α1-adrenergic receptor

体外活性：多沙唑嗪诱导的细胞凋亡被特定的 caspase-8 抑制剂阻断，支持 caspase-8 在多沙唑嗪诱导的细胞凋亡中的功能参与。多沙唑嗪增加 FADD 募集和随后的 caspase-8 激活，表明 Fas 介导的细胞凋亡是多沙唑嗪在前列腺细胞中作用的潜在机制。多沙唑嗪和考来烯胺同样可将血浆总胆固醇、LDL 加 VLDL 胆固醇以及总甘油三酯平均分别降低 46%、61% 和 45%。 Doxazosin 在 HL-1 细胞系中诱导 DNA 损伤和细胞死亡。多沙唑嗪治疗会降低新生大鼠心肌细胞原代培养物中的细胞活力，Hoechst 染料活体染色表明多沙唑嗪诱导成人心肌细胞原代培养物中的细胞凋亡。 Doxazosin 通过消除细胞对纤连蛋白和胶原涂层表面的粘附并通过潜在的 VEGF 表达下调来抑制细胞迁移，从而拮抗 VEGF 介导的 HUVEC 细胞血管生成反应。

多沙唑嗪还可将平均动脉压降低 18%，而不影响所有仓鼠的心率。多沙唑嗪导致 BabeTGF-β1 感染的小鼠前列腺重建 (MPR) 的湿重显着降低。

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

175.02

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

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.57 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (4.57 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (4.57 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。