Cardiovascular Effects of Alpha-Blockers Used for the Treatment of Symptomatic BPH: Impact on Safety and Well-Being

Mey, Christian de

doi:10.1159/000052284

Cited by 48 publications

(21 citation statements)

References 68 publications

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“…These observations suggest that ␣ 1B -adrenoceptors are more important for blood pressure regulation, and that compounds having reduced activity at ␣ 1B -sites compared with other ␣ 1 -adrenoceptors would be expected to cause fewer cardiovascular side effects than classical ␣ 1 -antagonists (Take et al, 1998), supporting the concept that an ␣ 1A -selective compound would be useful in BPH (Hancock et al, 1998a). Tamsulosin causes fewer hypotensive side effects in clinical practice (de Mey, 1998) and in animal studies (Hancock et al, 1998a,b), despite only moderate differences (Յ20 fold) in affinity at ␣ 1A -compared with either ␣ 1B -or ␣ 1D -adrenoceptors (Hancock, 1996). However, several highly selective ␣ 1A -antagonists intended to be uroselective, including REC 15/2739 (Leonardi et al, 1997) and Ro-70-0004 (Williams et al, 1999), failed to improve both voiding and irritative symptoms in the clinic, such that the hypothesis of ␣ 1A -selectivity correlating to uroselectivity remains unproven.…”

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confidence: 99%

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Hancock

Buckner²,

Brune³

et al. 2002

J Pharmacol Exp Ther

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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...

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confidence: 99%

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Hancock

Buckner²,

Brune³

et al. 2002

J Pharmacol Exp Ther

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“…Although headache and dizziness were reported, these AEs were not associated with orthostatic hypotension in our studies. Although it has been reported that tamsulosin HCl, a selective antagonist of α 1A -adrenoceptors, which are not present in the blood vessels, shows less frequent orthostatic hypotension than conventional α1-antagonists, [17][18][19] our results show that administering tamsulosin HCl after meal is preferred to taking in fasted state in order to prevent orthostatic hypotension. Our results also showed hypotensive potential of concomitant administration of tadalafil and tamsulosin HCl, but SBP was relatively less influenced than DBP, and dizziness, a symptom related to the decrease of DBP, was reported in 2 subjects (5.8%) only in fed study.…”

Section: Discussionmentioning

confidence: 53%

Pharmacokinetics and safety profiles of tadalafil/tamsulosin HCl fixed-dose combination capsule under fasted and fed condition in healthy volunteers

Jin

Yoo

et al. 2016

Transl Clin Pharmacol

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Co-administration of tadalafil and tamsulosin HCl in patients with benign prostate hyperplasia and erectile dysfunction is increasing in clinical settings. Development of fixed-dose combination (FDC) of tadalafil and tamsulosin HCl could contribute to improving patients' adherence and treatment efficacy. We evaluated the pharmacokinetics and safety profiles of a newly developed fixed-dose combination capsule of tadalafil 5 mg/tamsulosin HCl 0.4 mg in comparison with co-administration of each formulation in healthy volunteers under fasted and fed conditions. Two randomized, openlabel, single-dose, two-way, crossover studies were completed in 29 subjects under fasted condition, and 33 subjects under fed condition. Serial blood sample collection for PK analysis was conducted up to 72 hours after dosing, and PK parameters were calculated using non-compartmental analysis. Geometric mean ratios and 90% confidence intervals of the C max and AUC last were used to evaluate comparative bioavailability. In both fasted and fed condition studies, the bioequivalence was established. The most common adverse drug reactions were orthostatic hypotension and headache with no statistical difference between treatment groups. All subjects with orthostatic hypotension recovered at follow-up test. Although changes in vital signs from baseline were statistically significant, there were no subjects with systolic blood pressure < 90 mmHg and there were no clinically meaningful signs or symptoms associated. FDC of tadalafil and tamsulosin HCl can be an alternative to co-administration of individual drugs for providing better compliance. Changes in blood pressure should be kept in mind when tadalafil and tamsulosin HCl are co-administered in clinical settings.

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“…5,7,8 Although several studies have shown that α-blocker therapy could improve cerebral blood flow after treatment for 4-8 weeks, 20,21 acute hypotension associated with anti hypertensive therapy could precipitate cerebral hypoperfusion and ischemic stroke. [2][3][4]11 One possible explanation of our findings was that patients without underlying hypertension were vulnerable to the first-dose effect of α-blockers and contributed to the observed increase in risk of ischemic stroke in the early initiation period of α-blockers in the whole study population.…”

Section: Discussionmentioning

confidence: 99%

“…5 Nevertheless, they have inherent adverse cardiovascular effects, including dizziness and hypotension, especially soon after initiation (known as the first-dose effect), because of their effects on lowering blood pressure. 5,7,8 Researchers have reported an increase in the risk of hypotension-related adverse events, including hypotension, syncope and fractures, during the initiation period of α-blocker therapy. 9 Our research group found that the use of α-blockers was associated with an increased risk of hip and femur fractures during the early initiation period among older men without hypertension.…”

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confidence: 99%

Risk of ischemic stroke during the initiation period of α-blocker therapy among older men

Lai

Kuo

Chen

et al. 2015

CMAJ

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Cardiovascular Effects of Alpha-Blockers Used for the Treatment of Symptomatic BPH: Impact on Safety and Well-Being

Cited by 48 publications

References 68 publications

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Pharmacokinetics and safety profiles of tadalafil/tamsulosin HCl fixed-dose combination capsule under fasted and fed condition in healthy volunteers

Risk of ischemic stroke during the initiation period of α-blocker therapy among older men

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Cardiovascular Effects of Alpha-Blockers Used for the Treatment of Symptomatic BPH: Impact on Safety and Well-Being

Cited by 48 publications

References 68 publications

Preclinical Pharmacology of Fiduxosin, a Novel α1-Adrenoceptor Antagonist with Uroselective Properties

Preclinical Pharmacology of Fiduxosin, a Novel α1-Adrenoceptor Antagonist with Uroselective Properties

Pharmacokinetics and safety profiles of tadalafil/tamsulosin HCl fixed-dose combination capsule under fasted and fed condition in healthy volunteers

Risk of ischemic stroke during the initiation period of α-blocker therapy among older men

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Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties