A Single Dose Study of the Safety, Blood Levels and Biological Effects of Aes-103 Compared to Placebo in Subjects With Stable Sickle Cell Disease

Summary

The purpose of this study is to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of Aes-103 (active ingredient 5-hydroxymethyl-2-furfural \[5-HMF\]) compared with placebo in subjects with stable sickle cell disease (SCD). Safety will be measured by monitoring adverse events (AEs), electrocardiograms (ECGs), vital signs, and laboratory values. Pharmacokinetics of Aes-103 will be measured over time in plasma, red blood cell hemolysate and binding of Aes-103 to hemoglobin. Pharmacodynamic effects will be assessed by measuring partial pressure of oxygen at which 50% of hemoglobin is saturated with oxygen (p50) while breathing normal air, blood oxygen levels (SpO2), ex-vivo antisickling effects in a hypoxic environment, and by imaging related changes in tissue blood flow and oxygen levels.

Timeline

Start

2012-05-12

Primary completion

2013-06-07

Completion

2013-06-07

Publications

• Background Abdulmalik O, Safo MK, Chen Q, Yang J, Brugnara C, Ohene-Frempong K, Abraham DJ, Asakura T. 5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells. Br J Haematol. 2005 Feb;128(4):552-61. doi: 10.1111/j.1365-2141.2004.05332.x.
• Background Buchanan G, Vichinsky E, Krishnamurti L, Shenoy S. Severe sickle cell disease--pathophysiology and therapy. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S64-7. doi: 10.1016/j.bbmt.2009.10.001. Epub 2009 Oct 9.
• Background Czok G. [Tolerance of 5-hydroxymethylfurfural (HMF). 2d communication: pharmacologic effects]. Z Ernahrungswiss. 1970 Dec;10(2):103-10. doi: 10.1007/BF02021840. No abstract available. German.
• Background Germond JE, Philippossian G, Richli U, Bracco I, Arnaud MJ. Rapid and complete urinary elimination of [14C]-5-hydroxymethyl-2-furaldehyde administered orally or intravenously to rats. J Toxicol Environ Health. 1987;22(1):79-89. doi: 10.1080/15287398709531052.
• Background Godfrey VB, Chen LJ, Griffin RJ, Lebetkin EH, Burka LT. Distribution and metabolism of (5-hydroxymethyl)furfural in male F344 rats and B6C3F1 mice after oral administration. J Toxicol Environ Health A. 1999 Jun 11;57(3):199-210. doi: 10.1080/009841099157764.
• Background Lo Coco F, Novelli V, Valentini C, Ceccon L. High-performance liquid chromatographic determination of 2-furaldehyde and 5-hydroxymethyl-2-furaldehyde in fruit juices. J Chromatogr Sci. 1997 Dec;35(12):578-83. doi: 10.1093/chromsci/35.12.578.
• Background Matzi V, Lindenmann J, Muench A, Greilberger J, Juan H, Wintersteiger R, Maier A, Smolle-Juettner FM. The impact of preoperative micronutrient supplementation in lung surgery. A prospective randomized trial of oral supplementation of combined alpha-ketoglutaric acid and 5-hydroxymethylfurfural. Eur J Cardiothorac Surg. 2007 Nov;32(5):776-82. doi: 10.1016/j.ejcts.2007.07.016. Epub 2007 Sep 4.
• Background Mitchell BL. Sickle cell trait and sudden death--bringing it home. J Natl Med Assoc. 2007 Mar;99(3):300-5.
• Background Mrochek JE, Rainey WT Jr. Identification and biochemical significance of substituted furans in human urine. Clin Chem. 1972 Aug;18(8):821-8. No abstract available.
• Background Murkovic M, Pichler N. Analysis of 5-hydroxymethylfurfual in coffee, dried fruits and urine. Mol Nutr Food Res. 2006 Sep;50(9):842-6. doi: 10.1002/mnfr.200500262.
• Background Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008 Mar 27;358(13):1362-9. doi: 10.1056/NEJMct0708272. No abstract available.
• Background Prior RL, Wu X, Gu L. Identification and urinary excretion of metabolites of 5-(hydroxymethyl)-2-furfural in human subjects following consumption of dried plums or dried plum juice. J Agric Food Chem. 2006 May 17;54(10):3744-9. doi: 10.1021/jf0601113.
• Background Simonian TA. [Toxico-hygienic characteristics of oxymethylfurfural]. Vopr Pitan. 1969 Jan-Feb;28(1):54-8. No abstract available. Russian.
• Background Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health. 2006;29(4):245-54.

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Indications