ABSTRACT
Sickle cell leg ulcers are often debilitating, refractory to healing, and prone to recurrence. Healing of leg ulcers was incidentally observed during dose-ranging trials of Arginine Butyrate in beta haemoglobinopathies. Here, a controlled Phase II trial was performed in sickle cell patients who had lower extremity ulcers refractory to standard care for at least 6 months. Patients were randomized to receive standard local care alone (Control Arm) or standard care with Arginine Butyrate administered 5 d/week (Treatment Arm), for 12 weeks. Ulcers were photographed weekly, traced, and ulcer areas were calculated by computerized planimetry and compared between the two study arms. Twenty-seven study courses were evaluated. Control Arm subjects had 25 ulcers with a mean area of 25·7 cm(2) initially and 23·2 cm(2) after 12 weeks; 2/25 (8%) healed completely. Treatment Arm subjects had 37 ulcers with a mean area of 50·6 cm(2) initially and 28·3 cm(2) at 12 weeks; 11/37 of these (30%) healed completely. After 3 months, proportions of ulcers which healed were 6/25 (24%) and 29/37 (78%), in the Control and Treatment Arms respectively (P < 0·001). These findings strongly suggest that Arginine Butyrate merits further evaluation for the treatment of refractory sickle cell leg ulcers in larger trials.
Subject(s)
Anemia, Sickle Cell/complications , Arginine/analogs & derivatives , Butyrates/therapeutic use , Leg Ulcer/drug therapy , Adult , Arginine/therapeutic use , Chronic Disease , Female , Humans , Leg Ulcer/etiology , Leg Ulcer/pathology , Male , Middle Aged , Prospective Studies , Treatment Outcome , Wound Healing/drug effects , Young AdultABSTRACT
Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV(+) lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV(+) lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV(+) lymphoid malignancies which are refractory to other regimens.
