No abstract

While the dose range for which alpha 1 agonists affect urethral pressure was adequately predicted by any of the 3 methods used, the leak point pressure assay described has the advantage of being a dynamic test that directly evaluates efficacy to protect against leakage caused by increases in abdominal pressure. This leak point pressure test appears be useful for the preclinical evaluation of compounds used to treat stress urinary incontinence.

In this study, we used a novel conscious dog model to evaluate the uroselectivity of selected α₁-antagonists either approved for human use or in clinical development for the treatment of symptomatic benign prostatic hyperplasia (BPH) and compared those results to their in vitro binding and functional affinities at α_1A, α_1B, and α_1D receptor subtypes. Conscious dogs were instrumented acutely with a balloon catheter for the measurement of changes in prostatic intraurethral pressure (IUP) and chronically with implantable telemetry devices for the measurement of arterial pressure. The pressor effects of the α₁-agonist phenylephrine (PE) on IUP and mean arterial pressure (MAP) were compared before and at various time points after oral doses of either terazosin, doxazosin, tamsulosin or Rec 15/2739 (SB 216469). At submaximal doses, terazosin and doxazosin blocked PE-induced increases in MAP to a greater extent than increases in IUP. Tamsulosin blocked both parameters equally at the lowest and highest doses; however, at the intermediate dose, IUP was blocked more than MAP. Rec 15/2739 at each dose always blocked IUP to a greater extent than MAP. While the in vivo uroselectivity of these agents was predicted by radioligand binding and in vitro functional selectivity for the α_1A subtype over α_1B and α_1D subtypes, results from conscious dog experiments indicate that estimates of in vivo uroselectivity also depend upon dose and the time after administration. Our conscious canine model provides the basis for frequent and repeated evaluation of uroselectivity parameters over many hours, thus providing a pharmacological profile of compound effects perhaps more relevant to clinical practice.

Benign prostatic hyperplasia (BPH), common in aging males, is often treated with ␣ 1 -adrenoceptor antagonists. To minimize hypotensive and other side effects, compounds with selective antagonist activity at ␣ 1A -and ␣ 1D -(compared with ␣ 1B -) adrenoceptors were evaluated that would block lower urinary tract ␣ 1 -adrenoceptors in preference to cardiovascular ␣ 1B -adrenoceptors. 9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydroABT-980) was tested in radioligand binding assays, isolated tissue bioassays, intraurethral pressure (IUP) tests in isoflurane-anesthetized dogs, and blood pressure analyses in spontaneously hypertensive rats (SHR). Fiduxosin had higher affinity for cloned human ␣ 1a -(0.16 nM) and ␣ 1d -adrenoceptors (0.92 nM) in radioligand binding studies compared with ␣ 1b -adrenoceptors (25 nM) or in isolated tissue bioassays [pA 2 values of 8.5-9.6 for ␣ 1A -receptors in rat vas deferens or canine prostate strips, 8.9 at ␣ 1D -adrenoceptors (rat aorta), compared with 7.1 at ␣ 1B -adrenoceptors (rat spleen)]. Furthermore, the compound antagonized putative ␣ 1L -adrenoceptors in the rabbit urethra (pA 2 value of 7.58). Fiduxosin blocked epinephrineinduced increases in canine IUP (pseudo-pA 2 value of 8.12), eliciting only transient decreases in mean arterial blood pressure (MAP) in SHR. The area under the curve (AUC 0360 min) for the hypotensive response was dose related with a log index value for fiduxosin of 5.23, indicating a selectivity of 770-fold comparing IUP to MAP effects. Preferential antagonism of ␣ 1A -and ␣ 1D -versus ␣ 1B -adrenoceptors in vitro, blockade of putative ␣ 1L -sites in vitro, and selective effects on lower urinary tract function versus blood pressure in vivo by fiduxosin suggest the potential utility of this compound for the treatment of BPH.Benign prostatic hyperplasia (BPH), a change in the size, composition, and function of the prostate gland, leads to obstruction of the bladder and urethra in middle-aged and elderly males. The enlarged prostate is composed of glandular epithelium and a large stromal component containing mostly smooth muscle (Shapiro and Lepor, 1991). Although the term BPH might suggest that symptoms arise exclusively from increased organ size causing mechanical obstruction of urine flow, no correlation between prostate size and symptom severity has been shown (Shapiro and Lepor, 1995). Rather, an important "dynamic" component to BPH results from alterations in sympathetic control of prostatic smooth muscle tone, mediated primarily through ␣ 1 -adrenoceptor mecha- ; DMSO, dimethyl sulfoxide; PE, phenylephrine; IUP, intraurethral pressure; EPI, epinephrine; SHR, spontaneously hypertensive rats; MAP, mean arterial blood pressure; AUC, area under the curve; pED 50 , negative logarithm of the molar dose of compound required to elicit a reduction in blood pressure for 60 min to a point midway between hypertensive and normotensive; ANOVA, analysis of variance; K i , inhibition constant as a measure of drug affinity for a receptor, equivalent to the concentra...

Fiduxosin is a new ␣ 1 -adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the ␣ 1 -adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC 50 values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC 50 values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC 50 /IUP IC 50 , were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of ␣ 1 -adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an ␣ 1a -/␣ 1d -subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular ␣ 1 -adrenoceptors in human and should be a novel, long-acting, uroselective ␣ 1 -adrenoceptor antagonist.␣ 1 -Adrenoceptor antagonists represent first-line therapy for the pharmacological treatment of benign prostatic hyperplasia (BPH), in part by relaxing prostatic smooth muscle (Lowe, 1999). Fiduxosin (ABT-980) is a novel ␣ 1 -adrenoceptor antagonist. Compared with other clinical agents, such as terazosin, doxazosin, and tamsulosin, fiduxosin exhibits a somewhat different ␣ 1 -adrenoceptor subtype selectivity profile. Radioligand binding potencies at human ␣ 1a -, ␣ 1b -, and ␣ 1d -adrenoceptors are reported to be 1.81, 1.16, and 0.67 nM for terazosin; 0.79, 0.80, and 0.81 nM for doxazosin; 0.03, 0.60, and 0.06 nM for tamsulosin; and 0.16, 24.89, and 0.92 nM for fiduxosin, respectively (Hancock et al., 1998b(Hancock et al., , 2002, showing fiduxosin to be selective for ␣ 1a -and ␣ 1d -adrenoceptors compared with ␣ 1b -adrenoceptors to a greater extent than tamsulosin.Accumulating data suggest that extraprostatic ␣ 1 -adrenoceptors in bladder, spinal cord, ganglia, or nerve terminals may also contribute to ameliorating the irritative and voiding symptoms of BPH (Fitzpatrick, 2000;Schwinn and Michelotti, 2000). Three subtypes of ␣ 1 -adrenoceptors are known to exist, ␣ 1A -, ␣ 1B -, and ␣ 1D -adr...