title: Pharmacokinetics and pharmacodynamics of tucaresol, an antisickling agent, in healthy volunteers.
abstract: 1. Tucaresol is an orally administered antisickling agent which increases the oxygen affinity of haemoglobin. 2. The pharmacokinetics, effects on moderate graded exercise and psychometric performance of tucaresol were examined in a double-blind, placebo-controlled, parallel groups study in 12 healthy men. 3. Three doses of tucaresol were given at 48 h intervals intended to modify 15, 25 and 32.5% of a subject's haemoglobin to a high affinity form (%MOD). 4. Mean peak %MOD was 34%. Mean Cmax values in plasma and erythrocytes were 81.4 and 1459 micrograms ml-1, respectively. 5. Heart rate, compared with baseline, increased in the tucaresol group with the greatest changes at the highest %MOD and workload. There were no differences between groups in psychometric test performance. 6. Three volunteers on active drug developed fever, rash and tender cervical lymphadenopathy with onset 7-10 days from the start of dosing, suggesting an immune mechanism. 7. The acute increase in oxygen affinity with tucaresol is physiologically well-tolerated, but the utility of tucaresol in the management of sickle cell disease will depend on the identification of a dosing regimen with a lower incidence of drug allergy.
authors.affiliation: Department of Clinical Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, UK.
authors.forename: P E
authors.initials: PE
authors.lastname: Rolan
authors.forename: A J
authors.initials: AJ
authors.lastname: Mercer
authors.forename: R
authors.initials: R
authors.lastname: Wootton
authors.forename: J
authors.initials: J
authors.lastname: Posner
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001547:Benzaldehydes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D001565:Benzoates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D015444:Exercise / Q000502:physiology; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006454:Hemoglobins / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D000637:Transaminases / Q000097:blood; D044465:White People
chemical_list: D001547:Benzaldehydes; D001565:Benzoates; D006454:Hemoglobins; D000637:Transaminases; C059629:tucaresol; D010100:Oxygen