An investigation of components of variance and tachyphylaxis in a placebo-controlled intravenous tyramine study.
OBJECTIVE
To explore inter- and intra-volunteer variability for the dose of intravenous tyramine eliciting a 20 mmHg increase in systolic blood pressure from baseline (TYR20) and to evaluate potential tachyphylaxis.


METHODS
Twelve healthy volunteers received blinded placebo-controlled ascending and descending sequences of intravenous tyramine injections on two separate occasions. The TYR20 was derived by linear interpolation, using three interventions to deal with missing data.


RESULTS
Analysis of covariance (ancova) demonstrated no significant difference in TYR20 between sequences, regardless of the missing data methodology applied. Inter-volunteer variability was 2.4-3.4 times larger than within-volunteer variability. No evidence of tachyphylaxis was seen using either the sign test or generalized additive models.


CONCLUSIONS
Since inter-volunteer variability was greater than intra-volunteer variability, a crossover study design would be a more efficient study design, and the descending sequence of injections could be omitted since tachyphylaxis was not demonstrated.
Cantarini
M V
MV
Experimental Medicine Department, AstraZeneca, Macclesfield, Cheshire, UK. mireille.cantarini@astrazeneca.com
Watkins
C L
CL
Growcott
J
J
Hughes
A M
AM
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D013566:Sympathomimetics / Q000008:administration & dosage*; D013618:Tachyphylaxis / Q000502:physiology*; D014439:Tyramine / Q000008:administration & dosage*
D013566:Sympathomimetics; D014439:Tyramine