What Is Entacapone?

Entacapone (E) -2-cyano-3- (3,4-dihydroxy-5-nitrophenyl) -N, N-diethyl-2-acrylamide, yellow Powder, molecular formula is C14H15N3O5, molecular weight is 305.28600, density is 1.392g / cm3, melting point is 162-1630C, boiling point is 526.6ºC at 760 mmHg. Clinically, it is mainly used as an adjuvant for levodopa for the treatment of Parkinson's disease.

Chinese name: Entacapone
Foreign name: Flurbiprofen
CAS number: 130929-57-6

Molecular formula: C14H15N3O5
Molecular weight: 305.28600
Melting point: 162-163

Entacapone compounds

Entacapone Basic Information

Chinese name

Chinese alias: (2 E ) -2-cyano-3- (3,4-dihydroxy-5-nitrophenyl) -N, N-diethyl-2-acrylamide; ( E) -2- Cyano-3- (3,4dihydroxy-5-nitrobenzene) -N, N diethylacrylamide; Antocapone F · S; Antocapone; ( E ) -2-cyano- 3- (3,4-dihydroxy-5-nitrophenyl) -N, N -diethyl-2-acrylamide;

English name: entacapone

English alias: OR-611; Comtes; 2-Cyano-N, N-diethyl-3- (3,4-dihydroxy-5-nitrophenyl) propenamide; Comtess; Entacapone;

CAS number: 130929-57-6

Molecular formula: C ₁₄ H ₁₅ N ₃ O ₅

Chemical structure:

Molecular weight: 305.28600

Exact mass: 305.10100

PSA: 130.38000

LogP: 2.30458 ^[1]

Entacapone materialized properties

Appearance and properties: yellow powder

Density: 1.392g / cm ³

Melting point: 162-163 ° C

Boiling point: 526.6ºC at 760 mmHg

Flash point: 272.3ºC

Refractive index: 1.641

Vapor pressure: 1.05E-11mmHg at 25 ° C ^[1]

Entacapone molecular structure data

1. Molar refractive index: 79.12

2. Molar volume (cm3 / mol): 219.2

3. Isotonic specific volume (90.2K): 629.8

4. Surface tension (dyne / cm): 68.1

5. Polarizability (10-24cm3): 31.36 ^[2]

Entacapone Computational Chemistry Data

1. Hydrophobic parameter calculation reference value (XlogP): 2.1

2.Number of hydrogen-bonded donors: 2

3.Number of hydrogen bond acceptors: 6

4.Number of rotatable chemical bonds: 4

5.Number of tautomers: 16

6. Topological molecular polar surface area 130

7.Number of heavy atoms: 22

8.Surface charge: 0

9.Complexity: 500

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 1

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 1 ^[2]

Entacapone synthesis

1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of N, N-diethylcyanoacetamide and a catalytic amount of piperidine acetate were dissolved in 40 ml of dry ethanol and stirred overnight to obtain 2.23 g crude product, yield 73%, melting point 153 156 .

2. Heat at 90 ° C and dissolve 3.0kg of crude product in 8.0kg of acetic acid (or formic acid) containing 80gHBr (or 40gHCl). Slowly cool to 20 ° C and stir at this temperature for 20h, then stir at 15 ° C for 6h. The precipitated crystals were collected by filtration, and carefully washed with a cold (4 ° C) 1L toluene-acetic acid (1: lv / v) mixture, and then with 1L of cold toluene. Drying under vacuum at 45 ° C, 2.4 kg crystalline pure entacapone, yield 80%, mp162 ~ 163 . ^[1]

Entacapone uses

COMT inhibitor for the treatment of Parkinson's disease.

This product is a new generation of COMT (catechol-O-methyltransferase) inhibitor, a highly effective COMT inhibitor with strong selectivity, low toxicity, and oral activity. It is used in the treatment of Parkinson's disease and can effectively inhibit O-methylation of levodopa increases the bioavailability of levodopa in the center, reduces its dosage and number of medications, and improves the movement fluctuations caused by long-term treatment of levodopa. The patient is well tolerated, but the action time is longer. Short (2h). ^[1]

Introduction to Entacapone Compounds

Entacapone drug name:

[Common name] Entacapone

[Product Name] Comtan® Comtan

[English name] Entacapone Tablets

Chinese Phonetic Alphabet En Ta Ka Peng Pian

Entacapone ingredients:

Active Ingredient: Entacapone

Chemical name: (E) -2-cyano-3- (3,4-dihydroxy-5-nitrophenyl) -N, N-diethyl-2-acrylamide

Molecular formula: C14H15N3O5

Molecular weight: 305.28

Entacapone category:

Chemicals & Biological Products >> Nervous System Drugs >> Anti-Parkinson's Disease and Other Dyskinesia Drugs >> Anti-Parkinson's Disease Drugs

Entacapone traits:

This product is an orange-brown oval film-coated tablet, which is yellow after removing the coating.

Entacapone indications:

This product can be used as an adjunct to the standard drugs levodopa / benzidazide or levodopa / carbidopa. It is used to treat Parkinson's disease and end-of-dose phenomenon (symptom fluctuation) that cannot be controlled by the above drugs.

Entacapone Usage and Dosage:

Method of administration: This product is an oral preparation and should be taken at the same time as levodopa / benzyrazide or levodopa / carbidopa. The prescription information of these levodopa preparations is also applicable when combined with this product. This product can be taken at the same time or with food (see [Pharmacokinetics]).

Dosage: 0.2g (one tablet) of this product is given each time the levodopa / dopa decarboxylase inhibitor is taken. The maximum recommended dose is 0.2g (one tablet) 10 times a day, which is 2g of this product.

This product enhances the efficacy of levodopa. Therefore, to reduce dopaminergic adverse reactions associated with levodopa, such as dyskinesias, nausea, vomiting, and hallucinations, it is often necessary to adjust the dose of levodopa within the first few days to weeks of treatment with this product. Depending on the clinical manifestations of the patient, the daily dose of levodopa can be reduced by 10% -30% by extending the dosing interval and / or reducing each dose of levodopa. If the treatment of this product is interrupted, the dose of other anti-Parkinson's treatment drugs, especially levodopa, must be adjusted to reach a level sufficient to control the symptoms of Parkinson's disease.

This product increases the bioavailability of standard levodopa / benzirazide formulations by 5-10% more than the standard levodopa / carbidopa bioavailability. Therefore, patients taking levodopa / benserazide preparations need to reduce the amount of levodopa to a large extent when starting the combination. Renal insufficiency does not affect the pharmacokinetics of this product, so no dose adjustment is needed. However, for patients undergoing dialysis, consideration should be given to extending the interval between medications (see [Pharmacokinetics]).

This product has not been studied in patients under 18 years of age, so it is not recommended for patients under this age.

Entacapone adverse reactions:

In the double-blind, placebo-controlled phase III clinical trial, very common adverse reactions were found to be dyskinesia, nausea, and abnormal urine color. Common adverse reactions in double-blind placebo-controlled studies were diarrhea, increased symptoms of Parkinson's disease, dizziness, abdominal pain, insomnia, dry mouth, fatigue, hallucinations, constipation, dystonia, hyperhidrosis, hyperkinesia, headache, legs Spasm, confusion, nightmares, falls, orthostatic hypotension, dizziness, and tremors.

Most of the adverse reactions of this product are related to enhancing dopaminergic activity, and most often occur at the beginning of treatment. Reducing the dose of levodopa can reduce the severity and incidence of these adverse events. Another major type of adverse reaction is gastrointestinal symptoms, including nausea, vomiting, abdominal pain, constipation, and diarrhea. This product can make urine become reddish brown, but this phenomenon is not harmful. Usually the adverse reactions of this product are mild to moderate. The most common adverse reactions that led to discontinuation of treatment were gastrointestinal symptoms (such as diarrhea, 2.5%) and dopaminergic symptoms (such as dyskinesia, 1.7%). In clinical studies, the incidence of dyskinesias (27%), nausea (11%), diarrhea (8%), abdominal pain (7%), and dry mouth (4.2%) was higher in patients with entacapone than in the placebo group. Some adverse events, such as dyskinesia, nausea, and abdominal pain, are more common in the high-dose (1.4-2g / d) group than in the low-dose group. Treatment with this product has reported a slight decrease in hemoglobin, red blood cell count, and hematocrit. The mechanism may be related to reduced iron intake from the gastrointestinal tract. After receiving long-term treatment of this product (6 months), clinically significant hemoglobin levels decreased in 1.5% of patients. ^[3]

Rarely, clinically significant elevations of liver enzymes have been reported.

The adverse drug reactions listed in Table 1 were collected from Entacapone's clinical studies and post-marketing use.

Adverse reactions are listed in descending order according to their frequency of occurrence; the following provisions are adopted:

Very common (³1 / 10); common (³1 / 100, <1/10); uncommon and uncommon (³1 / 1000, <1/100); rare (³1 / 10000, <1/1000); very rare ( <1/10000), unknown unknown (cannot be evaluated based on available data, because valid evaluation results cannot be obtained from clinical trials or epidemiological studies).

A case report has shown that the use of levodopa by Entacapone is associated with daytime drowsiness and sudden onset of sleep (see [Precautions] for the effects on driving and operating machinery).

Individual case reports indicate the occurrence of malignant nerve block syndrome (NMS), especially after sudden reductions or discontinuations of entacapone and other dopaminergic drugs.

Case reports include cholestatic hepatitis. Case reports include malignant nerve block syndrome and rhabdomyolysis (see [Precautions]).

Patients with Parkinson's disease, after receiving dopamine agonists and other dopaminergic treatments, such as entacapone in combination with levodopa, especially when used in large doses, have reported symptoms of pathological gambling, increased libido, and hypersexuality. These symptoms It is usually reversed after the drug dose is reduced or treatment is terminated.

Entacapone Taboo:

Known to be allergic to this product or any other component

Hepatic insufficiency (see [Pharmacokinetics])

This product is not suitable for patients with pheochromocytoma because it has the risk of increasing hypertension crisis

It is contraindicated to use non-selective MAO (MAO-A and MAO-B) inhibitors (such as phenelzine, tranylcypromine) simultaneously with this product. Similarly, the simultaneous use of selective MAO-A inhibitors and selective MAO-B inhibitors is contraindicated.

This product can be used in combination with selegiline (selective MAO-B inhibitor), but the daily dose of the latter cannot exceed 10 mg (see [Drug Interactions]).

Patients with a previous history of malignant nerve block syndrome (NMS) and / or non-traumatic rhabdomyolysis are contraindicated.

Entacapone notes:

Patients with Parkinson's disease occasionally develop rhabdomyolysis or malignant nerve blocker syndrome (NMS) secondary to severe dyskinesia. Cases of rhabdomyolysis have been reported in patients receiving entacapone treatment.

NMS, including rhabdomyolysis and high fever, motor symptoms (tonicity, myoclonus, tremor), altered mental status (such as irritability, confusion, coma), high fever, autonomic dysfunction (tachycardia, blood pressure Stable) and increased serum creatine phosphokinase. In individual cases, only certain symptoms and / or signs may appear.

Cases of NMS have been reported, especially after abrupt reductions or discontinuation of entacapone and other dopaminergic drugs. Therefore, if necessary, the withdrawal process should be slow for entacapone and other dopaminergic drugs. However, if symptoms and / or signs still occur after a slow withdrawal, you need to increase the dose of levodopa.

Entacapone should be used with caution in patients with ischemic heart disease.

Due to its mechanism of action, this product may interfere with the metabolism of catechol-containing structural drugs and enhance their effect. Therefore, for those patients receiving drugs that are metabolized through COMT, such as limetrol, isoprenaline, epinephrine, norepinephrine, dopamine, dobutamine, a-methyldopa, and apo Morphine should be given with caution (see [Drug Interactions]).

This product is always used as an adjunct to levodopa treatment. Therefore, the precautions for levodopa treatment should also be taken into account in the treatment of this product. This product increases the bioavailability of standard levodopa / benzyrazine formulations by 5-10% more than the standard levodopa / carbidopa bioavailability. Drugs are more likely to have adverse dopaminergic reactions during treatment. In order to reduce dopaminergic adverse reactions related to levodopa, it is usually necessary to adjust the dosage of levodopa within the first few days to weeks of the treatment of this product according to the clinical manifestations of the patient (see [Dosage and Administration] and [Adverse Reactions]) .

This product may aggravate orthostatic hypotension caused by levodopa. This product should be used with caution when patients are taking other drugs that can cause orthostatic hypotension.

In clinical studies, adverse effects of dopaminergic reactions, such as dyskinesias, are more common when this product is combined with dopamine receptor agonists (such as bromocriptine), selegiline, or amantadine compared with placebo in combination with the above drugs. . When starting this product, you may need to adjust the dose of other anti-Parkinson's drugs.

Entacapone in combination with levodopa has reported cases of excessive lethargy and sleep onset during the day.

For patients with diarrhea, it is recommended to track their weight to avoid possible excessive weight loss. Suspected long-term or persistent diarrhea associated with entacapone may be a sign of colitis. In the case of long-term or persistent diarrhea, entacapone should be discontinued and appropriate medical treatment and investigation of patients should be considered.

For patients with progressive anorexia, weakness, and short-term weight loss, a systemic medical assessment including liver function should be considered.

Patients with Parkinson's disease who have received dopamine agonists and other dopaminergic treatments, such as entacapone in combination with levodopa, have reported pathological gambling, increased libido, and hypersexual symptoms.

Kedan® tablets contain sucrose and should not be used in a very small number of patients with genetic disorders who have fructose intolerance, glucose-galactose malabsorption, or invertase-isomaltase deficiency.

Impact on the ability to drive and operate machinery

Entacapone in combination with levodopa can cause dizziness and other orthostatic symptoms. Therefore, use caution when driving and operating machinery.

Patients with drowsiness and / or sudden onset after receiving entacapone and levodopa should be advised not to drive or perform any work that requires alertness (such as operating machinery ), Or you may cause serious injury or death to yourself or others (see [Precautions]).

Entacapone medication for pregnant and lactating women:

In animal studies, when the concentration of this product was significantly higher than the therapeutic concentration, no obvious teratogenic or primary fetal toxicity was found. However, there is no experience with this product in pregnant women, so it is not recommended for use during pregnancy.

In animal tests, this product can be excreted through milk. Its safety to infants is still unknown, and therefore should not be breast-fed during the treatment of this product.

Entacapone medication for the elderly:

No dosage adjustment is needed for the elderly.

Entacapone Drug Interactions:

No interaction was observed between this product and carbidopa at the recommended dose. The pharmacokinetic interaction between this product and benzirazine has not been studied. In a single-dose study of healthy volunteers, no interactions were observed between this product and imipramine, and this product and morph Clobamide. Similarly, no interaction between this product and selegiline was observed in repeated dosing studies in patients with Parkinson's disease. However, this product and several of the following drugs include MAO-A inhibitors, tricyclic antidepressants, norepinephrine reuptake inhibitors such as desipramine, maprotiline, venlafaxine, and catechins Drugs whose phenol structure is metabolized by COMT (such as catechol-structured compounds: Rimitrolol, cloprolin, adrenaline, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apo Clinical experience with morphine and paroxetine interactions is limited. These drugs should be used with caution in combination with entacapone (see [Precautions]).

This product can form chelate with iron in the gastrointestinal tract, and the interval between taking this product and iron preparations is at least 2-3 hours (see [Adverse Reactions]). This product binds to human albumin binding site II, which also binds to other drugs such as diazepam and ibuprofen. No clinical studies have been conducted on the interactions with diazepam and non-steroidal anti-inflammatory drugs. In vitro experiments showed that no significant displacement reaction occurred at drug treatment concentrations.

Due to its affinity for cytochrome P450 2C9 in vivo, entacapone may affect drugs that need to be metabolized by isoenzymes, such as: S-warfarin. Although a study of drug interactions in healthy volunteers showed that entacapone did not change the plasma concentration of S-warfarin, the AUC of R-warfarin increased by an average of 18%. The INR value increased by an average of 13% [CI906-19%]. Therefore, it is recommended to control the INR value when starting entacapone treatment in patients receiving warfarin.

Entacapone overdose:

In the post-marketing data, in the case of entacapone overdose cases, the maximum daily dose of entacapone was 16,000 mg. Acute symptoms and signs in these overdose cases include blurred consciousness, decreased activity, lethargy, muscle weakness, discoloration of the skin, and urticaria.

Entacapone clinical trials:

In two phase III double-blind studies, a total of 376 patients with end-of-dose motor fluctuations in Parkinson's disease were given entapacarb or placebo while giving levodopa / dopa decarboxylase inhibitors. The above studies are listed in Table 2. In Study I, the daily "open" period (hours) was assessed by the family diary, and in Study II the "open" period was assessed by the proportion.

Entacapone Pharmacology and Toxicology:

This product is a catechol-O-methyltransferase (COMT) inhibitor. It is a reversible, specific COMT inhibitor that acts primarily on the periphery and is used concurrently with levodopa preparations. This product reduces L-dopa metabolism to 3-O-methyldopa (3-OMD) by inhibiting COMT enzyme. This increases the bioavailability of levodopa and increases the total amount of levodopa available in the brain, a role that has been demonstrated in clinical trials. Clinical trials have shown that levodopa plus this product can extend the "on" time by 16% and shorten the "off" time by 24%. This product mainly inhibits COMT enzymes in peripheral tissues. COMT inhibition in red blood cells is closely related to the plasma concentration of this product, which confirms the reversibility of COMT inhibition.

Entacapone pharmacokinetics:

Absorption: This product varies greatly within and between individuals. Oral 200mg of this product, usually reach the peak plasma concentration (Cmax) in about 1 hour. The drug is mainly metabolized by first pass. The bioavailability of a single oral entacapone was 35%. Food had no significant effect on the absorption of entacapone.

Distribution: After absorption from the gastrointestinal tract, this product is quickly distributed in peripheral tissues with a distribution volume of 20L. About 92% of the drugs are cleared in the beta phase and the clearing half-life is 30 minutes. The total clearance is about 800ml / min.

This product is widely combined with plasma proteins, mainly with albumin. Within the therapeutic concentration range, the unbound portion of human plasma is about 2%. At the therapeutic concentration, this product does not replace other drugs that are widely bound with proteins (such as warfarin, salicylic acid, buta pine, diazepam), and any of these drugs is at the therapeutic concentration or higher There will be no significant replacement for this product.

Metabolism: A small amount of the (E) isomer of entacapone is converted to the (Z) isomer. (E) Isomers account for 95% of entacapone AUC. (Z) Isomers and other trace metabolites account for the remaining 5%.

Results of in vitro studies using human liver microsome preparations showed that entacapone was able to inhibit cytochrome P450 2C9 (IC50 ~ 4M). Entacapone has little or no inhibitory effect on other types of isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19).

Elimination: Elimination of this product is mainly through non-kidney metabolic pathways. It is estimated that 80-90% of the drug is excreted in feces, but it has not been confirmed in humans. About 10-20% of this product is excreted in the urine, and only a small amount appears in the urine as a prototype. Most of the drugs (95%) excreted in the urine are combined with glucuronic acid. Only about 1% of metabolites found in urine are oxidized.

Affected population: The pharmacokinetic characteristics of this product are similar in young and old people. Patients with mild to moderate hepatic insufficiency (Child-Pugh classifications A and B) have slowed drug metabolism and increased plasma concentrations of this product during the absorption and clearance phases. Renal insufficiency does not affect the pharmacokinetics of this product, but in patients undergoing dialysis treatment, consideration should be given to extending the dosing interval. ^[3]

Entacapone Expert Reviews

Entacapone is a highly selective and potent catecholamine oxygen-methyltransferase (COMT) inhibitor. However, it rarely penetrates the blood-cerebrospinal fluid barrier and acts mainly in the intestine. Adjuvant medication for levodopa. ^[4]