The pharmacokinetics, tolerability and pharmacodynamics of tucaresol (589C80; 4[2‐formyl‐3‐hydroxyphenoxymethyl] benzoic acid), a potential anti‐sickling agent, following oral administration to healthy subjects.

Abstract

(67) ,ug m1-1, respectively, at the highest dose. Median tmax in plasma was 6.5 h and in erythrocytes 24.5 h, when approximately 60% of the administered dose was in the target tissue. Plasma drug concentrations fell biexponentially with commencement of the apparent terminal elimination phase at approximately 24 h. The terminal elimination half-life from plasma increased with dose (r = 0.77; P < 0.0001) from 133-190 h at 400 mg to a mean (s.d.) of 289 (30) h at 3600 mg. Erythrocyte drug concentrations declined monoexponentially with a half-life that was always shorter than the apparent terminal halflife in plasma: overall mean (95% CI) of t1/2 erythrocyte/t1/2 plasma ratio was 0.57 (0.53, 0.61). The erythrocyte AUC/plasma AUC ratio increased with dose (r = 0.67; P < 0.001). 4 The proportion of haemoglobin modified to a form with high oxygen affinity (% MOD) increased in a dose-related manner above doses of 800 mg reaching 19-26% after the 3600 mg dose. The % MOD was directly proportional to erythrocyte drug concentrations and declined in parallel during the elimination phase. 5 The drug was well tolerated, with no clear effects on resting or exercise heart rates or blood pressures. Small increases in reticulocyte counts were seen following doses of 2800 and 3600 mg suggesting stimulation of erythropoiesis.

Marked Enhancement of the Antigen-Specific Immune Response by Combining Plasmid DNA-Based Immunization with a Schiff Base-Forming Drug

“…This provides an advantage in the application of this drug in pDNA vaccination protocols. Furthermore, since tucaresol has been shown to be systemically active (30,33), there may be no need for local coadministration of pDNA and tucaresol, as shown here by combining i.m. pDNA injection with s.c. injection of tucaresol.…”

“…This costimulatory function results in a covalent and reversible reaction that works via binding to the amine-rich groups on T cells, which leads to T-cell-receptor-independent signaling (7). The effect of tucaresol is thought to be CD2 mediated (7,29,32,33). Our observations demonstrate that this approach is able to overcome the low efficacy commonly associated with pDNA-based vaccination (11).…”

“…Several clinical studies have been performed involving injection of tucaresol in healthy volunteers and in sickle cell anemia patients, focusing on its ability to modify hemoglobin, and recently it has also been studied for treatment of other conditions, such as metastatic melanoma (7,29,32,33). Therefore, a therapeutic strategy that combines DNA vaccination and tucaresol administration, e.g., in immunotherapy for melanoma patients, may benefit not only from the indirect adjuvant effect of tucaresol but also from its direct therapeutic effect.…”

“…Since tucaresol is an orally bioavailable drug (29), the combination of intradermal "ballistic" delivery of pDNA with oral administration of tucaresol may prove to be a very attractive mode of immunization, particularly under conditions where parenteral immunizations should be avoided due to risks of blood-borne infections from contaminated needles or cultural stigmata associated with injections (33,36). It is therefore noteworthy that tucaresol also significantly enhances the specific immune response induced by gene gun-based pDNA vaccination (J. Charo, J.…”

Protective Efficacy of a DNA Influenza Virus Vaccine Is Markedly Increased by the Coadministration of a Schiff Base-Forming Drug

“…It has been shown that tucaresol binds to cell surface molecules on the T cells and provides a costimulatory signal which is different from that induced by TCR signaling (7). Nonetheless, tucaresol has been clinically used and proven to be efficiently taken up and to be safe even in doses substantially higher than those used here (27,28). This could provide a significant incentive for clinical testing of a vaccine combination that contains a P-NP-based pDNA and tucaresol.…”