Effects of TAK-802, a novel acetylcholinesterase inhibitor, and tamsulosin, an alpha1-adrenoceptor antagonist, and their synergistic effects on the urodynamic characteristics in a guinea-pig model of functional bladder outlet obstruction.
OBJECTIVE
To investigate the effects of TAK-802, a potent acetylcholinesterase inhibitor, and tamsulosin, an alpha1-adrenoceptor antagonist, and their concomitant administration on the urodynamic characteristics in a guinea-pig model of functional bladder outlet obstruction.


METHODS
Cystometry was performed in urethane-anaesthetized guinea pigs, and various urodynamic variables, including the maximum flow rate (Qmax), voiding efficiency, maximum intravesical pressure (Pvesmax) and intravesical pressure at Qmax (PvesQmax), were measured before and after administration of the drugs in combination and alone.


RESULTS
Continuous intravenous infusion of phenylephrine, an alpha1-adrenoceptor agonist (1-6 microg/animal/min), dose-dependently decreased the Qmax and voiding efficiency, and increased the Pvesmax and PvesQmax, possibly by constricting urethral smooth muscle. In this functional urethral constriction model, both TAK-802 at 1 and 10 microg/kg and tamsulosin at 3 and 10 microg/kg (intravenously) caused increasing effects on the Qmax and voiding efficiency. The effects were more apparent with combined exposure. Although the Pvesmax was dose-dependently increased by TAK-802 alone, the effects were completely abolished by concomitant treatment with tamsulosin.


CONCLUSIONS
These results suggest that TAK-802 and tamsulosin have synergistic effects in increasing the Qmax and voiding efficiency, and TAK-802 does not inhibit the decreasing effect of tamsulosin on urethral resistance. That TAK-802 increased Pves when administered alone implies that monotherapy using an acetylcholinesterase inhibitor should be withheld in patients with voiding dysfunction caused by obvious bladder outlet obstruction with benign prostatic hyperplasia, to avoid disorders of the upper urinary tracts, and it should be used with an alpha1-adrenoceptor antagonist. Whether TAK-802 combined with an alpha1-adrenoceptor antagonist confers additional clinical benefit is not yet known.
Nagabukuro
Hiroshi
H
Pharmaceutical Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. nagabukuro_hiroshi@takeda.co.jp
Hashimoto
Tadatoshi
T
Iwata
Masashi
M
Doi
Takayuki
T
D000110:Acetylcholinesterase; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D007262:Infusions, Intravenous; D008297:Male; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D011758:Pyrroles / Q000627:therapeutic use*; D015363:Quinolones / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D000077409:Tamsulosin; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy*; D016055:Urinary Retention / Q000188:drug therapy; D014563:Urodynamics
D000317:Adrenergic alpha-Antagonists; D058671:Adrenergic beta-1 Receptor Antagonists; D002800:Cholinesterase Inhibitors; D011758:Pyrroles; D015363:Quinolones; D013449:Sulfonamides; C496138:8-(3-(1-((3-fluorophenyl)methyl)-4-piperidinyl)-1-oxopropyl)-1,2,5,6-tetrahydro-4H-pyrrolo(3,2,1-ij)quinolin-4-one; D000110:Acetylcholinesterase; D000077409:Tamsulosin