Muscarinic receptors [1]

In vitro activity: -hyoscyamine increases the turnover number of GTPase activity from 0.19 min-1 to 2.11 min-1 in the steady-state kinetic measurements. R-(+)-hyoscyamine results in displacement of [3H]NMS binding to the muscarinic acetylcholine receptor subtypes (m1-m5) with pKi value of 8.67, 8.51, 7.46, 8.56 and 8.53, respectively. Hyoscyamine prevents the agonist-induced stimulation of cAMP production with EC50 of 7.8 nM in CHO cells. S-(-)-hyoscyamine enhances the forskolin-stimulated synthesis of cyclic AMP in rat cardiac (both atrial and ventricular) membranes by up to 24%.

The length of the migrating MMC cycle is prolonged by L-Hyoscyamine (Daturine; 5–20 mg/kg; IV)[1].

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Intravenous administration of L-Hyoscyamine (Daturine) in rats significantly altered the migrating myoelectric complex (MMC) pattern in the small intestine. It prolonged the duration of the MMC cycle and inhibited the propagation of phase III contractions of MMC, which was attributed to its antagonistic effect on muscarinic receptors [1]

Animal/Disease Models: Rats[1]
Doses: 5, 10, 20 mg/kg
Route of Administration: IV
Experimental Results: Prolonged the migrating myoelectric complex (MMC) cycle length.

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Male Wistar rats were fasted for 24 hours before the experiment, with free access to water. L-Hyoscyamine (Daturine) was dissolved in physiological saline and administered intravenously at a specific dose. Myoelectric activity of the small intestine was recorded using implanted electrodes for a continuous period to monitor MMC changes [1]
- Female domestic swine (20-25 kg) were acclimated before the experiment. Atropine (which can be converted to L-Hyoscyamine (Daturine) in vivo) was administered intravenously. Blood samples were collected at predetermined time points (0, 5, 15, 30, 60, 120, 240, 480, 720 minutes) via a jugular vein catheter for the determination of R- and S-hyoscyamine concentrations [2]

Absorption, Distribution and Excretion
Hyoscyamine is completely absorbed via sublingual and oral routes, but precise data on Cmax, Tmax, and AUC are not yet clear. Most hyoscyamine is excreted in the urine as the unmetabolized parent compound. Metabolism/Metabolites Hyoscyamine exists primarily in its unmetabolized form, but a small amount is hydrolyzed to tropine and tropine acid. Rabbit liver homogenates containing (-)-hyoscyamine acylhydrolase can hydrolyze (-)-hyoscyamine to tropine and (-)-tropine acid, but not (+)-hyoscyamine. Biological Half-Life The half-life of hyoscyamine is 3.5 hours. L-hyoscyamine (datulin) (S-hyoscyamine) was detected in plasma as the major enantiomer after intravenous injection of atropine in pigs. Enantioselective LC-ESI MS/MS analysis showed that S-hyoscyamine was rapidly absorbed into the systemic circulation and could be detected within 5 minutes after administration. The lower limit of quantitation of this analytical method was sufficient to track changes in S-hyoscyamine concentration over 12 hours [2].

Hepatotoxicity
Although hyoscyamine has been widely used for decades, it has not been found to be associated with elevated liver enzymes or clinically significant liver damage. Its high safety profile is likely due to its low daily dose and limited duration of use. References on the safety and potential hepatotoxicity of anticholinergic drugs are listed after the "Overview of Anticholinergic Drugs" section. Drug Category: Gastrointestinal Drugs; Anticholinergic Drugs Interactions Levohyoscyamine (0.3 mg/kg) inhibits salivation induced by cholinergic and adrenergic drugs in mice without affecting the associated temperature response. When administered 30 minutes before an adrenergic salivating agent, it does not inhibit salivation induced by D-amphetamine sulfate but still reduces salivation induced by L-isoproterenol tartrate.

[1]. Regulatory role of 5-HT and muscarinic receptor antagonists on the migrating myoelectric complex in rats. Eur J Pharmacol. 2003 Apr 25;467(1-3):211-8.

[2]. Application of an enantioselective LC-ESI MS/MS procedure to determine R- and S-hyoscyamine following intravenous atropine administration in swine. Drug Test Anal. Mar-Apr 2012;4(3-4):194-8.

(S)-Atropine is an atropine with a 2S configuration, its function is related to (S)-tropinic acid, and it is the conjugate base of (S)-atropineon. Hyoscyamine is a tropane alkaloid, the levorotatory isomer of atropine, and is usually extracted from plants in the Solanaceae family. The earliest research literature on the effects of hyoscyamine dates back to 1826. Due to its antimuscarinic properties, hyoscyamine is widely used for various treatments. Although hyoscyamine is available in the United States, it has not been approved by the FDA. Hyoscyamine is a natural plant alkaloid derivative and anticholinergic drug used to treat mild to moderate nausea, motion sickness, overactive bladder, and allergic rhinitis. Hyoscyamine has not been shown to cause elevated liver enzymes or clinically significant acute liver injury.
L-Hyoscopolamine has been reported to be present in Scopolia parviflora, Cyphanthera odgersii, and other organisms with relevant data.
Hyoscopolamine is a belladonna alkaloid derivative, a levorotatory form of racemic atropine isolated from Hyoscyamus niger or Atropa belladonna, and possesses anticholinergic activity. As a non-selective competitive antagonist of muscarinic receptors, hyoscyamine inhibits the parasympathetic activity of acetylcholine on salivary glands, bronchial glands, sweat glands, and the eyes, heart, bladder, and gastrointestinal tract. These inhibitory effects lead to reduced secretion of saliva, bronchial mucus, gastric juice, and sweat. Furthermore, its inhibitory effect on smooth muscle can prevent bladder contraction and reduce gastrointestinal motility.
Atropine 3(S)-endoform isomer. See also: Atropine (note moved to); Hyoscyamine (note moved to).

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Drug Indications
Since hyoscyamine is not approved by the FDA, there are no officially approved indications. Intravenous hyoscyamine has been used to reduce gastric motility, alleviate pancreatic pain and secretions, aid in gastrointestinal imaging, treat anticholinesterase poisoning, treat certain partial atrioventricular block, improve renal visualization, and relieve symptoms of biliary colic and renal colic. Intravenous hyoscyamine is also used preoperatively to reduce oral and respiratory secretions, thus facilitating intubation. Oral hyoscyamine is used to treat functional bowel disorders, relieve symptoms of biliary colic and renal colic, and relieve symptoms of acute rhinitis.

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Mechanism of Action
Hyoscyamine competitively and nonselectively antagonizes muscarinic receptors in smooth muscle, myocardium, sinoatrial node, atrioventricular node, exocrine node, gastrointestinal tract, and respiratory tract. Antagonism of muscarinic M1, M4, and M5 receptors in the central nervous system can lead to cognitive impairment; antagonism of M2 receptors in the sinoatrial and atrioventricular nodes can lead to increased heart rate and atrial contractility; antagonism of M3 receptors in smooth muscle can lead to decreased intestinal peristalsis, bladder contraction, salivation, gastric juice secretion, bronchial secretion, and sweating, increased bronchiectasis, pupillary dilation, and ciliary muscle paralysis. The main action of antimuscarinic drugs is to competitively antagonize the effects of acetylcholine and other muscarinic agonists. …The receptors affected are peripheral structures stimulated or inhibited by muscarinic substances, namely exocrine glands, smooth muscle, and cardiac muscle. Responses to postganglionic cholinergic nerve stimulation are also inhibited…but not as readily as responses to cholinesterase injection. /Antimuscarinic Drugs/

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Therapeutic Uses
Adjunctive drugs, anesthetics; antiarrhythmic drugs; antidotes; bronchodilators; muscarinic antagonists; mydriatics; parasympathetic blockers
/L-hyoscyamine is a/racemic mixture…/levorotatory isomer of/levorotatory atropine/, therefore half of atropine is hyoscyamine. Since the dextrorotatory isomer has almost no activity, hyoscyamine is approximately twice as potent as atropine. Its effects and uses are the same as general antimuscarinic drugs, but hyoscyamine is not used in ophthalmology and has minimal effect on inhibiting gastric acid secretion. …Its use is mainly limited to antispasmodics.
Ten male patients with chronic duodenal ulcers underwent enhanced histamine tests before and after treatment with the optimal effective dose of long-acting levorotatory hyoscyamine 0.84 mg (three times daily). During treatment, gastric acid secretion increased, but the amount of secretion decreased significantly, while pepsin and intrinsic factor secretion remained unchanged. In healthy volunteers, levohyoscyamine (0.6 mg, twice daily) significantly affected salivary secretion. Compared to pyrazinamide, levohyoscyamine significantly delayed gastric emptying. Levohyoscyamine inhibited 51% of swallowing-induced esophageal peristalsis. It also affected pupil size and near point distance. For more complete data on the therapeutic uses of (-)-hyoscyamines (a total of 6), please visit the HSDB records page.

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Pharmacodynamics
Hyoscyamine has not been approved by the FDA and therefore has no official indication. However, it is used as an anticholinergic agent in various treatments. Hyoscyamine has a short duration of action and may require multiple daily doses. Patients should be informed of the risks and symptoms of anticholinergic toxicity.

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L-hyoscyamine (datulin) is a key mechanism for regulating intestinal MMC as a muscarinic receptor antagonist[1].
Atropine can be converted into L-hyoscyamine (datulin) (S-hyoscyamine) and its enantiomer R-hyoscyamine in pigs. The enantioselective LC-ESI MS/MS method is a reliable tool for quantifying these two enantiomers in plasma[2].

C17H23NO3

289.37

289.167

101-31-5

L-Hyoscyamine sulfate;620-61-1;L-Hyoscyamine-d3

154417

White to off-white solid powder

1.2±0.1 g/cm3

429.8±45.0 °C at 760 mmHg

108.5ºC

213.7±28.7 °C

0.0±1.1 mmHg at 25°C

1.581

1.53

1

4

5

21

353

3

CN1[C@@H]2CC[C@H]1CC(C2)OC(=O)[C@H](CO)C3=CC=CC=C3

RKUNBYITZUJHSG-VFSICIBPSA-N

InChI=1S/C17H23NO3/c1-18-13-7-8-14(18)10-15(9-13)21-17(20)16(11-19)12-5-3-2-4-6-12/h2-6,13-16,19H,7-11H2,1H3/t13-,14+,15?,16-/m1/s1

[(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] (2S)-3-hydroxy-2-phenylpropanoate

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: ≥ 2.5 mg/mL (8.64 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 (8.64 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 (8.64 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: 30% Propylene glycol , 5% Tween 80 , 65% D5W: 5 mg/mL

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