Disease relevance of doxazosin

• Furthermore, the inhibitory effects of a low dose of TCV-116 on cardiac hypertrophy and altered gene expressions of TGR(mRen2)27 were greater than those of doxazosin (alpha 1-adrenergic receptor blocker) combined with atenolol, despite their similar hypotensive effects [1].
• Recent evidence from our laboratory has demonstrated that alpha1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis in prostate epithelial and smooth muscle cells in patients with benign prostatic hypertrophy (BPH; J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999) [2].
• These findings provide the first evidence that the apoptotic activity of the quinazoline-based alpha1-adrenoceptor antagonists (doxazosin and terazosin) against prostate cancer cells is independent of: (a) their capacity to antagonize alpha1-adrenoceptors; and (b) the hormone sensitivity status of the cells [3].
• Furthermore, an in vivo efficacy trial demonstrated that doxazosin administration (at tolerated pharmacologically relevant doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in a significant inhibition of tumor growth [2].
• Doxazosin, an alpha 1-adrenergic inhibitor, has been shown to decrease hypertension and plasma lipids, especially total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), thus reducing certain risk factors associated with increased incidence of cardiovascular disease [4].

Psychiatry related information on doxazosin

• Doxazosin and Y-27632 may be the alternatives for the treatment of erectile dysfunction associated with BPH [5].
• Pharmacotherapeutic stature of doxazosin and its role in coronary risk reduction [6].
• Diurnal exposure profile in rats from dietary administration of a chemical (doxazosin) with a short half-life: interplay of age and diurnal feeding pattern [7].
• Renal hemodynamic effects of captopril and doxazosin during slight physical activity in hypertensive patients with type-1 diabetes mellitus [8].
• Psychometric properties were assessed on a sample of 131 patients with BPH who were receiving treatment with doxazosin gastrointestinal therapeutic system (GITS) [9].

High impact information on doxazosin

• Heterogeneity was significant between trials because of high risk of cardiovascular events on doxazosin in one trial, and high risk of stroke on captopril in another; but systolic pressure differed between groups in these two trials by 2-3 mm Hg [10].
• We randomized 11-week-old LVH rats to chronic treatment with the endothelin receptor antagonist bosentan (Bos, 100 mg. kg-1. d-1, n=14), the alpha1-receptor antagonist doxazosin (Dox, 1 mg. kg-1. d-1, n=12), or vehicle (Cont, n=14) [11].
• Bos (93%; P<0.0001 versus Cont) but not Dox (42%; P=0.8465 versus Cont) ameliorated the survival rate at 17 weeks (Cont; 36%) [11].
• The single intra-arterial infusion of yohimbine, as well as doxazosin, resulted in vasodilation [12].
• The effect of doxazosin on recruitment of Fas-associated death domain (FADD) and procaspase-8 to the Fas receptor was examined via analysis of death-inducing signaling complex formation [13].

Chemical compound and disease context of doxazosin

• Neither doxazosin nor terazosin exerted a significant effect on the rate of cell proliferation in prostate cancer cells [2].
• The calculated 10-year risk for the development of coronary heart disease was reduced significantly (p < 0.001) by 28% in the doxazosin group and by 19% in the captopril group [14].
• METHODS: Each treatment was taken for 1 month, preceded by a 2-week single-blind run-in period, in which the patients received a low dose of doxazosin (study A) or enalapril (study B) to enable recruitment of patients with moderate or severe hypertension [15].
• Platelet alpha2-adrenoceptor alterations in patients with essential hypertension are normalized after treatment with doxazosin but not propranolol [16].
• Combination treatment with propiverine hydrochloride plus doxazosin controlled release gastrointestinal therapeutic system formulation for overactive bladder and coexisting benign prostatic obstruction: a prospective, randomized, controlled multicenter study [17].

Biological context of doxazosin

• Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediated pathway [13].
• Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis [2].
• In hypertension, doxazosin reduces blood pressure both at rest and during exercise by reduction of systemic vascular resistance without precipitating substantial reflex cardiac stimulation [18].
• We examined the effects of dox on murine and human pituitary tumor cell proliferation in vitro and in vivo. dox treatment inhibited proliferation of murine pituitary tumor cells, induced G(0)-G(1) cell cycle arrest, and reduced phosphorylated retinoblastoma levels [19].
• Doxazosin resulted in dramatic downregulation of the 189 isoform of VEGF in maspin transfectants, while a fivefold induction of Smad4 mRNA expression was detected in those cells after 24 h of treatment [20].

Anatomical context of doxazosin

• Furthermore, human normal prostate epithelial cells exhibited a very low sensitivity to the apoptotic effects of doxazosin compared with that observed for the malignant prostate cells [3].
• Previous studies have demonstrated that the alpha(1)-adrenergic receptor antagonist doxazosin (Dox) inhibits multiple mitogenic signaling pathways in human vascular smooth muscle cells [21].
• Since it is not known for certain which alpha-adrenergic receptors mediate renal vasoconstriction in human essential hypertension, we infused either doxazosin (n = 7) or yohimbine (n = 7) into the renal arteries of hypertensive subjects immediately prior to diagnostic angiography [22].
• In contrast, pretreatment with the alpha 1-adrenergic receptor antagonist doxazosin (200 ng) injected into the nucleus tractus solitarius did not alter these responses [23].
• Doxazosin, a well established treatment in patients with bothersome lower urinary tract symptoms from benign prostatic hyperplasia (BPH), is available in a new controlled-release formulation, doxazosin gastrointestinal therapeutic system (GITS) [24].

Associations of doxazosin with other chemical compounds

• In this study, to identify the precise molecular mechanism underlying this apoptosis induction, we examined whether doxazosin and terazosin (both piperazinyl quinazolines) affect prostate growth via an alpha1-adrenoceptor-independent action [3].
• Mean arterial blood pressure (114 +/- 2 mmHg) was similar in all groups before initiating antihypertensive therapy and declined to 102 +/- 2 (captopril), 103 +/- 1 (nifedipine), and 103 +/- 2 (doxazosin) mmHg (P < 0.001) [25].
• There were no significant differences in HDL apolipoprotein (apo) A-I or low-density lipoprotein apoB between the drugs, but atenolol decreased the ratio of HDL-C to apoA-I, and doxazosin increased this ratio, differences that were statistically significant (P < .002) [26].
• Enalapril (128 +/- 1 mmHg) and doxazosin (132 +/- 2 mmHg) decreased mean blood pressure compared with control levels (148 +/- 1 mmHg) (P < .01) [27].
• In contrast, despite a hypotensive effect comparable to these two drug treatments, doxazosin (an alpha 1-blocker) alone or manidipine (a calcium antagonist) did not normalize these altered gene expressions of SHR [28].

Gene context of doxazosin

• RESULTS: alpha-1 Adrenoceptor antagonist doxazosin of 2 mumol/l reduced fibronectin protein in MPCM-injured female mesangial cells by 31 +/- 1.03% (P < 0.001) and by 9.5 +/- 0.3% (P = 0.01) in male mesangial cells [29].
• Strikingly, we found that doxazosin induces deregulation of genes implicated in DNA replication and repair, such as GADD45A, XRCC5 and PRKDC [30].
• These facts, together with the demonstration of the ability of doxazosin to bind DNA, allowed us to propose a novel mechanism of action for doxazosin in prostate cancer cells that implies DNA-damage mediated apoptosis by down-regulation of XRCC5 and PRKDC genes [30].
• Although caspase-1 inhibitor completely abolished the production of IL-18, anti-IL-18 mAb and caspase-1 inhibitor partially inhibited the increase in ICAM-1 and CD40 expression induced by doxazosin, prazosin, and terazosin [31].
• The effect of doxazosin on cell attachment of maspin-expressing prostate cancer cells was evaluated on collagen- and fibronectin-coated plates [20].

Analytical, diagnostic and therapeutic context of doxazosin

• Quantitative microarray assays were done in PC-3 and BPH-1 cells after treatment with doxazosin (25 micromol/L, 6 and 24 hours) to identify the early gene changes [13].
• Western blot analysis revealed activation of caspase-8 and caspase-3 within the first 6 to 12 hours of treatment with doxazosin in both PC-3 and BPH-1 cells [13].
• Plasma glucose, insulin, and free fatty acid (FFA) concentrations during the OGTT were similar in all groups before antihypertensive treatment and did not change with captopril and nifedipine; after doxazosin, plasma glucose and FFA concentrations during the OGTT decreased (both P < 0.05) without change in plasma insulin response [25].
• The antihypertensive efficacy and pharmacokinetics of a single 1 mg oral dose of doxazosin were investigated in five healthy male volunteers, six patients with renal failure not on hemodialysis, and four patients with end-stage renal failure studied between two hemodialyses [32].
• Both doxazosin and yohimbine caused an increased vasodilatory effect in the sodium-depleted versus the control group (228 +/- 42 versus 83 +/- 13% and 192 +/- 24 versus 95 +/- 8%, respectively; P < 0.05) [33].

References