α1-adrenergic receptor

Doxazosin additionally lowers mean arterial pressure in hamsters by 18% without changing heart rate.[2] Doxazosin significantly lowers the wet weight of mouse prostate reconstitution (MPR) infected with BabeTGF-beta 1.[5]

Absorption, Distribution and Excretion
Most doxazosin metabolites are eliminated in the feces. /Salt not specified/
Well absorbed from gastrointestinal tract; bioavailability is about 65%. /Salt not specified/
Elimination: Fecal: Unchanged drug, about 5%; metabolites, 63 to 65%. Renal: 9%. /Salt not specified/

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Metabolism / Metabolites
Metabolized extensively in the liver. Although several active and inactive metabolites have been identified (2-piperazinyl, 6' and 7'-hydroxy,6' and 7'-O-desmethyl, and 2-amino), there is no evidence that they are present in substantial amounts. /Salt not specified/

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Biological Half-Life
The half-life of doxazosin is approximately 20 hours ... /Salt not specified/
Elimination /half life/: 19 to 22 hours; does not appear to be significantly influenced by age or mild to moderate renal impairment. /Salt not specified/

Interactions
Antihypertensive effects of doxazosin may be reduced when the medication is used concurrently with these agents; indomethacin, and possibly other /nonsteroidal anti-inflammatory drugs/ NSAIDs, may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained. /Salt not specified/
Concurrent use may slightly increase the serum concentration of doxazosin; however, the clinical significance of this increase is not known. /Salt not specified/
Antihypertensive effects may be potentiated when these medications /other hypertension-producing medications/ are used concurrently with doxazosin; although some antihypertensive and/or diuretic combinations are frequently used to therapeutic advantage, dosage adjustments are necessary during concurrent use. /Salt not specified/
Antihypertensive effects of doxazosin may be reduced when it is used concurrently with these agents /sympathomimetics/; the patient should be carefully monitored to confirm that the desired effect is being obtained. /Salt not specified/
For more Interactions (Complete) data for DOXAZOSIN MESYLATE (9 total), please visit the HSDB record page.

[1]. Cancer Res . 2006 Jan 1;66(1):464-72.

[2]. Atherosclerosis . 1991 Nov;91(1-2):35-49.

[3]. Circulation . 2003 Jan 7;107(1):127-31.

[4]. J Cell Biochem . 2005 Feb 1;94(2):374-88.

[5]. Prostate . 1997 Nov 1;33(3):157-63.

Doxazosin Mesylate is the mesylate salt form of doxazosin, a quinazoline compound with smooth muscle relaxing activity. Doxazosin mesylate selectively antagonizes alpha-1-adrenergic receptors in smooth muscle of the bladder neck and prostate, thereby relaxing the smooth muscle and decreasing the obstruction and urethral resistance seen with benign prostate hyperplasia (BPH). This may improve BPH symptoms. This agent also blocks alpha-1-adrenergic receptors in peripheral vascular smooth muscle, which leads to vasodilatation and a subsequent decrease in peripheral vascular resistance.
A prazosin-related compound that is a selective alpha-1-adrenergic blocker.
See also: Doxazosin (has active moiety).

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Mechanism of Action
Selective alpha1-adrenergic blocker related to prazosin, q.v. /Salt not specified/
Blocks postsynaptic alpha 1 receptors and cause vasodilation /Salt not specified/
Hypertension: Blockade of alpha1-adrenergic receptors by doxazosin results in peripheral vasodilation, which produces a fall in blood pressure because of decreased peripheral vascular resistance. Benign prostatic hyperplasia: Relaxation of smooth muscle in the bladder neck, prostate, and prostate capsule produced by alpha1-adrenergic blockade results in a reduction in urethral resistance and pressure, bladder outlet resistance, and urinary symptoms. /Salt not specified/
Previous studies have demonstrated that the alpha(1)-adrenergic receptor antagonist doxazosin (Dox) inhibits multiple mitogenic signaling pathways in human vascular smooth muscle cells. This broad antiproliferative activity of Dox occurs through a novel mechanism unrelated to its blocking the alpha(1)-adrenergic receptor. Flow cytometry demonstrated that Dox prevents mitogen-induced G(1)-->S progression of human coronary artery smooth muscle cells (CASMCs) in a dose-dependent manner, with a maximal reduction of S-phase transition by 88+/-10.5% in 20 ng/mL platelet-derived growth factor and 1 micromol/L insulin (P+I)-stimulated cells (P<0.01 for 10 micromol/L Dox versus P+I alone) and 52+/-18.7% for 10% FBS-induced mitogenesis (P<0.05 for 10 micromol/L Dox versus 10% FBS alone). Inhibition of G(1) exit by Dox was accompanied by a significant blockade of retinoblastoma protein (Rb) phospstimulated quiescent CASMCs to progress through G(1) and enter the S phase. E2F-mediated G(1) exit was not affected by Dox, suggesting that it targets events upstream from Rb hyperphosphorylation. Downregulation of the cyclin-dependent kinase inhibitory protein p27 is important for maximal activation of G(1) cyclin/cyclin-dependent kinase holoenzymes to overcome the cell cycle inhibitory activity of Rb. In Western blot analysis, p27 levels decreased after mitogenic stimulation (after P+I, 43+/-1.8% of quiescent cells [P<0.01 versus quiescent cells]; after 10% FBS, 55+/-7.7% of quiescent cells [P<0. 05 versus quiescent cells]), whereas the addition of Dox (10 micromol/L) markedly attenuated its downregulation (after P+I, 90+/-8.3% of quiescent cells [P<0.05 versus P+I alone]; after 10% FBS, 78+/-8.3% of quiescent cells [P<0.05 versus 10% FBS alone]). Furthermore, Dox inhibited cyclin A expression, an E2F regulated gene that is essential for cell cycle progression into the S phase. The present study demonstrates that Dox inhibits CASMC proliferation by blocking cell cycle progression from the G(0)/G(1) phase to the S phase. This G(1)-->S blockade likely results from an inhibition of mitogen-induced Rb hyperphosphorylation through prevention of p27 downregulation. /Salt not specified/
For more Mechanism of Action (Complete) data for DOXAZOSIN MESYLATE (6 total), please visit the HSDB record page.

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Therapeutic Uses
Doxazosin is indicated for the treatment of both the urinary outflow obstruction and the obstructive and irritative symptoms associated with benign prostatic hyperplasia (BPH). Obstructive symptoms are hesitation, intermittency, dribbling, weak urinary stream, and incomplete emptying of the bladder; while irritative symptoms include nocturia, daytime frequency, urgency, and burning. Doxaxosin may be used in nomotensive or hypertensive patients. In normotensive patients with BPH, doxazosin does not appear to significantly lower blood pressure. In hypertensive patients with BPH, both conditions are effectively treated with doxazosin. The long term effects of doxazosin on the incidence of acute urinary obstruction or other complications of BPH or on the need for surgery have not yet been determined. /Included in US product labeling/ /Salt not specified/
Doxazosin is indicated in the treatment of hypertension. /Included in US product labeling/ /Salt not specified/
Antihypertensive; in treatment of benign prostatic hypertrophy. /Salt not specified/
Evaluation of atherosclerosis is important in the treatment of hypertension. To evaluate the preventive effects of a small amount of alpha-blockade, arterial and endothelial dysfunction were measured by noninvasive tests, i.e., pulse wave velocity, acceleration plethysmography and strain-gauge plethysmography, in patients with essential hypertension. Fifteen patients (65+/-3 years old) with essential hypertension (WHO stage I or II) were analyzed in this study. We performed noninvasive evaluations to measure aortic stiffness and endothelial dysfunction, in addition to measuring blood pressure, cholesterol profile, and levels of cells adhesion molecules and nitric oxide before and 6 and 12 months after the start of doxazosin treatment (1.0 mg/day). Blood pressure and heart rate did not significantly change during treatment. The pulse wave velocity index was significantly reduced both at 6 (7.72+/-0.23 m/s; p<0.05) and 12 (7.34+/-0.26 m/s; p<0.05) months after the start of treatment compared to the pretreatment level that at baseline. There was also a significant improvement in b/a after 12 months (-0.46+/-0.04; p<0.05) and in d/a after 6 months (-0.38+/-0.03; p<0.05) and 12 months (-0.39+/-0.03; p=0.05) compared to the pretreatment values. Moreover, reactive hyperemia evaluated by strain-gauge plethysmography after 6 months (1.34+/-0.11; p<0.05) and 12 months (1.49+/-0.16; p<0.05) was significantly improved compared to that before treatment, and NOx was significantly increased after 12 months (89.7+/-15.7 micromol/l; p<0.005). These data suggest that a low dose of doxazosin may play an important role in improving arterial stiffness and endothelial dysfunction without changing cardiac hemodynamics. /Salt not specified/
For more Therapeutic Uses (Complete) data for DOXAZOSIN MESYLATE (18 total), please visit the HSDB record page.

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Drug Warnings
Adverse effects occurring most frequently during doxazosin mesylate therapy for hypertension include dizziness, headache, drowsiness, lack of energy (eg, lethargy, fatigue), nausea, edema, and rhinitis. In patients receiving the drug for benign prostatic hyperplasia (BPH), the most frequent adverse effects are dizziness, headache, fatigue, edema, dyspnea, abdominal pain, and diarrhea. The frequency of adverse effects in controlled clinical trails generally has been lower in patients receiving doxazosin for BPH than in those receiving the drug for hypertension; however, dosages employed for this condition also generally have been lower than those for hypertension. /Salt not specified/
While adverse effects occur frequently in patients receiving the drug, most are mild to moderate in severity, and discontinuance of doxazosin secondary to adverse effects was required in only 7% of patients with hypertension during clinical trials. The principal reasons for discontinuance in patients with hypertension were postural effects in 2% of patients and edema, malaise/fatigue, and heart rate disturbance each in about 0.7% of patients. In controlled clinical trials in patients with hypertension, only dizziness (including postural effects), weight gain, somnolence, and malaise/fatigue occurred at rates significantly greater than those for placebo; postural effects and edema appeared to be dose related. Only dizziness, fatigue, hypotension, edema, and dyspnea occurred significantly more frequently with the drug than placebo in controlled clinical trials for BPH; dizziness and dyspnea appeared to be dose-related. /Salt not specified/
Besides dizziness ..., headache is the most common adverse nervous system effect associated with doxazosin therapy, occurring in about 14 or 10% of patients receiving the drug for hypertension or benign prostatic hyperplasia (BPH), respectively. Somnolence occurs in 5 or 3% of such patients, respectively, and pain in 2% of patients. Nervousness occurs in about 2% of patients receiving doxazosin for hypertension, and insomnia and anxiety occur in 1.2 and 1.1%, respectively, of those receiving the drug for BPH; insomnia occurs in 1% of hypertensive patients. Adverse nervous system effects occurring in 0.5-1% of patients include paresthesia, kinetic disorders, ataxia, hypertonia, hypoesthesia, agitation, depression, and decreased libido. Paresis, tremor, twitching, confusion, migraine, paroniria, amnesia, emotional lability, impaired concentration, abnormal thinking, and depresonalization have been reported in less than 0.5% of patients, but a causal relationship to the drug has not been established. /Salt not specified/
Nausea, diarrhea, and dry mouth are the most common adverse GI effects of doxazosin in hypertensive patients, occurring in 3, 2, and 2% of such patients, respectively, and abdominal pain, diarrhea, dyspepsia, nausea, and dry mouth are the most common in those with benign prostatic hyperplasia (BPH), occurring in 2.4, 2.3, 1.7, 1.5, and 1.4% of such patients, respectively; dyspepsia occurs in 1% of hypertensive patients. Constipation and flatulence occur in 1% of patients receiving the drug for hypertension. Increased appetite, anorexia, fecal incontinence, and gastroenteritis have been reported in less than 0.5% of hypertensive patients but not directly attributed to the drug. Vomiting has been reported during postmarketing experience with doxazosin. /Salt not specified/
For more Drug Warnings (Complete) data for DOXAZOSIN MESYLATE (12 total), please visit the HSDB record page.

C24H29N5O8S

547.58

547.173

C, 52.64; H, 5.34; N, 12.79; O, 23.37; S, 5.85

77883-43-3

Doxazosin; 74191-85-8; Doxazosin-d8 hydrochloride; 1219803-95-8

62978

White to off-white solid powder

718ºC at 760 mmHg

275-277ºC

388ºC

2.886

2

12

4

38

770

0

S(C([H])([H])[H])(=O)(=O)O[H].O1C2=C([H])C([H])=C([H])C([H])=C2OC([H])([H])C1([H])C(N1C([H])([H])C([H])([H])N(C2N=C(C3=C([H])C(=C(C([H])=C3N=2)OC([H])([H])[H])OC([H])([H])[H])N([H])[H])C([H])([H])C1([H])[H])=O

VJECBOKJABCYMF-UHFFFAOYSA-N

InChI=1S/C23H25N5O5.CH4O3S/c1-30-18-11-14-15(12-19(18)31-2)25-23(26-21(14)24)28-9-7-27(8-10-28)22(29)20-13-32-16-5-3-4-6-17(16)33-20;1-5(2,3)4/h3-6,11-12,20H,7-10,13H2,1-2H3,(H2,24,25,26);1H3,(H,2,3,4）

[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone;methanesulfonic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)