1. Previous reports of the effects of alpha 2-adrenoceptor stimulation on gastric secretion are inconsistent because it was not clear whether the compounds were activating alpha 2-adrenoceptors and/or newly described imidazoline receptors. In the present experiments, the effects of moxonidine, an I1-imidazoline receptor agonist and antihypertensive agent, on gastric secretion and on experimental gastric mucosal injury were examined.
2. Moxonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) potently inhibited basal (non-stimulated) gastric acid secretion in conscious rats with an ED50 of 0.04 mg kg-1. Two hours following administration of the highest dose of moxonidine (1.0 mg kg-1), gastric acid output was completely suppressed. Moxonidine also significantly increased intragastric pH, at the two highest doses.
3. The alpha 2-adrenoceptor agonist, clonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) decreased basal acid secretion at the lowest dose (37%) and at the highest dose (46%), while the intermediate dose did not affect gastric acid output.
4. In an ethanol-induced model of gastric mucosal injury, moxonidine decreased the length of lesions at the lowest and highest doses (0.01 and 1.0 mg kg-1) as well as the number of the lesions, at the highest dose (1.0 mg kg-1).
5. In pylorus-ligated rats, moxonidine significantly decreased acid secretion (all doses), total secretory volume (1.0 mg kg-1) as well as pepsin output (1.0 mg kg-1).
6. In comparison to clonidine, moxonidine appears to be a more potent anti-secretory and gastric-protective compound. These data indicate a potential role for imidazoline receptor agonists in the management of gastroduodenal diseases associated with hypertension. The relative contribution of the central and peripheral effects of moxonidine to these gastrointestinal actions remains to be determined.

Gastric acid secretion
Male Sprague-Dawley rats (180 ± 1Og at the start of the study) were implanted with chronic indwelling gastric cannulae as described previously (Pare et al., 1977). After a 14-day recovery period, all cannulae remained firmly attached and produced no untoward effects. Secretory testing in sessions of 3 h occurred in the following sequence: vehicle (saline 1.0 ml kg-'), moxonidine 0.01 mg kg-', 0.1 mg kg-'. 1.0 mg kg-' i.p. and vehicle again. Each of these sessions was separated by a 96 h period. Within each secretory testing session, a baseline collection was followed by the injection (i.p.) of the vehicle or moxonidine and two subsequent post treatment collections. Thus, each animal served as its own control and all drug treatments were preceded by a 1 h baseline collection period in which no injection occurred. All drug treatments were both preceded and followed by vehicle injections. The volume of secretion was recorded and aliquots of each sample were titrated to pH 7.0 with 0.01 M NaOH in a Mettler DL-21 autotitrator. The results are expressed as limol h-'. For purposes of comparison, other animals were prepared as described above, but given vehicle and clonidine at doses of 0.01, 0.1 and 1.0mgkg-' i.p. as described as above.
Ethanol-induced gastric mucosal injury
Rats (n = 5 per group) were randomly assigned to treatment conditions. They were deprived of food, but not water, for 24 h prior to being given 1.0 ml of 75% (v/v) ethyl alcohol (Canadian Industrial Alcohols and Chemicals Ltd., Corbyville, Ontario, Canada) p.o. by gavage (Robert et al., 1979). Vehicle or moxonidine at doses of 0.01, 0.1, or 1.0mg kg-' was given i.p. 5 min prior to ethanol. Following ethanol and drug treatment, rats were returned to individual cages without food or water for 2 h, after which time they were killed by cervical dislocation. The stomachs were removed, everted, washed and fixed in 10% (v/v) buffered formalin and the number and cumulative length (in millimeters) of gastric glandular mucosal injury determined under a dissecting microscope with an ocular micrometer by a treatment-'blinded' observer.

Absorption, Distribution and Excretion
90% of an oral dose is absorbed with negligible interference from food intake or first pass metabolism, resulting in a high bioavailability of 88%.
Elimination is nearly entirely via the kidneys with a majority (50 -75%) of overall moxonidine being eliminated unchanged through renal excretion. Ultimately, more than 90% of a dose is eliminated by way of the kidneys within the first 24 hours after administration, with only approximately 1% being eliminiated via faeces.
1.8±0.4L/kg.
Administered twice daily due to short half life. However, lower dosage adjustments and close monitoring is necessary in elderly and renal impairment patients due to reduced clearance. In particular, the exposure AUC can increase by about 50% following a single dose and at steady state in elderly patients and moderately impaired renal function with GFR between 30-60 mL/min can cause AUC increases by 85% and decreases in clearence to 52 %.

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Metabolism / Metabolites
Biotransformation is unimportant with 10-20% of moxonidine undergoing oxidation reactions to the primary 4,5-dehydromoxonidine metabolite and a guanidine derivative by opening of the imidazoline ring. The antihypertensive effects of these 4,5-dehydromoxonidine and guanidine metabolites are only 1/10 and 1/100 the effect of moxonidine. Oxidation on either the methyl group (pyrimidine ring) or on the imidazole ring of moxonidine results in the formation of the hydroxylmethyl moxonidine metabolite or the hydroxy moxonidine metabolite. The hydroxy moxonidine metabolite can be further oxidized to the dihydroxy metabolite or it can lose water to form the dehydrogenated moxonidine metabolite, which itself can be further oxidized to form an N-oxide. Aside from these Phase I metabolites, Phase II metabolism of moxonidine is also evident with the presence of a cysteine conjugate metabolite minus chlorine. Nevertheless, the identification of the hydroxy moxonidine metabolite with a high level of dehydrogenated moxonidine metabolite in human urine samples suggests that dehydrogenation from the hydroxy metabolite to the dehydrogenated moxonidine metabolite represents the primary metabolic pathway in humans. The cytochromes P450 responsible for the metabolism of moxonidine in humans have not yet been determined. Ultimately, the parent moxonidine compound was observed to be the most abundant component in different biological matrices of urinary excretion samples, verifying that metabolism only plays a modest role in the clearance of moxonidine in humans.

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Biological Half-Life
Plasma elimination half life is 2.2 - 2.3 hours while renal elimination half life is 2.6-2.8 hours.

Protein Binding
About 10% of moxonidine is bound to plasma proteins.

J Cardiovasc Pharmacol.2004Feb;43(2):306-11;J Hum Hypertens.1997 Oct;11(10):629-35;Br J Pharmacol.1995 Feb;114(4):751-4.

Moxonidine is an organohalogen compound and a member of pyrimidines.
Moxonidine is a new-generation centrally acting antihypertensive drug approved for the treatment of mild to moderate essential hypertension. It is suggested to be effective in cases where other agents such as thiazides, beta-blockers, ACE inhibitors, and calcium channel blockers are not appropriate or irresponsive. As well, moxonidine has been shown to present blood pressure-independent beneficial effects on insulin resistance syndrome.

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Drug Indication
For the treatment of mild to moderate essential or primary hypertension. Effective as most first-line antihypertensives when used as monotherapy.
FDA Label
Treatment of hypertension

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Mechanism of Action
Stimulation of central alpha 2-adrenergic receptors is associated with sympathoadrenal suppression and subsequent reduction of blood pressure. As this class was further explored it was discovered that sympathoadrenal activity can also be suppressed by a second pathway with a newly discovered drug target specific to imidazolines. Specifically, moxonidine binds the imidazoline receptor subtype 1 (I1) and to a lesser extent αlpha-2-adrenoreceptors in the RSV causing a reduction of sympathetic activity, reducing systemic vascular resistance and thus arterial blood pressure. Moreover, since alpha-2-adrenergic receptors are considered the primary molecular target that facilitates the most common side effects of sedation and dry mouth that are elicited by most centrally acting antihypertensives, moxonidine differs from these other centrally acting antihypertensives by demonstrating only low affinity for central alpha-2-adrenoceptors compared to the aforementioned I1-imidazoline receptors.

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Pharmacodynamics
Antihypertensive agent whose site of action is the Central Nervous System (CNS), specifically involving interactions with I1- imidazoline and alpha-2-adrenergic rececptors within the rostral ventrolateral medulla (RSV).

C9H12CLN5O

241.68

241.073

75438-57-2

Moxonidine hydrochloride;75536-04-8;Moxonidine-d4;1794811-52-1

4810

Typically exists as solid at room temperature

1.5±0.1 g/cm3

364.7±52.0 °C at 760 mmHg

40-43 °C(lit.)

174.3±30.7 °C

0.0±0.8 mmHg at 25°C

1.681

0.84

2

4

3

16

275

0

CC1=NC(OC)=C(NC2=NCCN2)C(Cl)=N1

WPNJAUFVNXKLIM-UHFFFAOYSA-N

InChI=1S/C9H12ClN5O/c1-5-13-7(10)6(8(14-5)16-2)15-9-11-3-4-12-9/h3-4H2,1-2H3,(H2,11,12,15)

4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methylpyrimidin-5-amine

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)

Solubility in Formulation 1: ≥ 2 mg/mL (8.28 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 20.0 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 mg/mL (8.28 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 20.0 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 mg/mL (8.28 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 20.0 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.)