α2a-adrenergic receptor ( pEC50 = 8.25 ); α2b-adrenergic receptor ( pEC50 = 7.01 ); α2c-adrenergic receptor ( pEC50 < 5 )

Guanabenz administered intravenously (i.v.) at doses of 0.1 mg/kg induces a rise in blood pressure that lasts for a while before decreasing cardiac output, contractile force, and heart rate in dogs that have been put to sleep. This effect depends on the presence of sympathetic tone. Guanabenz inhibits the pressor response to different procedures that cause the general sympathetic nervous system to fire. Additionally, guanabenz opposes reactions triggered by sympathetic nerve stimulation[4]. Injecting guanabenz at doses up to 0.5 mg/kg causes a reduction in heart rate and blood pressure in rats and dogs with hypertension who are not under anesthesia[5].

Absorption, Distribution and Excretion
Guanabenz undergoes extensive first-pass hepatic metabolism. Its elimination half-life is 7-14 hr, and its renal clearance is 0.09-0.131 l/min. Less than 2% is excreted unchanged in the urine. About 80% of a dose is excreted in urine in the first 24 hr.
Following oral administration, at least 70-80% of a dose of guanabenz acetate is absorbed. The effect of food on the absorption of guanabenz acetate has not been determined. Following oral administration of the drug in fasting individuals, peak plasma guanabenz concentrations usually occur within 2-5 hr. Following a single 16 mg oral dose, peak plasma guanabenz concentrations average 2.4-2.7 ng/ml (range: 1.2-5.2 ng/ml) in fasting healthy individuals and 7.8 ng/ml (range: 3-16 ng/ml) in fasting individuals with hepatic impairment (chronic alcohol-induced liver disease). ... Such alterations in these patients may result from enhanced oral bioavailability (secondary to portosystemic shunting and/or decreased intrinsic clearance) and decreased hepatic clearance of guanabenz.
The hypotensive effect of guanabenz acetate begins within 1 hr after oral administration and peaks within 2-7 hr. The duration of hypotensive effect is variable; the manufacturer states that the hypotensive effect is substantially diminished within 6-8 hr and that blood pressure returns to baseline values within 12 hr; however, the hypotensive effect of a single dose can persist for 12 or more hr.
Information on the distribution of guanabenz is limited. Following iv administration in rats, guanabenz is rapidly and extensively distributed into the CNS; brain concentrations of the drug are 3-70 times higher than concurrent plasma concentrations. In humans, guanabenz appears to be extensively distributed. The apparent steady state volume of distribution of guanabenz averages approximately 93 and 147 l/kg after 16 and 32 mg oral doses, respectively. The apparent volume of distribution of guanabenz appears to be substantially decreased in patients with hepatic impairment.
For more Absorption, Distribution and Excretion (Complete) data for GUANABENZ ACETATE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Guanabenz is extensively metabolized. The site(s) of guanabenz metabolism has not been determined, but the drug probably undergoes extensive firstpass metabolism. Guanabenz is metabolized principally by hydroxylation to form (E)-p-hydroxyguanabenz (4-hydroxyguanabenz), which is largely conjugated with glucuronic acid. A small fraction of guanabenz is cleaved at the benzal carbon to form 2,6-dichlorobenzyl alcohol, which is apparently completely conjugated. A small fraction of guanabenz also apparently undergoes N-glucuronidation. Other minor metabolites include (Z)-guanabenz and possibly (Z)-p-hydroxyguanabenz (Z-isomer of 4-hydroxyguanabenz); these metabolites are apparently almost completely conjugated. Numerous other, unidentified metabolites are also formed. The (Z)-isomer of guanabenz appears to have about 25% of the hypotensive activity of the unchanged drug following oral administration. Animal studies indicate that (E)-p-hydroxyguanabenz is inactive following oral administration but produces a slight hypotensive effect following intraperitoneal administration of large doses. Other metabolites of guanabenz are inactive.
About 10% of an oral dose of guanabenz is excreted in urine as (E)-p-hydroxyguanabenz, 25% as the glucuronide conjugate of (E)-p-hydroxyguanabenz, 1% as unchanged guanabenz, 5% as guanabenz conjugates, 1% as (Z)-guanabenz, 1% as (Z)guanabenz conjugates, less than 1% possibly as (Z)-p-hydroxyguanabenz, 2% as (Z)-p-hydroxyguanabenz conjugates, 2% as 2,6-dichlorobenzyl alcohol conjugates, and the remainder as unidentified metabolites and their conjugates.

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Biological Half-Life
The elimination half-life of guanabenz following single oral doses of the drug in healthy adults has been variably reported to average 4-14 hr (range: 3.5-21 hr); In one well-designed study, the elimination half-life averaged 12-14 hr. In patients with hepatic impairment, the half-life of the drug is only slightly prolonged. The elimination half-life of guanabenz also may be prolonged in patients with renal impairment.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of guanabenz during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
Additive CNS depression may occur when guanabenz is administered concomitantly with other CNS depressants including alcohol, phenothiazines, barbiturates, or benzodiazepines.
When guanabenz is administered with other hypotensive agents, including diuretics, the hypotensive effect of guanabenz may be increased.
Guanabenz, administered concurrently with antidiabetic agents (eg, insulin, chlorpropramide), does not appear to interfere with the control of blood glucose concentration.

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Non-Human Toxicity Values
LD50 Rat oral 126 mg/kg
LD50 Mouse oral 150 mg/kg

[1]. Biochem Pharmacol . 1998 Apr 1;55(7):1035-43.

[2]. J Biol Chem . 2000 Jan 28;275(4):2376-80.

[3]. PLoS One . 2008 Apr 23;3(4):e1981.

[4]. J Pharmacol Exp Ther . 1970 Feb;171(2):276-87.

[5]. Experientia . 1969 Oct 15;25(10):1066-7.

Guanabenz acetate is a dichlorobenzene. It has a role as a geroprotector.
Guanabenz Acetate is the orally bioavailable, acetate salt form of guanabenz, a centrally-acting alpha-2 adrenergic receptor agonist, with anti-hypertensive and potential antineoplastic, cytoprotective and bone resorption inhibitory activities. Upon oral administration, guanabenz suppresses endoplasmic reticulum (ER) stress by inhibiting the stress-induced dephosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2a), thereby enhancing the phosphorylation level of eIF2a. This causes elF2a-mediated downregulation of the Rac1 pathway, upregulates the expression of activating transcription factor 4 (ATF4), which plays a key role in osteoblastogenesis, and downregulates the expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), which is a transcription factor that plays a key role in osteoclastogenesis. This enhances osteoblastogenesis and suppresses osteoclastogenesis. Altogether, this promotes new bone formation and prevents bone degradation. In addition, guanabenz blocks the proliferation, survival, motility and invasiveness of tumor cells through the eIF2a-mediated downregulation of Rac1 signaling. Rac1, a Ras-related small GTPase belonging to the Rho family, plays a key role in tumor cell proliferation, survival and motility.
An alpha-2 selective adrenergic agonist used as an antihypertensive agent.
See also: Guanabenz (has active moiety).

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Mechanism of Action
Guanabenz is a central alpha 2-adrenoreceptor agonist. Its antihypertensive action appears to result from a decrease in sympathetic outflow from the brain to the peripheral circulatory system following stimulation of central alpha 2-adrenoreceptors. Peripherally it has a presynaptic alpha-receptor stimulant action and a guanethidinelike neuron-blocking action. There does not appear to be a physical dependence liability of the morphine type.
The affinity of guanabenz for the alpha2-adrenergic receptor is greater than that for the alpha1-adrenergic receptor. The central effects of the drug in the lower brain stem result in reduced peripheral sympathetic activity and a reduction in systolic and diastolic blood pressure. Following iv or oral administration of guanabenz in animals, an initial hypertensive response to the drug occurs and is caused by direct peripheral alpha2-adrenergic stimulated vasoconstriction; however, oral guanabenz usually does not produce an initial increase in blood pressure in hypertensive patients. Guanabenz induced bradycardia appears to result principally from central alpha2-agonist effects, although a peripheral alpha2-agonist effect on the heart may also be involved. In animals, guanabenz induced bradycardia results from inhibition of sympathetic nervous system activity and activation of cholinergic nervous system activity. Although guanabenz is not a true adrenergic blocking agent, the drug produces some postganglionic alpha (similar to guanethidine) and beta-adrenergic blockade and decreases the response to peripheral sympathetic nerve stimulation in animals. Cardiac output, left ventricular ejection fraction, and left ventricular stroke volume remain unchanged during long term therapy with the drug.

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Therapeutic Uses
Adrenergic alpha-Agonists; Antihypertensive Agents; Sympatholytics
Guanabenz is used in the management of hypertension. The efficacy of guanabenz in hypertensive patients is similar to that of other adrenergic inhibitors such as clonidine, methyldopa, or beta-adrenergic blocking agents (eg, pindolol, propranolol).
Guanabenz may be particularly useful in hypertensive patients whose baseline catecholamine concentrations are markedly elevated and whose hypertension is characterized by increased sympathetic activity. The drug may also be useful in the treatment of hypertension that is predominantly of the systolic form, commonly occurring in patients 60 years of age and older. Because guanabenz does not appear to induce sodium retention, the drug is useful in patients who develop secondary renal or cardiac induced sodium retention during therapy with clonidine or methyldopa. Guanabenz has been used in diabetic hypertensive patients with no adverse effect on control or therapy of diabetes; the drug has also been effective in hypertensive patients with chronic obstructive pulmonary disease, including asthma, chronic bronchitis, or emphysema. As with other hypotensive agents, treatment with guanabenz is not curative; after withdrawal of the drug, blood pressure returns to pretreatment levels or greater.
Guanabenz has been used alone or in combination with naltrexone in the management of opiate withdrawal in patients physically dependent on opiates and undergoing detoxification. Guanabenz has also been used as an analgesic in a limited number of patients with chronic pain; use of the drug permitted a reduction in opiate dosage or discontinuance of opiate therapy in these patients, but additional study is necessary. /Use is not currently included in the labeling approved by the FDA/
For more Therapeutic Uses (Complete) data for GUANABENZ ACETATE (6 total), please visit the HSDB record page.

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Drug Warnings
Because of the risk of rebound or "overshoot" hypertension, patients receiving guanabenz should be warned of the danger of missing doses or stopping the drug without consulting their physician. When guanabenz therapy must be interrupted for surgery, the drug should be discontinued slowly over several days, if possible, to avoid precipitating the withdrawal syndrome. If necessary, parenteral hypotensive therapy should be administered throughout the period that oral medication cannot be given; oral guanabenz should be resumed as soon as possible.
Guanabenz should be used with caution and blood pressure monitored carefully in patients with hepatic and/or renal impairment, since the pharmacokinetics of the drug may be altered in such patients. The drug also should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, and/or cerebrovascular disease. Guanabenz should also be used with caution in geriatric patients since they may be more sensitive to the hypotensive and sedative effects of the drug.
Because of the potential sedative effect of guanabenz, patients should be warned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (eg, operating machinery, driving a motor vehicle). Additive CNS depression may occur when guanabenz is administered concomitantly with other CNS depressants including alcohol, phenothiazines, barbiturates, or benzodiazepines, and patients should be warned that their tolerance for CNS depressants may be decreased.
Although guanabenz has been used in the management of hypertension in a limited number of children 12 yr of age and older, further study on the use of the drug in these patients is necessary. Safety and efficacy of guanabenz in children younger than 12 yr of age have not been established; therefore, the manufacturer does not recommend use of the drug in these children.
For more Drug Warnings (Complete) data for GUANABENZ ACETATE (12 total), please visit the HSDB record page.

C10H12CL2N4O2

291.13

290.034

C, 41.26; H, 4.15; Cl, 24.35; N, 19.24; O, 10.99

23256-50-0

23256-50-0 (acetate); 5051-62-7

5702062

White to off-white solid powder

405.7ºC at 760 mmHg

227-229ºC (decomposition)

199.1ºC

8.63E-07mmHg at 25°C

3.092

3

4

2

18

259

0

ClC1C([H])=C([H])C([H])=C(C=1/C(/[H])=N/N=C(\N([H])[H])/N([H])[H])Cl.O([H])C(C([H])([H])[H])=O

MCSPBPXATWBACD-GAYQJXMFSA-N

InChI=1S/C8H8Cl2N4.C2H4O2/c9-6-2-1-3-7(10)5(6)4-13-14-8(11)12;1-2(3)4/h1-4H,(H4,11,12,14);1H3,(H,3,4)/b13-4+;

acetic acid;2-[(E)-(2,6-dichlorophenyl)methylideneamino]guanidine

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 (8.59 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 (8.59 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 (8.59 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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Solubility in Formulation 4: 4% DMSO +30%PEG 300 +ddH2O: 5mg/mL

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