Cisplatin can react in a nonenzymatic manner with water in vivo to form monoaquo & diaquo species following dissociation of the chloride groups. These metabolites extensively bind to protein (>90%) & thus have minimal cytotoxicites but the non-protein bound, ultrafilterable reactive species are cytotoxic.
IDENTIFICATION: Cisplatin is an antineoplastic cytostatic drug. Cisplain is deep yellow solid. Soluble in water, and in sodium chloride solution. Slowly changes from the cis to the trans form in aqueous solution. Soluble in dimethylformamide. Insoluble in most common solvents. Indications: Cisplatin is indicated for the following conditions: Single agent for the treatment of transitional cell bladder carcinoma that is no longer amenable to local treatment such as surgery and/or radiation therapy. Locally advanced or metastatic transitional cell carcinoma involving the renal pelvis, ureter, bladder and/or urethra. In combination with radiation treatment to treat bilharzial bladder cancer and together with doxorubicin and cyclophosphamide to treat locally advanced bladder cancer. The palliative treatment of recurrent or metastatic squamous cell carcinomas of the head or neck. Treatment of lung cancer, principally as a component of various chemotherapeutic regimens in the treatment of non-small cell lung carcinomas. It is often combined with other agents such as etoposide, vinblastine or vindesine to obtain a better response rate in lung cancer. Its use alone has some value but in combination the results are more noticeable in the palliative treatment of recurrent or advanced squamous cell carcinoma of the cervix and metastatic testicular carcinoma. Other types of carcinomas in which cisplatin has been tried included the following: osteogenic sarcoma, neuroblastoma and recurrent brain tumors in children, advanced esophageal carcinoma and advanced prostatic carcinoma. In combination with agents such as bleomycin, methotrexate, vincristine or vinblastine, fluorouracil in various regimes (all together or singularly depending on the protocol and the carcinoma type). Combinations of these agents have been reported to have a better response rate than if cisplatin were used alone. HUMAN EXPOSURE: Summary: Main Risks and Target Organs: The main risks experienced during cisplatin therapy and overdosage include nephrotoxicity, electrolyte disturbances, myelosuppression, neurotoxicity, anaphylactic reactions and ototoxicity. Nausea and vomiting can be severe. Rarer risks include cardiovascular effects, ocular effects, and hepatic effects. Most effects of overdosage are not usually seen immediately, but occur several days to months after the event. The causes of death from an overdose from cisplatin include myelosuppression, renal failure and tetany. Summary of Clinical Effects: Renal toxicity is cumulative and seen usually after several courses of cisplatin or after overdose. Disturbances in electrolytes can be a long term manifestation due to the cisplatin induced renal tubular dysfunction. Hypomagnesemia, hypocalcemia and hypokalemia are commonly seen in cisplatin induced renal toxicity and can persist for months after termination of therapy. Hematological effects of cisplatin (myelosuppression and anemia) are cumulative and in overdosage the hematopoietic system must be supported to prevent complications of infection. Cisplatin induces marked nausea and vomiting in almost all patients. Anaphylactoid reactions have occurred during normal therapy with cisplatin and must be treated vigorously. Cisplatin causes electrolyte disturbances which are a direct result of cisplatin induced renal tubular dysfunction. Cisplatin causes marked excretion of calcium, magnesium and potassium and to a lesser extent zinc, copper and amino acids. These disturbances must be corrected to prevent complications. Clinical features: Renal toxicity is manifested by an increase in serum creatinine, BUN, serum uric acid and/or a decrease in creatinine clearance and glomerular filtration rate. The renal impairment is a direct result of cisplatin induced renal tubular damage leading ultimately to renal failure. Disturbances have been seen in serum electrolytes due principally to cisplatin induced renal tubular dysfunction. Patients subsequently develop Hypomagnesemia, hypocalcemia and hypokalemia and to a lesser extent hypophosphatemia and hyponatremia. Cisplatin produces marked nausea and vomiting in almost all patients to the extent that some patients experience anticipatory nausea and vomiting. Diarrhea has also occurred but with less frequency than nausea and vomiting. Ototoxicity develops in various degrees on cisplatin therapy. In larger and prolonged dosing with cisplatin the ototoxicity can be irreversible. Myelosuppression is a common problem seen as leucopenia, thrombocytopenia and anemia and if severe enough can cause the death of the patient. Myelosuppression can be cumulative. Anaphylactoid reactions can occur when cisplatin is given. Cardiovascular effects are rare but include bradycardia, left bundle branch block and congestive heart failure. Hepatic enzyme activities in the sera become elevated including AST (SGOT) and ALT (SGPT). Precautions: Extreme care should be taken by persons preparing and administering cisplatin and those handling the urine of treated patients. Routes of entry: Cisplatin is not effective when administered orally. Dermal: Cisplatin is not administered dermally. Avoid dermal contact and absorption during administration. Eye: Eye contamination may be a possible source of poisoning during intravenous administration of cisplatin. Parenteral: Cisplatin is only available in the injectable form. The parenteral routes, intravenous, intra-arterial and intraperitoneal, have all been used in cisplatin therapy and poisoning would most likely occur by these three routes. Absorption by route of exposure: Intravenous: Totally absorbed after intravenous use. Rapid intravenous injection of cisplatin over 1 to 5 minutes or rapid intravenous infusion over 15 minutes or one hour, results in peak plasma concentrations immediately. When cisplatin is administered by intravenous infusion over 6 to 24 hours the plasma concentrations of total platinum increase gradually during the infusion and reach peak concentrations immediately following the end of the infusions. When mannitol is given at the same time as cisplatin, the peak plasma concentrations of non protein-bound platinum appears to be increased. Intra-arterial: When cisplatin is administered by intra-arterial infusion, the local tumor exposure of the drug is increased as compared with intravenous administration. Intraperitoneal: Cisplatin is rapidly and well absorbed systemically following intraperitoneal administration. This route gives 50 to 100% plasma concentration in comparison with the intravenous route. Intraperitoneal fluid concentration of the drug is greatly increased as compared with intravenous administration. Distribution by route of exposure: Following the intravenous administration of Cisplatin, the drug is widely distributed into body fluids and tissues. The highest concentrations can be seen in the kidneys, liver and intestines, and can persist for up to 2 to 4 weeks. However, concentrations can also be found in the muscles, bladder, testes, prostate, pancreas and spleen. Cisplatin has also been found in the following tissues; small and large intestines, adrenals, heart, lungs, lymph nodes, thyroid, gall bladder, thymus, cerebrum, cerebellum, ovaries and uterus. Platinum appears to accumulate in body tissues following administration of cisplatin and has been detected in many of these tissues for up to 6 months after the last dose of the drug. Platinum also has been found in leucocytes and erythrocytes. Cisplatin and any platinum-containing products are rapidly and extensively bound to tissue and plasma proteins, including albumin, gamma-globulins and transferrin. Binding to tissue and plasma proteins appears to be essentially irreversible with the bound platinum remaining in plasma during the lifespan of the albumin molecule. Protein binding increases with time and less than 2 to 10% of platinum in blood remains unbound several hours after intravenous administration of cisplatin. The extent of protein binding is about 90% and this occurs essentially within the first two hours after a dose. Penetration into the central nervous system (CNS) does not occur readily. The resultant levels are low in the CNS, but significant amounts of cisplatin can be detected in intracerebral tumor tissue and edematous brain tissue adjacent to the tumor. In healthy brain tissue concentrations appear to be low. Metabolism: The metabolic fate of cisplatin has not been completely elucidated. There is little evidence to date that the drug undergoes enzymatic biotransformation. The cisplatin molecule has chloride ligands on it and it is believed that these are displaced by water thus forming positively charged platinum complexes that react with nucleophilic sites. Their rate and extent depends on the strength, concentration and accessibility of the nucleophiles. The chemical identities of the metabolites of cisplatin have been found but have yet to be identified. There is a strong possibility that cisplatin and its metabolites undergo enterohepatic circulation. Elimination by route of exposure: Intact cisplatin and its metabolites are excreted principally in urine. It occurs predominantly via glomerular filtration but there is some evidence that secretion and reabsorption of cisplatin and its metabolites also occurs. Initially renal clearance of total platinum equals creatinine clearance and represents elimination of non-protein bound platinum molecules including intact cisplatin. As extensive protein binding occurs then clearance declines rapidly, resulting in a prolonged excretory phase. The ultimate rate of fall of total plasma platinum concentration is governed by the rate of degradation of plasma proteins bearing bound platinum. A small amount of cisplatin is excreted via the bile and saliva. Elimination half-life of cisplatin (Adults): Normal renal function: 2 to 72 hr. End stage renal disease: 1 to 240 hr. Mode of Action: Toxicodynamics: Cisplatin appears to be cycle-phase nonspecific and will cause cell death in all cells. It is in those cells which turn over rapidly (tumor cells, skin cells, gastrointestinal cells, bone marrow cells) that cell death will occur at a faster rate than other cells with a slower turnover rate (e.g. muscle cells). Cisplatin exerts its antineoplastic activity when it has the cis-configuration and without a charge on the molecule. The trans-configuration is inactive. Pharmacodynamics: Cisplatin complex moves through cell membranes in an unionized form and this is achieved in the relatively high chloride concentration in the plasma. Intracellularly the concentration of chloride ions is lower than in the plasma and the chloride ligands on the cisplatin complex are displaced by water. The result is the formation of positively charged platinum complexes that are toxic to cells. The cisplatin molecule binds to the DNA molecule at the guanine bases and thus inhibits DNA synthesis, protein and RNA synthesis (the latter two are inhibited to a lesser degree). The drug forms intrastrand and interstrand cross links in the DNA molecule and appears to correlate well with the cytotoxicity of the drug. The tumor cells amass an overburden of mutations which lead eventually to the cell's death. Cisplatin also has immunosuppressive, radiosensitizing and antimicrobial properties. The exact mechanism of action of cisplatin is not yet understood but the drug has biochemical properties similar to those of bifunctional alkylating agents. Human Data: Adults: The major toxicity caused during cisplatin treatment is dose related and cumulative. For example, renal tubular function impairment can occur during the second week of therapy and if higher doses or repeated courses of cisplatin are given then irreversible renal damage can occur. Teratogenicity: There is positive evidence of human fetal risk, so the benefits in pregnant women must be weighed against the risk. Interactions: Nephrotoxic drugs: Cisplatin produces cumulative nephrotoxicity that can be potentiated by nephrotoxic drugs (aminoglycosides, cephalosporins and amphoteracin). Aminoglycosides: Concurrent administration of aminoglycosides within 1-2 weeks of cisplatin therapy has been associated with an increased risk of nephrotoxicity and renal failure. Therefore aminoglycosides should be used with extreme care during treatment. Cisplatin ototoxicity is enhanced with the use of loop diuretics. ANIMAL STUDIES: Cisplatin is carcinogenic in animals. Mutagenicity: Cisplatin is mutagenic in bacterial cultures and produces chromosome aberrations in animal cells in tissue cultures.
Evaluation: There is limited evidence in humans for the carcinogenicity of etoposide. There is sufficient evidence in humans for the carcinogenicity of etoposide given in combination with cisplatin and bleomycin. There is inadequate evidence in experimental animals for the carcinogenicity of etoposide. Overall evaluation: Etoposide is probably carcinogenic to humans (Group 2A). In reaching this evaluation, the Working Group noted that etoposide causes distinctive cytogenetic lesions in leukemic cells that can be readily distinguished from those induced by alkylating agents. The short latency of these leukemias contrasts with that of leukemia induced by alkylating agents. Potent protein masked DNA breakage and clastogenic effects occur in human cells in vitro and animal cells in vivo. Etoposide in combination with cisplatin or bleomycin is carcinogenic to humans. /Etoposide in combination with cisplatin or bleomycin/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
顺铂：合理预期为人类致癌物。
Cisplatin: reasonably anticipated to be a human carcinogen.
The RNA synthesis in vitro by Escherichia coli RNA polymerase were found to be highly sensitive to cis-platin inhibition. The degree of inhibition was in proportion to the length of time of template preincubation with cisplatin. It was found that adriamycin significantly enhanced the inhibitory effect of cisplatin & the total effect was greater than the sum of the effects of each drug used individually.
A549 lung cancer cells were treated simultaneously with cisplatin (0, 1.25, 2.5, and 5 ug/ml) and other cytotoxic agents. Cisplatin additively incr the cytotoxic effects of etoposide, mitomycin C, adriamycin, 5-fluorouracil and 1-beta-D-arabinofuranosylcytosine, but antagonized those of vincristine, vindesine, vinblastine and podophyllotoxin. The antagonism between cisplatin and vincristine was also observed with HT29 colon cancer cells, NC65 renal carcinoma cells and A431 epidermoid carcinoma cells when these cells were simultaneously exposed to both agents. When A549 cells were exposed to cisplatin and vincristine sequentially (6 hr incubation with each agent), the antagonism between them was evident when the cells were pretreated with cisplatin, but not when treated in the opposite sequence.
AFTER RAPID IV ADMIN /TO HUMAN PATIENTS/ ... THE DRUG HAS AN INITIAL ELIMINATION HALF-LIFE IN PLASMA OF 25-50 MIN; CONCNS OF TOTAL DRUG, BOUND & UNBOUND, FALL THEREAFTER, WITH A HALF-LIFE OF 24 HR OR LONGER. MORE THAN 90% OF THE PLATINUM IN THE BLOOD IS COVALENTLY BOUND TO PLASMA PROTEINS. HIGH CONCNS ... ARE FOUND IN THE KIDNEY, LIVER, INTESTINES, & TESTES, BUT THERE IS POOR PENETRATION INTO THE CNS.
THE DRUG HAS A BIPHASIC PLASMA-DECAY CURVE WITH AN INITIAL HALF-LIFE OF 22 MIN (PROBABLY ELIMINATION) IN DOGS. HIGH TISSUE CONCNS HAVE BEEN FOUND IN KIDNEY, LIVER, OVARY, TESTIS, & UTERUS.
AFTER IV INJECTION OF ANIMALS WITH CISPLATIN, PLASMA LEVELS DECLINE BIPHASICALLY. 24 HR URINARY EXCRETION OF PLATINUM IS EXTENSIVE WITH A FINAL URINARY RECOVERY OF 70-90%. PLATINUM IS INITIALLY DISTRIBUTED IN NEARLY ALL OF THE TISSUES, WITH THE HIGHEST LEVELS IN KIDNEY, LIVER, OVARY, UTERUS, SKIN & BONE, BUT THERE IS NO PREFERENTIAL UPTAKE OF PLATINUM BY TUMORS.
AFTER IV ADMIN, MANY SPECIES (RAT, MOUSE, DOG) SHOW THE SAME GENERAL ORGAN DISTRIBUTION. ALL TISSUES TAKE UP PLATINUM, FOLLOWED WITHIN THE FIRST HR BY AN ACCUMULATION IN KIDNEY, LIVER, MUSCLE & SKIN. AFTER 24 HR, TISSUE:PLASMA DRUG RATIOS ARE GREATER THAN 1 IN OTHER TISSUES; THESE ARE MAINTAINED FOR AT LEAST A WK IN DOGS ... UP TO 4 WK AFTER A SINGLE DOSE, PLATINUM IS STILL DETECTABLE IN KIDNEY, LIVER, SKIN & LUNG. ... 18 HR AFTER IV INJECTION /OF RADIOACTIVE PLATINUM/ INTO RABBITS, KIDNEY & LIVER SHOWED THE HIGHEST LEVELS OF RADIOACTIVITY.
Coordination complexes, and methods for preparing by combinatorial methods, assaying and using the same
申请人：——
公开号：US06806289B1
公开（公告）日：2004-10-19
The present invention provides novel coordination complexes, methods for synthesizing and identifying coordination complexes using combinatorial techniques, and assaying for their activity. In certain embodiments, the subject coordination complexes contain platinum,
Mesomorphism and luminescence in coordination compounds and ionic salts based on pyridine-functionalized β-diketones. Influence of the pyridine nitrogen position
作者：Carlos Martínez-Ceberio、M. Carmen Torralba、Frederico Duarte、Santiago Herrero、Mercedes Cano、Carlos Lodeiro、Cristián Cuerva
DOI：10.1016/j.molliq.2023.122290
日期：2023.9
compounds of the type [MCl2(LZN)2] (M = Zn(II), Pd(II), Pt(II); Z = 3, 4). Particularly, coordination of L4N towards Pt(II) give rise to the cationic species [Pt(NH3)2(L4N)2]2+. Otherwise, protonation of the pyridine moiety was strategically used to obtain a novel series of pyridinium ionic salts of the type (HLZN)nA (n = 1, A = Cl; n = 2, A = MCl4, M = Zn(II), Pd(II), Pt(II); Z = 3, 4). The neutral or
在 3 位或 4 位具有吡啶氮原子（分别为 L 3N和 L 4N ）的吡啶官能化β-二酮已被用作构建单元，以获得具有介晶和发光行为的两个新化合物家族。β-二酮与锌 (II)、钯 (II) 和铂 (II) 金属中心的N -吡啶配位允许合成 [MCl 2 (L ZN ) 2 ] 类型的中性配位化合物 (M = Zn (II)、Pd(II)、Pt(II)；Z = 3、4)。特别地，L 4N与 Pt(II) 的配位产生阳离子物种 [Pt(NH 3 ) 2 (L4N ) 2 ] 2+。否则，吡啶部分的质子化被策略性地用于获得一系列新型吡啶鎓离子盐，类型为 (HL ZN ) n A (n = 1, A = Cl; n = 2, A = MCl 4 , M = Zn( II)、Pd(II)、Pt(II)；Z = 3、4)。络合物的中性或离子性质，以及β-二酮配体和中性和阴离子络合物中的金属中心，对介晶行
Oxidative halogenation of cisplatin and carboplatin: synthesis, spectroscopy, and crystal and molecular structures of Pt(<scp>iv</scp>) prodrugs
作者：Timothy C. Johnstone、Sarah M. Alexander、Justin J. Wilson、Stephen J. Lippard
DOI：10.1039/c4dt02627f
日期：——
A series of Pt(IV) prodrugs has been obtained by oxidative halogenation of either cisplatin or carboplatin. Iodobenzenedichloride is a general reagent that cleanly provides prodrugs bearing axial chlorides without the need to prepare intervening Pt(IV) intermediates or handle chlorine gas. Elemental bromine and iodine afford Pt(IV) compounds as well, although in the case of the iodine-mediated oxidation
