Effect of Fiduxosin, an Antagonist Selective for α_1A- and α_1D-Adrenoceptors, on Intraurethral and Arterial Pressure Responses in Conscious Dogs

Abstract

Fiduxosin is an ␣ 1 -adrenoceptor antagonist with higher affinity for ␣ 1A -adrenoceptors and for ␣ 1D -adrenoceptors than for ␣ 1B -adrenoceptors. Our hypothesis is that such a compound with higher affinity for subtypes implicated in the control of lower urinary tract function and lower affinity for a subtype implicated in the control of arterial pressure could result in a superior clinical profile for the treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction. The purpose of this study was to evaluate the potency and selectivity of fiduxosin for effects on prostatic intraurethral pressure (IUP) versus mean arterial pressure (MAP) relative to current clinical standards, terazosin and tamsulosin, in conscious dogs. Phenylephrine (PE)-induced increases in IUP and MAP were determined before and at various time points after an oral dose of each antagonist. Hypotensive potency was also determined. All three antagonists caused dose-and time-dependent blockade of the IUP and MAP pressor effects of PE. The IUP ED 50 values of fiduxosin, tamsulosin, and terazosin were 0.24, 0.004, and 0.23 mg/kg p.o., respectively. The corresponding MAP ED 50 values were 1.79, 0.006, and 0.09 mg/kg p.o. The rank order of IUP selectivity (ratio) was fiduxosin (7.5-fold), tamsulosin (1.5-fold), and terazosin (0.4 ϭ 2.5-fold MAP-selective). Tamsulosin and terazosin caused dose-dependent hypotension, whereas no change in arterial pressure was seen after fiduxosin. These data, illustrating a superior selectivity profile of fiduxosin, are consistent with our hypothesis.Lower urinary tract symptoms (LUTS) refer to a constellation of irritative (filling) and obstructive (voiding) symptoms such as frequency, urgency, and slow flow. LUTS is more frequent and severe in older age groups and has a strong negative impact on the quality of life of those affected (Garraway et al., 1991;Girman et al., 1994Girman et al., , 1995Kirby, 2000). Although LUTS may have a number of underlying etiologies, it is often attributed in older men to benign prostatic enlargement resulting in bladder outlet obstruction. In this subset of cases, it is referred to as symptomatic or clinical benign prostatic hyperplasia (BPH). In the United States, an estimated 5.6 million men suffer, a number that is expected to double by the year 2025 due to increased life expectancy (Chapple, 1999).␣ 1 -Adrenoceptor antagonists represent first-line pharmacotherapy for the treatment of LUTS suggestive of benign prostatic obstruction (BPO). Cloning and pharmacological studies suggest the presence of three distinct subtypes of ␣ 1 -adrenoceptors (␣ 1A , ␣ 1B , and ␣ 1D ) (Hancock, 1996;Zhong and Minneman, 1999). Several studies have shown that the ␣ 1A -subtype predominates in the human prostate and that it mediates the contractile effects of norepinephrine in this tissue (Lepor et al., 1993;Forray et al., 1994;Taniguchi et al., 1997). Despite the proven safety and utility of nonselective ␣ 1 -adrenoceptor antagonists such as terazosin and doxazosin in...

Image-Based Chemical Screening Identifies Drug Efflux Inhibitors in Lung Cancer Cells

“…Most compound dosages were adopted from literature. The dosages were CGS-15943 1mg/kg (24), 8-(3-chlorostyryl) caffeine 5 mg/kg (25), fluspirilene 1 mg/kg (26), fiduxosin hydrochloride 3 mg/kg (27), fluphenazin dihydrochloride 3 mg/kg (28), SB 228357 5 mg/kg (29), PQ 401 50 mg/kg (30), DMCM hydrochloride 3 mg/kg (31). PRL-3 inhibitor I has not been studied in vivo previously, 10 mg/kg was used in this study.…”

α1‐, α2‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

“…However, the contribution of the prostate appears to dominate because phenylephrine‐induced IUP elevations were about 80% smaller in prostate‐ablated male, castrated male or female as compared to prostate‐intact rats (Akiyama et al ., 1999). The systemic administration of α 1 ‐adrenoceptor agonists such as noradrenaline, adrenaline or phenylephrine has been shown to increase IUP in anaesthetized rats (Guilmard et al ., 1996; Martin et al ., 1997; Akiyama et al ., 1999), anaesthetized cats (Lefevre‐Borg et al ., 1993) and anaesthetized dogs (Breslin et al ., 1993; Kenny et al ., 1994; 1996; Testa et al ., 1997; Witte et al ., 1997; 2002; Pulito et al ., 2000; Eltze et al ., 2001) and conscious dogs (Brune et al ., 2002). Similar IUP elevations have also been produced by the systemic administration of α 1A ‐selective agonists such as A 61603 (Knepper et al ., 1995).…”

“…Similar IUP elevations have also been produced by the systemic administration of α 1A ‐selective agonists such as A 61603 (Knepper et al ., 1995). Agonist‐induced IUP elevations were inhibited by various α 1 ‐adrenoceptor antagonists, including the clinically used alfuzosin (Lefevre‐Borg et al ., 1993; Kenny et al ., 1994; Guilmard et al ., 1996; Martin et al ., 1997; Testa et al ., 1997; Akiyama et al ., 1999), doxazosin (Kenny et al ., 1994; 1996; Martin et al ., 1997; Witte et al ., 2002), tamsulosin (Breslin et al ., 1993; Kenny et al ., 1994; 1996; Martin et al ., 1997; Testa et al ., 1997; Akiyama et al ., 1999; Pulito et al ., 2000; Brune et al ., 2002; Witte et al ., 2002) and terazosin (Breslin et al ., 1993; Kenny et al ., 1994; Martin et al ., 1997; Testa et al ., 1997; Witte et al ., 1997; 2002; Akiyama et al ., 1999; Brune et al ., 2002). Similar inhibition was also obtained when IUP elevations had been induced by stimulation of the hypogastric nerves (Lefevre‐Borg et al ., 1993; Leonardi et al ., 1997; Sato et al ., 2001), indicating its physiological relevance.…”

Establishment of an indicator cell system for hepatitis C virus

“…Among the 1300 compounds screened here, we identified fiduxosin hydrochloride and flunarizine dihydrochloride as anti-HCV agents. Fiduxosin is known as an alpha1-adrenoceptor antagonist (39). Previous screening of a whole-genome siRNA library has shown that knockdown of alpha-1 adrenoceptor A, B, or D expression significantly reduces the replication of the genotype 1b subgenomic replicon (44), suggesting that alpha-1 adrenoceptors participate in the replication of HCV.…”

“…6b). Although fiduxosin and flunarizine are known to be antagonists of alpha-1 adrenoceptor (39) and T-type calcium ion channels (40), respectively, the mechanisms by which they inhibit HCV propagation are not known. These results indicate that the Huh7OK1/TG-Luc cell line is applicable for a reliable cell-based assay for high-throughput screening of anti-HCV drugs.…”