Perrotti Pasquale, Dominici Patrizia, Grossi Enzo, Antropoli Carmine, Giannotti Guglielmo, Cusato Maria, Regazzi Mario, Cerutti Renata
Chirurgia Gastroenterologica, Department of Gastroenterology, 'A. Cardarelli' Hospital, Naples, Italy.
Clin Drug Investig. 2009;29(4):243-56. doi: 10.2165/00044011-200929040-00003.
This study aimed to assess whether topical anorectal application of an ointment containing nifedipine (0.3% w/w) and lidocaine (lignocaine) [1.5% w/w] to patients undergoing Milligan-Morgan haemorrhoidectomy achieves pharmacologically relevant serum concentrations of the active ingredients and has any haemodynamic effects or adverse effects.
A single dose of 3 g of study ointment was circumferentially applied inside the anus to 24 patients (17 males and 7 females) aged 23-71 years (mean +/- SD: 42.9 +/- 4.9 years) during postoperative dressing after Milligan-Morgan haemorrhoidectomy from March 2007 to January 2008. Blood samples for the determination of nifedipine and lidocaine serum concentrations were drawn before surgery and at 20, 40, 60, 90, 120, 240, 360, 480 and 720 minutes after application. Serum concentrations of nifedipine and lidocaine were determined by a high-performance liquid chromatography method in order to calculate pharmacokinetic parameters. Patients' BP, heart rate and ECG readings were monitored during the study.
Chromatographic signals of nifedipine were sporadically observed in only five patients (20.8%), consistent with therapeutically negligible concentrations and insufficient to permit calculation of any pharmacokinetic parameters. The serum concentrations of nifedipine in these five patients ranged from 5.9 to 18.8 ng/mL. Lidocaine concentrations were detectable in all patients. The means +/- SD and medians of pharmacokinetic parameters for lidocaine were as follows: maximum serum concentration (C(max)) 245.1 +/- 370.8 ng/mL, 73.6 ng/mL; time to reach C(max) (t(max)) 69.2 +/- 78.3 minutes, 40 minutes; area under the serum concentration-time curve from 0 to 6 hours (AUC(6)) 756.5 +/- 1254.1 ng.h/mL, 238.2 ng.h/mL. Only three patients had maximum serum concentrations above 1000 ng/mL (1037.8, 1044.75 and 1364.1 ng/mL). These outlier concentrations were four to five times lower than the threshold of CNS lidocaine toxicity (5000-6000 ng/mL). No serious local or systemic adverse events were observed throughout the study, and no subjects developed arrhythmias or significant ECG changes. Neither BP nor mean heart rate varied significantly after application of a single dose.
This study demonstrates that single-dose topical application of an ointment containing nifedipine (0.3% w/w) and lidocaine (1.5% w/w) to patients undergoing Milligan-Morgan haemorrhoidectomy is safe to use. Following application onto damaged anorectal mucosa, nifedipine and lidocaine are absorbed into the bloodstream in small quantities that do not have any major implications for the safety of the product. Further studies are required to evaluate nifedipine and lidocaine concentrations in serum using a multiple-dose regimen.
本研究旨在评估对接受Milligan - Morgan痔切除术的患者在肛门直肠局部应用含硝苯地平（0.3% w/w）和利多卡因（1.5% w/w）的软膏后，是否能达到具有药理学意义的活性成分血清浓度，以及是否有任何血流动力学效应或不良反应。
2007年3月至2008年1月期间，在Milligan - Morgan痔切除术后的换药过程中，将3 g单剂量的研究软膏环形涂抹于24例患者（17例男性和7例女性）的肛门内，患者年龄在23 - 71岁（平均±标准差：42.9±4.9岁）。在手术前以及涂抹后20、40、60、90、120、240、360、480和720分钟采集血样，用于测定硝苯地平和利多卡因的血清浓度。采用高效液相色谱法测定硝苯地平和利多卡因的血清浓度，以计算药代动力学参数。在研究过程中监测患者的血压、心率和心电图读数。
仅在5例患者（20.8%）中偶尔观察到硝苯地平的色谱信号，这与治疗上可忽略不计的浓度一致，不足以计算任何药代动力学参数。这5例患者中硝苯地平的血清浓度范围为5.9至18.8 ng/mL。所有患者的利多卡因浓度均可检测到。利多卡因药代动力学参数的平均值±标准差和中位数如下：最大血清浓度（C(max)）245.1±370.8 ng/mL，73.6 ng/mL；达到C(max)的时间（t(max)）69.2±78.3分钟，40分钟；0至6小时血清浓度 - 时间曲线下面积（AUC(6)）756.5±1254.1 ng·h/mL，238.2 ng·h/mL。仅3例患者的最大血清浓度高于1000 ng/mL（1037.8、1044.75和1364.1 ng/mL）。这些异常浓度比中枢神经系统利多卡因毒性阈值（5000 - 6000 ng/mL）低四至五倍。在整个研究过程中未观察到严重的局部或全身不良事件，且无受试者发生心律失常或明显的心电图变化。单次给药后血压和平均心率均无显著变化。
本研究表明，对接受Milligan - Morgan痔切除术的患者单次局部应用含硝苯地平（0.3% w/w）和利多卡因（1.5% w/w）的软膏使用安全。涂抹于受损的肛门直肠黏膜后，硝苯地平和利多卡因少量吸收入血，对产品安全性无重大影响。需要进一步研究采用多剂量方案评估血清中硝苯地平和利多卡因的浓度。
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