顺铂的药理及肾毒性的研究
顺铂肾毒性
Cisplatin Nephrotoxicity:A Review XIN YAO,MD;KESSARIN PANICHPISAL,MD;NEIL KURTZMAN,MD; KENNETH NUGENT,MDABSTRACT:Background:Cisplatin is a major antineo-plastic drug for the treatment of solid tumors,but it has dose-dependent renal toxicity.Methods:We reviewed clinical and experimental literature on cisplatin nephro-toxicity to identify new information on the mechanism of injury and potential approaches to prevention and/or treatment.Results:Unbound cisplatin is freely filtered at the glomerulus and taken up into renal tubular cells mainly by a transport-mediated process.The drug is at least partially metabolized into toxic species.Cisplatin has multiple intracellular effects,including regulating genes,causing direct cytotoxicity with reactive oxygen species,activating mitogen-activated protein kinases, inducing apoptosis,and stimulating inflammation and fibrogenesis.These events cause tubular damage and tu-bular dysfunction with sodium,potassium,and magne-sium wasting.Most patients have a reversible decrease in glomerular filtration,but some have an irreversible de-crease in glomerular filtration.Volume expansion and sa-line diuresis remain the most effective preventive strategies. Conclusions:Understanding the mechanisms of injury has led to multiple approaches to prevention.Furthermore,the experimental approaches in these studies with cisplatin are potentially applicable to other drugs causing renal dysfunc-tion.KEY INDEXING TERMS:Cisplatin;Toxicity;Acute renal insufficiency;Apoptosis;Reactive oxygen species. [Am J Med Sci2007;334(2):115–124.]C isplatin is a major antineoplastic drug used forthe treatment of solid tumors.Its chief dose-limiting side effect is nephrotoxicity;20%of patients receiving high-dose cisplatin have severe renal dys-function.Cisplatin-DNA crosslinks cause cytotoxic lesions in tumors and other dividing cells.DNA-damaging agents usually have less toxicity in non-proliferating cells,yet the quiescent proximal tubule cells are selectively damaged by cisplatin.The mech-anism for this renal cell injury has been the focus of intense investigation for many years,and recent studies suggest that inflammation,oxidative stress injury,and apoptosis probably explain part of this injury.Understanding the mechanism(s)for this side effect should allow clinicians to prevent and/or treat this problem better and provides a model for investi-gating drug-induced nephrotoxicity in general.1–3PathogenesisCisplatin Uptake into Renal CellsUptake of cisplatin is mainly through the organic transporter pathway.The kidney accumulates cis-platin to a greater degree than other organs and is the major route for its excretion.The cisplatin con-centration in proximal tubular epithelial cells is about5times the serum concentration.4The dispro-portionate accumulation of cisplatin in kidney tissue contributes to cisplatin-induced nephrotoxicity.5In the rat,cisplatin excretion occurs predominantly by glomerular filtration and to a lesser extent by se-cretion.There is no evidence of tubular reabsorption. Cisplatin is accumulated by peritubular uptake in both the proximal and distal nephrons.5,6The S3segment of the proximal tubule accumulates the highest con-centration of cisplatin,followed by the distal collect-ing tubule and the S1segment in the proximal tubule.6In addition to a transporter-mediated pro-cess,cisplatin enters the cell through passive diffu-sion.7The contribution of active uptake by a trans-port system and passive diffusion through the cellular membrane may vary at different sites. Transporter mediated uptake is likely the major pathway in renal cells.6The organic cation trans-porter(OCT2)is the critical transporter for cispla-tin uptake in proximal tubules in both animals and humans.Transport mediated by these membrane proteins is polyspecific,electrogenic,voltage-depen-dent,bi-directional,pH-independent,and Naϩ-inde-pendent.Three isoforms of OCT have been identified in humans.OCT2is the main OCT in the kidney, OCT1is the main isoform of the liver,and OCT3is widely expressed,especially in the placenta.Cispla-tin is not transported through human OCT1,which may help explain its organ-specific toxicity.Carbo-platin and oxaliplatin,the less nephrotoxic ana-From the Department of Internal Medicine,Texas Tech Univer-sity Health Science Center,Lubbock,Texas.Submitted October6,2006;accepted in revised form January4, 2007.Correspondence:Dr.Kenneth Nugent,Department of Internal Medicine,Texas Tech University Health Science Center,36014th Street,Lubbock,TX79430(E-mail:Kenneth.Nugent@).logues of cisplatin,have no interaction with human OCT2.8Cimetidine,an organic cation competitor for the transport at human OCT2,reduces cisplatin-induced proximal tubule cell apoptosis.9Diabetic animals have reduced gene and protein expression of OCT isotypes and are resistant to cisplatin toxic-ity.10Whether these transporters mediate cisplatin entry into tumor cells is unknown.A recent study demonstrates that a different transporter system, the copper transport protein1regulates the uptake of cisplatin in human ovarian cancer cells.11 Cisplatin MetabolismConversion of cisplatin to nephrotoxic molecules in the proximal tubule cells is required for cell injury.12 The highest concentration of cisplatin is found in cytosol,mitochondria,nuclei,and microsomes.4Cis-platin is conjugated to glutathione and then metab-olized through a␥-glutamyl transpeptidase and a cysteine S-conjugate-lyase–dependent pathways to a reactive thiol,a potent nephrotoxin.␥-Glutamyl transpeptidase is located on the cell surface,whereas cysteine-S-conjugate-lyase is an intracellular en-zyme.Inhibition of these2enzymes has no effect on the uptake of cisplatin into the kidney but reduces nephrotoxicity.Inhibition of␥-glutamyl transpepti-dase activity,however,renders cisplatin inactive as an antitumor drug.Whether inhibition of cysteine S-con-jugate-lyase affects the antitumor activity of cispla-tin is not known.12,13The only report of cysteine S-conjugate-lyase activity in tumor cells shows a very low level of activity in some human renal cell carcino-mas.14Cisplatin can form monohydrated complexes by hydrolytic reactions.The monohydrated complex is more toxic to the renal cells than cisplatin but it is not kidney specific.The normal low intracellular chloride concentrations promote its ing hyper-tonic saline to reconstitute cisplatin can decrease the amount of monohydrated complex formed.This ap-proach attenuates nephrotoxicity but may also com-promise its antitumor activity.15Biochemical Changes in the Renal CellCisplatin induces specific gene changes.Genes in-volved in drug resistance(MDR1,P-gp),in cytoskele-ton structure and function(Vim,Tubb5,Tmsb10, Tmsb4x,Anxa2),in cell adhesion(Spp1,Col1a1,Clu, Lgals3),in apoptosis(cytochrome c oxidase subunit I, BAR,heat-shock protein70-like protein,Bax),in tis-sue remodeling(clusterin,IGFBP-1,TIMP-1),and in detoxification(Gstm2,Gstp2)are upregulated after cisplatin-induced injury.Genes downregulated by cis-platin include those that localize to the proximal tu-bules(Odc1,Oat,G6pc,Kap),those that control intra-cellular calcium homeostasis(SMP-30),and those that encode growth factors or their binding proteins(Egf, Ngfg,Igfbp3,Ghr).These gene changes are associated with cisplatin damage to proximal tubules,tissue re-modeling,and regeneration.16–18Cisplatin-induced nephrotoxicity is mediated by mitogen-activated protein kinase(MAPK)intracellu-lar signaling pathways.The MAPK pathways are a series of parallel cascades of serine/threonine kinases that are activated by diverse extracellular physical and chemical stresses.They regulate cell proliferation, differentiation,and survival.The3major MAPK path-ways terminate in the extracellular regulated kinase (ERK),p38,and Jun N-terminal kinase/stress-acti-vated protein kinase(JNK/SAPK)enzymes.The ERK pathway is typically activated by extracellular growth factors and has been linked to both cell survival and cell death.The p38and JNK/SAPK pathways are activated by a variety of stresses,for example,oxi-dants,UV irradiation,hyperosmolality,and inflam-matory cytokines;they have been linked to cell death. Cisplatin was recently shown to activate all three MAPKs in the kidney,both in vitro and in vivo.19ERK and p38function as an upstream signal stimulating tumor necrosis factor-␣(TNF-␣)production.ERK also activates caspase3,which controls apoptosis in renal tubular cells.Phosphorylated-ERK is exclusively local-ized in the distal nephron;therefore ERK1/2activa-tion may mediate distal nephron injury.Whether the ERK pathway contributes to proximal tubule injury is not clear,but certain responses in the distal nephron could induce adjacent proximal tubule injury through autocrine and paracrine processes.20P38activation mediates proximal tubule cells injury.Stimulation of p38is mediated by hydroxyl radicals,which are in-duced by cisplatin.21The JNK/SAPK pathway in the cisplatin-induced nephrotoxicity has not been well studied.Intracellular Events that Damage Renal CellsThe in vivo mechanisms of cisplatin nephrotoxic-ity are complex and involve oxidative stress,apopto-sis,inflammation,and fibrogenesis.High concentra-tions of cisplatin induce necrosis in proximal tubule cells,whereas lower concentrations induce apoptosis through a caspase-9–dependent pathway.22The major pathways in cisplatin-induced acute tubular cell injury are shown in Figure1and summarized in Table1.Oxidative stress injury is actively involved in the pathogenesis of cisplatin-induced acute kidney in-jury.Reactive oxygen species(ROS)directly act on cell components,including lipids,proteins,and DNA,and destroy their structure.ROS are produced via the xanthine-xanthine oxidase system,mito-chondria,and NADPH oxidase in cells.In the pres-ence of cisplatin,ROS are produced through all these pathways and are implicated in the pathogen-esis of acute cisplatin-induced renal injury.23Cispla-tin induces glucose-6-phosphate dehydrogenase and hexokinase activity,which increase free radical pro-duction and decrease antioxidant production.24It increases intracellular calcium level which activatesCisplatin NephrotoxicityNADPH oxidase and to stimulates ROS production by damaged mitochondria.23Superoxide anion(O2●),25 hydrogen peroxide(H2O2),26and hydroxyl radical (●OH)27are increased in cisplatin-treated kidneys. These free radicals damage the lipid components of the cell membrane by peroxidation and denature proteins,which lead to enzymatic inactivation.Free radicals can also cause mitochondrial dysfunction.24 Antioxidant enzymes are inhibited by cisplatin, and renal activities of superoxide dismutase,glu-tathione peroxidase,and catalase are significantly decreased.28,29Antioxidants melatonin,30vitamin C26,and vitamin E31have been shown to prevent cisplatin-induced acute nephrotoxicity.The role of oxidant-antioxidant systems in chronic nephrotoxic-ity is uncertain.Reactive nitrogen species have also been studied in cisplatin-induced nephrotoxicity.The renal content of peroxynitrite and nitric oxide is increased in cisplatin-treated rats.32,33Peroxynitrite causes changes in pro-tein structure and function,lipid peroxidation,chemical cleavage of DNA,and reduction in cellular defenses by oxidation of thiol pools.Cisplatin-induced nitrosative stress and nephrotoxicity are attenuated by FeTPPS-treatment,a soluble complex which metabolizes per-oxynitrite.These data suggest that peroxynitrite is involved,to some degree,in cisplatin-induced nephro-toxicity and protein nitration.32However,it isstill Figure1.Major pathways in cisplatin-induced acute tubular cell injury.Table1.Selected Summary of Drug Metabolism and Toxic ProcessesProcess RelevancePharmacokinetics and excretion Renal excretion Drug concentration in tubulesCellular uptake and metabolism Transporter mediated Inhibition-reduced uptakeIntracellular hydration Increased toxicityGenomic effects Gene upregulation Caspase3¡apoptosisGene downregulation Superoxide dismutase¡1ROSDirect toxic effects ROS Lipid peroxidationMitochondrial injury1ROS,2ATP productionIndirect toxic effects MAPK pathways1TNF-␣production activate apoptosisOrgan effects:histology Tubular injury Apoptosis,necrosisOrgan effects:function2Tubular function Na,K,Mg wastingTherapy Limit toxicity,if preventionfails,see Table2Not available yet,possible approach-stop apoptosis ATP,Adenosine triphosphate;MAPK,mitogen-activated protein kinase;ROS,reactive oxygen species;TNF-␣,tumor necrosis factor-␣.Yao et alcontroversial whether nitric oxide plays a toxic role in kidney injury.24,32,33Hypoxia and mitochondrial injury are involved in cisplatin nephrotoxicity.Pathological changes in cis-platin-induced nephrotoxicity occur mainly in the S3 segment of the proximal tubule in the outer stripe of the outer medulla.This zone of the kidney is more susceptible to ischemic insult,and injury to this segment occurs in other toxic acute renal failure models.34Hypoxic tubules in the outer medulla have been identified by pimonidazole staining in cisplatin nephrotoxicity.Analyses using serial sections indi-cate that a significant portion of hypoxic cells are proximal tubular cells.35Therefore,hypoxia may have an important role in cisplatin-induced nephro-toxicity,and this probably develops during the de-creased renal blood observed during the initial phase of cisplatin nephrotoxicity.However,hypoxia-inducible factor1(HIF-1)is activated in the S3seg-ment of proximal tubules in cisplatin injury in vivo. HIF-1is a transcription factor that mediates cellu-lar responses to hypoxia,including angiogenesis, erythropoiesis,and glycolytic adaptation.Dominant negative HIF-1␣-subunit animals have increased susceptibility to cisplatin injury mediated by apopto-sis which was associated with the increased release of cytochrome c,loss of mitochondrial membrane potential,and increased caspase9activity.35There-fore,the net effect of hypoxia in cisplatin-induced renal injury is uncertain.Apoptosis is now recognized as an important mode of cell death in normal and pathologic states. Caspase1,8,and9are initiator caspases that acti-vate caspase3,which is the principal executioner caspase in renal tubules apoptosis.This process may proceed through either activation of an extracellular surface receptor pathway or an intracellular mito-chondrial pathway.DNA fragments and oxidative stressors initiate the mitochondrial pathway that results in caspase9activation.36Engagement of a cell surface receptor with extracellular tumor necro-sis factor-␣(TNF-␣)activates caspase8.37Both pathways may be involved in cisplatin-injured kid-ney.In addition,cisplatin can induce a very rapid Fas clustering into the membrane lipid rafts and elicit apoptosis cascade in the absence of Fas ligand. This pathway has been implicated in its cytotoxicity of cancer cells.Whether it is involved in nephrotox-icity is unknown.38Caspase1directly activates caspase3in cisplatin-induced renal injury model. Caspase1also increases interleukin1(IL-1)lev-els and contributes to the inflammation in the cis-platin-treated kidney.Cisplatin-induced apoptosis and ATN are reduced in caspase1-deficient mice.39 DNA fragmentation associated with cisplatin-in-duced nephrotoxicity depends on deoxyribonuclease I,a highly active endonuclease I,which represents approximately80%of the total endonuclease activ-ity in the kidney.Primary renal tubular epithelial cells isolated from deoxyribonuclease I knockout an-imals are resistant to cisplatin injury in vitro.40 Cisplatin induces a series of inflammatory changes that mediate renal injury.Recent evidence indicates that inflammation has an important role in the patho-genesis of cisplatin-induced renal injury.Cisplatin in-creases degradation of IB in a time-dependent man-ner and increases nuclear factor-B(NF-B)binding activity.These events lead to the enhanced renal expres-sion of TNF-␣.Other cytokines,such as transcribing growth factor-(TGF-),monocyte chemoattractant pro-tein-1(MCP-1),intercellular adhesion molecule(ICAM), hemeoxygenace-1,TNF receptor1(TNFR1),and TNF receptor2(TNFR2),are also increased in kidneys by cisplatin.41TNF-␣has a central role in mediating the renal injury.It induces apoptosis,produces reactive oxy-gen species,and coordinates the activation of a large network of chemokines and cytokines in the kidney. Inhibitors of TNF-␣production(GM6001and pentoxifyl-line)and TNF-␣neutralizing antibody reduce serum and kidney TNF-␣protein levels from30%to nearly100%. They blunt the cisplatin-induced increases in TGF-, RANTES,MIP-2,and MCP-1mRNA.42In addition,the TNF-␣inhibitors ameliorate cisplatin-induced renal dys-function by50%and reduce cisplatin-induced structural damage.42TNF-␣-deficient mice are markedly protected against cisplatin nephrotoxicity.43Cisplatin can also induce fibrosis around the af-fected tubules,accompanied by infiltration of mac-rophages and lymphocytes.In a rat model that re-ceived2mg/kg body weight cisplatin injections once weekly for7weeks,fibrotic lesions progressively developed in the corticomedullary junction as early as week1and reached a maximum at week5.44All renal damages were repaired during a19-week ob-servation period after cessation of cisplatin treat-ment by a reduction in fibrotic tissues and by re-placement with regenerated renal tubules.The healing was accompanied by decreases in BUN and creatinine concentrations.44Extensive renal tubulo-interstitial fibrosis has been shown in a patient45 and in other large animals46treated with multiple courses of cisplatin chemotherapy.Macrophages play an important role in renal interstitial fibrosis via production of TGF-1and TNF-␣;these fibro-genic factors mediate induction of myofibroblastic cells capable of producing extracellular matrices.47 In summary,cisplatin causes direct tubular injury through multiple mechanisms.Significant interac-tions among these various pathways may occur dur-ing this injury.For example,TNF-␣induces apopto-sis,produces ROS,and coordinates the activity of a network of cytokines that all contribute to cellular injury.However,it also triggers the expression of inducible nitric oxide synthase,increases the pro-duction of nitric oxide,and enhances HIF-1activity in normoxic renal tubule cells,events that could limit injury.48How much each pathway and the interactions among these pathways contribute toCisplatin Nephrotoxicitythe cisplatin nephrotoxicity has not been deter-mined(Figure1).Pathophysiological Effects of Cisplatin Injury Unbound cisplatin is filtered at the glomerulus (80%of a dose is excreted in24hours).Renal blood flow can decrease within3hours after cisplatin infusion,and glomerular filtration rate(GFR)falls after the decrease in renal blood flow.49The media-tors responsible for the fall in renal blood flow and GFR have not been determined,and neither calcium channel blockers nor angiotensin converting enzyme inhibitors reverse cisplatin-induced ARF.50The changes in GFR and renal blood flow probably re-flect increased renal vascular resistance secondary to tubular-glomerular feedback from increased so-dium chloride delivery to the macula densa.49Intra-tubular obstruction does not play a primary role in cisplatin-induced nephrotoxicity.50Most patients re-ceiving cisplatin treatment have stable renal func-tion.Twenty-five percent of patients have reversible azotemia for1to2weeks after treatment.51How-ever,a significant minority of patients have a pro-gressive decline in renal function.Irreversible renal failure can occur with large doses and with multiple courses.51,52Increased age,renal radiation,and al-cohol ingestion increase toxicity.53The proximal tubular dysfunction observed in cis-platin nephrotoxicity precedes alterations in renal hemodynamics.Forty-eight to72hours after cispla-tin administration,there is impaired proximal and distal tubular reabsorption and increased vascular resistance.51Acute toxicity causes decreased mito-chondrial function,decreased ATPase activity,al-tered cell cation content,and altered solute trans-port.49,51The expression patterns of outer medullary water channels aquaphorin1and2,of sodium trans-porters,including the Na,K-ATPase(a-subunit)and the Na,K,2Cl-cotransporter,and of the type III Na,H-exchanger,are decreased in a cisplatin-treated rat model.Hence,cisplatin treatment results in im-paired tubular reabsorption and decreased urinary concentration.51,54The effect on sodium and water transport represents an early change in cisplatin tox-icity since the inhibition of the transporters occurs in rats without elevation of BUN and creatinine.51,55 There is decreased sodium reabsorption in the proxi-mal tubule and decreased sodium and water reabsorp-tion in distal tubule.This causes increased excretion of sodium and water.5,55Polyuria uniformly accompanies cisplatin administration and occurs in2distinct phases.The first phase occurs within the first24to48 hours after administration.It is characterized by de-creased urine osmolality but stable GFR.It is probably prostaglandin mediated and can be prevented by va-sopressin and aspirin.This early phase polyuria usu-ally resolves spontaneously.The second phase starts between72and96hours after cisplatin administra-tion and is characterized by a decreased GFR.It is associated with medullary urea cycling defect which results in decreased medullary tonicity and impaired NaCl transport in the proximal tubule and thick as-cending limb of the loop of Henle.This phase does not respond to either drug.50,56Most patients waste so-dium,potassium,magnesium,and calcium in their urine and some have orthostatic hypotension.50,51,57,58 Pathological Changes in the Kidney Cisplatin nephrotoxicity primarily causes tubulo-interstitial lesions.In animal models cisplatin dam-ages the proximal tubules,specifically the S3seg-ment of the outer medullary stripe.Mitochondrial swelling and nuclear pallor occur in the distal nephron.The glomerulus has no obvious morpho-logic changes.49,56,59Only a few studies have de-scribed the pathological results associated with cis-platin-induced nephrotoxicity in humans.49,56,59,60 The site of injury involves either the distal tubule and collecting ducts or the proximal and distal tu-bules.49,56The sites affected probably depend on differences in dose and timing of biopsy specimens. Biopsies obtained3to60days after dosing reveal segmental degeneration,necrosis,and desquama-tion of the epithelial cells in the pars convoluta and pars recta of the proximal tubules and the distal tubules.60In patients with acute renal failure,the predominant lesion is acute necrosis and is located mostly in the proximal convoluted tubules.The se-verity of necrosis is dose-,concentration-,and time-dependent.There is no interstitial nephritis.56,59Pa-tients with chronic nephrotoxicity have focal acute tubular necrosis characterized by cystic dilated tu-bules lined by a flattened epithelium showing atyp-ical nuclei and atypical mitotic figures with hyaline casts.49Long-term cisplatin treatment and injury may cause cyst formation and interstitial fibrosis.49 Diagnostic Criteria for Cisplatin Injury Cisplatin-induced renal injury probably does not have unique diagnostic features.Many patients have changes in glomerular filtration which could be identified by more sensitive tests such as inulin clearance before there are changes in serum creati-nine and glomerular filtration measured by creati-nine collection.Urinary excretion of a proximal tu-bular injury markers,such as-2microglobulin, N-acetyl--D-glucosaminidase,and␣1-acid glycop-rotein,increase after cisplatin treatment.53There is little change in urine protein excretion.Urinalysis typically shows leukocytes,renal tubular epithelial cells,and granular casts.56A recent animal study demonstrated the presence of glucose,amino acids, and tricarboxylic acid cycle metabolites in the urine 2days after cisplatin exposure.If this altered met-abolic profile can be demonstrated in human stud-Yao et alies,it might be used to identify early cisplatin-induced nephrotoxicity.61Approaches to PreventionThese various approaches are summarized in Ta-ble2.Excretion and MetabolismVigorous hydration with saline and simultaneous administration of mannitol before,during,and after cisplatin administration significantly reduce cispla-tin-induced nephrotoxicity.This strategy has been accepted as the standard of care.49Recently,a ran-domized trial demonstrated that saline alone or with furosemide provides better renal protection than saline plus mannitol.62The mechanism for salt pro-tection is uncertain.Volume expansion with saline or hypertonic saline may increase the rate of cispla-tin excretion.63Salt also provides a high concentra-tion of chloride ions that prevent the dissociation of the chloride ions from the platinum molecule, thereby reducing the formation of the reactive, aquated species of cisplatin.64Alternatively,sodium ions may provide renal protection.A recent study demonstrated that saline does not alter the cellular accumulation of cisplatin but instead triggers a stress response within the cell that modifies sensi-tivity to cisplatin.The osmotic stress response de-creases the accessibility of cisplatin to DNA,induces proximal tubule cell resistance to apoptosis,and changes the metabolic activation of nephrotoxins. However,this approach may interfere with the an-tineoplastic activity of cisplatin by blocking tumori-cidal effects.65Cellular UptakeCarboplatin and oxiplatin are second-and third-generation platinum drugs that have been intro-duced into clinical use because of their reduced nephrotoxicity.They have no interaction with hu-man OTC2,and this reduces their entry into renal tubular cells.8,9The in vitro antitumor activity of carboplatin is quantitatively similar to cisplatin; clinical trials have demonstrated that carboplatin has comparable efficacy in treating ovarian cancer.50 It can be used in patients who can not take cisplatin either due to existing renal dysfunction or coadmin-istration of other nephrotoxic drugs.Although less severe than with cisplatin,dose-dependent nephro-toxicity has been observed.With carboplatin dosage at400mg/m2,only subclinical tubular damage oc-curs.Overt nephrotoxicity develops when the dosage reaches800mg/m2.Without hydration,patients have a36to61%reduction in creatinine clearance.49Table2.Potential Approaches to Prevention of Cisplatin-Induced Nephrotoxicity Pathogenesis Prevention Agent Mechanism of Prevention Reference Uptake by renal cell Glycation Decreases human OCT expression10,68Cimetidine Competes for the transport at human OCT28,9Carboplatin,Oxaliplatin Decreased interaction with human OCT28,9,50,55,66,67Sulfa-containing amino acid Blocks cisplatin transportation6Conversion to toxic compounds Normal saline Increases excretion,reduces formation oftoxic agents and induces osmotic stressresponse49,62,63,64,Procainamide Coordinates with cisplatin to form a lesstoxic complex70,71Cisplatin induced signal transduction Serum thymic factor Ameliorates sustained ERK activation79 U0126Decreases TNF-␣generation and caspase3activity20Oxidative stress injury Amifostine Binds free radicals and reduces platinum-DNA adduct formation76,77,78 Melatonin,vitamins C and E Decreases oxidative stress injury26,30,31 Allopurinol Inhibits xanthine oxidase to reduce ROSgeneration72 Ebselen Scavenges peroxynitrite to prevent lipidperoxidation72 Erdosteine Maintains intracellular redox state tosuppress oxidant stress24 Edaravone andN-acetylcysteineRepletes intracellular stores of glutathione73Inflammation Pentoxifylline,␣-MSH,IL-10,Inhibits production of TNF-␣82Salicylates Inhibit cyclooxygenase activity andprostaglandin synthesis,high dosesattenuate TNF-␣production41,81Fibrates Inhibit free fatty acid accumulation andsuppress apoptosis83ERK,Extracellular regulated kinase;IL-10,interleukin10;MAPK,mitogen-activated protein kinase;␣-MSH,␣-melanocyte stimulating hormone;OCT,organic cation transporter;ROS,reactive oxygen species;TNF-␣,tumor necrosis factor-␣.Cisplatin Nephrotoxicity。
中医药抗顺铂肾毒性的研究进展
配合西药综合治疗，对改善肾功能、延缓病情收到较满意的效果。 邱玉文等Ｉ“Ｉ以长坤冲剂（北芪、党参、泽泻、吴茱萸等８味药按一定 比例制成２．６９／ｍＬ药液）连续８ ｄ灌胃，能明显降低顺铂引起的大 鼠尿素氮（ＢＵＮ）升高，同时肾组织学损害也明显减轻，临床对顺铂 化疗患者有较好保护作用ｔｕ Ｊ。章杰“，Ｉ在临床用药中体会到，复方丹 参片（每次３片，３次／ｄ）、六味地黄丸（每次６ ｇ，２次／ｄ）在防治顺 铂肾毒性方面有良好疗效。
２．２
单味中药及其提取物 通过动物实验及临床实践发现，中药黄芪能明显减轻顺铂所
致的肾损害，增强顺铂的抗肿瘤活性，能替代或部分替代常规大剂 量顺铂化疗的水化治疗，尤其适用于心肺功能不全不能耐受水化 的患者““”ｌ。陈妍等‘１９Ｉ报道，临床口服冬虫夏草对顺铂引起的肾 损害有明显的改善作用。灵芝多糖可能通过提高超氧化物歧化酶 （ＳＯＤ）活性，清除顺铂诱发生成的氧自由基，抑制血液和肾皮质组 织脂质过氧化反应，减轻顺铂肾毒性，但不影响顺铂的抗肿瘤活 性㈨。２Ｉ。陈知航等【２３１报道，绿茶多酚（ＧＴＰ）灌胃预处理可抑制顺铂 引起的谷胱甘肽过氧化酶（ＧＳＨ—Ｐｘ）活性下降，并能促进铂经尿排 泄，减轻了顺铂的肾毒性。田同荣㈨１在临床实践中对大剂量顺铂治 疗的患者采用饮绿茶的方法，收到了同样的效果。刘晓华等ｍ。６｜发 现，川Ｉ芎嗪（ＴＭＰ）通过明显降低Ｂａｘ／Ｂｃｌ２比值呈剂量依赖性降低 顺铂肾损伤。李昱辰等（２７１通过体内、体外实验观察到姜黄素（ＣＭＮ） 可明显减轻顺铂引起的肾脏损伤，但对顺铂抗肿瘤细胞增殖作用 无明显影响。刘勇等［２ｓ１报道，大蒜素、沙棘油对顺铂肾损害有明显 的预防作用，尤其第５天预防作用显著。南海波等Ｌ２。１研究认为，水 飞蓟宾（ＳＢ）可能通过清除自由基、抑制脂质过氧化形成、提高机体 抗氧化能力而起到预防顺铂肾毒性的作用。
顺铂致急性肾损伤的研究进展
顺铂致急性肾损伤的研究进展孟晓燕【摘要】顺铂为临床上广泛应用治疗多种实体肿瘤的化疗药物,但在正常组织器官中的不良反应,尤其是肾毒性限制了其临床应用.应用顺铂治疗后,大约1/3的患者可出现肾功能异常,甚至急性肾损伤.近年关于顺铂不良反应的研究聚焦于顺铂肾毒性的发生机制,尤其是在引起肾小管上皮细胞死亡、炎性反应的信号转导通路方面.最近自噬也被证实参与顺铂导致地细胞损伤,虽然已发现一些预防顺铂肾毒性的方法,但大多数保护方法均较局限,因此,更好地理解顺铂肾毒性作用机制,对于顺铂肾毒性防治将具有十分重要意义.该文就顺铂致急性肾损伤作用机制研究进展作一综述.【期刊名称】《医学综述》【年(卷),期】2014(020)021【总页数】3页(P3949-3951)【关键词】顺铂;肾毒性;急性肾损伤【作者】孟晓燕【作者单位】广西医科大学第四附属医院肾内科,广西柳州545005【正文语种】中文【中图分类】R969.320世纪70年代以来，顺铂已被临床广泛用于治疗多种恶性肿瘤，包括睾丸癌、卵巢癌、膀胱癌、宫颈癌、头颈部恶性肿瘤以及小细胞或非小细胞肺癌等，是治疗实体肿瘤最有效和常用的药物之一，但在正常组织中的严重不良反应常限制其临床应用，顺铂不良反应有耳毒性、胃肠道毒性、骨髓抑制、变态反应及肾毒性[1-2]，其中肾毒性最常见，顺铂治疗后，约1/3患者出现肾功能障碍导致急性肾衰竭[1,3-4]，其剂量相关的肾毒性大大限制了临床应用。
目前顺铂致肾损伤机制仍未完全明确，近年研究发现炎症介质、坏死、凋亡、氧化应激、自噬等均可能为顺铂致急性肾损伤原因，该文就顺铂致急性肾损伤作用机制的研究进展予以综述。
1 炎性介质Deng等[5]发现抗炎因子白细胞介素10可减轻顺铂导致的肾组织损伤及肾小管上皮细胞的死亡，由此提出在顺铂肾毒性中，有大量促炎性反应细胞因子及趋化因子参与。
顺铂触发的炎性反应可引起肾组织损伤及功能障碍，出现急性肾损伤[6]。
顺铂作用机制
顺铂作用机制篇一：抗肿瘤药物顺铂对人肺癌A549细胞生抗肿瘤药物顺铂对人肺癌A549细胞生长的影响[摘要]目的：以体外培养的人肺腺癌A549细胞为研究对象，了解A549细胞不同生长发育时期的特性。
并观察经不同浓度顺铂、不同时间长度处理后，对A549生长的抑制作用，观察这种抑制作用的性质，为顺铂对人肺腺癌的分子生物学治疗提供理论依据。
方法：体外培养A549 细胞，以血球计数板检测不同时期A549细胞生长情况，观察其形态变化，并绘制生长曲线；用呈浓度梯度的顺铂处理人肺癌A549细胞,观察顺铂对A549细胞生长的影响；再用特定浓度的顺铂处理A549细胞不同时间，检测顺铂对A549细胞生长的影响。
结果：正常生长的A549细胞，细胞数目增长最快的时间段为96~108h，倍增时间为27.6小时。
用浓度为1μg/ml、2μg/ml、5μg/ml、10μg/ml、15μg/ml、20μg/ml的顺铂溶液处理A549细胞48小时后，A549细胞数目从8*10降至2.7*10，用2μg/ml、5μg/ml 的顺铂浓度分别处理A549细胞不同时间，2μg/ml浓度下，抑制率从3.57%上升至24.59%；5μg/ml时，抑制率从8.32%升至42.24%。
结论：顺铂对A549细胞生长的抑制作用随着浓度的升高而变强。
当顺铂浓度为2、5μg/ml时，对肺腺癌细胞A549的抑制最为显著。
随着顺铂处理时间的增长，其对A549细胞生长的抑制率逐步变高。
用5μg/ml 顺铂作用于A549细胞时，作用12h~24h时的抑制最为显著。
[主题词]:人肺癌A549细胞；顺铂；生长抑制 55ABSTRACTObjective: To culture human lung adenocarcinoma cell A549 in vitro, and study growingdevelopment in different growth stage. Investigate the influences on A549 cells at vary Cisplatin concentration and in various time quantum.Methods: In order to culture A549 cells in vitro, use hemocytometer to test growthism of A549 cells at different growth period. Observe its morphological changes and draw growth curve of A549 cells. Use Cisplatin in concentration gradient to stimulate A549 cells, and examine its effect onA549 cells; use Cisplatin to stimulate A549 cells in various time quantum, and investigate its influences.Results: The fastest growing period of A549 cells cultured in normal condition was 96 to 108 hours, and the double time was 27.6 hours. After 48 hours of stimulation of cisplatin at 1~20μg/ml, the amount decreased from8*105/ml to 2.7*105/ml. Use 2μg/ml、5μg/ml cisplatin to stimulate A549 cells in various time quantum, under 2μg/ml, the inhib ition rate rise from 3.57% to 24.59%;5μg/ml, it was from 8.32% to 42.24%.Conclusion:The inhibition rate of A549 cells stimulated by cispltin grew along with the concentration of Cisplatin and reaction time quantum. At 2、5μg/ml, cisplatin’s inhibition is the most markable; At 2、5μg/ml，there’s the most notable impact on A549 cells in 12 to 24 hours.[Key Words] Human Lung Cancer Cell A549; Cisplatin(DDP); Growth inhibition.目录综述 ........................................................................... .. (1)1. 癌症 ........................................................................... .. (1)1.1.1.2. 癌症概述 ........................................................................... ............................. 1 癌症的治疗 ........................................................................... . (2)2. 致癌药物――顺铂简介............................................................................ . (2)2.1．顺铂的发现 ........................................................................... .. (3)2.2．顺铂的作用机制 ........................................................................... .. (3)2.3．顺铂的耐药性 ........................................................................... .. (4)3．肿瘤和细胞周期 ........................................................................... ........................ 4 实验设计 ........................................................................... (6)1．研究目的 ........................................................................... .. (6)2．实验方案设计 ........................................................................... . (6)3．研究意义 ........................................................................... .. (7)4．材料与方法 ........................................................................... (7)4.1．材料 ........................................................................... .. (7)4.2．主要仪器 ........................................................................... .. (7)4.3．主要试剂与耗材 ........................................................................... (7)4.4．主要试剂配制 ........................................................................... .. (9)5．实验步骤 ........................................................................... .. (10)5.1．冻存细胞的复苏 ........................................................................... . (10)5.2．细胞的传代 ........................................................................... . (10)5.3. 细胞的计数 ........................................................................... . (11)5.4. A549细胞生长曲线特征 (11)5.5．用不同浓度顺铂对A549细胞生长的影响 (11)5.6．用顺铂处理不同时间，顺铂对A549细胞生长抑制率的影响 (12)5.7．统计学分析 ........................................................................... (12)6. 实验结果 ........................................................................... .. (12)6.1．人肺腺癌A549细胞生长曲线特征 (12)6.2．不同浓度顺铂对A549细胞生长的影响 (14)6.3．用顺铂处理不同时间，顺铂对A549细胞生长抑制率的影响 (16)7. 讨论 ........................................................................... (18)8. 结果与展望 ........................................................................... ................................ 20 翻译 ........................................................................... .................................................................. 21 参考文献 ........................................................................... ....................................................... 33 致谢 ........................................................................... .................................. 错误！未定义书签。
顺铂作用机制
顺铂作用机制ethods: In order to culture A549 cells in vitro, use hemocytometer to test gro216，全称为顺式-二氯-反式-乙酸（氨环已胺）合铂（Ⅳ），是第一个进入临床试验的口服铂（Ⅳ）药物。
由美国施贵宝公司、英国Johnson Matthey公司和癌症研究所共同开发。
与顺铂无交叉耐药，与鬼臼素有协同抗癌作用，毒性为骨髓抑制，Ⅱ期单药临床研究表明，该药对小细胞肺癌、顽固性前列腺癌有效，对其它一些癌种的临床试验正在进行之中。
此外，在28个进入临床的铂类抗癌药物中,因疗效欠佳或毒副作用大而被淘汰的药物有近20个.如顺铂类化合物的环戊胺铂、铂蓝、环丙胺铂、乙二胺丙二酸铂等；卡铂类化合物的恩络铂、僧尼铂、NK-121等；环已二胺类化合物的环硫铂、DACCP等，四价铂类化合物的奥玛铂等。
目前，全世界的科学家们仍在继续寻找综合评价优于顺铂和卡铂的新一代药物。
同时，还在进一步研究顺铂和卡铂的联合用药方案，以扩大它们在癌症治疗中的适应证和提高疗效。
篇三：顺铂肾毒性机制及其防护的研究进展顺铂肾毒性机制及其防护的研究进展顺铂(CDDP)是一种高效广谱的抗肿瘤药，容易引起胃肠道反应、骨髓抑制、耳毒性等不良反应。
尤其是它在肾脏中高聚集、高排泄、高代谢，其肾毒性作用尤为突出。
统计显示[1]，临床顺铂化疗肾损害发生率为25%_35%，如何降低其肾毒性，是目前急需解决的课题。
1 顺铂肾毒性机制顺铂在高氯环境下活性低，但当其进入低氯的细胞内液后活性增高，很快发生水合解离，生成带正电荷的水合配离子，受DNA静电引力的作用，向细胞核迁移，形成 cis-［Pt(NH3)2］2/DNA加合物。
加合作用改变了DNA 正常复制模版的功能，引起DNA复制障碍，从而抑制肿瘤细胞的分裂[2]。
顺铂的肾毒性是否与这一机制有关尚未明确。
研究表明，氧化性损伤是顺铂肾毒性的机制之一。
顺铂 说明书
顺铂（Cisplatin）说明书1. 产品概述顺铂是一种白色结晶性化合物，属于铂类抗肿瘤药物。
它是一种广谱抗癌药物，被广泛用于治疗多种类型的恶性肿瘤，包括卵巢癌、膀胱癌、头颈部癌、肺癌等。
2. 药理学作用顺铂通过与DNA结合，干扰DNA的复制和转录过程，从而阻止肿瘤细胞的增殖和分裂。
此外，它还能通过诱导细胞凋亡和抑制血管生成来抑制肿瘤生长。
3. 适应症顺铂适用于以下恶性肿瘤的治疗： - 卵巢癌 - 膀胱癌 - 头颈部鳞状细胞癌 - 肺癌4. 使用方法和剂量4.1 使用方法顺铂通过静脉注射给药。
在给药前应进行充分的液体补充和预防性使用抗恶心药物。
4.2 剂量剂量应根据患者的体表面积、肿瘤类型和临床情况进行个体化调整。
通常的剂量范围为每平方米体表面积50-120毫克。
5. 不良反应5.1 常见不良反应•恶心、呕吐•骨髓抑制（贫血、白细胞减少、血小板减少）•肾毒性（尿频、尿量减少、肾功能异常）•神经毒性（周围神经病变、感觉异常）5.2 严重不良反应•过敏反应（包括过敏性休克）•耳毒性（听力下降或丧失）6. 注意事项6.1 孕妇禁用顺铂对胎儿有明显的胚胎毒性和致畸作用，孕妇禁用。
6.2 肾功能监测顺铂具有一定的肾毒性，使用期间需要监测肾功能，避免肾损害。
6.3 抗恶心药物联合使用顺铂治疗期间，建议联合使用抗恶心药物，以减轻恶心和呕吐症状。
7. 药物相互作用7.1 耳毒性增强顺铂与其他耳毒性药物（如氨基糖苷类抗生素）联合使用时，可能增加耳毒性作用。
7.2 骨髓抑制增强顺铂与其他具有骨髓抑制作用的药物（如放射线治疗、其他化疗药物）联合使用时，可能增加骨髓抑制的风险。
8. 贮藏要求顺铂应存放在阴凉、干燥处，避免阳光直射。
禁止与氧化剂和还原剂混合贮存。
9. 包装规格常见包装规格为10毫克/瓶、50毫克/瓶、100毫克/瓶等。
10. 生产厂家和联系方式本产品由XX公司生产，如有任何问题，请联系客服电话：XXX-XXXXXXX。
顺铂说明书
顺铂注射液说明书【药品名称】通用名：顺铂注射液英文名：Cisplatin Injection 汉语拼音名：Shunbo Zhusheye 本品主要成份为顺铂。
化学名：（顺）二氨二氯铂化学结构式：分子式：Cl2H6N2Pt 分子量：【性状】本品为无色或几乎无色的澄明液体。
【药理毒理】1．药理作用本品为金属铂类络合物，属周期性非特异性抗肿瘤药。
具有抗瘤谱广、对厌氧细胞有效的特点。
本品在细胞低氯环境中迅速解离，以水合阳离子的形式与细胞内生物大分子结合（主要靶点为DNA）形成链间、链内交联或蛋白质DNA交联，从而破坏DNA的结构和功能。
2．毒理研究（1）生殖毒性本品孕妇应用可导致胎儿损害。
小鼠试验中本品表现出致畸性和胚胎毒性。
若妊娠期间应用，或给药期间发现怀孕，应告之患者其对胎儿的潜在危害性。
应劝告有生育可能的妇女避免怀孕。
有报道在人乳汁中检测到本品，故建议母亲应用本品时中止授乳。
（2）遗传毒性本品在细胞试验中表现出致突变性，使组织培养的动物细胞出现染色体畸变。
（3）致癌毒性进行了BDIX(共50只)给药的致癌性试验，本品腹腔给药3周，1mg/kg/周，结果首次给药的455天内，33只动物死亡，其中13只死于恶性肿瘤；12只为白血病，1只为肾脏纤维肉瘤。
【药代动力学】据文献报道，本品静脉给药后迅速吸收，分布于全身各组织：肾、肝、卵巢、子宫、皮肤、骨等含量较多，脾、胰、肠、心、肌肉、脑中较少，瘤组织无选择性分布。
大部分和血浆蛋白结合，代谢呈双相性：T1/2α为25~49分钟，T1/2β为58~73小时。
药物自体内消除缓慢，主要经肾脏排泄，5日内尿中回收铂为给药量的27~54%，胆道也可排除顺铂与其降解产物，但量较少。
腹腔给药使腹腔器官的药物浓度较静脉给药时高~8倍，对治疗卵巢癌有利。
【适应症】小细胞与非小细胞肺癌、睾丸癌、卵巢癌、宫颈癌、子宫内膜癌、前列腺癌、膀胱癌、黑色素瘤、肉瘤、头颈部肿瘤及各种鳞状上皮癌和恶性淋巴癌。
注射用顺铂临床应用
注射用顺铂临床应用
顺铂是一种广泛应用于临床的抗肿瘤药物，具有较高的抗癌活性和广泛的抗肿瘤谱，被认为是肿瘤化疗的重要药物之一。
本文将探讨注射用顺铂在临床应用中的相关内容。
顺铂的药理作用主要通过与DNA形成交联加以破坏细胞的DNA结构，抑制DNA合成和细胞分裂，从而达到抗肿瘤的效果。
顺铂广泛应用于多种实体瘤和恶性肿瘤的治疗，如卵巢癌、肺癌、膀胱癌、乳腺癌等。
在这些肿瘤的治疗中，顺铂常常与其他药物联合应用，形成化疗方案，取得较好的疗效。
在临床应用中，顺铂有着较强的毒副作用，如造血抑制、肾毒性、神经毒性等。
因此，在使用顺铂进行治疗时，需要密切监测患者的血常规、肝肾功能等指标，及时调整用药方案，避免毒副作用的发生。
除了单药治疗外，顺铂也常与其他抗肿瘤药物联合应用，以增强疗效或减轻毒副作用。
例如，顺铂与依环磷酰胺、长春新碱等化疗药物联合应用，可用于治疗多种恶性肿瘤，提高治疗的有效率。
总的来说，注射用顺铂是一种重要的抗肿瘤药物，在临床应用中发挥着重要作用。
通过合理的使用和密切监测，可以最大限度地发挥其抗肿瘤活性，提高患者的生存质量和生存期。
希望未来能有更多的研究和临床实践，进一步完善顺铂的临床应用。
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顺铂的药理及肾毒性的研究
发表时间：2017-09-11T14:05:53.637Z 来源：《心理医生》2017年22期作者：辛丽霜
[导读] 探讨顺铂的药理作用，临床应用及肾毒性的影响。
（黑龙江省社会康复医院黑龙江哈尔滨 150030）
【摘要】目的：探讨顺铂的药理作用，临床应用及肾毒性的影响。
方法：对顺铂的药理作用，应用及发生肾毒性的研究进行分析，对我院2015年1月—2016年6月期间肿瘤科应用顺铂为主要联合化疗治疗的恶性肿瘤患者，对大剂量和分割剂量治疗患者的尿液NAG活性变化及显著性检验进行分析。
结果：顺铂后第一、八日两组均显示尿液NAG活性增高,第十八天基本恢复正常。
大剂量组顺铂后第1、8日尿液NAG活性与分割剂量组同期比较,差异均有高度显著性意义(P<0.05)。
结论：顺铂是恶书生肿瘤患者治疗方案中的重要成分，是一个广谱有效的抗肿瘤药，肾毒性和致吐作用是顺铂最常见的限剂量毒性。
【关键词】顺铂；药理作用；应用剂量；肾毒性
【中图分类号】R95 【文献标识码】A 【文章编号】1007-8231（2017）22-0339-02 顺铂对多种实体肿瘤均有效，如睾丸肿瘤、乳腺癌、肺癌、头颈部癌、卵巢癌、骨肉瘤及黑色素瘤等。
为当前联合化疗中最常用的药物之一。
不良反应主要为消化道反应、肾脏毒性、骨髓抑制及听神经毒性，与所用剂量的大小及总量有关。
1.资料与方法
1.1 一般资料
选取2015年1月—2016年6月期间肿瘤科应用顺铂为主要联合化疗治疗的恶性肿瘤患者50例，其中男37例，女13例，年龄39～76岁，平均年龄58.5±3.5岁。
胃肠癌19例，乳腺癌19例，肺癌6例，鼻咽癌6例，均无化疗禁忌证。
1.2 方法
采用大剂量治疗25例，分割剂量25例，大剂量治疗顺铂70～90mg/次，第一天静滴，持续3小时左右，用药前水化1000～1500ml，用药后4小时肌注速尿20～40mg利尿。
分割剂量顺铂30mg/次，第1～3天连用，静滴每次持续3小时左右，用药前水化500～1000ml，其它同大剂量治疗。
1.3 观察指标
对化疗前和化疗后第一天，第八天，第十八天留晨尿测定尿肌肝以酶单位与尿肌肝比值μ/g·Cr表示[1]。
2.结果
顺铂前大剂量组（30.58±5.95）μ/g·Cr，分割剂量组（28.18±4.22）μ/g·Cr，顺铂给药后第一天大剂量组（54.58±8.59）μ/g·Cr，分割剂量组（35.08±4.82）μ/g·Cr，第八天大剂量组（69.25±10.98）μ/g·Cr，分割剂量组（35.57±6.83）μ/g·Cr，第十八天大剂量组（32.37±8.98）μ/g·Cr，分割剂量组（29.67±4.33）μ/g·Cr。
顺铂后第一、八日两组均显示尿液NAG活性增高，第十八天基本恢复正常。
大剂量组顺铂后第1、8日尿液NAG活性与分割剂量组同期比较，差异均有高度显著性意义(P＜0.05)。
3.讨论
顺铂为周期非特异性药物。
能与 DNA结合形成交叉键，从而破坏DNA的功能不能再复制；高浓度时也抑制RNA及蛋白质的合成。
进入人体后可扩散通过带电的细胞膜。
在Cl-离子浓度高的条件下较稳定，进入细胞后由于细胞内Cl-浓度低，药物水解为阳离子水化物，具有类似烷化剂的双功能基团的作用，主要与DNA链上的碱基作用[2]。
顺铂对多种实体肿瘤均有效，如睾丸肿瘤、乳腺癌、肺癌、头颈部癌、卵巢癌、骨肉瘤及黑色素瘤等。
为当前联合化疗中最常用的药物之一。
肾毒性和致吐作用是顺铂最常见的限剂量毒性。
前者表现为肾小球滤过率降低，肾小管变性坏死，低血钾、低血镁、肾衰竭。
甘露醇可延迟顺铂与肾小管蛋白的结合，合用甘露醇有保护作用。
硫代硫酸钠可在肾小管形成高浓度，中和顺铂的毒性。
顺铂引起的严重呕吐，可为皮质激素和5-HT受体拮抗剂有效制止。
顺铂的神经毒性包括耳毒性、外周神经毒性等。
耳毒性表现为高频听力下降，外周神经毒性表现为袜筒一手套样感觉异常和疼痛。
小剂量和大剂量动物毒理学研究预测了顺铂肾毒性的出现比率。
动物肾损害与用药剂量有关，其次与蓄积量有关[3]。
使用顺铂引起的形态学改变，包括显微镜下的上皮细胞变性和近端肾小管坏死，伴随顺铂治疗出现的白蛋白尿和小分子蛋白尿。
尽管未探测到肾小球本身的损害，但可看到包曼囊的细胞浆中有电子致密物聚积。
给予顺铂后，老鼠肾组织学改变超微结构分析显示，近端和远端肾小管上皮细胞内的线粒体肿胀。
给药后不久，基底膜变厚和电子密集，尖端胞饮细胞的囊泡融合成大泡。
给药后数天溶酶体的体积和数量都增多，最后破裂。
对接受大剂量顺铂(≥3mg／kg)后2～29d内死亡的患者，进行死后检查，所有研究者生前都进行过水化或甘露醇利尿治疗。
急性肾脏改变包括皮质肿胀，髓质充血，远曲小管和集合管的灶状凝固性坏死。
髓质有炎症细胞反应。
同时可观察到远曲小管节段性扩张，非典型合胞体核的上皮细胞，透明和颗粒管型。
但未观察到肾小球改变。
但这些改变是非特异性的，不能被看作顺铂作用的特征性病征。
肾功能改变的患者进行肾活检显示，肾小管上皮细胞水肿变性，基底膜增厚，轻度间质纤维化。
在早期顺铂的经验用药——每3～4周给药100mg/m2的基础上，目前有2种治疗方案：1d内给完药或每天20mg/m2连续5d给药。
不管选择哪种方案，要想增加顺铂的使用，均要求更安全的给药方法。
对这两种方案检测结果显示，延长顺铂的给药时间，和通过伴随使用大量胃肠外输液和利尿，达到增强水化的作用。
这些变化可以减少肾毒性的发生率和严重性，同时对药物治疗的有效率影响不明显。
顺铂的连续注射给药方案，保留甚至提高了原用药总量(100mg/m2)，但仅有6％～13%出现短暂的Scr上升，而无急性肾功能衰竭发生。
恶心、呕吐以及氮质血症发生率明显下降，提示早期顺铂的给药治疗方案所引起的胃肠道和肾脏毒性，与高峰血药浓度有关。
呕吐的减少对肾毒性的减轻起直接作用。
人们试图通过给予盐水和袢利尿剂(呋塞米)，或渗透性利尿剂(甘露醇)达到最适水化。
从而保持顺铂用药期间的有效排尿量。
对肾小球功能的测定分析，包括肾小管重吸收磷酸盐，尿血葡萄糖比，总尿蛋白，总游离免疫球蛋白轻链的分泌，均未发现任何持续或蓄积异常。
因此，通过对这组水化良好的患者的详细评估说明，顺铂治疗，即使是原有肾疾病患者，也不一定会出现临床肾毒性。
【参考文献】
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[2]廖英俊，金亚平，汤浩.多种药物联合应用对小鼠顺铂肾毒性的拮抗作用[J].中国药理学与毒理学杂志，2009，23(3):219-224.
[3]曾健，劳山.顺铂肾毒性机制及其防护的研究进展[J].中国实用医药，2008，3(10):194-195.。