In human pancreatic ductal adenocarcinoma cells, biperiden (29.6 μg/ml, 72 hours) can dramatically induce apoptosis and limit proliferation at high doses [1].

Biperiden (ip, 10 mg/kg, daily, for 3 weeks) reduces tumor size by 83% in mice subcutaneously xenografted with Panc-1 human pancreatic ductal adenocarcinoma cells [1]. Biperiden (ip, 8 mg/kg, every 8 hours for 10 days) reduces spontaneous seizure frequency and extracellular hippocampal glutamate levels, while causing a long-term decrease in hippocampal excitability [2].

Cell Proliferation Assay[1]
Cell Types: Panc-1, Panc-2 and BxPC3 Human pancreatic ductal adenocarcinoma cells
Tested Concentrations: 29.6 μg/mL
Incubation Duration: 72 hrs (hours)
Experimental Results: Visibly diminished nuclear c-Rel translocation after 72 hrs (hours) Inhibits cell proliferation.

Animal/Disease Models: Using Panc-1 human pancreatic ductal adenocarcinoma cells subcutaneously (sc) (sc) transplanted into mice [1]
Doses: 10 mg/kg
Route of Administration: intraperitoneal (ip) injection; daily; 3 weeks
Experimental Results: tumor size diminished by 83%.

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Animal/Disease Models: Male Wistar rat (200-250 g) [2]
Doses: 8 mg/kg
Route of Administration: intraperitoneal (ip) injection; once every 8 hrs (hrs (hours)); 10 days
Experimental Results: Late epileptic seizures were diminished by about three times without affecting mood Memory impairment.

Absorption, Distribution and Excretion
Bioavailability: 87% Serum concentrations were 4-5 ng/mL 1 to 1.5 hours after a single oral dose of 4 mg. Plasma concentrations (0.1-0.2 ng/mL) were detectable within 48 hours after administration. In rats, the absorption rate was 87% 6 hours after oral administration of 250 mg/kg. This study investigated the subcellular distribution in the brain, heart, and lungs of rats following intravenous administration of high doses (3.2 mg/kg) of piperidone (BP), trihexyphenidyl (TP), and (-)-quinine cyclobenzyl ester (QNB). The subcellular distribution of clinically used BP or TP was consistent with that of the typical potent central muscarinic receptor antagonist QNB. The concentration-time curves of these drugs in brain tissue subcellular components exhibited two types, both showing a slow decline and paralleling plasma concentrations. Subcellular distribution in the brain and heart depended on the protein content of each component. The postnuclear component (P2) of the drug typically accounts for 3-5 times higher percentages of total concentration in lung tissue than in the heart. Studies have shown that drug distribution in the lungs differs from that in the brain and heart, and its high affinity is independent of the protein content of the lysosomal-containing P2 component. On the other hand, compared to the high-dose group, low-dose (650 ng/kg) 3H-QNB showed increased percentages of each component in total concentration in brain tissue at synaptic membranes and synaptic vesicles, but decreased at the nucleus and cytoplasm. These results suggest that although the tissue concentration-time curves of anticholinergic drugs appear to decrease in parallel with plasma concentrations, their subcellular distribution exhibits multiple patterns across different tissues. This study investigated the pharmacokinetics of Biperiden in six healthy volunteers and compared them with pharmacodynamics (pupil size, accommodation, self-emotional ratings). A single-blind crossover design was used, with participants receiving either placebo or Biperiden (4 mg, commercially available tablets). Biperiden is rapidly absorbed after a lag time of 0.5 hours, with a half-life of 0.3 hours, reaching a peak plasma concentration of 5 ng/mL after 1.5 hours. Biperiden exhibits good tissue permeability (distribution half-life of 0.6 hours; total volume of distribution to central volume of distribution ratio of 9.6), a terminal half-life of 18 hours at plasma concentration, and an oral clearance of 146 L/hr. Pharmacodynamic peak concentrations lag behind peak plasma concentrations by 1 hour (self-assessment) to 4 hours (adaptability assessment). Metabolism/Metabolites: The metabolism of Biperiden is not fully elucidated, but hydroxylation is involved. Biperiden metabolism is not fully elucidated, but hydroxylation is involved. Biological Half-Life: A single-blind crossover design was used, with placebo and Biperiden (4 mg, commercially available tablets) as controls. Biperiden is rapidly absorbed after a lag time of 0.5 hours, with a half-life of 0.3 hours, ... Biperiden exhibits good tissue permeability (distribution half-life of 0.6 hours; total distribution volume to central distribution volume ratio of 9.6), and a terminal half-life of 18 hours at plasma concentration, ...

Toxicity Summary
Parkinson's disease is thought to be caused by an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the striatum. The mechanism of action of centrally active anticholinergic drugs (such as Biperiden) is thought to involve competitive antagonism of acetylcholine on striatal cholinergic receptors, thereby restoring this balance. Hepatotoxicity
There are no reports of Biperiden causing elevated serum transaminases, but no prospective studies have been conducted to assess its effect on serum enzyme levels. Although Biperiden has been used for over 50 years, there are no reports of it causing liver injury in the literature, and even if liver injury does occur, it must be due to an extremely rare cause. Probability Score: E (Unlikely to cause clinically significant liver injury).
Drug Class: Anti-Parkinson's Disease Drugs
Subclass: Anticholinergic Drugs: Benzatropine, Trihexyphenidyl
Protein Binding Rate
60%
Toxicity Data
LD₅₀ = 760 mg/kg (oral in rats).
Interactions
In rats, the anticholinergic drug biperiden exhibits pharmacokinetic interactions with [3(H)]quinine cyclobenzyl ester ([3(H)]QNB) or [3(H)]N-methylhyoscyamine. The concentration of [3(H)]NMS is affected by the order of administration. Drug concentrations in different tissues were determined after intravenous injection of [3(H)]QNB or [3(H)]NMS (325 ng kg⁻¹). Biperiden (6.4 mg kg⁻¹) was administered 5 minutes before, concurrently with, or 20 minutes after injection of [3(H)]QNB or [3(H)]NMS. When Biperiden was administered concurrently with or before [3(H)]QNB, the distribution of [3(H)]QNB in brain regions and other tissues was reduced; after 4 hours, the ratio of [3(H)]QNB distribution in experimental animals to that in control animals ranged from 0.15 to 0.9. When Biperiden was administered after [3(H)]QNB, the distribution of [3H]QNB in brain tissue and other tissues was significantly higher than in the other two treatment groups (P < 0.01). However, for [3(H)]NMS, the order of administration had no effect on the distribution of the drug in brain tissue and other tissues (except the kidneys). In in vitro studies, at the crude synaptosome membrane, when biperiden was added before [3(H)]QNB, the concentration of [3(H)]QNB was 87% of the equilibrium control concentration after 2 hours; while when biperiden was added after [3(H)]QNB, the concentration was 56% of the equilibrium control concentration after 2 hours. In both cases, the concentration of [3(H)]NMS reached equilibrium within 30 minutes. These results suggest that differences in binding and dissociation rate constants at potential sites of action lead to the influence of dosing order on pharmacokinetic interactions.
Concomitant use of biperiden with other drugs with anticholinergic effects (e.g., opioid agonists, phenothiazines and other antipsychotics, tricyclic antidepressants, quinidine, antihistamines) may increase the risk of adverse anticholinergic reactions. To identify molecules affected by the combined use of antipsychotics and antimuscarinic drugs (a commonly prescribed medication for preventing extrapyramidal side effects of antipsychotics), researchers investigated gene expression profiles in the frontal cortex of mice. After 14 consecutive days of administration of the typical antipsychotic haloperidol (2 mg/kg) and the brain-high-affinity muscarinic receptor antagonist Biperiden (2 mg/kg), researchers examined approximately 500 mRNAs associated with synaptic function. The results showed a significant decrease in the levels of mRNAs related to the ubiquitin-associated system following the combination therapy. However, haloperidol or Biperiden alone had little effect on the levels of these mRNAs. This result indicates that the combination of haloperidol and Biperiden specifically affects the ubiquitin-associated system.

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Non-human toxicity values
Canine oral LD50: 340 mg/kg / Biperiden hydrochloride/
Canine intravenous LD50: 222 mg/kg / Biperiden lactate/
Rat intraperitoneal LD50: 270 mg/kg / Biperiden lactate/
Rat oral LD50: 750 mg/kg
For more complete non-human toxicity data for Biperiden (7 types), please visit the HSDB record page.

[1]. Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer. Int J Cancer. 2020 Mar 15;146(6):1618-1630.

[2]. Modification of the natural progression of epileptogenesis by means of biperiden in the pilocarpine model of epilepsy. Epilepsy Res. 2017 Dec;138:88-97. doi: 10.1016/j.eplepsyres.2017.10.019. Epub 2017 Oct 29.

[3]. Effects of two anticholinergic drugs, trospium chloride and biperiden, on motility and evoked potentials of the oesophagus. Aliment Pharmacol Ther. 1998 Oct;12(10).

[4]. Identification of novel functional inhibitors of acid sphingomyelinase. PLoS One. 2011;6(8).

[5]. Antiparkinson drugs used as prophylactics for nerve agents: studies of cognitive side effects in rats. Pharmacol Biochem Behav. 2008 Jun;89(4):633-8.

Biperiden belongs to the piperidine class of compounds and is a derivative of N-propylpiperidine, in which the methyl hydrogen is replaced by a hydroxyl, phenyl, and 5-norbornene-2-yl group. It is a muscarinic receptor antagonist that acts on the central and peripheral nervous systems and is used to treat various types of Parkinson's disease. It has multiple functions, including as a muscarinic receptor antagonist, parasympathetic blocking agent, anti-Parkinson's disease drug, anti-movement disorder drug, and antidote for sarin poisoning. Biperiden belongs to the piperidine class of compounds and is a tertiary amine and tertiary alcohol compound. It is a muscarinic receptor antagonist that acts on the central and peripheral nervous systems. It has been used to treat arteriosclerotic Parkinson's disease, idiopathic Parkinson's disease, and post-encephalitis Parkinson's disease. It is also used to relieve extrapyramidal symptoms caused by phenothiazine derivatives and reserpine. Biperiden is an anticholinergic drug. The mechanism of action of Biperiden is as a cholinergic antagonist.
Biperiden is an oral anticholinergic drug primarily used for the symptomatic treatment of Parkinson's disease and movement disorders. No elevation of serum enzymes has been observed during Biperiden treatment, and even clinically significant acute liver injury is extremely rare.
It is a muscarinic receptor antagonist with effects on both the central and peripheral nervous systems. It has been used to treat atherosclerotic, idiopathic, and post-encephalitis Parkinson's syndromes. It has also been used to relieve extrapyramidal symptoms induced by phenothiazine derivatives and reserpine. [PubChem]
A muscarinic receptor antagonist with effects on both the central and peripheral nervous systems. It has been used to treat atherosclerotic, idiopathic, and post-encephalitis Parkinson's disease. It has also been used to relieve extrapyramidal symptoms induced by phenothiazine derivatives and reserpine.

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Drug Indications
Used as adjunctive therapy for various types of Parkinson's disease, and to control extrapyramidal symptoms induced by antipsychotic medications.

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Mechanism of Action
Parkinson's disease is believed to be caused by an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the striatum. The mechanism of action of centrally acting anticholinergic drugs (such as Biperiden) is thought to involve competitive antagonism of acetylcholine on striatal cholinergic receptors, thereby restoring balance.
Acriton is a weak peripheral anticholinergic drug. Therefore, it has certain antisecretory, antispasmodic, and mydriatic effects. In addition, acriton also has nicotine blocking activity. Parkinson's disease is believed to be caused by an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the striatum. The mechanism of action of centrally acting anticholinergic drugs (such as acriton) is thought to involve competitive antagonism of acetylcholine on striatal cholinergic receptors, thereby restoring balance. Like other antimuscarinic drugs in the trihexyphenidyl class, Biperiden has an atropine-like blocking effect on peripheral structures innervated by the parasympathetic nervous system, including smooth muscle. In addition to its antispasmodic, acid-suppressing, and mydriatic effects, Biperiden is approximately 6 times more potent than atropine and 5 times more potent than trihexyphenidyl (by weight) in experimental animals.

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Therapeutic Uses
Biperiden is used as adjunctive therapy for various types of Parkinson's disease, with apparent superior efficacy in post-encephalitis and idiopathic Parkinson's disease compared to the atherosclerotic type. Biperiden typically relieves muscle stiffness, reduces sweating and salivation, improves gait, and to some extent reduces tremor. Biperiden is also used to relieve the signs of Parkinson's disease and extrapyramidal symptoms induced by antipsychotic drugs (such as phenothiazines). Although tabon has been used as an adjunct therapy for other extrapyramidal diseases and unrelated spastic disorders such as multiple sclerosis, cerebral palsy, and spinal cord injury, its efficacy in these diseases requires further investigation. To investigate the effects of antidotes on tabon-induced neurotoxicity, researchers administered the organophosphate drug tabon intramuscularly to rats. The efficacy of the first-line antidote, consisting of the acetylcholinesterase reactivator olbidoxime and one of four anticholinergic drugs (atropine, benzazine, biperiden, and scopolamine), was compared. The progression of tabon-induced neurotoxicity was assessed using a functional observational scale. Experimental animals and control groups were observed 24 hours and 7 days after administration of tabon or saline. Results were compared with those of animals that did not receive anticholinergic drugs (oxime only) and control rats that received saline instead of tabon. Antidote treatment with centrally acting anticholinergic drugs (benazine, Biperiden, scopolamine) showed a higher neuroprotective effect than antidote treatment containing atropine. To investigate the effects of drug pretreatment (PANPAL or pyridostigmine combined with Biperiden) and antidote treatment (oxime HI-6 combined with atropine) on soman-induced neurotoxicity, male albino rats were injected with a lethal dose of soman (54 g/kg, intramuscular; 100% LD50) and observed at 24 hours and 7 days post-poisoning. Soman neurotoxicity was assessed using functional observation scales and automated measurements of motor activity. Both drug pretreatment and antidote treatment eliminated some neurotoxic effects observed 24 hours post-poisoning. Drug pretreatment (PANPAL) Studies have shown that combined treatment with pyridostigmine and Biperiden (pyridostigmine and Biperiden) and an antidote more effectively eliminates saman-induced neurotoxicity in rats 24 hours after saman poisoning, superior to either drug pretreatment or the antidote alone. Comparing two drug pretreatment regimens, pyridostigmine combined with Biperiden appears to be more effective than PANPAL (pyridostigmine and Biperiden) in eliminating saman-induced neurotoxicity symptoms. Seven days after saman poisoning, only combined treatment with pyridostigmine, Biperiden, and an antidote can completely eliminate saman-induced neurotoxicity symptoms. Therefore, our results confirm that drug pretreatment combined with an antidote not only protects experimental animals from the lethal effects of saman but also eliminates most of the saman-induced neurotoxicity symptoms in poisoned rats. Drug pretreatment regimens containing pyridostigmine and Biperiden appear to be more effective. Compared to PANPAL, this product is more effective. Eliminates neurotoxicity symptoms caused by Soman.

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Drug Warnings
Case reports of confusion, euphoria, agitation, and behavioral disturbances have been reported in susceptible patients. Furthermore, central anticholinergic syndrome may occur even with correct prescription of anticholinergic drugs, although this is more common in cases of overdose. Concomitant use of anticholinergic drugs and drugs with secondary anticholinergic effects may also lead to central anticholinergic syndrome. Caution should be exercised in patients diagnosed with glaucoma, although no significant increase in intraocular pressure has been observed after oral or parenteral administration. Caution should be exercised when using this product in patients with benign prostatic hyperplasia, epilepsy, or arrhythmias. Drowsiness may occasionally occur; patients driving or operating any other potentially dangerous machinery should be informed of this possibility. As with other drugs acting on the central nervous system, alcohol consumption should be avoided. [Note: The last sentence appears to be incomplete and possibly refers to a separate topic about medications.] During treatment, Biperiden should be used with caution, or it may be contraindicated in patients with predisposition to anticholinergic effects. When using Biperiden, the usual precautions and contraindications for antimuscarinic drugs should be followed. Adverse reactions of Biperiden are primarily due to its anticholinergic effects. Dry mouth and blurred vision are common and dose-related. Gastrointestinal upset may occur and can be relieved by taking the medication before or after meals. Drowsiness, dizziness, and confusion are less common. Rare adverse reactions include transient psychotic reactions, euphoria or disorientation, agitation, behavioral abnormalities, urinary retention, and hematuria. In some severe cases of Parkinson's syndrome, tremor may worsen as spasms subside. Furthermore, at least one patient with Parkinson's syndrome developed generalized choreiform movements after the addition of Biperiden. Levodopa-carbidopa treatment. Reduced rapid eye movement (REM) sleep has been reported, manifested as a decrease in REM sleep latency. Prolonged and decreased percentage of REM sleep time.
It is unclear whether Biperiden is excreted into breast milk. Because many drugs are excreted into breast milk, breastfeeding women should use Biperiden with caution.
For more complete data on Biperiden (of 8), please visit the HSDB records page.

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Pharmacodynamics
Biperiden is a weak peripheral anticholinergic drug. Therefore, it has certain antisecretory, antispasmodic, and mydriatic effects. In addition, Biperiden also has nicotinic blocking activity. Injectable Biperiden is an effective and reliable drug for treating acute exacerbations of extrapyramidal disorders that sometimes occur during nerve block therapy. Symptoms such as akathisia, kinesia, kinesiatic tremor, rigidity, oculomotor crisis, spasmodic torticollis, and profuse sweating are significantly reduced or disappear. Injectable Biperiden can rapidly control these drug-induced disturbances.

311.224

514-65-8

Biperiden hydrochloride;1235-82-1;Biperiden lactate;7085-45-2

2381

White to off-white solid powder

1.1±0.1 g/cm3

462.1±40.0 °C at 760 mmHg

114ºC

224.5±26.0 °C

0.0±1.2 mmHg at 25°C

1.583

4.01

1

2

5

23

422

0

OC([C@H]1C[C@@H]2C=C[C@H]1C2)(CCN3CCCCC3)C4=CC=CC=C4

YSXKPIUOCJLQIE-UHFFFAOYSA-N

InChI=1S/C21H29NO/c23-21(19-7-3-1-4-8-19,11-14-22-12-5-2-6-13-22)20-16-17-9-10-18(20)15-17/h1,3-4,7-10,17-18,20,23H,2,5-6,11-16H2

1-(2-bicyclo[2.2.1]hept-5-enyl)-1-phenyl-3-piperidin-1-ylpropan-1-ol

Biperiden KL-373 KL 373

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)

DMSO : ~50 mg/mL (~160.53 mM)
H2O : ~1.82 mg/mL (~5.84 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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