经门静脉途径灌注化疗时5-Fu在肝脏和血液中的浓度和药动学特点

目的研究经门静脉途径灌注化疗时5-Fu在肝脏和血液中的浓度和药动学特点,并与外周静脉注射化疗相比较,探讨区域性门静脉灌注化疗的优势。方法 24只Wistar大鼠随机分组后分别经门静脉插管区域灌注及经外周静脉注射5-Fu,剂量均为20 mg/kg。采用高效液相色谱法(HPLC)测定两组给药后5、10、20、30、45、60、90、120、180 min不同时间点血浆和肝脏组织中5-Fu的浓度,对比两组5-Fu在肝脏和血浆中的药动学数据。对比两组的穿透比率、穿透指数及治疗优势度。结果经外周静脉注射5-Fu时,肝脏组织中的药物峰浓度(Cmax)和药物时量曲线下面积(AUC)分别为(13.79±4.56)μg/g及(342.20±108.20)μg·h/ml;血浆中的Cmax和AUC分别为(36.85±5.96)μg/g及(842.00±158.00)μg·h/ml。经门静脉灌注时,肝脏组织中的Cmax和AUC分别为(28.21±4.46)μg/g及(733.60±180.30)μg·h/ml;血浆中的Cmax和AUC分别为(21.02±4.06)μg/g及(529.80±111.50)μg·h/ml。门静脉灌注化疗与外周静脉注射相比的治疗优势度为3.37。结论与外周静脉注射全身化疗比较,区域性门静脉灌注5-Fu化疗可显著提高肝脏组织中的药物时-量作用强度,同时减少化疗药物在外周血中的分布,可作为肝癌化疗有效的给药途径     

超选择子宫动脉与外周静脉灌注化疗宫颈癌组织内铂浓度的研究

目的:对比卡铂超选择子宫动脉与外周静脉灌注化疗子宫颈癌组织内的药物浓度。方法:选择经病理活组织证实为宫颈癌、且癌灶较大易于取材的患者13例,随机分为超选择子宫动脉灌注化疗组(A组)和外周静脉灌注化疗组(B组),以卡铂300mg/m2,一次性给药。在灌注后0min、10min、20min分别钳取宫颈癌组织,用原子吸收光谱法测定其标本内铂离子浓度。结果:(1)峰值及曲线形态:A组癌组织铂离子浓度的高峰值出现在化疗结束后即刻,且随时间的延长而快速下降,呈一下降曲线;B组峰值出现在化疗后10分钟,随时间的延长呈一弓背向上的下降曲线。前者的峰值是后者的2.79倍,差异有统计学意义(P<0.05)。(2)灌注化疗结束后即刻,A组宫颈癌组织内铂离子浓度是B组的3.75倍,差异有统计学意义(P<0.05)。(3)A组癌组织内铂离子药时曲线下面积(AUC0～20min)是B组的2.10倍,差异有显著意义(P<0.05)。结论:无论癌组织内铂离子峰浓度还是AUC0～20min,超选择子宫动脉灌注化疗组均较外周静脉组明显增高,为评价动脉化疗疗效提供了基础理论依据及临床药代动力学参数。     

顺铂—乙基纤维素微球动脉灌注治疗舌癌药代动力学研究

以家兔为实验动物，在实验基础上对晚期舌癌病人进行舌动脉顺铂＝乙基纤维素微球动脉灌注化疗，普通顺铂作对照，对动物及人体血浆和组织中铂的浓度进行检测。结果：ＤＤＰ－Ｍｃ具有峰值不高，但较高的药物浓度却能国长时间地保持于组织中，提高了药物在局部组织中的含量和处长药物在组织中的滞留时间。     

用于肺癌治疗的带缓释化疗药栓塞装置在动物体内的特性研究

目的研究用于肺癌治疗的带缓释化疗药栓塞装置,在动物体内的栓塞、药物释放特性及对羊肺组织的影响,评价其应用的可行性.方法用镍-钛记忆合金支架、Ivalon泡沫海棉及顺铂制备栓塞装置.采用萨能妈山羊12只,随机分为带药栓塞组和灌注组(对照组),每组6只.带药栓塞组在介入下于右下肺动脉置入带缓释化疗药(顺铂2 mg/kg)的栓塞装置,并造影,然后开胸置右下肺静脉抽血管,对照组在开胸下置右下肺静脉抽血管后行右下肺动脉灌注顺铂(2 mg/kg),两组术后均定时抽血测右下肺静脉及外周血顺铂浓度、外周血气和血常规,3天后处死动物行病理解剖.结果带药栓塞组栓塞即刻造影肺动脉均未完全阻塞,3天后造影及处死后解剖均见已完全阻塞,栓塞后动物无明显并发症,带药栓塞组1、2、8 h测得的肺静脉血药浓度均高于灌注组(P＜0.05),其曲线下面积也高于肺脉灌注组(P＜0.05),而外周血顺铂浓度大多均未高于肺动脉灌注组.结论此装置可以经介入的方法置入肺动脉内,栓塞后对动物羊肺组织的影响小,有利于提高肺组织局部药物的浓度,同时能降低外周血循环中的药物浓度.     

比较卡铂盆腔动脉化疗栓塞与单纯动脉灌注化疗的动物实验研究

背景与目的:动脉灌注化疗与动脉栓塞可提高肿瘤组织局部药物浓度和延长药效时间,但哪一种方法在临床药代动力学上更有优势,目前尚无定论.本研究的目的是比较超液态碘油卡铂盆腔动脉化疗栓塞与卡铂单纯动脉灌注化疗后,犬子宫组织及血浆中铂(Pt)离子浓度的分布.方法:选择实验用雌犬14只,随机分为盆腔动脉化疗栓塞组(A组)7只和盆腔动脉单纯灌注组(B组)7只.A、B组分别将卡铂(12 mg/kg)溶于超液态碘油(0.2 ml/kg)和5%葡萄糖(0.2 ml/kg)中,注入双髂内动脉.然后在不同的时间点分别取子宫组织及静脉血,用原子吸收光谱法测定上述标本内的Pt离子浓度.结果:(1)A、B两组子宫组织Pt离子浓度曲线均为单峰曲线,峰值分别为(215.0±17.6)μg/g和(211.3±40.1)μg/g,两组无显著性差异(P＞0.05).(2)A、B两组子宫组织Pt离子药时曲线下面积(AUC0～240min)分别为(13.9±3.9)mg·min·g-1和(5.9±0.6)mg·min·g-1,两组有显著性差异(P＜0.01).(3)A、B两组血浆中Pt离子峰值分别为(8.7±12.5)μg/g和(16.7±3.6)μg/g,AUC0～240min分别为(0.5±0.1)mg·min·g-1和(1.2±0.4)mg·min·g-1,均有显著性差异(P＜0.01).结论:与卡铂单纯动脉灌注化疗相比,动脉化疗栓塞能有效提高并保持局部组织内的Pt浓度,降低血浆中Pt浓度,从而提高局部化疗效果、降低全身毒副作用.     

热灌注联合化疗治疗恶性胸腔积液54例

 目的　观察用大剂量长时间的温热生理盐水灌注加局部化疗药物灌注治疗恶性胸腔积液的疗效。方法　将54例随机分为热灌注＋局部化疗药物灌注组（A组）及单纯抽液＋局部化疗药物灌注组（B组）； A组采用加热至45 ℃ 5000 ml生理盐水做胸腔内持续灌注100 ~ 120 min，5 ~ 7 d后再行灌注1次，然后注入冻干顺铂等化疗药物，B组仅行胸腔抽液，再注入冻干顺铂等化疗药物。结果　A组总有效率为 92.6 %，B组为51.8 %，两组差异有统计学意义（P＝0.0085）。结论　用热灌注法治疗恶性胸腔积液，能明显提高恶性胸腔积液的疗效，不良反应小。     

经不同途径区域灌注氟尿嘧啶在肝癌、肝组织及血浆中的浓度差异

背景与目的:肝动脉、肝门静脉灌注区域化疗是肝癌的重要治疗手段,本研究探讨区域性灌注化疗时氟尿嘧啶(fluorouracil,5-FU)在大鼠肝癌和肝脏组织及血浆中的分布,为临床肝脏肿瘤化疗提供参考。方法:将24只荷瘤大鼠随机分为4组,分别经外周静脉(尾静脉)、肝动脉、肝门静脉或结扎肝动脉后经肝门静脉灌注5-FU,剂量为20 mg/kg。采用高效液相色谱法测定肝癌、肝脏组织及血浆中5-FU的含量,并计算药物在血浆、肝脏和肝癌组织间的穿透比率。结果:结扎肝动脉的肝门静脉组5-FU浓度在肝脏和肝癌组织中最高,分别为(22.1±9.5)μg/g和(16.4±7.2)μg/g;其次为肝动脉组;肝门静脉组5-FU浓度在肝癌组织中的浓度较低,为(8.9±3.7)μg/g;外周静脉组5-FU浓度在肝脏和肝癌组织中的药物浓度均为最低,肝癌组织中的浓度仅为(4.3±2.2)μg/g。在血浆中的5-FU浓度正好相反,外周静脉组浓度最高(26.8±12.5)μg/m L,肝动脉组(16.4±9.7)μg/m L、结扎肝动脉的肝门静脉组(15.9±10.1)μg/m L和肝门静脉组(14.9±8.5)μg/m L等3组浓度相近,均明显低于外周静脉组(P<0.05)。5-FU的肝癌/血浆穿透比率依次为结扎肝动脉的肝门静脉组(103.47%),肝动脉组(92.94%),肝门静脉组(59.58%)和外周静脉组(16.08%)。结论:与外周静脉注射全身化疗比较,区域性灌注化疗可显著提高肝癌和肝脏组织中的药物浓度,同时减少化疗药物在外周血中的分布,其中经结扎肝动脉的肝门静脉灌注和经肝动脉灌注是肝癌区域性化疗2种较好的途径。     

超选择子宫动脉与外周静脉灌注化疗宫颈癌组织内铂浓度的研究

目的：对比卡铂超选择子宫动脉与外周静脉灌注化疗子宫颈癌组织内的药物浓度。方法：选择经病理活组织证实为宫颈癌、且癌灶较大易于取材的患者13例，随机分为超选择子宫动脉灌注化疗组（A组）和外周静脉灌注化疗组（B组），以卡铂300mg／m^2，一次性给药。在灌注后0min、10min、20min分别钳取宫颈癌组织，用原子吸收光谱法测定其标本内铂离子浓度。结果：（1）峰值及曲线形态：A组癌组织铂离子浓度的高峰值出现在化疗结束后即刻，且随时间的延长而快速下降，呈一下降曲线；B组峰值出现在化疗后10分钟，随时间的延长呈—弓背向上的下降曲线。前者的峰值是后者的2．79倍，差异有统计学意义（P〈0．05）。（2）灌注化疗结束后即刻，A组宫颈癌组织内铂离子浓度是B组的3．75倍，差异有统计学意义（P〈0．05）。（3）A组癌组织内铂离子药时曲线下面积（AuCo-20min）是B组的2．10倍，差异有显著意义（P〈0．05）。结论：无论癌组织内铂离子峰浓度还是AUC0-20min，超选择子宫动脉灌注化疗组均较外周静脉组明显增高，为评价动脉化疗疗效提供了基础理论依据及临床药代动力学参数。     

善得定诱导卡铂腹腔淋巴化疗的实验研究

 为探讨善得定对腹腔化疗中淋巴药物浓度的影响,对16只兔腹腔注入卡铂50mg十生理盐水100ml,实验组加用善得定,分取门静脉血、外周血、淋巴液,应用原子吸收光谱法测定样本铂浓度.结果显示:实验组淋巴铂浓度达峰后可维持较高水平,其药-时曲线下面积(AUC)显著增加.外周血铂浓度却下降明显.提示:在卡铂腹腔化疗中应用善得定能提高化疗药物在淋巴中的作用效能,达到诱导腹腔淋巴化疗的目的.同时又可进-步减轻化疗药物的全身毒副反应.     

顺铂直接注入大白鼠肺组织的实验研究

选用大白鼠５８只随机分组，对照组鼠肺内局部注入生理盐水，实验组注入大、小剂量不同的顺铂。结果表明：对照组与实验组注射局部均出现不同程度的组织反应（局部充血、水肿、炎性细胞浸润、出血等），以大剂量组反应最重，而且该组大白鼠食量减少，体重下降，全身反应亦最重，小剂量组及对照组则全身反应校轻、体重及食量均增加．大部分大白鼠损伤在注药后４周内恢复，少数大剂量组的大白鼠４周后仍可见间质性肺炎。提示：肺癌患者若局部用顺铂应注意选择药物浓度及间隔时间。     

Reduced systemic drug exposure by combining intraarterial cis-diamminedichloroplatinum(II) with hemodialysis of regional venous drainage

During cancer chemotherapy toxicity to normal tissues often limits the tolerable dose. To increase drug delivery to tumor while maintaining tolerable systemic exposure, regional treatments, such as intraarterial drug delivery, have been used. Despite intraarterial delivery, systemic toxicity often remains the dose-limiting sensitivity. If systemic drug exposure could be reduced after intraarterial infusion, the intraarterial dose could be increased, which should increase the therapeutic response. We compared the pharmacokinetic advantage after cisplatin infusion into the internal carotid artery to that obtained after infusing cisplatin into the internal carotid artery during extracorporeal removal of cisplatin from the jugular blood by hemodialysis. Four patients with malignant gliomas received intracarotid cisplatin, 100 mg/m2 over 60 min, every 4 weeks. During one treatment, while cisplatin was infused into the internal carotid artery, the jugular blood was dialyzed extracorporeally at 300 ml/min and returned to the inferior vena cava. Seventy to 96% of the free platinum that entered the dialyzer was removed. By aspirating blood from the jugular vein at 300 ml/min, 30-79% of the ipsilateral carotid blood was collected for extracorporeal circulation. Hemodialysis of the cerebral venous drainage during intracarotid infusion reduced the systemic exposure to cisplatin by 51-61% when compared to the exposure from internal carotid artery infusion without hemodialysis. The pharmacokinetic advantage (brain/body exposure ratio) was increased from 3 to 5/1 during internal carotid artery infusion alone to as much as 15/1 during treatment combining intracarotid infusion with hemodialysis of the jugular blood. Systemic toxicity now limits the dose of cisplatin that can be administered safely. Increased tumor exposure without increased systemic toxicity may be possible with the technique described and greater doses of cisplatin. Assuming no associated local toxicities, the results of the current study indicate that the dose of intracarotid cisplatin can be increased while maintaining tolerable systemic exposure.     

Reduced ability to clear ultrafilterable platinum with repeated courses of cisplatin

Ultrafilterable plasma and urinary levels of platinum were quantitated for 24 hours after the first- and fourth-course infusion of cisplatin (CDDP) to seven patients. Four patients received 80 mg/m2 and three patients received 100 mg/m2 CDDP as a 2-hour infusion. The area under the curve (AUC) of ultrafilterable platinum, average renal clearance (CIR) of ultrafilterable platinum, and percentage of the platinum dose excreted in urine (% E) were determined for each infusion over the 26-hour period of the study. The AUC was higher in all patients after the fourth-course infusion, with a median increase of 74%. The median CLR was 494 mL/min (range, 214 to 996 mL/min) for the first course and decreased to 156 mL/min (range, 108 to 271 mL/min) for the fourth-course infusion (P less than .02). The median % E was 29.2% (range, 19.6% to 37.7%) for the first course and decreased to 19.9% (range, 12.4% to 25.9%) for the fourth-course infusion (P less than .02). There was no difference in creatinine clearance for the two infusions (median, 94 mL/min; P greater than .05). Urinary excretion of B2-microglobulin (B2-MG) and N-acetyl-B-glucosaminidase (NAG) was highly variable between patients and did not provide a useful predictor of changes in renal function. Four courses of CDDP therapy resulted in significantly reduced renal elimination of platinum in patients, probably through a reduction in the secretion of the drug in the proximal tubule of the kidney. The results suggest that increased antitumor effect and toxicity could occur in patients receiving sequential courses of cisplatin.     

Administration in a hypotonic solution is preferable to dose escalation in intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in rats.

An animal model of intraperitoneal (i.p.) cisplatin chemotherapy using hypotonic solutions of sodium chloride has been developed as a treatment for peritoneal carcinomatosis. The concentrations of platinum in the plasma and in the i.p. fluid of Donryu rats were measured after i.p. injection of hypotonic (103 or 154 mosm/l) and isotonic (308 mosm/l) solutions that contained an equal amount of cisplatin. The maximum concentration (Cmax) and the area under the curve of concentration versus time (AUC) of platinum in the plasma increased proportionately with increases in the dose of cisplatin and they were significantly higher in rats given cisplatin in hypotonic solutions than in those given the drug in isotonic solution. The Cmax and AUC of total platinum were similar for the solution of 103 mosm/l with 2.5 mg/kg cisplatin and the isotonic solution with 5.0 mg/kg cisplatin. The Cmax and AUC of free platinum in the plasma did not increase with increases in the dose of cisplatin in isotonic solution but did increase after hypotonic injection. However, the solutions of lower osmolarity gave a decreased AUC of platinum in the i.p. fluid. Hypotonic conditions continued for 30 min at most after i.p. injection of hypotonic solutions. When the same dose of cisplatin was given to rats with tumors derived from AH100B carcinoma cells, the amount of platinum taken by i.p. solid tumors from the solution of 103 mosm/l was about twice that from the isotonic solution and was much the same as that taken up from the isotonic solution with twice the amount of cisplatin. These results indicate that hypotonic i.p. cisplatin chemotherapy might be preferable to escalation of the dose of i.p. cisplatin in the treatment of peritoneal carcinomatosis.     

Comparison of antiemetic activity of chloropromazine and high doses of metoclopramide in cisplatin-based chemotherapy

High dose metoclopramide and different phenothiazines are widely used antiemetics in cancer patients receiving chemotherapy. In a prospective randomized study we compared the antiemetic efficacy of high dose metoclopramide (M) and chloropromazine (C). We also tested the role of dexamethasone (D) when combined with either of these drugs. A total of 165 patients were randomly allocated to 5 groups with 33 patients in each group. Group A received only M, group B: M + D, group C: C + D, group D: M + D + C and group E: M + C. All patients received combination chemotherapy with cisplatin for the first time and were evaluated only once in order to exclude anticipatory nausea and vomiting. Patients in group C had less antiemetic protection than the other groups (p less than 0.001). Groups A, B, D, E, had more or less equal antiemetic efficacy, although the efficacy in group B was somewhat better; this difference was not statistically significant. Side-effects were minimal. Chloropromazine seemed to protect patients who received metoclopramide from extrapyramidal manifestations. In conclusion the results suggest that high dose metoclopramide has a better antiemetic effect than chloropromazine, dexamethasone is a helpful adjuvant drug when used in combination with an effective antiemetic agent, and chloropromazine and dexamethasone may prevent the extrapyramidal side-effects that can occur when metoclopramide is used as single antiemetic drug.     

Pharmacokinetics and pharmacodynamics of serum platinum of gynecologic cancer patients treated with nedaplatin

Nedaplatin (cis-diammine glycolate platinum) is one of the effective platinum agents for gynecologic carcinoma. In order to assess the pharmacokinetics and pharmacodynamics of serum platinum of gynecologic cancer patients treated with nedaplatin, we calculated 10 course AUCs (area under the curve) of the free and total platinum from blood samples of 4 patients. Peak serum platinum concentrations were dependent on infusion times. In the case of a patient with renal dysfunction or ascites, the concentration of serum platinum tended to stay at a high level for a long time. Serum-free platinum ratios were maintained longer than cisplatin. Low dose nedaplatin administration and divided administration were effective, but total AUC was not so great. The relation between AUC ratio (free platinum AUC/total platinum AUC) and dose/m(2) was not clarified.     

Pharmacokinetic study of intralesional cisplatin for the treatment of hepatocellular carcinoma.

BACKGROUND: In the current study the authors examined the pharmacokinetics of direct intralesional injection of cisplatin/epinephrine/bovine collagen gel in patients with hepatocellular carcinoma and cirrhosis. METHODS: Six patients with cirrhosis and unresectable hepatocellular carcinoma received a direct intralesional injection (range, 6.7-26.7 mg) into their tumors under ultrasonographic guidance. The authors determined the total cisplatin (Pt) concentration in the plasma and urine and nonprotein-bound free Pt in plasma ultrafiltrate using flameless atomic absorption spectrometry. Data from individual patients were analyzed to calculate the pharmacokinetic parameters via a noncompartmental method for constant infusion. To demonstrate that the changes in pharmacokinetics are not related to the underlying cirrhosis, a similar methodology was applied to measure the pharmacokinetic parameters of four similar patients who were treated with cisplatin, 75 mg/m(2), as a 1-hour intravenous infusion. RESULTS: The time to attain maximum concentration of total Pt after intralesional injection was dose-dependent and ranged from 2-13 hours. The concentration-time curve was biphasic in nature. The initial half-life of total Pt in patients who received an intralesional injection varied with the cisplatin dose. The initial half-life for cisplatin doses < 15 mg was approximately 9 hours and the initial half-life at higher cisplatin doses (> 15 mg) was approximately 25 hours. The area under the curve (AUC) was dose-dependent with values ranging from 38-150 microm/mL x hour. Pharmacokinetic parameters for free Pt (ultrafiltrate) were significantly different. The time to attain maximum concentration (t-max) and terminal half-life were shorter and the average AUC was approximately 100-fold lower than total Pt. After the intravenous infusion of cisplatin, the t-max for total and free Pt was 1.3 hours and 1.1 hours, respectively. The terminal half-life and average AUC for total Pt was 194 hours and 247 microg/mL per hour, respectively, and its corresponding parameters for free Pt after intravenous infusion were much lower, similar to the findings for the intralesional injection. CONCLUSIONS: The prolonged t-max and initial half-life noted with the intralesional injection of cisplatin/epinephrine/collagen gel are consistent with its proclaimed ability to retain cisplatin at the tumor and delay its release in systemic circulation. The kinetics of intralesional cisplatin injection also suggest local sequestration of the drug in the injected site. Parameters of intravenous cisplatin infusion in cirrhotic patients are similar to those of patients from the historic control group.     

Phase I and pharmacological study of an oxaliplatin and carboplatin combination in advanced malignancies.

BACKGROUND: Phase I and pharmacokinetic study to determine the maximal tolerated dose and the recommended dose, as well as the optimal sequence of a carboplatin/oxaliplatin combination delivered every 3 weeks. PATIENTS AND METHODS: Patients received either carboplatin [area under the curve (AUC)-based individually calculated dose (starting dose AUC 4 mg.min/ml), 1 h intravenous (i.v.) infusion] followed by oxaliplatin (110 mg/m(2), 2 h i.v. infusion), every 3 weeks, or the reverse sequence. RESULTS: Sixteen patients were included and only one dose level was assessed. In group A, 10 patients received 23 cycles of carboplatin followed by oxaliplatin. In group B, 6 patients received 20 cycles with the reverse sequence. Delayed recovery from hematological toxicities was treatment-limiting, with mainly moderate thrombocytopenia and neutropenia as dose-limiting toxicities for group A (5 of 10 patients for each) and thrombocytopenia for group B (3 of 6 patients). No febrile neutropenia or grade 3/4 non-hematological toxicity occurred. Pharmacokinetic analysis showed similar mean total platinum AUCs for the two groups: 37.2 +/- 13.7 and 33.6 +/- 9.9 mg.h/l, respectively. One complete response and two partial responses (World Health Organization-International Union Against Cancer criteria, response rate 18.8%) were seen in ovarian, Fallopian and neuroendocrine carcinomas, respectively. CONCLUSIONS: This platinum combination appears feasible and active at the dose of AUC 4 mg.min/ml for carboplatin (Chatelut formula) and oxaliplatin 110 mg/m(2); however, it does not allow a significant increase in platinum dose-intensity delivery.     

Phase I study and pharmacological analysis of cis-diammine(glycolato)platinum (254-S; NSC 375101D) administered by 5-day continuous intravenous infusion

A phase I study of cis-diammine(glycolato)platinum (254-S; NSC 375101D) was conducted in 15 patients with refractory or relapsing malignancy by 5-day continuous i.v. infusion. Three to 5 patients per dose were given 50, 75, 87.5, or 100 mg/m2/120 h (10-20 mg/m2 daily for 5 days). Toxicity evaluation and pharmacokinetic analysis were performed in 15 and 14 patients, respectively. Thrombocytopenia and neutropenia were the dose-limiting toxicities at the maximum tolerated dose of 87.5 mg/m2/120 h (17.5 mg/m2/day); however, nonhematological toxicities including renal toxicity, nausea and vomiting, and peripheral neuropathy were mild and well tolerated. The nadir of platelets and neutrophils was observed 4 and 5 weeks, respectively, after the initiation of drug infusion. Plasma and urine samples were obtained during and after infusion for quantification by atomic absorption spectrophotometry of total and free platinum levels derived from 254-S. The maximum level of total platinum was obtained after 120 h of infusion, whereas the steady state concentration of free platinum in the patients given 75 mg/m2 or more was over 0.1 microgram/ml. Free platinum levels declined monophasically, with half-lives of 0.65-2.56 h/100 mg/m2 dose. The mean area under the concentration versus time curve (AUC) in the patients treated with 75 mg/m2 was 1069 micrograms/ml, which was similar to that obtained in the patients receiving 100 mg/m2 of 254-S by i.v. drip infusion over 30 min. There was a direct correlation between the dose administered and the AUC of platinum (R = 0.757, P = 0.002) or the steady state plasma concentration of free platinum (R = 0.763, P = 0.002). The percentage of platinum excreted in urine 144 h after the initiation of infusion ranged from 73.1 to 100% for each dose level. No significant relationship was established between creatinine clearance in patients before treatment and the AUC or steady state concentration of free platinum. The plasma platinum AUC showed a linear correlation with the percentage of change in leukocytes [formula: see text] (R = 0.736, P = 0.003). In conclusion, the recommended phase II dose for a continuous infusion of 254-S is 75.5 mg/m2/120 h every 6 hours.     

培美曲塞二钠联合洛铂或顺铂在晚期肺腺癌中的疗效观察

目的：比较洛铂和顺铂联合培美曲塞二钠治疗晚期肺腺癌的近期疗效及不良反应。方法65例晚期肺腺癌患者,随机分为2组,A组为顺铂联合培美曲塞二钠,共32例;B组为洛铂联合培美曲塞二钠,共33例。 A组常规水化利尿处理,培美曲塞二钠500 mg／m2,滴注10 min,培美曲塞给药结束30 min后再给予顺铂滴注,顺铂75 mg／m2滴注超过2 h,21天为1个周期。 B组培美曲塞二钠500 mg／m2,滴注10 min,后静脉滴注洛铂30 mg／m2,21天为1个周期。2组常规预服地塞米松（或相似药物）并接受叶酸和维生素B的补充治疗。每周评价一次不良反应,2个周期后评价近期疗效。结果2组治疗近期客观有效率比较,差异无统计学意义（χ2＝0．373,P＞0．05）;A、B组骨髓抑制导致白细胞减少率分别为87．50％和81．82％,且白细胞减少均以Ⅰ～Ⅱ度为主。血小板减少A组发生率为71．88％,而B组为84．85％,也是均以Ⅰ～Ⅱ度为主。恶心呕吐发生率A组为90．63％,B组为72．73％,通过比较,差异有统计学意义（P＜0．05）。结论洛铂联合培美曲塞二钠疗效较好,不良反应较小且易控。     

Supraophthalmic carotid infusion with low dose cisplatin and BCNU for malignant glioma

Summary Arterial infusion of select chemotherapeutic agents has been shown to deliver increased drug concentration to brain tumors with reduced systemic toxicity. In this study, nine patients with histologically confirmed malignant glioma received cisplatin 110 mg and BCNU 300 mg fixed dose. All patients had received standard doses of cranial radiation after their initial surgical procedures. In three patients, intraoperative modification of the cerebral circulation was accomplished prior to the actual infusion because the vascular supply of the tumor arose from major arteries other than a single internal carotid artery. Supraophthalmic catheterization technique was employed. No neurological deficits occurred post infusion. The radiographic response rate was 25%. No responses were seen in patients who received less than 69 mg/M² cisplatin this combination. The longest survival is 11+ months in a patient with anaplastic astrocytoma. Our first thirteen patients received cisplatin 150–200 mg and BCNU 300 mg for each infusion with a response rate of 83% in evaluable patients. Since modest reduction in cisplatin dose dramatically reduced the response rate, future studies should be directed at fine tuning the dose of this drug, or at neutralizing recirculating drug after its high dose first pass through the arterial circulation.