How Effective Is Lamivudine for Hepatitis B?

Lamivudine's English name is Lamivudine and its chemical name is 2'3'-dideoxy-3'-thiocytidine (2'-3'deoxy-3'-thiocytidine), also known as 3-TC, which is white Or off-white crystalline powder, soluble in water, slightly soluble in methanol, specific rotation is -97 ° to -99 ° It is a nucleoside analog, an antiviral drug, and has a competitive inhibitory effect on the synthesis and extension of viral DNA strands.

Chinese name: Lamivudine
Foreign name: lamivudine

CAS number: 134678-17-4
Molecular formula: C8H11N3O3S

Lamivudine compounds

Lamivudine Basic Information

Chinese name: lamivudine

Chinese alias: (2R-cis) -4-amino-1- (2-hydroxymethyl-1,3-oxothan-5-yl) -1H-pyrimidin-2-one; lamivudine; Lamivudine impurity A; lamivudine;

English name: lamivudine

English alias: Lamivudine; Heptivir; Zeffix; (-)-1-[(2R, 5S) -2- (Hydroxymethyl) -1,3-oxathiolan-5-yl] cytosine; 4-Amino-1-((2R, 5S) -2- (hydroxymethyl) -1,3-oxathiolan-5-yl) pyrimidin-2 (1H) -one; cent; 3TC; Heptovir; Zefix; 2 ', 3'-Dideoxy-3'-thiacytidine; Epivir ; Hepitec; 3 & L-SddC;

CAS number: 134678-17-4

Molecular formula: C ₈ H ₁₁ N ₃ O ₃ S

Structural formula:

Molecular weight: 229.25600

Exact mass: 229.05200 ^[1]

PSA: 115.67000

Lamivudine physical properties

Appearance and properties: white crystalline powder

Density: 1.73g / cm ³

Melting point: 177 ° C

Boiling point: 475.4ºC at 760 mmHg

Flash point: 241.3ºC

Refractive index: -142 ° (C = 1, MeOH)

Storage conditions: Freezer ^[1]

Vapor pressure: 4.91E-11mmHg at 25 ° C

Lamivudine molecular structure data

1. Molar refractive index: 54.14

2. Molar volume (cm / mol): 132.2

3. Isometric Zhang Rong (90.2K): 394.6

4. Surface tension (dyne / cm): 79.3

5. Dielectric Constant: None available

6. Polarizability (10cm): 21.46

7. Mass of single isotope: 229.052111 Da

8. Nominal mass: 229 Da ^[2]

9. Average mass: 229.2562 Da

Lamivudine Computational Chemical Data

1. Hydrophobic parameter calculation reference value (XlogP): None

2.Number of hydrogen-bonded donors: 2

3.Number of hydrogen bond acceptors: 4

4.Number of rotatable chemical bonds: 2

5.Number of tautomers: 3

6. Topological molecular polar surface area 113

7.Number of heavy atoms: 15

8.Surface charge: 0

9.Complexity: 331

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 2

12. Uncertain number of atomic stereocenters: 0

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]

Lamivudine synthesis method

1. The compound (I) is subjected to a selective 6-O-sulfonylation reaction, followed by acetylation to obtain the compound (II) in a yield of 96.7%. Compound (II) was reacted with acetic acid as a solvent and 3 moL of hydrogen bromide / L acid (45%, W / V), and brominated to obtain compound (III) in a yield of 99%. Bromide (III) and 3.3 moI. The potassium salt of ethyl xanthate was refluxed in acetone and thio-cyclized; then, it was hydrolyzed with ammonia in methanol to obtain compound (IV) with a 72% yield in two steps. Compound (IV) was purified by column chromatography as a crystalline solid. Compound (IV) is treated with 1.4 moles of sodium periodate to ring-open 2,3-cis diol; then the aldehyde formed is reduced with sodium borohydride, and the diol is protected in the form of a ketal to obtain the compound (V), yield 60%. The compound (V) is silanized to protect the remaining primary alcohol, and the ketal is removed to obtain the compound (VI) in a yield of 63%. The diol in compound (VI) is oxidized with lead tetraacetate, and further oxidized with pyridinium dichromate to obtain compound (VII). The oxidation method does not affect sulfur. Compound (XII) was oxidized with lead tetraacetate to obtain Compound (XII) with a yield of 66% [calculated as Compound (VI)]. Compounds (XII) and (XII) were condensed in dichloroethane using TMSOTf as a Lewis acid catalyst to obtain Compound (X) in a yield of 64%. There are also isomers of compound (X), which are half the amount of compound (X), and they can be separated by silica gel chromatography. Compound (X) was deacetylated with ammonia-methanol to obtain a yield of 73%; and then desilanized with tetra-n-butylammonium fluoride to obtain lamivudine with a yield of 75%.

2. Dissolve 5 g of acetoxy-2- (diphenyl tert-butylsilylmethyl) -1,3-oxetane and 4-acetamino-2-trimethylsilylpyrimidine Dichloroethane is condensed under Lewis acid catalysis, and then acetyl group is removed by hydrolysis with ammonia-methanol. Finally, trimethylsilyl group is removed by hydrolysis with tetra-n-butylammonium fluoride in tetrahydrofuran to obtain Lamiv set. ^[2]

Lamivudine uses

1. Antiviral drugs for hepatitis B.

2. Antiviral drugs for the treatment of hepatobiliary diseases

3. Drugs for hepatobiliary diseases.

4. Lamivudine is widely accepted as a new nucleoside analog, and it is the most effective and most representative nucleoside analog in clinical application. The product name after listing in China is He Puding. ^[2]

Lamivudine Pharmacopoeia Standard

Lamivudine source (name), content (potency)

This product is (-)-1-[(2R, 5S) -2- (hydroxymethyl) -1,3-oxetane-5-yl] cytosine. Calculated based on anhydrous and solvent-free substances, lamivudine (C8H11N3O3S) should be 97.5% to 102.0%. ^[3]

Lamiv traits

This product is white or off-white crystalline powder.

This product is soluble in water and slightly soluble in methanol.

Lamivudine melting point

The melting point of this product (Appendix VIC of the second edition of the Pharmacopoeia 2010) is 174 ~ 179 ° C.

Lamivudine specific rotation

Take this product, accurately weigh it, dissolve it with water and quantitatively dilute it to make a solution containing about 5mg per 1ml, and measure it according to law (Appendix VI E of the Pharmacopoeia Part II of 2010 Edition), with a specific rotation of -97 ° to -99 °. ^[3]

Lamivudine identification

(1) The infrared light absorption spectrum of this product should be consistent with the control spectrum ("Infrared Spectra of Drugs" 975). If inconsistent, take this product and the lamivudine reference substance to dissolve in methanol, and measure after volatilization. The infrared light absorption spectrum of this product should be the same as that of the lamivudine reference substance.

(2) The retention time of the main peak of the test solution should be consistent with the retention time of the lamivudine peak in the system suitability solution. ^[3]

Lamivudine check

Color of solution

Take this product, weigh it accurately, add water to dissolve and quantitatively dilute it to make a solution containing about 50mg per 1ml. According to the UV-Vis spectrophotometry (Appendix IV A of Pharmacopoeia Part II of the 2010 edition), use a 4cm quartz absorption cell at 440nm. Measured at the wavelength, the absorbance must not exceed 0.3.

relative substance

Take an appropriate amount of this product, accurately weigh, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 0.5mg per 1ml, as a test solution; take an appropriate amount, and dilute with mobile phase to make about 1ml. A 0.5 g solution was used as a control solution. Accurately weigh the appropriate amount of the salicylic acid reference substance, add the mobile phase to dissolve and quantitatively dilute it to make a solution containing 0.5 g per 1 ml, and use it as the reference substance solution. According to the chromatographic conditions under the content determination item, measure 20l of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity, so that the peak height of the main component chromatographic peak is about 20% of the full range, and then accurately measure the test solution and control. 10 l each of the solution and the reference solution were injected into the liquid chromatograph respectively, and the chromatogram was recorded to 3 times the retention time of the main peak of the test solution. If there are impurity peaks in the chromatogram of the test solution, salicylic acid should not exceed 0.1% by the peak area calculated by the external standard method. The peak areas of other impurities are multiplied by their respective correction factors and compared with the main peak area of the control solution. The corrected peak area of should not be greater than 3 times (0.3%) of the main peak area of the control solution; the corrected peak area of impurity should not be greater than 2 times (0.2%) of the main peak area of the control solution, and the area of other single impurity peaks should not be larger than the main peak of the control solution. Area (0.1%), the total amount of impurities must not exceed 0.6% (the relative retention time and correction factor of each impurity peak are shown in the table below). ^[3]

Impurities	Relative retention time	Correction factor
Cytosine	0.28	0.6
Uracil	0.32	2.2
Impurity	0.36	1.0
Impurity	0.91	1.0
Lamivudine	1.00	1.0
Impurity	1.45	2.2
Other unknown impurities	-	1.0

Lamivudine enantiomer

Take an appropriate amount of this product, add water to dissolve and dilute to make a solution containing about 0.25mg per 1ml as the test solution; take an appropriate amount and dilute with water to make a solution containing about 0.75g per 1ml as a control solution. Measured according to high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 edition), using -cyclodextrin bonded silica gel as the filler; 0.1mol / L ammonium acetate solution-methanol (95: 5) as the mobile phase. The wavelength is 270nm; the column temperature is 15-30 ° C, and the flow rate is 1.0ml per minute. Take about 2.5mg of Lamivudine Resolution Mixture A (containing the Lamivudine and Lamivudine enantiomers), put it in a 10ml volumetric flask, add water to dissolve and dilute to the mark, shake well, as system applicability Measure 10 l of the solution and inject it into the liquid chromatograph. The resolution between the lamivudine peak and the lamivudine enantiomer should be not less than 1.5. Measure 10l of the control solution and inject it into the liquid chromatograph. Adjust the detection sensitivity so that the peak height of the chromatographic peak of the main component is about 10% of the full range. . The area of the lamivudine enantiomer in the test solution should not be greater than the area of the main peak of the control solution (0.3%).

Residual solvents -methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, dichloromethane, triethylamine, tetrahydrofuran and N, N-dimethylformamide

Take 0.2ml of 2-pentanone, place it in a 100ml measuring flask, dilute to the mark with dimethyl sulfoxide-water (1: 1), shake it well, and use it as an internal standard stock solution. Precisely measure 20ml and place it in a 200ml measuring bottle. Dilute to the mark with dimethyl sulfoxide-water (1: 1), shake well, as an internal standard solution; accurately weigh 300 mg of methanol, 500 mg of absolute ethanol, 500 mg of isopropanol, 60 mg of dichloromethane, 100 mg of triethylamine, N, N-dimethylformamide 88mg, ethyl acetate 500mg, isopropyl acetate 500mg and tetrahydrofuran 72mg, put in the same 200ml volumetric flask, dilute to the mark with dimethyl sulfoxide-water (1: 1), shake well As a reference stock solution, 5ml is precisely measured and placed in a 50ml measuring bottle. 5ml of the internal standard stock solution is precisely added, diluted to the mark with dimethylsulfoxide-water (1: 1), and shaken as the reference solution. Take about 0.5g of this product, weigh it accurately, add 10ml of internal standard solution precisely, shake to dissolve, and use it as the test solution. According to the residual solvent determination method (Appendix P, the third method of the Pharmacopoeia of the 2010 edition, the third method), a 6% cyanopropylphenyl-94% methyl polysiloxane capillary column (such as HP-624, 105m × 0.53mm × 3m), inlet temperature is 150 ° C, split ratio is 10: 1, initial column temperature is 40 ° C, hold for 5 minutes, then increase to 100 ° C at a temperature increase rate of 5 ° C per minute, and then at 10 ° C per minute. The heating rate was increased to 200 ° C for 5 minutes, the carrier gas flow rate was 5 ml per minute, and the detector temperature was 250 ° C. Accurately measure 1 l of each of the test solution and the reference solution, and inject them into the gas chromatograph, record the chromatogram, and calculate the peak area ratio based on the internal standard method. Triethylamine must not exceed 0.032%. Others should meet the requirements. ^[3]

Ether, n-hexane and toluene

Weigh 500mg of ether, 29mg of n-hexane and 89mg of toluene accurately, place them in the same 100ml measuring flask, dilute to the mark with N, N-dimethylacetamide, shake well, and use it as a reference stock solution. Precisely measure 5ml and place it in 50ml. In a measuring bottle, dilute to the mark with N, N-dimethylacetamide, shake well, and accurately measure 5ml, place it in the headspace bottle as a reference solution; take another 0.5g of this product, accurately weigh, and place in the headspace In a bottle, 5 ml of N, N-dimethylacetamide was precisely added, and shaken as a test solution. Measured according to the residual solvent determination method (Appendix P of the second edition of the Pharmacopoeia of 2010, P method 2), using a 6% cyanopropylphenyl-94% methyl polysiloxane capillary column (such as HP-624, 75m × 0.53mm × 3m), inlet temperature is 200 ° C, split ratio is 3: 1, initial column temperature is 40 ° C, hold for 5 minutes, and then rise to 200 ° C at a temperature increase rate of 10 ° C per minute, hold for 5 minutes, carrier gas flow The speed is 5 ml per minute, the detector temperature is 250 ° C, the headspace bottle equilibrium temperature is 90 ° C, and the equilibration time is 30 minutes. Take the test solution and the reference solution for headspace injection, record the chromatogram, and calculate the peak area according to the external standard method, which should meet the requirements. ^[3]

Moisture

Take this product and measure it according to the Moisture Determination Method (Appendix M of the 2010 Pharmacopoeia Part II M Method A). The moisture content must not exceed 0.2%.

Residue on ignition

Take 1.0g of this product and check it according to law (Appendix N of Part Two of the 2010 Pharmacopoeia). The residual residue shall not exceed 0.1%.

Heavy metal

Take the residue left under the item of burning residue and inspect it according to law (Appendix H of the second edition of the Pharmacopoeia of 2010 Edition, the second method H), containing no more than 20 parts per million of heavy metals.

Lamivudine determination

It was determined by high performance liquid chromatography (Annex V D of Part Two of the Pharmacopoeia, 2010 Edition).

Chromatographic conditions and system suitability tests

Use octadecylsilane bonded silica as filler (Zorbax XDB-C18, 250mm × 4.6mm, 5m, or equivalent column); use 0.025mol / L ammonium acetate solution (take 1.9g ammonium acetate, add 900ml water) Dissolve, adjust the pH to 3.8 with glacial acetic acid, and dilute with water to 1000 ml)-methanol (95: 5) as the mobile phase; detection wavelength is 277 nm; column temperature is 35 ° C. Take appropriate amounts of cytosine reference substance and uracil reference substance, add mobile phase to dissolve and dilute to make a solution containing 10 g per 1 ml, as the solution (1). Another 5mg of Lamivudine Resolution Mixture B (containing Lamivudine and impurity II) was placed in a 10ml volumetric flask, 2ml of mobile phase was added, shaken to dissolve, and 1ml of solution (1) was added precisely. Dilute the mobile phase to the mark, shake well, and use it as a system suitability solution. Measure 10 l, inject it into the liquid chromatograph, and record the chromatogram. The resolution between the peaks of cytosine, uracil, impurity II and lamivudine should meet the requirements. ^[3]

Assay

Take an appropriate amount of this product, accurately weigh it, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 0.25mg per 1ml. Take a precise amount of 10l, inject it into a liquid chromatograph, and record the chromatogram; Product, the same method. The peak area is calculated according to the external standard method, and the result is obtained by subtracting the content of the lamivudine enantiomer. ^[3]

Lamivudine pharmacology and toxicology

Lamivudine pharmacology

Lamivudine is a nucleoside antiviral drug that has a strong inhibitory effect on hepatitis B virus (HBV) in vitro and experimentally infected animals. Lamivudine can be metabolized to produce lamivudine triphosphate in HBV-infected cells and normal cells. It is the active form of lamivudine and is both an inhibitor of HBV polymerase and a substrate of this polymerase. Lamivudine triphosphate is incorporated into the viral DNA strand and blocks viral DNA synthesis. Lamivudine triphosphate does not interfere with the metabolism of deoxynucleosides in normal cells. It has a weak inhibitory effect on mammalian DNA polymerase and , and has almost no effect on the DNA content of mammalian cells. Lamivudine has no obvious toxicity to the structure, DNA content and function of mitochondria. The serum HBV DNA test results of most hepatitis B patients show that lamivudine can rapidly inhibit HBV replication, and its inhibitory effect continues throughout the treatment process. At the same time, serum transaminase is reduced to normal, and long-term application can significantly improve the inflammatory changes of liver necrosis and reduce or prevent the progress of liver fibrosis. ^[4]

Lamivudine toxicology

Genotoxicity

Lamivudine did not show mutagenic activity in microbial mutagenicity experiments and in vitro cell transformation experiments, but it showed weak mutagenic activity in experiments with human lymphocytes and mouse lymphoma cultured in vitro. Rats were given lamivudine 2000 mg / kg orally (the blood concentration was 60-70 times the recommended clinical dose for patients with chronic hepatitis B), and no significant genotoxicity was seen.

Reproductive toxicity

Rats were administered lamivudine 4000mg / kg / day orally (blood concentration was 80-120 times human clinical blood concentration), and their fertility and survival, growth, and development of offspring were not significantly affected.

Rats and rabbits received lamivudine 4000 and 1000 mg / kg / day orally (the blood concentration was about 60 times the human clinical recommended dose blood concentration), and neither showed significant teratogenic effects. When the blood drug concentration of rabbits is close to that of human clinically recommended doses, early embryo mortality will increase. However, when the blood drug concentration of the rat reached 60 times the blood concentration of the human clinically recommended dose, no such phenomenon occurred. Studies on pregnant rats and rabbits have shown that lamivudine can pass through the placenta and into the fetus. There are no adequate and well-controlled clinical studies of lamivudine in pregnant women.

The lamivudine concentration in the milk of lactating rats was similar to that in plasma.

Carcinogenicity:

The results of long-term carcinogenicity tests in rats and mice show that when the exposure levels reached 34 times (mouse) and 200 times (rat) the human clinical exposure level, no obvious carcinogenicity was shown. ^[5]

Lamivudine pharmacokinetics

Lamivudine is well absorbed after oral administration. Adults taking lamivudine 0.1 g orally reach a peak drug concentration Cmax of 1.1-1.5 g / mL in about 1 hr, and the bioavailability is 80-85%. Taking lamivudine with food can delay Tmax by 0.25-2.5 hr and decrease Cmax by 10-40%, but the bioavailability remains the same. The results of intravenous administration studies show that the average distribution capacity of lamivudine is 1.3 L / Kg and the average system clearance is 0.3 L / h / kg. Lamivudine is mainly (> 70%) cleared by the kidney through the organic cation transport system. The elimination half-life is 5-7 hr. In the therapeutic dose range, the pharmacokinetics of lamivudine are linear and the plasma protein binding rate is low. In vitro studies have shown that the binding rate to serum albumin is <16-36%. Lamivudine can enter the cerebrospinal fluid through the blood-brain barrier. Lamivudine is mainly excreted through the kidneys based on drug prototypes. Kidney excretion accounts for about 70% of total clearance, and only 5-10% is metabolized into trans sulfur oxide derivatives. Patients with renal insufficiency will affect the excretion of lamivudine. This product is not recommended for patients with creatinine clearance <30 mL / min. Liver damage does not affect the drug metabolism process of lamivudine. For elderly patients with decreased renal excretion due to aging, lamivudine metabolism does not change significantly, only when creatinine clearance is <30 mL / min. influences. ^[4]

Lamivudine indication

Chronic hepatitis B with hepatitis B and hepatitis B virus replication.

[Patient's Choice] 1. Suitable for treating chronic hepatitis B. According to the National Viral Hepatitis Prevention and Control Program, the diagnosis of chronic hepatitis B is not restricted, and the age is 16 years or older, and meets the following criteria. · HBeAg-positive, HBV DNA-positive (HBV DNA-positive refers to the dot blot method, not PCR-positive. Those who have the conditions can be used for quantitative determination of HBV DNA. Where there is no condition to detect HBV DNA, HBeAg-positive shall prevail. · HBeAg-negative, anti-HBe-positive, and HBV DNA-positive patients are also considered to be suitable for treatment if they have pre-C region mutations. · ALT is above normal and bilirubin is below 50 mol / L (3.0 mg / dL). 2. Not suitable for treatment objects · Autoimmune liver disease. · Hepatic liver disease: such as hepatolenticular degeneration, Wilson disease, hemochromatosis, alpha antitrypsin deficiency and so on. · Bone marrow suppression: hemoglobin <10g / L, white blood cells <4x109 / L, platelets <80x109 / L Doctor's order). Have obvious heart, brain, nerve, psychosis and unstable diabetes. Pregnant women. ^[4]

Dosage of lamivudine

This product should be used under the guidance of a doctor experienced in the treatment of chronic hepatitis B. The recommended dose is 100 mg once a day, either before or after a meal.

Lamivudine course

For HBeAg-positive patients, according to existing research data, it is recommended to apply this product for at least one year, and HBeAg seroconversion (ie, HBeAg to negative, HBeAb positive) occurs after treatment, HBV DNA to negative, normal ALT, after continuous 2 The test is confirmed at least 3 months apart to confirm that the curative effect is solidified, and the treatment may be considered to be terminated.

For HBeAg-negative patients, a suitable course of treatment has not been determined. In the case of HBsAg seroconversion or treatment failure (HBVDNA level or ALT level continues to increase), treatment can be considered to be discontinued.

For patients considering YMDD mutation, if their HBVDNA and ALT levels are still lower than before treatment, they can continue to take the drug under close observation and strengthen supportive treatment if necessary. If their HBVDNA and ALT continue to be above the pre-treatment level, follow-up should be strengthened, and doctors should take appropriate treatment depending on the specific condition under close supervision. If HBeAg seroconversion is confirmed after two tests at least 3 months apart, HBV DNA becomes negative, and treatment may be discontinued. For patients with decompensated liver function or cirrhosis, it should not be easily stopped, and symptomatic liver protection treatment should be strengthened.

If HBVDNA and ALT continue to be above the pre-treatment levels during treatment, HBeAg seroconversion does not occur in patients who are HBeAg-positive before treatment, suggesting that treatment is ineffective, and treatment may be discontinued. For patients who have other clinical indications such as liver histological examination showing progress of the disease and liver function decompensation or cirrhosis, it should not be easily stopped, and symptomatic liver protection treatment should be strengthened.

If lamivudine treatment is discontinued, the doctor should follow up with the patient closely for at least 4 months after stopping the drug (the frequency of follow-up depends on the patient's situation), and regularly check the levels of ALT and bilirubin, HBVDNA and HBeAg. Prevent recurrence of hepatitis. After 4 months, patients can be followed up according to clinical needs.

Lamivudine impaired renal function:

Due to decreased renal clearance, serum lamivudine concentrations (area under the curve at the time of drug administration) in patients with moderate to severe renal impairment have increased after taking this product. Therefore, for patients with chronic hepatitis B with serum creatinine clearance <50ml / min, the dosage of this product should be reduced. Do the dose adjustments as shown in the table below.

Creatinine clearance (ml / min) First dose daily maintenance dose

30 ~ 50 20 ml (100 mg) 10 ml (50 mg)

15 ~ 30 20ml (100mg) 5ml (25mg)

5 to 15 7 ml (35 mg) 3 ml (15 mg)

5 to 7 ml (35 mg) 2 ml (10 mg)

Lamivudine liver impairment:

Data from studies of patients with severe liver dysfunction, including patients with advanced liver disease who are awaiting liver transplantation, indicate that unless the patient has renal impairment, pure liver dysfunction alone will not have a significant effect on the pharmacokinetics of lamivudine. The results of the pharmacokinetic study suggest that it is not necessary to adjust the dosage for patients with moderate or severe liver damage. ^[5]

Lamivudine adverse reactions:

A number of serious adverse events reported during the use of Lamiv regularly reported in warnings and cautions (lactic acidosis and severe liver enlargement with steatosis, exacerbation after treatment for hepatitis B, pancreatitis, and medication (Emergence of viral mutations associated with decreased sensitivity and reduced treatment response).

Clinical studies in patients with chronic hepatitis B have shown that most patients are well tolerated by lamivudine. The incidence of adverse events was similar in patients in the lamivudine and placebo groups. See the table below for details. The most common adverse events were discomfort and fatigue, respiratory infections, headaches, abdominal discomfort and pain, nausea, vomiting, and diarrhea. The following adverse reactions were also observed in 2,200 stage IV clinical studies conducted in China: 1 case of dry mouth, 1 case of systemic scarlet fever-like rash, 1 case of phosphocreatine activity and platelet reduction, and 1 case of hospitalization for severe hepatitis.

Observations in clinical activities: The following events were discovered during lamivudine approval during clinical use. Because these incidents came from voluntary reports from a group of unknown populations, estimates of incidence cannot be made. These events are included because of their severity, frequency of reporting, possible causality with lamivudine, or a combination of all these factors.

Digestive system: gastritis; endocrinology and metabolism: hyperglycemia; whole body: weakness; blood and lymphatic system: anemia, dysregulation of pure red blood cells, lymphadenopathy, splenomegaly.

Liver and pancreas: lactic acidosis and steatosis, pancreatitis, exacerbation of hepatitis after treatment (see warnings and precautions); allergies: allergic reactions, rubella; musculoskeletal: rhabdomyolysis;

Nervous system: paresthesia, peripheral neuropathy; respiratory system: abnormal breathing sounds / wheezing.

Skin: Hair loss, itching, rash. ^[5]

Lamivudine Taboo

Those who are allergic to lamivudine or any other ingredient in the preparation are contraindicated. ^[5]

Lamivudine considerations

Patients should be reminded that lamivudine is not a drug that can cure hepatitis B. Patients must take medication under the guidance of a specialist with experience in hepatitis B treatment. They cannot stop the medication on their own, and they need to be monitored regularly during treatment. ALT levels should be measured at least every 3 months and HBV DNA and HBeAg every 6 months.
Patients with HBsAg-positive but normal ALT levels, even if HBeAg and / or HBV DNA are positive, should not start lamivudine treatment. Follow-up observations should be performed regularly and reconsidered based on changes in the condition.
With the extension of lamivudine treatment time, a YMDD variant of hepatitis B virus can be detected in some patients, and this variant has reduced sensitivity to lamivudine (see [Clinical Research Section]). If the patient's clinical condition is stable and HBVDNA and ALT levels are still lower than before treatment, continue treatment and observe closely. A small number of patients with YMDD mutations, due to the reduced effect of lamivudine, may show recurrence of hepatitis, and HBVDNA and ALT levels may rise to pre-treatment levels or above. Some patients with YMDD mutations, especially those with liver decompensation or cirrhosis, have rarely reported serious disease progression leading to serious consequences or even death. It is also possible to stop lamivudine in this case As the disease progresses, it is not appropriate to discontinue lamivudine in patients with liver decompensation or cirrhosis during lamivudine treatment. Therefore, if YMDD mutations are suspected, clinical and laboratory monitoring should be enhanced to help make treatment decisions.
To date, there is no data on the long-term efficacy of lamivudine in the treatment of hepatitis B with hepatitis D or hepatitis C. There is limited data on lamivudine in HBeAg-negative patients, or patients who are also receiving immunosuppressive therapy, including tumor chemotherapy.
If HBeAg-positive patients discontinue this product before seroconversion, or those who discontinue treatment due to poor treatment results, some patients may have exacerbated hepatitis, mainly manifested by the reappearance of HBV DNA and elevated serum ALT.
If lamivudine treatment is discontinued (see Dosage and Administration), the patient's clinical condition and serum liver function indicators (ALT and bilirubin levels) should be regularly monitored for at least 4 months, and follow-up should be performed according to clinical needs. There is insufficient data on restarting lamivudine in patients who have relapsed hepatitis after stopping treatment.
For patients with organ transplantation or advanced liver disease such as decompensated cirrhosis, the risk of viral replication is greater and the prognosis is poor. Safety and efficacy have not been established in this group of patients. There is not enough clinical research data to approve lamivudine for the treatment of patients with organ transplantation or advanced liver disease such as decompensated cirrhosis. According to relevant foreign clinical research data, the reasonable application of lamivudine can improve the short-term survival rate of patients with decompensated liver function. In these patients, lamivudine should not be stopped. However, as an antiviral drug, lamivudine cannot reverse the end-stage changes of the liver structure and its complications. Therefore, other (including liver transplantation) more effective treatments should be considered for these patients. For patients with HIV infection, if you are receiving or plan to receive lamivudine or lamivudine-zidovudine combination therapy, you should maintain the recommended dose of lamivudine for HIV infection (usually 150 mg each time) , Twice daily, and combined with other antiretroviral drugs). For patients with concurrent HIV infection who do not need antiretroviral therapy, such as lamivudine alone for chronic hepatitis B, there may be HIV mutations.
There is currently no data on the use of this product in pregnant women, so routine hepatitis B immunization should still be performed on newborns.
Impact on driving and operating ability: There is currently no research on the effect of lamivudine on driving or operating ability. In addition, the results of pharmacological studies of drugs cannot accurately predict the adverse effects of lamivudine on these activities. ^[5]

Lamivudine warns:

Lactic acidosis / severe enlargement with steatosis: During the treatment of HIV-infected patients with high-dose nucleosides, lactic acidosis has been reported, including fatal cases, often with severe hepatomegaly and liver Steatosis. Such events are occasionally reported in patients with hepatitis B and decompensated liver disease, and treatment should be discontinued once clinical signs and laboratory findings suggest lactic acidosis occur.
Hepatitis worsens after treatment: clinical signs and laboratory evidence of worsening hepatitis have occurred after stopping lamivudine treatment (except for the reappearance of HBVDNA often observed after stopping treatment, mainly through elevated serum ALT To test these evidences. After 1 year of treatment, the patients were observed for 16 weeks after stopping the drug. The incidence of ALT elevation is shown in the table below). Although most events appear to be self-limiting, deaths have been reported in some cases. It is unclear whether there is a causal relationship with the termination of lamivudine treatment. After discontinuation of treatment, patients must be closely monitored for at least several months through clinical and laboratory follow-up. There is no sufficient evidence to determine whether restarting treatment can alter the course of hepatitis after treatment.
Table of post-treatment ALT elevations in 2 placebo-controlled studies
Pancreatitis: There are reports of pancreatitis and peripheral nervous system disease (or paresthesia) in patients receiving HIV (HIV) infection treated with this product. ^[5]

Lamivudine for pregnant and lactating women:

Lamivudine pregnancy:

The safety of this product for pregnant women has not been established. Animal reproduction studies have shown that it is not teratogenic and has no effect on female and male reproductive capacity. When pregnant rabbits are administered a drug equivalent to a human therapeutic dose, the chance of early embryo death can be increased. Lamivudine can be transported across the placenta by passive transport, and serum drug concentrations in newborns are similar to those in the mother and umbilical cord.

There is currently no information on the use of this product for pregnant women, so it is not appropriate to become pregnant while taking this medicine.

For women who accidentally conceive during lamivudine use, the possibility of hepatitis recurrence after stopping lamivudine treatment must be considered, and whether to terminate the pregnancy must be weighed with the patient and his family to discuss.

Lamivudine breastfeeding:

After oral administration, the concentration of lamivudine in breast milk is similar to that in plasma (ranging from 1 to 8 g / ml (4.4-34.9 mol / L)), so it is recommended that women who are taking the drug do not breastfeed infants. ^[5]

Lamivudine Drug Interactions:

Due to the low drug metabolism and plasma protein binding rate of this product, and the primary elimination of the drug through the kidney, the incidence of potential interactions with other drug metabolites is very low.

Lamivudine is mainly eliminated in the form of active organic cations. Interactions should be considered when used concurrently with drugs that have the same excretion mechanism, especially when the drug's primary clearance pathway is active renal secretion through an organic cation transport system (such as trimethoprim). Other drugs (such as ranitidine and cimetidine) cleared by this mechanism have been shown to have no interaction with lamivudine.

Drugs that are mainly excreted in the form of active organic anions or filtered through the glomerulus do not undergo significant clinically significant interactions with lamivudine.
Lamivudine and trimethoprim (160mg) / sulfamethoxazole (800mg) at the same time can increase the exposure of lamivudine by 40%. However, lamivudine does not affect the pharmacokinetics of trimethoprim / sulfamethoxazole. Therefore, there is no need to adjust the dose of lamivudine unless the patient has impaired renal function.

When lamivudine and zidovudine were taken at the same time, a moderate increase in Cmax of zidovudine was observed, about 28%, but no significant change in system bioavailability (area under the curve at the time of drug). Zidovudine does not affect the pharmacokinetic properties of lamivudine (see Pharmacokinetics).

Lamivudine and interferon are used at the same time, there is no pharmacokinetic interaction between the two; no clinically observed lamivudine and commonly used immunosuppressive agents (such as cyclosporine A) Obvious adverse interactions. No formal studies have been conducted on this.

When lamivudine and zalcitabine are used simultaneously, lamivudine may inhibit the latter's intracellular phosphorylation. It is therefore recommended not to use both drugs at the same time. ^[5]

Lamivudine overdose:

In limited data on the consequences of acute overdose in humans, no deaths have occurred and patients have recovered. No special signs or symptoms were seen after overdose.

Although there is no relevant research on this, if an overdose occurs, the patient should be monitored and given regular supportive treatment as required. Because lamivudine can be removed by dialysis, continuous hemodialysis can be used when overdose and clinical symptoms or signs appear. ^[5]

Lamivudine application

Lamivudine is used as an antiviral drug for the treatment of hepatobiliary diseases caused by hepatitis B virus infection.

Lamivudine's English name is Lamivudine, and its chemical name is 2'3'-dideoxy-3'-thiocytidine (2'-3'deoxy-3'-thiocytidine), also known as 3-TC. The product name after listing in China is He Puding. Randomized controlled clinical trials at home and abroad show that daily oral administration of 100 mg can significantly inhibit HBV DNA levels, and the HBeAg seroconversion rate increases with treatment time. HBeAg-positive patients are treated with HBeAg serum 1, 2, 3, 4 and 5 years after treatment. Conversion rates were 22%, 29%, 40%, 47%, and 50%, respectively [1-3]; those with higher ALT levels before treatment generally had higher HBeAg seroconversion rates [56-60]. Long-term treatment can reduce inflammation and reduce the incidence of liver fibrosis and cirrhosis [1,2]. Randomized controlled clinical trials have shown that this drug can reduce the incidence of liver decompensation and HCC (hepatocellular carcinoma) [21]. Patients with decompensated liver cirrhosis can also improve liver function and prolong survival [61-63]. The results of foreign studies have shown that lamivudine has similar efficacy and safety to children with chronic hepatitis B [64,65].

For patients with hepatitis B liver transplantation, lamivudine is used before transplantation; after transplantation, lamivudine combined with HBIG can significantly reduce HBV reinfection after liver transplantation, and can reduce the dose of HBIG.

Lamivudine for hepatitis B

It is difficult to completely eliminate HBV. Both interferon and nucleotide analogs can only inhibit the replication of hepatitis B virus. After short-term treatment (1 year), patients' HBV DNA levels will rebound sharply, which proves that the treatment of hepatitis B requires "Changzhi "Jiuan"; while achieving long-term treatment, standard medication should not be ignored. Even drug resistance leads to disease progression. Therefore, long-term medication and standard medication must be used during treatment.

Curative effect

The efficacy of antiviral therapy depends on whether it can reduce the incidence of cirrhosis and liver cancer. Four oral antiviral drugs have a good effect on inhibiting hepatitis B virus replication and e-antigen conversion, but only lamivudine has more than 10 The clinical data of delaying disease progression and reducing liver cirrhosis caused by liver cancer. Studies show that lamivudine antiviral treatment can reduce the incidence of liver cirrhosis by 55% and liver cancer by 51% after 3 years of treatment Hepatic fibrosis was completely reversed in 18.8% of patients. It can be seen that only long-term treatment of drugs with good curative effect can make patients benefit the most. Patients need to pay more attention to the long-term treatment effect when choosing antiviral drugs.

side effect

Hepatitis B patients receiving nucleoside (acid) analogs must receive long-term treatment or even life-long treatment. Adverse reactions caused by these drugs have also received widespread attention. The risks of solid tumors in animal experiments bother doctors and patients. The reports of adverse reactions caused by the application of nucleoside (acid) analogs, such as myopathy, nephrotoxicity, peripheral neuropathy, lactic acidosis, etc., are the focus of attention. Once these side effects caused by drugs are not taken in time, they are likely to be life-threatening. Therefore, attaching great importance to the safety of oral antiviral drugs, and testing CK and other indicators regularly play a positive role in adhering to long-term treatment. Comparing 4 oral antiviral drugs, lamivudine has been on the market for ten years, and it is the earliest drug on the market for oral antiviral drugs for treating chronic hepatitis B. It is the most widely used and has good safety.

Precautions

The clinical situation and virological indicators of patients should be checked regularly by an experienced hepatitis specialist during treatment.

Hepatitis may worsen after a few patients stop using lamivudine. Therefore, if the product is discontinued, the patient should be closely observed, and if hepatitis worsens, consideration should be given to re-using the product.

For patients with creatinine clearance <30ml / min, this product is not recommended.

This product should not be used during pregnancy, except in special circumstances, doctors consider using this product is beneficial to pregnant women. Patients in the first three months of pregnancy should not use this product. Breastfeeding women do not need to stop breastfeeding. Unless lamivudine is more dangerous to the baby than to the mother.

There is no data showing that pregnant women can inhibit the mother-to-child transmission of hepatitis B virus after taking this product. Therefore, newborns should still be routinely immunized against hepatitis B.

During the treatment of this product, patients cannot be prevented from infecting others through sexual contact or blood-borne transmission, so appropriate protective measures should still be taken.

When lamivudine is used together with drugs with the same excretion mechanism (such as trimethoprim), the blood concentration of lamivudine can be increased by 40%, which is not clinically significant, but patients with renal impairment should pay attention.

Lamivudine inhibits virality

Lamivudine is a nucleoside analog, while nucleotides are the raw materials for the synthesis of human genetic material DNA and RNA (DNA and RNA are actually many nucleotides lined up in a long string). Nucleoside analogs mimic the structure of nucleotides, but do not have the function of nucleotides. Therefore, in the process of DNA synthesis, nucleoside analogs can be incorporated, but they cannot synthesize nucleic acid chains with normal functions, thereby terminating the replication of the virus. Lamivudine mimics cytosine, and its structure is different from human's natural cytosine structure. It can only act on viruses and has no side effects on the human body. Lamivudine is widely accepted by doctors and patients as a new nucleoside analog, and it is a representative nucleoside analog with good curative effect in clinical application. Its mechanism of action is to inhibit viral DNA polymerase and reverse transcriptase activities, and has a competitive inhibitory effect on the synthesis and extension of viral DNA strands.

Lamivudine other

The course of treatment, the 2011 new edition of the "Guide" states that the total course of treatment for hepatitis B should reach at least 2 years. And, the longer the consolidation treatment time is reached, the lower the patient's recurrence rate, even if the indication for stopping treatment is reached, which is completely consistent with the 2010 version of the new China Hepatitis B Prevention and Treatment Guidelines for the treatment time of chronic hepatitis B patients. A survey on the medication time and relapse rate of treated patients showed that the relapse rate of patients with consolidation therapy was less than 1 year, and the recurrence rate of patients could reach 61.9%. Conversely, the recurrence rate of patients with consolidation therapy longer than 1 year was only 8.7%.

Lamivudine time

Lamivudine can be taken for a long time. Lamivudine is the longest-to-market and most clinically experienced antiviral drug. Long-term standardized treatment can effectively reduce and delay disease progression. The Guide states that the ultimate goal of hepatitis B treatment is to "reduce the development of cirrhosis and liver cancer." And a landmark 4006 three-year study in the field of hepatitis B treatment found that after 32 months of treatment with a nucleoside drug (lamivudine), the disease progression can be reduced by 55%, and the incidence of liver cancer can be reduced by 51%. The 10-year follow-up results of lamivudine even found that adherence to long-term oral antiviral treatment can not only significantly improve liver fibrosis, and even reverse early liver cirrhosis in some patients.

Lamivudine side effects

1. After taking lamivudine, 10% of patients have transient elevations of amylase and lipase.

2. After long-term administration, patients who have been treated for more than 6 months may have mutations in HBV DNA polymerase (commonly called YMDD mutations). However, the study also believes that continued application of lamivudine in this case still has clinical effects.

3. Lamivudine is well tolerated in all patient populations studied. In the Phase II and Phase III clinical trials, there was no increase in the incidence of related adverse reactions due to the increase in total dose and prolonged treatment. Recommended reading Entecavir.

4. Long-term treatment of lamivudine can significantly delay the disease progression of patients with HBeAg-positive chronic hepatitis B (P <0.005) and reduce the incidence of cirrhosis and liver cancer. Some scholars have studied and observed the long-term efficacy of lamivudine in the treatment of HBeAg-positive chronic hepatitis B patients for 5 years. The results show that lamivudine can continuously inhibit virus replication and maintain ALT normalization. The HBeAg seroconversion rate increases with treatment time, and the proportion of patients with HBeAg seroconversion is 80%.

5. Although lamivudine has a significant effect on hepatitis B, mutations in hepatitis B virus can occur in patients treated with lamivudine for more than 6 months. After 1 year of treatment, the incidence of hepatitis B virus mutations was 10% to 20%, and the incidence of mutations increased with the extension of treatment time.

Adverse effects of long-term lamivudine use

Lamivudine is a nucleoside antiviral drug, which is mainly applicable to the treatment of adult patients with chronic hepatitis B. It can effectively inhibit the replication of the virus and promote the repair and regeneration of damaged liver cells. This medicine has a certain therapeutic effect, but it should not be taken for a long time, mainly because:

Lamivudine usually needs to be taken for a long time and has a long course of treatment, but many patients respond. During the long-term use of this medicine, many adverse problems will occur, such as causing patients to have some adverse symptoms, such as dizziness and headache. , Fatigue, nausea, vomiting, indigestion, etc. In fact, these adverse symptoms are not the patients' most concern, because in addition, long-term use of this drug will lead to drug resistance, and it is not easy to stop the drug, because once the drug is stopped Improper, it is likely to cause the disease to rebound again, seriously affecting the early treatment effect, so many patients think that this drug should not be taken for a long time.

Lamivudine withdrawal criteria

After long-term treatment with lamivudine, HBV polymerase gene mutations can occur and drug resistance can occur. After the drug is abruptly stopped, the mutant strains of the virus and the remaining wild strains may reactivate and accelerate replication, so some patients will appear The "bounce" phenomenon after stopping the drug, HBV-DNA, HBeAg reverted to positive, transaminase increased, individual patients may even develop jaundice and liver function decompensation, and the condition worsens, so those who take lamivudine should not suddenly stop .

Stopping lamivudine is really very particular about it, and it really can't be stopped at will. Experts recognize the suspension of lamivudine as follows: 1. The lamivudine treatment cycle is longer, at least 18 months or more.

One year after chronic hepatitis B patients took lamivudine, HBeAg turned to anti-HBe? HBV-DNA turned negative, liver function was normal, symptoms had disappeared, and they should be taken for half a year. If there is no change, consider discontinuing the drug.

Before treatment, patients with chronic hepatitis B are negative for HBeAg, but HBV-DNA is positive. Lamivudine must be taken for 2 years. After HBV DNA becomes negative, drug withdrawal may be considered.

If chronic hepatitis B patients take lamivudine treatment, if transaminase (ALT) is significantly increased to more than 500 units, and even jaundice is found, the drug should not be easily stopped at this time, and other antiviral drugs should be combined (please consult an online doctor ), Combined with high-dose thymosin and hepatoprotective drugs, symptomatic treatment, do not consider discontinuation of the drug until half a year after the condition is stable.

6ALT<500HBV DNA

YMDDALT

1~2e/e3~61

If hepatitis B virus mutates, drug resistance will develop. The manifestation of the mutation is that the hepatitis B virus DNA changes from negative to positive, and serum ALT rises again. This mutation occurs early in the medication for half a year, and later in a few years. It has been reported that the incidence of drug resistance during the 1 year of drug use is 10% to 25%, and with the extension of the drug treatment time, the number of drug resistance also increased. If taking lamivudine for more than 6 months, ALT is elevated, and the hepatitis B virus DNA is positive or the titer is increased. The possibility of hepatitis B virus mutation should be considered. However, if ALT is more than 5 times higher than normal, and liver function deteriorates, lamivudine should be discontinued, and other causes that can aggravate liver disease, such as alcoholism, drug use, taking other drugs, etc. Beware of other hepatitis virus infections or complications of hepatocellular carcinoma. If it is indeed caused by mutations in hepatitis B virus, other antiviral drugs (such as famciclovir) can be used and liver protection treatment should be strengthened.

If it recurs, the treatment is:

Introduce the characteristics and precautions of the drug in detail before use, and apply lamivudine on the premise that the patient promises to abide by the doctor's order.

Periodic review of liver function and viral replication indicators during medication. Liver function will be reviewed once every 15 days after starting the medication, and once every 2-4 months after normal liver function. HBV-DNA can be checked once every 1-2 months, and HBv-DNA can be checked once every 3 months. Review HBeAg 4 months after taking the medicine. Generally speaking, HBV-DNA and HBeAg should be consolidated for 3 months before the appointment can be stopped.

(3) After the condition improves, patients are often urged to take medicines on time to eliminate the confusion of the so-called "new drugs" and "specific drugs" in patients' hearsay in order to prevent patients from stopping lamivudine and switching to other drugs, causing the disease to recur.

Sequential treatment with interferon and other drugs or combination therapy with antiviral drugs such as matrine at the end of the course of treatment. It can also be used with lamivudine at the same time as other antiviral drugs, or combined with traditional Chinese medicine to treat symptoms, which is beneficial to prevent or reduce recurrence.

After long-term application of lamivudine in a few patients with HBv mutation, you can consider switching to stikaca or adefovir. It is reported that they still have a good effect on the drug-resistant virus that has developed mutations.