三磷酸胞苷二钠防治草酸铂外周神经毒性的临床观察

目的 寻找预防和治疗奥沙利铂 (草酸铂 )外周神经毒性的有效药物。方法 对 70例使用草酸铂治疗的胃癌和大肠癌患者 ,于给草酸铂前一天使用三磷酸胞苷二钠作预防组 (30例 ) ,另收集以草酸铂治疗的胃肠癌症患者 4 0例 ,于草酸铂开始治疗的第 4周起使用三磷酸胞苷二钠作为对照组 ,观察并对比两组外周神经毒性发生情况。结果 预防组较对照组毒性反应明显减少 ,对照组中出现外周神经毒性的 15例患者 ,在使用三磷酸胞苷二钠后 ,外周神经毒性的发生率显著降低 ,程度明显减轻。

丹参在防治顺铂耳毒性中对豚鼠耳蜗血管纹的作用

目的探讨丹参在防治顺铂耳毒性中对豚鼠血管纹的作用。方法将 1 8只豚鼠随机分成 3组 ,对照组连续 5d腹腔注射生理盐水 2ml/ (kg·d) ,丹参组连续 7d肌注丹参 8g/ (kg·d) ,第 3d时加腹腔注射顺铂 2ml/(kg·d) ,观察豚鼠的一般状况和耳廓反应。应用电反应测听仪测试听觉阈值 ,应用激光多普勒探测耳蜗血流的变化 ,并铺片观察血管纹的改变 ,统计学处理。结果丹参组豚鼠实验后一般情况较顺铂组明显减轻 ,除 3只豚鼠耳廓反应迟缓外 ,余反应灵敏 ,听觉阈值为 (32 .5± 7.5 )dB ,耳蜗底转血流测试为 1 5 5 .8mV ,与对照组相比均无显著性改变 (P <0 .0 1 )。耳蜗铺片显示红细胞聚集及血管扩张程度较轻 ,偶尔可见到细胞碎片及溶解 ,未见血池现象。结论丹参通过改善血管纹功能 。

含草酸铂化疗方案治疗大肠癌神经毒性的临床研究

目的 :研究含草酸铂方案治疗晚期大肠癌所引起的外周感觉神经毒性 ,并探讨其发生机制和治疗方法。方法 :对 2 3例大肠癌患者运用含草酸铂方案治疗 6个周期 ,定期观察患者外周感觉神经毒性表现 ,并对其进行分析。结果 :共计 2 1例患者 (91% )出现Ⅰ～Ⅱ度的速发型感觉神经障碍 ,而 5例患者 (2 1% )出现迟发型感觉神经障碍 ,在 8～ 16周内均可恢复 ,并且肌电图检查mcv及scv未见异常。结论 :含草酸铂方案所引起的外周神经毒性较轻 ,可恢复。

灵芝注射液和顺铂对荷瘤大鼠血和肾中超氧化物歧化酶和丙二醛含量的影响

本文观察了灵芝注射液和顺铂对荷瘤大鼠血液、肾皮质区组织匀浆中超氧化物歧化酶(SOD)的活性和醛(MDA)的含量变化。结果表明,灵芝注射液具有拟 SOD 活性作用,可以清除顺铂诱发产生的氧自由基,降低血液和肾皮质脂质过氧化反应,抑制了顺铂引起的肾毒性作用。并提示:大剂量的灵芝注射液能保护肾脏,预防顺铂肾毒性。

Clinical study of FOLFOX4 regimen for patients of advanced hepatocellular carcinoma

Objective:The aim of our study was to observe the efficiency and toxicity of oxaliplatin (L-OHP) combined with CF/5-FU in patients with advanced primary hepatocellular carcinoma.Methods:Twenty patients with advanced primary hepatocellular carcinoma had recurrence/metastasis after multiple courses of TACE (cisplatin and epirubicin,etc.).All patients were treated with FOLFOX4 regimen of the combination of oxaliplatin and leucovorin and 5-fluorouracil.Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred.The efficiency was evaluated according to RECIST criteria,and toxicities according to American National Cancer Institute Common Toxicity Criteria (NCI CTC),respectively.Results:Twenty patients were assessable for the objective efficiency and for toxicity.No patient achieved complete response (CR),4 patients were partial response (PR),8 patients were stable disease (SD),8 patients were disease progression (PD);Time to tumor progression (TTP) of the patients ranged from 1.5 to 4.8 months,median TTP was 2.2 months;Overall survival (OS) of the patients ranged from 3 to 10.2 months,median OS was 5 months.The 2 patients' serum AFP level decreasing.Sixteen patients relieved the symptoms obviously,stabilized or raised up Karnofsky Score.The toxicities were mainly grade I-II arrest of bone marrow (50%),mild neurotoxicity (30%) and mild reaction of gastrointestinal tract (40%).Conclusion:FOLFOX4 regimen is effective and safe for patients with advanced primary hepatocellular carcinoma.It can be worthy of further clinical investigation.

Thermotherapy enhances oxaliplatin-induced cytotoxicity in human colon carcinoma cells

AIM： To observe the synergistic effects of hyperthermia in oxaliplatin-induced cytotoxicity in human colon adenocarcinoma Lovo cells.

Casticin combination with Cisplatin in sub-toxic concentration induced apoptosis of human ovarian cancer HO-8910 cells in vitro

Objective: The aim of the study was to investigate the effect of Casticin (CAS) combination with Cisplatin (DDP) in sub-toxic concentration on apoptosis of human ovarian cancer HO-8910 cells in vitro and unravel the associated mechanisms. Methods: Human ovarian cancer HO-8910 cells were cultured in vitro. The inhibitory effect of CAS combination with DDP in sub-toxic concentration on viability of human ovarian cancer HO-8910 cells was evaluated by the MTT assay. Morphological changes of cell apoptosis were detected by Hoechst 33258 staining assay. Cell apoptosis rate was analyzed by flow cytometry. The protein expression level was analyzed by Western blot. Results: CAS in sub-toxic concentration and DDP in sub-toxic concentration could slightly inhibit Human ovarian cancer HO-8910 cells, but CAS combination with DDP in sub-toxic concentration significantly inhibited the growth of HO-8910 cells, and growth inhibition rate was increased drastically compared with the control group (P﹤0.01), and the inhibiting effect showed synergistic action. Human ovarian cancer HO-8910 cells showed the typical morphological changes of apoptosis and apoptosis rate markedly increased when they were exposed to CAS combination with DDP in sub-toxic concentration for 48 h. Western blot showed that the expression of bcl-2 protein was down-regulated and protein level of caspase-3 was activated by CAS combination with DDP in sub-toxic concentration. Conclusion: CAS combination with DDP in sub-toxic concentration could inhibit the cells growth and lead to cell apoptosis in human ovarian cancer HO-8910 cells. And the down-regulation of bcl-2 protein expression and activation of caspase-3 protein might contribute to CAS combination with DDP in sub-toxic concentration in human cancer HO-8910 cells.

Role of calcium and magnesium infusion in prevention of oxaliplatin neurotoxicity. A phase III trial

Objective： This study is a prospective randomized, double-blind, placebo-controlled study to evaluate the effect of calcium and magnesium （Ca/Mg） infusion on amelioration of oxaliplatin neuropathy, the dose-limiting toxicity. Methods： Sixty patients with resected colorectal carcinoma （CRC） planned to receive adjuvant oxaliplatin-containing regimen were randomly assigned to two arms; Arm A： patients received Ca/Mg were given as 1 gm Ca gluconate and 1 gm MgSO4 in 250 mL of intravenous （IV） solution over 30 rain pre and post oxaliplatin infusion, and Arm B： patients received 250 mL of IV solution without Ca/Mg over 30 min pre and post oxaliplatin infusion. Primary outcome was to assess percentage of patients with oxaliplatin-induced neurotoxicity. Neurotoxicity was assessed according to the National Cancer Institute Common Terminology Criteria forAdverse Events （NCI-CTCAE） version 3.0. Results： Sixty patients in both arms were assessed, 30 with Ca/Mg infusion and 30 without. Patients developed neurotoxicity in arm A were significantly lower than that in arm B after the end of treatment; 7 （23.3%） and 14 （46.6%） respectively （P 〈 0.05）, and significantly lower duration of neuropathy in months （8 ± 2.5 vs 18 ±3） respectively （P 〈 0.001）. Conclusion： Use of IV Ca/Mg showed a statistically significant reduction of peripheral neuropathy （PN） in patients with CRC receiving oxaliplatin in the adjuvant settings.

The efficacy and toxicity of modified docetaxel,cisplatin and 5-fluorouracil combination therapy for 27 patients with advanced stage gastric adenocarcinoma

Objective: The aim of this study was to evaluate the efficacy and toxicity of modified docetaxel, cisplatin and calcium folinate (CF)/5-fluorouracil (mDCF) combination therapy for 27 patients with recurrent or metastatic gastric adeno- carcinoma (R/MGC). Methods: From May 2006 to July 2007, 27 R/MGC patients (18 were male and 9 were female) with a median age of 49 years (range19-66) were consecutively enrolled. The mDCF protocol included 50 mg/m2 docetaxel for 1 day and 25 mg/m2 cisplatin on d2-3, 200 mg/m2 CF on d2-3 and 2000 mg/m2 5-fluorouracil (5-FU) CIV (continous infusion) for 46 h on d2-3, repeated every 2 weeks. Results: Twenty-seven patients were evaluable for efficacy and toxicity. A median of 4.5 cycles was given. One complete and 12 partial responses were observed for an overall intent to treat response rate (RR) 48.1% [95% CI (confidence intervals): 32%-64%]. Median time-to-progression (TTP) was 6.2 months and overall survival (OS) was 11.8 months. Twenty-seven (100%) patients experienced bone marrow suppression, and of them 48.9% were Grade 3-4 (16.3% were Grade 4). Two patients (7.4%) ceased chemotherapy because of bone marrow suppression. WHO Grade 1-4 non-hematological toxicity, such as oral mucositis, nausea/emesia, peripheral neuropathy, liver dysfunction, diarrhea, nephrotoxicity and cardiotoxicity, occurred in 59.2%、51.9%, 48.1%, 44.4%, 25.9%, 18.5% and 11.1% patients, respectively, and most of them were Grade 1-2. No patient died due to chemotherapy toxicity. Conclusion: mDCF regimen is effective in treating R/MGC with a high RR and long TTP/OS in this trial. Despite its severe hematotoxicity, this regimen has some advantages such as no cross-resistance with paclitaxel (paclitaxel-resistant patients RR 2/6). These results suggested that the mDCF regimen worth further investigation in clinical study of R/MGC treatment.

Attenuation of cisplatin induced ototoxicity by sound preonditioning through NO pathway

Objective：To explore the protective effect of sound preconditioning against ototoxicity induced by cisplatin and its possible mechanism with respect to the nitric oxide （NO） pathway. Methods： Albino guinea pigs were divided into silent control, CDDP,sound preconditioning and sound preconditioning＋CDDP groups. The animals of the CDDP group were injected with cisplatin intravenously 8 mg/kg b.w. The animals in the sound preconditioning were exposed to white noise at 85dB SPL, 5h/d, for 10 d （sound preconditioning）. The animals in the sound preconditioning＋CDDP group were treated with sound preconditioning first and then administrated with cisplatin intravenously 8 mg/kg b.w. Hearing thresholds of auditory brainstem responses （ABRs） of all animals were measured to evaluate hearing function. Hair cell loss was estimated via surface preparation. Cochlear tissue was assayed for measurement of NO level and immunohistochemistry method was used for inducible nitric oxide synthase （iNOS） analysis. Results： There was no significant difference between the silent control and sound preconditioning animals with respect to either functional or histological measures. Among the animals in the CDDP group, there was a significant elevation of threshold at the high test frequencies after administration compared with the silent control group （P〈0. 05）. Morphological examination showed that there was obvious loss of the OHC, especially in the third row of the basal turn. The NO level and immunoreactivity to iNOS in this group were higher and more intensive than those of the silent control group （P〈0. 05）. The ABR thresholds in the sound preconditioning ＋ CDDP group were much lower than those of the CDDP group （P〈0.05）. Slight sporadic loss of OHC was found in this group. The immunoreactivity to iNOS and the level of NO in cochlea decreased significantly compared with the CDDP group （P〈 0. 05）. Conclusion： It is suggested that sound preconditioning, to some extent, provides protective effect against ototoxicity of cisplatin. The excess synthesis of NO induced by the over-expressed of iNOS may be involved in the CDDP induced ototoxicity. The possible mechanism is related to suppression of the NO pathway.

Clinical observation of nedaplatin concurrent with radiotherapy for mid-advanced nasopharyngeal carcinoma and esophageal carcinoma

Objective: The aim of our study was to evaluate the short-term efficacy and the toxic reaction of nedaplatin concurrent with radiotherapy for mid-advanced nasopharyngeal carcinoma and esophageal carcinoma. Methods: Thirty-four patients were confirmed diagnosis with cancer by pathologic results. All patients were given 6MV X-ray for radiotherapy, Dt 66-70 Gy/33-35 f/6-7 w, concurrently administrated nedaplatin (30 mg/m2) once a week (6 times). Results: A total 34 patients were enrolled, of whom 33 patients were available for objective response, 1 patient of esophageal cancer quit for allergic reaction. The response rate (RR) of nedaplatin-contained therapy for nasopharyngeal carcinoma and esophageal carcinoma were 90.0% and 76.9%, respectively. The major toxic reaction was bone marrow suppression observed in 25 patients (73.5%), in which grade III aleukocytosis was observed in 3 patients (8.8%), grade III + IV thrombocytopenia in 3 patients (8.8%). And 6 patients (17.6%) showed gastrointestinal tract reaction. There were 4 patients with radiation esophagitis in the 13 patients with esophageal carcinoma. Conclusion: Nedaplatin can increase the therapeutic effect of radiation. Its incidence rate of bone marrow suppression is high, but the gastrointestinal tract reaction and renal toxicity is low and mild.

Prediction of nephrotoxicity induced by cisplatin combination chemotherapy in gastric cancer patients

AIM:To evaluate the treatment options for nephrotoxicity due to cisplatin combination chemotherapy.METHODS:We retrospectively reviewed patients who had received cisplatin combination chemotherapy for gastric cancer between January 2002 and December 2008.We investigated patients who had shown acute renal failure(ARF),and examined their clinical characteristics,laboratory data,use of preventive measures,treatment cycles,the amount of cisplatin administered,recovery period,subsequent treatments,and renal status between the recovered and unrecovered groups.RESULTS:Forty-one of the 552 patients had serum creatinine(SCR)levels greater than 1.5 mg/dL.We found that pre-ARF SCR,ARF SCR,and ARF glomerular filtration rates were significantly associated with renal status postARF between the two groups(P=0.008,0.026,0.026,respectively).On the receiver operating characteristic curve of these values,a 1.75 mg/dL ARF SCR value had 87.5%sensitivity and 84.8%specificity(P=0.011).CONCLUSION:Cessation or reduction of chemotherapy should be considered for patients who have an elevation of SCR levels during cisplatin combination chemotherapy.

Radiation therapy concurrent with weekly cisplatin therapy for loco-regionally advanced nasopharyngeal carcinoma:outcomes of a clinical trial

Objective:The purpose of this study was to define the maximum tolerated dose(MTD) by describing the doselimiting toxicity(DLT) of weekly cisplatin concurrently with conventional plus 3-dimensional conformal radiotherapy(CT + 3DCRT) in patients with loco-regionally advanced nasopharyngeal carcinoma(NPC).Methods:Patients with loco-regionally advanced NPC(III/IVa stage) were enrolled into a dose-escalating study.Toxicity was graded according to Common Terminology Criteria for Adverse Events version 3.0(CTCAE v3.0).MTD was defined when 2 of 6 patients developed DLT.The starting dose of cisplatin was 15 mg/m2/w,with a subsequent dose escalation of 5 mg/m2/w in cohorts of 3 new patients.CT + 3DCRT was given to the nasopharynx and the upper neck;the lower neck was treated by a single anterior field irradiation.The prescription dose was 70-80 Gy by 35-40 fractions to the nasopharynx gross tumor,and 66-70 Gy by 33-35 fractions to the positive neck lymph nodes.Results:From Jun.2008 to Sep.2009,24 patients received complete chemoradiotherapy,and all of them were eligible for toxicity evaluation.On the first five dose levels of 15 mg/m2/w and 35 mg/m2/w,no patient experienced DLT.On the next dose level of 40 mg/m2/w,1 patient experienced DLT of grade 3 myelosuppression for 1.4 weeks,and among the additional 3 patients,no one developed DLT.On the seventh dose level of 45 mg/m2/w,all the patients developed grade 3 myelosuppression for more than 1 weeks,and the dose-escalating trial stopped.The 23(95.8%) patients achieved clinical complete remission(CR) in the local site;22(91.7%) achieved CR in the regional site,and all patients got CR 3 months later.After a median follow-up of 16.4 months,1 patient developed liver metastases 2 months later,1 patient developed bone metastases 10 months later and 22 kept disease-free survival.Conclusion:The MTD of cisplatin weekly with concurrent CT + 3DCRT for local advanced NPC is 40 mg/m2/w,with myelosuppression as DLT.

Capecitabine plus cisplatin treatment in patients with advanced hepatocellular carcinoma

Objective： Hepatocellular carcinoma （HCC） is the sixth most common cancer in the world and the third leading cause of cancer related death globally. Parentral treatment of Egyptian patients of bilharziasis contributed to the high incidence of viral hepatitis, and subsequently liver cirrhosis and HCC. CapecJtabJne plus cJsplatJn protocol was evaluated regarding the efficacy and safety in patients with advanced HCC as first line chemotherapy. Methods： One hundred patients with advanced HCC were randomized to receive either capecitabine （1000 mg/m2） twice daily for fourteen days plus intravenous cisplatin （60 mg/m2） on day one to be repeated every three weeks with a maximum of six cycles or placebo （phase III trial）. Results： Baseline characteristics were comparable in both groups. According to Barcelona Clinic Liver Cancer Staging System, stage C was the most predominant （82% vs. 75%） in both groups. Median OS was 12 months versus 10 months in favor of the treated group （P value 〈 0.05）. Median TTP was significantly higher in the chemotherapy group （7 months vs. 4.5 months） as well as disease control rate （40% vs. 29%）, no patient had achieved complete response. Grade 3 toxicity was more pronounced in the treatment group, as regards vomiting and diarrhea （10% vs. 2%）, neurotoxicity （6% vs. 2%）, elevation of aminotransferase and bilirubin （9.8% vs. 4.9%）, hand and foot syndrome reaction was recorded only in chemotherapy group. Conclusion： Capecitabine plus cisplatin regimen showed modest antitumor activity with tolerable toxicity in patients with advanced HCC. Moreover, because of the significantly prolonged time to progression, we demand further attention to this convenient, outpatient, and economic profile based chemotherapy protocol.

Influence of Tamoxifen or the combination of Tamoxifen and Cisplatin on the growth of human lung adenocarcinoma A549 cells

The experiment aims to investigate the influence of Tamoxifen and the combination of Tamoxifen and Cisplatin （DDP） on the growth of human lung adenocarcinoma A549 cells. Methods： We treated human lung adenocarcinoma A549 cells with different concentrations of Tamoxifen, DDP and combination of DDP and Tamoxifen with non-toxicity for 72 h. Then we calculated the inhibition rate through MTT approach and detected the apoptosis rate by flow cytometry. The statistical analysis was performed with SPSS 13.0 software and statistical differences were determined by one-way ANOVA. The data were expressed as the mean ＋ standard deviation and all experiments were performed in three times. The value of P 〈 0.05 was considered to indicate a statistically significant difference. Results： 1. The inhibition rates of Tamoxifen with 2.5 pmol/L, 5 tJmol/L, 10 μmol/L, and 20 μmol/L on the growth of the A549 cells were 18.7%, 25.8%, 54% and 98.8%, respectively （P = 0.000）. Tamoxifen with concentration of 1 μmol/L has no obvious cytoxicity on the A549 cells （P 〉 0.05）. 2. As the increase concentration of Tarnoxifen, the S stage and G2/M of the A549 cells decreased while the G0/G1 increased. The apoptosis rate of Tamoxifen with 0 μmol/L, 0.1 μmol/L, 1 μmol/L and 10 μmol/L on the A549 cells were 6.51%, 8.91%, 17.97% and 42.7%, respectively. 3. The inhibition rates of combination of Tamoxifen with 1 μmol/L and DDP with 1.25 μg/mL, 2.5 μg/mL, 5 μg/mL, 10 μg/mL and 20 μg/mL on the A549 cells were 40.4%, 54.4%, 72.9%, 86.1% and 92.4%, respectively （P 〈 0.05）. Conclusion： Tamoxifen can inhibit the proliferation of human lung adenocarcinoma A549 cells and induce the apoptosis of the A549 cells. The combination of Tamoxifen with non-toxicity and DDP can improve the sensitivity of chemotherapy on the A549 cells.

Induction of apoptosis of human ovarian cancer cells by SGI-1776 combination with DDP in sub-toxic concentration in vitro

Objective： The aim of the study was to investigate the effect of SG1-1776 combination with DDP in sub-toxic concentration on induction of apoptosis of human ovarian cancer HO-8910 ceiis in vitro and to unravei the associated mechanisms. Methods： Human ovarian cancer HO-8910 cells were cultured in vitro. The inhibitory effect of SG1-1776 combination with DDP in sub-toxic concentration on induction on viability of human ovarian cancer HO-8910 cells was evaiuated by the MTT assay. Cell apoptosis rate was analyzed by flow cytometry. The proteins expression level related to apoptosis were analyzed by Western blot. Results： SG1-1776 combination with DDP in sub-toxic concentration significantiy inhibited the proliferation of human ovarian cancer HO-8910 cells, and proliferation inhibition rate was increased drastically compared with normai saline （NS） group or DDP group in sub-toxic concentration or SG1-1776 group in sub-toxic concentration （P 〈 0.01）. Apoptosis rate markedly increased after the treatment of SG1-1776 combination with DDP in sub-toxic concentration for 48 h. Western blot showed that the expression of bcl-2 protein was down-regulated and protein level of Bax and Cyto-c were depressed by SG1-1776 combination with DDP in sub-toxic concentration. Cenclusion： SG1-1776 combination with DDP in sub-toxic concentration could inhibit the cell proliferation and lead to cell apoptosis inhuman ovarian cancer HO-8910 cells, and its mechanism may be related to through mitochondrial apoptotic pathway.

Observe the efficacy of the air wave pressure therapeutic equipment in treatment of oxaliplatin nerve toxicity

Objective： The aim of this study was to observe the efficacy of air wave pressure therapeutic equipment in pre- vention of oxaliplatin-inducted neurotoxicity. Methods： Forty-five patients with colorectal cancer were randomly divided into treatment group and control group, treatment group were given the treatment of air wave pressure therapeutic equipment during chemotherapy with oxaliplatin, the control group were given preventive treatment, the oxaliplatin-inducted neurotoxicity was evaluated after each cycle of chemotherapy. Evaluate the chemotherapy efficacy after the third cycle and sixth cycle of chemotherapy. Results： The treatment group have lower incidence of peripheral nerve toxicity than the control group, the difference was statistically significant （X2= 13.93; P 〈 0.01）. Chemotherapy effect between the 2 groups was no significant difference （P 〉 0.05）. Conclusion： Treatment with air wave pressure therapeutic equipment can reduce the incidence of peripheral nerve toxicity during oxaliplatin chemotherapy.

Nrf2/ARE signaling protects against oxaliplatin-induced hepatotoxicity in mice

Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts （MEFs） and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2-/- mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-induced hepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.