient ischemic attacks. They were studied at least 6 weeks following the stroke. All patients had an occlusion of the relevant internal carotid artery. To identify preoperatively the patients with a compromised collateral circulation and hence reduced CBF due to reduced perfusion pressure, a cerebral vasodilatory stress test was performed using acetazolamide (Diamox). In normal subjects, Diamox has been shown to increase tomographic CBF without change of the flow distribution. In the present series 9 patients showed a significant redistribution of flow in favor of the non-occluded side (positive Diamox test). Two of these 9 patients showed even a paradoxical decrease in focal CBF preoperatively, i.e., a steal effect. These 2 patients were the only patients who improved in focal CBF after shunting. The remaining 9 patients all showed uniform flow responses (negative Diamox test), and none of these increased in focal CBF postoperatively. The finding of an unchanged flow map postoperatively confirmed that the low flow areas were not due to restricted flow via collateral pathways. However, an increase in the regional vasodilatory capacity was observed postoperatively in the majority of patients.

  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. PMID:26365207

  17. Evaluation of the cerebral vasodilatory capacity by the acetazolamide test before EC-IC bypass surgery in patients with occlusion of the internal carotid artery.

    PubMed

    Vorstrup, S; Brun, B; Lassen, N A

    1986-01-01

    Cerebral blood flow (CBF) was measured by xenon-133 inhalation tomography in 18 patients with cerebrovascular disease before and 4 months after extracranial-intracranial bypass surgery. Only patients who showed a reduced CBF in areas that were intact on the CT scan and relevant to the clinical and angiographical findings were operated. The majority of the patients had suffered a minor stroke with or without subsequent transient ischemic attacks. They were studied at least 6 weeks following the stroke. All patients had an occlusion of the relevant internal carotid artery. To identify preoperatively the patients with a compromised collateral circulation and hence reduced CBF due to reduced perfusion pressure, a cerebral vasodilatory stress test was performed using acetazolamide (Diamox). In normal subjects, Diamox has been shown to increase tomographic CBF without change of the flow distribution. In the present series 9 patients showed a significant redistribution of flow in favor of the non-occluded side ("positive" Diamox test). Two of these 9 patients showed even a paradoxical decrease in focal CBF preoperatively, i.e., a "steal" effect. These 2 patients were the only patients who improved in focal CBF after shunting. The remaining 9 patients all showed uniform flow responses ("negative" Diamox test), and none of these increased in focal CBF postoperatively. The finding of an unchanged flow map postoperatively confirmed that the low flow areas were not due to restricted flow via collateral pathways. However, an increase in the regional vasodilatory capacity was observed postoperatively in the majority of patients. PMID:3492787

  18. 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

  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. PMID:26838852

  20. 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

  1. 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

  2. Sulfonamide inhibition studies of the δ-carbonic anhydrase from the diatom Thalassiosira weissflogii.

    PubMed

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

    2014-01-01

    The δ-carbonic anhydrase (CA, EC 4.2.1.1) TweCA from the marine diatom Thalassiosira weissflogii has recently been cloned, purified and its activity/inhibition with anions investigated. Here we report the first sulfonamide/sulfamate inhibition study of a δ-class CA. Among the 40 such compounds investigated so far, 3-bromosulfanilamide, acetazolamide, ethoxzolamide, dorzolamide and brinzolamide were the most effective TweCA inhibitors detected, with KIs of 49.6-118nM. Many simple aromatic sulfonamides as well as dichlorophenamide, benzolamide, topiramate, zonisamide, indisulam and valdecoxib were medium potency inhibitors, (KIs of 375-897nM). Saccharin and hydrochlorothiazide were ineffective inhibitors of the δ-class enzyme, with KIs of 4.27-9.20μM. The inhibition profile of the δ-CA is very different from that of α-, β- and γ-CAs from different organisms. Although no X-ray crystal structure of this enzyme is available, we hypothesize that as for other CA classes, the sulfonamides inhibit the enzymatic activity by binding to the Zn(II) ion from the δ-CA active site. PMID:24314394

  3. 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

  4. 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. PMID:26525863

  5. 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

  6. The catalytic properties of murine carbonic anhydrase VII.

    PubMed

    Earnhardt, J N; Qian, M; Tu, C; Lakkis, M M; Bergenhem, N C; Laipis, P J; Tashian, R E; Silverman, D N

    1998-07-28

    Carbonic anhydrase VII (CA VII) appears to be the most highly conserved of the active mammalian carbonic anhydrases. We have characterized the catalytic activity and inhibition properties of a recombinant murine CA VII. CA VII has steady-state constants similar to two of the most active isozymes of carbonic anhydrase, CA II and IV; also, it is very strongly inhibited by the sulfonamides ethoxzolamide and acetazolamide, yielding the lowest Ki values measured by the exchange of 18O between CO2 and water for any of the mammalian isozymes of carbonic anhydrase. The catalytic measurements of the hydration of CO2 and the dehydration of HCO3- were made by stopped-flow spectrophotometry and the exchange of 18O using mass spectrometry. Unlike the other isozymes of this class of CA, for which Kcat/K(m) is described by the single ionization of zinc-bound water, CA VII exhibits a pH profile for Kcat/K(m) for CO2 hydration described by two ionizations at pKa 6.2 and 7.5, with a maximum approaching 8 x 10(7) M-1 s-1. The pH dependence of kcat/K(m) for the hydrolysis of 4-nitrophenyl acetate could also be described by these two ionizations, yielding a maximum of 71 M-1 s-1 at pH > 9. Using a novel method that compares rates of 18O exchange and dehydration of HCO3-, we assigned values for the apparent pKa at 6.2 to the zinc-bound water and the pKa of 7.5 to His 64. The magnitude of Kcat, its pH profile, 18O-exchange data for both wild-type and a H64A mutant, and inhibition by CuSO4 and acrolein suggest that the histidine at position 64 is functioning as a proton-transfer group and is responsible for one of the observed ionizations. A truncation mutant of CA VII, in which 23 residues from the amino-terminal end were deleted, has its rate constant for intramolecular proton transfer decreased by an order of magnitude with no change in Kcat/K(m). This suggests a role for the amino-terminal end in enhancing proton transfer in catalysis by carbonic anhydrase. PMID:9692974

  7. Ethoxyzolamide Inhibition of CO(2)-Dependent Photosynthesis in the Cyanobacterium Synechococcus PCC7942.

    PubMed

    Price, G D; Badger, M R

    1989-01-01

    Cells of the cyanobacterium, Synechococcus PCC7942, grown under high inorganic carbon (C(i)) conditions (1% CO(2); pH 8) were found to be photosynthetically dependent on exogenous CO(2). This was judged by the fact that they had a similar photosynthetic affinity for CO(2) (K(0.5)[CO(2)] of 3.4-5.4 micromolar) over the pH range 7 to 9 and that the low photosynthetic affinity for C(i) measured in dense cell suspensions was improved by the addition of exogenous carbonic anhydrase (CA). The CA inhibitor, ethoxyzolamide (EZ), was shown to reduce photosynthetic affinity for CO(2) in high C(i) cells. The addition of 200 micromolar EZ to high C(i) cells increased K(0.5)(CO(2)) from 4.6 micromolar to more than 155 micromolar at pH 8.0, whereas low C(i) cells (grown at 30 microliters CO(2) per liter of air) were less sensitive to EZ. EZ inhibition in high and low C(i) cells was largely relieved by increasing exogenous C(i) up to 100 millimolar. Lipid soluble CA inhibitors such as EZ and chlorazolamide were shown to be the most effective inhibitors of CO(2) usage, whereas water soluble CA inhibitors such as methazolamide and acetazolamide had little or no effect. EZ was found to cause a small drop in photosystem II activity, but this level of inhibition was not sufficient to explain the large effect that EZ had on CO(2) usage. High C(i) cells of Anabaena variabilis M3 and Synechocystis PCC6803 were also found to be sensitive to 200 micromolar EZ. We discuss the possibility that the inhibitory effect of EZ on CO(2) usage in high C(i) cells of Synechococcus PCC7942 may be due to inhibition of a ;CA-like' function associated with the CO(2) utilizing C(i) pump or due to inhibition of an internal CA activity, thus affecting CO(2) supply to ribulose bisphosphate carboxylase-oxygenase. PMID:16666544

  8. 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)

  9. Echographic studies of osmotic agents.

    PubMed

    Vucicevic, Z M; Tark, E; Ahmad, S

    1979-09-01

    The effectiveness of osmotic agents, acetazolamide (Diamox), urea, glycerol, and mannitol, and massages (5 and 10 minutes) for inducing hypotony in rabbit eyes was evaluated by ultrasonography. Mannitol was found to have the greatest hypotonic effect followed closely by urea and glycerol, then acetazolamide. The difference between the 5 and 10 minute massages was negligible. PMID:122221

  10. 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

  11. Hypokalemic periodic paralysis

    MedlinePlus

    ... that may be due to this condition include: Kidney stones (a side effect of acetazolamide) Irregular heartbeat during ... 2016:chap 99. Read More Breathing difficulty Carbohydrates Kidney stones Potassium test Thyrotoxic periodic paralysis Weakness Update Date ...

  12. PHARMACOLOGIC PROBING OF MERCURIC CHLORIDE-INDUCED RENAL DYSFUNCTION IN THE NEONATAL RAT

    EPA Science Inventory

    Acetazolamide, furosemide, chlorothiazide and amiloride are pharmacologic agents that act in the proximal tubule, loop of Henle, early distal tubule and late distal tubule, respectively. These diuretic agents were used to evaluate the functional integrity of discrete segments of ...

  13. Hypokalemic periodic paralysis

    MedlinePlus

    ... a vein (IV). Taking potassium supplements will not prevent attacks. Avoiding alcohol and eating a low-carbohydrate diet may help. A medicine called acetazolamide may be prescribed to prevent attacks. Your doctor may tell you to also ...

  14. Electrogenic active proton pump in Rana esculenta skin and its role in sodium ion transport.

    PubMed Central

    Ehrenfeld, J; Garcia-Romeu, F; Harvey, B J

    1985-01-01

    Kinetic and electrophysiological studies were carried out in the in vitro Rana esculenta skin, bathed in dilute sodium solution, to characterize the proton pump and coupling between sodium absorption (JNa+n) and proton excretion (JH+n). JNa+n and JH+n were both dependent on transepithelial potential (psi ms); hyperpolarizing the skin decreased JNa+n and increased JH+n; depolarization produced the opposite effects. Amiloride (5 X 10(-5) M) at a clamped psi ms of +50 mV inhibited JNa+n without affecting JH+n. Variations of psi ms or pH had identical effects on JH+n. Ethoxzolamide inhibited JH+n and simultaneously increased psi ms by 15-30 mV. These changes were accompanied by depolarization of the apical membrane potential psi mc from -47 to -25 mV and an increase in apical membrane resistance of 30%; no significant effects on basolateral membrane potential (psi cs) and resistance (Rb) nor on shunt resistance (Rj) were observed. The proton pump appears to be localized at the apical membrane. The proton pump was also inhibited by deoxygenation, oligomycin, dicyclohexylcarbodiimide and vanadate (100, 78, 83 and 100% inhibition respectively). The variations of JH+n and of the measured electrical currents were significantly correlated. These findings are supportive evidence of a primary active proton pump, electrogenic and strictly linked to aerobic metabolism. The current-voltage (I-V) relation of the proton pump was obtained as the difference in the I-V curves of the apical membrane extracted before and after proton-pump inhibition by ethoxzolamide during amiloride block of sodium transport. The proton-pump current (IP) was best described by a saturable exponential function of psi mc. Maximal pump current (ImaxP) was calculated to be 200 nequiv h-1 cm-2 at a psi mc of +50 mV and the pump reversal potential ERP was -130 mV. The effect of ethoxzolamide to depolarize psi mc was dependent on the relation between psi mc and ERP. Maximal induced depolarization occurred at a

  15. Testing the limits of sensitivity in a solid-state structural investigation by combined X-ray powder diffraction, solid-state NMR, and molecular modelling.

    PubMed

    Filip, Xenia; Borodi, Gheorghe; Filip, Claudiu

    2011-10-28

    A solid state structural investigation of ethoxzolamide is performed on microcrystalline powder by using a multi-technique approach that combines X-ray powder diffraction (XRPD) data analysis based on direct space methods with information from (13)C((15)N) solid-state Nuclear Magnetic Resonance (SS-NMR) and molecular modeling. Quantum chemical computations of the crystal were employed for geometry optimization and chemical shift calculations based on the Gauge Including Projector Augmented-Wave (GIPAW) method, whereas a systematic search in the conformational space was performed on the isolated molecule using a molecular mechanics (MM) approach. The applied methodology proved useful for: (i) removing ambiguities in the XRPD crystal structure determination process and further refining the derived structure solutions, and (ii) getting important insights into the relationship between the complex network of non-covalent interactions and the induced supra-molecular architectures/crystal packing patterns. It was found that ethoxzolamide provides an ideal case study for testing the accuracy with which this methodology allows to distinguish between various structural features emerging from the analysis of the powder diffraction data. PMID:21931906

  16. Carbonic anhydrase enzyme as a potential therapeutic target for experimental trichinellosis.

    PubMed

    Saad, Abeer E; Ashour, Dalia S; Abou Rayia, Dina M; Bedeer, Asmaa E

    2016-06-01

    Trichinellosis is a globally distributed helminthic infection. There is a considerable interest in developing new anti-helminthic drugs affecting all the developmental stages of Trichinella. Acetazolamide (carbonic anhydrase (CA) inhibitor) involves a novel mechanism of action by inhibiting such an essential enzyme for parasite metabolism. This work aimed to study the effect of acetazolamide against different stages of T. spiralis in experimental animals. Mice were divided into three groups: group I: infected and treated with acetazolamide on day 2 post infection (P.I.), group II: infected and treated with acetazolamide on day 12 P.I., and group III: infected non-treated. From each group, small intestine and muscles were removed for histopathological and immunohistochemical studies. Also, total adult and muscle larval count were estimated. We found that acetazolamide was effective in reduction of both adult and muscle larval counts. When given early, the effect was more pronounced on the adults (62.7 %). However, the efficacy of the drug against muscle larvae was increased when given late (63 %). Improvement of the intestinal histopathological changes was observed in all the treated groups. Degeneration of encysted larvae with minimal pathologic changes of infected skeletal muscle was observed in the treated groups. Expression of matrix metalloproteinase-9 showed a statistically significant decrease in the intestinal and muscle tissues in all treated groups as compared to the control group. In conclusion, the present study revealed that acetazolamide, carbonic anhydrase inhibitor, could be a promising drug against both adults and larvae of T. spiralis. PMID:26979731

  17. Multiscale modelling of pharmaceutical powders: Macroscopic behaviour prediction

    NASA Astrophysics Data System (ADS)

    Loh, Jonathan; Ketterhagen, William; Elliott, James

    2013-06-01

    The pharmaceutical industry uses computer models at many stages during drug development. Quantum and molecular models are used to predict the crystal structures of potential active pharmaceutical ingredients (APIs), whereas discrete element models are used to optimise the mechanical properties of mixtures of APIs and excipient powders. The present work combines the strengths of modelling from all of the mentioned length scales to predict the behaviour of macroscopic powder granules from first principles using the molecular and crystal structures of acetazolamide as an example API. Starting with a single molecule of acetazolamide, ab initio self-consistent field calculations were used to calculate the equilibrium gas phase structure, vibrational spectra, interaction energy with water molecules and perform potential energy scans. By using these results and following the CHARMM General Force Field parameterisation process, all of the parameters required to perform a molecular dynamics simulation were iteratively determined using the CHARMM program. Next, by using crystallographic data from literature, the monoclinic and triclinic forms of the acetazolamide crystal were simulated. Material properties like the Young's modulus and Poisson ratio, and surface energies have been calculated. These material properties are then used as input parameters in a discrete element model containing Thornton's plastic model and the JKR cohesive force to predict the behaviour of macroscopic acetazolamide powder in angle of repose tests and tabletting simulations. Similar methodologies can be employed in the future to evaluate at an early stage the performance of novel APIs and excipients for tabletting applications.

  18. PHARMACOLOGIC PROBING OF AMPHOTERICIN B-INDUCED RENAL DYSFUNCTION IN THE NEONATAL RAT

    EPA Science Inventory

    Pharmacologic Probing of Amphotericin B-Induced Renal Dysfunction in the Neonatal Rat. Gray, J.A., and Kavlock, R.J. (1988). Toxicol. Appl. Pharmacol. 93, 360-368. Acetazolamide, furosemide, chlorothiazide, and amiloride pharmacologic agents that act primarily in the proximal tub...

  19. Effects of competitive red blood cell binding and reduced hematocrit on the blood and plasma levels of (/sup 14/C)Indapamide in the rat

    SciTech Connect

    Lettieri, J.T.; Portelli, S.T.

    1983-02-01

    The effects of chlorthalidone and acetazolamide on the red blood cell binding of indapamide were investigated. Both drugs caused a substantial decrease in the amount of indapamide bound to the erythrocytes in vitro. This effect was demonstrated by a change in the indapamide blood/plasma ratio from approximately 6 in control samples, to a value of 1 when either of the displacing agents was added. Coadministration of acetazolamide with /sup 14/C-labeled indapamide to rats, resulted in a 5-fold drop in the blood levels of total radioactivity, relative to rats dosed with (/sup 14/C)indapamide alone. Concomitantly, there was a 2-fold increase in the plasma levels of total radioactivity after acetazolamide coadministration. In rats whose hematocrits had been reduced by extensive bleeding, there were only minor alterations in the blood/plasma partitioning of (/sup 14/C)indapamide. Thus, chlorthalidone and acetazolamide were able to displace indapamide from erythrocytes in vitro and in vivo, possibly by competition at a carbonic anhydrase binding site. The pharmacokinetics of drugs which are extensively bound to erythrocytes may be significantly altered by the presence of other agents capable of competitive binding.

  20. 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

  1. Synthesis of sulfonamide conjugates of Cu(II), Ga(III), In(III), Re(V) and Zn(II) complexes: carbonic anhydrase inhibition studies and cellular imaging investigations.

    PubMed

    Dilworth, Jonathan R; Pascu, Sofia I; Waghorn, Philip A; Vullo, Daniela; Bayly, Simon R; Christlieb, Martin; Sun, Xin; Supuran, Claudiu T

    2015-03-21

    Carbonic anhydrase IX (CA IX) is currently generating great interest as a marker of tumour hypoxia and a potential chemotherapeutic target. In order to test the principle that a CA IX inhibitor could be used for targeting PET or SPECT metallic radioisotopes to tumours we have prepared a number of conjugates involving aryl-sulfonamides or an acetazolamide derivative linked to a range of copper, indium, rhenium, 99m-technetium and zinc complexes. Radiolabelled (64)Cu and (99m)Tc analogues of the 'cold' Cu and some of the Re complexes were prepared in good radiochemical incorporation. Inhibition of various human carbonic anhydrase isoforms (I, II, IX and XII) was tested with the 'cold', non-radiolabelled complexes, and compared with an acetazolamide standard (AZA). The molecular structure of a new, tri-sulfonated porphyrin-labeled sulfonamide was determined using synchrotron X-ray crystallography. PMID:25711495

  2. 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

  3. 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.

  4. 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. PMID:25899916

  5. Incidence and Symptoms of High Altitude Illness in South Pole Workers: Antarctic Study of Altitude Physiology (ASAP)

    PubMed Central

    Anderson, Paul J.; Miller, Andrew D.; O’Malley, Kathy A.; Ceridon, Maile L.; Beck, Kenneth C.; Wood, Christina M.; Wiste, Heather J.; Mueller, Joshua J.; Johnson, Jacob B.; Johnson, Bruce D.

    2011-01-01

    Introduction: Each year, the US Antarctic Program rapidly transports scientists and support personnel from sea level (SL) to the South Pole (SP, 2835 m) providing a unique natural laboratory to quantify the incidence of acute mountain sickness (AMS), patterns of altitude related symptoms and the field effectiveness of acetazolamide in a highly controlled setting. We hypothesized that the combination of rapid ascent (3 hr), accentuated hypobarism (relative to altitude), cold, and immediate exertion would increase altitude illness risk. Methods: Medically screened adults (N = 246, age = 37 ± 11 yr, 30% female, BMI = 26 ± 4 kg/m2) were recruited. All underwent SL and SP physiological evaluation, completed Lake Louise symptom questionnaires (LLSQ, to define AMS), and answered additional symptom related questions (eg, exertional dyspnea, mental status, cough, edema and general health), during the 1st week at altitude. Acetazolamide, while not mandatory, was used by 40% of participants. Results: At SP, the barometric pressure resulted in physiological altitudes that approached 3400 m, while T °C averaged −42, humidity 0.03%. Arterial oxygen saturation averaged 89% ± 3%. Overall, 52% developed LLSQ defined AMS. The most common symptoms reported were exertional dyspnea-(87%), sleeping difficulty-(74%), headache-(66%), fatigue-(65%), and dizziness/lightheadedness-(46%). Symptom severity peaked on days 1–2, yet in >20% exertional dyspnea, fatigue and sleep problems persisted through day 7. AMS incidence was similar between those using acetazolamide and those abstaining (51 vs. 52%, P = 0.87). Those who used acetazolamide tended to be older, have less altitude experience, worse symptoms on previous exposures, and less SP experience. Conclusion: The incidence of AMS at SP tended to be higher than previously reports in other geographic locations at similar altitudes. Thus, the SP constitutes a more intense altitude exposure than might be expected considering physical

  6. Hepatic urea synthesis and pH regulation. Role of CO2, HCO3-, pH and the activity of carbonic anhydrase.

    PubMed

    Häussinger, D; Gerok, W

    1985-10-15

    In isolated perfused rat liver, urea synthesis from ammonium ions was dependent on extracellular HCO3- and CO2 concentrations when the HCO3-/CO2 ratio in the influent perfusate was constant (pH 7.4). Urea synthesis was half-maximal at HCO3- = 4 mM, CO2 = 0.19 mM and was maximal at HCO3- and CO2 concentrations above 20 mM and 0.96 mM, respectively. At physiological HCO3- (25 mM) and CO2 (1.2 mM) concentrations in the influent perfusate, acetazolamide, the inhibitor of carbonic anhydrase, inhibited urea synthesis from ammonium ions (1 mM) by 50-60% and led to a 70% decrease in citrulline tissue levels. Acetazolamide concentrations required for maximal inhibition of urea synthesis were 0.01-0.1 mM. At subphysiological HCO3- and CO2 concentrations, inhibition of urea synthesis by acetazolamide was increased up to 90%. Inhibition of urea synthesis by acetazolamide was fully overcome in the presence of unphysiologically high HCO3- and CO2 concentrations, indicating that the inhibitory effect of acetazolamide is due to an inhibition of carbonic-anhydrase-catalyzed HCO3- supply for carbamoyl-phosphate synthetase, which can be bypassed when the uncatalyzed intramitochondrial HCO3- formation from portal CO2 is stimulated in the presence of high portal CO2 concentrations. With respect to HCO3- supply of mitochondrial carbamoyl-phosphate synthetase, urea synthesis can be separated into a carbonic-anhydrase-dependent (sensitive to acetazolamide at 0.5 mM) and a carbonic-anhydrase-independent (insensitive to acetazolamide) portion. Carbonic-anhydrase-independent urea synthesis linearly increased with the portal 'total CO2 addition' (which was experimentally determined to be CO2 addition plus 0.036 HCO3- addition) and was independent of the perfusate pH. At a constant 'total CO2 addition', carbonic-anhydrase-dependent urea synthesis was strongly affected by perfusate pH and increased about threefold when the perfusate pH was raised from 6.9 to 7.8. It is concluded that the p

  7. The periplasmic alpha-carbonic anhydrase activity of Helicobacter pylori is essential for acid acclimation.

    PubMed

    Marcus, Elizabeth A; Moshfegh, Amiel P; Sachs, George; Scott, David R

    2005-01-01

    The role of the periplasmic alpha-carbonic anhydrase (alpha-CA) (HP1186) in acid acclimation of Helicobacter pylori was investigated. Urease and urea influx through UreI have been shown to be essential for gastric colonization and for acid survival in vitro. Intrabacterial urease generation of NH3 has a major role in regulation of periplasmic pH and inner membrane potential under acidic conditions, allowing adequate bioenergetics for survival and growth. Since alpha-CA catalyzes the conversion of CO2 to HCO3-, the role of CO2 in periplasmic buffering was studied using an alpha-CA deletion mutant and the CA inhibitor acetazolamide. Western analysis confirmed that alpha-CA was bound to the inner membrane. Immunoblots and PCR confirmed the absence of the enzyme and the gene in the alpha-CA knockout. In the mutant or in the presence of acetazolamide, there was an approximately 3 log10 decrease in acid survival. In acid, absence of alpha-CA activity decreased membrane integrity, as observed using membrane-permeant and -impermeant fluorescent DNA dyes. The increase in membrane potential and cytoplasmic buffering following urea addition to wild-type organisms in acid was absent in the alpha-CA knockout mutant and in the presence of acetazolamide, although UreI and urease remained fully functional. At low pH, the elevation of cytoplasmic and periplasmic pH with urea was abolished in the absence of alpha-CA activity. Hence, buffering of the periplasm to a pH consistent with viability depends not only on NH3 efflux from the cytoplasm but also on the conversion of CO2, produced by urease, to HCO3- by the periplasmic alpha-CA. PMID:15629943

  8. 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

  9. Pseudotumor cerebri: What We Have Learned from the Idiopathic Intracranial Hypertension Treatment Trial.

    PubMed

    Thakore, Rachel V; Johnson, Meredith A J; Krohel, Gregory B; Johnson, Lenworth N

    2016-01-01

    Idiopathic intracranial hypertension, also known as pseudotumor cerebri, is an unexplained increase in intracranial pressure associated with permanent severe visual loss in 25% of cases and debilitating headaches. The condition is often associated with obesity. The Idiopathic Intracranial Hypertension Treatment Trial, a large, randomized, collaborative clinical trial, evaluated the efficacy of acetazolamide with weight loss versus placebo with weight loss in participants. Herein, we describe the major components of the clinical trial and discuss its shortcomings. [Full article available at http://rimed.org/rimedicaljournal-2016-05.asp, free with no login]. PMID:27128512

  10. 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

  11. A carbonic anhydrase inhibitor as a potential modulator of cancer therapies.

    PubMed

    Teicher, B A; Liu, S D; Liu, J T; Holden, S A; Herman, T S

    1993-01-01

    Since several anticancer drugs are known to become more cytotoxic to cells in an acidic milieu, we have attempted to utilize the carbonic anhydrase inhibitor, Acetazolamide, to acidify the blood and tumor of C3H mice bearing the FSaIIC fibrosarcoma in order to sensitize tumor cells in vivo to CDDP, Melphalan, BCNU, SR4233 or PtCl4 (Fast Black)2 +/- hyperthermia. The direct cytotoxic interactions between the anticancer drugs and Acetazolamide were tested in FSaIIC cells in vitro with the monacidifying diuretic Chlorothrozide as a control. When cells were exposed to CDDP both diuretics protected against cytotoxicity in a dose dependent fashion. In contrast, cells exposed to Melphalan were minimally sensitized and those exposed to BCNU, SR4233, or PtCl4 (Fast Black)2 were essentially unaffected by the presence of the diuretic agents. Both diuretics were essentially non-toxic to cells in vitro, and, interestingly, both drugs markedly protected cells against hyperthermia under low pH conditions. In vitro, however, Acetzolamide produced a tumor growth delay of 2.3 days alone when given at 10 mg/kg i.p. once (the most effective dose) and produced additive growth delays with CDDP and Melphalan, but probably greater than additive delays with SR4233 and PtCl4 (Fast Black)2. When Acetazolamide was given daily for 5 days starting on the day the anticancer drugs were given once (day 7) essentially no further increase in tumor growth delay of nearly 16 days was observed versus only 4,6 days for the drug alone. When hyperthermia (43 degrees C min.) was delivered locally to the tumor after i.p. injection of the drugs, further growth delays were produced for every drug combination which probably were additive in extent. Blood and urine pH determinations revealed that a pH drop of 1 units occurred in the blood and a pH elevation of 1 to 21 units occurred in the urine 1 hr. after i.p. injection of Acetazolamide. These results indicate that this carbonic anhydrase inhibitor can add to

  12. Research on Susceptible Genes and Immunological Pathogenesis of Cutaneous Adverse Drug Reactions in Chinese Hans.

    PubMed

    Yang, Fangping; Yang, Ying; Zhu, Qinyuan; Chen, Sheng-An; Fu, Xiaodan; Yan, Sijia; Meng, Chunjie; Ma, Li; Sun, Xinfen; Xu, Jinhua; Luo, Xiaoqun; Xing, Qinghe

    2015-07-01

    Cutaneous adverse drug reactions (cADRs) include mild maculopapular exanthems (MPE), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). We used HLA high-resolution genotyping and genome wide association analysis (GWAS) to identify the genetic markers for cADRs induced by common culprit drugs in Han Chinese population. To further understand the immunopathogenesis of cADRs, and with the goal of developing treatment strategies, we compared the expression of cytoxic cytokines between the patients with cADRs and normal controls. Our data suggested that the carbamazepine induced SJS/TEN, allopurinol induced CADRs, methazolamide induced SJS/TEN and SASP induced DRESS were respectively strongly associated with HLA-B*15:02, HLA-B*58:01, HLA-B*59:01 and HLA-B*13:01. In addition, increased expression of cytotoxic cytokines in sera and tissues of cADRs patients were found, compared with healthy controls. Our findings may shed light on prediction and prevention of cADRs, provide clues to pathogenesis, and guide treatment strategies of these reactions. PMID:26067314

  13. Physiological adaptations of the intertidal rockpool teleost Blennius pholis L., to aerial exposure.

    PubMed

    Pelster, B; Bridges, C R; Grieshaber, M K

    1988-03-01

    Gas exchange, metabolism, ventilation, circulation and acid-base balance in water and air were investigated in Blennius pholis. The rates of gas exchange in water and air were similar with the RQ remaining around 0.8. Aerial gas exchange was equally divided between the head/gills and the tail region. Ventilatory adaptations involved a reduction in rate in air and the mode of ventilation changed from flow-through to tidal, with closed opercula. A transient bradycardia developed on transition to air before heart frequency (fH) returned to aquatic levels. During aerial exposure PvCO2 rose only by 1 Torr with a concomitant decrease in pH of 0.19 pH-units. At the same time a metabolic acidosis was observed which could not be fully accounted for by the formation of lactic acid in the blood, although tissue lactate levels did not change significantly. No histological evidence was found for the presence of carbonic anhydrase in the epithelial cells of the skin or the oesophagus to aid aerial CO2 excretion. Inhibition of CA activity by addition of methazolamide to blood, however, caused PvCO2 to rise by 3 Torr and pHv to decrease by 0.4 pH unit. It is concluded that B. pholis is physiologically well adapted to aerial exposure through adjustments in ventilation and circulation and that erythrocytic carbonic anhydrase plays a major role in CO2 transfer. PMID:3375606

  14. 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

  15. 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

  16. 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

  17. Pharmacologic manipulation of the flushing action of cerebrospinal fluid. Effect on CSF diatrizoate levels.

    PubMed

    Harnish, P P; Samuel, K

    1988-12-01

    The continual production and absorption of cerebrospinal fluid (CSF) provides for the dilution and removal of potentially toxic substances from the central nervous system (CNS). This study quantified changes in the CSF concentration of diatrizoate following pretreatment with various drugs that alter CSF production. Adult rats, pretreated with one of ten drugs or normal saline (control) and anesthetized, received sodium diatrizoate (2 mL/kg, IV). Blood and CSF were sampled 2 hours later, and the diatrizoate concentrations were measured. Serum diatrizoate levels in the control group averaged 144.3 micrograms/mL. There were no significant differences in serum levels between control and pretreated groups. The CSF diatrizoate concentration in the control group averaged 10.8 micrograms/mL. Pretreatment with acetazolamide, ritodrine, or probenecid resulted in a significant increase in the CSF concentration, to 24.7 micrograms/mL or 228% of control in the case of acetazolamide. Pretreatment with salicylate, carbachol, or aminophylline resulted in significantly lower CSF diatrizoate levels than control; 3.2 micrograms/mL (30% of control) for carbachol. Digoxin, furosemide, dibutyryl cAMP, or dexamethasone pretreatments had no significant effect on CSF diatrizoate concentrations. Thus, a wide range of drugs may significantly alter the concentration of diatrizoate in the CNS. Drug-induced changes in the rate of CSF production may be responsible for this action. PMID:2849595

  18. Can migraine prophylaxis prevent acute mountain sickness at high altitude?

    PubMed

    Kim, M W; Kim, M

    2011-11-01

    Acute mountain sickness (AMS) develops in people trekking at high altitude. The underlying mechanism is vasodilation due to low pressure of oxygen. However, individual susceptibility for AMS is unknown, thus, one cannot predict when or to whom it happens. Because AMS usually begins with headache, and because migraineurs are more vulnerable to AMS, we studied by the literatures review on the mechanism and clinical features in common, and assessed the treatment modalities for both disorders. This led to us the following hypothesis that, migraine prophylaxis may prevent or delay the onset of AMS at high altitude. Clinical features of AMS include nausea or vomiting when it progresses. Hypobaric hypoxia, dehydration or increased physical exertion trigger or aggravate both disorders. In migraine, cerebral vasodilation can happen following alteration of neuronal activity, whereas the AMS is associated with peripheral vessel dilation. Medications that dilate the vessels worsen both conditions. Acute treatment strategies for migraine overlap with to those of AMS, including drugs such as vasoconstrictors, or other analgesics. To prevent AMS, adaptation to high altitude or pharmacological prophylaxis, i.e., acetazolamide has been recommended. This carbonic anhydrase inhibitor lowers serum potassium level, and thus stabilizes membrane excitability. Acetazolamide is also effective on specific forms of migraine. Taken together, these evidences implicate that migraine prophylaxis may prevent or delay the onset of AMS by elevating the threshold for high altitude. PMID:21856088

  19. Pseudotumor Cerebri in a Child with Idiopathic Growth Hormone Insufficiency Two Months after Initiation of Recombinant Human Growth Hormone Treatment.

    PubMed

    Loukianou, Eleni; Tasiopoulou, Anastasia; Demosthenous, Constantinos; Brouzas, Dimitrios

    2016-01-01

    Purpose. To report a rare case of pseudotumor cerebri (PTC) in a child two months after receiving treatment with recombinant human growth hormone (rhGH) and to emphasize the need of close collaboration between ophthalmologists and pediatric endocrinologists in monitoring children receiving rhGH. Methods. A 12-year-old boy with congenital hypothyroidism started treatment with rhGH on a dose of 1,5 mg/daily IM (4.5 IU daily). Eight weeks later, he was complaining of severe headache without any other accompanying symptoms. The child was further investigated with computed tomography scan and lumbar puncture. Results. Computed tomography scan showed normal ventricular size and lumbar puncture revealed an elevated opening pressure of 360 mm H2O. RhGH was discontinued and acetazolamide 250 mg per os twice daily was initiated. Eight weeks later, the papilledema was resolved. Conclusions. There appears to be a causal relationship between the initiation of treatment with rhGH and the development of PTC. All children receiving rhGH should have a complete ophthalmological examination if they report headache or visual disturbances shortly after the treatment. Discontinuation of rhGH and initiation of treatment with acetazolamide may be needed and regular follow-up examinations by an ophthalmologist should be recommended. PMID:26966604

  20. Pseudotumor Cerebri in a Child with Idiopathic Growth Hormone Insufficiency Two Months after Initiation of Recombinant Human Growth Hormone Treatment

    PubMed Central

    Loukianou, Eleni; Tasiopoulou, Anastasia; Demosthenous, Constantinos; Brouzas, Dimitrios

    2016-01-01

    Purpose. To report a rare case of pseudotumor cerebri (PTC) in a child two months after receiving treatment with recombinant human growth hormone (rhGH) and to emphasize the need of close collaboration between ophthalmologists and pediatric endocrinologists in monitoring children receiving rhGH. Methods. A 12-year-old boy with congenital hypothyroidism started treatment with rhGH on a dose of 1,5 mg/daily IM (4.5 IU daily). Eight weeks later, he was complaining of severe headache without any other accompanying symptoms. The child was further investigated with computed tomography scan and lumbar puncture. Results. Computed tomography scan showed normal ventricular size and lumbar puncture revealed an elevated opening pressure of 360 mm H2O. RhGH was discontinued and acetazolamide 250 mg per os twice daily was initiated. Eight weeks later, the papilledema was resolved. Conclusions. There appears to be a causal relationship between the initiation of treatment with rhGH and the development of PTC. All children receiving rhGH should have a complete ophthalmological examination if they report headache or visual disturbances shortly after the treatment. Discontinuation of rhGH and initiation of treatment with acetazolamide may be needed and regular follow-up examinations by an ophthalmologist should be recommended. PMID:26966604

  1. Which medications are safe and effective for improving sleep at high altitude?

    PubMed

    Luks, Andrew M

    2008-01-01

    Given the well-established problems with sleep at high altitude, it is not uncommon for people planning trips to the mountains to seek advice from clinicians regarding pharmacologic options for improving sleep during their trip. This review article considers the various medications that have been studied for this purpose at high altitude with an emphasis on both their efficacy and safety. The available data support the use of either acetazolamide, temazepam, zolpidem or zaleplon in this environment. Other agents commonly used at sea-level such as eszopiclone and diphenhydramine have not been studied at high altitude but are likely safe to use given their mechanism of action and known side effects. Limited evidence suggests diazepam may cause hypoventilation at high altitude and its use in this environment should be discouraged. Insufficient data exist to determine which agent is most effective at altitude nor do we know whether combination therapy with acetazolamide and a hypnotic agent offers any benefits over monotherapy. PMID:18800955

  2. 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

  3. 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

  4. 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.

  5. Bicarbonate Availability for Vocal Fold Epithelial Defense to Acidic Challenge

    PubMed Central

    Durkes, Abigail; Sivasankar, M. Preeti

    2014-01-01

    Objectives Bicarbonate is critical for acid-base tissue homeostasis. In this study we investigated the role of bicarbonate ion transport in vocal fold epithelial defense to acid challenges. Acidic insults to the larynx are common in gastric reflux, carcinogenesis and metastasis, and acute inflammation. Methods Ion transport was measured in viable, porcine vocal fold epithelium. First, 18 vocal folds were exposed to either the carbonic anhydrase antagonist acetazolamide or to vehicle. Second, 32 vocal folds were exposed to either a control buffer or a bicarbonate-free buffer on their luminal or basolateral surface or both. Third, vocal folds were challenged with acid in the presence of bicarbonate-free or control buffer. Results The vocal fold transepithelial resistance was greater than 300 Ω*cm2, suggesting robust barrier integrity. Ion transport did not change after exposure to acetazolamide (p > 0.05). Exposure to bicarbonate-free buffer did not compromise vocal fold ion transport (p > 0.05). Ion transport increased after acid challenge. This increase approached statistical significance and was the greatest for the control buffer and for the bicarbonate-free buffer applied to the basolateral surface. Conclusions Bicarbonate secretion may contribute to vocal fold defense against acid challenge. Our data offer a potential novel role for bicarbonate as a therapeutic agent to reduce pH abnormalities in the larynx and prevent associated pathological changes. PMID:24574427

  6. 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

  7. Effects of acid-base variables and the role of carbonic anhydrase on oxalate secretion by the mouse intestine in vitro

    PubMed Central

    Whittamore, Jonathan M; Frost, Susan C; Hatch, Marguerite

    2015-01-01

    Hyperoxaluria is a major risk factor for calcium oxalate kidney stones and the intestine is recognized as an important extra-renal pathway for eliminating oxalate. The membrane-bound chloride/bicarbonate (Cl−/) exchangers are involved in the transcellular movement of oxalate, but little is understood about how they might be regulated. , CO2, and pH are established modulators of intestinal NaCl cotransport, involving Na+/H+ and Cl−/ exchange, but their influence on oxalate transport is unknown. Measuring 14C-oxalate and 36Cl fluxes across isolated, short-circuited segments of the mouse distal ileum and distal colon we examined the role of these acid-base variables and carbonic anhydrase (CA) in oxalate and Cl− transport. In standard buffer both segments performed net oxalate secretion (and Cl− absorption), but only the colon, and the secretory pathway were responsive to and CO2. Ethoxzolamide abolished net oxalate secretion by the distal colon, and when used in tandem with an impermeant CA inhibitor, signaled an intracellular CA isozyme was required for secretion. There was a clear dependence on as their removal eliminated secretion, while at 42 mmol/L was also decreased and eradicated. Independent of pH, raising Pco2 from 28 to 64 mmHg acutely stimulated net oxalate secretion 41%. In summary, oxalate secretion by the distal colon was dependent on , CA and specifically modulated by CO2, whereas the ileum was remarkably unresponsive. These findings highlight the distinct segmental heterogeneity along the intestine, providing new insights into the oxalate transport mechanism and how it might be regulated. PMID:25716924

  8. Influence of Cerebral Blood Flow on Central Sleep Apnea at High Altitude

    PubMed Central

    Burgess, Keith R.; Lucas, Samuel J.E.; Shepherd, Kelly; Dawson, Andrew; Swart, Marianne; Thomas, Kate N.; Lucas, Rebekah A.I.; Donnelly, Joseph; Peebles, Karen C.; Basnyat, Rishi; Ainslie, Philip N.

    2014-01-01

    Study Objectives: To further our understanding of central sleep apnea (CSA) at high altitude during acclimatization, we tested the hypothesis that pharmacologically altering cerebral blood flow (CBF) would alter the severity of CSA at high altitude. Design: The study was a randomized, placebo-controlled single-blind study. Setting: A field study at 5,050 m in Nepal. Patients or Participants: We studied 12 normal volunteers. Interventions: Between days 5 to10 at high altitude, CBF velocity (CBFv) was increased by intravenous (IV) acetazolamide (10 mg/kg) and reduced by oral indomethacin (100 mg). Measurements and Results: Arterial blood gases, hypoxic and hypercapnic ventilatory responses, and CBFv and its reactivity to carbon dioxide were measured awake. Overnight polysomnography was performed. The central apnea-hypopnea index was elevated following administration of indomethacin (89.2 ± 43.7 to 112.5 ± 32.9 events/h; mean ± standard deviation; P < 0.05) and was reduced following IV acetazolamide (89.2 ± 43.7 to 47.1 ± 48.1 events/h; P < 0.001). Intravenous acetazolamide elevated CBFv at high altitude by 28% (95% confidence interval [CI]: 22-34%) but did not affect ventilatory responses. The elevation in CBFv was partly mediated via a selective rise in partial pressure of arterial carbon dioxide (PaCO2) (28 ± 4 to 31 ± 3 mm Hg) and an associated fall in pH (P < 0.01). Oral indomethacin reduced CBFv by 23% (95% CI: 16-30%), blunted CBFv reactivity, and increased the hypercapnic ventilatory response by 66% (95% CI: 30-102%) but had no effect on PaCO2 or pH. Conclusion: Our findings indicate an important role for cerebral blood flow regulation in the pathophysiology of central sleep apnea at high altitude. Citation: Burgess KR, Lucas SJE, Shepherd K, Dawson A, Swart M, Thomas KN, Lucas RAI, Donnelly J, Peebles KC, Basnyat R, Ainslie PN. Influence of cerebral blood flow on central sleep apnea at high altitude. SLEEP 2014;37(10):1679-1687. PMID:25197804

  9. [Assessment of brain perfusion by arterial spin-labeling MR imaging in qusai-moyamoya disease associated with Graves' disease].

    PubMed

    Hayashi, Hisako; Kawatani, Masao; Ohta, Genrei; Kometani, Hiroshi; Ohshima, Yusei

    2014-07-01

    We report a case of 12-year-old girl with Graves' disease who had presented with deterioration in physical and scholastic performances since 10 years of age. She had an episode of atonic seizure and difficulty in speech. Brain MRI revealed formation of moyamoya vessels and a lesion suggestive of ischemic changes in the left frontal lobe. Because of uncontrollable thyrotoxicosis with anti-thyroid drug, she received a subtotal thyroidectomy. Two months later, she received a shunt operation between left superficial temporal artery and middle cerebral artery. The postoperative arterial spin-labeling MR imaging demonstrated an improvement of brain perfusion in left frontal lobe compared with the preoperative one, and provided comparable results of angiography and acetazolamide-challenged 150-gas PET. Thus, arterial spin-labeling MR imaging seems useful for follow-up evaluation of brain perfusion in qusai-moyamoya disease. PMID:25154228

  10. 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

  11. [A case of transient ischemic attack of hemodynamic origin induced by postprandial hypotension].

    PubMed

    Sakima, Hirokuni; Isa, Katsunori; Nakachi, Koh; Shiroma, Kanako; Tokashiki, Takashi; Ohya, Yusuke

    2014-01-01

    An 82-year-old man had a transient ischemic attack (TIA) with symptoms of consciousness disturbance and right hemiparesis while resting in a sitting position after breakfast. His symptoms improved around 1 h after onset when he lied in a supine position and received intravenous hydration. Duplex carotid ultrasonography revealed severe stenosis of the left common carotid artery. A decrease in the brain perfusion reserve was confirmed by acetazolamide-stress brain perfusion scintigraphy. Moreover, ambulatory blood pressure monitoring revealed a reduction in systolic blood pressure below 90 mmHg after each meal, indicating postprandial hypotension (PPH). The PPH was improved by oral administration of α-glucosidase inhibitor without any subsequent recurrences of TIA. The patient was diagnosed with TIA of hemodynamic origin that was induced by PPH and exhibited severe carotid stenosis. PPH is common in elderly people, and it should be recognized as a significant trigger for ischemic cerebrovascular disease. PMID:24583593

  12. 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

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

    PubMed

    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

  14. 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

  15. The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis.

    PubMed

    Ke, Qing; He, Fangping; Lu, Lingping; Yu, Ping; Jiang, Yajian; Weng, Chen; Huang, Hui; Yi, Xin; Qi, Ming

    2015-12-01

    Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next-generation sequencing to identify a mutation in the calcium channel, voltage-dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis. PMID:26433613

  16. 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.

  17. Exome analysis of connective tissue dysplasia: death and rebirth of clinical genetics?

    PubMed

    Wilson, Golder N

    2014-05-01

    Exome results are reported for two patients with connective tissue dysplasia, one refining a clinical diagnosis of Ehlers-Danlos to Marfan syndrome, the other suggesting arthrogryposis derived from maternofetal Stickler syndrome. Patient 1 had mutations in transthyretin (TTR), fibrillin (FBN1), and a calcium channel (CACNA1A) gene suggesting diagnoses of transthyretin amyloidosis, Marfan syndrome, and familial hemiplegic migraines, respectively. Patient 2 presented with arthrogryposis that was correlated with his mother's habitus and arthritis once COL2A1 mutations suggestive of Stickler syndrome were defined. Although DNA results often defy prediction by the best of clinicians, these patients illustrate needs for ongoing clinical scholarship (e.g., to delineate guidelines for management of mutations like that for hyperekplexia in Patient 2) and for interpretation of polygenic change that is optimized by clinical genetic/syndromology experience (e.g., suggesting acetazolamide therapy for Patient 1 and explaining arthrogryposis in Patient 2). PMID:24664531

  18. Update on the pathophysiology and management of idiopathic intracranial hypertension

    PubMed Central

    Biousse, Valérie; Bruce, Beau B.; Newman, Nancy J.

    2012-01-01

    Idiopathic Intracranial Hypertension (IIH) is a disease of unknown etiology typically affecting young, obese women, producing a syndrome of increased intracranial pressure without identifiable cause. Despite a large number of hypotheses and publications over the past decade, the etiology is still unknown. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue, and cerebral venous abnormalities are areas of active study regarding IIH’s pathophysiology. There continues to be no evidence-based consensus or formal guidelines regarding management and treatment of the disease. Treatment studies show that the diagnostic lumbar puncture is a valuable intervention beyond its diagnostic importance, and that weight management is critical. However, open questions remain regarding the efficacy of acetazolamide, cerebrospinal fluid shunting procedures, and cerebral transverse venous sinus stenting. PMID:22423118

  19. Novel sulfonamide bearing coumarin scaffolds as selective inhibitors of tumor associated carbonic anhydrase isoforms IX and XII.

    PubMed

    Chandak, Navneet; Ceruso, Mariangela; Supuran, Claudiu T; Sharma, Pawan K

    2016-07-01

    Four novel scaffolds consisting of total 24 compounds (1a-1o, 2a-2c, 3a-3c and 4a-4c) bearing aromatic sulfonamide and coumarin moieties connected through various linkers were synthesized in order to synergize the inhibition potential of both the moieties against four selected human carbonic anhydrase isoforms (hCA I, II, IX & XII). All compounds were found to be potent inhibitors of tumor associated hCA IX & XII while at the same time required large amounts to inhibit off-targeted housekeeping hCA I & II. Selectivity was more pronounced against hCA II over I, and hCA XII over IX. Results were compared with antitumor drug acetazolamide. One derivative 2b of series 2 was found to be a better selective inhibitor of hCA IX and XII. PMID:27137360

  20. [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

  1. [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. PMID:27079408

  2. Neuro-ophthalmology and neuro-otology update.

    PubMed

    Gold, Daniel R; Zee, David S

    2015-12-01

    This review summarizes topical papers from the fields of neuro-ophthalmology and neuro-otology published from August 2013 to February 2015. The main findings are: (1) diagnostic criteria for pseudotumor cerebri have been updated, and the Idiopathic Intracranial Hypertension Treatment Trial evaluated the efficacy of acetazolamide in patients with mild vision loss, (2) categorization of vestibular disorders through history and ocular motor examination is particularly important in the acute vestibular syndrome, where timely distinction between a central or peripheral localization is essential, (3) the newly described "sagging eye syndrome" provides a mechanical explanation for an isolated esodeviation that increases at distance in the aging population and (4) eye movement recordings better define how cerebellar dysfunction and/or sixth nerve palsy may play a role in other patients with esodeviations that increase at distance. PMID:26122540

  3. Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension.

    PubMed

    Bidot, Samuel; Bruce, Beau B

    2015-10-01

    Idiopathic intracranial hypertension (IIH) is a rare disorder occurring more frequently in obese women of childbearing age, resulting in increased intracranial pressure (ICP) from an unknown cause. Recent advances in epidemiology, imaging, and treatment have provided a better understanding of IIH in recent years, with better identification of visual risk factors and atypical forms of IIH, including fulminant IIH and spontaneous cerebrospinal fluid leaks, and a randomized clinical trial providing the rationale for the use of acetazolamide. In addition, a revised version of the modified Dandy criteria for the diagnosis of IIH was suggested in 2013, with better definition of IIH in adults and children; however, controversy regarding nomenclature has precluded its acceptance among IIH experts. Finally, questions regarding the best surgical strategy, the indications for venous sinus stenting, and the diagnostic role of the radiologic findings commonly seen in IIH have remained unanswered. PMID:26444398

  4. Complete ophthalmoplegia: A rare presentation of idiopathic intracranial hypertension

    PubMed Central

    Wani, Irfan Yousuf; Verma, Sawan; Wani, Mushtaq; Asimi, Ravouf; Sheikh, Saleem; Wani, Maqbool; Sheikh, Nawaz; Shah, Irfan; Mushtaq, Mudasir

    2015-01-01

    Idiopathic intracranial hypertension (IIH) is a disorder defined by clinical criteria that include signs and symptoms isolated to those produced by increased intracranial pressure (ICP; e. g., headache, papilledema, and vision loss), elevated ICP with normal cerebrospinal fluid (CSF) composition, and no other cause of intracranial hypertension evident on neuroimaging or other evaluations. The most common signs in IIH are papilledema, visual field loss, and unilateral or bilateral sixth cranial nerve palsy. Here we report a case of IIH presenting as headache with vision loss, papilledema, complete ophthalmoplegia with proptosis in one eye, and sixth cranial nerve palsy in the other eye. Patient was managed with acetazolamide, topiramate, and diuretics. Symptoms remained static and she was planned for urgent CSF diversion procedure. PMID:26713027

  5. [Characteristic neurological features, differential diagnostic criteria and medicinal treatment of idiopathic intracranial hypertension].

    PubMed

    Willenborg, K-D; Nacimiento, W

    2015-10-01

    Persistent headache and loss of visual acuity combined with papilledema are the predominant symptoms of idiopathic intracranial hypertension (IIH). The clinical signs are not different from those seen in other diseases with elevated intracranial pressure. To differentiate primary and secondary forms of increased intracranial pressure neuroimaging procedures and analysis of cerebrospinal fluid (CSF) are absolutely essential according to national and international guidelines. Lumbar puncture reveals an elevated opening pressure in cases of IIH as the only pathological finding. Treatment options are serial lumbar punctures combined with body weight reduction as well as medication with carbonic anhydrase inhibitors, such as acetazolamide and topiramate or diuretic therapy with furosemide. In some patients surgical options, e.g. optic nerve sheath fenestration, CSF shunting procedures including ventriculoperitoneal and lumboperitoneal shunt systems and bariatric surgery also have to be considered. In recent years modern neuroradiological procedures have also been applied (e.g. venous stenting in cases of sinus obstruction) in some centers. PMID:26377103

  6. Tonsillar Herniation After Lumbar Puncture in Idiopathic Intracranial Hypertension.

    PubMed

    Borire, Adeniyi A; Hughes, Andrew R; Lueck, Christian J

    2015-09-01

    A 30-year-old woman with coexisting renal tubular acidosis and idiopathic intracranial hypertension (IIH), treated with acetazolamide, experienced coning (cerebellar tonsillar herniation) after a lumbar puncture (LP). Brain magnetic resonance imaging at initial diagnosis of IIH showed minor tonsillar descent and computed tomographic venography revealed hypoplasia of the left transverse sinus. The patient previously had three uneventful LPs, all of which showed high opening pressures and normal cerebrospinal fluid composition. In retrospect, it was noted that her serum bicarbonate had fallen to 9 mmol/L (normal: 22-28 mm/L) 1 week before the LP. We hypothesize that the combination of cerebral edema (due to worsening metabolic acidosis), poor venous drainage, and preexisting minor tonsillar descent contributed to her post-LP coning. PMID:25786203

  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. Cystoid macular edema in a patient with Danon disease.

    PubMed

    Mack, Heather G

    2014-12-01

    To report a patient with Danon retinopathy with cystoid macular edema treated with topical dorzolamide 2% eye drops and oral acetazolamide. A 37-year-old Caucasian man with Danon disease treated with topical and oral carbonic anhydrase inhibitors participated in the study. Examinations performed before and during treatment included visual acuity (VA), spectral-domain optical coherence tomography, and electroretinography. Following total 48 weeks of treatment, VA decreased from 20/30 OD, 20/200 OS, to 20/40 OD, CF OS. The mean central retinal thickness was unchanged from baseline 263 μm OD , 226 μm OS, after treatment 283 μm OD and 202 μm OS. In our case, carbonic anydrase inhibitors were not effective. However, a general recommendation cannot be given based on a single case. PMID:23571262

  9. 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

  10. 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

  11. 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.

  12. 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. PMID:3129680

  13. 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

  14. 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

  15. Stimulation of chloride transport by HCO/sub 3/-CO/sub 2/ in rabbit cortical collecting tubule

    SciTech Connect

    Tago, K.; Schuster, V.L.; Stokes, J.B.

    1986-07-01

    The authors examined both the role of HCO/sub 3/-CO/sub 2/ in Cl transport as well as the effect of in vivo acid-base status on Cl transport by the rabbit cortical collecting tubule. The lumen-to-bath /sup 36/Cl tracer flux, expressed as the rate coefficient K/sub Cl/, was measured in either HEPES-buffered (CO/sub 2/-free) or HCO/sub 3/-CO/sub 2/-containing solutions. Amiloride was added to the perfusate to minimize the transepithelial voltage and thus the electrical driving force for Cl diffusion. Because K/sub Cl/ fell spontaneously with time in HCO/sub 3/-CO/sub 2/ solutions in the absence but not the presence of cAMP, they used cAMP throughout to avoid time-dependent changes. Acute in vitro removal of bath HCO/sub 3/-CO/sub 2/ reduced K/sub Cl/. Acetazolamide addition in HEPES-buffered solutions also lowered K/sub Cl/; K/sub Cl/ could be restored to control values by adding exogenous HCO/sub 3/-CO/sub 2/ in the presence of acetazolamide. In vivo acid-base effects on Cl transport were determined by dissecting tubules from either NaHCO/sub 3/-loaded or NH/sub 4/Cl-loaded rabbits. Most of this effect of HCO/sub 3/-CO/sub 2/ addition on K/sub Cl/ could not be accounted for by Cl-HCO/sub 3/ exchange; rather, it appeared due to stimulation of Cl self exchange. The data are consistent with /sup 36/Cl transport occurring via Cl-HCO/sub 3/ exchange as well as Cl self exchange. Both processes are acutely stimulated by HCO/sub 3/ and/or CO/sub 2/, and both are chronically regulated by in vivo acid-base status.

  16. Quantitative pharmacologic MRI in mice.

    PubMed

    Perles-Barbacaru, Teodora-Adriana; Procissi, Daniel; Demyanenko, Andrey V; Jacobs, Russell E

    2012-04-01

    Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a noninvasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in deferring brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique, with temporal resolution of one min at high magnetic field. The tissue half-life of the USPIOs was studied using a nonlinear detrending model. The three USPIOs are candidates for CBV weighted phMRI experiments, with r(2)/r(1) ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo-time of about 10 ms or longer results in a functional contrast to noise ratio (fCNR) > 75 after USPIO injection, with negligible decrease between 1.5-2 h. phMRI experiments were conducted at 7 T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters, and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI results showed that CBV was reduced in the normal mouse brain after cocaine challenge, with the largest effects in the nucleus accumbens, whereas after acetazolamide, blood volume was increased in both cerebral and extracerebral tissue. PMID:21793079

  17. Perspective: Update on Idiopathic Intracranial Hypertension

    PubMed Central

    Bruce, Beau B.; Biousse, Valérie; Newman, Nancy J.

    2011-01-01

    Purpose Provide an update on various features of idiopathic intracranial hypertension. Design Perspective. Methods Selected articles on the epidemiology, clinical and imaging features, natural history, pathophysiology, and treatment of idiopathic intracranial hypertension were reviewed and interpreted in the context of the authors’ clinical and research experience. Results Idiopathic intracranial hypertension is primarily a disease of obese women of childbearing age, but it can affect patients of any weight, sex, and age. Although a relatively rare disorder, idiopathic intracranial hypertension’s associated costs in the U.S. entail hundreds of millions of dollars. Even following treatment, headaches are frequently persistent and may require the continued involvement of a neurologist. Quality of life reductions and depression are common among idiopathic intracranial hypertension patients. However, visual dysfunction, especially visual field abnormalities, represents the major morbidity of this disorder, and serial automated perimetry remains the primary mode of patient monitoring. Patients who are men, black, very obese, or anemic are at higher risk of visual loss. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue, and cerebral venous abnormalities are areas of active study regarding idiopathic intracranial hypertension’s pathophysiology. Treatment studies show that lumbar puncture is a valuable treatment (in addition to its crucial diagnostic role) and that weight management is critical. However, open questions remain regarding the efficacy of acetazolamide, CSF diversion procedures, and cerebral venous stenting. Conclusions Many questions remain unanswered about idiopathic intracranial hypertension. Ongoing studies, especially an ongoing NIH-funded clinical trial of acetazolamide, should provide more insight into this important, yet poorly understood syndrome of isolated intracranial hypertension. PMID:21696699

  18. 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

  19. 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.

  20. Investigation of tubular handling of bicarbonate in man. A new approach utilizing stable carbon isotope fractionation.

    PubMed Central

    Burbea, Z H; Luz, B; Lazar, B; Winaver, J; Better, O S

    1983-01-01

    Two alternative mechanisms have been proposed for tubular reabsorption of bicarbonate: (a) H+ secretion and CO2 reabsorption and (b) direct reabsorption of HCO-3. In an attempt to differentiate between the two mechanisms, the present study utilized the natural abundance of stable carbon isotopes (13C, 12C) in the urinary total CO2. This novel methodology used mass spectrometric analysis of 13C/12C ratios in urinary total CO2 under normal conditions and during acetazolamide treatment. Blood and respiratory CO2 were analyzed to yield reference values. The results demonstrate that alkaline urine is preferentially enriched with 13C relative to the blood. It is suggested that this fractionation results from reaction out of isotopic equilibrium in which HCO-3 converts to CO2 during the reabsorption process in the distal nephron. The presence of carbonic anhydrase in the proximal nephron results in rapid isotopic exchange between CO2 and HCO-3 and keeps them in isotopic equilibrium. The ratio of urinary 13C/12C increases strikingly after acetazolamide administration and consequent inhibition of carbonic anhydrase in the proximal tubule. Although it is possible that in the latter case high HCO-3 generates the CO2 (ampholyte effect), the isotope fractionation indicates that CO2 rather than HCO-3 is reabsorbed. In contrast, at low urinary pH and total CO2 values, the carbon isotope composition approaches that of blood CO2. This indicates rapid CO2 exchange between urine and blood, through luminal membrane highly permeable to CO2. These results could be anticipated by a mathematical model constructed to plot 13C concentration of urinary total CO2. It is concluded that the mechanism of HCO-3 reclamation in man (and, by inference, in other mammals as well) works by conversion of HCO-3 to CO2 and reabsorption of CO2. PMID:6417168

  1. 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

  2. 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

  3. Effectiveness of spray congealing to obtain physically stabilized amorphous dispersions of a poorly soluble thermosensitive API.

    PubMed

    Kulthe, Viraj Vitthal; Chaudhari, Pravin Digambar

    2014-12-01

    An amorphous phase produced by micronization up to the molecular or colloidal level of a poorly soluble drug having low lipophilicity can distinctly enhance its solubility characteristics. However, though dispersing the molten mass of a poorly water-soluble drug within polymeric matrix has been found to be most effective in formation of molecular dispersions, the drug molecules which melt at high temperature also accompanied by decomposition, such as acetazolamide, are difficult to formulate as molecular dispersions. Hence, a method is proposed to obtain molecular dispersions of acetazolamide with poloxamer-237 by spray congealing under optimal heat treatment. Uniform molecular and/or colloidal dispersions of the drug were achieved with instantaneous solvent evaporation by mixing a drug solution with molten mass of the plasticizer matrix. Immobilization of dispersed drug molecules was effected subsequently through rapid solidification by spray congealing. Initial characterization of 1:1, 1:1.5, and 1:2 ratios of solid dispersions and devitrification study of an optimized (1:2) ratio ensured efficacy of the proposed method in formation of physically stabilized amorphous systems without thermal degradation and hence resulted in more than ninefold rise in solubility and more than 90% dissolution within initial 10 min. With 1:2 ratio, molecular dispersions could be achieved by initial solvent evaporation stage, which when subjected to spray congealing produced physically stable amorphous systems, without signs of thermal degradation. This study also proposes an opportunity for selection of those polymers with which the drug is immiscible in their fluid state, yet obtaining molecular dispersions. PMID:24934386

  4. Optic nerve sheath diameter is not related to high altitude headache: a randomized controlled trial.

    PubMed

    Lawley, Justin Stevan; Oliver, Samuel James; Mullins, Paul; Morris, Daniel; Junglee, Naushad Ali; Jelleyman, Charlotte; Macdonald, Jamie Hugo

    2012-09-01

    The mechanism of high altitude headache (HAH) remains unknown. The aim of this study was to determine experimentally whether optic nerve sheath diameter (ONSD), as an indicator of intracranial pressure, is related to HAH. Following sea level measurements at 3 and 12 hours (SL), 23 subjects were passively transported to high altitude (3777 m, HA) via cable car. HAH, ONSD, arterial oxygen saturation (Spo(2)), and fluid balance were determined at 3, 12, 24, and 36 hours. After 12 hours exposure to HA, subjects were classified by visual analogue scale (VAS) as either HAH positive (HAH+) or HAH negative (HAH-). Acetazolamide (250 mg) or placebo was then randomly prescribed at 15, 20, and 28 hours. Outcome means were compared via analysis of variance, and relationships between variables were analyzed by longitudinal regression. Acetazolamide had no statistically significant effect on HAH (p=0.63) or ONSD (p=0.98), but produced a negative fluid balance (p<0.01) (and also increased Spo(2) in exploratory analyses). Spo(2) was lower in HAH+ than HAH- [85 (3)% versus 88 (2)%, p=0.03). Nevertheless, ONSD increased similarly in HAH+ and HAH- (interaction p=0.90). ONSD also remained significantly elevated above SL values for the entire HA period [SL, 5.2 (0.5) versus HA, 5.6 (0.5) mm, p<0.01], despite headache resolving with acclimatization [VAS: SL, 1/100 (3) mm versus HA 3 h, 9/100 (13); 12 h, 10/100 (14); 24 h, 8/100 (12); 36 h, 1/100 (4) mm, p<0.01]. Furthermore, HAH was significantly correlated with Spo(2) (β=-1.39, p<0.01) but not with ONSD (β=0.59, p=0.57). These data do not support that intracranial pressure is associated with the development or amelioration of mild HAH. Clinical trial registration NCT01288781. PMID:22994519

  5. 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

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

    PubMed Central

    Occhipinti, Rossana; Boron, Walter F.

    2014-01-01

    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. PMID:24965587

  7. 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

  8. Apical ammonium inhibition of cAMP-stimulated secretion in T84 cells is bicarbonate dependent.

    PubMed

    Worrell, Roger T; Best, Alison; Crawford, Oscar R; Xu, Jie; Soleimani, Manoocher; Matthews, Jeffrey B

    2005-10-01

    Normal human colonic luminal (NH(4)(+)) concentration ([NH(4)(+)]) ranges from approximately 10 to 100 mM. However, the nature of the effects of NH(4)(+) on transport, as well as NH(4)(+) transport itself, in colonic epithelium is poorly understood. We elucidate here the effects of apical NH(4)(+) on cAMP-stimulated Cl(-) secretion in colonic T84 cells. In HEPES-buffered solutions, 10 mM apical NH(4)(+) had no significant effect on cAMP-stimulated current. In contrast, 10 mM apical NH(4)(+) reduced current within 5 min to 61 +/- 4% in the presence of 25 mM HCO(3)(-). Current inhibition was not simply due to an increase in extracellular K(+)-like cations, in that the current magnitude was 95 +/- 5% with 10 mM apical K(+) and 46 +/- 3% with 10 mM apical NH(4)(+) relative to that with 5 mM apical K(+). We previously demonstrated that inhibition of Cl(-) secretion by basolateral NH(4)(+) occurs in HCO(3)(-)-free conditions and exhibits anomalous mole fraction behavior. In contrast, apical NH(4)(+) inhibition of current in HCO(3)(-) buffer did not show anomalous mole fraction behavior and followed the absolute [NH(4)(+)] in K(+)-NH(4)(+) mixtures, where K(+) concentration + [NH(4)(+)] = 10 mM. The apical NH(4)(+) inhibitory effect was not prevented by 100 microM methazolamide, suggesting no role for apical carbonic anhydrase. However, apical NH(4)(+) inhibition of current was prevented by 10 min of pretreatment of the apical surface with 500 microM DIDS, 100 microM 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS), or 25 microM niflumic acid, suggesting a role for NH(4)(+) action through an apical anion exchanger. mRNA and protein for the apical anion exchangers SLC26A3 [downregulated in adenoma (DRA)] and SLC26A6 [putative anion transporter (PAT1)] were detected in T84 cells by RT-PCR and Northern and Western blots. DRA and PAT1 appear to associate with CFTR in the apical membrane. We conclude that the HCO(3)(-) dependence of apical NH(4)(+) inhibition of secretion is

  9. 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

  10. CO2 chemosensing in rat oesophagus

    PubMed Central

    Akiba, Y; Mizumori, M; Kuo, M; Ham, M; Guth, P H; Engel, E; Kaunitz, J D

    2016-01-01

    Background Acid in the oesophageal lumen is often sensed as heartburn. It was hypothesised that luminal CO2, a permeant gas, rather than H+, permeates through the epithelium, and is converted to H+, producing an afferent neural signal by activating chemosensors. Methods The rat lower oesophageal mucosa was superfused with pH 7.0 buffer, and pH 1.0 or pH 6.4 high CO2 (PCO2 = 260 Torr) solutions with or without the cell-permeant carbonic anhydrase (CA) inhibitor methazolamide (MTZ, 1 mM), the cell-impermeant CA inhibitor benzolamide (BNZ, 0.1 mM), the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine (CPZ, 0.5 mM) or the acid-sensing ion channel (ASIC) inhibitor amiloride (0.1 mM). Interstitial pH (pHint) was measured with 5′,6′-carboxyfluorescein (5 mg/kg intravenously) loaded into the interstitial space, and blood flow was measured with laser-Doppler. Results Perfusion of a high CO2 solution induced hyperaemia without changing pHint, mimicking the effect of pH 1.0 perfusion. Perfused MTZ, BNZ, CPZ and amiloride all inhibited CO2-induced hyperaemia. CA XIV was expressed in the prickle cells, with CA XII in the basal cells. TRPV1 was expressed in the stratum granulosum and in the muscularis mucosa, whereas all ASICs were expressed in the prickle cells, with ASIC3 additionally in the muscularis mucosa. Conclusions The response to CO2 perfusion suggests that CO2 diffuses through the stratum epithelium, interacting with TRPV1 and ASICs in the epithelium or in the submucosa. Inhibition of the hyperaemic response to luminal CO2 by CA, TRPV1 and ASIC inhibitors implicates CA and these chemosensors in transduction of the luminal acid signal. Transepithelial CO2 permeation may explain how luminal H+ equivalents can rapidly be transduced into hyperaemia, and the sensation of heartburn. PMID:18682519

  11. The Role of Epithelial Sodium Channel ENaC and the Apical Cl-/HCO3- Exchanger Pendrin in Compensatory Salt Reabsorption in the Setting of Na-Cl Cotransporter (NCC) Inactivation

    PubMed Central

    Patel-Chamberlin, Mina; Varasteh Kia, Mujan; Xu, Jie; Barone, Sharon; Zahedi, Kamyar; Soleimani, Manoocher

    2016-01-01

    Background The absence of NCC does not cause significant salt wasting in NCC deficient mice under basal conditions. We hypothesized that ENaC and pendrin play important roles in compensatory salt absorption in the setting of NCC inactivation, and their inhibition and/or downregulation can cause significant salt wasting in NCC KO mice. Methods WT and NCC KO mice were treated with a daily injection of either amiloride, an inhibitor of ENaC, or acetazolamide (ACTZ), a blocker of salt and bicarbonate reabsorption in the proximal tubule and an inhibitor of carbonic anhydrases in proximal tubule and intercalated cells, or a combination of acetazolamide plus amiloride for defined durations. Animals were subjected to daily balance studies. At the end of treatment, kidneys were harvested and examined. Blood samples were collected for electrolytes and acid base analysis. Results Amiloride injection significantly increased the urine output (UO) in NCC KO mice (from 1.3 ml/day before to 2.5 ml/day after amiloride, p<0.03, n = 4) but caused only a slight change in UO in WT mice (p>0.05). The increase in UO in NCC KO mice was associated with a significant increase in sodium excretion (from 0.25 mmol/24 hrs at baseline to 0.35 mmol/24 hrs after amiloride injection, p<0.05, n = 4). Daily treatment with ACTZ for 6 days resulted in >80% reduction of kidney pendrin expression in both WT and NCC KO mice. However, ACTZ treatment noticeably increased urine output and salt excretion only in NCC KO mice (with urine output increasing from a baseline of 1.1 ml/day to 2.3 ml/day and sodium excretion increasing from 0.22 mmole/day before to 0.31 mmole/day after ACTZ) in NCC KO mice; both parameters were significantly higher than in WT mice. Western blot analysis demonstrated significant enhancement in ENaC expression in medulla and cortex of NCC KO and WT mice in response to ACTZ injection for 6 days, and treatment with amiloride in ACTZ-pretreated mice caused a robust increase in salt

  12. The effect of carbon dioxide on the intracellular pH and buffering power of snail neurones.

    PubMed Central

    Thomas, R C

    1976-01-01

    1. Intracellular pH (pHi) was measured using pH-sensitive glass micro-electrodes. The effects on pHi of CO2 applied externally and HCO3-, H+ and NH4+ injected iontophoretically, were investigated. 2. The transport numbers for iontophoretic injection into aqueous micro-droples were found by potentiometric titration to be 0-3 for HCO3- and 0-94 for H+. 3. Exposure to Ringer, pH 7-5, equilibrated with 2-2% CO2 caused a rapid, but only transient, fall in pHi. Within 1 or 2 min pHi began to return exponentially to normal, with a time constant of about 5 min. 4. When external CO2 was removed, pHi rapidly increased, and then slowly returned to normal. The pHi changes with CO2 application or removal gave a calculated intracellular buffer value of about 30 m-equiv H+/pH unit per litre. 5. Injection of HCO3- caused a rise in pHi very similar to that seen on removal of external CO2. 6. The pHi responses to CO2 application, CO2 removal and HCO3- injection were slowed by the carbonic anhydrase inhibitor acetazolamide. 7. H+ injection caused a transient fall in pHi. In CO2 Ringer pHi fell less and recovered faster than in CO2-free Ringer. Calculation of the internal buffer value from the pHi responses to H+ and HCO3- injection gave very similar values. 8. The internal buffer value (measured by H+ injection) was greatly increased by exposure to CO2 Ringer. Acetazolamide reduced this effect of CO2, suggesting that the function of intracellular carbonic anhydrase may be to maximize the internal buffering power in CO2. 9. It was concluded that the internal HCO3- was determined primarily by the CO2 level and pHi, that internal HCO3- made a large contribution to the buffering power, and that after internal acidfication pHi was restored to normal by active transport of H+, OH- or HCO3- across the cell membrane. The active transport was much faster in CO2 than in CO2-free Ringer. PMID:4614

  13. 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

  14. [Mountaineering and altitude sickness].

    PubMed

    Maggiorini, M

    2001-06-01

    Almost every second trekker or climber develops two to three symptoms of the high altitude illness after a rapid ascent (> 300 m/day) to an altitude above 4000 m. We distinguish two forms of high altitude illness, a cerebral form called acute mountain sickness and a pulmonary form called high altitude pulmonary edema. Essentially, acute mountain sickness is self-limiting and benign. Its symptoms are mild to moderate headache, loss of appetite, nausea, dizziness and insomnia. Nausea rarely progresses to vomiting, but if it does, this may anticipate a progression of the disease into the severe form of acute mountain sickness, called high altitude cerebral edema. Symptoms and signs of high altitude cerebral edema are severe headache, which is not relieved by acetaminophen, loss of movement coordination, ataxia and mental deterioration ending in coma. The mechanisms leading to acute mountain sickness are not very well understood; the loss of cerebral autoregulation and a vasogenic type of cerebral edema are being discussed. High altitude pulmonary edema presents in roughly twenty percent of the cases with mild symptoms of acute mountain sickness or even without any symptoms at all. Symptoms associated with high altitude pulmonary edema are incapacitating fatigue, chest tightness, dyspnoe at the minimal effort that advances to dyspnoe at rest and orthopnoe, and a dry non-productive cough that progresses to cough with pink frothy sputum due to hemoptysis. The hallmark of high altitude pulmonary edema is an exaggerated hypoxic pulmonary vasoconstriction. Successful prophylaxis and treatment of high altitude pulmonary edema using nifedipine, a pulmonary vasodilator, indicates that pulmonary hypertension is crucial for the development of high altitude pulmonary edema. The primary treatment of high altitude illness consists in improving hypoxemia and acclimatization. For prophylaxis a slow ascent at a rate of 300 m/day is recommended, if symptoms persist, acetazolamide at a

  15. Cerenkov specific contrast agents for detection of pH in vivo

    PubMed Central

    Czupryna, Julie; Kachur, Alexander V.; Blankemeyer, Eric; Popov, Anatoliy V.; Karp, Joel S.; Delikatny, E. James

    2015-01-01

    We report the design, testing and in vivo application of pH sensitive contrast agents designed specifically for Cerenkov imaging. Radioisotopes used for positron emission tomography (PET) emit photons via Cerenkov radiation. The multispectral emission of Cerenkov radiation allows for selective bandwidth quenching, where a band of photons are quenched by absorption by a functional dye. Under acidic conditions, 18F-labeled derivatives emit the full spectrum of Cerenkov light. Under basic conditions, the dyes change color and a wavelength-dependent quenching of Cerenkov emission is observed. METHODS Mono and di-18F-labeled derivatives of phenolsulfonphthalein (phenol red) and meta-cresolsulfonphthalein (cresol purple) were synthesized by electrophilic fluorination. Cerenkov emission was measured at different wavelengths as a function of pH in vitro. Intramolecular response was measured in fluorinated probes; intermolecular quenching by mixing phenolphthalein with 18F FDG. Monofluorocresol purple (MFCP) was tested in mice treated with acetazolamide to cause urinary alkalinization and Cerenkov images compared to PET images. RESULTS Fluorinated pH indicators were produced with radiochemical yields of 4-11% at >90% purity. Selective Cerenkov quenching was observed intramolecularly with difluorophenol red or MFCP, and intermolecularly in phenolphthalein 18F-FDG mixtures. The probes were selectively quenched in the bandwidth closest to the indicator’s absorption maximum (λmax) at pHs above the indicator pKa. Addition of acid or base to the probes resulted in reversible switching from unquenched to quenched emission. In vivo, the bladders of acetazolamide-treated mice exhibited a wavelength-dependent quenching in Cerenkov emission, with the greatest reduction occurring near the λmax. Ratiometric imaging at two wavelengths showed significant decreases in Cerenkov emission at basic pH and allowed the estimation of absolute pH in vivo. CONCLUSIONS We have created contrast

  16. 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.

  17. 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

  18. 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.

  19. Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms.

    PubMed

    Buemi, Maria Rosa; De Luca, Laura; Ferro, Stefania; Bruno, Elvira; Ceruso, Mariangela; Supuran, Claudiu T; Pospíšilová, Klára; Brynda, Jiří; Řezáčová, Pavlína; Gitto, Rosaria

    2015-09-18

    A set of heteroaryl-N-carbonylbenzenesulfonamides has been designed, synthesized, and screened as inhibitors of human carbonic anhydrases (hCAs). The new sulfonamide derivatives were tested against hCA I, hCA II, hCA VII, hCA IX, and hCA XII isoforms using acetazolamide (AAZ, 1) and topiramate (TPM, 2) as reference compounds. Six compounds were low nanomolar inhibitors of tumor-associated hCA IX isoform (Ki values < 10 nM); among them we identified three arylsulfonamides showing unexpected inefficacy over brain distributed hCA VII isoform (hCA IX/hCA VII selectivity ratio > 1500 for compound 5c). Thus, these compounds can offer the opportunity to highlight the interactions preventing the inhibition of hCA VII mainly expressed in central nervous system. Thereby, we used structural and computational techniques to study in depth the interaction with hCAs. In an effort to confirm the inhibitory action we determined crystal structures of five selected heteroaryl-N-carbonylbenzenesulfonamides (4a, 4b, 4e, 5c, and 5e) in complex with hCA II. Moreover, to explore the lack of inhibitory effects of selected compounds (e.g.4b and 5c) we also performed docking studies into hCA VII catalytic site. PMID:26276436

  20. Photooxidation of dinitrophenylhistidine-200 human carbonic anhydrase B.

    PubMed

    Kandel, M; Gornall, A G; Lam, L K; Kandel, S I

    1975-05-01

    Partial inactivation of tau-dinitrophenylhistidine-200 human carbonic anhydrase B, induced by visible light, followed first order kinetics (k(app) = 6.05 times 10-2 min-1). After 50 min the tau-dinitrophenylhistidine (tau-DNP-histidine) content decreased to a negligible level, but the illuminated enzyme retained, at pH 7.6, approximately 9.2 percent of the esterase activity of the native enzyme. The following lines of evidence suggest that the loss of activity results from the destruction of tau-DNP-histidine-200. (1) No significant loss of amino acid other than tau-DNP-histidine was detected after illumination. (2) The rate of loss of activity correlated well with the loss of tau-DNP-histidine. (3) In the photooxidized enzyme the DNP moiety was retained but had lost the characteristic sensitivity of tau-DNP-histidine to nucleophilic attack. Titration of the illuminated enzyme with acetazolamide indicated that the residual activity is an intrinsic property of the modified enzyme. The chromatographically purified photooxidized enzyme migrated as a single band on isoelectrofocusing in polyacylamide gel, and at pH 7.6 possessed 7.5 percent esterase activity relative to the native enzyme. By establishing effective destruction of histidine-200, it can be concluded that neither the pi N nor, as previously shown, the tau N of histidine-200 is critical for the catalysis. PMID:237619

  1. High-altitude medicines: a short-term genotoxicity study.

    PubMed

    Ghosh, Manosij; Biswas, Dhrubojyoti; Mukherjee, Anita

    2010-08-01

    People live in the mountains distributed across the world and are exposed to reduced inspired oxygen and lower barometric pressure along with other factors that lead to high-altitude diseases. The present study was conducted to examine what extent of marketed medicines used in the management of high-altitude sickness has been tested for their genotoxic activity. Comet assay or the single-cell gel electrophoresis was utilized to evaluate genotoxicity of the six medicines on human peripheral whole blood cells and isolated lymphocytes at the concentrations 250 microg/mL, 500 microg/mL and 1 mg/mL. The comet assay endpoints included percentage Tail DNA (% Tail DNA) and olive tail moment (OTM) as they were considered to be sensitive and reliable scores across different laboratories. The results show that dexamethasone, deriphylline and furosemide can induce significant DNA damage in human whole blood and lymphocytes alike. Acetazolamide, ibuprofen and nifedipine show no genotoxic effect, neither on human whole blood nor on human lymphocytes. Taking into account the results of genotoxicity, it will be a prudent choice to restrict the use of these compounds for longer periods, until more information on the in vitro mutagenicity and in vivo genotoxicity studies are available. PMID:20504830

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. Angioid streaks - a rare cause of neovascular glaucoma. Case report.

    PubMed

    Ungureanu, E; Geamanu, A; Careba, I; Grecescu, M; Gradinaru, S

    2014-01-01

    Rationale. Neovascular glaucoma is the type of glaucoma most refractory to treatment. The most frequent causes are those associated with retinal hypoxia, such as proliferative diabetic retinopathy, central retinal vein occlusion, branch retinal vein occlusion, central retinal arterial occlusion, ischemic ocular syndrome etc. Rare causes of neovascular glaucoma are multiple and are due to VEGF synthesis associated with chorioretinal inflammations or degenerations. We present a case with neovascular glaucoma associated with an extremely rare cause, angioid streaks Objective. The objective of our prsentation was to asses efficacy of the 5-FU associated trabeculectomy following bevacizumab intravitreal administration Methods and results. Case report of a 48 years old female patient which presented at the emergency room with painful red left eye. At presentation best corrected left eye visual acuity was 1/10, intraocular pressure was 36 mm Hg. Examination established the diagnosis of Neovascular glaucoma associated with angioid streaks. After intravenous Manitol, oral Acetazolamide and topical treatment with fixed combination timolol-brinzolamide, topical steroid and mydriatic intraocular pressure decreased. Intravitreal bevacizumab injection was performed, followed after 3 weeks by trabeculectomy. Discussion. Angioid streaks are an extremely rare cause of neovascular glaucoma. The treatment is similar to the treatment for other causes of neovascular glaucoma. PMID:27057253

  8. Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety.

    PubMed

    Sethi, Kalyan K; Vullo, Daniella; Verma, Saurabh M; Tanç, Muhammet; Carta, Fabrizio; Supuran, Claudiu T

    2013-10-01

    A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000nM), but were moderately effective, as hCA II inhibitors (Kis of 47-190nM) and poor hCA VII inhibitors (Kis in the range of 54-175nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234nM and hCA XII with inhibition constants in the range of 6.1-197nM with high selectivity ratio. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here. PMID:23965175

  9. 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

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

    PubMed Central

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

    2014-01-01

    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. PMID:24895391

  11. 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

  12. Angioid streaks - a rare cause of neovascular glaucoma. Case report.

    PubMed Central

    Ungureanu, E; Geamanu, A; Careba, I; Grecescu, M; Gradinaru, S

    2014-01-01

    Rationale. Neovascular glaucoma is the type of glaucoma most refractory to treatment. The most frequent causes are those associated with retinal hypoxia, such as proliferative diabetic retinopathy, central retinal vein occlusion, branch retinal vein occlusion, central retinal arterial occlusion, ischemic ocular syndrome etc. Rare causes of neovascular glaucoma are multiple and are due to VEGF synthesis associated with chorioretinal inflammations or degenerations. We present a case with neovascular glaucoma associated with an extremely rare cause, angioid streaks Objective. The objective of our prsentation was to asses efficacy of the 5-FU associated trabeculectomy following bevacizumab intravitreal administration Methods and results. Case report of a 48 years old female patient which presented at the emergency room with painful red left eye. At presentation best corrected left eye visual acuity was 1/10, intraocular pressure was 36 mm Hg. Examination established the diagnosis of Neovascular glaucoma associated with angioid streaks. After intravenous Manitol, oral Acetazolamide and topical treatment with fixed combination timolol-brinzolamide, topical steroid and mydriatic intraocular pressure decreased. Intravitreal bevacizumab injection was performed, followed after 3 weeks by trabeculectomy. Discussion. Angioid streaks are an extremely rare cause of neovascular glaucoma. The treatment is similar to the treatment for other causes of neovascular glaucoma PMID:27057253

  13. The human carbonic anhydrase isoenzymes I and II (hCA I and II) inhibition effects of trimethoxyindane derivatives.

    PubMed

    Taslimi, Parham; Gulcin, Ilhami; Ozgeris, Bunyamin; Goksu, Suleyman; Tumer, Ferhan; Alwasel, Saleh H; Supuran, Claudiu T

    2016-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) had six genetically distinct families described to date in various organisms. There are 16 known CA isoforms in humans. Human CA isoenzymes I and II (hCA I and hCA II) are ubiquitous cytosolic isoforms. Acetylcholine esterase (AChE. EC 3.1.1.7) is a hydrolase that hydrolyzes the neurotransmitter acetylcholine relaying the signal from the nerve. In this study, some trimethoxyindane derivatives were investigated as inhibitors against the cytosolic hCA I and II isoenzymes, and AChE enzyme. Both hCA isozymes were inhibited by trimethoxyindane derivatives in the low nanomolar range. These compounds were good hCA I inhibitors (Kis in the range of 1.66-4.14 nM) and hCA II inhibitors (Kis of 1.37-3.12 nM) and perfect AChE inhibitors (Kis in the range of 1.87-7.53 nM) compared to acetazolamide as CA inhibitor (Ki: 6.76 nM for hCA I and Ki: 5.85 nM for hCA II) and Tacrine as AChE inhibitor (Ki: 7.64 nM). PMID:25697270

  14. Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII.

    PubMed

    Ibrahim, Hany S; Abou-Seri, Sahar M; Tanc, Muhammet; Elaasser, Mahmoud M; Abdel-Aziz, Hatem A; Supuran, Claudiu T

    2015-10-20

    New series of benzenesulfonamide derivatives incorporating pyrazole and isatin moieties were prepared using celecoxib as lead molecule. Biological evaluation of the target compounds was performed against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely against the human isoforms hCA I, II (cytosolic), IX and XII (transmembrane, tumor-associated enzymes). Most of the tested compounds efficiently inhibited hCA I, II and IX, with KIs of 2.5-102 nM, being more effective than the reference drug acetazolamide. Compounds 11e, 11f, 16e and 16f were found to inhibit hCA XII with Ki of 3.7, 6.5, 5.4 and 7.2 nM, respectively. Compounds 11e and 16e, with 5-NO2 substitution on the isatin ring, were found to be selective inhibitors of hCA IX and hCA XII. Docking studies revealed that the NO2 group of both compounds participate in interactions with Asp132 within the hCA IX active site, and with residues Lys67 and Asp130 in hCA XII, respectively. PMID:26408817

  15. 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. PMID:26778292

  16. Management of vestibular migraine.

    PubMed

    Bisdorff, Alexandre R

    2011-05-01

    Vestibular migraine is considered to be the second most common cause of vertigo and the most common cause of spontaneous episodic vertigo. The duration of attacks varies from seconds to days, usually lasting minutes to hours, and they mostly occur independently of headaches. Long-lasting individual attacks are treated with generic antivertiginous and antiemetic drugs. Specific antimigraine drugs are unlikely to be very effective for rescue. The mainstay of the management of vestibular migraine is prophylactic medication. To date, there are no controlled trials available; the body of knowledge builds on case series and retrospective or observational studies. Most drugs are also used for the prevention of migraine headaches. The choice of medication should be guided by its side effect profile and the comorbidities of patients. Betablockers such as propanolol or metoprolol are preferred in patients with hypertension but in the absence of asthma. Anticonvulsants include topiramate when patients are obese, valproic acid and lamotrigine. Lamotrigine is preferred if vertigo is more frequent than headaches. Calcium antagonists include verapamil and flunarizine. If patients have anxiety, tricyclic antidepressants such as amitryptiline or nortryptiline or SSRIs and benzodiazepines such as clonazepam are recommended. Acetazolamide is effective in rare genetic disorders related to migraine-like episodic ataxia; however, its place in vestibular migraine is still to be established. Nonpharmacological measures such as diet, sleep, hygiene and avoidance of triggers are recommended as they are for migraine. Vestibular rehabilitation might be useful when there are complications such as loss of confidence in balance or visual dependence. PMID:21694818

  17. Migraine-associated vertigo: diagnosis and treatment.

    PubMed

    Cha, Yoon-Hee

    2010-04-01

    Migraine-associated vertigo has become a well-recognized disease entity diagnosed based on a clinical history of recurrent vertigo attacks unexplained by other central or peripheral otologic abnormalities, which occurs in the patient with a history of migraine headaches. There is no international agreement on what spectrum of symptoms should be covered under this diagnosis, or what terminology should be used. The headaches and vestibular symptoms of migraine-associated vertigo may not be temporally associated, which often obscures the association. Diagnostic tests usually show nonspecific abnormalities that are also seen in patients with migraine who do not experience vestibular symptoms. Management generally follows the recommended treatment of migraine headaches, and includes dietary and lifestyle modifications and medical treatment with beta blockers, calcium channel blockers, and tricyclic amines. Small case series show that acetazolamide and lamotrigine appear to be more effective for the vertigo attacks than headaches. Vestibular rehabilitation has also been shown to be helpful in several studies. In this review, the epidemiologic and clinical features of the disorder, as well as the current state of knowledge on pathophysiology, diagnostic testing, and treatment are described. PMID:20352586

  18. [Pharmacotherapy of Vestibular Disorders, Nystagmus and Cerebellar Disorders].

    PubMed

    Feil, K; Böttcher, N; Kremmyda, O; Muth, C; Teufel, J; Zwergal, A; Brandt, T; Strupp, M

    2015-09-01

    There are currently different groups of drugs for the pharmacotherapy of vertigo, nystagmus and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications and antidepressants, anticonvulsants, aminopyridines as well as acetyl-DL-leucine. In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but currently there is not sufficient evidence for a general recommendation. There is insufficient evidence to support the view that 16 mg t. i. d. or 48 mg t. i. d. betahistine has an effect in Menière's disease. Therefore, higher dosages are recommended. In animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There has been no RCT on the efficacy of beta-blockers or topiramate but one RCT on flunarizine in vestibular migraine. Based on clinical experience, a treatment analogous to that for migraine without aura can be recommended. Acetyl-DL-leucine improved cerebellar ataxia (two observational studies); it also accelerated central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on treatment of vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT). PMID:26421856

  19. Posterior Ciliary Artery Occlusion Caused by Hyaluronic Acid Injections Into the Forehead

    PubMed Central

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

    2016-01-01

    Abstract 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

  20. Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations.

    PubMed

    Kim, Hunmin; Hwang, Hee; Cheong, Hae Il; Park, Hye Won

    2011-11-01

    Primary hypokalemic periodic paralysis (HOKPP) is an autosomal dominant disorder manifesting as recurrent periodic flaccid paralysis and concomitant hypokalemia. HOKPP is divided into type 1 and type 2 based on the causative gene. Although 2 different ion channels have been identified as the molecular genetic cause of HOKPP, the clinical manifestations between the 2 groups are similar. We report the cases of 2 patients with HOKPP who both presented with typical clinical manifestations, but with mutations in 2 different genes (CACNA1Sp.Arg528His and SCN4A p.Arg672His). Despite the similar clinical manifestations, there were differences in the response to acetazolamide treatment between certain genotypes of SCN4A mutations and CACNA1S mutations. We identified p.Arg672His in the SCN4A gene of patient 2 immediately after the first attack through a molecular genetic testing strategy. Molecular genetic diagnosis is important for genetic counseling and selecting preventive treatment. PMID:22253645

  1. SPECT functional brain imaging. Technical considerations.

    PubMed

    Devous, M D

    1995-07-01

    The technical aspects of functional brain single-photon emission computed tomography (SPECT) imaging, referring primarily to the most common SPECT brain function measure--regional cerebral blood flow--are reviewed. SPECT images of regional cerebral blood flow are influenced by a number of factors unrelated to pathology, including tomographic quality, radiopharmaceuticals, environmental conditions at the time of radiotracer administration, characteristics of the subject (e.g., age, sex), image presentation, and image processing techniques. Modern SPECT scans yield excellent image quality, and instrumentation continues to improve. The armamentarium of regional cerebral blood flow and receptor radiopharmaceuticals is rapidly expanding. Standards regarding the environment for patient imaging and image presentation are emerging. However, there is still much to learn about the circumstances for performances and evaluation of SPECT functional brain imaging. Challenge tests, primarily established in cerebrovascular disease (i.e., the acetazolamide test), offer great promise in defining the extent and nature of disease, as well as predicting therapeutic responses. Clearly, SPECT brain imaging is a powerful clinical and research tool. However, SPECT will only achieve its full potential in the management of patients with cerebral pathology through close cooperation among members of the nuclear medicine, neurology, psychiatry, neurosurgery, and internal medicine specialties. PMID:7626833

  2. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature.

    PubMed

    Nachbauer, Wolfgang; Nocker, Michael; Karner, Elfriede; Stankovic, Iva; Unterberger, Iris; Eigentler, Andreas; Schneider, Rainer; Poewe, Werner; Delazer, Margarete; Boesch, Sylvia

    2014-05-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant inherited neurological disorder that is characterized by paroxysmal episodes of ataxia. The causative gene for EA2 is CACNA1A which codes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel (Cav2.1). We detected a novel point mutation in the CACNA1A gene in a large Austrian family. All ten affected family members harbored a heterozygous c.3089+2T>C nucleotide exchange in intron 19. In silico modeling demonstrated a loss of the splice site of exon 19 by the mutation, which most likely results in exon skipping without frameshifting or use of an alternative splice site.Clinically, the family exhibited frequent ataxic episodes accompanied by headache in some individuals, which showed a good treatment response to acetazolamide or aminopyridine. Interictal phenotype variability was high ranging from an unremarkable clinical examination to a progressive cerebellar syndrome. Detailed cognitive testing with standardized neuropsychological tests revealed specific deficits in various domains including memory,executive functions and visual abilities. Moreover, a striking coincidence of socio-phobic behavior and anxiety disorders was detected within this family, which interfered with activities of daily living and has to be taken in consideration in EA2 patient management. We here characterize the phenotype of this novel CACNA1A mutation,review the respective literature and discuss implications on diagnosis and patient management. PMID:24658662

  3. 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. PMID:24768804

  4. 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. PMID:25468264

  5. 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. PMID:24836863

  6. A negative cranial computed tomographic scan is not adequate to support a diagnosis of pseudotumor cerebri.

    PubMed

    Said, Rana R; Rosman, N Paul

    2004-08-01

    A 10-year-old boy with daily headache for 1 month and intermittent diplopia for 1 week was found to have a unilateral partial abducens palsy and bilateral papilledema; otherwise, his neurologic examination showed no abnormalities. A cranial computed tomographic (CT) scan was normal. Lumbar puncture disclosed a markedly elevated opening pressure of > 550 mm of cerebrospinal fluid with normal cerebrospinal fluid. Medical therapy with acetazolamide for presumed pseudotumor cerebri was begun. Magnetic resonance imaging (MRI) of the brain, done several days later because of continuing symptoms, unexpectedly showed multiple hyperintensities of cerebral white matter on T2-weighted and fluid-attenuated inversion recovery images. Despite high-dose intravenous methylprednisolone for possible demyelinating disease, he failed to improve. A left temporal brain biopsy followed and disclosed an anaplastic oligodendroglioma. In a patient with features indicating pseudotumor cerebri, a negative cranial CT scan is not adequate to rule out underlying pathology; thus, MRI of the brain should probably always be performed. A revised definition of pseudotumor cerebri could better include "normal MRI of the brain" rather than "normal neuroimaging." PMID:15605471

  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. [Treatment of idiopathic intracranial hypertension by endovascular improvement of venous drainage of the brain].

    PubMed

    Aguilar-Pérez, M; Henkes, H

    2015-10-01

    Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a syndrome of elevated intracranial pressure (ICP) in the absence of any known causative factor. Most patients with IIH respond to weight reduction, repeated lumbar punctures and carbonic anhydrase inhibitors, such as acetazolamide and topiramate to reduce cerebrospinal fluid (CSF) production. Despite a number of pathogenetic theories, the cause of IIH remains unknown. With the availability of magnetic resonance (MR) venography and cerebral angiography, venous disease is increasingly being discussed as the etiology of IIH, with a high proportion of patients presenting with nonthrombotic unilateral or bilateral dural venous sinus stenoses. Based on this observation, endovascular stenting of stenotic dural sinuses in patients with IIH has gained popularity. Whether dural venous sinus stenoses are the cause or the consequence of increased ICP is still under debate. In patients with failure of conservative treatment or non-compliance, a more aggressive treatment, such as CSF shunting or surgical optic nerve fenestration, should be performed. For approximately 13 years endovascular stenting of the stenotic sinuses has been used and discussed as an alternative and effective treatment of IIH. Since the first report in 2002, individual cases and case series have been published demonstrating that stents immediately lower the venous pressure gradient, which is associated with clinical improvement. This effect occurs within days or weeks and is permanent in many cases. PMID:26400795

  9. 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

  10. Pseudotumour cerebri in acute promyelocytic leukemia on treatment with all-trans-retinoic acid (ATRA) - an experience from a tertiary care centre.

    PubMed

    Ahmad Tali, Manzoor; Bashir, Yasir; Bhat, Shuaeb; Manzoor, Fahim; Bashir, Nusrat; Geelani, Sajad; Rasool, Javid; Waheed Mir, Abdul

    2015-08-01

    Acute promyelocytic leukemia (APML) is considered to be sensitive to all-trans-retinoic acid (ATRA) which acts as a differentiating agent. ATRA is considered to be a well-tolerated agent and is known to achieve complete remission in acute promyelocytic leukemia. However, a few cases on long term all-trans-retinoic acid (ATRA) use can develop pseudotumor cerebri. Out of 32 patients with APML who were treated in our Centre over a 4-year-period, we encountered 6 patients who developed ATRA-related pseudotumor cerebri while on maintenance treatment. The patients ranged from 12 to 40 years of age. 3 patients complained of unbearable headache, 2 of diplopia and 1 of gross reduction in visual acuity. CT scans and MRI did not reveal any intracranial lesions. Cerebrospinal fluid (CSF) examination was normal with CSF manometry revealing a high CSF pressure (average of 345mmH2O). Fundoscopy revealed papilledema in 5 patients and optic atrophy in 1 patient. The patients were successfully managed with decrease dose/discontinuation of ATRA, use of acetazolamide, corticosteroids and therapeutic CSF drainage. PMID:26277671

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

    PubMed

    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

  12. Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions.

    PubMed

    Markey, Keira A; Mollan, Susan P; Jensen, Rigmor H; Sinclair, Alexandra J

    2016-01-01

    Idiopathic intracranial hypertension is a disorder characterised by raised intracranial pressure that predominantly affects young, obese women. Pathogenesis has not been fully elucidated, but several causal factors have been proposed. Symptoms can include headaches, visual loss, pulsatile tinnitus, and back and neck pain, but the clinical presentation is highly variable. Although few studies have been done to support evidence-based management, several recent advances have the potential to enhance understanding of the causes of the disease and to guide treatment decisions. Investigators of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) reported beneficial effects of acetazolamide in patients with mild visual loss. Studies have also established weight loss as an effective disease-modifying treatment, and further clinical trials to investigate new treatments are underway. The incidence of idiopathic intracranial hypertension is expected to increase as rates of obesity increase; efforts to reduce diagnostic delays and identify new, effective approaches to treatment will be key to meeting the needs of a growing number of patients. PMID:26700907

  13. 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

  14. [Mountain sickness].

    PubMed

    Bultas, Jan

    2015-01-01

    Mountaineering brings many health risks, one of which is mountain sickness. Its mildest form - acute mountain sickness - is mainly characterized by subjective symptoms (headache, loss of appetite, insomnia, weakness, nausea and rarely also vomiting). Advanced and life-threatening forms are characterized by tissue edema - cerebral or pulmonary high altitude edema. The common denominator of these acute forms is the low oxygen tension leading to hypoxemia and tissue ischemia. Sum of maladaptive or adaptive processes can modify the clinical picture. Underlying mechanisms of the chronic forms of pulmonary disease are the adaptation processes - pulmonary hypertension and polycythemia leading to heart failure.The only causal therapeutic intervention is to restore adequate oxygen tension, descend to lower altitudes or oxygen therapy. Pharmacotherapy has only a supportive effect. The prophylaxis includes stimulation of the respiratory center by carbonic anhydrase inhibitors (acetazolamide) antiedematous treatment with glucocorticoids (dexamethasone), increase lymphatic drainage of the lungs and brain by β2-agonists (salmeterol) or mitigation of pulmonary hypertension by calcium channel blockers or phosphodiesterase-5 inhibitors (sildenafil or tadalafil). PMID:26750624

  15. 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.

  16. Contemporary Insights and Novel Treatment Approaches to Central Sleep Apnea Syndrome in Heart Failure

    PubMed Central

    Grayburn, Ryan L.; Kaka, Yaquta; Wilson Tang, W. H.

    2014-01-01

    Opinion Statement Central sleep apnea (CSA) is a common and under-diagnosed condition commonly associated with Cheyne-Stokes respiration. It is particularly prevalent in the heart failure population affecting up to 40% of all patients with heart failure. The pathophysiology associated with CSA is based on the underlying effects of hypoventilation and hyperventilation, with neurologic dysregulation of respiratory control as the primary defect. However, therapeutic options are limited due to the prevailing perception that CSA is a consequence, rather than cause of morbidity and mortality. At present, the main focus remains treating the underlying problem (ie intensifying heart failure therapeutics, decongestion), while additional suggestions of using acetazolamide, progesterone, nocturnal oxygen, and theophylline have not been validated with contemporary clinical trials. Positive pressure ventilation is currently the primary recommendation for all patients with sleep-disordered breathing (CSA included), and in some patients may effectively reduce the apnea-hypopnea index. However, significant research is ongoing to determine how to treat this complex patient population. PMID:24874028

  17. 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

  18. The many faces of Glut1 deficiency syndrome.

    PubMed

    Tzadok, Michal; Nissenkorn, Andreea; Porper, Keren; Matot, Israel; Marcu, Shai; Anikster, Yair; Menascu, Shay; Bercovich, Dani; Ben Zeev, Bruria

    2014-03-01

    Glucose transporter protein type 1 deficiency syndrome is a metabolic disorder manifesting as cognitive impairment, acquired microcephaly, epilepsy, and/or movement disorder caused by mutations in the SLC2A1 gene. We describe a cohort of isolated and familial cases of glucose transporter protein type 1 deficiency syndrome, emphasizing seizure semiology, electroencephalographic (EEG) features, treatment response and mutation pathogenicity. SLC2A1 mutations were detected in 3 sporadic and 4 familial cases. In addition, mutations were identified in 9 clinically unaffected family members in 2 families. The phenotypic spectrum of glucose transporter protein type 1 deficiency is wider than previously recognized, with considerable intra-familial variation. Diagnosis requires either hypoglycorrachia followed by SLC2A1 sequencing or direct gene sequencing. A ketogenic diet should be the first line of treatment, but more flexible diets, like the Atkins modified diet, can also be followed. Carbonic anhydrase inhibitors, such as acetazolamide or zonisamide, can be effective for seizure control. PMID:23340081

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

    PubMed Central

    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

  20. Bicarbonate-water interactions in the rat proximal convoluted tubule. An effect of volume flux on active proton secretion

    PubMed Central

    1984-01-01

    The effect of volume absorption on bicarbonate absorption was examined in the in vivo perfused rat proximal convoluted tubule. Volume absorption was inhibited by isosmotic replacement of luminal NaCl with raffinose. In tubules perfused with 25 mM bicarbonate, as raffinose was increased from 0 to 55 to 63 mM, volume absorption decreased from 2.18 +/- 0.10 to 0.30 +/- 0.18 to -0.66 +/- 0.30 nl/mm X min, respectively, and bicarbonate absorption decreased from 131 +/- 5 to 106 +/- 8 to 91 +/- 13 pmol/mm X min, respectively. This bicarbonate-water interaction could not be attributed to dilutional changes in luminal or peritubular bulk phase bicarbonate concentrations. Inhibition of active proton secretion by acetazolamide abolished the effect of volume flow on bicarbonate absorption, which implies that the bicarbonate reflection coefficient is close to 1 and eliminates the possibility of solvent drag across the tight junction. When the luminal bicarbonate concentration was varied, the magnitude of the bicarbonate-water interaction increased with increasing luminal bicarbonate concentration. The largest interaction occurred at high luminal bicarbonate concentrations, where the rate of proton secretion has been previously shown to be independent of luminal bicarbonate concentration and pH. The results thus suggest that a peritubular and/or cellular compartment exists that limits bicarbonate diffusion, and where pH changes secondary to bicarbonate-water interactions (solute polarization) alter the rate of active proton secretion. PMID:6096481

  1. 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

  2. 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

  3. 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

  4. Pharmacotherapy of vestibular and cerebellar disorders and downbeat nystagmus: translational and back-translational research.

    PubMed

    Strupp, Michael; Zwergal, Andreas; Feil, Katharina; Bremova, Tatiana; Brandt, Thomas

    2015-04-01

    There are currently eight groups of drugs for the pharmacotherapy of vertigo, nystagmus, and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications; antidepressants, anticonvulsants, aminopyridines, and acetyl-DL-leucine ("the eight A's"). In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but there is not sufficient current evidence for a general recommendation. There is also insufficient evidence that 48 or 144 mg/day betahistine has an effect in Ménière's disease. Therefore, higher dosages are currently recommended; in animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one yet not randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There are so far no RCTs on vestibular migraine, so currently no treatment can be recommended. Acetyl-dl-leucine improves cerebellar ataxia (three observational studies); it also accelerates central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT). PMID:25903394

  5. 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

  6. 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

  7. 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. PMID:3081508

  8. 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

  9. 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

  10. 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.

  11. cAMP stimulation of HCO3- secretion across airway epithelia.

    PubMed

    Welsh, M J; Smith, J J

    2001-07-01

    To test for the presence of HCO(3)(-) transport across airway epithelia, we measured short-circuit current in primary cultures of canine and human airway epithelia bathed in a Cl(-)-free, HCO(3)(-)/CO(2)-buffered solution. cAMP agonists stimulated a secretory current that was likely carried by HCO(3)(-) because it was absent in HCO(3)(-)-free solutions. In addition, the cAMP-stimulated current was inhibited by the carbonic anhydrase inhibitor, acetazolamide, and by the apical addition of a blocker of cystic fibrosis transmembrane conductance regulator (CFTR), diphenylamine-2-carboxylate. The current was dependent on Na(+) because it was inhibited by removing Na(+) from the submucosal solution and by inhibition of the Na(+)-K(+)-ATPase with ouabain. The cAMP-stimulated current was absent in cystic fibrosis (CF) airway epithelia. These data suggest that cAMP agonists can stimulate HCO(3)(-) secretion across airway epithelia and that CFTR may provide a conductive pathway for HCO(3)(-) movement across the apical membrane. PMID:11875274

  12. 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

  13. Myopia and Inflammation

    PubMed Central

    Herbort, Carl P.; Papadia, Marina; Neri, Piergiorgio

    2011-01-01

    The correlation between myopia and intraocular inflammation has rarely been explored. The aim of this article is to review myopic changes induced by inflammatory diseases and inflammatory diseases related to myopia, followed by a discussion on inflammatory choroidal neovascularization. Clinical cases are used to illustrate these conditions. The review does not include inflammatory conditions caused by surgical interventions employed for treatment of myopia. Uveitic conditions that can induce a myopic shift include sclero-choroidal inflammation, lens induced myopia due to steroid cataracts, juvenile idiopathic arthritis (JIA) induced myopia, and transient drug induced myopia due to sulfonamides and acetazolamide used for treatment of ocular toxoplasmosis and inflammatory cystoid macular edema, respectively. Most inflammatory conditions related to myopia are conditions involving the choriocapillaris. These include multifocal choroiditis and/or punctate inner choroiditis, multiple evanescent white dot syndrome and acute idiopathic blind spot enlargement. It can be hypothesized that fragility of the choriocapillaris due to particular anatomic changes due to myopia, together with unknown immunogenetic factors predispose myopic eyes to primary inflammatory choriocapillaropathies. PMID:22454750

  14. Myopia and inflammation.

    PubMed

    Herbort, Carl P; Papadia, Marina; Neri, Piergiorgio

    2011-10-01

    The correlation between myopia and intraocular inflammation has rarely been explored. The aim of this article is to review myopic changes induced by inflammatory diseases and inflammatory diseases related to myopia, followed by a discussion on inflammatory choroidal neovascularization. Clinical cases are used to illustrate these conditions. The review does not include inflammatory conditions caused by surgical interventions employed for treatment of myopia. Uveitic conditions that can induce a myopic shift include sclero-choroidal inflammation, lens induced myopia due to steroid cataracts, juvenile idiopathic arthritis (JIA) induced myopia, and transient drug induced myopia due to sulfonamides and acetazolamide used for treatment of ocular toxoplasmosis and inflammatory cystoid macular edema, respectively. Most inflammatory conditions related to myopia are conditions involving the choriocapillaris. These include multifocal choroiditis and/or punctate inner choroiditis, multiple evanescent white dot syndrome and acute idiopathic blind spot enlargement. It can be hypothesized that fragility of the choriocapillaris due to particular anatomic changes due to myopia, together with unknown immunogenetic factors predispose myopic eyes to primary inflammatory choriocapillaropathies. PMID:22454750

  15. Synthesis and characterization of complexes of a novel proton transfer salt and their inhibition studies on carbonic anhydrase isoenzymes.

    PubMed

    İlkimen, Halil; Yenikaya, Cengiz; Sarı, Musa; Bülbül, Metin; Tunca, Ekrem; Dal, Hakan; Baş, Metin

    2015-04-01

    A novel proton transfer compound (HClABT)(+)(HDPC.H2DPC)(-) (1) and its Fe(III), Co(II), Ni(II) and two different Cu(II) complexes (2-6) have been prepared and characterized by spectroscopic techniques. Additionally, single crystal X-ray diffraction techniques were applied to all complexes. All compounds, including acetazolamide (AAZ) as the control compound, were also evaluated for their in vitro inhibition effects on human hCA I and hCA II for their hydratase and esterase activities. Although there is no inhibition for hydratase activities, all compounds have inhibited the esterase activities of hCA I and II. The comparison of the inhibition studies of 1-6 to parent compounds, ClABT and H2DPC, indicates that 1-6 have superior inhibitory effects. The inhibition effects of 2-6 are also compared to the inhibitory properties of the simple metal complexes of ClABT and H2DPC, revealing an improved transfection profile. Data have been analysed by using a one-way analysis of variance for multiple comparisons. PMID:24758349

  16. Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A

    PubMed Central

    Han, Ji-Yeon

    2011-01-01

    Familial hyperkalemic periodic paralysis (HYPP) is an autosomaldominant channelopathy characterized by transient and recurrent episodes of paralysis with concomitant hyperkalemia. Mutations in the skeletal muscle voltage-gated sodium channel gene SCN4A have been reported to be responsible for this disease. Here, we report the case of a 16-year-old girl with HYPP whose mutational analysis revealed a heterozygous c.2111C>T substitution in the SCN4A gene leading to a Thr704Met mutation in the protein sequence. The parents were clinically unaffected and did not have a mutation in the SCN4A gene. A de novo SCN4A mutation for familial HYPP has not previously been reported. The patient did not respond to acetazolamide, but showed a marked improvement in paralytic symptoms upon treatment with hydrochlorothiazide. The findings in this case indicate that a de novo mutation needs to be considered when an isolated family member is found to have a HYPP phenotype. PMID:22253644

  17. Elevated Intraocular Pressure after Descemet Stripping Automated Endothelial Keratoplasty in Patients with a Trabeculectomy: A Case Series

    PubMed Central

    Chan, Elsie; Ang, Ghee Soon; George Kong, Yu Xiang

    2015-01-01

    ABSTRACT We report a case series of three patients with previous trabeculectomies who developed elevated intraocular pressure (IOP) in the immediate postoperative period after routine Descemet stripping automated endothelial keratoplasty (DSAEK). All patients had functioning trabeculectomies preoperatively, and developed elevated IOP between 41 and 69 mm Hg within 24 hours following DSAEK surgery. The IOP was successfully controlled in all patients with topical IOP-lowering medications and oral acetazolamide, with the addition of ocular massage and release of aqueous for two patients. Thereafter, all patients maintained well-controlled IOPs. Patients with trabeculectomies should be followed-up closely immediately after DSAEK to monitor for raised IOP. The mechanism for this pressure rise is uncertain, but may involve air in the trabeculectomy sclerostomy or bleb resulting in blockage of aqueous flow. How to cite this article: Sheales MPH, Chan E, Ang GS, Kong YXG. Elevated Intraocular Pressure after Descemet Stripping Automated Endothelial Keratoplasty in Patients with a Trabeculectomy: A Case Series. J Curr Glaucoma Pract 2015;9(3):100-103. PMID:26997845

  18. 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

  19. Secondary prevention of HAPE in a Mount Everest summiteer.

    PubMed

    Dunin-Bell, Ola; Boyle, Suzanne

    2009-01-01

    Climbers who have suffered a previous episode of high altitude pulmonary edema (HAPE) are at significantly increased risk of developing it again on return to high altitude. In spite of the high mortality associated with HAPE, some climbers are willing to take this risk in order to summit the tallest mountains in the world. This is a case report of a climber who suffered an episode of HAPE partway up Mount Everest. He was determined to complete his summit attempt that same climbing season, which would involve a return to extreme altitude less than 3 weeks following recovery. Based on experimental evidence suggesting that sildenafil, salmeterol, and acetazolamide may have therapeutic value for both the prevention and treatment of HAPE, he used these medications for secondary prevention. He was able to successfully reach the summit of Mount Everest and return to base camp without any evidence of recurrence of pulmonary edema. This provides clinical evidence that medication can be used to increase the safety margin for HAPE-susceptible individuals traveling to extremely high altitudes. PMID:19775220

  20. Common High Altitudes Illnesses a Primer for Healthcare Provider

    PubMed Central

    Mohsenin, Vahid

    2015-01-01

    Exposure to high altitude imposes significant strain on cardiopulmonary system and the brain. As a consequence, sojourners to high altitude frequently experience sleep disturbances, often reporting restless and sleepless nights. At altitudes above 3,000 meters (9,800 ft) almost all healthy subjects develop periodic breathing especially during NREM sleep. Sleep architecture gradually improves with increased NREM and REM sleep despite persistence of periodic breathing. The primary reason for periodic breathing at high altitude is a hypoxic-induced increase in chemoreceptor sensitivity to changes in PaCO2 – both above and below eupnea, leading to periods of apnea and hyperpnea. Acetazolamide improves sleep by reducing the periodic breathing through development of metabolic acidosis and induced hyperventilation decreasing the plant gain and widening the PCO2 reserve. This widening of the PCO2 reserve impedes development of central apneas during sleep. Benzodiazepines and GABA receptor antagonist such as zolpidem improve sleep without affecting breathing pattern or cognitive functions. PMID:27057512

  1. Return to Activity at Altitude After High-Altitude Illness

    PubMed Central

    DeWeber, Kevin; Scorza, Keith

    2010-01-01

    Context: Sports and other activities at high altitude are popular, yet they pose the unique risk for high-altitude illness (HAI). Once those who have suffered from a HAI recover, they commonly desire or need to perform the same activity at altitude in the immediate or distant future. Evidence Acquisition: As based on key text references and peer-reviewed journal articles from a Medline search, this article reviews the pathophysiology and general treatment principles of HAI. Results: In addition to the type of HAI experienced and the current level of recovery, factors needing consideration in the return-to-play plan include physical activity requirements, flexibility of the activity schedule, and available medical equipment and facilities. Most important, adherence to prudent acclimatization protocols and gradual ascent recommendations (when above 3000 m, no more than 600-m net elevation gain per day, and 1 rest day every 1 to 2 ascent days) is powerful in its preventive value and thus strongly recommended. When these are not practical, prophylactic medications (acetazolamide, dexamethasone, salmeterol, nifedipine, or phosphodiesterase inhibitors, depending on the type of prior HAI) may be prescribed and can reduce the risk of illness. Athletes with HAI should be counseled that physical and mental performance may be adversely affected if activity at altitude continues before recovery is complete and that there is a risk of progression to a more serious HAI. Conclusion: With a thoughtful plan, most recurrent HAI in athletes can be prevented. PMID:23015950

  2. Practical aspects in the management of hypokalemic periodic paralysis

    PubMed Central

    Levitt, Jacob O

    2008-01-01

    Management considerations in hypokalemic periodic paralysis include accurate diagnosis, potassium dosage for acute attacks, choice of diuretic for prophylaxis, identification of triggers, creating a safe physical environment, peri-operative measures, and issues in pregnancy. A positive genetic test in the context of symptoms is the gold standard for diagnosis. Potassium chloride is the favored potassium salt given at 0.5–1.0 mEq/kg for acute attacks. The oral route is favored, but if necessary, a mannitol solvent can be used for intravenous administration. Avoidance of or potassium prophylaxis for common triggers, such as rest after exercise, high carbohydrate meals, and sodium, can prevent attacks. Chronically, acetazolamide, dichlorphenamide, or potassium-sparing diuretics decrease attack frequency and severity but are of little value acutely. Potassium, water, and a telephone should always be at a patient's bedside, regardless of the presence of weakness. Perioperatively, the patient's clinical status should be checked frequently. Firm data on the management of periodic paralysis during pregnancy is lacking. Patient support can be found at . PMID:18426576

  3. 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

  4. 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

  5. Understanding of Altitude Illness and Use of Pharmacotherapy Among Trekkers and Porters in the Annapurna Region of Nepal.

    PubMed

    Havryliuk, Tatiana; Acharya, Bhuwan; Caruso, Emily; Cushing, Tracy

    2015-09-01

    We surveyed Nepali porters and guides as well as English- and non-English-speaking trekkers on their knowledge of altitude illness and its treatment during trekking expeditions to the Annapurna region of Nepal. From March 15 to April 15, 2014, Nepali porters and visiting trekkers were surveyed regarding their ability to recognize and treat altitude illness in Manang, Nepal (3540 m). Their personal use of medications and home remedies and presence of acute mountain sickness (AMS) symptoms were also assessed. 504 subjects were surveyed, including 108 Nepalis. Overall incidence of AMS symptoms was 16%, 5% among Nepalis, and 21% among trekkers. Subjects recognized that headache (88%) was one of the symptoms of AMS, however many reported not knowing the symptoms of high altitude pulmonary edema (40%) or high altitude cerebral edema (42%). 58% of subjects reported carrying and 16% reported taking acetazolamide, while only 2 (0.4%) respondents took dexamethasone. The majority of subjects reported that they would be able to recognize (67%) and treat (62%) altitude illness. Trekkers reported a higher incidence of AMS symptoms than Nepalis. Although most respondents recognized symptoms of AMS, both Nepalis and trekkers lacked knowledge regarding more serious presentations of altitude illness, thus both groups were overconfident in their ability to recognize and treat altitude illness. PMID:26244262

  6. Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes.

    PubMed

    Desaphy, Jean-François; Gramegna, Gianluca; Altamura, Concetta; Dinardo, Maria Maddalena; Imbrici, Paola; George, Alfred L; Modoni, Anna; Lomonaco, Mauro; Conte Camerino, Diana

    2013-10-01

    Myotonia congenita (MC) is caused by loss-of-function mutations of the muscle ClC-1 chloride channel. Clinical manifestations include the variable association of myotonia and transitory weakness. We recently described a cohort of recessive MC patients showing, at a low rate repetitive nerves stimulation protocol, different values of compound muscle action potential (CMAP) transitory depression, which is considered the neurophysiologic counterpart of transitory weakness. From among this cohort, we studied the chloride currents generated by G190S (associated with pronounced transitory depression), F167L (little or no transitory depression), and A531V (variable transitory depression) hClC-1 mutants in transfected HEK293 cells using patch-clamp. While F167L had no effect on chloride currents, G190S dramatically shifts the voltage dependence of channel activation and A531V reduces channel expression. Such variability in molecular mechanisms observed in the hClC-1 mutants may help to explain the different clinical and neurophysiologic manifestations of each ClCN1 mutation. In addition we examined five different mutations found in compound heterozygosis with F167L, including the novel P558S, and we identified additional molecular defects. Finally, the G190S mutation appeared to impair acetazolamide effects on chloride currents in vitro. PMID:23933576

  7. Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes☆

    PubMed Central

    Desaphy, Jean-François; Gramegna, Gianluca; Altamura, Concetta; Dinardo, Maria Maddalena; Imbrici, Paola; George, Alfred L.; Modoni, Anna; LoMonaco, Mauro; Conte Camerino, Diana

    2013-01-01

    Myotonia congenita (MC) is caused by loss-of-function mutations of the muscle ClC-1 chloride channel. Clinical manifestations include the variable association of myotonia and transitory weakness. We recently described a cohort of recessive MC patients showing, at a low rate repetitive nerves stimulation protocol, different values of compound muscle action potential (CMAP) transitory depression, which is considered the neurophysiologic counterpart of transitory weakness. From among this cohort, we studied the chloride currents generated by G190S (associated with pronounced transitory depression), F167L (little or no transitory depression), and A531V (variable transitory depression) hClC-1 mutants in transfected HEK293 cells using patch-clamp. While F167L had no effect on chloride currents, G190S dramatically shifts the voltage dependence of channel activation and A531V reduces channel expression. Such variability in molecular mechanisms observed in the hClC-1 mutants may help to explain the different clinical and neurophysiologic manifestations of each ClCN1 mutation. In addition we examined five different mutations found in compound heterozygosis with F167L, including the novel P558S, and we identified additional molecular defects. Finally, the G190S mutation appeared to impair acetazolamide effects on chloride currents in vitro. PMID:23933576

  8. Efficient Expression and Crystallization System of Cancer-Associated Carbonic Anhydrase Isoform IX.

    PubMed

    Leitans, Janis; Kazaks, Andris; Balode, Agnese; Ivanova, Jekaterina; Zalubovskis, Raivis; Supuran, Claudiu T; Tars, Kaspars

    2015-11-25

    Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considered to be a marker for cellular hypoxia that it is not produced in most normal tissues. CA IX contributes to the acidification of the extracellular matrix, which, in turn, favors tumor growth and metastasis. Therefore, CA IX is considered to be a promising anti-cancer drug target. However, the ability to specifically target CA IX is challenging due to the fact that the human genome encodes 15 different carbonic anhydrase isoforms that have a high degree of homology. Furthermore, structure-based drug design of CA IX inhibitors so far has been largely unsuccessful due to technical difficulties regarding the expression and crystallization of the enzyme. Currently, only one baculovirus-produced CA IX structure in complex with a nonspecific CA inhibitor, acetazolamide, is available in Protein Data Bank. We have developed an efficient system for the production of the catalytic domain of CA IX in methylotrophic yeast Pichia pastoris. The produced protein can be easily crystallized in the presence of inhibitors, as we have demonstrated for several 2-thiophene-sulfonamide compounds. We have also observed significant differences in the binding mode of chemically identical compounds to CA IX and CA II, which can be further exploited in the design of CA IX-specific inhibitors. PMID:26522624

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. Update on the pharmacotherapy of cerebellar and central vestibular disorders.

    PubMed

    Kalla, Roger; Teufel, Julian; Feil, Katharina; Muth, Caroline; Strupp, Michael

    2016-04-01

    An overview of the current pharmacotherapy of central vestibular syndromes and the most common forms of central nystagmus as well as cerebellar disorders is given. 4-aminopyridine (4-AP) is recommended for the treatment of downbeat nystagmus, a frequent form of acquired persisting fixation nystagmus, and upbeat nystagmus. Animal studies showed that this non-selective blocker of voltage-gated potassium channels increases Purkinje cell excitability and normalizes the irregular firing rate, so that the inhibitory influence of the cerebellar cortex on vestibular and deep cerebellar nuclei is restored. The efficacy of 4-AP in episodic ataxia type 2, which is most often caused by mutations of the PQ-calcium channel, was demonstrated in a randomized controlled trial. It was also shown in an animal model (the tottering mouse) of episodic ataxia type 2. In a case series, chlorzoxazone, a non-selective activator of small-conductance calcium-activated potassium channels, was shown to reduce the DBN. The efficacy of acetyl-DL-leucine as a potential new symptomatic treatment for cerebellar diseases has been demonstrated in three case series. The ongoing randomized controlled trials on episodic ataxia type 2 (sustained-release form of 4-aminopyridine vs. acetazolamide vs. placebo; EAT2TREAT), vestibular migraine with metoprolol (PROVEMIG-trial), cerebellar gait disorders (sustained-release form of 4-aminopyridine vs. placebo; FACEG) and cerebellar ataxia (acetyl-DL-leucine vs. placebo; ALCAT) will provide new insights into the pharmacotherapy of cerebellar and central vestibular disorders. PMID:27083881

  15. 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

  16. 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

  17. 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.

  18. 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

  19. A versatile polypeptide platform for integrated recognition and reporting: affinity arrays for protein-ligand interaction analysis.

    PubMed

    Enander, Karin; Dolphin, Gunnar T; Liedberg, Bo; Lundström, Ingemar; Baltzer, Lars

    2004-05-17

    A molecular platform for protein detection and quantification is reported in which recognition has been integrated with direct monitoring of target-protein binding. The platform is based on a versatile 42-residue helix-loop-helix polypeptide that dimerizes to form four-helix bundles and allows site-selective modification with recognition and reporter elements on the side chains of individually addressable lysine residues. The well-characterized interaction between the model target-protein carbonic anhydrase and its inhibitor benzenesulfonamide was used for a proof-of-concept demonstration. An affinity array was designed where benzenesulfonamide derivatives with aliphatic or oligoglycine spacers and a fluorescent dansyl reporter group were introduced into the scaffold. The affinities of the array members for human carbonic anhydrase II (HCAII) were determined by titration with the target protein and were found to be highly affected by the properties of the spacers (dissociation constant Kd=0.02-3 microM). The affinity of HCAII for acetazolamide (Kd=4 nM) was determined in a competition experiment with one of the benzenesulfonamide array members to address the possibility of screening substance libraries for new target-protein binders. Also, successful affinity discrimination between different carbonic anhydrase isozymes highlighted the possibility of performing future isoform-expression profiling. Our platform is predicted to become a flexible tool for a variety of biosensor and protein-microarray applications within biochemistry, diagnostics and pharmaceutical chemistry. PMID:15146511

  20. 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

  1. Hypoxia Silences Retrotrapezoid Nucleus Respiratory Chemoreceptors via Alkalosis

    PubMed Central

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

    2015-01-01

    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 (ΔfR) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔVT) followed the same trend. The effect of hypoxia on ΔfR was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). ΔfR 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. PMID:25589748

  2. Structure and inhibition studies of a type II beta-carbonic anhydrase psCA3 from Pseudomonas aeruginosa.

    PubMed

    Pinard, Melissa A; Lotlikar, Shalaka R; Boone, Christopher D; Vullo, Daniela; Supuran, Claudiu T; Patrauchan, Marianna A; McKenna, Robert

    2015-08-01

    Carbonic anhydrases (CAs) are metallo-enzymes that catalyze the reversible hydration of carbon dioxide into bicarbonate and a proton. The β-class CAs (β-CAs) are expressed in prokaryotes, fungi, plants, and more recently have been isolated in some animals. The β-CA class is divided into two subclasses, termed type I and II, defined by pH catalytic activity profile and active site structural configuration. Type I β-CAs display catalytic activity over a broad pH range (6.5-9.0) with the active site zinc tetrahedrally coordinated by three amino acids and a hydroxide/water. In contrast, type II β-CAs are catalytically active only at a pH 8 and higher where they adopt a functional active site configuration like that of type I. However, below pH 8 they are conformationally self-inactivated by the addition of a fourth amino acid coordinating the zinc and thereby displacing the zinc bound solvent. We have determined the structure of psCA3, a type II β-CA, isolated from Pseudomonas aeruginosa (P. aeruginosa) PAO1 at pH 8.3, in its open active state to a resolution of 1.9 Å. The active site zinc is coordinated by Cys42, His98, Cys101 and a water/hydroxide molecule. P. aeruginosa is a multi-drug resistant bacterium and displays intrinsic resistance to most of the currently used antibiotics; therefore, there is a need for new antibacterial targets. Kinetic data confirm that psCA3 belongs to the type II subclass and that sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid are micromolar inhibitors. In vivo studies identified that among six tested inhibitors representing sulfonamides, inorganic anions, and small molecules, acetazolamide has the most significant dose-dependent inhibitory effect on P. aeruginosa growth. PMID:26068018

  3. Physiological and molecular biological characterization of intracellular carbonic anhydrase from the marine diatom Phaeodactylum tricornutum.

    PubMed

    Satoh, D; Hiraoka, Y; Colman, B; Matsuda, Y

    2001-08-01

    A single intracellular carbonic anhydrase (CA) was detected in air-grown and, at reduced levels, in high CO(2)-grown cells of the marine diatom Phaeodactylum tricornutum (UTEX 642). No external CA activity was detected irrespective of growth CO(2) 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 beta-type CAs. Even though the zinc-ligand amino acid residues were shown to be completely conserved, the amino acid residues that may constitute a CO(2)-binding site appeared to be unique among the beta-CAs so far reported. PMID:11500545

  4. Identification and expression of cotton (Gossypium hirsutum L.) plastidial carbonic anhydrase.

    PubMed

    Hoang, C V; Wessler, H G; Local, A; Turley, R B; Benjamin, R C; Chapman, K D

    1999-12-01

    Four carbonic anhydrase (CA) cDNA clones were isolated from a 48 h dark-grown cotton (Gossypium hirsutum L.) seedling cDNA library. Nucleotide sequence analysis revealed two different CA isoforms designated GhCA1 and GhCA2. The encoded polypeptides possess N-terminal serine/threonine-rich regions indicative of plastid transit peptides, and approximately 80% sequence identity to other plant plastidial beta-CAs. The GhCA1 cDNA encodes a nearly complete preprotein of 323 amino acids with a molecular mass of 34.9 kDa and a predicted mature protein of 224 amino acids with a molecular mass of 24.3 kDa. Eleven nucleotide differences within ORFs of GhCA1 and GhCA2 result in 5 conservative amino acid substitutions. The 3' GhCA2 untranslated region contains five additional substitutions and one single nucleotide addition. GhCA1 clones, nearly full-length or with 70% of the transit peptide deleted, were expressed as LacZ alpha fusion proteins in E. coli. Lysates of these strains contained 9-fold higher levels of CA activity as compared to untransformed controls and this activity was inhibited by CA-specific inhibitors. Sulfanilamide, acetazolamide, ethoxyzolamide, each at 10 mM, inhibited recombinant CA activity approximately 50%, 65%, and 75%, respectively. In plant tissue homogenates these inhibitors reduced CA activity by 50%, 70%, and 95%, respectively. Although CA activity was bighest in extracts of mature cotton leaves, probing total RNA with GhCA1 revealed CA transcript levels to be highest in the cotyledons of dark-grown cotton seedlings. Collectively, our data indicate the presence of a plastid-localized CA in cotyledons of germinated seeds, suggesting a role for CA in postgerminative growth. PMID:10682348

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

    PubMed Central

    Onken, Horst; Moffett, David F.

    2015-01-01

    ABSTRACT 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. PMID:25944920

  6. 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

  7. 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

  8. Abnormal Excitability and Episodic Low-Frequency Oscillations in the Cerebral Cortex of the tottering Mouse

    PubMed Central

    Cramer, Samuel W.; Popa, Laurentiu S.; Carter, Russell E.; Chen, Gang

    2015-01-01

    The Ca2+ channelopathies caused by mutations of the CACNA1A gene that encodes the pore-forming subunit of the human Cav2.1 (P/Q-type) voltage-gated Ca2+ channel include episodic ataxia type 2 (EA2). Although, in EA2 the emphasis has been on cerebellar dysfunction, patients also exhibit episodic, nonmotoric abnormalities involving the cerebral cortex. This study demonstrates episodic, low-frequency oscillations (LFOs) throughout the cerebral cortex of tottering (tg/tg) mice, a widely used model of EA2. Ranging between 0.035 and 0.11 Hz, the LFOs in tg/tg mice can spontaneously develop very high power, referred to as a high-power state. The LFOs in tg/tg mice are mediated in part by neuronal activity as tetrodotoxin decreases the oscillations and cortical neuron discharge contain the same low frequencies. The high-power state involves compensatory mechanisms because acutely decreasing P/Q-type Ca2+ channel function in either wild-type (WT) or tg/tg mice does not induce the high-power state. In contrast, blocking l-type Ca2+ channels, known to be upregulated in tg/tg mice, reduces the high-power state. Intriguingly, basal excitatory glutamatergic neurotransmission constrains the high-power state because blocking ionotropic or metabotropic glutamate receptors results in high-power LFOs in tg/tg but not WT mice. The high-power LFOs are decreased markedly by acetazolamide and 4-aminopyridine, the primary treatments for EA2, suggesting disease relevance. Together, these results demonstrate that the high-power LFOs in the tg/tg cerebral cortex represent a highly abnormal excitability state that may underlie noncerebellar symptoms that characterize CACNA1A mutations. PMID:25855180

  9. 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

  10. Trabeculectomy Improves Vessel Response Measured by Dynamic Vessel Analysis (DVA) in Glaucoma Patients

    PubMed Central

    J, Michael Selbach; Schallenberg, Maurice; Kramer, Sebastian; Anastassiou, Gerasimos; Steuhl, Klaus-Peter; Vilser, Walthard; Kremmer, Stephan

    2014-01-01

    Purpose : To determine the effects of surgical IOP reduction (trabeculectomy) on retinal blood flow parameters in glaucoma patients using Dynamic Vessel Analysis (DVA). Methods : 26 eyes of 26 patients with progressive primary open-angle glaucoma (POAG) despite maximal topical therapy were examined before and after trabeculectomy. The responses of the retinal vessels to flickering light provocation were measured with DVA the day before surgery and 4 to 6 weeks after trabeculectomy. Between 3 and 4 weeks before surgery all local therapies were stopped and a systemic therapy with acetazolamide and conservative free topic steroidal eye drops was started. Results : In 19 patients (73%), an inadequate response to the flicker stimulation was measured preoperatively. In these patients, the maximum dilation of arteries and veins was reduced significantly as compared to healthy eyes. In this group, the maximum dilation of the arteries following the flicker provocation improved from 1.4% before to 3.8% following trabeculectomy (p<0.01). In retinal veins, this parameter increased from 3.1% to 4.6% (p<0.05). In the 7 patients whose arterial and venous reactions to flickering light provocation preoperatively did not differ from healthy eyes, there was no significant change after surgery. The initial baseline values of arteries and veins (MU) did not deviate significantly in both groups. Conclusion : POAG patients with progressive disease and impaired vascular regulation profit from IOP lowering trabeculectomy concerning vascular reactivity and dilative reserve, indicating a possible improvement of retinal perfusion following effective IOP control. Future studies with long-term follow-up must determine the clinical importance of these findings for the treatment of glaucoma patients. PMID:25352934

  11. 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

  12. Loss of inhibitory tone on spinal cord dorsal horn spontaneously and nonspontaneously active neurons in a mouse model of neuropathic pain.

    PubMed

    Medrano, Maria Carmen; Dhanasobhon, Dhanasak; Yalcin, Ipek; Schlichter, Rémy; Cordero-Erausquin, Matilde

    2016-07-01

    Plasticity of inhibitory transmission in the spinal dorsal horn (SDH) is believed to be a key mechanism responsible for pain hypersensitivity in neuropathic pain syndromes. We evaluated this plasticity by recording responses to mechanical stimuli in silent neurons (nonspontaneously active [NSA]) and neurons showing ongoing activity (spontaneously active [SA]) in the SDH of control and nerve-injured mice (cuff model). The SA and NSA neurons represented 59% and 41% of recorded neurons, respectively, and were predominantly wide dynamic range (WDR) in naive mice. Nerve-injured mice displayed a marked decrease in the mechanical threshold of the injured paw. After nerve injury, the proportion of SA neurons was increased to 78%, which suggests that some NSA neurons became SA. In addition, the response to touch (but not pinch) was dramatically increased in SA neurons, and high-threshold (nociceptive specific) neurons were no longer observed. Pharmacological blockade of spinal inhibition with a mixture of GABAA and glycine receptor antagonists significantly increased responses to innocuous mechanical stimuli in SA and NSA neurons from sham animals, but had no effect in sciatic nerve-injured animals, revealing a dramatic loss of spinal inhibitory tone in this situation. Moreover, in nerve-injured mice, local spinal administration of acetazolamide, a carbonic anhydrase inhibitor, restored responses to touch similar to those observed in naive or sham mice. These results suggest that a shift in the reversal potential for anions is an important component of the abnormal mechanical responses and of the loss of inhibitory tone recorded in a model of nerve injury-induced neuropathic pain. PMID:26934510

  13. Exclusive localization of carbonic anhydrase in bacteriocytes of the deep-sea clam Calyptogena okutanii with thioautotrophic symbiotic bacteria.

    PubMed

    Hongo, Yuki; Nakamura, Yoshimitsu; Shimamura, Shigeru; Takaki, Yoshihiro; Uematsu, Katsuyuki; Toyofuku, Takashi; Hirayama, Hisako; Takai, Ken; Nakazawa, Masatoshi; Maruyama, Tadashi; Yoshida, Takao

    2013-12-01

    Deep-sea Calyptogena clams harbor thioautotrophic intracellular symbiotic bacteria in their gill epithelial cells. The symbiont fixes CO2 to synthesize organic compounds. Carbonic anhydrase (CA) from the host catalyzes the reaction CO2 + H2O ↔ HCO3(-) + H(+), and is assumed to facilitate inorganic carbon (Ci) uptake and transport to the symbiont. However, the localization of CA in gill tissue remains unknown. We therefore analyzed mRNA sequences, proteins and CA activity in Calyptogena okutanii using expression sequence tag, SDS-PAGE and LC-MS/MS. We found that acetazolamide-sensitive soluble CA was abundantly expressed in the gill tissue of C. okutanii, and the enzyme was purified by affinity chromatography. Mouse monoclonal antibodies against the CA of C. okutanii were used in western blot analysis and immunofluorescence staining of the gill tissues of C. okutanii, which showed that CA was exclusively localized in the symbiont-harboring cells (bacteriocytes) in gill epithelial cells. Western blot analysis and measurement of activity showed that CA was abundantly (26-72% of total soluble protein) detected in the gill tissues of not only Calyptogena clams but also deep-sea Bathymodiolus mussels that harbor thioautotrophic or methanotrophic symbiotic bacteria, but was not detected in a non-symbiotic mussel, Mytilus sp. The present study showed that CA is abundant in the gill tissues of deep-sea symbiotic bivalves and specifically localizes in the cytoplasm of bacteriocytes of C. okutanii. This indicates that the Ci supply process to symbionts in the vacuole (symbiosome) in bacteriocytes is essential for symbiosis. PMID:24031050

  14. 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

  15. 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. PMID:25589748

  16. The pH low insertion peptide pHLIP Variant 3 as a novel marker of acidic malignant lesions

    PubMed Central

    Tapmeier, Thomas T.; Moshnikova, Anna; Beech, John; Allen, Danny; Kinchesh, Paul; Smart, Sean; Harris, Adrian; McIntyre, Alan; Engelman, Donald M.; Andreev, Oleg A.; Reshetnyak, Yana K.; Muschel, Ruth J.

    2015-01-01

    Current strategies for early detection of breast and other cancers are limited in part because some lesions identified as potentially malignant do not develop into aggressive tumors. Acid pH has been suggested as a key characteristic of aggressive tumors that might distinguish aggressive lesions from more indolent pathology. We therefore investigated the novel class of molecules, pH low insertion peptides (pHLIPs), as markers of low pH in tumor allografts and of malignant lesions in a mouse model of spontaneous breast cancer, BALB/neu-T. pHLIP Variant 3 (Var3) conjugated with fluorescent Alexa546 was shown to insert into tumor spheroids in a sequence-specific manner. Its signal reflected pH in murine tumors. It was induced by carbonic anhydrase IX (CAIX) overexpression and inhibited by acetazolamide (AZA) administration. By using 31P magnetic resonance spectroscopy (MRS), we demonstrated that pHLIP Var3 was retained in tumors of pH equal to or less than 6.7 but not in tissues of higher pH. In BALB/neu-T mice at different stages of the disease, the fluorescent signal from pHLIP Var3 marked cancerous lesions with a very low false-positive rate. However, only ∼60% of the smallest lesions retained a pHLIP Var3 signal, suggesting heterogeneity in pH. Taken together, these results show that pHLIP can identify regions of lower pH, allowing for its development as a theranostic tool for clinical applications. PMID:26195776

  17. Abnormal excitability and episodic low-frequency oscillations in the cerebral cortex of the tottering mouse.

    PubMed

    Cramer, Samuel W; Popa, Laurentiu S; Carter, Russell E; Chen, Gang; Ebner, Timothy J

    2015-04-01

    The Ca(2+) channelopathies caused by mutations of the CACNA1A gene that encodes the pore-forming subunit of the human Cav2.1 (P/Q-type) voltage-gated Ca(2+) channel include episodic ataxia type 2 (EA2). Although, in EA2 the emphasis has been on cerebellar dysfunction, patients also exhibit episodic, nonmotoric abnormalities involving the cerebral cortex. This study demonstrates episodic, low-frequency oscillations (LFOs) throughout the cerebral cortex of tottering (tg/tg) mice, a widely used model of EA2. Ranging between 0.035 and 0.11 Hz, the LFOs in tg/tg mice can spontaneously develop very high power, referred to as a high-power state. The LFOs in tg/tg mice are mediated in part by neuronal activity as tetrodotoxin decreases the oscillations and cortical neuron discharge contain the same low frequencies. The high-power state involves compensatory mechanisms because acutely decreasing P/Q-type Ca(2+) channel function in either wild-type (WT) or tg/tg mice does not induce the high-power state. In contrast, blocking l-type Ca(2+) channels, known to be upregulated in tg/tg mice, reduces the high-power state. Intriguingly, basal excitatory glutamatergic neurotransmission constrains the high-power state because blocking ionotropic or metabotropic glutamate receptors results in high-power LFOs in tg/tg but not WT mice. The high-power LFOs are decreased markedly by acetazolamide and 4-aminopyridine, the primary treatments for EA2, suggesting disease relevance. Together, these results demonstrate that the high-power LFOs in the tg/tg cerebral cortex represent a highly abnormal excitability state that may underlie noncerebellar symptoms that characterize CACNA1A mutations. PMID:25855180

  18. Hemodynamic Significance of Internal Carotid or Middle Cerebral Artery Stenosis Detected on Magnetic Resonance Angiography

    PubMed Central

    Seo, Hyo Jung; Pagsisihan, Jefferson R.; Choi, Seung Hong; Cheon, Gi Jeong; Chung, June-Key; Lee, Dong Soo; Kang, Keon Wook

    2015-01-01

    Purpose We evaluated hemodynamic significance of stenosis on magnetic resonance angiography (MRA) using acetazolamide perfusion single photon emission computed tomography (SPECT). Materials and Methods Of 171 patients, stenosis in internal carotid artery (ICA) and middle cerebral artery (MCA) (ICA-MCA) on MRA and cerebrovascular reserve (CVR) of MCA territory on SPECT was measured using quantification and a 3-grade system. Stenosis and CVR grades were compared with each other, and their prognostic value for subsequent stroke was evaluated. Results Of 342 ICA-MCA, 151 (44%) presented stenosis on MRA; grade 1 in 69 (20%) and grade 2 in 82 (24%) cases. Decreased CVR was observed in 9% of grade 0 stenosis, 25% of grade 1, and 35% of grade 2. The average CVR of grade 0 was significantly different from grade 1 (p<0.001) and grade 2 stenosis (p=0.007). In quantitative analysis, average CVR index was -0.56±7.91 in grade 0, -1.81±6.66 in grade 1 and -1.18±5.88 in grade 2 stenosis. Agreement between stenosis and CVR grades was fair in patients with lateralizing and non-lateralizing symptoms (κ=0.230 and 0.346). Of the factors tested, both MRA and CVR were not significant prognostic factors (p=0.104 and 0.988, respectively), whereas hypertension and renal disease were significant factors (p<0.05, respectively). Conclusion A considerable proportion of ICA-MCA stenosis detected on MRA does not cause CVR impairment despite a fair correlation between them. Thus, hemodynamic state needs to be assessed for evaluating significance of stenosis, particularly in asymptomatic patients. PMID:26446655

  19. Preventing Flow-Metabolism Uncoupling Acutely Reduces Axonal Injury after Traumatic Brain Injury

    PubMed Central

    Mironova, Yevgeniya A.; Chen, Szu-Fu; Richards, Hugh K.; Pickard, John D.

    2012-01-01

    Abstract We have previously presented evidence that the development of secondary traumatic axonal injury is related to the degree of local cerebral blood flow (LCBF) and flow-metabolism uncoupling. We have now tested the hypothesis that augmenting LCBF in the acute stages after brain injury prevents further axonal injury. Data were acquired from rats with or without acetazolamide (ACZ) that was administered immediately following controlled cortical impact injury to increase cortical LCBF. Local cerebral metabolic rate for glucose (LCMRglc) and LCBF measurements were obtained 3 h post-trauma in the same rat via 18F-fluorodeoxyglucose and 14C-iodoantipyrine co-registered autoradiographic images, and compared to the density of damaged axonal profiles in adjacent sections, and in additional groups at 24 h used to assess different populations of injured axons stereologically. ACZ treatment significantly and globally elevated LCBF twofold above untreated-injured rats at 3 h (p<0.05), but did not significantly affect LCMRglc. As a result, ipsilateral LCMRglc:LCBF ratios were reduced by twofold to sham-control levels, and the density of β-APP-stained axons at 24 h was significantly reduced in most brain regions compared to the untreated-injured group (p<0.01). Furthermore, early LCBF augmentation prevented the injury-associated increase in the number of stained axons from 3–24 h. Additional robust stereological analysis of impaired axonal transport and neurofilament compaction in the corpus callosum and cingulum underlying the injury core confirmed the amelioration of β-APP axon density, and showed a trend, but no significant effect, on RMO14-positive axons. These data underline the importance of maintaining flow-metabolism coupling immediately after injury in order to prevent further axonal injury, in at least one population of injured axons. PMID:22321027

  20. The enzyme carbonic anhydrase as an integral component of biogenic Ca-carbonate formation in sponge spicules☆

    PubMed Central

    Müller, Werner E.G.; Schröder, Heinz C.; Schlossmacher, Ute; Neufurth, Meik; Geurtsen, Werner; Korzhev, Michael; Wang, Xiaohong

    2013-01-01

    The inorganic scaffold of the spicules, the skeletal elements of the calcareous sponges, is formed of calcium carbonate (CaCO3). The growth of the approximately 300-μm large spicules, such as those of the calcareous sponge Sycon raphanus used in the present study, is a rapid process with a rate of about 65 μm/h. The formation of CaCO3 is predominantly carried out by the enzyme carbonic anhydrase (CA). The enzyme from the sponge S. raphanus was isolated and prepared by recombination. The CA-driven deposition of CaCO3 crystallites is dependent on temperature (optimal at 52 °C), the pH value of the reaction assay (7.5/8.0), and the substrate concentration (CO2 and Ca2+). During the initial phase of crystallite formation, ≈40 μm large round-shaped deposits are formed that remodel to larger prisms. These crystal-like prisms associate to each other and form either rope-/bundle-like aggregates or arrange perfectly with their smaller planes along opposing surfaces of the sponge spicule rays. The CA-dependent CaCO3 deposition can be inhibited by the CA-specific inhibitor acetazolamide. The Michaelis–Menten constant for the CA-driven mineralization has been determined to be around 8 mM with respect to CaCO3. The deposits formed have a Martens hardness of ≈5 GPa. The data presented here highlights for the first time that calcite deposition in the sponge system is decisively controlled enzymatically. This data will contribute to the development of new strategies applicable for the fabrication of novel biomaterials. PMID:24251096

  1. 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. PMID:27293673

  2. Non-specific inhibitors of aquaporin-4 stimulate S100B secretion in acute hippocampal slices of rats.

    PubMed

    Zanotto, Caroline; Abib, Renata Torres; Batassini, Cristiane; Tortorelli, Lucas Silva; Biasibetti, Regina; Rodrigues, Letícia; Nardin, Patrícia; Hansen, Fernanda; Gottfried, Carmem; Leite, Marina Concli; Gonçalves, Carlos-Alberto

    2013-01-23

    Aquaporin-4 (AQP-4) is the principal brain water channel and is predominantly expressed in astrocytes suggesting its dynamic involvement in water homeostasis in brain tissue. Due to the co-localization of AQP-4 and inward rectifier K(+) channels Kir 4.1, a functional coupling between these proteins has been proposed. AQP-4 has a putative role in the physiopathology of brain disorders including epilepsy and trauma. S100B is a calcium-binding protein expressed and secreted by astrocytes, and commonly used as a parameter of astroglial activation. Here, we investigate a possible link between AQP-4 activity (and Kir 4.1) and S100B secretion in hippocampal slices of rats of different ages using non-specific inhibitors of AQP-4 (AZA, acetazolamide and TEA, tetraethylammonium) and Kir 4.1 (barium chloride). We found that blockade of AQP-4 with TEA and AZA produced an increase in S100B secretion in young rats, compatible with an astroglial activation observed in many conditions of brain injury. On the other hand, BaCl(2) induced Kir 4.1 inhibition caused a decrease in S100B secretion. Both channels, AQP-4 and Kir 4.1, exhibited a similar ontogenetic profile, in spite of the functional uncoupling, in relation to S100B secretion. Moreover, we found a significant increase in the S100B secretion basal levels with the increasing of animal age and the incubation with high levels of potassium resulted in a decrease of S100B secretion in 30 and 90-day old rats. These data, together with previous observations from gap junctions and glutamate transport of astrocytes, contribute to characterize the operational system involving astroglial activation, particularly on S100B secretion, in brain disorders. PMID:23142267

  3. [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. PMID:26856268

  4. Treatment of epilepsy in women of childbearing age.

    PubMed

    Taly, A B; Sharda, C; Mohan, P K

    1985-05-01

    This article updates the literature on the treatment of epilepsy in women of reproductive age. Specific areas discussed include the effect of menstruation on seizure frequency, use of oral contraceptives (OCs), the effect of pregnancy on epilepsy, the effect of seizures on pregnancy and the fetus, the impact of antiepileptic drugs on the fetus, medical termination of pregnancy, breast feeding, and the risk of epilepsy in offspring. Exacerbtion of seizure activity is often seen in premenstrual and menstrual phases, and cyclic use of acetazolamide and/or progesterone (which exerts a protective effect against seizures) is recommended. OCs appear to have only a minor impact on epilepsy and the metabolism of antiepileptic drugs. On the other hand, these drugs can influence the metabolism and effectiveness of OCs. Concomitant use of OCs and antiepileptics can result in a higher incidence of acne and hirsutism, increased intermenstrual bleeding, and failure of contraception. The incidence of contraceptive failure is higher with low-dose estrogen OCs. In general, pregnancy appears to have an unfavorable effect on cerebral dysrrhythmia in epileptics. Possible causes for the increase in seizure frequency during pregnancy include psychological, hormonal, metabolic, and pharmacokinetic factors. The effect of epilepsy and antiepileptics on offspring is unclear. There appears to be an increased risk of spontaneous abortion and stillbirths in women taking antiepileptic drugs. In addition, a 3-fold increase in the incidence of congenital malformations has been noted in these women. The risks of birth defects are greater when there is a family history of birth defects, when the father is also epileptic, when a previous pregnancy resulted in a malformed child, when seizures during pregnancy are poorly controlled, and when multipel antiepileptic drugs are used in high doses. Although offspring may inherit the epileptic trait, they do not always manifest the disease. PMID:4044506

  5. 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

  6. Efficacy of NSAIDs for the prevention of acute mountain sickness: a systematic review and meta-analysis

    PubMed Central

    Pandit, Anil; Karmacharya, Paras; Pathak, Ranjan; Giri, Smith; Aryal, Madan R.

    2014-01-01

    Background Acute mountain sickness (AMS) can occur in anyone going to a high altitude. Non-steroidal anti-inflammatory drugs (NSAIDs) have been studied for the prevention of AMS with mixed results. In this systematic review, we analyze all existing data on the use of NSAIDs to prevent AMS using the Lake Louise Scoring System (LLSS) in different randomized clinical trials (RCTs). Methods Electronic literature searches for relevant studies were identified through MEDLINE, EMBASE, SCOPUS, and Cochrane library up to June 2013. RCTs involving NSAIDs compared to placebo in patients undergoing ascent to a height of at least 3,800 m were included. Odds ratios (OR) were calculated and combined using fixed-effect model meta-analysis if I 2=0%. Differences between groups were calculated using the inverse variance of the standard mean differences. Between-study heterogeneity was assessed using the I 2 statistics. Results In three clinical trials involving 349 patients, AMS using LLSS occurred in 26.92% of patients on NSAIDs and 43.71% on placebo (OR 0.43; CI [confidence interval] 0.27–0.69, I 2=0%, p=0.0005), NNT=6. Minor outcome of end point Spo2 was not significant in the two groups (IV=0.74; 95% CI −0.20–1.69, I 2=81%, p=0.12). Similarly, a change in Spo2 from baseline was also not significant in the two groups (IV=0.05; 95% CI −0.28–0.37, I 2=44%, p=0.78). Conclusion NSAIDs might be a safe and effective alternative for the prevention of AMS. However, further larger population studies and studies comparing NSAIDs to acetazolamide and dexamethasone in the future may provide further data to its relative efficacy. PMID:25317267

  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. PMID:26481430

  8. 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. PMID:26041446

  9. Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay.

    PubMed

    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 the present 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 treatment strategies. There are currently no effective treatments, but some anti-epileptic drugs targeting the GABA system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical anti-seizure medication decreases seizures in 4 patients. In contrast to previous reports, the ketogenic diet and fasting produce 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 improve 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, our 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

  10. 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

  11. 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

  12. 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

  13. 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

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

    PubMed Central

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

    2016-01-01

    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. PMID:26041446

  15. 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

  16. Epithelial anion transporter pendrin contributes to inflammatory lung pathology in mouse models of Bordetella pertussis infection.

    PubMed

    Scanlon, Karen M; Gau, Yael; Zhu, Jingsong; Skerry, Ciaran; Wall, Susan M; Soleimani, Manoocher; Carbonetti, Nicholas H

    2014-10-01

    Pertussis disease, characterized by severe and prolonged coughing episodes, can progress to a critical stage with pulmonary inflammation and death in young infants. However, there are currently no effective treatments for pertussis. We previously studied the role of pertussis toxin (PT), an important Bordetella pertussis virulence factor, in lung transcriptional responses to B. pertussis infection in mouse models. One of the genes most highly upregulated in a PT-dependent manner encodes an epithelial transporter of bicarbonate, chloride, and thiocyanate, named pendrin, that contributes to asthma pathology. In this study, we found that pendrin expression is upregulated at both gene and protein levels in the lungs of B. pertussis-infected mice. Pendrin upregulation is associated with PT production by the bacteria and with interleukin-17A (IL-17A) production by the host. B. pertussis-infected pendrin knockout (KO) mice had higher lung bacterial loads than infected pendrin-expressing mice but had significantly reduced levels of lung inflammatory pathology. However, reduced pathology did not correlate with reduced inflammatory cytokine expression. Infected pendrin KO mice had higher levels of inflammatory cytokines and chemokines than infected pendrin-expressing mice, suggesting that these inflammatory mediators are less active in the airways in the absence of pendrin. In addition, treatment of B. pertussis-infected mice with the carbonic anhydrase inhibitor acetazolamide reduced lung inflammatory pathology without affecting pendrin synthesis or bacterial loads. Together these data suggest that PT contributes to pertussis pathology through the upregulation of pendrin, which promotes conditions favoring inflammatory pathology. Therefore, pendrin may represent a novel therapeutic target for treatment of pertussis disease. PMID:25069981

  17. 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

  18. 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

  19. A novel method to study cerebrospinal fluid dynamics in rats

    PubMed Central

    Karimy, Jason K.; Kahle, Kristopher T.; Kurland, David B.; Yu, Edward; Gerzanich, Volodymyr; Simard, J. Marc

    2014-01-01

    Background Cerebrospinal fluid (CSF) flow dynamics play critical roles in both the immature and adult brain, with implications for neurodevelopment and disease processes such as hydrocephalus and neurodegeneration. Remarkably, the only reported method to date for measuring CSF formation in laboratory rats is the indirect tracer dilution method (a.k.a., ventriculocisternal perfusion), which has limitations. New Method Anesthetized rats were mounted in a stereotaxic apparatus, both lateral ventricles were cannulated, and the Sylvian aqueduct was occluded. Fluid exited one ventricle at a rate equal to the rate of CSF formation plus the rate of infusion (if any) into the contralateral ventricle. Pharmacological agents infused at a constant known rate into the contralateral ventricle were tested for their effect on CSF formation in real-time. Results The measured rate of CSF formation was increased by blockade of the Sylvian aqueduct but was not changed by increasing the outflow pressure (0–3 cm of H2O). In male Wistar rats, CSF formation was age-dependent: 0.39±0.06, 0.74±0.05, 1.02±0.04 and 1.40±0.06 µL/min at 8, 9, 10 and 12 weeks, respectively. CSF formation was reduced 57% by intraventricular infusion of the carbonic anhydrase inhibitor, acetazolamide. Comparison with existing methods Tracer dilution methods do not permit ongoing real-time determination of the rate of CSF formation, are not readily amenable to pharmacological manipulations, and require critical assumptions. Direct measurement of CSF formation overcomes these limitations. Conclusions Direct measurement of CSF formation in rats is feasible. Our method should prove useful for studying CSF dynamics in normal physiology and disease models. PMID:25554415

  20. Control of ammonia distribution ratio across the liver cell membrane and of ureogenesis by extracellular pH.

    PubMed

    Rémésy, C; Demigné, C; Fafournoux, P

    1986-07-15

    The mechanisms involved in ammonia uptake by rat liver cells and the effects of changes in extracellular pH have been investigated in vivo and in vitro. When NH4Cl solutions were infused in the hepatic portal vein, ammonia uptake by the liver was practically quantitative up to about 1 mM in afferent blood. Ammonia transfer into hepatocytes was extremely rapid: for 2 mM ammonia in external medium, the intracellular concentration reached 5 mM within 10 s. Comparatively, [14C]methylamine influx was slower and the cell concentrations did not reach a steady-state level, probably in relation with diffusion into the acidic lysosomal compartment. Intracellular accumulation of ammonia was dependent on the delta pH across the plasma membrane: the distribution ratio (internal/external) was about 1 for an external pH of 6.8 and about 5 at pH 8. Urea synthesis was maximal at physiological pH and markedly declined at pH 7.05. This inhibition was not affected by manipulation of bicarbonate concentrations in the medium, down to 10 mM. Additional inhibition of ureogenesis by 100 microM acetazolamide was also observed, particularly at low concentrations of bicarbonate in the medium. Inhibition of ureogenesis when extracellular pH is decreased could be ascribed to a lower availability of the NH3 form. Assuming that NH3 readily equilibrates between the various compartments, the availability of free ammonia for carbamoyl-phosphate synthesis could be tightly dependent on extracellular pH. PMID:3089783

  1. Effects of inhibitors on chloride outflux from CSF

    SciTech Connect

    Nishimura, M.; Johnson, D.C.; Pappagianopoulos, P.; Kazemi, H.

    1986-03-05

    The regulation of the CSF (Cl/sup -/) plays a key role in CNS acid-base homeostasis. The authors have shown in previous studies that chloride influx from blood to CSF is largely dependent upon sodium-coupled carrier mediated movement. Therefore, the mechanism of chloride outflux from CSF to brain was evaluated in anesthetized dogs using ventricular-cisternal perfusion (VCP) with the short-lived isotope /sup 38/Cl/sup -/ and dextran. The outflux of /sup 38/Cl/sup -/ from CSF was determined from the different movements between /sup 38/Cl/sup -/ and dextran using a one compartment model. VCP was performed at a rate of 1.4 ml/min for 14 min, and then slowed to 0.28 ml/min. The /sup 38/Cl/sup -/ activity decreased to a steady state level about 12% lower than that of dextran within 40-50 minutes. Under control conditions (19 runs in 7 dogs), the rate of chloride outflux was 0.059 +/- 0.004 min/sup -1/ (mean +/- SE). It was not significantly changed after the inclusion of bumetanide (10/sup -5/ molar) in the VCP fluid (n=6), which inhibits sodium-coupled Cl/sup -/ transport, or with acetazolamide 4.5 x 10/sup -3/ molar (n=4) which inhibits carbonic anhydrase. The authors conclude that chloride outflux from CSF is not dependent upon sodium-coupled carrier mediated movement, which is in contrast with chloride influx from blood to CSF, nor is it dependent upon carbonic anhydrase activity.

  2. Bicarbonate secretion by rabbit proximal colon.

    PubMed

    Sullivan, S K; Smith, P L

    1986-10-01

    Stripped segments of proximal colon (1-6 cm distal to the ampulla caecalis coli) were studied in vitro in Ussing chambers under short-circuit conditions using the pH-stat technique. With glucose and HCO3-CO2 present in the serosal bathing solution only, proximal colon alkalinizes the luminal bathing solution at a rate of 2.1 +/- 0.2 mu eq X h-1 X cm-2 (n = 36). With HCO3-CO2 present in the luminal bathing solution alone, proximal colon does not significantly acidify or alkalinize the serosal bathing solution. Addition of glucose (10 mM) to the luminal bathing solution abolished luminal alkalinization. Removal of HCO3 and CO2 from the serosal bathing solution or replacement of O2 with N2 also abolished luminal alkalinization. Acetazolamide (0.1 mM) added to both bathing solutions did not alter the rate of luminal alkalinization. Ion-replacement studies revealed that the alkalinization process was highly dependent on the presence of Na in the bathing solutions and much less dependent on the presence of Cl. Furthermore, ouabain (0.1 mM) significantly reduced luminal alkalinization. As in rabbit ileum, serosal epinephrine (0.1 mM) did not alter luminal alkalinization but increased serosal alkalinization by a Na-dependent mechanism. These results suggest that luminal alkalinization results from a Na-dependent, active transcellular HCO3 transport process and that a Na-dependent HCO3 absorptive process is activated by adrenergic stimuli. PMID:3766731

  3. Interventions for the treatment of uveitic macular edema: a systematic review and meta-analysis

    PubMed Central

    Karim, Rushmia; Sykakis, Evripidis; Lightman, Susan; Fraser-Bell, Samantha

    2013-01-01

    Background Uveitic macular edema is the major cause of reduced vision in eyes with uveitis. Objectives To assess the effectiveness of interventions in the treatment of uveitic macular edema. Search strategy Cochrane Central Register of Controlled Trials, Medline, and Embase. There were no language or data restrictions in the search for trials. The databases were last searched on December 1, 2011. Reference lists of included trials were searched. Archives of Ophthalmology, Ophthalmology, Retina, the British Journal of Ophthalmology, and the New England Journal of Medicine were searched for clinical trials and reviews. Selection criteria Participants of any age and sex with any type of uveitic macular edema were included. Early, chronic, refractory, or secondary uveitic macular edema were included. We included trials that compared any interventions of any dose and duration, including comparison with another treatment, sham treatment, or no treatment. Data collection and analysis Best-corrected visual acuity and central macular thickness were the primary outcome measures. Secondary outcome data including adverse effects were collected. Conclusion More results from randomized controlled trials with long follow-up periods are needed for interventions for uveitic macular edema to assist in determining the overall long-term benefit of different treatments. The only intervention with sufficiently robust randomized controlled trials for a meta-analysis was acetazolamide, which was shown to be ineffective in improving vision in eyes with uveitic macular edema, and is clinically now rarely used. Interventions showing promise in this disease include dexamethasone implants, immunomodulatory drugs and anti-vascular endothelial growth-factor agents. When macular edema has become refractory after multiple interventions, pars plana vitrectomy could be considered. The disease pathophysiology is uncertain and the course of disease unpredictable. As there are no clear guidelines from

  4. 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

  5. Inhibition of carbonic anhydrase by parathyroid hormone and cyclic AMP in rat renal cortex in vitro.

    PubMed Central

    Beck, N; Kim, K S; Wolak, M; Davis, B B

    1975-01-01

    It has been demonstrated that parathyroid hormone (PTH) inhibits the proximal tubular reabsorption of bicarbonate, and increases the urinary excretion of that ion. There is also a qualitative similarity between the alterations of the proximal tubular reabsorption of phosphate, sodium, and water after PTH administration and after acetazolamide administration. These findings suggest that the renal effect of PTH is possibly mediated through the inhibition of carbonic anhydrase in proximal tubules. Therefore, a possible inhibitory effect of PTH on carbonic anhydrase was evaluated in the homogenate of rat renal cortex by an indicator titration method. Incubation of cortical homogenates with PTH for 10 min at 37degreesC inhibited carbonic anhydrase activity. The inhibitory effect of PTH was ATP-, Mg++-, and K+-dependent and temperature-dependent; inactivation of PTH by heating at 100degreesC abolished the effect of PTH both to activate adenylate cyclase and to inhibit carbonic anhydrase. Calcium 5 mM also partially abolished effects of PTH to activate adenylate cyclase and to inhibit carbonic anhydrase. The inhibitory effect of PTH on carbonic anhydrase was specific to renal cortex. Cyclic AMP, the intracellular messenger substance for PTH, also inhibited carbonic anhydrase in renal cortex. The cyclic AMP-induced inhibition was also Mg++ dependent and temperature dependent, and required preincubation at 37degreesC. But 5'-AMP, a metabolic derivative of cyclic AMP without its biological effect, had no inhibitory effect on carbonic anhydrase. All the above results are consistent with the hypothesis that PTH inhibits proximal tubular reabsorption of bicarbonate and phosphate through the inhibition of carbonic anhydrase, and that inhibitory effect is mediated through the cyclic AMP system. PMID:233968

  6. 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

  7. Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites

    SciTech Connect

    Louisse, Jochem; Verwei, Miriam; Sandt, Johannes J.M. van de; Rietjens, Ivonne M.C.M.

    2010-06-01

    Embryotoxicity of glycol ethers is caused by their alkoxyacetic acid metabolites, but the mechanism underlying the embryotoxicity of these acid metabolites is so far not known. The present study investigates a possible mechanism underlying the embryotoxicity of glycol ether alkoxyacetic acid metabolites using the methoxyacetic acid (MAA) metabolite of ethylene glycol monomethyl ether as the model compound. The results obtained demonstrate an MAA-induced decrease of the intracellular pH (pH{sub i}) of embryonic BALB/c-3T3 cells as well as of embryonic stem (ES)-D3 cells, at concentrations that affect ES-D3 cell differentiation. These results suggest a mechanism for MAA-mediated embryotoxicity similar to the mechanism of embryotoxicity of the drugs valproic acid and acetazolamide (ACZ), known to decrease the pH{sub i}in vivo, and therefore used as positive controls. The embryotoxic alkoxyacetic acid metabolites ethoxyacetic acid, butoxyacetic acid and phenoxyacetic acid also caused an intracellular acidification of BALB/c-3T3 cells at concentrations that are known to inhibit ES-D3 cell differentiation. Two other embryotoxic compounds, all-trans-retinoic acid and 5-fluorouracil, did not decrease the pH{sub i} of embryonic cells at concentrations that affect ES-D3 cell differentiation, pointing at a different mechanism of embryotoxicity of these compounds. MAA and ACZ induced a concentration-dependent inhibition of ES-D3 cell differentiation, which was enhanced by amiloride, an inhibitor of the Na{sup +}/H{sup +}-antiporter, corroborating an important role of the pH{sub i} in the embryotoxic mechanism of both compounds. Together, the results presented indicate that a decrease of the pH{sub i} may be the mechanism of embryotoxicity of the alkoxyacetic acid metabolites of the glycol ethers.

  8. 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. PMID:25888575

  9. Sensitization of Upper Airway Mechanoreceptors as a New Pharmacologic Principle to Treat Obstructive Sleep Apnea: Investigations with AVE0118 in Anesthetized Pigs

    PubMed Central

    Wirth, Klaus J.; Steinmeyer, Klaus; Ruetten, Hartmut

    2013-01-01

    Study Objectives: Drug treatment for obstructive sleep apnea (OSA) is desirable because at least 30% of patients do not tolerate continuous positive airway pressure (CPAP) treatment. The negative pressure reflex (NPR) involving superficially located mechanoreceptors in the upper airway (UA) is an important mechanism for UA patency inhibitable by topical UA anesthesia (lidocaine). The NPR may serve as a target for pharmacological intervention for a topical treatment of OSA. The objective was to determine the effect of pharmacological augmentation of the NPR on UA collapsibility. Design: We developed a model of UA collapsibility in which application of negative pressures caused UA collapses in spontaneously breathing α-chloralose-urethane anesthetized pigs as indicated by characteristic tracheal pressure and air flow changes. Setting: N/A. Patients or Participants: N/A. Interventions: N/A. Measurements and Results: The potassium channel blocker AVE0118 administered topically to the UA in doses of 1, 3, and 10 mg per nostril sensitized the NPR, shifting the mechanoreceptor response threshold for the genioglossus muscle to more positive pressures (P < 0.001; n = 6 per group) and dose-dependently inhibited UA collapsibility. Ten mg of AVE0118 prevented UA collapses against negative pressures of -150 mbar (P < 0.01) for > 4 h in all pigs, while in control pigs the UA collapsed at -50 mbar or less negative pressures. The effect of AVE0118 was abolished by UA lidocaine anesthesia. Acute intravenous administration of naloxone or acetazolamide was ineffective; paroxetine and mirtazepine were weakly effective and fluoxetine was moderately effective in line with reported clinical efficacy. Conclusion: Topical administration of AVE0118 to the UA is a promising pharmacologic approach for the treatment of OSA. Citation: Wirth KJ; Steinmeyer K; Ruetten H. Sensitization of upper airway mechanoreceptors as a new pharmacologic principle to treat obstructive sleep apnea

  10. 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

  11. 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

  12. Episodic ataxia type 2 manifests as epileptiform electroencephalographic activity with no epileptic attacks in two family members.

    PubMed

    Kaido, Misako; Furuta, Mitsuru; Nakamori, Masayuki; Yuasa, Yoshihito; Takahashi, Masanori P

    2016-04-28

    Here, we report two cases of episodic ataxia type 2 (EA2) in a 63-year-old woman and her 36-year-old daughter. The mother experienced recurrent attacks of cerebellar dysfunction lasting 4 to 5 hours since the age of 41 years. On several occasions, she was admitted to the emergency room, where she was diagnosed with epilepsy or stroke. Based on these diagnoses, she was treated with antiepileptic or anticoagulant drugs, but both treatments were eventually discontinued. The frequency of the attacks increased after the patient reached the age of 62. Interictal neurological examination demonstrated signs of slight cerebellar ataxia, i.e. saccadic eye movements, gaze-directed nystagmus, and mild truncal ataxia. Brain magnetic resonance imaging (MRI) showed cerebellar vermis atrophy. Electroencephalography (EEG) revealed various spike and wave patterns: solitary spikes, spike-and-slow wave complexes, and slow wave bursts. Photoparoxysmal response (PPR) type 3 was also observed. Treatment with acetazolamide abolished the patient's attacks almost completely. The daughter started experiencing 5- to 10-minute ataxic episodes at the age of 16 years. Based on her epileptiform EEG activities with PPR (type 2), antiepileptic drugs (valproate and zonisamide) were prescribed. Despite pharmacological treatment, the attacks recurred; however, their frequency gradually decreased with time, until they almost entirely disappeared when the patient was 33. Unfortunately, migraine-like headaches arose instead. Subtle truncal ataxia was observed during interictal periods. Sanger sequencing of the exons of the CACNA1A gene revealed a novel single base deletion (c.3575delA) in both patients. Despite the difference in age of onset and clinical course, both patients showed clearly epileptiform EEG activities without experiencing the concurrent epileptic episodes. Thus, EA2 is a disease that may be misdiagnosed as epilepsy or stroke in the field of emergency medicine. PMID:27025991

  13. 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

  14. 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

  15. 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

  16. Effect of genistein on basal jejunal chloride secretion in R117H CF mice is sex and route specific

    PubMed Central

    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/cm2, n=6, P<0.05) and a subgroup of nonresponders (12.05±6.59 μA/cm2, n=4), compared to 0Gd controls (29.3±6.5 μA/cm2, 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 of

  17. 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

  18. 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

  19. 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

  20. Action of gastrin in guinea pig oxyntic cells. Studies using quantitative cytochemistry.

    PubMed Central

    Heldsinger, A A; Vinik, A I

    1984-01-01

    The mechanism of action of gastrin was investigated using cytochemical quantitation of hydroxyl ion production (HIP) in guinea pig gastric oxyntic mucosa. The reaction depends upon the trapping of OH ions produced during gastric stimulation and is blocked by the benzimidazole, Hassle 149/94, which inhibits the K+ + H+-ATPase and by acetazolamide, an inhibitor of carbonic anhydrase activity. It is thus a measure of hydroxyl ions produced during stimulation of the oxyntic cell and reflects upon hydrogen ion production. Gastrin (2.5 X 10(-16) -2.5 X 10(-12) M) caused a linear dose-dependent stimulation of HIP in the oxyntic cells. The response was biphasic, with an early peak at 90 s and a secondary rise at 240 s, which persisted for 10 min. Natural human gastrin (sulfated and nonsulfated) and the active COOH-terminal octapeptide fragment of gastrin stimulated HIP, whereas the biologically inert NH2-terminal (1-13) fragment of gastrin had no effect. The activation of oxyntic cell HIP by gastrin was neutralized by an antiserum directed towards the COOH-terminus of gastrin and not by nonimmune serum. Cimetidine (10(-5) M) blocked 25% and atropine (10(-5) M) had no effect on gastrin-stimulated HIP. EGTA (10(-3) M) and LaCl3 (10(-3) M) inhibited the action of gastrin by 67 and 52%, respectively. The calmodulin antagonists, trifluoperazine (10(-5) M), pimozide (10(-5) M), and the naphthalene sulfonamides, W-7 and W-13 (10(-5) M), inhibited gastrin-stimulated HIP by 45.6 38.5, 42.3, and 37.2%, respectively. Higher doses of W-7 and W-13 (10(-4) M) inhibited gastrin-stimulated HIP by 83 and 67%. The Ca2+ ionophore, A23187 (10(-4) M), stimulated HIP. Thus, it appears that gastrin stimulation of HIP is complex. 25% of its action is via a histamine-dependent pathway. 45% of its action is dependent upon extracellular Ca2+. Its action is also in part dependent upon a Ca2+/calmodulin mechanism. PMID:6330172

  1. Hypoxia, not pulmonary vascular pressure, induces blood flow through intrapulmonary arteriovenous anastomoses

    PubMed Central

    Tremblay, Joshua C; Lovering, Andrew T; Ainslie, Philip N; Stembridge, Mike; Burgess, Keith R; Bakker, Akke; Donnelly, Joseph; Lucas, Samuel JE; Lewis, Nia CS; Dominelli, Paolo B; Henderson, William R; Dominelli, Giulio S; Sheel, A William; Foster, Glen E

    2015-01-01

    Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased with exposure to acute hypoxia and has been associated with pulmonary artery systolic pressure (PASP). We aimed to determine the direct relationship between blood flow through IPAVA and PASP in 10 participants with no detectable intracardiac shunt by comparing: (1) isocapnic hypoxia (control); (2) isocapnic hypoxia with oral administration of acetazolamide (AZ; 250 mg, three times a day for 48 h) to prevent increases in PASP; and (3) isocapnic hypoxia with AZ and 8.4% NaHCO3 infusion (AZ + HCO3–) to control for AZ-induced acidosis. Isocapnic hypoxia (20 min) was maintained by end-tidal forcing, blood flow through IPAVA was determined by agitated saline contrast echocardiography and PASP was estimated by Doppler ultrasound. Arterial blood samples were collected at rest before each isocapnic–hypoxia condition to determine pH, [HCO3–] and . AZ decreased pH (–0.08 ± 0.01), [HCO3–] (−7.1 ± 0.7 mmol l−1) and (−4.5 ± 1.4 mmHg; P < 0.01), while intravenous NaHCO3 restored arterial blood gas parameters to control levels. Although PASP increased from baseline in all three hypoxic conditions (P < 0.05), a main effect of condition expressed an 11 ± 2% reduction in PASP from control (P < 0.001) following AZ administration while intravenous NaHCO3 partially restored the PASP response to isocapnic hypoxia. Blood flow through IPAVA increased during exposure to isocapnic hypoxia (P < 0.01) and was unrelated to PASP, cardiac output and pulmonary vascular resistance for all conditions. In conclusion, isocapnic hypoxia induces blood flow through IPAVA independent of changes in PASP and the influence of AZ on the PASP response to isocapnic hypoxia is dependent upon the H+ concentration or . PMID:25416621

  2. 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.

  3. 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

  4. Catecholamine-induced changes in ion transport in short-circuited frog skin and the effect of beta-blockade.

    PubMed Central

    Tomlinson, R W; Wood, A W

    1976-01-01

    1. A method for measuring bidirectional Cl fluxes has been used to estimate net Cl movements in short-circuited frog skin and to compare these with the short-circuit current (Isc) and Na fluxes. 2. In some experiments bidirectional fluxes of both Na and Cl were measured simultaneously. It was found that the algebraic sum of the net fluxes of these two ions did not differ significantly from the values of Isc, either in untreated or catecholamine-treated skins, except for the half-hour period immediately after catecholamine addition. 3. The net effluxes of Cl produced by noradrenaline (1-6 X 10(-5)M), isoprenaline (8 X 10(-7)M) and adrenaline (6 and 15 X 10(-6)M) were of similar magnitude for each catecholamine. The magnitude of the Cl response measured as a flux ratio was related to a certain extent to the precatecholamine Cl conductance. 4. The net Na influx was increased by isoprenaline and reduced by noradrenaline. 5. Addition of the beta-adrenergic blocking agent oxprenolol (4-5 X 10(-5)M) to skins stimulated by catecholamine resulted in the disappearance of the net Cl movement and fall in skin conductance and Isc. This fall was similar in magnitude to, and correlated with the mean rise in Isc produced by isoprenaline, but of significantly greater magnitude in the case of noradrenaline. 6. The changes in Na influx were strongly associated with the changes in Isc following catecholamine addition. Similarly, the changes in Na efflux and Cl efflux were correlated, suggesting the Na fluxes to be dissociated, influx and efflux changes perhaps taking place at different loci. 7. Acetazolamide (1-2 X 10(-4)M), added either before or during the noradrenaline stimulation, had no effect on the Cl efflux response. 8. The tissue exchange of Cl from the outside bathing medium after 4 hr was greater in catecholamine-stimulated skins than in those in which the response had been blocked by oxprenolol. 9. These findings were taken to support a model entailing a neutral NaCl pump

  5. Carbonic Anhydrase Activity in Isolated Chloroplasts of Wild-Type and High-CO2-Dependent Mutants of Chlamydomonas reinhardtii as Studied by a New Assay.

    PubMed Central

    Katzman, G. L.; Carlson, S. J.; Marcus, Y.; Moroney, J. V.; Togasaki, R. K.

    1994-01-01

    In an assay of carbonic anhydrase (CA), NAH14CO3 soltution at the bottom of a sealed vessel releases 14CO2, which diffuses to the top of the vessel to be assimilated by photosynthesizing Chlamydomonas reinhardtii cells that have been adapted to a low-CO2 environment. The assay is initiated by illuminating the cells and is stopped by turning the light off and killing the cells with acid. Enzyme activity was estimated from acid-stable radioactivity. With bovine CA, 1.5 Wilbur-Anderson units (WAU) was consistently measured at 5- to 6-fold above background. Sonicated whole cells of air-adapted wild-type C. reinhardtii had 740 [plus or minus] 12.4 WAU/mg chlorophyll (Chl). Sonicated chloroplasts from a mixotrophically grown wall-less strain, cw-15, had 35.5 [plus or minus] 2.6 WAU/mg Chl, whereas chloroplasts from wall-less external CA mutant strain cia5/cw-15 had 33.8 [plus or minus] 1.9 WAU/mg Chl. Sonicated chloroplasts from the wall-less mutant strain cia-3/cw-15, believed to lack an internal CA, had 2.8 [plus or minus] 3.2 WAU/mg Chl. Sonicated whole cells from cia3/cw-15 had 2.8 [plus or minus] 7.8 WAU/mg Chl. Acetazolamide, ethoxyzolamide, and p-aminomethylbenzene sulfonamide (Mafenide) at 100 [mu]M inhibited CA in sonicated chloroplasts from cia-5/cw-15. Treatment at 80[deg]C for 10 min inhibited this CA activity by 90.8 [plus or minus] 3.6%. Thus, a sensitive 14C assay has confirmed the presence of a CA in cw-15 and cia-5/cw-15 chloroplasts and the lack of a CA in cia-3/cw-15 chloroplasts. Our results indicate that HCO3- is the inorganic carbon species that is accumulated by chloroplasts of Chlamydomonas and that chloroplastic CA is responsible for the majority of internal CA activity. PMID:12232275

  6. Cough, exertional, and other miscellaneous headaches.

    PubMed

    Sands, G H; Newman, L; Lipton, R

    1991-05-01

    , and MSG-induced headache. For the most part, avoidance of these stimuli can prevent the associated headache. Lastly, we reviewed headache provoked by high altitude and hypoxia. The headache is part of the syndrome of AMS during its early or benign stage and the later malignant stage of HACE. The pain can be exacerbated by exercise. The best treatment is prevention via slow ascent and avoidance of respiratory depressants. Acetazolamide and dexamethasone have proved useful in preventing this syndrome. PMID:2020226

  7. 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

  8. Rod phototransduction modulated by bicarbonate in the frog retina: roles of carbonic anhydrase and bicarbonate exchange.

    PubMed Central

    Donner, K; Hemilä, S; Kalamkarov, G; Koskelainen, A; Shevchenko, T

    1990-01-01

    1. Effects on rod phototransduction following manipulation of retinal CO2-HCO3- and H+ fluxes were studied in dark-adapted retinas of the frog and the tiger salamander. 2. Rod photoresponses to brief flashes of light were recorded from the isolated sensory retina as electroretinogram mass receptor potentials and from isolated rods by the suction-pipette technique. The experimental treatments were: (1) varying [CO2] + [HCO3-] in the perfusion fluid: (2) applying acetazolamide (AAA), which inhibits the enzyme carbonic anhydrase (CA); and (3) applying 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) which blocks exchange mechanisms transporting HCO3- across cell membranes. 3. The concentration of the internal transmitter of the rods, cyclic GMP, was biochemically determined from the rod outer segment layer of retinas that had been incubated in the same solutions as were used for perfusion in the electrophysiological experiments. 4. The introduction of 6 mM-sodium bicarbonate to replace half the buffer of a nominally CO2-HCO3(-)-free (12 mM-phosphate or HEPES, [Na+] constant) Ringer solution doubled the cyclic GMP concentration in the rod outer segment layer and increased the saturating response amplitude and the relative sensitivity of rods in the intact retina. 5. The introduction of 0.5 mM-AAA into bicarbonate-containing Ringer solution accelerated the growth of saturated responses and sensitivity. Incubation of the retina in AAA-bicarbonate Ringer solution elevated the concentration of cyclic GMP ninefold compared with the phosphate control. 6. No effects of switching to bicarbonate-AAA Ringer solution were observed in the photocurrent of isolated rods drawn into suction pipettes with only the outer segment protruding into the perfusion fluid. The target of AAA is probably the CA-containing Müller cell. 7. The introduction of DIDS into the perfusate (at normal pH 7.5) set off a continuous decay of photoresponses which finally abolished light sensitivity

  9. 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.

  10. 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.

  11. Near infrared spectroscopy--investigations in neurovascular diseases.

    PubMed

    Schytz, Henrik Winther

    2015-12-01

    , but not in patients with pure FHM phenotype. This suggests that the sensitivity to NO resides within the common migraine phenotypes rather than the FHM phenotype. Stimulation of the sphenopalatine ganglion (SPG) may lead to parasympathetic outflow and cause pain in cluster headache (CH). The fifth study therefore investigated pain and autonomic symptoms in relation to high or low SPG frequency stimulation in chronic CH patients. Cortical changes in oxygenated hemoglobin (HbO) were also recorded with NIRS and showed a moderate HbO increase, which was most pronounced on the ipsilateral CH side following high frequency stimulation. A possible application of NIRS to assess cerebral vascular changes due to sympathetic activity was investigated in obstructive sleep apnoea (OSA) patients, who have increased sympathetic activity and risk of stroke. Following successful continuous positive airway pressure (CPAP) therapy, OSA patients decreased their LFOs amplitude, which was interpreted as a marker of decreased sympathetic activity in cortical vessels. Finally, a novel hybrid technique, combining NIRS and ultrasound, was tested to detect CBF changes after acetazolamide injection in healthy volunteers using a cerebral flow index (CFI). The study showed an increase in CFI, which correlated with CBF measured with 133Xe-SPECT at 15 min. but not 60 min. Further methodological and explorative clinical studies are needed to assess the feasibility of ultrasound-tagged NIRS in clinical neurology. In summary, the thesis presents several novel approaches, by which NIRS may be used in clinical neurology, and potentials of NIRS to investigate complex mechanisms in neurovascular diseases. PMID:26621402

  12. 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