What Is Sibutramine?

Sibutramine is chemically named 1- (4-chlorophenyl) -N, N-dimethyl-A- (2-methylpropyl) cyclobutylmethylamine. It is a white crystalline powder, CAS No .: 106650-56-0, molecular formula: C17H26ClN. It is mainly used for the treatment of obesity.

Chinese name: Sibutramine
Foreign name: Sibutramine

CAS number: 106650-56-0
Molecular formula: C17H26ClN

Sibutramine compound profile

Sibutramine Basic Information

Chinese name

Chinese alias: West Quming; 1- (4-chlorophenyl) -N, N-dimethyl-A- (2-methylpropyl) cyclobutanamine;

English name: Sibutramine

English alias: 1- [1- (4-chlorophenyl) cyclobutyl] -N, N, 3-trimethylbutan-1-amine; Sibutramina [Spanish]; Medaria; (±) -Sibutramine; N, N-dimethyl-1- [ 1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine; Sibutramina; Sibutraminum; Reductil; N- {1- [1- (1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine; Sibutraminum [Latin ]; Butramin; Meridia;

CAS number: 106650-56-0

Molecular formula: C ₁₇ H ₂₆ ClN

Structural formula:

Molecular weight: 279.884800

Exact mass: 279.17500

PSA: 3.24000

LogP: 4.73800

Sibutramine physical and chemical properties

Properties: white crystalline powder

Melting point: 191-192 ° C ^[1]

Sibutramine molecular structure data

1. Molar refractive index: 83.76

2. Molar volume (cm / mol): 271.3

3. Isometric Zhang Rong (90.2K): 670.5

4. Surface tension (dyne / cm): 373.3

5. Dielectric Constant: None available

6. Polarizability (10cm): 33.2

7. Mass of single isotope: 279.175378 Da

8. Nominal mass: 279 Da

9. Average quality: 279.848 Da

Sibutramine Computational Chemistry Data

1. Hydrophobic parameter calculation reference value (XlogP): 5.4

2.Number of hydrogen bond donors: 0

3.Number of hydrogen bond acceptors: 1

4.Number of rotatable chemical bonds: 5

5.Number of tautomers: none

6. Topological molecular polar surface area 3.2

7.Number of heavy atoms: 19

8.Surface charge: 0

9.Complexity: 275

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 1

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

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

Sibutramine synthesis method

Mix p-chlorobenzoacetonitrile, KOH and acetonitrile at 25%: slowly drop in 1,3-dibromopropane. After dripping, stirring was continued for 1 h, distilled water was added, and extraction was performed with ethyl acetate. The extract was washed with water, saturated brine, and dried. It was filtered, concentrated under reduced pressure, and distilled. A fraction of 160 ° C / 2.13 kPa was collected to obtain compound (I) in a yield of 73% to 74%.

The magnesium flakes were dissolved in anhydrous THF, isobutyl bromide was added dropwise, and then reacted for 1 hour. Then, the anhydrous THF solution of compound (I) was slowly added dropwise, and the solution was refluxed for 4 hours and cooled to room temperature. It was dropped into a solution of KBH4 in isopropanol and refluxed for 4 h. It was allowed to cool, water was added, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine, and dried. It was filtered, and the filtrate was concentrated under reduced pressure and then distilled. A fraction of 170 ° C./0.67 kPa was collected to obtain a compound (II) in a yield of 76% to 79%.

Compound (II), formic acid and 1/2 formaldehyde solution were stirred at 90-92 ° C for 1 h. Add another 1/2 formaldehyde solution and continue the reaction for 1 h. Cool to room temperature, slowly pour into crushed ice with sodium hydroxide, then extract with ether. The extract was washed with saturated brine, water, and dried. After filtration, the filtrate was concentrated to give sibutramine, a yellowish-yellow color, with a yield of 94%. Analytical samples can be recrystallized with diethyl ether, melting point 52-53 ° C.

Sibutramine was dissolved in methanol, concentrated hydrochloric acid was added, and the reaction was performed at 50-60 ° C for 10 minutes. Recover methanol under reduced pressure to crystallize at least the amount, add water, stir, and cool in an ice bath. Filtration and washing gave sibutramine hydrochloride as a crude product, which was recrystallized from methanol-water to give sibutramine hydrochloride as white crystals, with a melting point of 194 ° C and a yield of 83%. ^[2]

Sibutramine use

1.5-HT reuptake inhibitor for the treatment of obesity.

2. As a norepinephrine and 5-HT reuptake inhibitor, sibutramine works mainly through its metabolites. It inhibits the cell's reuptake of monoamine information transmission factors such as 5-HT and norepinephrine, increases physiological satiety, reduces appetite, can also induce thermogenesis, increase energy expenditure, and reduce fat accumulation. It is used for the treatment of obesity that diet control, exercise can not reduce and control weight. ^[2]

Sibutramine pharmacological action

Sibutramine is a non-amphetamine-type appetite suppressant and has antidepressant properties. Sibutramine works mainly through its secondary (M1) and primary (M2) amine metabolites. Its mechanism of action is to inhibit the reuptake of norepinephrine, serotonin and dopamine, and increase satiety It also accelerates energy expenditure without significantly affecting the release of norepinephrine, serotonin, and dopamine. Studies have also shown that sibutramine and its amine active metabolites have no significant anticholinergic, antihistamine, and monoamine oxidase inhibitory effects. ^[3]

Sibutramine pharmacokinetics

After taking sibutramine orally for 8 weeks, the weight loss reached the maximum at 6 months, and the effect of multiple administrations could last for 12 months. The peak time of sibutramine was 1.2 h after oral administration, and the peak time of metabolites M1 and M2 was 3 to 4 hours. Oral bioavailability was 77%. Food can reduce the maximum concentration of metabolites M1 and M2 and delay the peak time, but the area under the curve of M1 and M2 does not change significantly, so the effect of food on drugs can be ignored. The protein binding rates of sibutramine, M1, and M2 were 97%, 94%, and 94%, respectively. The highest concentrations were found in the liver and kidneys after administration. Sibutramine undergoes a large number of first-pass metabolisms in the liver, forming two active metabolites M1 and M2. M1 and M2 are further metabolized to inactive M5 and M6. Oral clearance is 1 750L per hour. The elimination half-life of the parent drug is 1.1 hours, and the half-life of the metabolites M1 and M2 is longer, about 14-16 hours. 77% are excreted by the kidney, about 8% are excreted by feces, and metabolites M5 and M6 are excreted mainly by the kidney. Whether it is secreted via milk is unknown. ^[3]

Sibutramine indication

Sibutramine is suitable for obesity that cannot be reduced and controlled by exercise and diet control. It can reduce weight and maintain the lost weight. Treatment should be combined with a low-calorie diet and exercise. The recommended body mass index of obese patients should be 30kg / m or more and 27kg / m or more and accompanied by other risk factors (such as hypertension, diabetes, dyslipidemia, etc.) ^[3]

Sibutramine contraindications

1. People who are allergic to sibutramine and its ingredients;

2. Patients with anorexia nervosa;

3. Patients receiving monoamine oxidase inhibitors;

4. Patients receiving other central nervous system appetite suppressants;

5. Uncontrolled or poorly controlled hypertension patients;

6. Coronary heart disease, palpitations, arrhythmias;

7. Patients with cerebrovascular disease, stroke or transient ischemic attack;

8. severe liver and kidney dysfunction;

9. Pregnant women (sibutramine has teratogenic effects and no carcinogenic and mutagenic effects have been observed in animal tests);

10. Lactating women;

11. Organic obesity. ^[3]

Sibutramine dosage

The recommended starting dose is 10 mg each time, once a day, which can be taken alone or with food in the morning. If the weight loss is insufficient, the dose can be adjusted to 15 mg per day after 4 weeks. If the patient cannot tolerate the 10 mg dose, it can be reduced to 5 mg per day. The dose should be adjusted according to the patient's blood pressure and heart rate. It is not recommended to use a dose of more than 15 mg per day. ^[4]

Sibutramine adverse reactions

1. There have been reports of reversible thrombocytopenia. Sibutramine clinical trials found hemorrhagic bruising in 0.7% of patients.

2. Cardiovascular system: Sibutramine can cause tachycardia and elevated blood pressure.

3. Central nervous system: Common insomnia, dry mouth, and headache. It can also cause irritability, limb cramps, increased tension, abnormal thinking, and seizures. There have also been reports of irritability, sleep disturbances and anxiety. Although sibutramine can cause central nervous system irritation, it does not cause euphoria. Clinical studies have shown that sibutramine has no significant effect on the psychomotor and thinking behaviors of healthy volunteers, but because any drug that acts on the central nervous system has the potential to affect judgment, thinking, or motor skills, attention should be drawn.

4. Endocrine / metabolism: Sibutramine has no effect on blood sugar, and does not cause dyslipidemia and hyperuricemia. There have been reports of peripheral edema.

5. Digestive system: (1) Frequent appetite and constipation. May also cause diarrhea, abdominal pain, flatulence; (2) Sibutramine can cause abnormal liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), -L -Increases in glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase, and bilirubin, most of which are mildly elevated, often disappear with further treatment, without a clear dose-response relationship .

6. Respiratory system: There are reports of tracheitis and dyspnea.

7. Urogenital system: Interstitial nephritis and menstrual disorders have been reported.

8. Skin: Sibutramine can cause skin rash and dry skin. Itching may also occur during medication.

9. Others: Can still cause adverse reactions such as arthritis, fever, amblyopia. ^[3]

Sibutramine notes:

1. The treatment of obesity should be based on diet control and exercise.

2. Cushing's syndrome and obesity caused by hypothyroidism should be excluded from the scope of application of this product.

3 Patients with a history of hypertension should be used with caution.

4 As the formation of gallstones may be increased or aggravated, patients with gallstones should use this product with caution.

5. This product can cause pupil dilation and should be used with caution in patients with angle-closure glaucoma.

6. It should be used with caution in patients with a history of epilepsy and discontinued in patients with seizures.

7. May affect judgment, thinking or motor skills.

Sibutramine for pregnant and lactating women:

Teratogenic effects of this product have been observed in animal tests, but no carcinogenic and mutagenic effects have been observed. It is recommended that pregnant or lactating women not take this product.

Sibutramine for children:

The safety and effectiveness of this product for children under 16 years of age have not been established, so it is not recommended for children under 16 years of age.

Sibutramine medication for the elderly:

Due to the decreased heart, kidney and liver function of the elderly and the possibility of combined treatment with other diseases, the dose selection of the elderly should be careful. ^[4]

Interaction of sibutramine with other drugs

1. Combination of sibutramine with other central appetite suppressants may cause severe hypertension and tachycardia. Therefore, sibutramine is not allowed to be used in combination with other central appetite suppressants.

2.Sibutramine and dextromethorphan, dihydroergotine, ergotamine, fentanyl, lithium, pethidine, pentazocine, selective serotonin reuptake inhibitors, serotonin agonists When combined with tryptophan, it can cause high serotonin status and serotonin syndrome (hypertension, hypothermia, myoclonus, and abnormal mental state).

3. When sibutramine and cytochrome P4503A4 enzyme inhibitors are used simultaneously, the plasma concentration of sibutramine increases. Therefore, care should be taken when using drugs that affect the enzyme activity of cytochrome P4503A4. Inhibitors of cytochrome P4503A4 enzyme include ketoconazole, erythromycin, aceandromycin and cyclosporine; inducers are rifampin, macrolide antibiotics, phenytoin, carbamazepine, and phenobarbital And dexamethasone.

4. When combined with sibutramine and monoamine oxidase inhibitors, it can cause central nervous system toxicity or serotonin syndrome, and it is forbidden to use it in combination.

5. Sibutramine can affect blood pressure and heart rate, so caution should be taken when combined with other drugs that affect blood pressure and heart rate (such as those containing phenylpropanolamine, ephedrine or pseudoephedrine).

6. Sibutramine has no effect on ovulation suppression caused by oral contraceptives. Because no significant clinical interactions were seen, women taking sibutramine and oral contraceptives did not need to switch to other contraceptives. ^[3]

Sibutramine overdose

There are no specific antidote for overdose of this product, and the treatment methods include general methods to deal with overdose, such as ensuring that the breathing is unobstructed, monitoring the heart and important vital signs, and adopting symptomatic and supportive therapies; -blockers can be used with caution to control elevated Blood pressure and tachycardia. The effects of diuresis and hemodialysis have not been proven. ^[4]

Sibutramine expert review

In clinical trials, many patients taking sibutramine lost 5% to 10% of their body weight from baseline. In particular, abdominal fat and visceral fat were reduced by 18% and 19%, respectively. In addition, patients who lost more than 26% of their fat had significantly lower systolic blood pressure. ^[3]

Sibutramine suspension rules

Because of the increased risk of heart disease, the United States, Australia, the European Union and other countries have successively revoked the drug's licenses and ordered pharmaceutical factories to recall them.

In October 2010, Abbott Pharmaceuticals agreed to stop selling Meridia, a drug containing sibutramine, in the United States.

On October 30, 2010, the State Food and Drug Administration of the People's Republic of China announced the suspension of domestic production, sales, and use of sibutramine preparations and APIs, revoking its approval certification documents, and drugs that have been sold on the market should be recalled and destroyed by manufacturers. .

Sibutramine related events

Sibutramine incident introduction

Core tip: Tai Chi Group, a manufacturer of slimming capsules Qumei, said that Qumei's voluntary recall was not due to the requirements of the drug regulatory department. Previously, the same weight-loss pills containing sibutramine as Qumei were suspended in Europe and the United States. Domestic city

"Qumei" slimming capsules recalled Weight-loss products containing sibutramine on the market are still on sale.

The Beijing Times reported on October 30th that some citizens recently reported to this newspaper that the long-term "Qumei" slimming capsule (sibutramine hydrochloride capsule) that they have been taking for a long time is no longer available. I do not know why. "Qumei" manufacturer Taiji Group said that the company's voluntary recall was not due to the requirements of the drug regulatory department. Previously, the weight-loss medicines containing sibutramine as in "Qumei" were suspended in the EU and the United States.

Tips

Complete package can be returned directly

Ms. Zhang of Taiji Group News Center said that the company has set up return points in major retail pharmacies across the country. If the product packaging is complete, consumers can return to the pharmacy directly with a small shopping ticket; Call the hotline (4008877698) to return the goods.

Sibutramine market survey

"Qumei" Out of Stock Customers Suspicious

"Qumei" is a slimming medicine launched by Taiji Group in August 2000. Its main ingredient is sibutramine hydrochloride. Because there are star endorsements such as Gong Li and Fan Bingbing, they are star products in the diet market.

Citizen Ms. Li said that she has been taking "Qumei" for some time. When she went to the Golden Elephant Pharmacy to buy medicine the afternoon before, she found that "Qumei" was taken off the shelves. "I came back to search online and I couldn't buy this product. The salesperson at the pharmacy said, 'Qumei' will be taken off the shelf on the 25th of this month and will not be sold again in the future. I don't know what's wrong with this medicine."

Ms. Li said that when she took "Qumei", she always had side effects such as dry mouth and occasional constipation. This time the drug was quietly taken off the shelf. She was worried that there was a problem with the drug and she hoped that the manufacturer would give a reasonable explanation.

The staff of the sales department of Golden Elephant Pharmacy confirmed the day before that "Qumei" has been taken off the shelf on the 25th of this month due to the recall of the manufacturer. "This medicine will not be sold in the future. We have not been notified."

The reporter then logged in to the brand-new pharmacy, Dulwich Pharmacy, Jiashitang pharmacy and other websites to find that there were no "Qumei" sales.

Mr. Wu, who is responsible for drug sales in Beijing, Taiji Group said that the group has issued recall instructions. Except for some remote retail outlets, most outlets in Beijing have stopped selling "Qumei".

Sibutramine other manufacturers

Sibutramine news background

Main ingredients Europe and the United States are banned

Sibutramine is a central nervous system inhibitor with excitatory and antieating effects.

In 1997, sibutramine was approved by the US FDA for marketing. In that year, Abbott's weight loss product "Nometin" with sibutramine as its main ingredient was first listed in Mexico. For more than 10 years, similar products have been popular all over the world.

In 2005, the EU included "Normetine" as a "warning drug", saying it could trigger various risks such as stroke. In 2007, the Japanese Ministry of Health and Welfare reminded the public to be careful with weight-loss products containing sibutramine hydrochloride.

In January this year, the European Union's Committee on Medicinal Products for Human Use (CHMP) stated that sibutramine may increase the risk of heart disease and stroke among users, and suspended all sibutramine-containing diet pills for sale in the EU. The US FDA and the Australian Medical Product Agency (TGA) subsequently required manufacturers to modify product specifications to warn of the risks of medication.

On October 8, the FDA issued a document ordering "Nometin" to withdraw from the US market. Health Canada later said that Abbott was recalling "Nometin" in the country.

Sibutramine sector initiative

Doctors and patients must be informed of the risks of medication

On February 26 this year, the State Food and Drug Administration issued a message through its official website, saying that it closely follows the safety information of sibutramine. The news said that the State Drug Administration has asked the National Drug Adverse Reaction Monitoring Center to immediately analyze the adverse reaction reports and monitoring status of sibutramine-containing weight-loss drugs in China, and to conduct safety analysis of the use of such drugs in China. Analysis and evaluation.

At the same time, the State Administration of Drug Administration requires pharmaceutical manufacturers to immediately take appropriate measures to inform doctors and patients of the known drug risks serious effects of sibutramine in patients with high cardiovascular risk; immediate attention to known and potential risks Revised and improved the instructions, prompting safe and reasonable medication.

The State Food and Drug Administration said that it is paying close attention to the final results of the sibutramine cardiovascular endpoint trial (SCOUT) study, and will use the results to refer to the regulatory measures of other national drug regulatory authorities and take appropriate supervision in the light of China's situation. Measures.

The State Food and Drug Administration also reminded medical institutions and the public that all weight-loss drugs containing sibutramine are prescription drugs, and they must be used in strict accordance with the indications and dosages, and the response after the drug must be closely monitored to ensure the safety of drug use.

Statistics released by the State Administration of Drug Administration on the same day showed that from January 1, 2004 to January 15, 2010, the National Center for Adverse Drug Reaction Monitoring received a total of 298 reports of sibutramine-related adverse reactions. The main adverse reactions were: Heart palpitations, constipation, dry mouth, dizziness, insomnia, etc. are mostly adverse reactions that have been described in the instructions, and there are currently no deaths.

On October 30, the reporter sent a letter to the State Food and Drug Administration to inquire whether further measures would be taken on sibutramine-containing weight-loss drugs. As of press time, no response has been received.

Sibutramine Online Review

"Qumei" have been lively again recently. On October 30, the State Food and Drug Administration formally suspended 15 kinds of diet pills containing sibutramine, including Qumei and Nuometing. Chongqing Taiji Group, which produces Qumei, recently responded that it will no longer produce Qumei slimming capsules, but retain the "Qumei" brand. There is no compensation plan for consumers because they believe they meet the standards, and related products are currently off the shelf. Qumei, Nuometing, etc. can be described as old-famous brand-name weight-loss products. This time they were collectively stopped because they contained sibutramine, and sibutramine may increase the risk of cardiovascular disease. Sibutramine has been approved to enter China for 10 years. Due to the inclusion of sibutramine and Nometin, they have been delisted by Canada, the European Union, and Switzerland. Why is sibutramine "freedom" in China for a long time?

This can not help but mention the embarrassment of supervision. It seems that Taiji's refusal to pay compensation is justified. After the US FDA released the sibutramine risk report in mid-October, they took the initiative to recall Qumei Capsules before the drug regulatory department took the notice down. This sense of responsibility and speed of response is worthy of recognition. However, it would seem a bit far-fetched to reject various aftercare claims as a result. Even though sibutramine capsules are qualified products registered with the State Food and Drug Administration and comply with national standards, the reasons for refusing compensation are still insufficient.

"Conforming to national standards" does not necessarily pose no risk to consumer health. Moreover, previous food hygiene and safety incidents have been repeatedly warned. Compared with international standards, in the field of food and drugs, some of our testing standards, procedures and quality standards are seriously lagging behind, and there are even large terrible blank areas for testing. These blank areas are high-risk areas where food and drug safety risks are frequent.

From melamine to sibutramine, such chemical terms are sadly remembered by the public only after the risk has occurred. Before that, many similar chemical elements were hiding in these blank areas. The harm caused by the event has been long-lasting and obvious. At this time, if the quality "conforms to the standard" is used as the exemption card, the persuasive power is naturally limited, but it may cause public complaints.

On this issue, it is necessary for the regulatory authorities and production enterprises to work together. On the one hand, relevant public institutions should strengthen information collection and publicity. For example, the news that nometine containing sibutramine has been delisted by some countries for up to ten years should be announced in the country at the first time so that companies can learn from their experiences. Make adjustments quickly to avoid similar risks. If you turn a blind eye for a long time and wait until the hidden dangers erupt, the costs and risks may be out of control. In the past few years, the melamine haunt has been affected by this factor. I hope that the Qumei storm will not repeat the same mistakes.

After the Qumei storm, the agent of the spokesperson Fan Bingbing responded that Fan Bingbing had no discomfort when taking Qumei for March. This gambling response also reflects the embarrassment of "star endorsements over government supervision" on this issue, which is as sad as the color of the gambling life that had previously required "leaders to go down". Earlier relevant regulations have clarified the "joint responsibility" of celebrities in food and drug endorsements. However, in the context of melamine or sibutramine becoming potential rules in the industry, and even in accordance with the "national standards", it is frustrating to exist Under the premise that the blockbuster test is blank, even if the celebrity is fined and ruined, the effect of purifying the market is minimal. To put it bluntly, they ca nt even count the program patches. If the anti-virus software is in the dormant state at the same time, how can we count on Fan Bingbing to ensure that the product is safe with not taking discomfort in March?