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

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          Abstract

          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.

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          Improving the Quality of Reporting of Randomized Controlled Trials

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            New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation.

            In this review, we discuss the role of the tumour-associated carbonic anhydrase isoform IX (CAIX) in the context of pH regulation. We summarise recent experimental findings on the effect of CAIX on cell growth and survival, and present a diffusion-reaction model to help in the assessment of CAIX function under physiological conditions. CAIX emerges as an important facilitator of acid diffusion and acid transport, helping to overcome large cell-to-capillary distances that are characteristic of solid tumours. The source of substrate for CAIX catalysis is likely to be CO₂, generated by adequately oxygenated mitochondria or from the titration of metabolic acids with HCO₃⁻ taken up from the extracellular milieu. The relative importance of these pathways will depend on oxygen and metabolite availability, the spatiotemporal patterns of the cell's exposure to hypoxia and on the regulation of metabolism by genes. This is now an important avenue for further investigation. The importance of CAIX in regulating tumour pH highlights the protein as a potential target for cancer therapy.
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              Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion.

              Carbonic anhydrase IX (CAIX) is a membrane-associated carbonic anhydrase (CA), strongly induced by hypoxia. CAIX is overexpressed in a variety of tumor types and associated with increased metastasis and poor prognosis. An inhibitor of CAs, acetazolamide has been reported to inhibit invasion. We used RNA interference (RNAi) to examine the function of CAIX in MDA468 and MDA231 breast carcinoma cells, which express high levels of CAIX under hypoxia. Hypoxia-induced CA activity was completely blocked by specific RNAi (P < 0.01). RNAi-treated cells showed growth delay in dense monolayer culture and a 50% reduction in clonogenic survival under hypoxia. In the MDA468 cells, there was no effect of RNAi treatment on invasion. In a cell line that did not induce CAIX under hypoxia, RT112, we found no effect on the ability of cells transfected with CAIX to invade or migrate. Thus, CAIX plays an important role in the growth and survival of tumor cells under normoxia and hypoxia, making it a potential target for cancer therapy, but is not involved in invasion.
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                Author and article information

                Journal
                Pharmacol Res Perspect
                Pharmacol Res Perspect
                10.1002/(ISSN)2052-1707
                PRP2
                Pharmacology Research & Perspectives
                John Wiley and Sons Inc. (Hoboken )
                2052-1707
                19 May 2016
                June 2016
                : 4
                : 3 ( doiID: 10.1111/prp2.2016.4.issue-3 )
                : e00203
                Affiliations
                [ 1 ] Centres of Clinical Pharmacology and Biochemical Pharmacology William Harvey Research InstituteBarts, Queen Mary University of London London EC1M 6BQUnited Kingdom
                [ 2 ]The Health Centre Surrey RH8 OBQUnited Kingdom
                [ 3 ]Centre for Altitude Space and Extreme Environment Medicine UCL London N19 5LWUnited Kingdom
                [ 4 ] Medical Service Veterans Affairs Puget Sound Health Care SystemUniversity of Washington Seattle Washington USA 98108
                Author notes
                [*] [* ] Correspondence

                Erik R. Swenson, Departments of Medicine and Physiology, University of Washington, VA Puget Sound Health Care System, S‐111‐PULM, 1660 South Columbian Way, Seattle, WA 98108. Tel: 206 764 2668; Fax: 206 764 2659; E‐mail: eswenson@ 123456u.washington.edu

                Article
                PRP2203
                10.1002/prp2.203
                4876137
                27433337
                b52e8399-563a-4d4f-981e-9408a0955765
                © 2016 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 28 August 2015
                : 22 October 2015
                : 06 November 2015
                Page count
                Pages: 12
                Funding
                Funded by: University of Liverpool
                Funded by: Medical Expeditions
                Funded by: US National Institutes of Health
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                prp2203
                June 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:10.07.2016

                acetazolamide,acute mountain sickness,benzolamide,carbonic anhydrase inhibitor,high altitude,lorazepam,oxygen saturation,side effects

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