What Is Cisapride?

Cisapride is also known as Preborn; cisapride, with the chemical formula C23H29ClFN3O4, molecular weight 465.94500, is white to slightly beige powder, density: 1.29 g / cm3, melting point: 107-111ºC, boiling point: 605.4ºC at 760 mmHg. It belongs to benzamide derivative and is a new type of whole gastrointestinal prokinetic drug.

Chinese name: Cisapilli
Foreign name: Cisapride

Molecular weight: 465.95
CAS: NO.81098-60-4
Molecular formula: C23H29ClFN3O4

Brief introduction of cisapride compounds

Cisapride Basic Information

Chinese name

Chinese alias: Preborn; cisapride; (+/-)-cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3 -Methoxy-4-piperidinyl] -2-methoxybenzamide;

English name: cisapride

English alias: Alimix; CIPRIL; prepulsid; propulsid; Risamol; ACENALIN; Risamal;

CAS number: 81098-60-4

MDL number: MFCD03305346

EINECS number: 279-689-7

RTECS number: CU9372000

Molecular formula: C ₂₃ H ₂₉ ClFN ₃ O ₄

Structural formula:

Molecular weight: 465.94500

Exact mass: 465.18300 ^[1]

PSA: 86.05000

LogP: 4.26810

Physical properties of cisapride

Appearance and properties: white to slightly beige powder

Density: 1.29 g / cm ³

Melting point: 107-111ºC

Boiling point: 605.4ºC at 760 mmHg

Flash point: 319.9ºC

Refractive index: 1.591

Storage conditions: Keep in a cool, dry, dark location in a tightly sealed container or cylinder. Keep away from incompatible materials, ignition sources and untrained indliduals. Secure and label area. Protect containers / cylinders from physical damage. ^[1]

Cisapride Safety Information

Customs Code: 2942000000

WGK Germany: 2

Danger category code: R41

Safety instructions: S26-S39

RTECS number: CU9372000

Dangerous Goods Sign: Xi

Hazardous Substances Data 81098-60-4 ^[1]

Cisapride Toxicology Data

1. Acute toxicity: TDLo not reported in female route: 400 g / kg / 2D-I; TDLo not reported in female route: 200 g / kg;

Oral LD50 in rats: 4166mg / kg; LD50 in rat abdominal cavity: 3435mg / kg; LD50 in rat skin contact:> 2250mg / kg;

Intravenous injection of LD50 in rats: 27400 g / kg; oral LD50 of mice: 8715mg / kg; LD50 of mouse abdominal cavity:> 1mg / kg;

Mouse skin contact LD50:> 1mg / kg; mouse intravenous LD50: 32200g / kg;

2. Other multi-dose toxicity: rat oral TDLo: 14600 mg / kg / 52W-C; rat oral TDLo: 3600 mg / kg / 90D-I; ^[2]

Cisapride calculated chemical data

1. Reference value for calculation of hydrophobic parameters (XlogP): 3.4

2. Number of hydrogen-bonded donors: 2

3. Number of hydrogen bond acceptors: 7

4. Number of rotatable chemical bonds: 9

5. Number of tautomers: 3

6. Topological molecular polar surface area (TPSA): 86.1

7, the number of heavy atoms: 32

8. Surface charge: 0

9. Complexity: 581

10. Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 2

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0 ^[2]

15. Number of covalent bond units: 1

Cisapride uses

1. Gastrointestinal power drugs can strengthen and coordinate gastrointestinal movements, prevent food retention and reflux, and have antiemetic effects.

2. It also has a strong stabilization effect, which can be used as a treatment for mental illness. There is no blocking of dopamine receptors and direct stimulation of cholinergic receptors, so there are no corresponding side effects.

3. For gastroparesis, gastro-esophageal reflux, upper gastrointestinal discomfort, chronic constipation, pseudo-intestinal obstruction, etc. ^[1]

Cisapride production method

Dehydration amidation of 3-methoxy-4-aminopiperidine and 4-acetamino-2-methoxy-5-chlorobenzoic acid to form 4-acetamino-2-methoxy-5-chloro-N- ( 3-Methoxy-4-piperidinyl) benzamide, and then nitrogen alkylation reaction with p-fluorophenylchloropropyl ether, acidification and hydrolysis to produce cisapride. ^[2]

Cisapride pharmacopoeia standards

Main active ingredients of cisapride

This product contains anhydrous cisapride (C23H29ClFN3O4) should be 90.0% to 110.0% of the labeled amount. ^[3]

Cisapride traits

This product is a white tablet. ^[3]

Cisapride identification

(1) Take an appropriate amount of fine powder of this product (approximately 20 mg of anhydrous cisapride), add 4 ml of acetone, shake for 10 minutes, filter, and use the filtrate as a test solution; take another cisapride reference product Appropriate amount, add acetone to make a solution containing 5.2mg per 1ml, as a reference solution, test according to thin-layer chromatography (Chinese Pharmacopoeia 2000 edition, Appendix II V B), draw 1l of each of the two solutions; point at the same Whatman Kc-18F is a thin layer of reversed phase, using methanol-water-acetonitrile-concentrated ammonia solution (60: 25: 15: 1) as the developing agent. After being developed, it is dried and placed under an ultraviolet light (254nm) for inspection. The color and position of the main spots of the test solution should be the same as the main spots of the reference solution. ^[3]

(2) Take the solution under the content determination method and measure it in the wavelength range of 240 ~ 340nm according to the spectrophotometry (Chinese Pharmacopoeia 2000 Version Two Appendix IV A). The absorption spectra of the test solution and the reference solution should be consistent . ^[3]

Cisapilli Check

Content uniformity Take 1 tablet of this product, put it in a 200ml measuring bottle (100mg measuring bottle for 5mg specification), and add an appropriate amount of 0.01mol / L hydrochloric acid solution. After shaking for 30 minutes, add 40ml of methanol (5mg specifications plus 20ml of methanol), shake for 45 minutes, add 0.01mol / L hydrochloric acid solution to dilute to the mark, shake well, filter, and discard the initial filtrate.

Precisely take 25ml of the filtrate, place it in a 50ml measuring flask, add 0.01mol / L hydrochloric acid solution to dilute to the mark, shake well, and use it as the test solution; take another appropriate amount of cisapride monohydrate, weigh it accurately, add methanol production.

Each 1ml contains 0.52mg of solution. As a stock solution, accurately measure 5ml, place it in a 100ml measuring bottle, add 5ml of methanol, and add 0.01mol / L hydrochloric acid solution to dilute to the mark. Shake well as a reference solution. The test solution and the reference solution should be measured spectrophotometrically (Chinese Pharmacopoeia 2000 Edition Part II Appendix IV A), and the absorbance should be measured at a wavelength of 308nm.

Take this product for dissolution, according to the dissolution test method (Chinese Pharmacopoeia 2000 edition, Appendix X C, second method), take sodium chloride solution (take 20g of sodium chloride, put it in a 1000ml measuring bottle, add an appropriate amount of water and 7.0ml of hydrochloric acid Dissolve, dilute to the mark with water, shake to obtain 800ml as the solvent, rotate at 100 revolutions per minute, operate according to law, after 45 minutes, take an appropriate amount of solution, filter, discard the initial filtrate, and use the filtrate as a supply For the test solution, another 2 ml of the stock solution under the uniformity content was accurately measured, put into a 100 ml measuring bottle, diluted with the above sodium chloride solution to the mark, shake well, and used as a reference solution. Spectrophotometric method (Chinese Pharmacopoeia 2000 Appendix IV of the Second Edition of the Year Edition A), the absorbance was measured at a wavelength of 274 nm, and the dissolution amount of each piece was calculated. The limit was 75% of the labeled amount, which should meet the requirements.

Others should comply with the relevant provisions under the tablet (Chinese Pharmacopoeia 2000 Edition Appendix IIA). ^[3]

Determination of cisapride

Take 20 tablets of this product, accurately weigh, grind and weigh appropriately (approximately 10mg of cisapride), put in a 200ml measuring bottle, add 80ml of 0.01mol / L hydrochloric acid solution, shake for 30 minutes, add 40ml of methanol , Shake for 45 minutes, add 0.01mol / L hydrochloric acid solution to dilute to the mark, shake well, filter, discard the initial filtrate, accurately measure the continuous filtrate 25ml, put in a 50ml measuring flask, add 0.01mol / L hydrochloric acid solution to dilute to Scale, shake, and use it as the test solution; prepare the reference solution according to the content uniformity method, and use the spectrophotometry method (Chinese Pharmacopoeia 2000 Edition, Appendix II IV A) to measure the absorbance at a wavelength of 308nm. Calculate. ^[3]

Cisapride pharmacology and toxicology

Animal

(1) In isolated organs, it can prevent gastric relaxation, accelerate gastric motility, and coordinate the movement of the antrum, duodenum, small intestine, and large intestine.

(2) In dogs, it can enhance the digestive activity of the gastric antrum and duodenum, coordinate and strengthen gastric emptying, increase the peristalsis of the small and large intestines, and shorten the time of intestinal movement, but it does not affect gastric secretion.

(3) The mechanism of action is mainly to promote the physiological release of acetylcholine in the intestinal myenteric plexus.

(4) Does not stimulate muscarinic and nicotinic receptors, nor inhibits the activity of acetylcholinesterase.

(5) No dopamine receptor blocking effect at the therapeutic dose.

(6) Mainly distributed in stomach and intestine tissue.

2. Humans:

(1) Gastrointestinal tract dynamic effect:

Esophageal: Enhance esophageal motility and lower esophageal sphincter tension; prevent gastric contents from flowing back into the esophagus, and improve esophageal clearance.

Stomach: Increase the coordination between stomach and duodenum contractility and gastric antrum-duodenum; reduce duodenum-gastric reflux; improve gastric and duodenal emptying.

Intestine: strengthen the movement of the intestine and promote the transport of the small and large intestine.

3. Other effects:

(1) Due to the lack of the pseudocholine effect, the gastric acid secretion caused by basal and pentagastrin is not increased.

(2) Due to the relative lack of dopamine antagonist properties, plasma prolactin levels are hardly affected.

(3) Does not affect psychomotor sexual function, blood pressure, respiratory rate, body temperature, weight and anticoagulant function.

(4) The pharmacological effect begins 30 to 60 minutes after oral administration. ^[4]

Cisapride pharmacokinetics

1. Absorption is rapid and complete after oral administration, peak blood concentration is reached within 1 to 2 hours, and half-life is 10 hours. It is extensively metabolized by oxidative dehydrocarbonation and aromatic hydroxylation, and almost all metabolites pass through feces approximately equally , Urine excretion, breast milk excretion rarely.

2. The absolute bioavailability of oral administration is about 40%. The blood drug concentration increases proportionally with the oral dose (5-20 mg).

3. In the steady state, the blood concentration before oral administration of 5mg three times daily and 10mg three times daily before morning medication and peak plasma drug concentration levels fluctuated between 10-20ng / ml, 30-60ng / ml and 20-40ng respectively. / ml, 50 100ng / ml.

4. Pharmacokinetics and steady-state plasma concentrations have nothing to do with the duration of treatment, concomitant use of cimetidine can slightly increase oral bioavailability. Can be widely bound to plasma proteins (97.5%). ^[4]

Cisapride indications

Total gastrointestinal prokinetic drugs. Mainly used for functional dyspepsia, X-ray, endoscopic negative upper gastrointestinal discomfort, symptoms of early satiety, fullness after meals, decreased appetite, bloating, excessive belching, lack of appetite, nausea, vomiting or A complaint similar to ulcers (burning in the upper abdomen). It can also be used for the treatment of mild reflux esophagitis. ^[4]

Cisapride Specifications

5 mg (calculated as C23H29ClFN3O4). ^[4]

Xisha must be used

Orally, the total amount of 15 to 40 mg per day for adults is divided into 2 to 4 times according to the condition.

(1) General condition: 5mg once, 3 times a day.

(2) Severe condition: (gastroparesis, esophagitis, refractory constipation) 10 mg once, 3 times a day, or 10 mg once, 4 times a day, before meals and before bedtime. Or 20mg once, twice a day, before breakfast and before bedtime.

(3) Maintenance treatment of esophagitis: 10mg once a day, twice a day (before breakfast and before bedtime) or 20mg once a day (before bedtime), the dose can be doubled for those with severe illness.

(4) For the treatment of upper gastrointestinal dysfunction, it should be taken with certain drinks at least 15 minutes before meals and appropriate time before bedtime.

(5) For the treatment of constipation, the total daily dose should be taken twice. There are large differences among individuals regarding the dosage, daily frequency, course of treatment, and whether maintenance treatment is needed (sufficient once a day). Generally, symptoms can be improved within a week, but the ideal treatment effect for severe constipation may require 2 3 months. ^[4]

Cisapride adverse reactions

Due to the pharmacological activity of this product, transient abdominal cramps, diarrhea and diarrhea may occur. When abdominal cramps occur, the dose can be reduced by half; if diarrhea occurs after the medication for infants and young children, the dose should be reduced.
Occasional allergic reactions include rash, pruritus, urticaria, bronchospasm, mild transient headache or dizziness, and reports of dose-related frequent urination.
Very few reports of arrhythmia include ventricular tachycardia, ventricular fibrillation, apical torsional ventricular tachycardia, and prolonged QT. Most of these patients often take several other drugs at the same time-including drugs that inhibit the enzyme CYP3A4 enzyme-or they already have heart disease and risk factors for arrhythmia.
Rare reports of reversible liver dysfunction, with or without cholestasis. Although there have been cases of male and female breasts and lactation, the incidence (<0.1%) in large-scale surveillance studies did not exceed the common value of the general population, and all these events were reversible. Its causal relationship with cisapride is not clear.
It has been individually reported to affect the central nervous system, namely convulsive epilepsy, extrapyramidal response and frequent urination. ^[4]

Cisapride Taboo

Known allergic to this product is prohibited.
Drugs that inhibit the simultaneous use of potent or parenteral inhibitors of the CYP3A4 enzyme, including: triazole antifungals; macrolide antibiotics; HIV protease inhibitors; nafazodone.
Heart disease, arrhythmia, and QT interval prolongation are prohibited, and it is prohibited to use it with drugs that cause QT interval prolongation. Patients with water and electrolyte disorders are prohibited, especially those with hypokalemia and hypomagnesemia. Disabled; disabled with congenital QT prolongation or family history of congenital QT interval prolonged syndrome; disabled patients with pulmonary, liver, and renal dysfunction.
Disabled for infants and young children. ^[4]

Cisapride Notes

During the medication, attention should be paid to detecting the electrocardiogram.

Patients who can cause harm due to increased gastrointestinal movement must be used with caution.
Have a family history of sudden death, you must weigh the advantages and disadvantages and use this product with caution.
This product should not be used in patients with QTc interval greater than 450 milliseconds or patients with electrolyte disorders.
This product does not affect psychomotor sexual function, does not cause sedation and drowsiness. However, this product can accelerate the absorption of inhibitors of the central nervous system, such as barbiturates, alcohol, etc., so it should be given with caution. ^[4]

Cisapride for pregnant and lactating women

Animal reproductive toxicity and teratogenicity studies have shown that this product does not affect embryo formation, no primitive embryo toxicity, and no teratogenic effects. In a large number of population studies, cisapride does not increase fetal aberrations. But pregnant women, especially in the first trimester of pregnancy, should weigh the pros and cons.
Although the amount of milk excreted is small, it is recommended to avoid breastfeeding mothers. ^[4]

Cisapride for children

Use with caution.

Cisapride for the elderly

In elderly patients, due to the moderate delay in the elimination half-life of this product, the steady-state plasma concentration will generally increase, so the therapeutic dose should be reduced and used with caution. ^[4]

Cisapride drug interactions

The main metabolic pathway of this product is metabolism by CYP3A4 enzyme. Concomitant oral or parenteral use of drugs that inhibit this enzyme can lead to increased plasma cisapride levels, thereby increasing the risk of QT intervals and arrhythmias, which include ventricular tachycardia, ventricular fibrillation and apex Twisted ventricular tachycardia. So it is forbidden to take these drugs at the same time.

E.g:

Triazole antifungals: such as ketoconazole, itraconazole, miconazole, fluconazole.

Macrolide antibiotics: such as erythromycin, clarithromycin, aceandomycin.

HIV protease inhibitors: In vitro tests have shown that Ritonavir and Indinavir are strong inhibitors, while Saquinavir is a weak inhibitor.

Nefazodone.

It is forbidden to use this product at the same time as drugs that cause prolongation of QT interval. Such as: antiarrhythmic drugs (such as IA: quinidine, propidamine, procainamide; class III: amiodarone, sotalol); tricyclic antidepressants (such as amitriptyline) ;

Tetracyclic antidepressants (such as maprotiline); antipsychotics (such as phenothiazine and pimozide); antihistamines (such as astemizole and terfenadine); benzpredil; Pan group and so on.

When this product is taken with grapefruit juice, the oral bioavailability of cisapride will increase by about 50%. It is recommended to avoid taking it with grapefruit juice as much as possible.

Cimetidine can cause a slight increase in plasma concentrations of cisapride but has no clinical significance.

This product can accelerate gastric emptying and affect the drug absorption rate: drugs absorbed through the stomach can be reduced and drugs absorbed through the small intestine may increase (such as benzodiazepines, anticoagulants, acetaminophen, H2 receptor blockers Cut off, etc.).

When patients receive anticoagulants, the clotting time may increase. Therefore, it is recommended to check the clotting time to determine the appropriate dose of anticoagulant within a few days after the product is started and when it is stopped.

The sedative effects of benzodiazepines and alcohol may increase.

Most of the effects of this product on gastrointestinal motility can be blocked by anticholinergic drugs. For individual drugs related to this product, it is beneficial to monitor their plasma levels when determining the dosage. ^[4]

Cisapride overdose

Symptoms: Overdose often manifests as abdominal cramps and increased defecation. Rarely reported cases of prolonged QT interval and ventricular arrhythmias.
Infants (less than 1 year old) are disabled. Symptoms such as mild sedation, indifferent emotions, and lack of tension can occur when overdosed by mistake.

Treatment: Once overdose, it is recommended to take activated charcoal and observe the patient closely. It is recommended to pay close attention to the possibility of prolongation of the QT interval and factors that produce apical torsional ventricular tachycardia, such as the presence of electrolyte disturbances (especially hypokalemia or hypomagnesemia) and bradycardia. ^[4]

Cisapride storage

Sealed and stored in a cool and dry place. ^[4]