四氢叶酸钙对大剂量甲氨蝶呤化疗大鼠肠黏膜保护作用的研究

目的探讨不同剂量和时间四氢叶酸钙(calcium5-formyltetrahydrofolate,CF)对大剂量甲氨蝶呤(high-dose methotrexate,HDMTX)化疗大鼠肠黏膜的保护作用。方法实验分两部分,均分5组,设正常对照组(A组,腹腔注射生理盐水),和空白对照组(B组,腹腔注射MTX,不予CF解救)。第一部分:不同剂量CF对HDMTX化疗大鼠肠黏膜的保护作用。C组:1%CF解救组;D组:2%CF解救组;E组:8%CF解救组(百分数为CF总量占MTX的百分比)。C、D、E组腹腔注射MTX,于注射后12h肌注CF,A、B组肌注生理盐水,6小时一次,共7次。第二部分:不同时间CF对HDMTX化疗入鼠肠黏膜的保护作用,C组:12h解救组;D组:24h解救组;E组:30h解救组。C、D、E组腹腔注射MTX。C、D、E组分别于腹腔注射HDMTX后12、24、30h予肌注CF,CF总剂量为MTX的5%;A、B组于腹腔注射后24h分别肌注生理盐水,各组均6小时一次,共7次。于腹腔注射后78h处死存活大鼠,取空肠标本观察形态,测定绒毛长度和隐窝深度。结果两部分均A组肠壁厚弹性好,绒毛密集、排列整齐,B、C、D、E组肠壁充血水肿变薄,和A组比较,小肠绒毛变短,隐窝深度变浅,差异有统计学意义(P<0.05);第一部分B、C组改变较D、E组更明显(P<0.05);C组与B组比较差异无统计学意义(P>0.05);D组与E组比较差异无统计学意义(P>0.05)。第二部分B、E组改变较C、D组更显著(P<0.05);B组与E组比较差异无统计学意义(P>0.05);C组与D组比较差异无统计学意义(P>0.05)。结论CF对HDMTX所致大鼠肠黏膜损害有保护作用;其保护作用存在剂量和时间依赖性。     

不同时间四氢叶酸钙解救对大剂量甲氨喋呤化疗导致的大鼠肠黏膜损伤保护作用的研究

目的 观察不同时间四氢叶酸钙(CF)解救对大剂量甲氨喋呤(HD-MTX)化疗导致的大鼠肠黏膜组织形态学的改变、病死率及腹泻情况,探讨CF使用的适宜时机.方法 6周龄Wistar大鼠分5组.A组:正常对照组;B组:空白对照组;C、D、E组:实验组,分剐于腹腔注射HD-MTX后12、24、30h予以CF解救.观察各组大鼠病死率、腹泻情况及空肠大体形态,标本测肠黏膜绒毛长度和隐窝深度.结果 A组无腹泻,B、C、D、E组第2天开始出现腹泻,第3天全部出现腹泻,其中B、E组腹泻严重.A组肠壁无充血水肿,B、C、D、E组肠壁充血水肿变薄,其中B、E组最重.A组无死亡,C、D组各死亡3只,E组死亡4只,B组死亡6只.B、C、D、E组肠黏膜绒毛变短,肠隐窝变浅,与A组比较差异有统计学意义(P<0.05);C、D组与B组比较差异有统计学意义(P<0.05);B、E组间差异无统计学意义(P>0.05).结论 HD-MTX可致大鼠严重肠黏膜损伤,适宜时间CF解救可减轻HD-MTX对大鼠肠黏膜的损伤,但不能完全阻止其损伤.     

用甲氨蝶呤血浆浓度指导四氢叶酸钙解救的可行性

目的了解根据甲氨蝶呤(MTX)血浆浓度指导四氢叶酸钙(LCV)解救的可行性。方法18例患儿随机接受3种大剂量甲氨蝶呤(HD-MTX)方案共43例次。1 g/m2静滴36 h、3 g/m2和5 g/m2静滴24 h分别为14、16和13个疗程。荧光偏振免疫法测定MTX血浆水平。3组均用MTX血浆水平指导LCV解救。结果3组间稳态血浆水平(CpSS)、LCV解救总量比较有统计学意义(P<0.05),HD-MTX的CpSS、LCV总量随MTX剂量增加而增加。3组平均LCV/MTX值均<3%。患者均无不可逆的毒性反应发生。结论以MTX血浆水平指导LCV解救,3组解救开始时间推迟、剂量减少,毒副反应无显著增加,用MTX血浆质量浓度指导LCV解救方案是可行的。     

大剂量甲氨蝶呤治疗急性淋巴细胞白血病中甲酰四氢叶酸钙解救的研究进展

急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)是儿童时期常见的血液系统恶性肿瘤,大约占儿童急性白血病的80％[1].随着诊断分型技术的提高以及治疗方案的改进,目前ALL患儿长期无事件生存率(event-free survival,EFS)高达90％[1].系统化疗是各项治疗手段的...     

大剂量甲氨蝶呤化疗中应用甲酰四氢叶酸解救的研究

研究减少大剂量甲氨喋呤-四氢叶酸钙（ＨＤＭＴＸ－ＣＦ）疗法中ＣＦ用量的可行性。方法：对１７例病人的８６例次ＨＤＭＴＸ－ＣＦ采用两种不同的ＣＦ解救剂量,对ＨＤＭＴＸ常见的毒副作用一粘膜损害、肝、肾损害及骨髓抑制等进行观察对比。结果：在加强水化、碱化的条件下减少ＣＦ的解救剂量未增加以上各种毒性作用,病人的耐受性很好。结论：本文中所采用的减少ＣＦ剂量的ＨＤＭＴＸ－ＣＦ解救方案是切实可行的。     

不同首剂量四氢叶酸钙对氨甲喋呤治疗急性淋巴细胞白血病毒副作用的影响

强烈化学治疗(简称化疗)是当前治疗小儿急性淋巴细胞白血病的主要方法,定期大剂量氨甲蝶呤(high dose methotrexate,HD-MTX)化疗是预防髓外白血病的重要组成部分。但此方案对正常人体组织损害较大,故用药开始36h后给予四氢叶酸钙(Calcium folinate,CF)解救正常组织。对标准危险组急性淋巴细胞白血病(standard risk acute lymphoblastic leukemia,SR-ALL)患儿行HD-MTX化疗后首剂CF剂量为30mg／m^2或15mg／m^2,以后为15mg／m^2每6小时1次,共6～8次。     

大剂量氨甲蝶呤持续静脉滴注后四氢叶酸钙解救方案的研究

大剂量氨甲蝶呤(HD-MTX)结合四氢叶酸钙(LCV)解救目前已成为治疗儿童急性淋巴细胞白血病(ALL)的重要方案之一。由于LCV与ALL的预后存在相关性,故目前国内外的LCV用量呈减少趋势。我们对1g／m^2MTX持续静脉滴注(简称静滴)36h、3g／m^2和5g／m^2持续静滴24h的3种HD—MTX方案前瞻性地制定了根据MTX血浆浓度进行的个体化LCV解救方案,通过对毒性反应的分析以及与文献的对照了解其临床的可行性。     

大剂量甲氨蝶呤化疗后不同漱口方法预防口腔黏膜损伤的疗效观察

大剂量甲氨蝶呤（HD—MTX）化疗是目前应用最广泛的治疗白血病的方法,是预防急性淋巴细胞白血病髓外白血病和全身强化治疗的重要手段,但也引起了较多严重的并发症。HD—MTX化疗后除骨髓抑制外,最大的副作用是黏膜损伤,出现口腔黏膜感染,影响进食和服药,进而影响肿瘤治疗效果。通过对23例应用HD—MTX化疗患儿采用不同口腔护理液,观察口腔黏膜损伤程度,以期找到一种有效的口腔护理方法。     

富氢生理盐水对小肠缺血再灌注损伤大鼠肠黏膜屏障的保护作用

目的:探讨富氢生理盐水(HRS)对小肠缺血再灌注损伤(IIRI)大鼠肠黏膜屏障的影响。方法:将24只8周龄健康雄性SD大鼠按随机数字表法分为3组(每组8只)：假手术组、模型组和HRS组。HRS组大鼠在小肠缺血第30分钟时腹腔注射HRS(10 mL/kg);模型组大鼠在相同时间点腹腔注射9 g/L盐水(10 mL/kg)...     

大剂量甲氨蝶呤化疗中不同水化量与血药浓度的关系

目的探讨不同水化量对大剂量甲氨蝶呤(HD-MTX)血药浓度的影响,以及与不良反应的关系。方法以完成诱导、巩固阶段化疗后拟进入庇护所治疗的ALL患儿和非霍奇金淋巴瘤患儿为研究对象;采用自身对照的设计方案;每例患儿给予3、4次HD-MTX化疗,每例每次5 g.m-2,每例次的水化量分别为5 000 mL.m-2.d-1(5 L组)、4 000 mL.m-2.d-1(4 L组)和3 000 mL.m-2.d-1(3 L组),碱化量及四氢叶酸钙解救量均恒定。每例次化疗于开始用药后0 h、24 h、36 h、42 h、48 h、54 h采集外周静脉血样,并于开始用药后2 h(三联鞘注前)行腰椎穿刺留取脑脊液标本,用高效液相色谱分析仪测定其MTX浓度。结果12例患儿共进行了42例次HD-MTX化疗,共测定血药浓度238次。不同水化组之间各时间点的血药浓度相互比较,24 h MTX血药浓度测得值3 L组显著高于4 L组和5 L组,其不良反应无统计学差异。结论HD-MTX化疗时水化量的多少对MTX的血药浓度有一定的影响,尤其在开始用药后36 h内,二者成反比关系。化疗后的不良反应在3 000~5 000 mL.m-2.d-1...     

Disaccharidases Activity in the Intestinal Mucosa after Methotrexate Therapy

Disaccharidases activity in the intestinal mucosa samples of rats was examined after intragastric and intramuscular methotrexate therapy. Methotrexate was given on a twice a week schedule (1 mg/kg body weight). The animals were sacrificed after 2 weeks, 1 month, and 2 months of this therapy. A statistically significant but transient decrease of the lactase and maltose activity was found. The authors suggest studying the beneficial effect of low disaccharidase diet in the first period of methotrexate therapy in children treated with methotrexate.     

大剂量甲氨蝶呤治疗急性淋巴细胞白血病

目的探讨大剂量甲氨蝶呤(HD-MTX)治疗急性淋巴细胞白血病(ALL)在基层医院的可行性。方法对8例ALL患儿进行56次HD-MTX治疗,MTX剂量3 g/m2,同时水化碱化4 d,滴注MTX 36 h后开始四氢叶酸钙解救,首剂30 mg/m2,以后15mg/m2,1次/6 h,共8次。并观察其不良反应及疗效。结果接受HD-MTX治疗8例中,出现骨髓抑制(26/56次)占46.4%,消化道反应(24/56次)占42.9%,肝功能损害(13/56次)占23.2%,黏膜损害(12/56次)占21.4%,感染(5/56次)占8.93%,皮疹(3/56次)占5.36%,心脏损害(2/56次)占3.57%,出现肺弥漫性间质性浸润影、头痛各1例。主要不良反应发生率与HD-MTX疗程前后差异无显著性。随访8例ALL,仅1例发生中枢神经系统白血病(CNSL),该例为高危儿,发生时间为骨髓缓解(CR)后12个月。结论在基层医院不具备MTX监测及层流室条件下,只要在化疗前准备工作完善,水化碱化合理,四氢叶酸钙解救及时,HD-MTX治疗仍是安全可行的。     

四氢叶酸口服和注射解救豚鼠大剂量甲氨蝶呤毒性的比较

目的比较四氢叶酸(LV)注射与口服给药解救大剂量甲氨蝶呤(HD-MTX)毒性的效果,了解口服解救安全性。方法4周龄豚鼠分成空白对照组(9只)、口服解救组和注射解救组(各18只)。空白组不用任何药物;余二组腹腔注射MTX,24h后开始喂饲(口服组)或注射(注射组)LV解救。72h后检测血清ALT和肌酐(Cr)、肝组织蛋白水平、小肠黏膜酶活性及绒毛长度。结果口服组ALT异常高值1个、Cr异常高值1个,注射组有3个和1个;二组肝组织蛋白水平无显著差异[(15.2±3.7)mg/gvs(14.9±3.5)mg/gPa>0.05)],但均高于对照组[(12.1±2.6)mg/gPa<0.05]。口服组与注射组小肠黏膜碱性磷酸酶(ALP)、γ-谷氨酰转移酶活性及绒毛长度均无显著差异[(1.302±0.691)IU/cmvs(1.073±0.465)IU/cm、(0.034±0.019)IU/cmvs(0.028±0.017)IU/cm、(400.5±80.9)μmvs(419.6±60.8)μmPa>0.05),但明显低于对照组[(4.614±1.683)IU/cm、(0.119±0.068)IU/cm和(564.2±53.8)μmPa<0.05]。结论口服给药对HD-MTX引起肝、肾及小肠黏膜毒性的解救效果并不逊于注射给药,口服解救可安全地用于HD-MTX化疗。     

Safety and Efficacy of I-Leucovorin Rescue Following High-Dose Methotrexate for Osteosarcoma

High-dose methotrexate with leucovorin rescue (HDMTX-LCV) is an important component of regimens used in the treatment of osteosarcoma. As of this writing the commercially available form of leucovorin is a racemic mixture of d- and l-diastereoisomers; the l-isomer is the active component. This study describes the efficacy and safety of l-leucovorin in HDMTX-LCV regimens. Fifteen patients with osteosarcoma who were enrolled into or treated according to Pediatric Oncology Group protocols 8759 and 8651 received l-leucovorin (7.5 mg every 6 hours) in place of d,l-leucovorin following high-dose methotrexate. Safety data were collected for 1 week after each course or until any toxicities resolved. The mean number of l-leucovorin doses per course was 16.2 and the mean total dose per course was 126 mg. Adverse experiences were generally mild or moderate and occurred in 54 (60%) of 90 courses of l-leucovorin therapy. One l-leucovorin patient, who had inadequate methotrexate rescue, developed severe typhlitis. There were no instances of severe, acute methotrexate toxicity. Myelosuppression was seen but, in general, was not severe. These results support the conclusion that l-leucovorin effectively rescues patients from the toxicity of high-dose methotrexate. © 1995 Wi1ey-Liss, Inc.     

大剂量甲氨蝶呤治疗急性淋巴细胞白血病

目的研究3g/m2和5g/m2甲氨蝶呤(MTX)治疗急性淋巴细胞白血病(ALL)的血、脑脊液MTX浓度和不良反应。方法ALL患儿43例共接受98例次MTX3g/(m2·次)或5g/(m2·次)治疗,对两剂量组进行MTX血药质量浓度、脑脊液浓度及不良反应比较。结果1.MTX44、66h血药质量浓度与23hMTX血药质量浓度明显相关(P<0.05);2.不同个体间及同一个体不同时间使用同一给药方案血药质量浓度、脑脊液浓度水平差异较大;3.两剂量组不良反应发生率无明显差异(P>0.05),骨髓抑制、肝功能损害的MTX血药质量浓度无明显差异(P>0.05)。结论对于标危、高危ALL分别采用3、5g/(m2·次)的剂量是合理的,无严重不良反应发生。     

Interleukin 2 Immunotherapy in Children with Neuroblastoma after High-Dose Chemotherapy and Autologous Bone Marrow Transplantation

Four children with persistent neuroblastoma after marrow ablative chemoradiotherapy and autologous bone marrow transplantation received continuous infusion of recombinant interleukin 2, 75 to 120 days after the graft. Recombinant interleukin 2 therapy did not induce any major or nonreversible toxicity, hematological toxicity in particular. One patient entered complete remission for 9 months and a second patient had a long-lasting normalization of urinary catecholamine metabolites with more than 50% regression of bone marrow metastases (8 months). In three children, recombinant interleukin 2 and a second patient entered complete remission for 9 months therapy was followed by major increase and activation of circulating natural killer cells which amounted to 80% of the circulating mononuclear cells.     

Action of Intermediate Doses of Methotrexate on Dihydrofolate Reductase in Malignant Diseases

This report describes the effect of intermediate methotrexate (MTX) doses on dihydrofolate reductase (DHFR) activity in vivo in the leukocytes of 16 children with malignant diseases. The authors used a cytochemical technique, and the enzyme was studied in intact cells. The treatment protocols included MTX 500 mg—2 g/m² weekly with leucovorin rescue. The above doses of MTX partially inhibit DHFR. The reduction of enzyme activity was observed in leukocytes within 24 h after MTX infusion, and it was more obvious in the polymorphonucleas and the monocytes. Complete inhibition of enzyme activity was not observed. These results do not agree with those of previous reports using biochemical techniques, which showed that small amounts of MTX inhibit DHFR activity. Even the large doses of MTX used in this study do not completely inhibit enzyme activity. It would be worthwhile to test the effect of even larger doses of MTX to find out if DHFR activity is inhibited.     

Transient Encephalopathy Following a Single Exposure of High-Dose Methotrexate in a Child with Acute Lymphoblastic Leukemia

An episode of transient encephalopathy after the first course of intravenous high-dose methotrexate (HD-MTX; 1000 mg/m2) was observed in a 4-year-old girl with acute lymphoblastic leukemia. The neurological abnormalities took place 5 days after HD-MTX therapy. She experienced complex partial seizure and left hemiparesis, which resolved spontaneously in 5 days. Cranial computed tomographic scan and magnetic resonance imaging showed multiple low-density lesions in bilateral hemispheres. It is well appreciated that neurotoxicity from MTX follows prolonged exposures, often accompanying or following radiation therapy. To our knowledge, however, there have been no reports that such neurological complications developed following a single exposure of HD-MTX in patients with ALL. Follow-up electroencephalograms showed that she had periodic lateralized epileptiform discharges (PLEDS), suggesting functional deafferentation of cortical neurons following HD-MTX. Moreover, the serum and CSFMTX levels following a second low-dose course and her clinical course suggested that she had presumably central nervous system leukemia at the time of HD-MTX therapy, which might have been related to neurological complications. The pathogenesis of MTX-induced neurotoxicity is discussed.