Absorption, Distribution and Excretion
Guanadrel sulfate is rapidly and almost completely absorbed following oral administration. Peak plasma concentrations usually are achieved 1.5-2 hr after oral administration. The hypotensive effect of guanadrel sulfate usually has an onset of 0.5-2 hrs, peaks at 4-6 hr, and persists for 4-14 hr.
Approximately 20% of guanadrel is bound to plasma proteins over a wide concentration range. The drug is widely distributed into most body tissues and fluids. Little, if any, of the drug crosses the blood-brain barrier or distributes into the eye. It is not known whether guanadrel is distributed into milk or crosses the placenta in humans. The drug has been shown to cross the placenta in small concentrations in mice
Guanadrel is cleared from the body by both renal and nonrenal disposition. Its elimination is impaired in patients with renal insufficiency; total-body clearance was reduced by 4- to 5-fold in a group of patients with a clearance of creatinine averaging 13 ml per minute.
Approximately 40-50% of the drug is metabolized in the liver ... . Guanadrel and its metabolites are excreted principally in urine. Approximately 85% of an oral dose of the drug is excreted in urine within 24 hrs; 40-50% of the dose is excreted in urine unchanged.

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Metabolism / Metabolites
Approximately 40-50% of the drug is metabolized in the liver to 2,3-dihydroxypropylguanidine and several unidentified metabolites. The hypotensive activity of the metabolites is not known.

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Biological Half-Life
Plasma concentrations of guanadrel appear to decline in a biphasic manner. There is considerable interindividual variation in plasma half-life of the drug. In patients with normal renal function, guanadrel has a plasma half-life in the initial phase of about 2 hr (range: 1-4) and an elimination half-life of about 10-12 hr (range: 5-45).

Interactions
Tricyclic antidepressants, phenothiazines, and indirect-acting sympathomimetics (eg, ephedrine, phenylpropanolamine) may block the uptake of guanadrel into adrenergic neurons or reverse the hypotensive effect of guanadrel. Ephedrine has been shown to rapidly reverse the pharmacologic effects of guanadrel. Guanadrel may potentiate the pharmacologic activity of direct-acting sympathomimetic agents such as norepinephrine or phenylephrine.
Monoamine oxidase inhibitors reportedly antagonize the hypotensive effect of guanadrel; ... guanadrel is contraindicated in patients receiving MAO inhibitors and that these drugs should be discontinued for at least 1 week prior to administration of guanadrel.
Vasopressors should be administered with caution since guanadrel may enhance the pressor and arrhythmogenic responses to these drugs.
Caution should be exercised when tricyclic antidepressant therapy is discontinued in patients receiving guanadrel, particularly if discontinuance of the antidepressant is abrupt, since enhanced clinical effects (e.g., hypotension) of guanadrel may occur. Because many nonprescription cold, allergy, and asthma preparations contain sympathomimetic agents, patients receiving guanadrel should be warned not to use these preparations for self-medication unless first consulting with their physician or pharmacist.
For more Interactions (Complete) data for GUANADREL SULFATE (6 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 2220 mg/kg
LD50 Rat iv 26 mg/kg
LD50 Dog oral 225 mg/kg
LD50 Dog iv 45 mg/kg
For more Non-Human Toxicity Values (Complete) data for GUANADREL SULFATE (6 total), please visit the HSDB record page.

Guanadrel sulfate is an organic sulfate salt resulting from the reaction of 2 eq. guanadrel with 1 eq. sulfuric acid. A postganglionic adrenergic blocking agent formerly used for the management of hypertension, it has been largely superseded by other drugs less likely to cause orthostatic hypotension (dizzy spells on standing up or stretching). It has a role as an adrenergic antagonist and an antihypertensive agent. It contains a guanadrel(1+).
See also: Guanadrel (has active moiety).

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Mechanism of Action
Guanadrel is targeted uniquely to the peripheral adrenergic neuron, where it inhibits sympathetic function. The drug reaches its site of action by active transport into the neuron by the same transporter that is responsible for the reuptake of norephinephrine. In the neuron, guanadrel is concentrated within the neurosecretory vesicles, where it replaces norepinephrine. During chronic administration, guanadrel acts as a "substitute neurotransmitter," in that it is present in storage vesicles, it depletes the normal transmitter, and it can be released by stimuli that normally release norepinephrine. This replacement of norephinephrine with an inactive transmitter is probably the principal mechanism of its neuron-blocking action.
Guanadrel sulfate, like guanethidine, produces a selective block of efferent, peripheral sympathetic pathways. The drug depletes norepinephrine stores from adrenergic nerve endings and, unlike guanethidine, from the adrenal medulla; guanadrel also prevents the release of norepinephrine from adrenergic nerve endings in response to sympathetic nerve stimulation. Guanadrel reportedly depletes norepinephrine stores in the GI tract to a lesser extent than does guanethidine. Chronic administration of guanadrel results in an increased sensitivity of effector cells to catecholamines. Following oral administration of guanadrel, depletion of catecholamine stores produces a fall in blood pressure which usually, but not always, is accompanied by a 5 to 10 beat/min reduction in heart rate. Venous dilation and peripheral pooling of blood may cause a slight decrease or no change in cardiac output. Total peripheral resistance usually is decreased slightly.

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Therapeutic Uses
Antihypertensive Agents
Eleven patients with Graves' disease were treated with guanadrel sulfate and observed for changes in neuromuscular and cardiovascular manifestations. No notable changes in pulse rate or muscle strength were detected in either these patients during a 3-day pretreatment period or in 5 control patients with Graves' disease receiving placebo for 6 days. Thyroid hormone levels were not altered by 7 days of guanadrel sulfate therapy..., and no adverse side effects were encountered. Mean supine resting pulse fell from 102 +/- 6 (mean +/- SEM) to 90 +/- 3 beats/min (P<0.02). The patients' proximal and distal muscle strengths were initially decreased, when compared with healthy subjects, and improved substantially with guanadrel therapy. We conclude that guanadrel sulfate may be useful in the symptomatic management of patients with thyrotoxicosis.
Because of the availability of a number of drugs that lower blood pressure without producing orthostatic hypotension, guanadrel is not employed in the monotherapy of hypertension, and is used chiefly as an additional agent in patients who have not achieved a satisfactory antihypertensive effect on two or more other agents.

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Drug Warnings
Patients and clinicians should be aware of the possibility of marked guanadrel induced orthostatic hypotension and its consequences of dizziness, weakness, and fainting. Clinicians should monitor both erect and supine blood pressures, as supine blood pressures alone may not reveal the possibility of orthostatic hypotension. Patients should be cautioned to avoid sudden or prolonged standing (especially in the morning) or exercise and should be advised of measures to take if dizziness or weakness occurs (eg, lying or sitting down). A hot environment, alcohol ingestion, or fever may aggravate postural hypotension. Because of the risk of orthostatic hypotension, the drug should be used cautiously in geriatric patients. Geriatric patients may be more sensitive to sympathetic inhibition than younger patients, because they frequently have impaired cardiovascular reflexes, making them more susceptible to hypotension.
Guanadrel should be used cautiously in patients with bronchial asthma, since asthma may be aggravated by catecholamine depletion in these patients and because sympathomimetic amines used in the treatment of asthma may interfere with the hypotensive effect of guanadrel. The drug also should be used with caution in patients with peptic ulcer disease, as this condition may be aggravated by a guanadrel induced relative increase in parasympathetic tone.
Guanadrel therapy should be discontinued 2-3 days prior to elective surgery to reduce the possibility of cardiovascular collapse and cardiac arrest during anesthesia. If emergency surgery is necessary, the anesthesiologist should be advised that the patient is receiving the drug and preanesthetic and anesthetic agents should be administered cautiously and in reduced dosage. Vasopressors should be administered with caution since guanadrel may enhance the pressor and arrhythmogenic responses to these drugs.
Guanadrel should be used with caution in patients who may be adversely affected by sodium and water retention; however, concomitant use of a diuretic will usually overcome this effect.
For more Drug Warnings (Complete) data for GUANADREL SULFATE (19 total), please visit the HSDB record page.

C10H21N3O6S

311.35524

311.115

22195-34-2

40580-59-4 (Parent)

68552

White to off-white crystalline powder
Crystals from methanol/ethanol

1.39 g/cm3

387.9ºC at 760 mmHg

235ºC

188.4ºC

1.618

2.164

6

10

4

35

326

0

C1CCC2(CC1)OCC(CNC(=N)N)O2.C1CCC2(CC1)OCC(CNC(=N)N)O2.OS(=O)(=O)O

RTEVGQJRTFFMLL-UHFFFAOYSA-N

InChI=1S/2C10H19N3O2.H2O4S/c2*11-9(12)13-6-8-7-14-10(15-8)4-2-1-3-5-10;1-5(2,3)4/h2*8H,1-7H2,(H4,11,12,13);(H2,1,2,3,4)

2-(1,4-dioxaspiro[4.5]decan-3-ylmethyl)guanidine;sulfuric acid

Guanadrel Sulfate Hyloride Hylorel

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.)