地高辛单克隆抗体的研究——Ⅲ.特异性单克隆抗体救治豚鼠重度地高辛中毒及抗体处理后强心甙正性肌力作用观察

应用高亲和力的特异性单克隆抗体救治豚鼠重度地高辛中毒,成功率84.9％。当用单克隆抗体消除地高辛对豚鼠离体心房的正性肌力作用后,再给予毒毛旋花子甙K或G,仍表现明确的正性肌力效应。结果表明,高度特异、质地均一、来源无限的单克隆抗体,是一种有希望的洋地黄中毒特效解救剂。     

肝肾功能不全心衰患者地高辛血药浓度监测及个体化给药

目的 测定肝肾功能不全心衰患者地高辛血药浓度，为临床合理用药提供参考。方法 用荧光偏振免疫法测定167例肝肾功能不全心衰患者地高辛有效血药浓度，对地高辛血药浓度与疗效关系进行分析。结果 以文献报道的0．8～2．0ng／ml为地高辛有效血药浓度范围，23例患者〈0．8ng／ml，其心力衰竭缓解率较低（30．4％），63例在有效血药浓度范围内的患者心力衰竭缓解率较高（77．8％），〉2．0ng／ml的81例患者中毒反应发生率较高（58．1％）；肝肾功能越差，中毒发生率越高，肾功能不全患者尤甚。结论 临床测定地高辛血药浓度是必要的，尤其监测肝肾功能不全心衰患者地高辛血药浓度，实行个体化给药。     

乳汁中地高辛的药物动力学研究

地高辛系临床常用的强心甙药物之一。由于本品的治疗指数低、个体差异大、易产生中毒,给临床治疗带来了一定困难。近十年来,为确保用药的安全、有效,国内外对地高辛的药物动力学及个体化给药均已有大量的研究报告,而关于孕妇及授乳妇女本品的合理用药,尚少见报道。本实验采用萤光偏振免疫分析(FPIA)方法,以7名健康     

龙血竭栓对兔直肠破损黏膜刺激性和对豚鼠皮肤致敏性实验

目的:观察龙血竭栓的刺激性与致敏性。方法:以龙血竭栓对新西兰兔直肠破损黏膜单次及多次给药,观察其对兔直肠破损黏膜的刺激性;采用Buehler法对豚鼠皮肤给药,观察龙血竭栓对其致敏性。结果:新西兰兔直肠破损黏膜单次和多次给药,各剂量组动物给药后未见疼痛症状,粪便未见明显异常,肛门区域和肛门括约肌局部组织未见充血、水肿等现象,直肠破损黏膜未发现药物相关的明显组织病理学改变。Buehler实验龙血竭栓组动物过敏反应发生率为0%,实验期间未见任何过敏性反应症状。结论:龙血竭栓对兔直肠破损黏膜无刺激性,对豚鼠无致敏作用。     

果糖二磷酸钾盐对哇巴因诱导豚鼠心律失常的治疗作用研究

目的：研究果糖二磷酸钾盐对哇巴因诱导豚鼠心律失常的治疗作用。方法：60只豚鼠随机分为模型对照组、果糖二磷酸钾盐小剂量组、大剂量组、1，6-二磷酸果糖组、氯化钾组、门冬氨酸钾镁组。各组豚鼠四肢皮下插入针状电极，记录Ⅱ导联心电图和动态心电图．分离颈外静脉，缓慢推人相应药物，给药容量为1ml／100g。3分钟后。用微量静脉泵以0．053ml／min的速度恒速静脉注射0．0078％的哇巴因．     

庆大霉素中毒后豚鼠耳蜗毛细胞的再生

目的：通过庆大霉素中毒后不同时间豚鼠耳蜗毛细胞变化的观察，研究哺乳动物耳蜗毛细胞受损后能否再生。方法：将60只豚鼠随机分成庆大霉素组和生理盐水对照组。应用扫描电镜（SEM）技术并结合听脑干反应（ABR）测试，观察耳蜗毛细胞情况和ABR阀值变化。结果：庆大霉素组耳蜗毛细胞在30 d时ABR阈值有明显恢复，但未达到正常水平，同时耳蜗第三转有新生的静纤毛出现。结论：庆大霉素损伤后的毛细胞可以再生。     

189例地高辛测定结果回顾性分析

地高辛(Digoxin)作为一种强心甙药物,临床上常用于治疗心衰病人。然而地高辛的治疗剂量浓度与中毒浓度有一定的交叉。临床工作中发现,少数病例地高辛浓度>2ng/ml,甚至达到6ng/ml而未出现中毒现象;有少数病例地高辛浓度<2ng/ml,但已出现临床中毒现象。为了分析这一现象的原因,本文对1997年～1998年本中心所测定的189例地高辛浓度作一回顾性分析。现报告如下。 资料和方法 一、资料:所有病例均为我院住院病人,其中男性143例,女性46例;年龄3～84岁。病种分类:小     

聚乙二醇化重组人生长激素对离体豚鼠乳头肌细胞动作电位的影响

目的 探讨聚乙二醇化重组人生长激素(PEG-rhGH)对离体豚鼠乳头肌细胞动作电位的影响,并以重组人生长激素(rhGH)为阳性对照物比较二者的体外生物活性.方法 健康雄性DHP豚鼠12只,随机分为2组,PEG-rhGH干预组和rhGH干预组,每组6只.采用累计给药法和给药前后自身对照方法,分别观察不同质量浓度(1、5、...     

二氮嗪两种应用对豚鼠缺血再灌注心肌电生理特性的影响

目的：观察二氮嗪两种应用方式对缺血再灌注豚鼠心室乳头肌细胞电生理特性的影响。方法: 24只豚鼠随机分为对照组、实验组、预先给药组(各组8只)，取离体左室乳头肌标本。对照组37 ℃充氧台氏液平衡灌流80 min后，用4 ℃ St.Thommas液灌流停搏30 min，再行充氧台氏液复灌60 min。实验组除4 ℃ St.Thommas液含二氮嗪(100 μmol/L)外余步骤同对照组。预先给药组仅在平衡灌流60 min后改用二氮嗪(100 μmol/L)灌流10 min，冲洗10 min，余步骤同对照组。分别用玻璃微电极技术记录心室乳头肌细胞电生理特性的改变。结果: ⑴ 再灌注5 min、10 min实验组和预先给药组APD50、APD90均明显短于对照组(P<0.01，P<0.05)，而再灌注30 min又明显长于对照组(P<0.01，P<0.05)。⑵ 实验组和预先给药组再灌注30 min动作电位振幅(APA)、超射值(OS)、0期最大除极速度(Vmax) 恢复早于对照组，且复跳时间明显短于对照组(P<0.05)。⑶ 3组停搏后静息电位没有明显差异，预给药组停搏时间长于对照组(P<0.05)。结论: 含二氮嗪的St．Thomas停搏液对缺血再灌注豚鼠心室乳头肌细胞电生理特性的保护效果强于单纯的二氮嗪预先给药和传统的St．Thomas停搏液。     

地高辛抑制豚鼠心室肌细胞Na+,K+-ATP酶和人胚肾上皮细胞系HERG钾通道电流

强心苷类药对Na+,K+-ATP酶的作用在低浓度时为兴奋、在高浓度时呈抑制作用[1].应用膜片钳技术观察地高辛(Digoxin)对豚鼠心室肌细胞Na+,K+-ATP酶电流(Ip)的作用还未见报道.此外,由于很多药物的心脏不良反应是通过抑制人ether-a-go-go-related基因(HERG)编码的快速激活的延迟整流钾通道(Ikr)而引起QT间期延长和尖端扭转性室速(TdP)[2].本研究初步探讨地高辛对豚鼠心室肌细胞Ip电流和对人胚肾上皮细胞系(human embryonic kidney cell line,HEK-293)上HERG/Iκr钾通道的影响及地高辛治疗心功能不全和引起心脏毒性反应的机制.1材料与方法1.1动物、细胞系、质粒来源及地高辛配制:普通级豚鼠,8～12周龄,体质量250 ～ 300 g,雌雄不拘,由华中科技大学同济医学院实验动物学部提供[合格证号SCXK(鄂)2004-007].HEK-293细胞,中国科学院上海生科院细胞资源中心.编码Ikr的HERG基因的真核细胞表达载体pcgi-EGFPHERG(南京师范大学生命科学院张朝教授馈赠).地高辛(郑州大学药学院药物化学研究所提供)溶于二甲基亚砜中配制成10 mmol/L的母液.     

Digoxin poisoning and anuric acute renal failure: efficiency of the treatment associating digoxin-specific antibodies (Fab) and plasma exchanges

Digoxin-specific antibodies (Fab) are currently the treatment of choice for digoxin intoxication. These fragments bind to digoxin, leading to Fab-digoxin complexes, and promote the release of receptor-bound digoxin. These complexes are renally excreted. In the case of anuria, they could be dissociated and lead to renewed intoxication. In this case plasma exchanges are proposed. We report the case of an anuric patient with digoxin intoxication, treated with a Fab injection, followed by a plasma exchange 16 hours later, a second Fab injection was given followed by two plasma exchanges, 38 and 86 hours later. The disappearance of cardiac abnormalities showed the efficiency of the Fab, the drop in serum digoxin concentration and the high digoxin concentration in the exchanged plasma indicate effective elimination. The association of Fab and plasma exchanges could be proposed in the case of digoxin intoxication in the anuric patient.     

Digitalis intoxication and treatment with digoxin antibody fragments in renal failure

Summary Severe digitalis intoxication today is preferentially treated by intravenous infusion of Fab fragments of digoxin antibodies (Digitalis Antidot BM). The kinetics of Fab fragments in the circulation are well known when kidney function is normal or slightly impaired. There are no data available, however, in complete renal failure. We observed a patient with life-threatening digitalis intoxication (serum digoxin, 3.7 ng/ml) and anuria, who was treated successfully by 160 mg Fab fragments i.v. Serum digoxin and Fab fragment concentrations could be followed for 229 h. The extrarenal clearance of Fab fragments was lower (5.6 ml/min) than in patients with normal kidney function (10.9 ml/min). This finding suggests that lower doses than usual might be sufficient for treating patients with severe digitalis intoxication and renal failure.Abbreviations AUC area under the curve - FAB fragments digoxin antibody fragments - h hour     

The use of digoxin-specific Fab fragments for severe digitalis intoxication in children.

BACKGROUND. Because life-threatening digitalis intoxication is unusual in children, treatment with digoxin-specific-antibody Fab fragments (Fab) has rarely been reported. We describe the efficacy of Fab in the treatment of children with severe digitalis intoxication. METHODS. Twenty-nine children with intoxication due to digoxin (28) or digitoxin (1) received Fab at 21 participating hospitals between 1974 and 1986. Data were gathered about the patients' medical illnesses, doses and serum concentrations of digitalis, responses to Fab therapy, and outcomes. RESULTS. In the infants and young children with acute digoxin intoxication, the digoxin doses ranged from 0.30 to 0.96 mg per kilogram of body weight; two adolescents had severe intoxication after doses of only 0.20 and 0.26 mg per kilogram. The serum digoxin concentrations ranged from 3.0 to greater than 100 ng per milliliter (mean, 13.8). Atrioventricular block (present in 22 patients [76 percent]) was the most common sign of toxicity. All the patients in this series had severe disturbances of cardiac rhythm, hyperkalemia (mean serum potassium concentration, 5.4 mmol per liter), or both. In 27 patients (93 percent), digitalis toxicity resolved after the administration of Fab. Of the 19 patients for whom data were available on the timing of the response to Fab, 15 responded within 180 minutes. Three patients required retreatment with Fab. Seven died of complications unrelated to the administration of Fab. CONCLUSIONS. We recommend that Fab be used in the treatment of digitalis poisoning in infants and young children who have ingested greater than or equal to 0.3 mg of digoxin per kilogram, who have underlying heart disease, or who have a serum digoxin concentration of greater than or equal to 6.4 nmol per liter (greater than or equal to 5.0 ng per milliliter) in the elimination phase; and who also have a life-threatening arrhythmia, hemodynamic instability, hyperkalemia, or rapidly progressive toxicity. Adolescents, who are more sensitive to the toxic effects of digoxin than younger children, may require treatment with Fab after ingesting lower doses.     

Digitalis intoxication in geriatric in-patients. A prospective clinical study of the value of serum digitalis concentration measurement

A prospective clinical study of 66 geriatric in-patients mainly on digoxin treatment revealed digitalis intoxication in seven (11%). Over a two-month period another patient developed digoxin toxicity. The prevalences of anorexia, nausea and vomiting were significantly higher in patients with than without digitalis toxicity. The mean serum drug concentration was significantly higher in overdosed than in non-overdosed patients, but six patients had serum digoxin concentrations within or below the therapeutic range, and only two slightly above. Notably, maintenance digoxin therapy was unnecessary in five out of eight intoxicated patients. The value of determining serum digitalis concentrations in diagnosing clinical toxicity in geriatric in-patients is discussed.     

Digoxin-quinidine interaction in patients with renal failure

Summary Investigations were performed in order to study whether or not quinidine would exert similar effects on the serum digoxin concentration in patients with renal failure as in normal subjects. Fourteen out of fifteen patients showed a significant increase of the serum digoxin level after four days of quindine application. This indicates, that the quinidine effect is not solely caused by a decrease of the renal digoxin clearance, although nine patients, not being hemodialysed, revealed a correlation between their creatinine clearance and the rise of the serum digoxin concentration after quinidine. As however, the patients on hemodialysis did not show higher digoxin levels than those treated conservatively, it is suggested that the degree of the uremic intoxication might be responsible for the observed correlation.     

Digoxin and the geriatric in-patient. A randomized trial of digoxin versus placebo

The effects of oral digoxin and placebo in 41 geriatric in-patients were compared using a randomized, double-blind, cross-over method. The patients were in sinus rhythm or had atrial fibrillation. The observation period was two months on digoxin or placebo. Patients with symptoms of cardiac failure at rest or during light physical activity, X-ray signs of pulmonary congestion, proven need of digoxin therapy following earlier withdrawal, atrial fibrillation with a ventricular rate greater than 95 beats/min and patients in whom digitalis intoxication was suspected were excluded from the study. Five (14%) of 37 patients deteriorated during the placebo phase. Four of these developed rapid atrial fibrillation and one patient developed sinus tachycardia and symptoms of heart failure.     

Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications.

Administration of quinidine with digoxin increased serum digoxin concentrations in 79 patients and five volunteers. In 38 patients on a constant glycoside maintenance dose, the addition of quinidine to digoxin therapy resulted in a mean 2.5-fold increase (from 0.98 +/- 0.37 to 2.47 +/- 0.71 ng per milliliter, mean +/- 1 S.D.) (P less than 0.001). The addition of quinidine decreased renal glycoside clearance (from 91.6 +/- 27.8 to 40.6 +/- 15.8 ml per minute) (P less than 0.001). Unlike other investigations, our studies provided no evidence that quinidine displaced digoxin at specific cardiac binding sites. The elevated digoxin levels found during quinidine administration suggest a 30 to 50 per cent reduction of the digoxin dose. Adverse reactions to combined quinidine-digoxin therapy may be partly due to digitalis intoxication.     

Effect of antidigoxin monoclonal antibodies on cardiac disturbances caused by high concentrations of digoxin

Effect of high-affinity mouse monoclonal antidigoxin antibodies D22 on digoxin-induced cardiac disturbances is studied in guinea pigs injected with 0.5 mg/kg digoxin. Five minutes after digoxin injection, bradycardia, isolated extrasystoles, conduction disturbances, and changes in theST segment andQRS complex appear; digoxin concentration attains 0.2–0.4 μg/ml. Antidigoxin monoclonal antibodies injected 10 min after digoxin slightly reduce heart rate, prevent isolated extrasystoles, improve atrioventricular conduction, and normalize the amplitude of theST segment and the shape of theQRS complex. Serum digoxin concentration decreases to 0.015–0.03 μg/ml. These data suggest that monoclonal antidigoxin antibodies can be effectively used in acute digoxin intoxication. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 6, pp. 688–691, June, 1998     

Novel anti-digoxin monoclonal antibodies with different binding specificities for digoxin metabolites and other glycosides

Spleen cells of BALB/c mice immunized with a digoxin-bovine serum albumin conjugate were fused with P3-X63-Ag8.653 mouse myeloma cells. Seven monoclonal antibodies (MAb) selected by indirect ELISA were produced, purified and characterized. All the MAb were IgG1 isotypes. The apparent equilibrium association constants (Ka) of four of the MAb, determined by Scatchard analysis of the RIA data, ranged from 1 x 10(9) M-1 to 5.9 x 10(9) M-1. The estimated Ka values of the three other MAb were found to be between 4.8 x 10(7) M-1 and 5.9 x 10(8) M-1. Using digoxin and eighteen structurally-related compounds, the seven MAb could be divided into five groups based on their binding specificities assessed by an inhibition immunoenzymatic test. The MAb in Groups I and II, in particular, showed very different specificity profiles: the two MAb in Group I had low cross-reactivity with cardioinactive digoxin metabolites, whereas the high affinity MAb in Group II recognized all the digoxin metabolites tested. The MAb in Group I might be useful in a digoxin immunoassay and the Group II MAb in therapeutic reversal of digoxin intoxication.     

Digoxin and digitoxin elimination in man by charcoal hemoperfusion

Summary Since there is no widely used causal means of reducing the severity of massive digitalis intoxication the capability of hemoperfusion with coated activated charcoal to remove toxicologically relevant amounts of digoxin and digitoxin was evaluated in vitro and in man. At a blood flow rate of 100 ml/min the digoxin clearance by hemoperfusion in vitro was 51±8 ml/min in comparison to 24.3±11.3 ml/min by hemodialysis. The average hemoperfusion clearance of digitoxin was 31.7±13.4 ml/min, whereas almost no digitoxin was removed by hemodialysis. These clearance values point to the ability of hemoperfusion of eliminating digitalis glycosides from the blood. They do not clarify the essential question whether it is possible to lower the toxic concentrations in the tissues.In two patients being on hemoperfusion for other reasons, 0.5 mg digoxin were injected intravenously as a bolus 1 h prior to the beginning of hemoperfusion and 0.125 mg/h were infused continuously over 4h simultaneously with hemoperfusion. By an average digoxin clearance of 77 ml/min, only 5 and 4.5% of the dose given were removed by this procedure. In 2 patients receiving digitoxin under the same trial conditions an average of 24% of the digitoxin load were eliminated by 4 to 6 h hemoperfusion period although the clearance values obtained were below the clearance for digoxin.The lack of effectiveness in eliminating toxicological relevant amounts of digoxin is due to the quite high distribution volume which results in high tissue concentrations and low blood concentrations of the drug. On the other hand the effective removal of digitoxin is due to the appreciably smaller distribution volume and suggests that hemoperfusion may be a valuable method of rapid reversal of advanced digitoxin toxicity in man.Supported by a grant of Deutsche Forschungsgemeinschaft