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
This study investigated the pharmacokinetics and pharmacodynamics of procyclophosphamide (10 mg) after oral and intravenous administration in six healthy volunteers. Treatment was randomized, and the study was placebo-controlled and double-blind. Following oral administration, the mean peak plasma concentration was 116 ng/mL, and the mean bioavailability was 75%. After oral and intravenous administration, the mean volume of distribution, systemic clearance, and plasma elimination half-life of procyclophosphamide were 1 L/kg, 68 mL/min, and 12 hours, respectively. … Metabolisms/Metabolites Eight metabolites were isolated from rat urine following intraperitoneal injection of procyclophosphamide. 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-hydroxycyclohexyl)-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-pyrrolidinyl)-1-propanol, (1R,3R,4R,7R)- and (1R, 3-(1-pyrrolidinyl)-1-propanol and (1R,3S,4R,7R)- or (1R,3S,4R,7S)-1-(trans-3,trans-4-dihydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol were identified by comparison of thin-layer chromatography (TLC), gas chromatography-mass spectrometry (GLC-MS) and 13C nuclear magnetic resonance spectroscopy (13C-NMR). PMID: 6745301 Biological half-life
This study investigated the pharmacokinetics and pharmacodynamics of procyclodextrin (10 mg) after oral and intravenous administration in six healthy volunteers. The plasma elimination half-life of procyclophosphamide is 12 hours.

Toxicity Summary
Its mechanism of action is not fully understood. It is hypothesized that procyclophosphamide works by blocking central cholinergic receptors, thereby balancing cholinergic and dopaminergic activity in the basal ganglia. Many of its effects stem from its pharmacological similarity to atropine. Procyclophosphamide has an antispasmodic effect on smooth muscle and may cause mydriasis and decreased salivation. Protein Binding The binding rate to albumin is approximately 100%. Toxicity Data
LD50 = 60 mg/kg (mice, intravenous injection) Interactions This article describes two cases of chronic schizophrenia patients who had been taking long-acting antipsychotic medication and developed severe extrapyramidal symptoms after consuming large amounts of areca nut. This article proposes a mechanism to explain this effect: the pharmacological antagonism of arecoline, the active alkaloid component of areca nut, against the cholinergic antagonist procyclophosphamide. This study investigated the efficacy of a combined prophylactic regimen in rats against soman-induced lethality, seizures, and loss of brain morphology and functional integrity. Rats were subcutaneously implanted with a combined prophylactic regimen containing the reversible cholinesterase inhibitor physostigmine and the N-methyl-D-aspartate antagonist propranolol (an anticholinergic agent) for 3 days, followed by subcutaneous injection of soman (160 μg/kg, 1.3 LD50). The dosage of the micropump combined administration regimen was optimized to achieve an inhibition rate of 30-35% of blood cholinesterase activity by physostigmine and a blood concentration of 50-100 ng/ml (clinically usable dose) for propranolol. In contrast, the control group received an intraperitoneal injection of 1-[([4-(aminocarbonyl)pyridinium]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 125 mg/kg) 30 minutes before Soman attack to reduce rat mortality without affecting seizures. Soman induced severe limbic seizures and a 30% mortality rate, leading to increased blood-brain barrier permeability, neurological damage, learning and memory impairment, and functional impairment in HI-6 pretreated rats. At the optimal dose (physostigmine 72 μg/kg/hr + propranolol 432 μg/kg/hr) without affecting passive avoidance behavior, the combined regimen provided complete protection against Soman-induced lethality, seizures, blood-brain barrier opening, brain damage, learning and memory impairment, and functional impairment. In conclusion, it is recommended that the combined use of physostigmine and propranolol at appropriate doses can provide intensive care for patients with organophosphate poisoning, thereby improving survival and neuroprotection.
...In Wistar rats, prophylactic administration of donepezil (2.5 mg/kg) in combination with propranolol (3 or 6 mg/kg) significantly protected rats from lethal doses of soman (1.6 x LD50). No neuropathological changes were observed in rats receiving this combination treatment 48 hours after soman poisoning. Six hours after soman exposure, brain acetylcholinesterase (AChE) activity and acetylcholine (ACh) concentration were 5% and 188% of those in the control group, respectively. Twenty-four hours after soman poisoning, ACh concentrations returned to baseline levels, while AChE activity returned to 20% of those in the control group. At this point, the loss of functional muscarinic ACh receptors (17%) was evident, while nicotine receptors remained unaffected...
This study evaluated the preventive effect of a combination patch system containing physostigmine and propranolol on soman poisoning using dogs. Female beagle dogs (weighing 9-10 kg) were shaved on the abdomen and then fitted with a 7×7 cm patch containing 1.5% physostigmine and 6% propiconazole for 2 days. A challenge test was then performed by subcutaneous injection of consecutive doses (2-10 LD50) of soman. Alternatively, when the patch was used in combination, atropine (2 mg/dog) plus 2-iodophosphonate (600 mg/dog) or atropine plus 1-[([4-(aminocarbonyl)pyridinyl]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinyl (HI-6, 500 mg/dog) was administered intramuscularly 1 minute after soman poisoning. The LD50 of soman is 9.1 μg/kg. High doses (≥1.4 LD50) of soman can cause salivation, vomiting, defecation and diarrhea, tremors and seizures, and recumbency in dogs, leading to a 100% mortality rate within 24 hours. This prophylactic patch resulted in an average inhibition rate of 18.5-18.8% of blood cholinesterase activity by physostigmine and an average blood concentration of propranolol of 7.9-8.3 ng/mL. Compared to traditional antidotes atropine combined with pralidoxime (2.5 LD50) and HI-6 (2.7 LD50), it exhibited a higher protective rate (4.7 LD50). Notably, the patch significantly improved the protective rate when used in combination with atropine and HI-6 (9 LD50), but had no such effect when used with atropine combined with pralidoxime (5 LD50). Furthermore, this patch system significantly reduced soman-induced cholinergic symptoms and seizures, especially when used in combination with atropine and HI-6, eliminating brain damage and physical dysfunction up to 6 times the LD50 of soman poisoning. In conclusion, patch systems containing physostigmine and procyclophosphamide, especially when used in combination with atropine and HI-6, may be an option for improving survival rates in patients poisoned by nerve agents. For more complete data on the interactions of procyclophosphamides (12 in total), please visit the HSDB record page. Non-human toxicity values: Intraperitoneal LD50 in mice: 131 mg/kg Intravenous LD50 in mice: 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 composed of propan-1-ol with cyclohexyl and phenyl substitutions at the 1-position and pyrrolidine-1-yl substitutions at the 3-position. It is a muscarinic receptor antagonist, an anti-Parkinson's disease drug, and an anti-movement disorder drug. It is a tertiary alcohol belonging to the pyrrolidine class of compounds. Procyclidine is a muscarinic receptor antagonist capable of crossing the blood-brain barrier and is used to treat drug-induced extrapyramidal diseases and Parkinson's disease. Procyclidine is an anticholinergic drug. Its mechanism of action is as a cholinergic antagonist. Procyclidine is only present in individuals who have used or taken the drug. It is a muscarinic receptor antagonist capable of crossing the blood-brain barrier and is used to treat drug-induced extrapyramidal diseases and Parkinson's disease. Its mechanism of action is not fully understood. It is speculated that Procyclidine works by blocking central cholinergic receptors, thereby balancing cholinergic and dopaminergic activity in the basal ganglia. Many of its effects stem from its pharmacological similarity to atropine. Procyclidine has an antispasmodic effect on smooth muscle and may cause pupillary dilation and decreased salivation. It is a muscarinic receptor antagonist that crosses the blood-brain barrier and is used to treat drug-induced extrapyramidal disorders and Parkinson's disease. Drug Indications: Used to treat various types of Parkinson's disease and to control extrapyramidal reactions induced by antipsychotic drugs. Mechanism of Action: Its mechanism of action is not fully understood. It is believed that Procyclidine's mechanism of action is through blocking central cholinergic receptors, thereby balancing cholinergic and dopaminergic activity in the basal ganglia. Many of its effects stem from its pharmacological similarity to atropine. Procyclidine has an antispasmodic effect on smooth muscle and may cause pupillary dilation and decreased salivation. Pharmacological studies have shown that Procyclidine hydrochloride has atropine-like effect and an antispasmodic effect on smooth muscle. It is a potent mydriatic and inhibits salivation. Even at doses up to 4 mg/kg, it does not exhibit sympathetic ganglion blocking activity, as determined by observing whether the nictitating membrane's response to preganglionic electrical stimulation is suppressed.

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Therapeutic Use
Discontinued… Kemadrin (Procyclidine hydrochloride) tablets will continue to be available…until existing stock is depleted. Procyclidine Hydrochloride
Procyclidine is used as adjunctive therapy for various types of Parkinson's disease. In the symptomatic treatment of Parkinson's disease, Procyclidine is more effective at relieving muscle stiffness than tremor. It can be used in combination with other medications to treat more severe tremors, fatigue, weakness, and lethargy, as well as late-stage rigidity. Procyclidine is also used to relieve the signs of Parkinson's disease and extrapyramidal symptoms induced by antipsychotic drugs (such as phenothiazines). Clinical reports indicate that procyclophosphamide is generally effective in relieving extrapyramidal symptoms (dystonia, dyskinesia, akathisia, and Parkinson's disease) associated with the treatment of mental illnesses using phenothiazines and rauwolfia compounds. In addition to maximally reducing sedative-induced symptoms, it effectively controls drooling caused by nerve blocks. Furthermore, because procyclophosphamide does not produce the sedative side effects, it allows for more sustained treatment of patients' mental disorders. Clinical results in the treatment of Parkinson's disease show that most patients experience improvement in subjective symptoms, manifested as feeling well, increased alertness, reduced salivation, and significantly improved muscle coordination (confirmed by objective tests of hand dexterity and improved daily living abilities). This drug has a mild atropine-like effect, which may cause mydriasis, but this effect can be minimized by carefully adjusting the daily dose. For more complete data on the therapeutic uses of procyclophosphamide (13 in total), please visit the HSDB record page.

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Drug Warnings
…Patients with hypotension receiving procyclophosphamide should be closely monitored. Patients with mental disorders receiving procyclophosphamide to control drug-induced extrapyramidal reactions should also be closely monitored, especially at the beginning of treatment or during dose adjustments, as worsening of mental symptoms or toxic psychosis may occur.
Procyclophosphamide hydrochloride should not be used in angle-closure glaucoma, although simple glaucoma does not appear to be adversely affected.
Pediatric Use: The safety and efficacy of this drug in children have not been established; therefore, the use of procyclophosphamide hydrochloride in this age group requires a trade-off between the potential benefits and the potential harm to the child.
Pregnancy Warning: The safety of this drug during pregnancy has not been established; therefore, the use of procyclophosphamide hydrochloride in pregnant, lactating, or women of childbearing age requires a trade-off between the potential benefits and the potential harm to the mother and fetus.
For more complete data on drug warnings for procyclophosphamide (12 in total), please visit the HSDB records page.

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Pharmacodynamics
Procyclodextrin has atropine-like effects on peripheral structures innervated by the parasympathetic nervous system, including smooth muscle. Its antispasmodic effect is thought to be related to the blocking of central cholinergic receptors M1, M2, and M4. It is used to treat symptomatic Parkinson's disease and extrapyramidal dysfunction induced by antipsychotic drugs.

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.)