How Effective Is Glimepiride for Diabetes?

The chemical name of glimepiride is 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl]- Phenylsulfonyl] -3- (trans-4-methylcyclohexyl) -urea is a white crystalline powder, odorless and tasteless. It is soluble in chloroform, slightly soluble in methanol or ethanol, and insoluble in water or ether. The molecular formula is C24H34N4O5S, the molecular weight is 490.61600, the density is 1.29 g / cm3, and the melting point is 212.2-214.5 ° C.

The chemical name of glimepiride is 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl]- Phenylsulfonyl] -3- (trans-4-methylcyclohexyl) -urea is a white crystalline powder, odorless and tasteless. It is soluble in chloroform, slightly soluble in methanol or ethanol, and insoluble in water or ether. The molecular formula is C24H34N4O5S, the molecular weight is 490.61600, the density is 1.29 g / cm3, and the melting point is 212.2-214.5 ° C.

Chinese name

Glimepiride

Foreign name

glimepiride

CAS number

93479-97-1

Molecular formula

C24H34N4O5S

Introduction of Glimepiride Compound

Glimepiride Basic Information

Chinese name: glimepiride

Chinese alias: He Puding; Glipirole;

English name: glimepiride

English alias: amary; glimepirid; hoe490; Glimpiride; CLIMEPIRIDE;

CAS number: 93479-97-1

Molecular formula: C24H34N4O5S

Molecular weight: 490.61600

Structural formula:

Exact mass: 490.22500

PSA: 133.06000

LogP: 5.26540 ^[1]

Glimepiride physical and chemical properties

Appearance and properties: white crystal-like solid

Density: 1.29 g / cm3

Melting point: 212.2-214.5 ° C

Refractive index: 1.599

Storage conditions: room temperature ^[1]

Glimepiride production method

3-ethyl-2 .-, 5-dihydro-4-methyl-2-oxo 1H-pyrrole is reacted with phenethyl isocyanate, followed by chlorosulfonation with chlorosulfonic acid, and ammonolysis to sulfonamide. Finally, it is condensed with p-cyclohexyl isocyanate to obtain the product. ^[1]

Glimepiride uses

Mechanism of action: This product is a third-generation sulfonylurea long-acting anti-diabetic drug. Its mechanism of action is through binding to the sulfonylurea receptor on the surface of pancreatic -cells, which receptor is associated with ATP-sensitive K + (KATP) channels. The coupling causes the KATP channel to close, causing the cell membrane to depolarize, opening the voltage-dependent calcium channel, Ca2 + influx to promote the release of insulin, and inhibit liver glucose synthesis. In addition, Glimepiride can also increase cardiac glucose uptake through a non-insulin-dependent pathway, which may be due to the increased expression of two proteins, glucose transport factor 1,4. Glimepiride has a weak effect on cardiovascular KATP channels, so there are few adverse cardiovascular events. ^[1]

Glimepiride Pharmacopoeia Standard

The main active ingredients of Glimepiride

This product is 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl] -3- (Trans-4-methylcyclohexyl) -urea. ^[2]

Glimepiride

This product is white crystalline powder, odorless and tasteless.

This product is soluble in chloroform, very slightly soluble in methanol or ethanol, and insoluble in water or ether.

The melting point is 205 to 209 ° C. ^[2]

Glimepiride identification

(1) Take this product, add ethanol to make a solution containing 10 g per 1 ml, and determine it by spectrophotometry. It has a maximum absorption at a wavelength of 227 nm.

(2) The infrared absorption spectrum of this product should be consistent with the reference spectrum.

(3) Take about 0.1g of this product and mix it with 0.2g of potassium nitrate, heat to carbonize, then ash, let cool, and add 10ml of water to dissolve the residue. After filtration, the filtrate shows a sulfate identification reaction. ^[2]

Glimepiride inspection

Take 1.0g of chloride, add 50ml of water, boil, quickly cool, filter, add filtrate to 50ml with water, measure 25ml, check according to law, and compare with a control solution made of 7.0ml of standard sodium chloride solution. Thick (0.014%).

For the sulfate, take 25ml of the remaining filtrate under the above chloride and check it according to law. Compared with the control solution made of 2.0ml of standard potassium sulfate solution, it must not be more concentrated (0.040%).

Related substances were determined according to high performance liquid chromatography.

Chromatographic conditions and system suitability tests use octadecylsilane bonded silica as a filler; methanol-ammonium dihydrogen phosphate solution (take 1.725 g of ammonium dihydrogen phosphate, add 300 ml of water to dissolve, adjust the pH to 3.5 with 0.5 phosphoric acid) ( 6: 3) is mobile phase; detection wavelength is 226nm. The theoretical number of plates is calculated based on the Glimepiride peak and should not be less than 5000.

Take 25mg of this product by measuring method, accurately weigh it, put it in a 25ml measuring bottle, add methanol to ultrasonic treatment to dissolve it, and dilute with methanol to the mark. Shake well as the test solution; take 1ml precisely, place in a 200ml volumetric flask, dilute to the mark with mobile phase, shake well, and use it as the control solution (1); separately take the sulfonamide reference substance and ethyl sulfonamide formate control Each product is 12.5mg, accurately weighed, placed in a 50ml measuring bottle, sonicated with 10ml of methanol to dissolve it, diluted with mobile phase to the mark, and then diluted with mobile phase to make a solution containing 2.5g per 1ml as a reference. Solutions (2) and (3). Precisely measure 20 l of reference solution (2) and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of reference solution (2) is about 10 to 15% of full scale, and then accurately measure the reference solution (1), 20 l each of the reference solution (3) and the test solution were injected into the liquid chromatograph, and the chromatogram was recorded. The chromatogram of the test solution was recorded to twice the peak retention time of the main component. (2), (3) The peak area of the corresponding impurity peaks should not be larger than the peak area (0.5%) of the reference solution (2) and (3), and the sum of the peak areas of other impurity peaks should not be larger than the control solution (1 ) Peak area (0.5%).

Toluene 0.1g of this product, accurately weighed, determined according to the organic residual solvent determination method, the toluene content should not exceed 0.089%.

Take this product after losing weight and dry it at 105 to constant weight, and the weight loss should not exceed 0.5%.

Take 1.0g of this product for burning residue, and check the remaining residue according to law not to exceed 0.1%.

Residues left under the item of burning residue of heavy metals shall be inspected according to law, and the content of heavy metals shall not exceed 10 parts per million.

Take cyanide 0.5g of this product, check it according to law, and it should meet the requirements. ^[2]

Determination of Glimepiride

Take about 0.5g of this product, accurately weigh, add 100ml of neutral ethanol (the thymolphthalein indicator liquid is neutral), heat and dissolve, cool to room temperature, add 5 drops of thymolphthalein indicator liquid, titrate with sodium hydroxide Liquid (0.1mol / L) titration. Each 1ml of sodium hydroxide titration solution (0.1mol / L) is equivalent to 49.06mg of C24H34N4O5S. ^[2]

Glimepiride Compound Related Drugs

Glimepiride drug name:

[General name] Glimepiride dispersible tablets

[English name] Glimepiride Dispersible Tablets

[Chinese Pinyin] Ge Lie Mei Niao Fen San Pian ^[3]

Glimepiride

The main ingredient of this product is Glimepiride. } -Benzenesulfonyl} -3- (trans-4-methylcyclohexyl) -urea. Molecular formula: C24H34N4O5S, molecular weight: 490.6 ^[3]

Glimepiride Category:

Chemical Drugs and Biological Products >> Metabolic and Endocrine System Drugs >> Drugs Affecting Blood Glucose >> Hypoglycemic Drugs ^[3]

Glimepiride properties:

This product is a white tablet. ^[3]

Glimepiride indications:

It is suitable for type 2 diabetes where diet, exercise therapy and weight loss are not sufficient to control blood sugar.
Glimepiride dispersible tablets are not suitable for the treatment of type 1 diabetes (eg, diabetic patients with a history of ketoacidosis), diabetic ketoacidosis, or pre-diabetic coma or coma. ^[3]

Glimepiride specifications:

(1) 1.0mg; (2) 2.0mg ^[3]

Glimepiride Usage and dosage:

Dosage In principle, the dose of glimepiride dispersible tablets should be adjusted according to the target blood glucose level. The dose of glimepiride dispersible tablets must be the lowest dose sufficient to achieve the target metabolic control.
During treatment with glimepiride dispersible tablets, blood glucose and urine glucose levels must be measured regularly. In addition, periodic measurement of glycated hemoglobin is recommended.
Errors such as missed doses should not be corrected by taking larger doses of the medicine later.
Measures to deal with situations where medication cannot be taken at the prescribed time (especially forgetting to take it or not eating) or for various reasons cannot be taken on time must be discussed and agreed between the doctor and the patient.
If necessary, increase the starting dose and daily dose. Periodic monitoring of blood glucose is recommended for dose adjustment, and the recommended dose should be gradually increased. For example, every 1-2 weeks, gradually increase the dose to 2mg, 3mg, 3mg, 6mg daily.
Dosage range for patients with well-controlled diabetes. For patients with well-controlled diabetes, the daily dose is usually 1 mg to 4 mg of glimepiride dispersible tablets. Daily doses greater than 6 mg are more effective for only a few patients.
-Dosing distribution The doctor determines the timing and distribution of dosing according to the patient's current lifestyle. Generally, it can be taken once a day. It is recommended to take it immediately before breakfast. If you do not eat breakfast, take it immediately before the first meal.
It is important not to miss meals after taking the medicine.
Due to improved diabetes control and increased insulin sensitivity, the need for glimepiride may be reduced during treatment. Therefore, in order to avoid hypoglycemia, it is necessary to consider reducing the dose in time or discontinuing the glimepiride dispersible tablets. If the patient's weight, lifestyle changes, or other factors that increase sensitivity to hypoglycemia or hyperglycemia, dose adjustment should also be considered.
· Glimepiride dispersible tablets are a long-term treatment under normal treatment duration.
There is no clear dose relationship between switching from other oral hypoglycemic agents to glimepiride dispersible tablets and glimepiride dispersible tablets and other oral diabetes medications. When using glimepiride dispersible tablets instead of other oral hypoglycemic agents, the same approach as the initial dose starting at 1 mg per day is recommended. This also applies to patients who have previously used the highest dose of another oral diabetes treatment.
The efficacy and duration of previous diabetes treatments must be considered. Temporary discontinuation of medication may be required to avoid the risk of hypoglycemia due to additive effects.
· Change from insulin to glimepiride dispersing tablets Except for individual cases, patients with type 2 diabetes treated with insulin can be switched to glimepiride dispersing tablets.
The replacement of insulin with glimepiride dispersible tablets should be performed under the close monitoring of a doctor.
Usage This product is taken orally or after dispersing in water.
· Special population renal insufficiency Information on the use of glimepiride dispersible tablets is limited in patients with renal insufficiency. Patients with impaired renal function may be more sensitive to the hypoglycemic effect of glimepiride dispersible tablets (see [Pharmacokinetics]). ^[3]

Glimepiride adverse reactions:

Systemic flaccidity: occasionally allergic or pseudo allergic reactions may occur, such as pruritus, urticaria or rash. These mild reactions can develop into severe reactions with dyspnea and decreased blood pressure, sometimes to shock. If urticaria occurs, your doctor must be notified immediately.
In sporadic cases, decreased blood sodium levels and allergic vasculitis or skin photosensitivity may occur.
Hematological and lymphatic system flocculation: Hematological changes during the treatment of Glimepiride dispersible tablets; rare, thrombocytopenia, leukopenia, reduced red blood cells, agranulocytosis, hemolytic anemia, and whole blood cells in sporadic cases cut back.
Metabolic and nutritional disturbances: Due to the hypoglycemic effect of glimepiride dispersible tablets, hypoglycemia or prolonged hypoglycemia may occur based on information from other known sulfonylurea drugs.
Possible symptoms of hypoglycemia include headache, extreme hunger, nausea, vomiting, burnout, drowsiness, sleep disturbances, restlessness, aggressive behavior, decreased attention, impaired alertness and responsiveness, depression, confusion, speech disorders, Aphasia, visual disturbances, tremors, local paralysis, paresthesia, dizziness, weakness, loss of self-control, delirium, convulsions, lethargy and loss of consciousness and even coma, shallow breathing and bradycardia.
In addition, signs that adrenaline can regulate, such as sweating, wet skin, anxiety, tachycardia, high blood pressure, palpitations, angina pectoris, and arrhythmia.
The clinical symptoms of severe hypoglycemia may be similar to stroke.
When hypoglycemia is corrected, these symptoms can almost always be relieved.
Eye abnormalities: Especially at the beginning of treatment, temporary changes in vision may result from changes in blood glucose. The reason may be that a temporary change in tightness results in a change in the refractive power of the lens, which depends on blood glucose levels.
Gastrointestinal disorders: Gastrointestinal symptoms such as nausea, vomiting, and diarrhea may occasionally occur, with feeling of pressure or fullness in the upper abdomen, and abdominal pain.
In sporadic cases, hepatitis, elevated liver enzymes, and / or cholestasis and jaundice may occur, which may develop into life-threatening liver failure, but can be recovered after withdrawal of the glimepiride dispersible tablets. ^[3]

Glimepiride contraindications:

This product cannot be used in the following situations:
· Those who are allergic to glimepiride, other sulfonylureas, other sulfonamides or any of the ingredients in this product.
Women during pregnancy.
· Lactating women.
· Type I diabetes, diabetic coma, ketoacidosis patients have not accumulated experience about using glimepiride dispersible tablets for patients with severe liver damage and dialysis patients. For patients with severe liver damage, they should switch to insulin, and more importantly, Achieve optimal metabolic control. ^[3]

Glimepiride note:

WARNING: Under stressful conditions (eg, trauma, surgery, fever infections), blood glucose regulation may not be ideal, and it may be necessary to temporarily switch to insulin to maintain good metabolic control.
Precautions During the first few weeks of treatment, the risk of hypoglycemia may increase, and it is especially necessary to test carefully.
Factors that are prone to hypoglycemia include:
· Unwillingness or inability to cooperate (more common in elderly patients)
· Malnutrition, irregular eating time or missed meals · Dietary changes · Imbalance between physical exertion and carbohydrate intake · Use of alcoholic beverages, especially without meals · Impaired kidney function · Serious liver function damage · Overdose of Glimepiride dispersible tablets · Some decompensated endocrine system diseases that affect carbohydrate metabolism or reverse regulation of hypoglycemia (such as certain thyroid disorders and anterior pituitary or adrenal insufficiency)
· Combined with certain other drugs (see [Drug Interactions])
Use of Glimepiride dispersible tablets in the absence of indications. If these hypoglycemic risk factors are present, it is necessary to adjust the dose of Glimepiride disperse tablets or the entire treatment regimen. This also applies when a disease occurs or the patient's lifestyle changes during treatment.
For the elderly, when hypoglycemia gradually develops, patients with autonomic neuropathy, or a combination of beta-blockers, clonidine, reserpine, guanethidine, or other sympathetic blockers, reflect epinephrine response in the body The symptoms of hypoglycemia (see [Adverse Reactions]) may be mild or absent.
Almost all of the above symptoms of hypoglycemia disappeared immediately after oral carbohydrate (glucose or sucrose).
It is known from other sulfonylureas that despite the successful control of hypoglycemia, hypoglycemia will recur. Therefore, patients should still be closely monitored. Severe hypoglycemia requires immediate treatment and follow-up by the doctor, and in some cases, the patient needs hospitalization.
Patients with G6PD deficiency use sulfonylureas and have impaired responsiveness, especially after treatment has begun or changed, or when glimepiride dispersible tablets are taken irregularly. This may affect, for example, the ability to drive or operate a machine. ^[3]

Glimepiride for pregnant and lactating women:

Pregnancy: Glimepiride dispersible tablets are contraindicated during pregnancy. Otherwise there is danger of harming the fetus. Patients during pregnancy must switch to insulin. Patients planning to become pregnant should be notified to their doctor. These patients are advised to switch to insulin.
Breastfeeding: In order to prevent possible breast milk intake and possible child injury, lactating women are prohibited from taking glimepiride dispersible tablets. If necessary, patients must switch to insulin or stop breastfeeding. ^[3]

Glimepiride for children:

Research data on the safety and effectiveness of this product in children are lacking.
An experiment evaluating the pharmacokinetics, safety, and tolerability of a single dose of glimepiride 1 mg in 30 pediatric patients with type 2 diabetes (aged 10-17 years) showed an average ^[3]

Glimepiride for the elderly:

No special instructions or medical advice. ^[3]

Glimepiride Drug Interactions:

Based on experience with glimepiride dispersible tablets and other sulfonylureas, the following drug interactions need to be noted: Glimepiride is metabolized by cytokine P450 (CYP2C9). Glimepiride and CYP2C9 agonist (rifampin) or inhibitor (fluconazole) should be used together, taking into account possible effects.
Taking one of the following drugs that potentially cause blood sugar drop can cause hypoglycemia in some cases, such as:
Butepine, azapropion, hydroxybutrazon, insulin and oral hypoglycemic agents, salicylic acid, p-aminosalicylic acid, anabolic steroids and androgens, chloramphenicol, coumarin derivatives, fenflu Lamin, Finiladol, Fibrates, ACE Inhibitors, Fluoxetine, Guanethidine, Cyclophosphamide, Propylamine, Ifosfamide, Sulpyridone, Clarithromycin, Sulfa antibiotics, Tetracycline Family, monoamine oxidase inhibitors, quinolone antibiotics, probenecid, miconazole, pentoxifylline (parenteral high-dose administration), trotoquinoline, triammonium phosphate, fluconazole.
Taking one of the following medicines may reduce the effect of lowering blood sugar and increase blood sugar levels, such as:
Estrogen and progesterone, diuretics, thyroid hormones, corticosteroids, phenothiazines, epinephrine and other sympathomimetic drugs, nicotinic acid (high dose), laxatives (for long-term use), phenytoin, diazoxide, high Glucagon, barbiturates, rifampicin, acetazolamide.
H2 receptor antagonists, beta-blockers, clonidine, and reserpine may increase and reduce blood glucose lowering effects.
Under the influence of sympathetic drugs such as beta-blockers, clonidine, guanethidine, and reserpine, signs of hypoglycemic adrenaline reverse regulation may weaken or even disappear.
Acute or chronic alcohol intake may increase or decrease the hypoglycemic effect of glimepiride dispersible tablets in some unpredictable manner.
Glimepiride may increase or decrease the effect of coumarin derivatives. ^[3]

Glimepiride overdose:

Acute drug overdose and prolonged treatment with excessively high doses of glimepiride may lead to severe life-threatening hypoglycemia. Once an overdose of glimepiride dispersible tablets is found, the doctor must be notified immediately without delay. Patients must take sucrose immediately, and glucose if possible, unless the doctor knows to treat the drug overdose and have confidence in the patient's condition.
Careful monitoring is necessary until the doctor is certain that the patient is out of danger. It must be remembered that hypoglycemia may recur after initial recovery.
Sometimes hospitalization is necessary, even as a precautionary measure. Especially in severe overdose and severe reactions with signs such as loss of consciousness or other serious mental disorders, it is a medical emergency and requires immediate treatment and hospitalization. If the patient is unconscious, a concentrated glucose solution should be injected intravenously (for adults, for example, start with 40 ml of a 20% solution). Adults may consider intravenous, subcutaneous or intramuscular injection of glucagon at a dose of 0.5 mg to 1 mg.
Especially in the treatment of hypoglycemia after infants and children mistakenly take glimepiride dispersible tablets, glucose must be carefully controlled today, the risk of hyperglycemia must be considered, and blood glucose control should be controlled.
Patients ingesting life-threatening lemicarba dispersible tablets should be detoxified immediately (eg gastric lavage and medicinal charcoal).
After the completion of acute glucose replacement, it is usually necessary to administer glucose infusion intravenously at a lower concentration to ensure that hypoglycemia does not occur again. Patients' blood glucose levels should be carefully monitored for at least 24 hours. In severe cases of prolonged administration, the risk of hypoglycemia or repeated hypoglycemia may persist for several days. ^[3]

Glimepiride Pharmacology and Toxicology:

Pharmacological characteristics: For healthy people and patients with type 2 diabetes, Glimepiride can reduce blood glucose concentration, mainly by stimulating insulin release from beta cells of the islets. This effect is mainly based on increasing the responsiveness of islet cells to physiological concentrations of glucose. When an equal amount of blood glucose reduction was achieved, the insulin release from the low doses of glimepiride given to animals and healthy volunteers was smaller compared to glibenclamide. This is a fact suggesting that Glimepiride also has a significant effect beyond the islets (insulin sensitization and insulin mimetics).
In addition, compared to other sulfonylureas, glimepiride has a smaller effect on the cardiovascular system, it can reduce platelet aggregation, (animal and in vitro data), and leads to a significant reduction in atherosclerotic plaque formation (animals data).
Insulin release: Like all sulfonylureas, glimepiride regulates insulin secretion through the interaction of ATP-dependent potassium channels in the beta cell membrane of the islets. Unlike other sulfonylureas, glimepiride specifically binds to a 65KDa protein in pancreatic beta cells. This interaction between glimepiride and its binding protein determines the possibility of ATP-dependent potassium channels opening or closing.
Glimepiride closes potassium channels, induces -cell depolarization, and simultaneously opens voltage-sensitive potassium channels, causing calcium ions to flow into the cell. Eventually, the intracellular calcium concentration increases, and insulin release is stimulated by exocytosis.
Compared with glibenclamide, glibenclamide and its binding protein bind and separate more quickly and frequently. Therefore, it can be assumed that this high exchange rate characteristic of glimepiride and binding protein is the reason for its significant sensitization to glucose and protection of -cell desensitization and premature depletion.
Insulin sensitization: Glimepiride improves the normal effect of insulin on peripheral glucose uptake (human and animal data). Insulin-like effects: Glimepiride mimics the effects of insulin on peripheral grape uptake and liver glucose output.
Peripheral glucose is transferred into muscle and fat cells for uptake. Glimepiride directly increases the number of glucose transfer molecules in the plasma membrane of muscle and fat cells. Glimepiride increases the activity of glycosyl-phosphatidyl alcohol-specific phospholipase C. As a result, the cell's cAMP level decreases, resulting in a decrease in protein kinase A activity, which stimulates glucose metabolism.
Glimepiride inhibits glucose production in the liver by increasing the concentration of fructose 2,6-diphosphate in the cell, because fructose 2,6-diphosphate inhibits gluconeogenesis.
Effect on platelet aggregation and atherosclerotic plaque formation: Glimepiride can reduce platelet aggregation in vitro and in vivo. This effect may be caused by the selective inhibition of cyclooxygenase. Formation of thromboxane A, an important endogenous platelet aggregation factor.
Glimepiride significantly reduced atherosclerotic plaque formation in animals. Its potential mechanism remains to be elucidated.
Cardiovascular effects: Sulfonylureas also affect the cardiovascular system through ATP-sensitive calcium channels (see above). Compared to traditional sulfonylureas, glimepiride has a significantly smaller effect on the cardiovascular system (animal data). This may be explained by the specificity of its interaction with ATP-sensitive potassium channel binding proteins.
Pharmacodynamic properties The minimum oral dose for healthy individuals is approximately 0.6 mg. The effect of Glimepiride is dose-dependent and repeatable. In the case of taking glimepiride, the physiological response to decreased insulin secretion during intense exercise still exists. There was no significant difference in the effect of treatment, whether 30 minutes before meals or immediately before meals. Administration of once a day can well control the metabolism of patients with diabetes for 24 hours. In addition, in a clinical study, 12 of the 16 patients with renal insufficiency (creatinine clearance of 4-79 ml / min) achieved good metabolic control.
Although the hydroxy metabolites of glimepiride cause a small decrease in serum glucose in healthy subjects, this is only part of the overall effect of the drug.
Clinical effectiveness A 24-week clinical controlled trial of 285 randomized children with type 2 diabetes (ages 8-17 years) (glimepiride reached 8 mg per day or metformin reached 2000 mg per day) Both urea and metformin showed a significant reduction in HBAlc from baseline.
No significant differences were observed between the treatment groups. Glimepiride did not show non-inferiority to metformin. No new safety events were observed in children after glimepiride compared to adults with type 2 diabetes. There are no long-term efficacy and safety data on pediatric patients.
Preclinical toxicology study: Long-term toxicity: In rats, mice, and dogs, chronic and subchronic poisoning tests have shown reduced serum glucose levels and islet -cell shedding particles. These reactions are usually reversible and are considered to be pharmacodynamically related to this product. Canine chronic toxicity studies found that two dogs in the high-dose group (320 mg / kg body weight) developed cataracts. However, in vitro bovine lens studies and rat studies showed that glimepiride did not cause cataract toxicity and synergistic cataract toxicity.
Carcinogenicity: Rat studies have shown that this product has no potential carcinogenic toxicity. Due to the chronic stimulation of cells by this product, mouse tests have found that the incidence of islet cell proliferation and islet cell adenomas is increased.
Glimepiride was not found to be mutagenic and genotoxic.
Reproductive toxicity: Glimepiride given to rats has no adverse effects on fertility, pregnancy and childbirth. The fetus born after the diarrhea was slightly retarded. The mother rats were given high doses of this product, and humerus, femur, arthritis, and hip joint deformities appeared in their naturally born offspring. Oral administration of this product during late pregnancy and / or lactation in female rats results in an increase in stillbirths and limb deformities.
Glimepiride had no significant effect on the growth and development, sexual function, cognitive behavior, memory behavior or reproductive ability of the offspring. Glimepiride can be ingested by young rats through breast milk, and high doses of glimepiride can cause hypoglycemia in suckling young rats.
Rats and rabbits may have fetal malformations (such as eye deformities, fissures, and bone abnormalities), rabbits may have abortions and increased intrauterine mortality.
All reproductive toxicity may be the pharmacodynamic response of high-dose drugs, rather than the drug-specific toxicity. ^[3]

Glimepiride pharmacokinetics:

The bioavailability of glimepiride after oral administration is complete. Taken with meals does not affect absorption. The maximum serum concentration (Cmax) was reached orally (approximately 309 nmg / ml at 4 mg multiple doses) approximately 2.5 hours, and there was a linear relationship between the dose and Cmax and AUC (area under the time / concentration curve).
Glimepiride has a very low distribution volume (about 8.8 liters, roughly equivalent to the distribution space of albumin), high protein binding rate (> 99%), and low clearance (about 48ml / min).
Glimepiride is secreted into the milk of animals.
The average serum half-life is related to the serum concentration in the case of multiple doses, which is about 5 to 8 hours. A slightly longer half-life was observed after high-dose administration.
After a single dose of radiolabeled glimepiride, 58% of the radioactivity appeared in the urine and 35% in the feces. No prototype drug was detected in urine. Two metabolites that may be metabolized in the liver (the main enzyme is CYP2C9) were detected in urine and feces: hydroxy derivatives and carboxy derivatives. After oral administration of glimepiride, the half-lives of these metabolites are 3-6 hours and 5-6 hours, respectively.
Comparing single-day single-dose administration with multiple administrations, no significant difference was shown in the pharmacokinetics with very low intra-individual variability. No drug accumulation.
The pharmacokinetics of this product are similar for both men and women, as well as elderly (over 65 years) and young patients.
In a single word dosing and open trial of 15 patients with renal insufficiency, glimepiride (3mg) was administered to three groups of patients with different levels of average creatinine clearance (CLcr); (Group I, CLcr = 77.7 ml / min, n = 5), (group II, CLcr = 27.4ml / min, n = 3), (group III, CLcr = 9.4ml / min, n = 7). Glimepiride was well tolerated in all three groups. In patients with low creatinine clearance, the glimepiride clearance tends to increase and the mean plasma concentration tends to decrease. The most likely cause is a faster clearance due to a lower protein binding rate. Renal clearance of both metabolites is impaired. A 16-month multiple-dose titration experiment was performed on 16 patients with DIDDM with renal insufficiency. The dose range was 1-8 mg per day, and the results were consistent with the results observed after a single dose. . All patients with a CLcr below 22 ml / min need only a 1 mg daily dose to adequately control their blood glucose levels. In general, these patients do not have additional drug credits.
Whether glimepiride is dialyzable remains unclear.
The pharmacokinetics of this product after 5 non-diabetic bile duct surgery patients were similar to those of healthy subjects. ^[3]

Glimepiride Expert Review

According to foreign reports, a double-blind trial with glibenclamide has a total of 1,044 patients with type 2 diabetes in 49 medical centers. The effect of observation is similar for one year, but the dosage of glibenclamide is smaller than that of glibenclamide. Limepiride can control blood glucose for 24 hours at 4 mg per day, and there are fewer hypoglycemic patients than glibenclamide. It is especially suitable for people with type 2 diabetes that cannot be controlled by general sulfonylureas. A multi-center study of 1,000 patients with type 2 diabetes mellitus who took oral or glibenclamide as a control. The oral glibenclamide group took 1 to 8 mg per day, and the oral glibenclamide group took 2.5 to 20 mg before breakfast for 12 consecutive days. month. The results showed that the two groups were equivalent in controlling average blood glucose levels and glycated hemoglobin levels, but glimepiride had a more significant effect on lowering fasting blood glucose and C-peptide levels than glibenclamide. Compared with glibenclamide, this product can reduce the risk of hypoglycemia in newly diagnosed patients with type 2 diabetes and after changing the drug. Hypoglycemia caused by this product in the initial treatment is 50% lower than that of glibenclamide. In another study, 230 patients with type 2 diabetes were orally administered 1 to 6 mg of this product on an empty stomach or 40 to 160 mg of glidazid. The results showed that the two were equivalent in controlling fasting blood glucose concentration and glycated hemoglobin levels. In a randomized, double-blind, crossover study of 1,161 patients with diabetes for 15 weeks at 9 centers in the United States, patients with type 2 diabetes aged 40 to 80 years and weighing 90% to 150% of their ideal body weight, Oral hypoglycemic agents other than glimepiride were administered at least 4 weeks before the study to control blood glucose and the dose was stable. The above patients were orally administered 6 mg each time, once a day or 3 mg each time, twice a day. As a result, both administration methods can effectively control the patient's blood sugar in a short period of time, and they are well tolerated. The adverse reactions were similar to those in the placebo group. However, the administration method once a day can increase the compliance of patients, and is more suitable for patients with diabetes. According to domestic reports, a total of 40 healthy subjects (aged 18 to 50 years old, weighing 50 to 80 kg) were orally administered with 1 to 10 mg of this product each time in the General Hospital of the Chinese People's Liberation Army. , EEG, blood routine, urine routine, liver function, kidney function, electrolytes and other measured values were within the normal range. Only a few adverse reactions were seen, such as 8 cases of hypoglycemia, 2 cases of dizziness, and other transient side effects, suggesting that the Chinese population is well tolerated, and a 10 mg daily dose is safer. It is a new generation of sulfonylurea oral hypoglycemic drug with strong effect, long-lasting drug effect and long-term balanced hypoglycemic effect. It is a commonly used drug in clinical use of long-acting preparations. ^[4]