mAChR3/muscarinic acetylcholine receptor

分别使用光学显微镜和 MTT 测定评估人角膜基质 (HCS) 细胞的形态和活力，以评估毛果芸香碱的细胞毒性。暴露于浓度范围为 0.625 至 20 g/L 的毛果芸香碱的 HCS 细胞表现出形态学异常，包括细胞皱缩、细胞质空泡化、从培养基基质脱离和最终死亡，以及剂量和时间依赖性增殖迟缓。然而，当浓度低于 0.625 g/L 时，毛果芸香碱暴露组和对照组之间没有发现明显差异。 MTT法结果显示，毛果芸香碱浓度大于0.625 g/L后，HCS细胞活力随着时间和浓度的增加而降低（P<0.01或0.05），而毛果芸香碱浓度低于0.625 g/L时，HCS细胞活力随时间和浓度的增加而降低（P<0.01或0.05）。 0.625随着时间和浓度的增加而降低（P<0.01或0.05）。 g/L 与对照相比没有明显变化 [2]。在用去甲肾上腺素（10 至 200 nM）收缩的大鼠尾动脉的孤立部分中，部分毒蕈碱激动剂毛果芸香碱可引起浓度依赖性松弛，EC50 为 2.4 mM [3]。

在运动大鼠（EX）和对照大鼠（CN）中研究了毛果芸香碱对唾液分泌的影响。与 CN 大鼠相比，EX 大鼠由毛果芸香碱引起的唾液量显着增加（P<0.01）。相反，EX大鼠唾液中Na+含量显着低于CN大鼠(P<0.05)[1]。

用浓度为0.15625g/L至20.0g/L的毛果芸香碱处理HCS细胞后，通过光学显微镜和MTT法检测其形态和存活率。通过吖啶橙（AO）/溴化乙锭（EB）双重染色检测膜通透性、DNA断裂和超微结构。通过流式细胞术（FCM）测定DNA电泳和透射电子显微镜（TEM）、细胞周期、磷脂酰丝氨酸（PS）取向和线粒体跨膜电位（MTP）。ELISA检测胱天蛋白酶的激活[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
Following oral administration of pilocarpine 5mg three times daily in healthy male subjects, peak plasma drug concentrations of 15μg/L were reached in 1.25 hours. At the dose of pilocarpine 10mg three times daily, peak plasma drug concentrations of 41μg/L were reached in 0.85 hours. The rate of absorption is increased when taken with food. Following ophthalmic administration in healthy subjects, the overall median Tmax was 2.2 hours. The mean (SD) Cmax and AUC0-t were 897.2 (287.2) pg/mL and 2699 (741.4) hr x pg/mL, respectively. In patients with presbyopia, the mean Cmax and AUC0-t,ss values were 1.95 ng/mL and 4.14 ng x hr/mL, respectively. The median Tmax was 0.3 hours postdose with a range from 0.2 to 0.5 hours post-dose.
Pilocarpine and its degradation products are eliminated predominantly in the urine.
There is no information available.
There is no information available.
LITTLE DEFINITIVE INFORMATION IS AVAIL ON FATE & ELIMINATION OF PILOCARPINE. IT IS PARTLY DESTROYED IN BODY, BUT LARGER FRACTION IS EXCRETED IN URINE IN COMBINED FORM.
PILOCARPINE PENETRATES EYE WELL; AFTER TOPICAL INSTILLATION...
POISONING HAS OCCURRED FROM CUTANEOUS ABSORPTION.

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Metabolism / Metabolites
There is limited information available about the metabolism of pilocarpine in humans. Inactivation of pilocarpine can occur at neuronal synapses and probably in plasma. Pilocarpine is reported to undergo CYP2A6-mediated 3-hydroxylation to form stereoisomers of 3-hydroxypilocaripine. Pilocaripine also undergoes hydrolysis mediated by paraoxonase 1, a calcium-dependent esterase in plasma and the human liver. Pilocarpic acid is a possible metabolic product of hydrolysis. Pilocarpine metabolites are reported to possess negligible or no pharmacological activity.
Pilocarpine has known human metabolites that include 3-hydroxypilocarpine.
Possibly occurs at the neuronal synapses and in the plasma
Half Life: 0.76 hours

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Biological Half-Life
The elimination half-life was 0.76 and 1.35 hours following administration of a 5mg or lOmg dose 3 times daily, respectively. Following ophthalmic administration in healthy subjects, the half-life was 3.96 hours.

Toxicity Summary
Pilocarpine is a cholinergic parasympathomimetic agent. It increase secretion by the exocrine glands, and produces contraction of the iris sphincter muscle and ciliary muscle (when given topically to the eyes) by mainly stimulating muscarinic receptors.

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Hepatotoxicity
In clinical trials of pilocarpine, serum enzyme elevations were uncommon and no more frequent than with placebo. Despite, wide scale use, there have been no published reports of acute liver injury attributable to pilocarpine.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal use of ophthalmic pilocarpine did not adversely affect the breastfed infant. If ophthalmic pilocarpine is used during breastfeeding, monitor the infant for signs of cholinergic excess (diarrhea, lacrimation, and excessive salivation or urination), especially in younger, exclusively breastfed infants. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue.
Because no information is available on the use of oral pilocarpine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
A woman with glaucoma used a pilocarpine insert (Ocusert; strength not specified) in one eye while nursing (extent not stated) her newborn infant for 9 weeks. No adverse reactions were noted in the infant.[1]
A mother who was taking pilocarpine eye drops (concentration not stated) twice daily as well as 2 drops of timolol 0.5% eye drops daily and acetazolamide 250 mg orally twice daily and delivered a preterm infant at 36 weeks of gestation. The infant began 5 months of exclusive breastfeeding at 6 hours after birth. On day 2, the infant developed electrolyte abnormalities consisting of hypocalcemia, hypomagnesemia, and metabolic acidosis. The infant was treated with oral calcium gluconate and a single dose of intramuscular magnesium sulfate. Despite continued breastfeeding and maternal drug therapy, the infant's mild metabolic acidosis disappeared on day 4 of life and the infant was gaining weight normally at 1, 3 and 8 months, but had mild hypotonicity. The authors considered the metabolic effects to be caused by transplacental passage of acetazolamide that resolved despite the infant being breastfed. The infant gained weight adequately during breastfeeding, but had some mild, residual hypertonicity of the lower limbs requiring physical therapy.[2]
◉ Effects on Lactation and Breastmilk
Relevant published information in nursing mothers was not found as of the revision date. In animals, cholinergic drugs increase oxytocin release,[3] and have variable effects on serum prolactin.[4] Other centrally acting cholinergic drugs increase serum prolactin in humans.[5][6] The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Pilocarpine does not bind to human or rat plasma proteins over a concentration range of 5 to 25,000 ng/mL. The effect of pilocarpine on 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
Miotics; Muscarinic Agonists; Parasympathomimetics
PILOCARPINE IS USED IN TREATMENT OF GLAUCOMA... IT CAN ALSO BE GIVEN IN OINTMENT OR AS LAMELLAE. ...MIOTIC ACTION OF PILOCARPINE IS USEFUL IN OVERCOMING MYDRIASIS PRODUCED BY ATROPINE; ALTERNATED WITH MYDRIATICS...EMPLOYED TO BREAK ADHESIONS BETWEEN IRIS & LENS.
PILOCARPINE IS BETTER TOLERATED THAN ANY OTHER MIOTIC. /HCL/
PILOCARPINE IS MIOTIC OF CHOICE FOR INITIAL & MAINTENANCE THERAPY IN PRIMARY OPEN-ANGLE GLAUCOMA & MOST OTHER CHRONIC GLAUCOMAS. ...USED FOR EMERGENCY TREATMENT OF ACUTE ANGLE-CLOSURE GLAUCOMA.
For more Therapeutic Uses (Complete) data for PILOCARPINE (6 total), please visit the HSDB record page.

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Drug Warnings
/PILOCARPINE/...SHOULD NOT BE USED FOR LONG PERIODS IN SUCH CASES TO AVOID OR POSTPONE IRIDECTOMY BECAUSE ANY MIOTIC MAY TIGHTEN PUPIL AGAINST LENS & BLOCK FLOW OF AQUEOUS THROUGH PUPIL.

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Pharmacodynamics
Pilocarpine is a muscarinic agent that mediates diaphoretic, miotic, and central nervous system effects. Pilocarpine stimulates the secretion of various exocrine glands, such as sweat, lacrimal, salivary, and gastrointestinal glands. Following oral administration, pilocarpine increased the mean salivary flow rate by 2- to lO-folds than placebo. Its peak levels were maintained for at least one to two hours. Pilocarpine increases smooth muscle tone, contracts the pupillary and iris sphincter muscles, and induces miosis. 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

44.12

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

注意： 本产品在运输和储存过程中需避光。

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (12.00 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (12.00 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (12.00 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。