Propionyl-L-Carnitine Enhances Wound Healing and Counteracts Microvascular Endothelial Cell Dysfunction.

BACKGROUND: Impaired wound healing represents a high cost for health care systems. Endothelial dysfunction characterizes dermal microangiopathy and contributes to delayed wound healing and chronic ulcers. Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO) production and the increase of oxidative stress and inflammation. Propionyl-L-carnitine (PLC) is a natural derivative of carnitine that has been reported to ameliorate post-ischemic blood flow recovery. METHODS AND RESULTS: We investigated the effects of PLC in rat skin flap and cutaneous wound healing. A daily oral PLC treatment improved skin flap viability and associated with reactive oxygen species (ROS) reduction, inducible nitric oxide synthase (iNOS) and NO up-regulation, accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by up-regulation for iNOS, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and reduction of NADPH-oxidase 4 (Nox4) expression. In serum-deprived human dermal microvascular endothelial cell cultures, PLC ameliorated endothelial dysfunction by increasing iNOS, PlGF, VEGF receptors 1 and 2 expression and NO level. In addition, PLC counteracted serum deprivation-induced impairment of mitochondrial ß-oxidation, Nox4 and cellular adhesion molecule (CAM) expression, ROS generation and leukocyte adhesion. Moreover, dermal microvascular endothelial cell dysfunction was prevented by Nox4 inhibition. Interestingly, inhibition of ß-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction. CONCLUSION: PLC treatment improved rat skin flap viability, accelerated wound healing and dermal angiogenesis. The beneficial effects of PLC likely derived from improvement of mitochondrial ß-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction. Antioxidant therapy and pharmacological targeting of endothelial dysfunction may represent a promising tool for the treatment of delayed wound healing or chronic ulcers.

Thymosin α1 continues to show promise as an enhancer for vaccine response.

Thymosin α1 (Tα1) is an immune-modulating peptide that can be expected to improve response to vaccinations, as stimulated dendritic cells and T cells can act in concert to increase antibody production along with an improved cytotoxic response from the T cells themselves. Tα1 demonstrated efficacy in preclinical studies; subsequently, it was shown to enhance response to vaccinations in difficult-to-treat populations, including individuals immune suppressed due to age or hemodialysis, and leading to a decrease in later infections. During the 2009 pandemic outbreak of H1N1 influenza, mouse and ferret studies confirmed that the use of higher doses of Tα1 allowed for fewer injections than those used in the previous clinical studies. In addition, a clinical study with Focetria™ MF59-adjuvanted monovalent H1N1 vaccine showed that treatment with Tα1 twice provided an earlier and greater response to the vaccine (P < 0.01).

Current adjuvants and new perspectives in vaccine formulation.

Given the important role of adjuvants in prophylactic vaccines, identification and development of new adjuvants with enhanced efficacy and safety is necessary. The use of adjuvants with immunopotentiating properties that can direct the immune responses to humoral or cell-mediated immunity and can induce T-cell responses has made it possible to design more protective vaccines. Although current regulations focus on traditional adjuvants, notably aluminum and calcium salts, advances have been made in regulatory considerations. The regulatory agencies for the evaluation of medicinal products are actively drafting guidance on requirements for the evaluation of new adjuvants. This article briefly summarizes the most widely studied adjuvants in vaccination, including those licensed for human vaccines and the regulatory aspects relevant to adjuvant quality at development stages.

Studies of therapy with thymosin alpha1 in combination with pegylated interferon alpha2a and ribavirin in nonresponder patients with chronic hepatitis C.

Despite the use of combination therapy with pegylated interferon alpha2a (peg-IFN-alpha2a) + Ribavirin, a large proportion of patients with chronic hepatitis C (CHC) remain unresponsive to treatment. Thymosin alpha 1 (Talpha1) is an immunomodulator, which displays immunological and antiviral activities against hepatitis C virus (HCV) in preclinical clinical settings. The purpose of this study was to evaluate the efficacy and safety of a triple combination therapy with peg-IFN-alpha2a + Ribavirin + Talpha1 in CHC patients who were nonresponders to a previous course with peg-IFN-alpha2a + Ribavarin. The primary endpoint is the rate of sustained virological response (SVR). We designed a phase 3, randomized, double-blind, multicenter, prospective, placebo controlled study. Patients meeting selection criteria were randomized centrally (through IVR system) to receive either peg-IFN-alpha2a 180 mcg s.c. once weekly + Ribavirin 1000-1200 mg p.o. daily + Talpha1 1.6 mg s.c. twice weekly for 24 weeks. Patients who remained HCV-RNA positive after 24 weeks stopped treatment and were considered nonresponders. HCV-RNA negative patients continued treatment up to week 48. All patients were followed up for 24 additional weeks after the end of treatment for the evaluation of the SVR. From December 2004 to November 2006, 638 patients were screened in 52 European sites. Preliminary blinded safety analysis suggests that both regimens are well tolerated. Efficacy evaluation will be available after the opening of this blinded phase 3 trial, planned for May 2008.

Thymosin beta-4 and venous ulcers: clinical remarks on a European prospective, randomized study on safety, tolerability, and enhancement on 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.