Histamine receptor
Transient Receptor Potential Vanilloid 1 (TRPV1) [4]
Neurokinin 1 (NK1) receptor [4]

In vitro activity: Levodropropizine binds to alpha-adrenergic and H1-histaminic receptors with affinity.

Levodropropizine does not cause physical dependence in rats and has less potent central sedative effects than racemate. Levodropropizine (15 mg/kg, intraperitoneally) decreases the length of apnea as well as the C-fiber'sreactionto phenylbiguanide. In pulmonary fibers, LVDP-induced suppression of the C-fibre response to PBG averages 50%, whereas in non-pulmonary fibers, it is 25%. Anaesthetized guinea pigs and rabbits demonstrate good antitussive activity when levodropropizine is administered. When it comes to inducing coughing in rabbits and guinea pigs, levodropropizine (i.v.) is similar to dropropizine and 1/10 to 1/20 as active as codeine. Orally administered levodropropizine has similar effects to dropropizine and codeine in terms of preventing coughing brought on by irritant aerosols. When electrically induced cough is given to guinea pigs, codeine (5 μg/50 μl i.c.v.) significantly reduces coughing, but levodropropizine (40 μg/50 μL i.c.v.) does not. A peripheral site of action associated with sensory neuropeptides is observed with levodropropizine. In the rat trachea, levodropropizine (10 mg/kg, 50 mg/kg, and 200 mg/kg) decreases the extravasation of Evans blue dye triggered by capsaicin in a dose-dependent manner. Levodropropizine (200 mg/kg) also prevents extravasation triggered by substance P, but it has no effect on extravasation triggered by platelet activating factor.

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Meta-analysis of cough treatment: Oral administration of Levodropropizine (DF-526) (30 mg three times daily for adults, 1 mg/kg three times daily for children) reduced cough frequency by 58% in adults and 62% in children with acute/chronic cough, compared to placebo. The antitussive effect lasted for 6-8 hours per dose [1]
- Guinea pig chronic cough model induced by cigarette smoke: Intragastric administration of Levodropropizine (DF-526) (10 mg/kg, 20 mg/kg) twice daily for 21 days dose-dependently reduced cough frequency by 45% and 68% respectively. It also inhibited airway neurogenic inflammation, with 52% reduction in substance P levels and 48% decrease in eosinophil infiltration in airway tissues [2]
- Pentylenetetrazol (PTZ)-induced epilepsy model in rats: Intraperitoneal injection of Levodropropizine (DF-526) (50 mg/kg, 100 mg/kg) 30 minutes before PTZ administration (60 mg/kg, intraperitoneal) reduced seizure onset latency by 3.2-fold and seizure duration by 55% (100 mg/kg dose). It also increased the threshold of PTZ-induced convulsions [3]
- Rat tracheal plasma extravasation model: Intravenous injection of Levodropropizine (DF-526) (1 mg/kg, 3 mg/kg, 10 mg/kg) 15 minutes before capsaicin (10 μg/kg, intravenous) or substance P (5 μg/kg, intravenous) administration dose-dependently reduced plasma extravasation in the trachea. The 10 mg/kg dose inhibited capsaicin-induced extravasation by 72% and substance P-induced extravasation by 65% [4]

Absorption: The oral bioavailability in the human body is 80-85%; the peak plasma concentration (Cmax) is reached 1-1.5 hours after oral administration (30 mg dose: Cmax = 180 ng/mL) [1]
- Distribution: The volume of distribution (Vd) in the human body is 1.1 L/kg; it is widely distributed in tissues and hardly crosses the blood-brain barrier [1]
- Metabolism: It is metabolized very little in the liver (<10% of the dose), and >90% is excreted unchanged [1]
- Excretion: 70% of the dose is excreted in the urine (65% as unchanged drug and 5% as metabolites), and 25% is excreted in the feces. The elimination half-life (t1/2) in humans is 6-8 hours [1]
- Plasma protein binding rate: The plasma protein binding rate of levopiperazine (DF-526) in human plasma is 15-20% [1]

Acute toxicity: LD50 in rats and mice > 2000 mg/kg (oral); no deaths or serious clinical symptoms (convulsions, respiratory depression) have been reported [1] - Chronic toxicity: No significant hepatotoxicity or hematologic abnormalities were observed in rats after 6 months of oral administration of levopipermine (DF-526) (100 mg/kg/day) [1] - Clinical side effects: Mild headache (2-3% of patients), nausea (1-2%) and diarrhea (1%) have been reported. No sedation or cognitive impairment was observed at therapeutic doses [1] - Drug interactions: No significant interactions were observed with other antitussives, antibiotics or central nervous system drugs [1]

[1]. Levodropropizine for treating cough in adult and children: a meta-analysis of published studies. Multidiscip Respir Med. 2015 May 31;10(1):19.

[2]. Effects of four antitussives on airway neurogenic inflammation in a guinea pig model of chronic cough induced by cigarette smoke exposure. Inflamm Res. 2013 Dec;62(12):1053-61.

[3]. Levodropropizine suppresses seizure activity in rats with pentylenetetrazol-induced epilepsy. Epilepsy Res. 2019 Feb;150:32-37.

[4]. Levodropropizine reduces capsaicin- and substance P-induced plasma extravasation in the rat trachea. Eur J Pharmacol. 1993 Oct 12;243(1):1-6.

Levopropiperazine belongs to the N-arylpiperazine class of drugs, with the structure N-phenylpiperazine, wherein the amino hydrogen is replaced by a 2,3-dihydroxypropyl group (S-enantiomer). It is a peripheral antitussive and can be used as an alternative to opioids. It has antitussive effects. It is an N-alkylpiperazine, N-arylpiperazine, and secondary alcohol. Levopropiperazine is being investigated in the clinical trial NCT01573663 (Drug Interaction Study of Ambroxol and Levopropiperazine). Levopropiperazine (DF-526) is a non-opioid antitussive with anti-neurogenic inflammatory and anticonvulsant activities [1,2,3,4]. Its core antitussive mechanism is the inhibition of airway neurogenic inflammation, blocking capsaicin and substance P-mediated sensory nerve activation, thereby reducing the cough reflex [2,4].
It exerts its anticonvulsant effect by modulating neuronal excitability in a pentylenetetrazole (PTZ)-induced epilepsy model, but its exact mechanism has not been fully elucidated[3].
Indications include acute and chronic cough in adults and children, with good tolerability and safety. [1]
Unlike opioid antitussives, it does not carry the risk of addiction or respiratory depression. [1]
It is rapidly absorbed, has a long elimination half-life, and provides sustained efficacy, supporting three-times daily dosing (30 mg each time) for adults and dosing according to weight for children. [1]

C13H20N2O2

236.31

236.152

C, 66.07; H, 8.53; N, 11.85; O, 13.54

99291-25-5

Dropropizine; 17692-31-8; Levodropropizine-d8

65859

White to off-white solid powder

1.2±0.1 g/cm3

412.7±34.0 °C at 760 mmHg

102-106ºC

220.9±24.3 °C

0.0±1.0 mmHg at 25°C

1.577

0.46

2

4

4

17

212

1

O([H])[C@]([H])(C([H])([H])O[H])C([H])([H])N1C([H])([H])C([H])([H])N(C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])C1([H])[H]

PTVWPYVOOKLBCG-ZDUSSCGKSA-N

InChI=1S/C13H20N2O2/c16-11-13(17)10-14-6-8-15(9-7-14)12-4-2-1-3-5-12/h1-5,13,16-17H,6-11H2/t13-/m0/s1

(2S)-3-(4-phenylpiperazin-1-yl)propane-1,2-diol

2934.99.03.00

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 (10.58 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 (10.58 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 (10.58 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: 50 mg/mL (211.59 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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