Orally administered progesterone enhances sensitivity to triazolam in postmenopausal women.
An endogenously formed metabolite of progesterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-5 alpha-DHP) modulates the gamma-aminobutyric acid receptor complex and plays a physiologic role in brain excitability regulation. On the basis of in vitro observations of 3 alpha-OH-5 alpha-DHP-enhanced [3H]flunitrazepam binding, we investigated the potential clinical effect of coadministering oral progesterone and triazolam. Sixteen postmenopausal women were randomly assigned to receive either intravenous triazolam plus oral progesterone 300 mg (TRZPROG) or intravenous triazolam plus oral placebo (TRZ). Triazolam was infused until 0.5 mg was given or until a predetermined maximal response was attained. Pharmacodynamic evaluation included DSST, continuous performance test, hand-eye coordination, short-term memory, and sedation. Effect ratios were calculated as the ratio of area under the effect-time curve to area under the curve (AUC). Variants of the sigmoid Emax model were fit to the data from the three psychomotor performance tests. A triazolam dose of less than 0.5 mg was administered to seven of eight subjects in the TRZPROG and five of eight subjects in the TRZ group, resulting in lower triazolam AUC values for the TRZPROG than for the TRZ group (p = 0.0275). There was clear evidence for a pharmacodynamic interaction. Mean effect ratios for all tests were greater in the TRZPROG group than in the TRZ group (DSST, p = 0.0097; continuous performance test, p = 0.0338; hand-eye coordination, p = 0.0041). The TRZPROG group had lower EC50 values than the TRZ group (DSST, p = 0.0435; continuous performance test, p = 0.0381; hand-eye coordination, p = 0.0154).(ABSTRACT TRUNCATED AT 250 WORDS)
McAuley
J W
JW
Pharmacodynamic Research Center, School of Pharmacy, University of Pittsburgh, Pennsylvania, USA.
Reynolds
I J
IJ
Kroboth
F J
FJ
Smith
R B
RB
Kroboth
P D
PD
D000284:Administration, Oral; D000368:Aged; D000704:Analysis of Variance; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000187:drug effects / Q000523:psychology*; D011374:Progesterone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014229:Triazolam / Q000097:blood / Q000494:pharmacology*
D014229:Triazolam; D011374:Progesterone