Cisplatin, also known as cis-dichlorodiammonium platinum, is an anticancer drug containing platinum. It is orange yellow or yellow crystalline powder, slightly soluble in water, easily soluble in dimethylformamide, and can gradually be converted into trans and hydrolyzed in aqueous solution.Clinically, it can show curative effect on ovarian cancer, prostate cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer, osteosarcoma and other solid tumors.
On October 27, 2017, the list of carcinogens published by the International Agency for Research on Cancer of the World Health Organization (WHO) was preliminarily sorted out for reference, and cisplatin was included in the list of Category 2A carcinogens.[159]
Appearance: orange yellow to dark yellow crystalline powder[160]
Calculate chemical data
Reference value for drainage parameter calculation (XlogP): None
Number of hydrogen bond donors: 2
Number of hydrogen bond receptors: 4
Number of rotatable chemical bonds: 0
Number of tautomers: 0
Topological molecule polar surface area (TPSA): 2
Number of heavy atoms: 5
Surface charge: 0
Complexity: 0
Number of isotope atoms: 0
Determine the number of atomic structure centers: 0
Number of uncertain atomic structure centers: 0
Determine the number of chemical bond structure centers: 0
Number of uncertain chemical bond structure centers: 0
Number of covalent bond units: 5[160]
purpose
Cisplatin can combine with DNA to cause cross binding, thus damaging the function of DNA and inhibiting cell mitosis, so it is a cell non-specific drug.This product has a wide anti-tumor spectrum, and is used for head and neck squamous cell carcinoma, ovarian cancer, embryonic cell carcinoma, seminoma, lung cancer, thyroid cancer, lymphosarcoma, reticular cell sarcoma, etc.
Pharmacopoeia information
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source
This product is（Z）-Diammonium Dichloroplatinum.Calculated as dry product, including PtCltwo(NHthree)twoIt should be 98.0%~102.0%.
character
This product is a bright yellow to orange crystalline powder, odorless.
This product is easily soluble in dimethyl sulfoxideN,N-Dimethylformamide is slightly soluble in water and insoluble in ethanol.
identify
1. Take about 5mg of this product, add 1mL of sulfuric acid, and it will appear greyish green.
2. In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.
3. Take this product, add 0.9% sodium chloride solution to make a solution containing about 1mg per 1mL, and determine it by ultraviolet visible spectrophotometry (general rule 0401). There is maximum absorption at the wavelength of 301nm and minimum absorption at the wavelength of 247nm.
4. The infrared absorption spectrum of this product should be consistent with the control spectrum (spectrum set 297 figure).
inspect
Platinum content
Take about 0.5g of this product, weigh it accurately, burn it to constant weight at 400 ℃ according to the ignition residue inspection method (general rule 0841, but without adding sulfuric acid), and the weight of the residue obtained is the weight of platinum in the test volume.Calculated as dry product, the platinum content should be 64.6%~65.4%.
Chlorine content
Take 30mg of this product, precisely weigh it, and carry out organic destruction according to the oxygen bottle combustion method (general rule 0703). Use 20mL of sodium hydroxide test solution as the absorption solution. After the combustion is completed, shake it vigorously for several minutes, wash the bottle stopper and platinum wire with a small amount of water, incorporate the cleaning solution into the absorption solution, add 1 drop of bromophenol blue indicator solution, add 1 drop of dilute nitric acid until the solution turns yellow, and then add 1mL of dilute nitric acidFive drops of ethanol solution of 20mL ethanol and 1% diphenyl hydrazine were titrated with mercuric nitrate titrant (0.025mol/L). When the end point was near, shake vigorously, continue to titrate until the solution showed light rose red, and the titration results were corrected with blank test.Every 1mL of mercuric nitrate titrant (0.025mol/L) is equivalent to 1.773mg of chlorine (Cl), and the chlorine content should be 23.0%~24.3%.
Clarity of solution
Take 20mg of this product, add 20mL of 0.9% sodium chloride solution to dissolve it, and the solution should be clear.
acidity
Take the solution under the item of clarity of the solution and measure it according to the law (general rule 0631). The pH value should be 5.0~7.0.
Related substances
It is determined according to the high performance liquid chromatography (general rule 0512). It is operated in dark and newly prepared for clinical use.
Test solution: Take this product, add 0.9% sodium chloride solution to dissolve it and dilute it to make a solution containing about 0.2mg per 1mL.
Reference solution: precisely measure 1mL of the test solution, place it in a 50mL volumetric flask, dilute it to the scale with 0.9% sodium chloride solution, and shake it well.
Chromatographic conditions: octadecyl silane bonded silica gel is used as filler, 0.9% sodium chloride solution of 0.003mol/L heptane sulfonate sodium is used as mobile phase, detection wavelength is 220nm, and injection volume is 20 µ L.
System applicability requirements: the number of theoretical plates shall not be less than 3000 based on the cisplatin peak, and the resolution between the cisplatin peak and the adjacent impurity peak shall meet the requirements.
Determination method: Precisely measure the test solution and the reference solution, respectively inject them into the liquid chromatograph, and record the retention time of the chromatogram to the main component peak twice.
Limit: If there is an impurity peak in the chromatogram of the test solution, the impurity peak area with a relative retention time of about 0.87 multiplied by 0.569 shall not be greater than 0.5 times (1.0%) of the main peak area of the reference solution, and the impurity peak area with a relative retention time of about 1.2 multiplied by 1.356 shall not be greater than the main peak area of the reference solution (2.0%),The sum of the peak areas of other impurities shall not be greater than 0.25 times (0.5%) of the main peak area of the reference solution.
Loss on drying
Take about 0.1g of this product, dry it at 105 ℃ to constant weight, and the weight loss shall not exceed 0.5% (general rule 0831).
Assay
Determine according to the high performance liquid chromatography (general rule 0512), and operate in dark.
Test solution
Take an appropriate amount of this product, weigh it precisely, add 0.9% sodium chloride solution to dissolve it and dilute it quantitatively to prepare a solution containing about 40 µ g per 1mL.
Reference solution
Take cisplatin reference substance, weigh it precisely, add 0.9% sodium chloride solution to dissolve it and dilute it quantitatively to prepare a solution containing about 40 µ g per 1mL.
Chromatographic conditions and system suitability requirements
See related substances.
Assay
Accurately measure the test solution and the reference solution, respectively inject them into the liquid chromatograph, and record the chromatogram.Calculate by peak area according to external standard method.
category
Antineoplastic drugs.
Storage
Shading, sealed storage.
preparation
Cisplatin for injection.[161]
Brief Introduction to Drugs
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pharmacological action
Cisplatin, a commonly used metal platinum complex, plays an important role in the anti-tumor effect of platinum atoms in the molecule.But only cis is meaningful, and trans is invalid.It can cross connect with DNA strand, showing cytotoxicity.After dissolution, it can pass through charged cell membrane without carrier transport in vivo.Due to the low concentration of chloride ions in cells (4 mmol/L), the chloride ions are replaced by water, and the charge is positive. It has the function of a bifunctional group similar to an alkylating agent. It can combine with the bases of DNA in the nucleus to form three forms of cross-linking, causing DNA damage, destroying DNA replication and transcription, and inhibiting the synthesis of RNA and protein at high concentrations.Cisplatin has the advantages of broad anti-cancer spectrum, effective hypoxic cells, and strong effects. It has been widely used to treat testicular cancer, ovarian cancer, uterine cancer, bladder cancer, neck cancer, prostate cancer, brain cancer, and so on.However, cisplatin has certain toxicity in the treatment of cancer, which will cause side effects. Therefore, it is necessary to constantly look for analogues with less toxicity and similar clinical effects to cisplatin.So far, scientists around the world have synthesized and tested thousands of metal complexes related to cisplatin, and developed the second generation anti-cancer platinum complexes represented by carboplatin.The third generation of anticancer metal complexes have also been found, represented by titanium dichlorocene.These compounds have nothing to do with cisplatin from the chemical point of view, but they have a good effect on some cancerous changes with little effect of cisplatin treatment, and do not harm renal function.At present, a lot of research is still ongoing in this field, focusing on exploring the mechanism of anticancer activity of metal complexes at the molecular level.China has already produced cisplatin and carried out research in this regard.
Cisplatin is a non-specific drug for cell cycle and has cytotoxicity. Because cancer cells proliferate and synthesize more rapidly than normal cells, cancer cells are more sensitive to the cytotoxicity of this product, which can inhibit the DNA replication process of cancer cells, damage the structure on their cell membranes, and have a strong broad-spectrum anti-cancer effect.It is used for ovarian cancer, prostate cancer, testicular cancer and other malignant tumors of the urinary and reproductive system, with good curative effect.Combined with vincristine, cyclophosphamide and 5-fluorouracil, it has obvious effect on malignant lymphoma, breast cancer, head and neck squamous cell carcinoma, thyroid cancer osteosarcoma, etc.Cisplatin combined with radiotherapy has a prominent effect on advanced non-small cell lung cancer, nasopharyngeal cancer, esophageal cancer, etc. It also has a certain effect on liver cancer and soft tissue sarcoma.Cisplatin is a highly cumulative drug, which is prone to nephrotoxicity. Digestive tract reactions are common. Some patients have granulocytopenia, but it can recover within 7 to 14 days after drug withdrawal.
In addition, the DNA damage caused by this product may also change its antigenicity in the nucleus or on the cell surface, expose the previously hidden surface antigen, stimulate the immunosuppression of antibodies and play its cytotoxic role.[1]
Toxicological study
1. Reproductive toxicity
The use of this product by pregnant women may cause fetal damage.The product showed teratogenicity and embryotoxicity in mouse experiments.If it is used during pregnancy, or if pregnancy is found during drug administration, the patient should be informed of its potential harm to the fetus.Women who are likely to have children should be advised to avoid pregnancy.It is reported that this product has been detected in human milk. It is recommended that mothers stop lactation when using this product.
2. Genotoxicity
This product shows mutagenicity in cell experiment, causing chromosome aberration in tissue cultured animal cells.
3. Carcinogenicity
The carcinogenicity test of BDIX (50 in total) was carried out. The product was administered intraperitoneally for 3 weeks, 1mg/kg/week. Results Within 455 days of the first administration, 33 animals died, 13 of them died of malignant tumors;12 cases of leukemia, 1 case of renal hepatic fibrosarcoma.
Pharmacokinetics
[In vivo process] DDP is ineffective after oral administration. After intravenous injection, it begins to distribute most in liver, kidney, intestines and skin. After 18-24 hours, it accumulates most in kidney and least in brain tissue.It disappeared rapidly in plasma and showed a biphasic pattern.The initial plasma half-life is 25-49 minutes, and the plasma half-life after distribution is 55-73 hours.One hour after intravenous injection, the plasma content was about 10%, and 90% was bound to macromolecules such as plasma protein.The excretion rate was slow, 19%~34% was excreted in the urine within 1 day, and only 25%~44% was excreted in the urine within 4 days, but only 27%~43% of cisplatin was excreted in the body within 5 days after full dose injection;There is little excretion from the bile duct or intestinal tract, and the drug concentration in the abdominal organs during intraperitoneal administration is 2.5~8 times that of intravenous administration, which has synergistic effect on ovarian cancer and other treatments.
indication
Treatment of small cell and non small cell lung cancer, testicular cancer, ovarian cancer, cervical cancer, endometrial cancer, prostate cancer, bladder cancer, melanoma, sarcoma, head and neck tumors, and various squamous cell carcinomas and malignant lymphoma.
clinical application
DDP is one of the most commonly used drugs in current combined chemotherapy because of its broad spectrum of anticancer drugs, strong effect, synergistic effect with a variety of anti-tumor drugs, and no cross resistance.
(1) Reproductive system tumor: it has significant effect on ovarian cancer and testicular cancer.The combination chemotherapy of DDP and ADM can make more than 40% ovarian cancer achieve good curative effect;The combined chemotherapy of DDP, BLM and VLB has an effective rate of 80% and a cure rate of 60% for non spermatogenic testicular cancer.It can also be used for choriocarcinoma, cervical cancer and other reproductive system tumors.
(2) Head and neck cancer: nasopharyngeal cancer, thyroid cancer, laryngeal cancer, etc.
(3) It is also effective for bladder cancer, lung cancer, malignant lymphoma, breast cancer, renal cell cancer, prostate cancer, soft tissue sarcoma, and malignant melanoma.
(4) Others: malignant hydrothorax and ascites;Combined with radiotherapy, it has radiosensitization effect.
It is a first-line drug for the treatment of various solid tumors.The combination with VP-16 (EP scheme) is the first line scheme for treating SCLC or NSCLC, and the combination with MMC, IFO (IMP scheme), or NVB is the common scheme for treating NSCLC. The combination chemotherapy based on DDP is also the main treatment scheme for advanced ovarian cancer, osteosarcoma, and neuroblastoma, and the combination with ADMThe combination of CTX and others is effective for multiple site squamous cell carcinoma and transitional cell carcinoma, such as head and neck, cervical, esophageal and urinary tumors.
"PVB" (DDP, VLB, BLM) can treat most stage IV nonseminomatous testicular cancer, with a remission rate of 50%~80%.In addition, this product is a radiosensitizer, which is widely used abroad for local radiotherapy of stage IV inoperable NSCLC, to improve the efficacy and survival period.
taboo
It is forbidden for patients who are allergic to cisplatin and other platinum containing preparations, pregnant, lactating, bone marrow dysfunction, severe renal function damage, excessive water loss, chickenpox, herpes zoster, gout, hyperuricemia, recent infection and peripheral neuropathy caused by cisplatin.
Usage and dosage
Intravenous injection or intravenous drip: 20-30mg, or 20mg/m each timetwo20~30mL in normal saline, or 250~500mL in 5% glucose injection for intravenous drip. The first and eighth days of use are one cycle, usually repeated for 3~4 weeks, and can be interrupted for 3~4 cycles.
Large dose: 80 ～ 120mg/mtwo, once every three weeks, and pay attention to hydration at the same time to keep the urine volume of the patient at 2000~3000 mL, and mannitol can also be added for diuresis.
Intrathoracic and intraperitoneal injection: once every 7-10 days, 30~60mg each time.Abdominal cavity 100-160 mg each time.
Arterial injection: 20~30mL each time, which shall be injected by cannula, for 5 consecutive days as a cycle, and can be repeated every 3 weeks.Arterial perfusion is mainly used for head and neck tumors.
Adverse reactions
1. Kidney toxicity: after a single medium or large dose of medication, slight and reversible renal dysfunction may occasionally occur, and micro hematuria may occur.Repeated high-dose and short-term repeated use of drugs will lead to irreversible renal dysfunction, and in severe cases, renal tubular necrosis, resulting in anuria and uremia.
2. Digestive system: including nausea, vomiting, anorexia, diarrhea, etc., reactions often occur within 1~6 hours after administration, and the longest time does not exceed 24~48 hours.Liver dysfunction and increase of serum transaminase were occasionally seen, which could be recovered after drug withdrawal.
3. Hematopoietic system: white blood cells and (or) platelets are reduced, which is generally related to the dosage of drugs. Bone marrow suppression usually reaches its peak in about three weeks, and recovers in 4-6 weeks.
4. Ototoxicity: Tinnitus and high-frequency hearing loss may occur, which are mostly reversible and do not require special treatment.
5. Neurotoxicity: mostly seen in the total amount of more than 300mg/mtwoPeripheral nerve injuries were common in 40% of patients, which manifested as dyskinesia, myalgia, upper and lower limb sensory abnormalities, etc;A few patients may have brain dysfunction, epilepsy, retrobulbar optic neuritis, etc.
6. Allergic reactions: such as increased heart rate, decreased blood pressure, dyspnea, facial edema, allergic fever, etc., may occur.
7. Others:
Hyperuricemia: Leg swelling and joint pain often occur.
Cardiotoxicity: rare arrhythmia, ECG change, bradycardia or tachycardia, cardiac insufficiency, etc.
Immune system: immunosuppressive reaction will occur.
Gingival changes: There will be platinum deposits in the gums.
Local swelling may occur in the limbs of patients receiving arterial or intravenous injection.Pain, erythema, skin ulcer and local phlebitis are rare.There may also be hair loss, sperm, egg formation barriers and feminization of male breasts.
The occurrence of secondary non lymphocytic leukemia is related to the use of cisplatin chemotherapy.
Vascular diseases, such as cerebral ischemia, coronary artery ischemia, peripheral vascular disorders similar to Ravnaud syndrome and other side effects are rare, but may be related to the use of cisplatin.
matters needing attention
1. Using
(1) Large dosage (80~120mg/m) is appliedtwo）At the same time, hydration and diuresis must be carried out.The so-called hydration therapy is a kind of treatment method to reduce renal toxicity by hydration, promoting happiness and increasing the amount of chlorine in urine.Generally, 1000 mL of normal saline or glucose is dissolved before the administration of large dose DDP, and then chlorine is added and released.DDP was diluted with 200mL normal saline and then instilled.Before DDP administration, 125 mL of 20% mannitol was administered once, and 125 mL was added after DDP dripping to achieve the purpose of diuresis.Generally, the total amount of liquid per day is 3000~4000mL, and infusion starts 6~12h before DDP administration and continues until 6h after DDP administration;Some large doses of DDP are administered once, and the infusion lasts for 3 days. According to the urine volume, 40mg furosemide is administered intravenously each time during the infusion.
(2) In order to reduce toxic and side effects, more water should be drunk during medication;All kinds of antiemetics should be selected before use;At the same time, epinephrine, corticosteroids and antihistamines should be prepared for emergency use;After DDP is used, the effect can be consolidated by intramuscular injection of annaka.
(3) Blood, urine, liver and kidney functions should be monitored before, during and after medication.Its drug withdrawal finger tablet: WBC<3.5x10nine/50. Platelets<75x 10nine/L Persistent nausea and vomiting;Early renal toxicity, such as urinary leukocyte 10, red blood cell 10, tubular type 5/high power visual field;Serum creatinine>186-351mmol/L;Allergic reaction;Patients with history of kidney disease, poor renal function and otitis media were found in the course of medication.If the serum creatinine, urea nitrogen, white blood cells, platelets, etc. return to the normal level and the general condition is good, the drug can be repeated.
(4) This product can reduce the renal excretion of BLM and increase its pulmonary toxicity;In combination with aminoglycoside antibiotics, fatal renal failure may occur and the damage to the ear may be aggravated;Anti grade histamines, phenothiazines, etc. may mask the ototoxicity of DDP.
(5) DDP dissolves slowly in normal saline, and can be heated at about 30 ℃ to help dissolve by shaking, or solution preparation can be used.
2. The following patients should be careful with medication:
That is to say, he has a history of kidney disease, hematopoietic system dysfunction, auditory nerve dysfunction, received other chemotherapy or radiotherapy before medication, and peripheral neuritis caused by non cisplatin.
3. Before and after treatment, during treatment and before each course of treatment, the following examinations should be performed: liver and kidney function, whole blood count, blood calcium, auditory nerve function, nervous system function, etc.In addition, the whole blood count should be checked weekly during treatment.Usually, the next course of treatment can be repeated only after the organ function returns to normal.
4. During and after chemotherapy, both male and female patients need strict contraception.If you want to get pregnant after treatment, you need genetic counseling in advance.
5. Cisplatin may affect concentration, driving and mechanical operation.
6. This product should avoid contact with aluminum metal (such as aluminum injection needle, etc.).
7. During and after chemotherapy, patients must drink enough water.
Drugs for pregnant and lactating women
The use of this product in pregnant women may cause fetal damage. It is reported that this product has been detected in human milk, so it is recommended that lactating women stop lactation when using this product.Not for pregnant women.
Drug interaction
1. AndColchicine、ProbenecidorSulfopyrazoneWhen used together, cisplatin may increase the level of uric acid in the blood, so its dosage must be adjusted to control hyperuricemia and gout.
2. Antihistamines, phenothiazines, or thioxanthenes in combination with cisplatin may mask the symptoms of ototoxicity, such as tinnitus, vertigo, etc.
3. Cisplatin induced renal function damage can lead to toxic reaction of bleomycin (even small dose).
4. When used together with various bone marrow inhibitors or radiotherapy, the toxicity can be increased, and the dosage should be reduced.
5. Penicillin or other canthariding agents will weaken the activity of cisplatin.Therefore, this product should not be used together with cantharidin mixture.
6. Combined with ifosfamide, it will aggravate proteinuria and may increase ototoxicity.
7. During cisplatin chemotherapy, because other drugs with nephrotoxicity or ototoxicity (such as cephalosporins or aminoglycosides) will increase the toxicity of cisplatin, it is necessary to avoid combined use.Diuretics such as furosemide are prohibited to increase urine output.
8. Patients can receive virus vaccination at least three months after receiving cisplatin chemotherapy.
Overdose
The drug dose exceeds 120mg/mtwoIts toxicity increases, especially nephrotoxicity and myelotoxicity.
Substance toxicity
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Toxicity test data reported in literature and journals
number
Toxicity type
test method
Test object
Dosage
Toxic effect
one
acute toxicity
intravenous injection
Adult male
2140 μg/kg/5D-I
Kidney, ureter and bladder toxicity: changes in renal tubules
(including acute renal failure and acute tubular necrosis)
two
acute toxicity
intravenous injection
human beings
1500 μg/kg/6D-I
Ototoxicity - visual changes
Kidney, ureter and bladder toxicity - decreased renal function
Hemotoxicity - changes in bone marrow
three
acute toxicity
intravenous injection
human beings
500 μg/kg/13D-I
Kidney, ureter and bladder toxicity - changes in renal tubules (including acute renal failure and acute tubular necrosis)
Kidney, ureter and bladder toxicity - decreased renal function
