In somanvirus-infected rats and guinea pigs, procyclidine (subcutaneous injection, 0.3-6.0 mg/kg) plus physostigmine (PhS) improves protection in a dose-dependent way and totally avoids epileptic attacks[1].

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat, Dunkin-Hartley male guinea pig [1]
Doses: 0.3-6.0 mg/kg
Route of Administration: subcutaneous injection;
Experimental Results: The protective effect was enhanced at doses of 0.3, 1.0, 3.0 or 6.0 mg /kg, the protective effects in rats were increased by 1.92, 2.24, 3.95 and 5.07 times respectively, and the protective effects in guinea pigs were increased by 3.00, 3.25, 4.50 and 4.70 times respectively. Protects the integrity of the brain's nervous system and prevents Soman-induced severe brain damage to the hippocampus, cortex, amygdala and thalamus.

Absorption, Distribution and Excretion
The pharmacokinetics and pharmacodynamics of procyclidine (10 mg) after oral and intravenous administration were studied in six healthy volunteers. Treatment order was randomized and the study was placebo-controlled and conducted blind. After oral dosing the mean peak plasma concentration was 116 ng/mL and mean bioavailability was 75%. After both oral and intravenous dosing the mean values for the volume of distribution, total body clearance and plasma elimination half-life of procyclidine were in the order of 1 L/kg, 68 mL/min and 12 hr respectively. ...

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Metabolism / Metabolites
After intraperitoneal administration of procyclidine, eight metabolites were isolated from rat urine. They were identified as 1-(4-oxocyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(cis-4-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(trans-4-hydrocyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol , (1R,3R,4S,7R)- and (1R,3R,4S,7S)-1-(cis-3,cis-4-dihydroxycyclohexyl)-1-phenyl-3-(1-py rrolidinyl)- 1-propanol, (1R,3R,4R,7R)- and (1R,3R,4R,7S)-1-(cis-3,trans-4-dihydroxycyclohexyl)-1-phenyl- 3-(1-pyrrolidinyl)-1-propanol, and one of both (1R,3S,4R,7R)- or (1R,3S,4R,7S)- 1-(trans-3,trans-4-dihydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl )-1-propanol by comparative TLC, GLC-MS and 13C-NMR spectroscopy. PMID:6745301

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Biological Half-Life
The pharmacokinetics and pharmacodynamics of procyclidine (10 mg) after oral and intravenous administration were studied in six healthy volunteers. ... Plasma elimination half-life of procyclidine ... was .... 12 hr.

Toxicity Summary
The mechanism of action is unknown. It is thought that Procyclidine acts by blocking central cholinergic receptors, and thus balancing cholinergic and dopaminergic activity in the basal ganglia. Many of its effects are due to its pharmacologic similarities with atropine. Procyclidine exerts an antispasmodic effect on smooth muscle, and may produce mydriasis and reduction in salivation.

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Protein Binding
Approximately 100% bound to albumin.

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Toxicity Data
LD₅₀=60 mg/kg (IV in mice)

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Interactions
Two cases are described of chronic schizophrenic patients maintained on depot neuroleptics, who developed severe extrapyramidal symptoms following a period of heavy betel nut consumption. A mechanism for this effect is proposed based on the pharmacological antagonism of the anticholinergic agent, procyclidine, by the active alkaloid ingredient of the betel, arecoline.
The efficacy of a combinational prophylactic regimen on the lethality, convulsions, and loss of morphological and functional integrities of the brain induced by an organophosphate soman was investigated in rats. The rats were implanted subcutaneously with osmotic minipumps containing the combinational prophylactic regimen composed of physostigmine, a reversible cholinesterase inhibitor, and procyclidine, an N-methyl-D-aspartate antagonist possessing anticholinergic action, for 3 days, and intoxicated subcutaneously with soman (160 ug/kg, 1.3 LD50). The doses of combinational regimen in minipumps were optimized to achieve 30-35% inhibition of blood cholinesterase activity by physostigmine and 50-100 ng/ml of blood concentrations of procyclidine as clinically available doses, respectively. In comparison, 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 125 mg/kg) was administered intraperitoneally 30 min prior to the soman challenge in control groups to reduce mortality of rats without affecting convulsions. Soman induced profound limbic convulsions and 30% mortality, leading to increased blood-brain barrier permeability, neural injuries, learning and memory impairments, and physical incapacitation of survived rats pretreated with HI-6. The combinational regimen, at optimal doses without adverse effects on passive avoidance performances (72 ug/kg/hr of physostigmine plus 432 ug/kg/hr of procyclidine), exerted full protective effects against lethality, convulsions, blood-brain barrier opening, brain injuries, learning and memory impairments, and physical incapacitation induced by soman. Taken together, it is suggested that the combination of physostigmine and procyclidine, at adequate doses, could be a choice to provide the victims of organophosphate poisoning with chance of intensive care for survival and neuroprotection.
... Significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) /was observed/ when given prophylactically against a lethal dose of soman (1.6 x LD50) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 hr after soman intoxication. Six hours after soman exposure cerebral AChE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while AChE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point...
The prophylactic efficacy of a combinational patch system containing physostigmine and procyclidine against soman intoxication was evaluated using dogs. Female beagle dogs (body weights 9-10 kg) were shaved on the abdominal side, attached with a matrix-type patch (7x7 cm) containing 1.5% of physostigmine plus 6% procyclidine for 2 days, and challenged with subcutaneous injection of serial doses (2-10 LD50) of soman. Separately, in combination with the patch attachment, atropine (2 mg/dog) plus 2-pralidoxime (600 mg/dog) or atropine plus 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridiniu m (HI-6, 500 mg/dog) were injected intramuscularly 1 min after soman poisoning. The LD50 value of soman was determined to be 9.1 ug/kg, and high doses (> or = 1.4 LD50) of soman induced salivation, emesis, defecation and diarrhea, tremors and seizures, and recumbency of dogs, leading to 100% mortality in 24 hr. The prophylactic patch, which led to mean 18.5-18.8% inhibition of blood cholinesterase activity by physostigmine and mean 7.9-8.3 ng/mL of blood concentration of procyclidine, exerted a high protection ratio (4.7 LD50), in comparison with relatively-low effects of traditional antidotes, atropine plus 2-pralidoxime (2.5 LD50) and atropine plus HI-6 (2.7 LD50). Noteworthy, a synergistic increase in the protection ratio was achieved by the combination of the patch with atropine plus HI-6 (9 LD50), but not with atropine plus 2-pralidoxime (5 LD50). In addition, the patch system markedly attenuated the cholinergic signs and seizures induced by soman, especially when combined with atropine plus HI-6, leading to elimination of brain injuries and physical incapacitation up to 6 LD50 of soman poisoning. Taken together, it is suggested that the patch system containing physostigmine and procyclidine, especially in combination with atropine and HI-6, could be a choice for the quality survival from nerve-agent poisoning.
For more Interactions (Complete) data for PROCYCLIDINE (12 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 mouse intraperitoneal 131 mg/kg
LD50 mouse intravenous 60 mg/kg

[1]. Effects of combinational prophylactics composed of physostigmine and procyclidine on soman-induced lethality, seizures and brain injuries. Environ Toxicol Pharmacol. 2002 Jan;11(1):15-21.

[2]. Effects of procyclidine on eye movements in schizophrenia. Neuropsychopharmacology. 2003 Dec;28(12):2199-208.

Procyclidine is a tertiary alcohol that consists of propan-1-ol substituted by a cyclohexyl and a phenyl group at position 1 and a pyrrolidin-1-yl group at position 3. It has a role as a muscarinic antagonist, an antiparkinson drug and an antidyskinesia agent. It is a tertiary alcohol and a member of pyrrolidines.
A muscarinic antagonist that crosses the blood-brain barrier and is used in the treatment of drug-induced extrapyramidal disorders and in parkinsonism.
Procyclidine is an Anticholinergic. The mechanism of action of procyclidine is as a Cholinergic Antagonist.
Procyclidine is only found in individuals that have used or taken this drug. It is a muscarinic antagonist that crosses the blood-brain barrier and is used in the treatment of drug-induced extrapyramidal disorders and in parkinsonism. The mechanism of action is unknown. It is thought that Procyclidine acts by blocking central cholinergic receptors, and thus balancing cholinergic and dopaminergic activity in the basal ganglia. Many of its effects are due to its pharmacologic similarities with atropine. Procyclidine exerts an antispasmodic effect on smooth muscle, and may produce mydriasis and reduction in salivation.
A muscarinic antagonist that crosses the blood-brain barrier and is used in the treatment of drug-induced extrapyramidal disorders and in parkinsonism.

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Drug Indication
For the treatment of all forms of Parkinson's Disease, as well as control of extrapyramidal reactions induced by antipsychotic agents.

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Mechanism of Action
The mechanism of action is unknown. It is thought that Procyclidine acts by blocking central cholinergic receptors, and thus balancing cholinergic and dopaminergic activity in the basal ganglia. Many of its effects are due to its pharmacologic similarities with atropine. Procyclidine exerts an antispasmodic effect on smooth muscle, and may produce mydriasis and reduction in salivation.
Pharmacologic tests have shown that procyclidine hydrochloride has an atropine-like action and exerts an antispasmodic effect on smooth muscle. It is a potent mydriatic and inhibits salivation. It has no sympathetic ganglion- blocking activity in doses as high as 4 mg/kg, as measured by the lack of inhibition of the response of the nictitating membrane to preganglionic electrical stimulation.

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Therapeutic Uses
Discontinued ... Kemadrin (procyclidine hydrochloride) tablets will remain available ... until current supplies are deleted. /Procyclidine hydrochloride/
Procyclidine is used for the adjunctive treatment of all forms of parkinsonian syndrome. In the symptomatic treatment of parkinsonian syndrome, procyclidine appears to relieve muscle rigidity better than it does tremor. The drug may be combined with other agents in the treatment of more severe cases of tremor, fatigue, weakness, and sluggishness and in advanced rigidity. Procyclidine is also used for the relief of parkinsonian signs and symptoms of antipsychotic agent-induced (e.g., phenothiazines) extrapyramidal effects.
Clinical reports indicate that procyclidine often successfully relieves the symptoms of extrapyramidal dysfunction (dystonia, dyskinesia, akathisia, and parkinsonism) which accompany the therapy of mental disorders with phenothiazine and rauwolfia compounds. In addition to minimizing the symptoms induced by tranquilizing drugs, the drug effectively controls sialorrhea resulting from neuroleptic medication. At the same time, freedom from the side effects induced by tranquilizer drugs, as provided by the administration of procyclidine, permits a more sustained treatment of the patient's mental disorder.
Clinical results in the treatment of parkinsonism indicate that most patients experience subjective improvement characterized by a feeling of well-being and increased alertness, together with diminished salivation and a marked improvement in muscular coordination as demonstrated by objective tests of manual dexterity and by increased ability to carry out ordinary self-care activities. While the drug exerts a mild atropine-like action and therefore causes mydriasis, this may be kept minimal by careful adjustment of the daily dosage.
For more Therapeutic Uses (Complete) data for PROCYCLIDINE (13 total), please visit the HSDB record page.

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Drug Warnings
... Patients with hypotension receiving therapy with procyclidine should be observed closely. Patients with mental disorders receiving procyclidine for control of drug-induced extrapyramidal effects should also be carefully observed, especially at the beginning of therapy or during dosage adjustment, since worsening of mental symptoms or toxic psychosis can occur.
Procyclidine hydrochloride should not be used in angle-closure glaucoma although simple type glaucomas do not appear to be adversely affected.
Use in Children: Safety and efficacy have not been established in the pediatric age group; therefore, the use of procyclidine hydrochloride in this age group requires that the potential benefits be weighed against the possible hazards to the child.
Pregnancy Warning: The safe use of this drug in pregnancy has not been established; therefore, the use of procyclidine hydrochloride in pregnancy, lactation, or in women of childbearing age requires that the potential benefits be weighed against the possible hazards to the mother and child.
For more Drug Warnings (Complete) data for PROCYCLIDINE (12 total), please visit the HSDB record page.

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Pharmacodynamics
Procyclidine has an atropine-like action on parasympathetic-innervated peripheral structures including smooth muscle. It's antispasmodic effects are thought to be related to the blockage of central cholinergic receptors M1, M2 and M4. It is used to treat symptomatic Parkinsonism and extrapyramidal dysfunction caused by antipsychotic agents.

C19H29NO

287.43966

287.225

77-37-2

Procyclidine hydrochloride;1508-76-5

4919

Crystals from petroleum ether

1.057 g/cm3

433.5ºC at 760 mmHg

85.5-86.5°

205.7ºC

1.554

3.878

1

2

5

21

301

0

C1=CC=C(C=C1)C(CCN2CCCC2)(C3CCCCC3)O

WYDUSKDSKCASEF-UHFFFAOYSA-N

InChI=1S/C19H29NO/c21-19(17-9-3-1-4-10-17,18-11-5-2-6-12-18)13-16-20-14-7-8-15-20/h1,3-4,9-10,18,21H,2,5-8,11-16H2

1-cyclohexyl-1-phenyl-3-pyrrolidin-1-ylpropan-1-ol

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)