PhenoxybenzamineHCl (0-100 μM; 96 h) strongly suppresses the growth of U251 and U87MG cells [2]. PhenoxybenzamineHCl (10μM; 24 hours or 72 hours) inhibits the migration and invasion of U251 and U87MG cells [2]. Phenoxybenzamine Hydrochloride (10 μM; 12 h) stimulates LINGO-1 and inhibits the TrkB-Akt pathway [2]. Phenoxybenzamine (0.1 μM-1 mM; 0-16 hours) inhibits hippocampus cell death during oxygen and glucose deprivation [3]. Cell proliferation experiment [2]

Mice administered subcutaneously with phenoxybenzamine hydrochloride (20 nM) twice a day for 26 days demonstrate anticancer effects [2]. In a rat model of severe traumatic brain injury, phenoxybenzamine (1.0 mg/kg; intravenously; once daily for 30 days) shows neuroprotective benefits [3].

Cell proliferation experiment [2]
Cell Types: U251 and U87MG cell
Tested Concentrations: 0.1, 1, 10, 50 and 100 μM
Incubation Duration: 96 h
Experimental Results: Cell proliferation was Dramatically inhibited, the inhibition rate of U251 cells was 26.5%, and the inhibition rate of U251 cells was 26.5%. is 27.3% for U87MG cells at a concentration of 10 μM.

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Cell migration experiment [2]
Cell Types: U251 and U87MG Cell
Tested Concentrations: 10 μM
Incubation Duration: 24 h
Experimental Results: Obvious migration inhibition was observed, and the inhibition rates of U251 and U87MG were 28.6% and 39.8% respectively. Cell invasion analysis [2]
Cell Types: U251 and U87MG Cell
Tested Concentrations: 10 μM
Incubation Duration: 72 h
Experimental Results: The invasion ability of U251 and U87MG was Dramatically weakened, and the number of invasive cells per field of view dropped from 365/field to 132/field for U251. field (36.2%), U87MG is 444/field to 298/field (67.1%).

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Western Blot Analysis [2]
Cell Types: U251
Tested Concentrations: 10 μM
Incubation Duration: 12 h
Experimental Results: TrkB,

Animal/Disease Models: nude mice, U87MG tumor model [2]
Doses: 20 nM
Route of Administration: subcutaneous injection, 2 days apart, for 26 days.
Experimental Results: tumor cell reduction.

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Animal/Disease Models: Male Wistar rat (350–500 g), traumatic brain injury (TBI) model [3]
Doses: 1.0 mg/kg
Route of Administration: intravenously (iv) (iv)(iv), one time/day for 30 days
Experimental Results: Neurological severity score (NSS) and foot error scores on days 14, 21, and 30. Reduce cognitive impairment associated with severe TBI and reduce expression of pro-inflammatory genes.

Absorption, Distribution and Excretion
Approximately 20% to 30% of orally administered phenoxybenzamide is absorbed in its active form. Phenoxybenzamide is highly lipid-soluble at body fluid pH levels, and large doses may accumulate in adipose tissue. Following intravenous administration of phenoxybenzamide, over 50% of the radioactive material is eliminated within 12 hours, and over 80% within 24 hours, but small amounts remain in various tissues for at least a week. Phenoxybenzamide is not completely absorbed via the gastrointestinal tract and varies considerably among individuals; only about 20% to 30% of the drug is absorbed in its active form after oral administration. Phenoxybenzamide irreversibly binds to smooth muscle adrenergic receptors via alkylation, and once complete blockade is induced, this effect can last for several days. In NMRI mice, after intravenous administration of 0.54 mg (14)C-phenoxybenzamide, the hydrochloride remained in the bloodstream for 40 minutes. Radioactive material was subsequently found in brown fat, liver, and kidneys; relatively high radioactivity was observed in other organs, particularly the heart and central nervous system, and persisted for 4 days (bile excretion was an important clearance route). Four hours after intravenous injection of (14) C-phenoxybenzylamine hydrochloride into two anesthetized male Sprague-Dawley rats, the bile contained 29.3% and 32.8% of the administered radioactivity, respectively. /phenoxybenzylamine hydrochloride/

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Metabolism/Metabolites
The following urinary metabolites were identified after oral or intraperitoneal administration of (15) N-labeled phenoxybenzylamine hydrochloride to rats (20 mg/kg body weight) and oral administration to dogs (10 mg/kg body weight): N-benzyl-N-(p-hydroxyphenoxyisopropyl)amine was the major metabolite in both animals; N-benzyl-N-phenoxyisopropylamine was a minor metabolite in dogs, and trace amounts of this metabolite were also observed in the urine of rats only after intraperitoneal administration; phenoxyisopropylamine is a metabolite in dogs. 2-Benzylamino-1-propanol was detected in the urine of rats after intraperitoneal administration, but not after oral administration. /phenoxybenzylamine hydrochloride/
N-Benzyl-N-(p-hydroxyphenoxyisopropyl)amine was identified in the urine of two patients who took 10 mg of phenoxybenzylamine hydrochloride orally daily. /Phenoxybenzylamine Hydrochloride/

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Biological Half-Life
24 hours

The half-life of phenoxybenzylamine may be less than 24 hours. However, because the drug irreversibly inactivates α-adrenergic receptors, the duration of its effect depends not only on the presence of the drug but also on the rate of α-adrenergic receptor synthesis.

Interactions
Inhibition of compensatory vasoconstriction can also exacerbate the hypotensive effects of opioids and other vascular smooth muscle relaxants. Experimental hemorrhagic shock was induced in 50 dogs, and their metabolic status was assessed. Adrenergic blocking with phenoxybenzamide had a protective effect on metabolic status, but required less blood loss to achieve the same degree of hypotension. The best metabolic status was achieved with phenoxybenzamide in combination with propranolol (combined with an adrenergic blocker). Previous phenoxybenzamide use may reduce the pressor response to phenylephrine. Previous phenoxybenzamide use may block the pressor response to methoxyamine, potentially leading to severe hypotension. For more (complete) drug interaction data (11 in total) on phenoxybenzamide, please visit the HSDB record page.

[1]. Urapidil in the preoperative treatment of pheochromocytomas: a safe and cost-effective method. World J Surg. 2013 May;37(5):1141-6.

[2]. Anti-tumor activity of phenoxybenzamine hydrochloride on malignant glioma cells. Tumour Biol. 2016 Mar;37(3):2901-8.

[3]. Phenoxybenzamine is neuroprotective in a rat model of severe traumatic brain injury. Int J Mol Sci. 2014 Jan 20;15(1):1402-17.

According to an independent committee of scientific and health experts, phenoxybenzamine may be carcinogenic. Phenoxybenzamine is an aromatic amine. It is a long-acting alpha-adrenergic antagonist. It has been used to treat hypertension and as a peripheral vasodilator. Phenoxybenzamine is an alpha-adrenergic blocker. The mechanism of action of phenoxybenzamine is as an alpha-adrenergic antagonist. Phenoxybenzamine is a synthetic diphenylmethylamine alpha-adrenergic antagonist with antihypertensive and vasodilatory effects. Phenoxybenzamine non-selectively and irreversibly blocks postsynaptic alpha-adrenergic receptors in smooth muscle, thereby preventing vasoconstriction, relieving vasospasm, and reducing peripheral resistance. Reflex tachycardia may occur, and alpha2 receptor blockade can enhance norepinephrine release, thus exacerbating reflex tachycardia. Phenoxybenzamine is reasonably expected to be a human carcinogen.
Phenoxybenzamine is a long-acting alpha-adrenergic antagonist, previously used to treat hypertension and as a peripheral vasodilator.
See also: Phenoxybenzamine hydrochloride (salt form).
Indications

For the treatment of pheochromocytoma (malignant), benign prostatic hyperplasia, and malignant essential hypertension.
Mechanism of Action

Phenoxybenzamine exerts its therapeutic effect by blocking alpha receptors, leading to muscle relaxation and vasodilation. Vasodilation results in a decrease in blood pressure.
Alpha-adrenergic blockade is due to direct action on alpha-adrenergic receptors, unrelated to any effect on the basic response mechanisms of adrenergic neurons or effector cells.
Non-selective alpha-adrenergic blockade; phenoxybenzamine irreversibly binds to postganglionic alpha-adrenergic receptor sites, thereby preventing or reversing the effects of endogenous or exogenous catecholamines; has no effect on β-adrenergic receptors.
Phenoxybenzamine increases the turnover rate of peripheral norepinephrine, which is associated with increased tyrosine hydroxylase activity. In intact animals, these effects are likely primarily attributed to enhanced sympathetic activity, a reflexive response to alpha-adrenergic blockade, as this effect can be inhibited by ganglion blockers. Phenoxybenzamine also…increases the amount of neurotransmitter released with each nerve impulse. This appears to be due to the blockade of presynaptic α2 receptors, which mediate a negative feedback mechanism that inhibits norepinephrine release.
As the dose of the blocker increases, the dose-response curve of the agonist gradually shifts to the right as the number of available receptors decreases. When the number of functional receptors decreases to the point where the original maximal response cannot be achieved with a full agonist, the dose-response curve no longer shifts to the right; additional receptor blockers now result in inhibition of the maximal response.
For more complete data on the mechanisms of action of phenoxybenzamines (6 in total), please visit the HSDB record page.

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Therapeutic Uses
Adrenergic alpha receptor antagonist; antihypertensive drug; sympathomimetic drug; vasodilator
Previous Uses: Preoperative use of the adrenergic blocker phenoxybenzamine has been shown to improve cardiovascular and renal function associated with prolonged cardiopulmonary bypass after cardiac surgery. It has also been used to reduce renal vasospasm and improve renal perfusion, particularly perfusion of the outer cortical layer, for short-term kidney preservation for transplantation. Phenoxybenzamine can improve the survival rate of renal and hepatic cells during blood flow interruption, and the drug has been shown to improve the survival rate of experimental flaps.
Phenoxybenzamine is indicated for controlling hypertension and hyperhidrosis episodes in the treatment of pheochromocytoma, as a preoperative preparation, for the management of patients with surgical contraindications, and for the long-term management of patients with malignant pheochromocytoma.
Phenoxybenzamine…has been observed to relieve vasospasm in Raynaud's syndrome and reduce its sensitivity to cold. High spinal cord transection often leads to autonomic hyperreflexia, manifested as paroxysmal increases in blood pressure induced by skin and visceral stimuli, especially bladder stimulation. These vasopressor episodes and their associated signs and symptoms have been reported to be effectively controlled with phenoxybenzamide. Alpha-adrenergic blockers have been shown to be beneficial for heart failure with pulmonary edema and acute myocardial infarction, especially when pain exacerbates vasoconstriction. For more complete data on the therapeutic uses of phenoxybenzamide (14 in total), please visit the HSDB record page. Drug Warnings Due to the risk of severe hypotension when using this drug in cases of hypovolemia, intravenous administration must be slow, the patient must be continuously monitored, and blood or appropriate plasma volume expanders must be readily available to correct any volume depletion. Hemodynamic reactions. …Due to its irritant properties, injection should be limited to intravenous administration. /Halogenated alkylamine adrenergic blockers/ Phenoxybenzamide should not be used in patients with compensated congestive heart failure, and should be used with caution in cases of cerebral or coronary artery sclerosis or renal insufficiency. Side effects of phenoxybenzamine include: dry mouth, nasal congestion, drowsiness and fatigue, nausea and vomiting, palpitations, ejaculatory dysfunction, and retrograde ejaculation. Studies indicate that ejaculatory dysfunction is due to the inability of semen to be ejaculated into the posterior urethra, rather than retrograde ejaculation. /Phenoxybenzamine Hydrochloride/

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Pharmacodynamics
Phenoxybenzamine is indicated for controlling hypertension and hyperhidrosis caused by pheochromocytoma. If tachycardia is severe, a beta-blocker may be necessary concurrently. Phenoxybenzamine is a long-acting adrenergic alpha-receptor blocker that, when taken orally, produces and maintains a “chemical sympathectomy.” It increases blood flow to the skin, mucous membranes, and abdominal organs, and lowers blood pressure in both supine and upright positions. It has no effect on the parasympathetic nervous system. Phenoxybenzamine works by blocking alpha receptors at specific sites in the body. Alpha receptors are located in the muscles that lining the walls of blood vessels. When these receptors are blocked by phenoxybenzamine, the muscles relax and the blood vessels dilate. Vasodilation leads to a decrease in blood pressure.

C18H22CLNO

303.83

303.139

59-96-1

Phenoxybenzamine hydrochloride;63-92-3;Phenoxybenzamine-d5 hydrochloride;1329838-45-0;Phenoxybenzamine (benzyl-2,3,4,5,6-d5) (hydrochloride);1398065-71-8;Phenoxybenzamine-d5;1309283-11-1

4768

CRYSTALS FROM PETROLEUM ETHER

1.102g/cm3

381.5ºC at 760mmHg

38-40ºC

184.5ºC

1.559

4.194

0

2

8

21

262

0

C(N(CCCl)C(C)COC1C=CC=CC=1)C1C=CC=CC=1

QZVCTJOXCFMACW-UHFFFAOYSA-N

InChI=1S/C18H22ClNO/c1-16(15-21-18-10-6-3-7-11-18)20(13-12-19)14-17-8-4-2-5-9-17/h2-11,16H,12-15H2,1H3

N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine

Phenoxybenzamine NSC 37448 NSC37448 NSC-37448A688 A 688A-688

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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