Comprehensive understanding of Isotretinoin

Isotretinoin (Isotretinoin), also known as: 13-cis Tretinoin, Baofuling, Rocatane, Talsi and so on. Foreign trade names are: Accutane, Ro-4-3780, Accure, Isohexal, Isotrex, Oratane, Roaccutane, Roacutan, etc. Chemical name: 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2cis-4trans-6trans-8trans-nontetraenoic acid. It is a vitamin A drug developed by Roche in Switzerland. Clinically, it is mainly used to treat general infectious skin diseases, and it also has a certain effect on skin tumors.

Physical and chemical properties

Isotretinoin is yellow or light orange crystalline powder, almost insoluble in water, soluble in dichloromethane, slightly soluble in ethanol, unstable to light, heat and oxygen, melting point 174-177°C. Easy to oxidize, very sensitive to light below 500nm, trace metals, strong acid, high heat, etc.

Pharmacology

Isotretinoin inhibits the in vitro proliferation and DNA synthesis of human keratinocyte cell line Cole-16 cell line in a dose-dependent manner; reduces keratinocyte tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL- 6) The production has direct damage to the ultrastructure of keratinocytes and inhibits the expression of keratinocyte keratin. In addition, isotretinoin can inhibit the release of neutrophil superoxide anion formation solvent; inhibit neutrophil hyperplasia or restore neutrophil function to normal, and inhibit the formation of collagenase and gelatinase in the skin. To achieve the purpose of anti-inflammatory. The mechanism of isotretinoin inducing tumor cell differentiation is similar to the effect of steroid hormones, that is, isotretinoin is transported to the nucleus after binding to its receptor, modifying transcription genes, and affecting cell proliferation or differentiation. Isotretinoin regulates gene expression directly, not as a result of cell proliferation inhibition.

Pharmacokinetics

Isotretinoin is quickly absorbed after oral administration, reaching a peak within 2 to 3 hours, and then rapidly decreasing. Normal people take 40 mg/time orally, the blood concentration reaches 100 mg/ml after 1 hour, and about 200 mg/ml after 3 to 6 hours. The half-life of each patient after taking 25 mg isotretinoin is significantly different, with an average of 10-20 hours. Isotretinoin is oxidized in the liver and combined with glucuronic acid. The main metabolite is carboxylic acid, and it is removed from the feces in 2 to 5 days. All excretion in urine does not lead to accumulation of drugs.

Application

1. Treatment of moderate and severe acne Isotretinoin significantly inhibits sebum secretion, reduces the volume of sebaceous glands, reduces hair follicle keratosis, and leads to a decrease in the density of Propionibacterium acnes.

2. Treatment of malignant tumors

3. Treatment of condyloma acuminatum

4. Treat palmoplantar pustulosis

5. Infectious skin diseases Isotretinoin has no antibacterial effect, but it can reduce seborrhoea, dry skin and mucous membranes, and make Gram-negative bacteria that can grow in a wet environment lose their parasitic environment and achieve antibacterial purposes. Isotretinoin is treated at 0.47～1mg/kg per day for 1～3 months, and most patients are cured.

6. Anti-tumor effect

At a concentration of 4-8μmol/L, the inhibition rate of cancer cells can reach 35.4%, and the soft agar clone formation of Hep-2 cells is reduced to 19.5% of the control. Therefore, isotretinoin has a certain effect on gastric cancer and breast cancer. For multiple syringomas and lipocystic tumors, the effect is satisfactory, with isotretinoin 0.75 mg/kg daily, after 3 months of taking the drug, the damage becomes flat and soft, and the color becomes lighter and close to the skin color; after 6 months of treatment, most The skin is calm, especially the neck and axillary skin lesions have subsided. Laboratory studies have shown that it can inhibit the proliferation of squamous cell lines 886, 1483 and Sqccdyl, and promote the expression of squamous differentiation marker protein K1 keratin.

Adverse reactions

The main adverse reactions of isotretinoin are dry lips and cheilitis. External preparations can be used to relieve symptoms, and itching and scaling can be treated symptomatically. Eye irritation, nausea, nosebleeds, etc. are transient symptoms, which can be tolerated or disappear on their own with continued medication. Isotretinoin increases serum triglyceride content, which is related to its dosage. Approximately 25% of patients with daily doses ≥ 1 mg/kg have increased plasma triglyceride levels by 10% or more, accompanied by increased serum cholesterol and low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol. Isotretinoin can cause mild to moderate increase in liver enzymes, stop or reduce the dose to return to normal. Creatine phosphokinase value occasionally increased during treatment, so CPK value should be monitored in all patients taking medication. Once the CPK value is greater than 5 times the normal value, immediately stop the drug. In addition, the drug occasionally has hair loss, depression, insomnia, loss of libido and teratogenic effects, so it is contraindicated in pregnant women.

①Skin membrane wear: Almost all patients can have adverse reactions to skin membranes, most of which occur within a week, which are earlier adverse reactions, such as dry lips, dry eyes, dry nose membranes, etc.;

②Central nervous system: can lead to the occurrence of pseudo-brain tumors. It may also cause disorders of the mental system. Patients may experience emotional instability and mental abnormalities, and may even have rare adverse reactions such as aggressive behavior, depression, suicide attempts or suicidal behavior;

③Laboratory abnormalities: mainly elevated blood lipids and abnormal liver enzymes;

④ Teratogenic effects: Humans have serious teratogenic effects, including central nervous system malformations, cardiovascular system malformations, and facial malformations;

⑤Muscular system: the incidence of myalgia is approximately, in addition to joint pain;

⑥ Skeletal system: It is more common in adults, the most common are bone hypertrophy, tendon and bremsstrahlung.

Precautions

Isotretinoin may be teratogenic. According to reports by Luo Qiyuan and others, sufficient evidence shows that its teratogenic risk is similar to that of typical strong teratogenic drugs, and is more than 20 times higher than the natural occurrence rate. For foreign pharmaceutical companies who received this product during pregnancy during 1990, the ratio of normal babies to abnormal babies was 1:1, except for abortions. Therefore, advice: women of childbearing age or their spouses should strictly take contraceptive measures during the medication period and within 3 months before and after taking the medication. The liver function and blood lipid changes should be measured before and after taking the medicine. Dry mouth, dry lips, and dry skin will occur during the medication, and will disappear after stopping the medication.

Main reference materials

[1] Song Yongxi, Yao Li, Li Rong, Sui Yanhai. The pharmacological effects and clinical application of isotretinoin[J]. Journal of Harbin Medical University, 1998(06): 83-84.

[2] Xinxiang Method. The progress of clinical research on isotretinoin [J]. Shanghai Medicine, 2003(09):407-408.

[3] Chen Xuehong. Preparation of Isotretinoin Solid Lipid Nanoparticle Gel [D]. Huazhong University of Science and Technology, 2011.

[4]Tian Keping. The effect of isotretinoin on depression and quality of life in patients with moderate to severe acne vulgaris[D]. Central South University, 2014. [5] Luo Ying. Preparation method of isotretinoin[J]. Zhejiang Education College Journal, 2006(03): 67-70.

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