thymosin-beta(4) and Varicose-Ulcer

Thymosin β4 (Tβ4), a multifunctional peptide, has been used successfully in several clinical trials involving tissue repair and regeneration. The review will first update the current information on the common underlying cellular cascades and pathways that are basic to Tβ4's regenerative activity and second, on the current and potential uses of this protein in the clinic.. Significant advances in our understanding of the actions of Tβ4 have occurred in directing stem cell maturation and in regeneration and repair of injuries. Many of its activities directly affect the repair cascade following injury. Using PubMed, we summarize the discovery and isolation of Tβ4 as well as the studies on tissue repair, which have provided the scientific foundation for ongoing and projected trials in the treatment of eye injuries, dermal wounds, repair of the heart following myocardial infarction and healing of the brain following stroke, trauma or neurological diseases.. Based on its multifunctional activities during tissue regeneration in various animal studies, Tβ4 has the potential for new clinical applications such kidney and liver disease, as well as repair of spinal cord, bone and ligament damage. In addition, it may be useful in the treatment of a wide range of other applications, including the consequences of aging and viral infections.

Topics: Amino Acid Sequence; Animals; Epidermolysis Bullosa; Molecular Sequence Data; Pressure Ulcer; Regeneration; Spinal Cord; Thymosin; Varicose Ulcer; Wound Healing; Wounds and Injuries

Venous ulcers are responsible for about 70% of the chronic ulcers of the lower limbs. Standard of care includes compression, dressings, debridement of devitalized tissue, and infection control. Thymosin beta 4 (Tbeta4), a synthetic copy of the naturally occurring 43 amino-acid peptide, has been found to have wound healing and anti-inflammatory properties, and is thought to exert its therapeutic effect through promotion of keratinocyte and endothelial cell migration, increased collagen deposition, and stimulation of angiogenesis. To assess the safety, tolerability, and efficacy of topically administered Tbeta4 in patients with venous stasis ulcers, a double-blind, placebo-controlled, dose-escalation study was conducted in eight European sites (five in Italy and three in Poland) that enrolled and randomized 73 patients. The safety profile of all doses of administered Tbeta4 was deemed acceptable and comparable to placebo. Efficacy findings from this Phase 2 study suggest that a Tbeta4 dose of 0.03% may have the potential to accelerate wound healing and that complete wound healing can be achieved within 3 months in about 25% of the patients, especially among those whose wounds are small to moderate in size or mild to moderate in severity.

Topics: Administration, Topical; Cell Movement; Debridement; Double-Blind Method; Hormones; Humans; Immunologic Factors; Italy; Keratinocytes; Middle Aged; Placebos; Poland; Safety; Thymosin; Varicose Ulcer; Wound Healing

The objective of this double-blind, placebo-controlled, dose-escalation study is to evaluate safety, tolerability, and enhancement on healing of thymosin beta-4 (Tbeta-4) administered topically in patients with venous ulcers. Three groups of patients, coming from 10 sites, 5 from Italy and 5 from Poland, will be enrolled sequentially. Twenty-four patients within each group will be randomized to Tbeta-4 or placebo in a 3:1 ratio and will be treated with increasing doses of Tbeta-4. When review safety data show no-dose-limiting adverse events, a new group will be enrolled. So, the study design comprehends 72 patients treated for 84 days and followed for 14 days at the end of treatment. Blood samples will be taken on day 0 and at the end of treatment visit to measure plasma levels of Tbeta-4. Every week each patient is visited and blood samples are taken for clinical chemistry, hematology, coagulation, and urinalysis. Each ulcer is treated with debridement, if necessary, and compression therapy with standard compression stockings class 2. Efficacy parameters are incidence of healing defined as the percentage of patients who have complete closure of the index ulcer at day 84 and, mean time to complete healing. Ulcer area will be calculated by digital planimetry and photographic analysis. The study is ongoing and a total of 21 patients have been enrolled so far in the first treatment group at the lower dose. Patients' compliance and motivated and well-trained teams seem to be the most suitable parameters of a successfully conducted study.

Topics: Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Humans; Placebos; Prospective Studies; Safety; Thymosin; Varicose Ulcer; Wound Healing

Chronic nonhealing cutaneous wounds are a worldwide problem with no agent able to promote healing. A naturally occurring, endogenous repair molecule, thymosin beta 4 (Tβ4), has many biological activities that promote dermal repair. It is released by platelets at the site of injury and initiates the repair cascade. Tβ4 accelerated dermal healing of full-thickness punch wounds in various animal models, including normal rats and mice, steroid-treated rats, diabetic mice, and aged mice. Furthermore, in two phase 2 clinical trials of stasis and pressure ulcers, it was found to accelerate healing by almost a month in those patients that did heal. Tβ4 likely acts to repair and regenerate wounds by promoting cell migration and stem cell mobilization and differentiation, and by inhibiting inflammation, apoptosis, and infection. We conclude that Tβ4 is a multifunctional regenerative peptide important in dermal repair.

Topics: Animals; Clinical Trials, Phase II as Topic; Humans; Mice; Pressure Ulcer; Rats; Skin; Thymosin; Varicose Ulcer; Wound Healing