Nuessler V, Scheulen M E, Oberneder R, Kriegmair M, Goebel K J, Rathgeb F, Wurst W, Zech K, Wilmanns W
Klinikum Grosshadern, Medizinische Klinik und Poliklinik III, Munich, Germany.
Eur J Med Res. 1997 Feb 21;2(2):55-61.
Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.
地尼古地平（DNIG）是二氢吡啶衍生物尼古地平的R-对映体。DNIG对P-糖蛋白（P-gp）具有结合亲和力，因此推测它可阻断P-gp的转运机制。开展这项开放性I期研究，以确定静脉注射DNIG单药及与长春碱联合应用于转移性或局部晚期癌症患者时的最大耐受剂量（MTD）和安全性。此外，评估并比较各剂量组的DNIG血清水平，以研究静脉给药的剂量线性关系。该研究关于DNIG给药分为两部分。在第一部分中，患者连续4天每天接受4小时的DNIG治疗，并且在第3天额外接受0.15mg/kg的长春碱治疗。治疗从1mg/kg/4h开始，只要药物耐受性良好，剂量就增加。在第二部分中，患者接受多达三个疗程的4小时输注（5和7mg/kg/4h）的DNIG，随后连续输注48小时（5和7mg/kg/24h）。26例患者进入该试验并至少接受了一次DNIG输注；长春碱在4小时输注后立即给予。给予1至7个疗程，剂量为1-11mg/kg。5例患者出现剂量限制性毒性，表现为心血管不良事件，如血压下降、心率降低，1例患者出现III度房室传导阻滞。最常见的不良事件为恶心、头晕、呕吐、周围感觉异常、共济失调步态、轻度便秘、多尿、低钙血症；所有这些在停止输注后24小时内消失。在4小时内静脉输注DNIG后，发现DNIG血清浓度随剂量增加呈线性增加。持续2天或5天的长期输注方案导致DNIG血清水平相当稳定。MTD确定为5mg/kg/4h。推测DNIG持续输注的MTD高于5mg/kg/24h，但本研究未对此进行后续研究，这必须是后续试验的目标。
