Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: A placebo-controlled randomized phase iia trial (NOSTRA)

Journal of Neurotrauma

Volumn 31, Issue 19, 2014, Pages 1599-1606

  Stover, John F ^a   Belli, Antonio ^b   Boret, Henry ^c   Bulters, Diederik ^b   Sahuquillo, Juan ^d   Schmutzhard, Erich ^e   Zavala, Elisabeth ^f   Ungerstedt, Urban ^g   Schinzel, Reinhard ^h   Tegtmeier, Frank ^h  

^a UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^b UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST   (United Kingdom)

^c Military Teaching Hospital Sainte Anne   (France)

^d HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^e INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^f UNIVERSITY OF BARCELONA   (Spain)

^g KAROLINSKA INSTITUTE   (Sweden)

^h Vasopharm GmbH   (Germany)

Author keywords

clinical trial; microdialysis; NO synthase inhibition; traumatic brain injury

Indexed keywords

DRUG METABOLITE; NITRIC OXIDE SYNTHASE; PLACEBO; RONOPTERIN; 4-AMINO-TETRAHYDROBIOPTERIN; BIOPTERIN; ENZYME INHIBITOR; NEUROPROTECTIVE AGENT;

ACUTE KIDNEY FAILURE; ADULT; AGED; ARTICLE; BLOOD LEVEL; BRAIN METABOLISM; BRAIN PERFUSION; CLINICAL ARTICLE; COHORT ANALYSIS; CONTINUOUS INFUSION; CONTROLLED STUDY; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG DOSE INCREASE; DRUG EFFECT; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; ENZYME INHIBITION; FEMALE; GLASGOW OUTCOME SCALE; HUMAN; INTRACRANIAL PRESSURE; KIDNEY DYSFUNCTION; MALE; MAXIMUM PLASMA CONCENTRATION; MICRODIALYSIS; NEUROPROTECTION; PARAMETERS; PERFUSION PRESSURE; PHASE 2 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; SEPTIC SHOCK; STATISTICAL ANALYSIS; THERAPY INTENSITY LEVEL; TRAUMATIC BRAIN INJURY; TREATMENT OUTCOME; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; BRAIN INJURIES; CLINICAL TRIAL; DRUG EFFECTS; MIDDLE AGED; MULTICENTER STUDY; YOUNG ADULT;

ADULT; AGED; BIOPTERIN; BRAIN INJURIES; ENZYME INHIBITORS; FEMALE; GLASGOW OUTCOME SCALE; HUMANS; INTRACRANIAL PRESSURE; MALE; MICRODIALYSIS; MIDDLE AGED; NEUROPROTECTIVE AGENTS; NITRIC OXIDE SYNTHASE; YOUNG ADULT;

EID: 84907236116     PISSN: 08977151     EISSN: 15579042     Source Type: Journal    
DOI: 10.1089/neu.2014.3344     Document Type: Article

References (21)

1. Ghajar J. (2000). Traumatic brain injury. Lancet 356, 923-9
2. Maas AI, Roozenbeek B, and Manley GT. (2010). Clinical trials in traumatic brain injury: past experience and current developments. NeuroTherapeutics 7, 115-26
3. Guzik TJ, West NE, Pillai R, Taggart DP, and Channon KM. (2002). NO modulates superoxide release and peroxynitrite formation in human blood vessels. Hypertension 39, 1088-94
4. Gahm C, Holmin S, Wiklund PN, Brundin L, and Mathiesen T. (2006). Neuroprotection by selective inhibition of inducible nitric oxide synthase after experimental brain contusion. Journal of Neurotrauma 23, 343-54
5. Terpolilli NA, Zweckberger K, Trabold R, Schilling L, Schinzel R, Tegtmeier F, and Plesnila N. (2009). The novel nitric oxide synthase inhibitor 4-Amino-Tetrahydro-L-biopterine prevents brain edema formation and intracranial hypertension following traumatic brain injury in mice. Journal of Neurotrauma; 26, 1963-75
6. Werner ER, Pitters E, Schmidt K, Wachter H, Werner-Felmayer G, and Mayer B. (1996). Identification of the 4-Amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase. Biochemical Journal 320, 93-6
7. Carney NA and Ghajar J. (2007). Brain Trauma Foundation; Guidelines for the Management of Severe Traumatic Brain Injury (3rd edition). Journal of Neurotrauma 24, S1-S106
8. Lindroth P , and Mopper K. (1979). High performance liquid chromatographic determination of subpicomole amounts of amino acids by pre-column fluorescence derivatization with o-phthaldialdehyde. Anal. Chem. 51, 1667-74
9. Woitzik J, Abromeit N, and Schaefer F. (2001). Measurement of nitric oxide metabolites in brain microdialysates by a sensitive fluorometric high-performance liquid chromatography assay. Analytical Biochemistry 289, 10-7
10. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A, and Acute Kidney Injury Network (2007). Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Critical Care 11, R31-6
11. Uzan M, Tanriover N, Bozkus H, Gumustas K, Guzel O, and Kuday C. (2001). Nitric oxide metabolism in the cerebrospinal fluid of patients with severe head injury. Inflammation as a possible cause of elevated no metabolites. Surgical Neurology 56, 350-6
12. Orihara Y, Ikematsu K, Tsuda R, and Nakasono I. (2001). Induction of nitric oxide synthase by traumatic brain injury. Forensic Sci. Int. 123, 142-9
13. Werner ER and Schmitt HH. (2000). Pterin antagonists / anti-pterins. Handbook of Experimental Pharmacology 143, 137-57
14. Pfeiffer S, Gorren AC, Pitters E, Schmidt K, Werner ER, and Mayer B. (1997). Allosteric modulation of rat brain nitric oxide synthase by the pterin-site enzyme inhibitor 4-Amino-Tetrahydrobiopterin. Biochemical Journal 328, 349-52
15. Heemskerk S, Masereeuw R, Russel FG, and Pickkers P. (2009). Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury. Nature Reviews Nephrology 5, 629-40
16. Wang T. (2002). Role of iNOS and eNOS in modulating proximal tubule transport and acid-base balance. American Journal of Physiology Renal Physiology 283, F658-62
17. Ahmed SB, Fisher ND, and Hollenberg NK. (2007). Gender and the renal nitric oxide synthase system in healthy humans. Clinical Journal of the American Society of Nephrology 2, 926-31
18. Weinstein, J.R., and Anderson, S. (2010). The aging kidney: physiological changes. Advances in Chronic Kidney Disease 17, 302-307
19. Cherian, L., Hlatky, R., and Robertson, C.S. (2004). Nitric oxide in traumatic brain injury. Brain Pathol. 14, 195-201
20. Tisdall, M.M., Rejdak, K., Kitchen, N.D., Smith, M., and Petzold, A. (2013). The prognostic value of brain extracellular fluid nitric oxide metabolites after traumatic brain injury. Neurocritical Care 19, v65-68
21. Maas, A.I., Harrison-Felix, C.L., Menon, D., Adelson, P.D., Balkin, T., Bullock, R., Engel, D.C., Gordon, W., Langlois-Orman, J., Lew, H.L., Robertson, C., Temkin, N., Valadka, A., Verfaellie, M., Wainwright, M., Wright, D.W., and Schwab, K. (2011). Standardizing data collection in traumatic brain injury. J. Neurotrauma 28, 177-187