Tucaresol increases oxygen affinity and reduces haemolysis in subjects with sickle cell anaemia

Abstract

The primary pathophysiological event in sickling is the intracellular polymerization of deoxygenated haemoglobin S. Tucaresol (589C80;4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a substituted benzaldehyde, was designed to interact with haemoglobin to increase oxygen affinity and has been shown to inhibit sickling in vitro. We administered tucaresol to sickle cell patients in the steady state to examine the anti-sickling effect in vivo. Oral doses of tucaresol or placebo were given to nine stable sickle cell patients (aged 17-39 years; tucaresol, six; placebo, three) for 10 d. The first two patients on tucaresol were scheduled to receive a loading dose of 800 mg or 1200 mg (depending on bodyweight) for the first 4 d, followed by maintenance doses of 200 or 300 mg for the next 6 d. Due to concerns over the sharp rise in haematocrit in one patient, subsequent cohorts received 300 mg tucaresol daily throughout the dosing period. The oxygen affinity of haemoglobin S was increased in all patients receiving tucaresol, with between 10% and 24% of the haemoglobin modified, dependent on dose. In all patients on tucaresol, haemolysis was reduced with rises in haemoglobin of 0.9- 3.7 g/dl (mean 2.2 g/dl), falls in lactate dehydrogenase of 16-52%, and a halving of the irreversibly sickled cell counts. These effects were apparent within a few days and persisted for 1-2 weeks following discontinuation of the drug. Three of the six patients on tucaresol developed fever and cervical lymphadenopathy, with onset between days 7 and 11 from start of drug. Further evaluation of the tolerability and efficacy of tucaresol in sickle cell patients is necessary.

Activity of the Novel Immunomodulatory Compound Tucaresol against Experimental Visceral Leishmaniasis

“…Tucaresol has proved effective against experimental models of cytomegalovirus and murine colon adenocarcinoma and has been shown to be biologically active as an immunopotentiator, favoring a Th1 response in patients with malignant melanoma (29,36). Tucaresol was well tolerated at doses of 400 mg/kg of body weight in phase I and II melanoma trials (29), and an elimination half-life of 1 week was shown in other studies (4). The costimulatory potential of tucaresol, as well as its ability to bias immunity toward a cellmediated T-helper-cell response, suggests that it could prove to be of therapeutic benefit against chronic infectious diseases such as VL, which is characterized by its ability to induce T-cell anergy (26).…”

A Rational Approach to Drug Development: The Exploratory Phase

“…The scientific rationale for this biomarker was based on the observation that HbS polymerization is inhibited when 20-30% of hemoglobin is maintained in the oxy-conformation. Measurements of %MOD were included in the initial phase I studies and used to guide dose tucaresol dosage in the initial patient studies (55,56).…”

The contribution of clinical pharmacology surrogates and models to drug development—a critical appraisal

“…We were also able to make accurate predictions about the likely clinical dose based on the use of this required to test this hypothesis. During the time while surrogate, as in sickle cell disease patients, %MOD levels predicted to be likely to be therapeutic were associated with substantial reductions in several haematological indices of haemolysis [23]. These tests however are also surrogates, but more closely related to the basic pathology and hence can be regarded as more proximate to the disease than %MOD.…”