title: Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstruction.
abstract: OBJECTIVE
  To evaluate the urodynamic effects of fesoterodine, a new antimuscarinic agent, alone and combined with doxazosin, in a rat model of partial urethral obstruction (PUO), as 35-83% of men with bladder outlet obstruction (BOO) secondary to benign prostatic hyperplasia (BPH) have overactive bladder (OAB) syndrome, and as the combination of alpha(1)-adrenoceptor- and muscarinic-receptor antagonists has been proposed to be beneficial for these patients.
  
  
  METHODS
  Thirty-seven male Sprague-Dawley rats (250 g) had surgically induced PUO; 2 weeks later they were evaluated by cystometry with no anaesthesia or any restraint. After a 1-h period either 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine, previously known as SPM 7605), doxazosin or a combination of both, was given intravenously (0.1 mg/kg body weight), and cystometry was continued for another 45 min. Fifteen healthy, age-matched rats served as a control.
  
  
  RESULTS
  At 2 weeks after surgery the obstructed rats had an greater bladder weight, threshold pressure (TP) and micturition frequency (MF), and lower bladder capacity (BCap) and micturition volume (MV) than the controls. 5-HMT did not cause urinary retention in obstructed rats, but decreased TP, maximum pressure (MP), spontaneous bladder activity (SA) and, paradoxically, increased MF. Doxazosin alone decreased TP, MP, MF and increased BCap and MV. 5-HMT and doxazosin together did not depress the ability to empty the bladder, and showed decreased TP, MP and SA.
  
  
  CONCLUSIONS
  5-HMT, alone and in combination, did not impair the voiding ability in obstructed rats. Doxazosin counteracted some of the 'negative' effects of 5-HMT in this model (increase of MF) and did not attenuate the 'positive' effects (decrease of bladder SA). In this model, the combination of 5-HMT and doxazosin appeared to be urodynamically safe and well tolerated.
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA.
authors.forename: Claudius
authors.initials: C
authors.lastname: Füllhase
authors.forename: Roberto
authors.initials: R
authors.lastname: Soler
authors.forename: Christian
authors.initials: C
authors.lastname: Gratzke
authors.forename: Marina
authors.initials: M
authors.lastname: Brodsky
authors.forename: George J
authors.initials: GJ
authors.lastname: Christ
authors.forename: Karl-Erik
authors.initials: KE
authors.lastname: Andersson
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D017292:Doxazosin / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D008297:Male; D018727:Muscarinic Antagonists / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014524:Urethral Obstruction / Q000188:drug therapy* / Q000503:physiopathology; D014563:Urodynamics / Q000187:drug effects* / Q000502:physiology
chemical_list: D000317:Adrenergic alpha-Antagonists; D001559:Benzhydryl Compounds; D018727:Muscarinic Antagonists; C526675:fesoterodine; D017292:Doxazosin