A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease

American Journal of Hematology

Volumn 89, Issue 7, 2014, Pages 709-713

  Reid, Marvin E ^a   El Beshlawy, Amal ^b   Inati, Adlette ^c   Kutlar, Abdullah ^d   Abboud, Miguel R ^e   Haynes, Johnson ^f   Ward, Richard ^g   Sharon, Bruce ^h   Taher, Ali T ⁱ   Smith, Wally ^j   Manwani, Deepa ^k   Ghalie, Richard G ^l  

^a UNIVERSITY OF THE WEST INDIES   (Jamaica)

^b Cairo University   (Egypt)

^c Hospital Bir Hassan   (Lebanon)

^d MEDICAL COLLEGE OF GEORGIA   (United States)

^e AMERICAN UNIVERSITY OF BEIRUT   (Lebanon)

^f UNIVERSITY OF SOUTH ALABAMA   (United States)

^g TORONTO GENERAL HOSPITAL   (Canada)

^h UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

ⁱ Chronic Care Center Hazmieh   (Lebanon)

^j VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^k CHILDREN S HOSPITAL AT MONTEFIORE   (United States)

^l HemaQuest Pharmaceuticals   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

2,2 DIMETHYLBUTYRATE; AMYLASE; ANTISICKLING AGENT; ASPARTATE AMINOTRANSFERASE; BUTYRIC ACID DERIVATIVE; FOLIC ACID; HEMOGLOBIN F; HQK 1001; HYDROXYUREA; PLACEBO; SHORT CHAIN FATTY ACID; TRIACYLGLYCEROL LIPASE; UNCLASSIFIED DRUG;

ABDOMINAL PAIN; ACUTE PANCREATITIS; ADULT; AMYLASE BLOOD LEVEL; ARTICLE; CHILD; CLINICAL EVALUATION; COMPARATIVE EFFECTIVENESS; CONTROLLED STUDY; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; FEMALE; FEVER; GLOBIN GENE; HUMAN; LIMB PAIN; MAJOR CLINICAL STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MULTICENTER STUDY; NAUSEA; PAIN ASSESSMENT; PHARMACODYNAMICS; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL; RISK ASSESSMENT; SICKLE CELL ANEMIA; SICKLE CELL BETA THALASSEMIA; SIDE EFFECT; TREATMENT DURATION; VOMITING;

ADMINISTRATION, ORAL; ADOLESCENT; ADULT; ANEMIA, SICKLE CELL; ANTISICKLING AGENTS; BUTYRATES; CHILD; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; FEMALE; FETAL HEMOGLOBIN; HUMANS; MALE; MIDDLE AGED; PLACEBOS; YOUNG ADULT;

EID: 84902827324     PISSN: 03618609     EISSN: 10968652     Source Type: Journal    
DOI: 10.1002/ajh.23725     Document Type: Article

References (15)

1. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337:762-769.
2. Pace BS, White GL, Dover GJ, et al. Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo. Blood 2002;100:4640-4648.
3. Mankidy R, Faller DV, Mabaera R, et al. Short-chain fatty acids induce γ-globin gene expression by displacement of a HDAC3-NCoR repressor complex. Blood 2006;108:3179-3186.
4. Pace BS, Sangerman JI, Boosalis MS, et al. Next generation clinical-stage HbF inducers exhibit multiple molecular actions in vitro and in vivo and offer personalized therapeutic regimens. Blood 2013;122:560.
5. Boosalis MS, Bandyopadhyay R, Bresnick EH, et al. Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation. Blood 2001;7:3259-3267.
6. Castaneda S, Boosalis MS, Emery D, et al. Enhancement of growth and survival and alterations in Bcl-family proteins in beta-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives. Blood Cells Mol Dis 2005;35:217-226.
7. Perrine SP, Mankidy R, Boosalis MS, et al. Erythroid Kruppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. Eur J Haematol 2009;82:466-476.
8. Kutlar A, Ataga K, Reid M, et al. A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease. Am J Hematol 2012;87:1017-1021.
9. Kutlar A, Reid ME, Anati A, et al. A dose-escalation phase IIa study of 2, 2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Am J Hematol 2013;88:E255-E260.
10. Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: Properties, applications, and interpretation. Health Qual Life Outcomes. 2003;1:79.
11. Boosalis SM, Bandyopadhyay R, Bresnick EH, et al. Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation. Blood 2001;97:3259-3267.
12. Atweh GF, Sutton M, Nassif I, et al. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood 1999;93:790-797.
13. Sher GD, Ginder GD, Little J, et al. Extended therapy with intravenous arginine butyrate in patients with β-hemoglobinopathies. N Engl J Med 1995;332:1606-1610.
14. Stamatoyannopoulos G, Blau CA, Nakamoto B, et al. Fetal hemoglobin induction by acetate, a product of butyrate catabolism. Blood 1994;84:3198-3204.
15. Watkins JB, Klaassen CD. Choleretic effect of structural analogs of valproic acid in the rat. Res Commun Chem Pathol Pharmacol 1983;39:355-366.