mAChR3/muscarinic acetylcholine receptor

The morphology and viability of human corneal stromal (HCS) cells were assessed using light microscopy and the MTT assay, respectively, in order to assess the cytotoxicity of pilocarpine. HCS cells exposed to pilocarpine at concentrations ranging from 0.625 to 20 g/L exhibited morphological abnormalities, including cell shrinkage, cytoplasmic vacuolization, detachment from the culture matrix, and eventual death, as well as dose- and time-dependent proliferation retardation. At concentrations lower than 0.625 g/L, however, no discernible difference was found between the pilocarpine exposure group and the control group. The MTT assay results demonstrated that HCS cell viability decreased with increasing time and concentration following treatment with pilocarpine at a concentration greater than 0.625 g/L (P<0.01 or 0.05), whereas cell viability of HCS cells treated with pilocarpine at a concentration lower than 0.625 decreased with increasing time and concentration (P<0.01 or 0.05). g/L did not change appreciably from the control [2]. In isolated segments of rat tail arteries constricted with norepinephrine (10 to 200 nM), the partial muscarinic agonist pilocarpine elicits concentration-dependent relaxation with an EC50 of 2.4 mM [3].

The effects of pilocarpine on salivation were investigated in exercised (EX) and control (CN) rats. Saliva volume caused by pilocarpine was considerably higher in EX rats compared to CN rats (P<0.01). Conversely, EX rats' saliva had a considerably lower Na+ content than CN rats' (P<0.05)[1].

After HCS cells were treated with pilocarpine at a concentration from 0.15625 g/L to 20.0 g/L, their morphology and viability were detected by light microscopy and MTT assay. The membrane permeability, DNA fragmentation and ultrastructure were examined by acridine orange (AO)/ethidium bromide (EB) double-staining. DNA electrophoresis and transmission electron microscopy (TEM), cell cycle, phosphatidylserine (PS) orientation and mitochondrial transmembrane potential (MTP) were assayed by flow cytometry (FCM). And the activation of caspases was checked by ELISA[3].

0.5 mg/kg; i.p. Rats: Male, 10-week-old Wistar rats are assigned to one of two groups, exercise (EX, n=6) and control (CN, n=6). The EX rats are kept for 40 days in cages with a running wheel (SN-451), allowing them to undertake voluntary exercise, while the CN rats are kept in cages with the running wheel locked. On the 40th day, Pilocarpine-induced saliva is measured as follows. Briefly, the rats are anesthetized, preweighed cotton was placed in their mouths sublingually, and Pilocarpine (0.5 mg/kg) is intraperitoneally injected to induce saliva secretion. Each cotton ball is then changed every 10 min for 1 h. The collected cotton balls are weighed again, and the mass of saliva secreted is calculated by subtracting the initial from the final weight.

Absorption, Distribution and Excretion
In healthy male subjects, after oral administration of 5 mg pilocarpine three times daily, the peak plasma concentration reached 15 μg/L after 1.25 hours. After oral administration of 10 mg pilocarpine three times daily, the peak plasma concentration reached 41 μg/L after 0.85 hours. Co-administration with food accelerates absorption. In healthy subjects, the overall median time to peak concentration (Tmax) after ocular administration was 2.2 hours. The mean (standard deviation) Cmax and AUC0-t were 897.2 (287.2) pg/mL and 2699 (741.4) hr × pg/mL, respectively. In patients with presbyopia, the mean Cmax and AUC0-t,ss values were 1.95 ng/mL and 4.14 ng × hr/mL, respectively. The median time to peak concentration (Tmax) after administration was 0.3 hours, ranging from 0.2 to 0.5 hours. Pilocarpine and its degradation products are mainly excreted in urine. No relevant information is available. No relevant information is available. There is currently no definitive information regarding the metabolism and excretion of pilocarpine. It is partially destroyed in the body, but most of it is excreted in urine in conjugated form. Pilocarpine can penetrate the eyes well; after topical eye drops… Poisoning due to skin absorption has been reported. Metabolites/Metabolites Limited information is available regarding the metabolism of pilocarpine in the human body. Inactivation of pilocarpine may occur at neuronal synapses or in the plasma. It has been reported that pilocarpine undergoes a CYP2A6-mediated 3-hydroxylation reaction to produce the stereoisomer of 3-hydroxypilocarpine. Pilocarpine can also be hydrolyzed in plasma and human liver by paraoxonase 1 (a calcium-dependent esterase). Pilocarpine acid may be a metabolite of this hydrolysis. It has been reported that the metabolites of pilocarpine have little or no pharmacological activity. Known metabolites of pilocarpine include 3-hydroxypilocarpine. It may occur at neuronal synapses and in plasma. Half-life: 0.76 hours. Following three daily doses of 5 mg or 10 mg, the elimination half-lives are 0.76 hours and 1.35 hours, respectively. After ocular administration in healthy subjects, the half-life is 3.96 hours.

Toxicity Summary
Pilocarpine is a cholinergic parasympathomimetic drug. It primarily works by stimulating muscarinic receptors, increasing exocrine gland secretion, and causing contraction of the iris sphincter and ciliary muscle (when applied topically). Hepatotoxicity
Elevated serum enzyme levels were uncommon in clinical trials of pilocarpine, and the incidence was not significantly different from the placebo group. Although pilocarpine is widely used, there are no published reports of acute liver injury caused by pilocarpine.

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Effects During Pregnancy and Lactation
◉ Use During Lactation Overview Limited information suggests that maternal use of ophthalmic pilocarpine does not have adverse effects on breastfed infants. If ophthalmic pilocarpine is used during lactation, the infant should be closely monitored for signs of cholinergic overdose (diarrhea, lacrimation, excessive salivation, or excessive urination), especially in younger exclusively breastfed infants. To significantly reduce the amount of medication entering breast milk after using eye drops, press the tear duct near the corner of the eye for at least 1 minute, then blot away excess medication with absorbent tissue.
Since there is currently no information on the use of oral pilocarpine during breastfeeding, it may be more preferable to choose other medications, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
A woman with glaucoma used pilocarpine implant (Ocusert; dosage not specified) in one eye during 9 weeks of breastfeeding (breastfeeding time not specified). No adverse reactions were observed in the infant. [1]
A mother used pilocarpine eye drops (concentration not specified) twice daily, 2 drops of 0.5% timolol eye drops twice daily, and 250 mg of acetazolamide orally twice daily, and was born prematurely at 36 weeks of gestation. The infant was exclusively breastfed for 5 months starting 6 hours after birth. On the second day after birth, the infant developed electrolyte disturbances, manifested as hypocalcemia, hypomagnesemia, and metabolic acidosis. The infant received oral calcium gluconate and a single intramuscular injection of magnesium sulfate. Despite continued breastfeeding and maternal medication, the infant’s mild metabolic acidosis resolved on day 4 after birth and he gained weight normally at 1, 3 and 8 months, but had mild hypotonia. The authors believe that these metabolic disturbances were caused by acetazolamide transplacental transport and eventually subsided despite breastfeeding. The infant gained weight normally during breastfeeding but had mild residual hypertonia in the lower extremities, requiring physical therapy. [2] ◉ Effects on lactation and breast milk As of the revision date, no published information was found on lactating mothers. In animal studies, cholinergic drugs increased oxytocin release [3] and had varying effects on serum prolactin. [4] Other centrally acting cholinergic drugs increased serum prolactin levels in humans. [5][6] Prolactin levels in established lactating mothers may not affect their ability to breastfeed.

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Protein Binding
Pilocarpine does not bind to human or rat plasma proteins in the concentration range of 5 to 25,000 ng/mL. The effect of pilocarpine on the plasma protein binding of other drugs has not been evaluated.

[1]. Matsuzaki K, et al. Daily voluntary exercise enhances pilocarpine-induced saliva secretion and aquaporin 1 expression in rat submandibular glands. FEBS Open Bio. 2017 Dec 7;8(1):85-93.
[2]. Tonta MA, et al. Pilocarpine-induced relaxation of rat tail artery by a non-cholinergic mechanism and in the absence of an intact endothelium. Br J Pharmacol. 1994 Jun;112(2):525-32.
[3]. Yuan XL, et al. Cytotoxicity of pilocarpine to human corneal stromal cells and its underlying cytotoxic mechanisms. Int J Ophthalmol. 2016 Apr 18;9(4):505-11.
[4]. Wang RF, et al. Post-treatment with the GLP-1 analogue liraglutide alleviate chronic inflammation and mitochondrial stress induced by Status epilepticus. Epilepsy Res. 2018 Mar 9;142:45-52.

Therapeutic Uses
Pilocarpine; muscarinic receptor agonist; parasympathomimetic agent. Pilocarpine is used to treat glaucoma… It can also be formulated as an ointment or tablet. …The miotic effect of pilocarpine helps overcome mydriasis caused by atropine; it can be used alternately with mydriatics… It is used to separate adhesions between the iris and lens. Pilocarpine is better tolerated than any other miotic. /Hydrochloride/ Pilocarpine is the miotic of choice for initial and maintenance treatment of primary open-angle glaucoma and most other chronic glaucoma. …For emergency treatment of acute angle-closure glaucoma. For more complete data on the therapeutic uses of pilocarpine (6 types), please visit the HSDB record page.

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Drug Warning
/Pilocarpine/...should not be used for extended periods in such cases to avoid or postpone iridectomy, as any miotic agent can cause pupillary constriction, impeding the flow of aqueous humor through the pupil.

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Pharmacodynamics
Pilocarpine is a muscarinic drug with diaphoretic, miotic, and central nervous system effects. Pilocarpine can stimulate the secretion of various exocrine glands, such as sweat glands, lacrimal glands, salivary glands, and gastrointestinal glands. After oral administration of pilocarpine, the mean salivary flow rate increases 2 to 10 times compared to the placebo group, and its peak concentration is maintained for at least 1 to 2 hours. Pilocarpine can increase smooth muscle tone, constrict the pupil and iris sphincter, and cause pupillary constriction. Because pilocarpine may affect all five muscarinic receptor subtypes, it is associated with parasympathetic side effects.

C11H16N23O2

208.2569

208.121

C, 63.44; H, 7.74; N, 13.45; O, 15.36

92-13-7

Pilocarpine Hydrochloride;54-71-7;Pilocarpine nitrate;148-72-1

5910

OIL OR CRYSTALS
NEEDLES

1.2±0.1 g/cm3

431.8±18.0 °C at 760 mmHg

34℃

215.0±21.2 °C

0.0±1.0 mmHg at 25°C

1.585

-0.09

0

3

3

15

245

2

C(C1=CN=CN1C)[C@H]1COC(=O)[C@H]1CC

QCHFTSOMWOSFHM-WPRPVWTQSA-N

InChI=1S/C11H16N2O2/c1-3-10-8(6-15-11(10)14)4-9-5-12-7-13(9)2/h5,7-8,10H,3-4,6H2,1-2H3/t8-,10-/m0/s1

2(3H)-Furanone, 3-ethyldihydro-4-((1-methyl-1H-imidazol-5-yl)methyl)-, (3S,4R)-

AI3-50523 AI3 50523 AI350523

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ~100 mg/mL (~480.17 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.00 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 (12.00 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 (12.00 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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 (Please use freshly prepared in vivo formulations for optimal results.)