A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers

McMahon, Lillian; Tamary, Hannah; Askin, Melissa; Adams-Graves, Patricia; Eberhardt, Robert T.; Sutton, Millicent; Wright, Elizabeth C.; Castañeda, Serguei A.; Faller, Douglas V.; Perrine, Susan P.

doi:10.1111/j.1365-2141.2010.08395.x

Cited by 55 publications

(48 citation statements)

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“…We summarize our approach to patients with SCD and ulcers, with recommendations based on our experience in the clinic as well as a critical review of the literature. Unfortunately, as a rare complication of a rare disease, there are few therapeutic trials of any kind and even fewer randomized controlled studies to provide clear evidence to guide practice in the clinic [7,8].…”

Section: Introductionmentioning

confidence: 99%

Critical Reviews: How we treat sickle cell patients with leg ulcers

Minniti

Kato

2015

American J Hematol

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The past five decades have seen an improvement in the mortality and morbidity of sickle cell disease (SCD) because of prophylaxis against infectious complications, improved and expanded red cell transfusions, implementation of hydroxyurea therapy, and advances in supportive care. Now that the majority of patients in the western hemisphere reaches adulthood, end organ diseases are frequent, which include vasculopathic complications such as chronic leg ulcers. The management of patients with leg ulcers requires the hematologist to lead a team of health care professionals, and investigates the presence of associated, but potentially still occult signs of vasculopathy, such as pulmonary hypertension, renal disease, priapism and retinopathy. These complications may be asynchronous, and long term careful screening is indicated, in order to ensure early diagnosis and intervention. It is crucial to address both the immediate consequences of pain, infection and disability, and long term effects on quality of life, employment and stigma associated with chronic ulceration. Recent insights into their pathophysiology may have practical implications. We propose a holistic approach to the management of patients' physical and emotional problems and mechanisms of ulcers formation and delayed healing. An overview of topical and systemic therapies for chronic ulcers is given, with the understanding that wound care therapy is best left to the wound specialists, medical and surgical, with whom the hematologist must keep an open line of communication. In the absence of evidence-based guidelines, our opinion is based on both a critical review of the literature and our personal clinical and research experience. Am. J. Hematol. 91:22-30, 2016. V C 2015 Wiley Periodicals, Inc. Clinical CasesCase 1. A 49 year old African American woman with sickle cell anemia, bilateral hip replacements for avascular necrosis of the femoral head, pulmonary arterial hypertension documented by pulmonary artery catheterization, and history of laser treatment and vitrectomy for proliferative retinopathy and vitreous hemorrhage, presented with a very painful ulcer at the right malleolus. She has had three previous ulcers, on both legs, the first at age 32 years, attributed to excessive standing at her job, no trauma, which had responded to topical care and healed within few months of presentation. At that time she was not taking hydroxyurea, but has been taking it now for longer than 10 years with good fetal hemoglobin response: 17%. This current ulcer developed while she was experiencing high personal stress but no physical trauma. She rarely experiences vaso-occlusive pain crisis and has very infrequent hospitalizations. She was referred to the wound care service and after 7 months of unfruitful therapies, including surgical debridement, MIST ultrasound therapy, antibiotics, and compressions, she was started on monthly transfusions and her ulcer healed 5 months later. She has had consistently elevated serum lactate dehydrogenase (LDH) (>600 IU/L), serum dire...

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Section: Introductionmentioning

confidence: 99%

Critical Reviews: How we treat sickle cell patients with leg ulcers

Minniti

Kato

2015

American J Hematol

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“…Healing of these ulcers occurs 20 times more slowly than healing of similar types of refractory vascular lower extremity wounds [17]. Common preventative measures include reducing trauma with properly fitted shoes, minimizing venous stasis with compression stockings, and patient education.…”

Section: Treatmentmentioning

confidence: 99%

Cutaneous Manifestations of Sickle Cell Disease

Jones¹,

Blinder²,

Anadkat³

2013

OJBD

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“…Due to low bioavailability and rapid metabolism, arginine butyrate had to be given by continuous intravenous infusion in large volumes, which limits its use in chronic conditions [11][12][13][14]. Due to low potency and bioavailability, sodium phenylbutyrate required as many as 40 tablets daily resulting in compliance issues [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…Agents capable of reactivating g-globin gene expression fall into several major groups, including cytotoxic agents (e.g., hydroxyurea) [1][2][3][4], DNA methyltransferase (DMT-1) inhibitors (e.g., azacytidine and decitabine) [5][6][7][8], histone deacetylase (HDAC) inhibitors (e.g., trichostatin, vorinostat, panobinostat, arginine butyrate, sodium phenylbutyrate, and valproic acid) [9][10][11][12][13][14][15][16][17][18], and erythropoietic agents [19,20]. The primary mechanism of action of hydroxyurea, the only drug approved to reduce the frequency of painful crises in SCD, is believed to be through increased Hb F [21].…”

Section: Introductionmentioning

confidence: 99%

A dose‐escalation phase IIa study of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer, in sickle cell disease

et al. 2013

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-dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/b 0 thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n 5 15), 40 mg/kg (n 5 18) and 50 mg/kg (n 5 19), either alone (n 5 21) or with hydroxyurea (n 5 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases 4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases 1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. Am. J. Hematol. 88:E255-E260, 2013.

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A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers

Cited by 55 publications

References 50 publications

Critical Reviews: How we treat sickle cell patients with leg ulcers

Critical Reviews: How we treat sickle cell patients with leg ulcers

Cutaneous Manifestations of Sickle Cell Disease

A dose‐escalation phase IIa study of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer, in sickle cell disease

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