Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron.
A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP, 200 mg) combined with carbidopa (CBD, 100 mg + 50 mg) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A randomized, double-blind, placebo-controlled, four-way crossover trial was performed in 12 healthy male volunteers. The 5-HTP/CBD-challenge was combined with two oral anti-emetics (granisetron, 2 mg or domperidone, 10 mg) to investigate its reliability when side-effects are suppressed. The neuroendocrine response (serum cortisol and prolactin), the side-effect profile [Visual Analogue Scale Nausea (VAS)] and vomiting subjects per treatment were the main outcome measures. Compared to 5-HTP/CBD/placebo, 5-HTP/CBD/ granisetron had no impact on cortisol [% change with 95% confidence interval: -7.1% (18.9; 6.5)] or prolactin levels [-9.6% (-25.1; 9.1)]; 5-HTP/CBD/domperidone increased cortisol [+13.0% (-4.2; 33.4)], and increased prolactin extensively [+336.8% (245.7; 451.9)]. Compared to placebo, VAS Nausea increased non-significantly with granisetron [+7.6 mm (-1.3; 16.5)], as opposed to domperidone [+16.2 mm (7.2; 25.2)] and 5-HTP/CBD/placebo [+14.7 mm (5.5; 23.8)]. No subjects vomited with granisetron, compared to two subjects treated with 5-HTP/CBD/placebo and five subjects with domperidone. Compared with 5-HTP/CBD/placebo, granisetron addition decreased C(max) of 5-HTP statistically significantly different (from 1483 to 1272 ng/ml) without influencing AUC(0- infinity). Addition of granisetron to the combined 5-HTP/CBD challenge suppresses nausea and vomiting without influencing the neuroendocrine response or pharmacokinetics, enhancing its clinical applicability in future psychiatric research and drug development.
Jacobs
G E
GE
Centre for Human Drug Research, Leiden, The Netherlands, Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. gjacobs@chdr.nl
Kamerling
I M C
IM
de Kam
M L
ML
Derijk
R H
RH
van Pelt
J
J
Zitman
F G
FG
van Gerven
J M A
JM
D006916:5-Hydroxytryptophan / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000932:Antiemetics / Q000494:pharmacology; D019540:Area Under Curve; D002230:Carbidopa / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D018592:Cross-Over Studies; D004294:Domperidone / Q000494:pharmacology*; D015259:Dopamine Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D017829:Granisetron / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control; D011388:Prolactin / Q000097:blood; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control; D055815:Young Adult
D006916:5-Hydroxytryptophan; D018687:Antidepressive Agents, Second-Generation; D000932:Antiemetics; D002230:Carbidopa; D004294:Domperidone; D015259:Dopamine Agents; D017829:Granisetron; D006854:Hydrocortisone; D011388:Prolactin