Muscarinic acetylcholine receptors (muscarinic receptor antagonist). [2]

MMC migration cycle length can be increased by L-hyposcyamine sulfate (Daturine sulfate; 5–20 mg/kg; iv) [1].

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In conscious fasted rats with implanted intestinal electrodes, intravenous administration of Hyoscyamine sulfate hydrate (as L-hyoscyamine) at doses of 5, 10, and 20 mg/kg prolonged the migrating myoelectric complex (MMC) cycle length from a baseline of 17.6 ± 1.2 min to 31.4 ± 6.5 min at the highest dose (P = 0.05). The compound had no significant effect on the duration or propagation velocity of phase III of the MMC. Saline control showed no effect. [1]
In anesthetized domestic swine, intravenous injection of atropine sulfate (equivalent to 83.3 µg/kg atropine free base, which corresponds to 41.6 µg/kg of S-hyoscyamine) resulted in maximum plasma concentration (Cmax) of S-hyoscyamine at 24.1 ± 0.4 ng/mL measured 2 minutes post-injection (tmax). The concentration-time profile of S-hyoscyamine followed a biphasic decay consistent with a two-compartment open model, with an initial distribution half-life (t1/2α) of 2.9 ± 1.2 min and a terminal elimination half-life (t1/2β) of 43 ± 3 min. The area under the curve (AUC) for S-hyoscyamine was 307 ± 26 min·ng/mL. No stereoselective differences in distribution or elimination were observed between S- and R-hyoscyamine in swine. [2]

An enantioselective enzymatic assay was developed to quantify S- and R-hyoscyamine in plasma. The method utilized the stereoselective hydrolysis of S-hyoscyamine by atropinesterase (AtE) present in rabbit serum. Plasma samples (85 µL) were incubated separately with either human serum (15 µL, 33% v/v, which lacks atropinesterase) or rabbit serum (15 µL, 33% v/v, containing atropinesterase) for 20 minutes at 37°C. The rabbit serum hydrolyzed S-hyoscyamine to inactive metabolites, leaving R-hyoscyamine intact. After incubation, samples were precipitated with acetonitrile (200 µL), and the supernatant was diluted with solvent A containing internal standard (d3-cocaine). The remaining R-hyoscyamine concentration was measured by LC-ESI-MS/MS, and S-hyoscyamine concentration was calculated as the difference between total hyoscyamine (from human serum incubation) and R-hyoscyamine. Control experiments confirmed that swine plasma did not inhibit atropinesterase activity. [2]

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

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For the rat MMC study, male rats were anesthetized with pentobarbital (50 mg/kg intraperitoneally). Bipolar stainless steel electrodes were implanted into the small intestinal wall at 5, 15, and 25 cm distal to the pylorus, and a jugular vein catheter was implanted for drug administration. After at least 7 days of recovery, conscious fasted (18 h) rats were placed in Bollman cages. Myoelectric activity was recorded for 60 min as control, then Hyoscyamine sulfate hydrate (as L-hyoscyamine) was given as an intravenous bolus injection (0.1 mL/100 g body weight) immediately after the fifth MMC activity front passed the first electrode. Doses tested were 5, 10, and 20 mg/kg. Saline was used as negative control. Recordings continued for at least 60 min post-injection. [1]
For the swine pharmacokinetic study, male castrated York-Landrace cross pigs (20.0 ± 1.5 kg) were anesthetized with 5% isoflurane in 100% oxygen, followed by maintenance at ~2% isoflurane in 30% oxygen. An intravenous line was placed for fluid replacement, and an arterial catheter was inserted for blood sampling. After reaching steady-state anesthesia, each animal received a single intravenous injection of atropine sulfate monohydrate (100 µg/kg, corresponding to 83.3 µg/kg atropine free base, which contains 41.6 µg/kg of S-hyoscyamine). Blood samples were collected into EDTA tubes at various time points over 180 minutes, centrifuged at 3000×g for 10 min at 4°C, and plasma was stored at -80°C until analysis. [2]

In anesthetized swine after intravenous administration of atropine sulfate (83.3 µg/kg free base, i.e., 41.6 µg/kg S-hyoscyamine), the pharmacokinetic parameters for Hyoscyamine sulfate hydrate (S-hyoscyamine) were: Cmax = 24.1 ± 0.4 ng/mL; tmax = 2 min; initial distribution half-life (t1/2α) = 2.9 ± 1.2 min; terminal elimination half-life (t1/2β) = 43 ± 3 min; AUC = 307 ± 26 min·ng/mL. The concentration-time profile was biphasic and fitted a two-compartment open model. No stereoselective differences in distribution, metabolism, or elimination were observed between S- and R-hyoscyamine in swine, as the ratio of the two enantiomers remained equimolar throughout the 180-min experiment. [2]

[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.

Atropine sulfate is the sulfate of atropine, a natural alkaloid isolated from the plant Atropa belladonna. Atropine acts as a competitive antagonist of muscarinic cholinergic receptors, inhibiting parasympathetic nerve excitation and thus eliminating its effects. It can cause tachycardia, inhibit secretion, and relax smooth muscle. (NCI04)
Hyoscyamus sulfate is the sulfate of a belladonna alkaloid derivative, also a levorotatory racemic atropine isolated from the plants Hyoscyamus niger or Atropa belladonna, and possesses anticholinergic activity. Hyoscyamine is a non-selective, competitive muscarinic receptor antagonist that 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. Hyoscyamine is an alkaloid, originally extracted from belladonna (Atropa belladonna), but also found in other plants, primarily those in the Solanaceae family. Hyoscyamine is the 3(S)-endoisomer of atropine.

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Drug Indications
Treatment of Myopia

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Hyoscyamine sulfate hydrate (as L-hyoscyamine) is the most active component of the racemic belladonna alkaloids in atropine. In the rat MMC model, its inhibitory effect on small bowel motility was weaker compared to 5-HT3 and 5-HT4 receptor antagonists (alosetron and piboserod), which at 0.5 mg/kg completely abolished MMC or prolonged cycle length to >60 min, whereas L-hyoscyamine required 20 mg/kg to prolong cycle length to 31.4 min. [1]
S-hyoscyamine acts as a competitive muscarinic receptor antagonist, and rising plasma concentrations cause tachycardia, mydriasis, CNS excitation, hallucinations, coma, and death. It is clinically used for pre-anesthesia medication, ophthalmologic procedures, and therapy of anticholinesterase (organophosphorus) poisoning. In contrast to S-hyoscyamine, the R-enantiomer does not antagonize acetylcholine at muscarinic receptors. The racemic mixture (atropine) is typically administered, but enantioselective pharmacokinetics differ between humans and swine. In humans, significant differences between R- and S-hyoscyamine have been reported, whereas in swine, no stereoselective differences were observed in this study. [2]

C34H48N2O10S

676.8173

676.302

620-61-1

L-Hyoscyamine; 101-31-5

5927

White to off-white solid powder

205-206ºC

-28 ° (C=5, H2O)

4.101

4

12

10

47

434

0

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

HOBWAPHTEJGALG-LFQBMQRVSA-N

InChI=1S/2C17H23NO3.H2O4S/c2*1-18-13-7-8-14(18)10-15(9-13)21-17(20)16(11-19)12-5-3-2-4-6-12;1-5(2,3)4/h2*2-6,13-16,19H,7-11H2,1H3;(H2,1,2,3,4)/t2*13-,14+,15?,16-;/m11./s1

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : ~25 mg/mL (~73.87 mM)

Solubility in Formulation 1: 2.5 mg/mL (7.39 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (7.39 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 (7.39 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.)