What Is Cisplatin Nephrotoxicity?
Cisplatin is an orange-yellow or yellow crystalline powder. Melting point 268-272 ° C (decomposed). Slightly soluble in water, easily soluble in dimethylformamide. It can be gradually converted to trans and hydrolyzed in aqueous solution. Clinically used in ovarian cancer, prostate cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer and osteosarcoma and other solid tumors can show efficacy.
- Chinese name
- Cisplatin
- Foreign name
- cisplatin
- CAS number
- 15663-27-1
- Molecular formula
- Cl2H4N2Pt
- Cisplatin is an orange-yellow or yellow crystalline powder. Melting point 268-272 ° C (decomposed). Slightly soluble in water, easily soluble in dimethylformamide. It can be gradually converted to trans and hydrolyzed in aqueous solution. Clinically used in ovarian cancer, prostate cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer and osteosarcoma and other solid tumors can show efficacy.
Introduction to cisplatin compounds
Basic information of cisplatin
- Chinese name: cisplatin
- Chinese alias: cis-dichlorodiaminoplatinum; cis-dichlorodiaminoplatinum; cis-dichlorodiaminoplatinum; cis-dichlorodiaminoplatinum; cisplatin; cis-diaminedichloroplatinum (II ); (Z) -diaminodichloroplatinum; cis-diaminedichloroplatinum;
- English name: cisplatin
- English alias: cis-Dichlorodiammine platinum (II); cis-Dichlorodiamineplatinum (II); cis-Diamminedichloroplatinum (II); cis-Diammineplatinum (II) dichloride; cis-Platinum (II) diammine dichloride; cis-Diamineplatinum (II) dichloride; cis-Diammineplatinum dichloride; Cisplatin; cis-Diammineplatinum (II) dichloride (cis-Dichlorodiammine platinum (II);
- CAS number: 15663-27-1
- MDL number: MFCD00011623
- EINECS number: 239-733-8
- RTECS number: TP2455000
- PubChem number: 24871609
- Molecular formula: Cl 2 H 6 N 2 Pt
- Structural formula:
- Molecular weight: 300.05
- PSA: 52.04000
- LogP: 1.59590
Physical and chemical properties of cisplatin
- Appearance and properties: orange-yellow to dark yellow solid or powder
- Density: 3.7
- Melting point: 270ºC
- Stability: Stable. Incompatible with oxidizing agents, aluminium, antioxidants.
- Storage conditions: Store in a cool, dry, well-ventilated area away from incompatible substances. Poison room locked. Keep containers tightly closed.
Cisplatin safety information
- Symbol: GHS05GHS06GHS08
- Signal Word: Danger
- Hazard statement: H300; H318; H350
- Cautionary statements: P201; P264; P280; P301 + P310; P305 + P351 + P338; P308 + P313
- Packing level: II
- Hazard category: 6.1 (a)
- Customs Code: 2932999099
- Dangerous Goods Transport Code: UN 1851/3288
- WGK Germany: 3
- Danger category code: R45; R25; R41
- Safety instructions: S53-S26-S39-S45
- RTECS number: TP2455000
- Dangerous goods mark: T [1]
Cisplatin calculated chemical data
- 1. Reference value for calculation of hydrophobic parameters (XlogP):
- 2. Number of hydrogen-bonded donors: 2
- 3. Number of hydrogen bond acceptors: 4
- 4. Number of rotatable chemical bonds: 0
- 5. Number of tautomers:
- 6. Topological molecular polar surface area (TPSA): 2
- 7, the number of heavy atoms: 5
- 8. Surface charge: 0
- 9. Complexity: 0
- 10. Number of isotope atoms: 0
- 11. Determine the number of atomic stereocenters: 0
- 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: 5
Synthetic method of cisplatin
- By potassium tetrachloroplatinate complexed with ammonium chloride and ammonia.
Cisplatin uses
- The product can bind to DNA, cause cross-linking, thereby destroying the function of DNA, and inhibiting cell mitosis. It is a cell non-specific drug. This product has a wide anti-tumor spectrum and is used in head and neck squamous cell carcinoma; ovarian cancer; embryonic cell carcinoma; seminoma cell tumor; lung cancer; thyroid cancer; [2]
Cisplatin Safety Terminology
- S53Avoid exposure-obtain special instructions before use.
- Avoid contact. Obtain special instructions before use.
- S26In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
- After accidental contact with eyes, rinse immediately with plenty of water and seek medical advice.
- S39Wear eye / face protection.
- Wear goggles or a mask.
- S45In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.)
- In case of accident or if you feel unwell, seek medical advice immediately (show the label if possible).
Cisplatin risk terminology
- R45May cause cancer.
- May cause cancer.
- R25Toxic if swallowed.
- Toxic if swallowed.
- R41Risk of serious damage to the eyes.
- Serious damage to eyes.
Cisplatin Pharmacopoeia Standard
Cisplatin source (name), content (potency)
- This product is (Z) -diaminodichloroplatinum. Calculated on dry basis, Cl2H6N2Pt should be 98.0% 102.0%.
Cisplatin traits
- This product is bright yellow to orange yellow crystalline powder; odorless. This product is soluble in dimethyl sulfoxide, slightly soluble in dimethylformamide, slightly soluble in water, and insoluble in ethanol.
Cisplatin identification
- (1) Take about 5mg of this product and add 1ml of sulfuric acid, then it will be gray-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 measure it by ultraviolet-visible spectrophotometry (Appendix IVA of Pharmacopoeia Part Two of the 2010 edition). Absorption, with minimal absorption at a wavelength of 247 nm.
- (4) The infrared light absorption spectrum of this product should be consistent with the control spectrum (Figure 297 of "Infrared Spectra of Drugs").
Cisplatin check
- Platinum content
- Take about 0.5g of this product, weigh it accurately, and check the burning residue test method (Appendix N in Part II of the Pharmacopoeia of 2010, but do not add sulfuric acid), and burn to 400C at constant temperature. The weight of the obtained residue is used in the test amount. Contains platinum weight. Based on the dry product, the platinum content should be 64.6% to 65.4%.
- Chlorine content
- Take 30mg of this product, accurately weigh it, and perform organic destruction according to the oxygen bottle combustion method (Appendix C of the second edition of the Pharmacopoeia 2010), using 20ml of sodium hydroxide test solution as the absorption solution. After the combustion is completed, shake vigorously for several minutes. Rinse the bottle stopper and platinum wire with a small amount of water, add the washing solution to the absorption solution, add 1 drop of bromophenol blue indicator solution, and add dilute nitric acid until the solution turns yellow, and then add 1 ml of dilute nitric acid, 20 ml of ethanol, and 1% diphenylhydrazone. 5 drops of hydrazine in ethanol solution, titrated with mercury nitrate titration solution (0.025mol / L), shaken vigorously near the end point, and continued the titration until the solution became light rose red, and the results of the titration were corrected with a blank test. Each 1ml of mercury nitrate titration solution (0.025mol / L) is equivalent to 1.737mg of chlorine (Cl), and the chlorine content should be 23.0% to 24.3%.
- Clarity of the solution
- Take 20mg of this product, add 20ml of 0.9% sodium chloride solution to dissolve, the solution should be clear.
- acidity
- Take the solution under the clarity of the solution and determine it according to the law (Appendix VIH of Part Two of the 2010 Pharmacopoeia). The pH value should be 5.0 7.0.
- relative substance
- Protect from light. Take this product, add 0.9% sodium chloride solution to dissolve and dilute it to make a solution containing about 0.2mg per 1ml, as a test solution (provisional new); precisely measure 1ml, put it in a 50ml measuring bottle, use 0.9 The% sodium chloride solution was diluted to the mark, shaken, and used as a control solution. According to the chromatographic conditions under the content determination item, take 20 l of the control solution and inject it into the liquid chromatograph, and adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 15% of the full scale. Then, 20 l of each of the test solution and the control solution were precisely measured, and injected into the liquid chromatograph respectively, and the chromatogram was recorded to double the peak retention time of the main component. 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 must not be greater than 0.5 times (1.0%) the main peak area of the control solution, and the impurity peak area with a relative retention time of about 1.2 After multiplying by 1.356, the area of the main peak of the control solution (2.0%) should not be greater than the sum of the areas of other impurity peaks should not be greater than 0.25 (0.5%) of the main peak area of the control solution.
- Loss on drying
- Take about 0.1g of this product and dry to constant weight at 105 ° C, and the weight loss should not exceed 0.5% (Appendix L of Part Two of the Pharmacopoeia, 2010 Edition).
Determination of cisplatin content
- It was determined by high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 Edition).
- Chromatographic conditions and system suitability tests
- Octadecylsilane-bonded silica gel was used as the filler; 0.003mol / L sodium heptanesulfonate in 0.9% sodium chloride solution was used as the mobile phase; the detection wavelength was 220nm. The number of theoretical plates calculated from the cisplatin peak is not less than 3000, and the resolution of the cisplatin peak and adjacent impurity peaks should meet the requirements.
- Assay
- Protect from light. Take an appropriate amount of this product, accurately weigh it, add 0.9% sodium chloride solution to dissolve and quantitatively dilute it to make a solution containing about 40 g per 1 ml. Precisely measure 20 l into the liquid chromatograph and record the chromatogram; take another cisplatin control Product, the same method. Calculate the peak area according to the external standard method. [3]
Cisplatin Compound Drug Description
Cisplatin pharmacological action
- Cisplatin is also known as cisplatin, cisplatin, DDP, tin-platinum, diplatin, cis-dichlorobisaminoplatinate, and is a commonly used metal platinum complex. The platinum atom in the molecule is resistant to it. The role of tumors is significant. But only cis makes sense, trans does not work. Can be cross-linked with DNA strands, showing cytotoxic effects. After dissolution, it can pass through the charged cell membrane without carrier transport in the body. Due to the low concentration of chloride ion in the cell (4mmol / L), the chloride ion is replaced by water and the charge is positive. It has a similar function as the alkylating agent bifunctional group, and can combine with the bases of DNA in the cell nucleus to form three forms. Cross-linking can cause DNA damage, disrupt DNA replication and transcription, and also inhibit RNA and protein synthesis at high concentrations. Cisplatin has the advantages of wide anti-cancer spectrum, effective hypoxia cells, and strong action. It has been widely used in the treatment of 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 and can cause side effects. Therefore, it is necessary to constantly find analogs with less toxicity and similar clinical effects to cisplatin. So far, scientists from various countries have synthesized and tested thousands of metal complexes related to cisplatin, and developed second-generation anticancer platinum complexes represented by carbon platinum. Third generation anti-cancer metal complexes have also been discovered, represented by titanium dichlorocene. These compounds have nothing to do with cisplatin from a chemical point of view, but they have better effects on certain cancers that have little effect on cisplatin treatment and do not harm kidney function. A lot of research is continuing in this field, focusing on exploring the mechanism of anticancer activity of metal complexes at the molecular level. China has produced cisplatin and is conducting research in this area.
- Cisplatin is a cell cycle non-specific drug with cytotoxicity. Since cancer cells proliferate and synthesize more quickly than normal cells, cancer cells are more sensitive to the cytotoxic effects of this product, which can inhibit the DNA replication process of cancer cells. It also damages the structure on its cell membrane and has a strong broad-spectrum anticancer effect. For ovarian cancer, prostate cancer, testicular cancer and other malignant tumors of the genitourinary system, with good curative effect. Combined with vincristine, cyclophosphamide, and 5-fluorouracil, it is effective for malignant lymphoma, breast cancer, squamous cell carcinoma of the head and neck, and osteosarcoma of thyroid cancer. Cisplatin combined with radiation therapy has outstanding effects on advanced non-small cell lung cancer, nasopharyngeal cancer, and esophageal cancer. It also has certain effects on liver cancer and soft tissue sarcoma. Cisplatin is a strong accumulation drug, which is prone to nephrotoxicity and gastrointestinal reactions are common. Some patients have granulocytopenia, but it can recover within 7 to 14 days after discontinuation.
- In addition, the DNA damage of this product may change its antigenicity in the nucleus or cell surface, expose the original hidden surface antigen, stimulate the immune suppression of the antibody and exert its cytotoxic effect. [4]
. Cisplatin . Toxicology
(1) Reproductive toxicity This product can cause fetal damage in pregnant women. This product showed teratogenicity and embryo toxicity in mouse experiments. If used during pregnancy, or if pregnancy is found during administration, the patient should be informed of its potential harm to the fetus. Women with childbearing potential should be advised to avoid pregnancy. There have been reports of this product detected in human milk, suggesting that mothers discontinue lactation when using this product.
(2) Genotoxicity This product shows mutagenicity in cell experiments, causing chromosomal aberrations in tissue cultured animal cells.
(3) Carcinogenicity The carcinogenicity test of BDIX (50 animals in total) was performed. This product was administered intraperitoneally for 3 weeks at 1 mg / kg / week. As a result, 33 animals died within 455 days of the first administration, of which 13 animals died. He died of malignant tumors; 12 leukemias and 1 liver and liver fibrosarcoma.
Cisplatin pharmacokinetics
- [In vivo process] DDP is not effective orally. After intravenous injection, DDP begins to be distributed most in the liver, kidneys, small and large intestines, and skin. After 18 to 24 hours, the accumulation in the kidney is the largest, and the brain tissue is the least. Disappears rapidly in plasma and is biphasic. The initial plasma half-life is 25 to 49 minutes, and the plasma half-life is 55 to 73 hours after distribution. One hour after intravenous injection, the plasma content is about 10%, and 90% is bound to large molecules such as plasma proteins. Excretion is slow, 19% to 34% are excreted in urine within 1 day, and only 25% to 44% are excreted in urine within 4 days, but only 27% to 43% of cisplatin is excreted within 5 days after full dose injection; The biliary or intestinal tract is rarely excreted, and the concentration of the drug in the abdominal organs when administered intraperitoneally is equivalent to 2.5-8 times that of intravenous administration, which has a synergistic effect on the treatment of ovarian cancer. [5]
Cisplatin indications:
- 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 lymphomas . [5]
Clinical application of cisplatin
- DDP has a wide anticancer spectrum, strong effects, synergistic effects with multiple antitumor drugs, and no cross-resistance. It is one of the most commonly used drugs in combined chemotherapy.
- kidney
- (2) Head and Neck Cancer: Nasopharyngeal Cancer, Thyroid Cancer, and Laryngeal Cancer.
- (3) It is also effective for bladder cancer, lung cancer, malignant lymphoma, breast cancer, renal cell carcinoma, prostate cancer, soft tissue sarcoma, and malignant melanoma.
- (4) Others: malignant pleural and ascites fluid; used in combination with radiotherapy, it has a radiosensitizing effect.
- First-line treatment for a variety of solid tumors. Combined with VP-16 (EP regimen) is a first-line regimen for treating SCLC or NSCLC, combined with MMC, IFO (IMP regimen), or NVB is a common regimen for treating NSCLC. DDP-based combined chemotherapy is also advanced ovarian cancer, bone and flesh The main treatment options for tumors and neuroblastomas are effective in combination with ADM, CTX, etc. on multiple-site squamous cell carcinoma and transitional cell carcinoma, such as head and neck, cervical, esophagus, and urinary tract tumors.
- "PVB" (DDP, VLB, BLM) can treat most stage IV non-spermatogonial testicular cancer with a remission rate of 50% to 80%. In addition, this product is a radiotherapy sensitizer. It is widely used abroad in the local radiotherapy of stage IV non-operative NSCLC, which can improve the efficacy and improve the survival time.
Cisplatin contraindications:
- People who are allergic to cisplatin and other platinum-containing preparations, pregnancy, lactation, hypofunction of bone marrow, severe renal impairment, dehydration, chickenpox, shingles, gout, hyperuricemia, recent infections, and Peripheral neuropathy and other patients are disabled. [5]
Cisplatin dosage
- Intravenous injection or intravenous drip: 20-30mg, or 20mg / m2 each time, intravenously dissolved in 20-30ml of normal saline, or intravenously dripped in 250-500ml of 5% glucose injection. On the first day and The eighth day of use is one cycle, which is usually repeated for three to four weeks. Intermittent medication can be used for three to four cycles.
- Large dose: 80 120mg / m2, once every 3 weeks. At the same time, pay attention to hydration to keep the patient's urine volume at 2000 3000ml. You can also add mannitol to diuretic.
- Intrathoracic injection: 30 ~ 60mg once every 7 to 10 days. The intraperitoneal cavity is 100-160mg each time.
- Arterial injection: 20-30ml each time, the bolus is intubated in the middle, once every 5 days is a cycle, and can be repeated every 3 weeks. Arterial infusion is mainly used for head and neck tumors.
Cisplatin adverse reactions
- 1. Renal toxicity: After a single medium or large dose, slight and reversible renal dysfunction may occasionally occur, and trace hematuria may occur. Repeated high-dose and short-term repeated medications will cause irreversible renal dysfunction, and in severe cases, renal tubular necrosis will lead to anuria and uremia.
- 2. Digestive system: including nausea, vomiting, decreased appetite, and diarrhea. The reaction usually occurs within 1 to 6 hours after administration, and the longest does not exceed 24 to 48 hours. Occasionally hepatic dysfunction and increased serum transaminase can be recovered after withdrawal.
- 3. Hematopoietic system: It shows the decrease of white blood cells and / or platelets, which is generally related to the dosage of the drug. Bone marrow suppression generally peaks in about 3 weeks and recovers in 4 to 6 weeks.
- 4, ototoxicity: tinnitus and high-frequency hearing loss can occur, mostly reversible, without special treatment.
- 5. Neurotoxicity: It is more common in patients with a total amount of more than 300mg / , and peripheral nerve injuries are more common, manifested as dyskinesia, myalgia, and paresthesia in the upper and lower limbs; a small number of patients may have brain dysfunction, and epilepsy may also occur Posterior neuritis.
- 6, allergic reactions: such as increased heart rate, lower blood pressure, dyspnea, facial edema, allergic fever reactions, etc., may occur.
- 7. Others:
- Hyperuricemia: Swelling of the legs and joint pain often occur.
- Plasma electrolyte disorders: hypomagnesemia, hypocalcemia, muscle cramps.
- Cardiotoxicity: Rarely, arrhythmia, changes in electrocardiogram, bradycardia or tachycardia, and cardiac insufficiency.
- Immune system: An immunosuppressive response occurs.
- Gum changes: Platinum metal deposits in the gums.
- Patients may experience local swelling of their limbs through arterial or intravenous injections. Pain, erythema and skin ulcers, and local phlebitis are rare. Hair loss, sperm, egg formation disorders, and feminization of male breasts may also occur.
- The emergence of secondary non-lymphocytic leukemia is related to the use of cisplatin chemotherapy.
- Vascular lesions, such as cerebral ischemia, coronary ischemia, and peripheral vascular disorders like Ravnaud syndrome are rare, but may be related to cisplatin use.
Precautions for cisplatin
- 1.Use
- (1) When using larger doses (80 ~ 120mg / m2), hydration and diuresis must be performed at the same time. So-called
- nerve
- (2) In order to reduce toxic and side effects, drink plenty of water during the medication period; various antiemetics should be selected before medication; at the same time, epinephrine, corticosteroids, and antihistamines should be reserved for emergency use; after the DDP, sodium natrium can be injected by muscle To strengthen the curative effect.
- (3) Blood, urine and liver and kidney functions should be monitored before, during and after administration. The discontinued finger tablets are: white blood cells <3.5x 109 / L, platelets <75x 109 / L persistent nausea, vomiting; early renal toxicity such as urine white blood cells 10, red blood cells 10, casts 5 / high field of view above; serum creatinine > 186 351mmol / L; allergic reactions; patients with history of kidney disease, renal dysfunction and otitis media found during the medication. If serum creatinine, urea nitrogen, white blood cells, platelets, etc. have returned to normal levels, and the general condition is good, the medication can be repeated.
- (4) This product can reduce renal excretion of BLM and increase its lung toxicity; combined with aminoglycoside antibiotics can cause fatal renal failure and may aggravate ear damage; anti-grade weaving drugs, phenothiazines, etc. may Masking ototoxicity of DDP.
- (5) DDP dissolves slowly in physiological saline. It can be heated at about 30 ° C with shaking to help dissolve, or a solution preparation can be used.
- 2. The following patients are particularly cautious:
- He has a history of kidney disease, hematopoietic system insufficiency, auditory nerve dysfunction, other chemotherapy or radiation treatment before treatment, and peripheral neuritis caused by non-cisplatin.
- 3. Before and after treatment, during the treatment and before each course of treatment, the following examinations should be performed: liver, kidney function, whole blood count, blood calcium, auditory nerve function, and nervous system function. In addition, a full blood count should be checked weekly during treatment. It is usually necessary to wait until the organ function returns to normal before repeating the next course of treatment.
- 4. Both male and female patients need strict contraception during and after chemotherapy. If you want to get pregnant after treatment, you need genetic counseling in advance.
- 5. Cisplatin may affect your ability to focus, drive, and operate machinery.
- 6. This product should avoid contact with aluminum metal (such as aluminum metal needles, etc.).
- 7. Patients must drink enough water during and after chemotherapy.
Cisplatin medication for pregnant and lactating women:
- This product can cause fetal damage in pregnant women. It has been detected in human milk. Therefore, it is recommended that lactating women discontinue breastfeeding when using this product. Disable pregnant women.
Cisplatin drug interactions
- (1) When combined with colchicine, probenecid or sulfinpyrazone, since cisplatin may increase the level of uric acid in the blood, its dose must be adjusted to control hyperuricemia and gout.
- (2) The combination of antihistamine, phenothiazine or thioxanthene with cisplatin may mask the symptoms of ototoxicity, such as tinnitus and dizziness.
- (3) Cisplatin-induced impairment of renal function can lead to toxic effects of bleomycin (even small doses).
- (4) Used together with various bone marrow inhibitors or radiation therapy, it can increase the toxic effect, and the dosage should be reduced.
- (5) Penicillamine or other chelating agents can reduce the activity of cisplatin. Therefore, this product should not be applied at the same time as the admixture.
- (6) Combination with ifosfamide will increase proteinuria and may increase ototoxicity.
- (7) During cisplatin chemotherapy, since other drugs with nephrotoxicity or ototoxicity (such as cephalosporins or aminoglycosides) will increase the toxicity of cisplatin, they should be avoided in combination.
- Prohibit diuretics such as furosemide to increase urine output.
- (8) Patients should not be vaccinated with the virus until at least three months after receiving cisplatin chemotherapy.
Cisplatin formulation specifications
- Injection: 10mg / branch, 20mg / branch, 30mg / branch, 50mg / branch.
Cisplatin overdose
- When the drug dosage exceeds 120mg / m2, its toxicity increases, especially renal toxicity and bone marrow toxicity.
Cisplatin storage
- Store in a light-proof, airtight room. [5]
Cisplatin toxicity
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2. Kidney, ureter and bladder toxicity-decreased renal function 3. Hematological toxicity-other changes |
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2. Skin and accessory toxicity-skin corrosion (after local exposure) |
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2. Gastrointestinal toxicity-excessive exercise, diarrhea 3. Hematological toxicity-orthocytic anemia |
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2. Gastrointestinal toxicity-excessive exercise, diarrhea 3. Hematological toxicity-orthocytic anemia |
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2. Gastrointestinal toxicity-excessive exercise, diarrhea 3. Hematological toxicity-orthocytic anemia |
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3. Hematological toxicity-methemoglobin, carboxyhemoglobin appear |
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2. Nutritional and metabolic system toxicity-weight loss or weight loss rate 3. Chronic disease-related toxicity-death |
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2. Hematological toxicity-changes in bone marrow 3. Skeletal muscle toxicity-other changes |
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2. Blood toxicity-changes in white blood cell counts 3. Blood toxicity-changes in platelet counts |
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3. Biochemical toxicity-inhibit or induce catalase |
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2. Hematological toxicity-changes in bone marrow 3. Chronic disease-related toxicity-death |
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3. Hematological toxicity-changes in bone marrow |
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2. Nutritional and metabolic system toxicity-weight loss or weight loss rate 3. Chronic disease-related toxicity-death |
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2. Skin and accessory toxicity-tumor 3. Reproductive toxicity-placental tumor |
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2. Lung, chest or respiratory toxicity-tumor |
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2. Lung, chest or respiratory toxicity-tumor |
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2. Lung, chest or respiratory toxicity-tumor |
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2. Reproductive toxicity-fetal toxicity (such as fetal dysplasia but not death) 3. Reproductive toxicity-affecting the live birth index of newborns |
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2. Reproductive toxicity-changes in testis, epididymis, and vas deferens |
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2. Reproductive toxicity-changes in testis, epididymis, and vas deferens 3. Reproductive toxicity-changes in prostate, seminal vesicles, Cobb's glands, and accessory glands |
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2. Reproductive toxicity-abnormal development of the musculoskeletal system 3. Reproductive toxicity-affects the behavior of newborns |
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2. Reproductive toxicity-other changes |
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2. Reproductive toxicity-changes in testis, epididymis, and vas deferens |
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- [6-162]