急性淋巴细胞白血病患儿甲氨蝶呤化疗中血药浓度的监测

目的:通过血药浓度监测,提高对小儿急性淋巴细胞白血病大剂量甲氨蝶呤化疗的有效性和安全性。方法:以接受55次1.5~4.0g/m2的大剂量甲氨蝶呤化疗的27例急性淋巴细胞白血病患儿为研究对象,定时采血测定甲氨蝶呤血药浓度,根据甲氨蝶呤静脉滴注结束时(12h)血药浓度评价化疗的有效性,根据甲氨蝶呤消除末端血药浓度决定四氢叶酸钙救援方案。结果:2.0、3.0、4.0g/m2剂量组的甲氨蝶呤静脉滴注结束时(12h)血药浓度维持在渗透浓度(2×10-5mol/L)以上的化疗次数分别占75%、92.1%、100%;仅1例患儿出现大面积皮肤粘膜损伤,其余无不可逆的严重不良反应发生。结论:进行甲氨蝶呤血药浓度监测有利于掌握好甲氨蝶呤和四氢叶酸钙的救援剂量,从而保证化疗的有效性和安全性。     

用群体药物动力学方法分析大剂量甲氨蝶呤持续静滴时间和解救开始时间

目的：探讨急性淋巴系恶性肿瘤患儿的大剂量甲氨蝶呤（HDMTX）持续静滴时间及四氢叶酸钙（LCV）解救的开始时间。方法：27例患儿典接受三种HDMTX方案治疗99例次,1g／m^2静滴36h、3g／m^2静滴24h和5g/m^2静滴24h分别为14、58和27例次。荧光偏振免疫法（FPIA）测定MTX血浓度,NONMEM软件进行模型拟合和群体药动学参数的计算,计算不同时间的MTX浓度。结果：HDMTX静滴为二室模型分布．三种HDMTX方案的MTX血药浓度达到稳态的时间为8-11h。MTX由分布相转入消除相的时间为MTX静滴结束后的12h左右（10-17．4h）。结论：HDMTX的持续静滴时间不应少于8～11h,LCV开始解救的中位时间为MTX静滴结束后的12h．最晚不应超过MTX静滴结束后的17．5h。     

Cytarabine-induced cerebellar syndrome: case report and literature review

High-dose cytarabine (HDARAC) therapy is an effective regimen in treating refractory leukemias. A typical regimen is cytarabine 3 g/m2 iv over one to three hours q 12h for a total of 8 to 12 doses. This case report illustrates the neurotoxicity unique to HDARAC. The patient received two cycles of HDARAC over the course of a ten-week period. During the first treatment, dysarthria and ataxia were seen after completion of the patient's eighth and final dose of HDARAC. These symptoms resolved over a period of five days. Six weeks later a more severe syndrome of dysarthria and ataxia developed during a second cycle of treatment. These symptoms worsened over 24 hours despite discontinuation of therapy, then gradually decreased in severity but persisted until his death two months later. The neurotoxicity seen with HDARAC is dose-related and has occurred in up to 60 percent of treated patients. The incidence of cerebellar toxicity approaches 30 percent, with irreversible ataxia reported in up to 16.7 percent. Because the cerebellar toxicity may be worsened by continuation of therapy after initial onset of symptoms, prompt termination of HDARAC is recommended.     

Resumption of high-dose methotrexate after methotrexate-induced nephrotoxicity and carboxypeptidase G2 use.

PURPOSE: The successful resumption of high-dose methotrexate in a 13-year-old boy with recurrent anaplastic large-cell lymphoma (ALCL) who suffered renal dysfunction after a 24-hour infusion of high-dose methotrexate and required treatment with carboxypeptidase G(2) (CPDG(2) ) is described. SUMMARY: A 13-year-old boy who had been diagnosed in 2001 with stage I ALCL was admitted to the hospital in February 2005 after he developed a smaller left axillary mass in the area of his original mass. Recurrent ALCL was diagnosed, and treatments were initiated based on branch K3 of the protocol published in the non-Hodgkin's lymphoma-Berlin-Frankfurt-Münster (NHL-BFM) trial 90. In the NHL-BFM 90 protocol, all AA and BB courses include high-dose methotrexate therapy, which consists of aggressive alkalinized hydration, methotrexate 5 g/m(2) given as an i.v. infusion over 24 hours, and leucovorin rescue. During course BB2, the boy's serum methotrexate values exceeded NHL-BFM goals at 36, 42, and 48 hours. Because the patient's elimination of methotrexate remained slow and his serum creatinine level remained above normal limits, CPDG(2) was obtained for the treatment of methotrexate toxicity. The patient tolerated the CPDG(2) without adverse effects, and the patient's serum methotrexate concentration decreased from 14.47 to 0.66 microM. The patient went on to complete six courses based on the protocol. High-dose methotrexate was resumed at 50% then 100% of the original dose. He is currently in remission on maintenance therapy. CONCLUSION: A 13-year-old boy with recurrent ALCL had methotrexate-induced nephrotoxicity following high-dose methotrexate. The resultant delayed methotrexate clearance required the standard therapies as well as use of investigational CPDG(2). High-dose methotrexate was successfully resumed.     

泛影葡胺致肾移植术后患者急性喉头水肿

1例29岁肾移植术后男性患者因移植肾功能不全行移植肾增强cT检查,静脉注射泛影葡胺注射液20m1（12g）。12h后患者出现咽部不适、分泌物增多,伴颈部轻度肿大。20h后其不适症状加重且伴有呼吸困难、吞咽困难、声音嘶哑等症状,查体发现颈部明显肿大、增粗,全身轻度水肿。立即静脉注射地塞米松10mg,雾化吸入布地奈德1mg,同时行心电监护及吸氧等治疗。约4h后患者病情缓解,2d后过敏症状消失。     

高剂量甲氨蝶呤为主的联合化疗致急性肾损害及其与基因型的关系

1例21岁男性何杰金淋巴瘤患者,在母供髓干细胞移植前用甲氨蝶呤3.0g,异环磷酰胺2.0g,吉西他滨1.0g,长春瑞宾20mg,波替单抗2.05mg,L-门冬酰胺酶10000U,泼尼松100mg联合化疗。24h后出现少尿,SCr246μmol/L,BUN16.3mmol/L,尿酸497mmol/L。36h甲氨蝶呤血药浓度为25μmol/L。肾部超声检查示肾脏密度分布欠均匀,右上极可见2.1cm×2.3cm无回声液区。诊断：急性肾损害。给予四氢叶酸钙200mg/3h,加强水化、碱化尿液及血液透析。患者甲氨蝶呤血药浓度下降,SCr、BUN逐渐恢复正常。分析其母亲外周血淋巴细胞、患者外周血淋巴细胞、患者口腔上皮细胞亚甲基四氢叶酸还原酶C677T基因型示C：T分别为1：1、1：1和1：1.5,提示患者的肾损害可能与基因型有关。     

Pharmacokinetic interaction between high-dose methotrexate and oxacillin

An 18-year-old man received two high-dose methotrexate cycles for the treatment of an osteosarcoma. Fifteen grams of methotrexate were infused over 6 hours. During the second cycle, co-administration of oxacillin (1g/8h) resulted in prolonged and marked elevation of methotrexate plasma concentrations. The patient experienced acute toxicity with renal failure, myelosuppression, mucitis, fever, and dermatologic abnormalities. After an initial improvement with folinic acid rescue and hemodialysis, the patient died. Oxacillin may thus inhibit the elimination of methotrexate.     

静脉滴注大剂量甲氨蝶呤致亚急性神经中毒

1例20岁男性患者因骨肉瘤给予2个周期大剂量甲氨蝶呤化疗(8 g/m2)。第2次化疗后第7天,患者突然出现言语不畅、左手麻木、恶心、乏力,后逐渐进展为失语、双上肢强直、双下肢麻木。实验室检查:白细胞计数12.5×109/L,红细胞计数3.6×1012/L,血红蛋白111 g/L,血小板计数101×109/L。头部CT扫描未见异常。给予吸氧。约3 h后症状好转。第2天下午患者在无诱因情况下又出现相似症状。颅脑磁共振成像、弥散加权成像、脑电图、心脏多普勒超声、颈动脉超声检查均正常。静脉滴注马来酸桂哌齐特和胞磷胆碱,2 d后症状消失。     

注射用盐酸头孢吡肟致过敏性休克1例

1例56a女性患者,因肺部感染静脉滴注注射用盐酸头孢吡肟2g＋0.9%氯化钠注射液100mL。用药2min后患者出现全身皮肤潮红,约20min后出现头晕、黑朦、心悸等,BP47/23mmHg,SPO286%,立即停药、吸氧,并给予甲泼尼龙、地塞米松、葡萄糖酸钙、多巴胺、羟乙基淀粉130/0.4氯化钠注射液等治疗,4h后生命体征平稳。     

口服甲氨蝶呤引起腹痛、腹泻及骨髓抑制

1名72岁女性类风湿关节炎患者，口服甲氨蝶呤2．5mg，2次／d，1周后出现腹痛，腹泻，遂停药并服用诺氟沙星、小檗碱，但症状未缓解。入院后血常规检查显示WBC 1．6×10^9／L，RBC2．7×10^12／L，Hb86g／L，PLT 51×10^9／L，给予粒细胞集落刺激因子、左氧氟沙星等治疗，但外周全血细胞进行性下降，大便由水样便转为黏液血便，皮肤出现瘀点及瘀斑。给予肌内注射亚叶酸钙15mg，3次／d。入院第4天，患者WBC0．5×10^9／L，Hb73/L，PLT11×10^9／L。给予静脉输注血小板、压积红细胞，继续行补液、止血、抗感染等治疗。1周后，患者腹痛、腹泻症状缓解，复查血常规：WBC4．9×10^9／L，Hb76g／L，PLT70×10^9／L。2年后随访，血常规正常。     

长春瑞滨注射液致过敏性休克1例

1例55a男性患者,因下咽癌综合治疗后肝转移,静脉输入长春瑞滨注射液40mg＋0.9%氯化钠注射液100mL,滴速80滴·min-1。滴完后10min左右患者出现吸气性呼吸困难,伴喉鸣音,全身湿冷,BP189/105mmHg,HR129次·min-1,R28次·min-1,SPO293%～81%。5min后出现神志不清,R12次·min-1,HR45次·min-1,SPO259%,血压为0。立即给予地塞米松10mg静注,吸痰,给氧5L·min-1。行气管插管给予简易呼吸仪器助通气时,患者出现心跳、呼吸骤停,立即给予盐酸肾上腺素1mg皮下注射,胸外心脏按压,1min后患者呼吸、心跳恢复,再经约1h的抢救和治疗,患者神志清醒并逐渐恢复。     

Prolongation and enhancement of serum methotrexate concentrations by probenecid

The disappearance of methotrexate (MTX) from the serum after an intravenous bolus injection and intravenous infusion was studied over 24 hours in eight and four patients respectively. Probenecid given at the same time as the bolus injection delayed the disappearance of MTX from the serum and resulted in enhanced concentrations throughout the 24 hours studied. At 24 hours the mean concentration was four times higher than in patients not given probenecid. Overall serum concentrations were even greater than those in patients who had received MTX by intravenous infusion. We suggest that smaller doses of MTX may be given and treatment costs thereby reduced if probenecid is given in addition.     

Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning?

BACKGROUND: The optimal route and duration of administration for N-acetyl-cysteine in the management of acetaminophen (paracetamol) poisoning are controversial. It has been stated on the basis of a selected post-hoc analysis that oral N-acetylcysteine is superior to intravenous N-acetylcysteine in presentations later than 15 hours. AIM OF STUDY: To investigate the efficacy of intravenous or oral N-acetylcysteine. PATIENTS AND METHODS: We analyzed a series of acetaminophen poisonings treated with a protocol including activated charcoal and intravenous N-acetylcysteine. The outcomes assessed included use of N-acetylcysteine, adverse effects of intravenous N-acetylcysteine, and the occurrence of hepatotoxicity (transaminase > 1000 U/L). We incorporated these results in a meta-analysis of previously reported series of acetaminophen poisonings to compare the outcomes from intravenous and oral N-acetylcysteine use. RESULTS: Of 981 patients admitted over 10 years, 4% (40) presented later than 24 hours and 10% (100) had concentrations of acetaminophen that indicated a probable or high risk of hepatotoxicity. The 30 patients who developed hepatotoxicity presented later, took larger amounts, had higher concentrations, and received N-acetylcysteine later than those who did not. No patients received a liver transplant but 2 patients died (one after referral to a transplant unit and one just before). Adverse reactions to intravenous N-acetylcysteine occurred in 6% (12/205) of patients but none prevented completion of the treatment. In the meta-analysis, those with probable or high risk concentrations had similar outcomes with intravenous (pooled n = 341) and oral N-acetylcysteine (pooled n = 1462) administration. Rates of hepatotoxicity for those treated within 10 hours (3 and 6%), late (10-24 hours: 30 and 26%), and overall (0-24 hours: 16 and 19%) were all similar. The proportion of patients classified as presenting later than 10 hours is much greater in the oral N-acetylcysteine studies (64%) than in many of the intravenous N-acetylcysteine studies (38%, 44%, and 63%). CONCLUSIONS: The differences claimed between oral and intravenous N-acetylcysteine regimes are probably artifactual and relate to inappropriate subgroup analysis. A shorter hospital stay, patient and doctor convenience, and the concerns over the reduction in bioavailability of oral N-acetylcysteine by charcoal and vomiting make intravenous N-acetylcysteine preferable for most patients with acetaminophen poisoning.     

Fatal acute encephalomyelitis after a single dose of intrathecal methotrexate

A 40-year-old Hispanic man with acute lymphoblastic leukemia was treated with a single dose of intrathecal methotrexate 12 mg for prophylaxis against leptomeningeal spread of tumor. The day after methotrexate administration, the patient complained of severe back pain and urinary retention. The diagnosis of encephalomyelitis was made on day 3 after methotrexate administration, and by day 6 mechanical ventilation was begun secondary to ascending paralysis. By day 8 the patient was comatose, with minimal signs of brain activity and little hope for recovery; on day 12 he died. Although neurotoxicity is a frequent complication of methotrexate therapy, fatal acute neurotoxicity is extremely uncommon, especially in adults. The mechanisms of methotrexate toxicity remain unclear, and no effective treatment exists to prevent its occurrence. This patient rapidly progressed from mild neurotoxicity to fatal encephalopathy after one dose of intrathecal methotrexate during his third cycle of chemotherapy. Clinicians should be aware of the signs and symptoms of neurotoxicity during treatment, as well as predisposing factors that put patients receiving methotrexate at risk for neurotoxic effects.     

Pharmacokinetics of glucarpidase in subjects with normal and impaired renal function

Glucarpidase (formerly known as carboxypeptidase G2 or CPG2) is being evaluated for the adjunctive treatment of patients experiencing, or at risk of, methotrexate toxicity attributable to its delayed elimination. Delayed elimination of methotrexate can occur in patients with methotrexate-induced renal toxicity. In this study, glucarpidase pharmacokinetics were assessed in volunteer subjects with normal (n = 8) and severely impaired (n = 4) renal function. Each subject received a single intravenous dose of glucarpidase 50 U/kg (equivalent to 114.5 microg/kg) infused over 5 minutes. The mean maximum serum concentration (C(max)) for glucarpidase in renally impaired subjects was 2.9 microg/mL, the mean half-life (t(1/2)) was 10.0 hours, and the mean area under the serum concentration-time curve from time zero to infinity (AUC(0-infinity)) was 24.5 microg x h/mL. Similar values were found in subjects with normal renal function (mean C(max) 3.1 microg/mL, mean t(1/2) 9.0 hours, and mean AUC(0-infinity) 23.4 microg x h/mL). The results indicated little effect of renal impairment on the serum pharmacokinetics of glucarpidase.     

头孢孟多酯钠致精神异常

1例76岁男性患者,因腰椎间盘髓核摘除术术后,静脉滴注头孢孟多酯钠1g 溶于0.9 %氯化钠注射液250 mL 预防感染.滴注20 min 后,患者出现意识模糊、燥动不安、对答不切题.立即停药,给予消炎、镇静等处理,4h 后患者精神异常症状消失.继续给予止血、制酸治疗,患者未有不适症状出现.     

硫酸镁救治乌头碱中毒致顽固性室性心律失常

1例46岁男性患者误服生草乌、川乌粉约5 g后3 h出现意识障碍、全身抽搐;心电图检查示心室扑动,心率110次/min。立即电除颤,静脉推注胺碘酮,未复律。再次静脉推注胺碘酮,同时静脉推注利多卡因100 mg和15%硫酸镁8 ml（1 g）,复律。心电监护示频发多源多形性室性期前收缩。继续持续静脉泵入胺碘酮和利多卡因。1 min后,再次出现多形性室性心动过速（室速）,心率180~190次/min。静脉推注胺碘酮和利多卡因以及电复律均无效。再次静脉推注硫酸镁8 ml（1 g）,室速仍存在但频率逐渐降至160~170次/min。遂第3次静脉推注硫酸镁8 ml（1 g）,心率140~150次/min。10 min后,第4次静脉推注硫酸镁8 ml（1 g）,心律转复。1 h后给予患者行血液灌流,最初1 h出现4次多形性室速,每次静脉推注硫酸镁（1~1 g）均有效。次日,患者恢复正常,心电图示窦性心律,心率75次/min。     

碘普罗胺370致过敏性休克死亡

1名44岁女性静脉曲张患者,行增强CT检查前,给予碘普罗胺370100ml,0.9%氯化钠注射液40ml,地塞米松10mg,高压注射器静脉团注,速度约为2.5ml/s。注入完毕,患者即出现意识丧失,呼吸、心跳停止。立即给予心肺复苏、气管插管、抗休克药物等抢救,2h多后患者死亡。尸检报告提示多器官组织嗜酸性粒细胞浸润,肺水肿,喉头、会厌水肿。     

进行性肌阵挛癫痫患者口服苯妥英钠致非惊厥性癫痫持续状态

1例16岁女性进行性肌阵挛癫痫患者,口服苯妥英钠0.15 g、1次/12 h治疗1周后出现非惊厥性癫痫持续状态,脑电图呈全导持续性棘慢波节律。7周后入我院,立即将苯妥英钠减量至0.05 g,2次/d,2 d后停用,同时给予患者丙戊酸钠0.3 g,1次/8 h;氯硝西泮1 mg,1次/12 h;左乙拉西坦0.25 g,1次/12 h。治疗第3天患者肌阵挛发作消失,治疗第6天脑电图示散在棘慢波、慢波,住院12 d,病情平稳出院。     

重组人脑利钠肽治疗急性失代偿性心力衰竭的临床研究

目的：探讨冻干重组人脑利钠肽（rhBNP）对急性失代偿性心力衰竭的治疗效果和安全性。方法：选取40例急性失代偿性心力衰竭患者随机分为rhBNP组（n=20）和对照组（n=20）。rhBNP组以rhBNP1.5μg／kg静脉注射后,再以0.0075μg／kg持续静脉泵入：对照组持续静脉泵入硝普钠。观察治疗前、治疗48h后心肌酶水平、心脏超声指标、每小时尿量的变化。安全性评估采用用药过程中及用药后定期测量血压、心率．并记录用药过程中的不良事件。结果：治疗48h后rhBNP组心肌酶水平、LVEF、每小时尿量均显著优于常规对照组（P〈0.05或P〈0.01）。rhBNP组的不良事件与对照组相比无差异。结论：rhBNP能显著改善急性失代偿性心力衰竭患者的血流动力学及全身临床状况．其安全性与硝普钠相似。