Orally Given Capsaicinoids do not Modify the Absorption, Metabolism, and Excretion of Aspirin and its Platelet Aggregation in Human Male Healthy Subjects (Human Clinical Pharmacological Phase. I. Examinations)

Backgrounds : 1. The acetylsalicylic acid (ASA, Aspirin) is very frequently used in the every day medical practice as platelet aggregation, analgetic, antipyretic agent in patients with myocardial infarction, prevention of stroke, different thrombophylic events and in different groups of patients and healthy subjects, however, it produces frequently serious gastrointestinal mucosal damage (bleeding, ulceration and perforation); 2. The gastrointestinal mucosal protection was proved by capsaicin(oids), when it (those) was (were) orally given in the doses, which are able to stimulate the capsaicin-sensitive afferent nerve fibers in animal experiments and human observations. Aims of this study were: 1. To evaluate the different pharmacokinetic parameters of capsaicin(oids) (given in doses in stimulatory doses of capsaicin-sensitive afferent nerves) in healthy male volunteers; 2. To study the action of capsaicin(oids) on the co-administration of ASA pharmacokinetic parameters and some pharmacological effect of ASA on the epinephrine-induced platelet aggregation, and 3. To follow strictly the internationally and the human clinical pharmacologically accepted pathway of the pharmaceutical production of a new drug combination [ASA + capsaicin(oids)] for the human medical therapy. Materials and Methods . 1. Fifteen human healthy male subjects were included into this human classical clinical pharmacological phase I., 2. The observations were carried out according to the “Protocol of Study” (protocol number: 1.4.1; EudraCT number: 2000-007048-32), which was permitted by the Hungarian Institute of Pharmacy (dated by June 4, 2009) and by the Hungarian Ethics of Committee for Clinical Pharmacology, Hungarian Medical Research Council (dated by March 1, 2009); 3. The criteria of inclusion and exclusion of healthy male subjects for this study were very strictly identified, 4. The screening and collection of the healthy males were maximally 2 weeks before the starting of study. 5. The phase I. examination covers 5 different sequences (7 days in each), and one week was the post study period, 6. The time-table of examinations (including a short hospitalization time, 3 days for washout, post-study examinations, food and fluid intakes, etc.) were determined, 7. The schedule of the administration of drugs [ASA alone, ASA + capsaicin(oids) – given orally in doses of 400 and 800µg, or placebo] was fixed by the protocol, 8. The human healthy male subjects were randomly treated, 9. The blood samples were obtained from the brachial vena (pre-dose, 0.10, 0.20, 0.40 1.00, 1.30, 2, 4, 6, 10, 12, 16 and 24 hours post dose), 10. The capsaicin and dihydrocapsaicin measured by HPLC, ASA and salicylic acid by HPLC from the plasma of healthy volunteers (during the first 24 hours period) and 11. The effects of capsaicinoids alone, ASA alone, and their combinations were studied on the epinephrine-induced platelet aggregation, 12. Different pharmacokinetic parameters ( C max , T max , AUC 0-tlast , AUC 0- ∞ , mean residence time, MRT ) of ASA and salicylic acid were calculated and these results and were compared in treated groups [ASA alone vs . ASA plus capsaicin(oids) 400 µg vs . ASA plus capsaicin(oids) 800 µg], 12. The extents of platelet aggregation produced by ASA alone and in different combination with capsaicin(oids) on the epinephrine-induced platelet aggregation. Results : 1. The healthy male volunteers tolerated well the different drug candidate combinations, and their applications were safe, 2. Neither capsaicin nor dihydrocapsaicin could be detected in any samples of plasma volunteers after oral application of capsaicin(oids) (given orally in doses of 400 µg and 800 µg) in time period of 0 to 24 hours; 3. The pharmacokinetic parameters of ASA and salicylic acid did not differ in groups treated with ASA alone vs . ASA plus 400 µg capsaicin(oids) vs . ASA plus 800 µg capsaicin(oids), 4. The capsaicin(oids) does (do) not modify the epinephrine-induced platelet aggregation induced by ASA, meanwhile the different doses of capsaicin(oids) alone have no direct effect of the epinephrine-induce platelet aggregation. Conclusions : 1. The capsaicin(oids) acts(act) locally in the gastrointestinal tract (indicating that we used a good selection of bioadhesive compounds for pharmaceutical preparation of ASA + capsaicin(iods) combination, 2. The results of these phase I. examinations offer us a further possibility to carry out forthcoming phase II. and III. examinations in patients.