Rieke J W, Hafermann M D, Johnson J T, LeVeque F G, Iwamoto R, Steiger B W, Muscoplat C, Gallagher S C
Division of Radiation Oncology, Virginia Mason Medical Center, Seattle, WA 98111.
Int J Radiat Oncol Biol Phys. 1995 Feb 1;31(3):661-9. doi: 10.1016/0360-3016(94)00361-N.
Pilocarpine hydrochloride administered in either a fixed-dose or in a dose-titration protocol three times a day for 12 weeks was evaluated for its ability to relieve symptoms of postradiation xerostomia and to improve saliva production. The studies were randomized, double-blind, placebo-controlled, multicenter clinical trials. A total of 369 patients who had received at least 40 Gy of radiation to the head and neck with clinically significant xerostomia were enrolled in the two studies. In the dose-titration study, 162 patients were enrolled and they received a thrice daily regimen of 2.5 mg tablets for first 4 weeks, 5.0 mg tablets for the second 4 weeks, and 10.0 mg tablets for last 4 weeks of a 12-week study. Patients in the titration study were allowed to down titrate following at least one dose escalation to alleviate bothersome side effects, if any. In the fixed dose study, 207 patients received either placebo, 5.0 mg, or 10.0 mg tablets t.i.d. for 12 weeks.
Patients were evaluated for symptomatic relief by responding to questionnaires using visual analog scales and categorical questions; and, for saliva production by sialometry. Questionnaires measured relief of intraoral dryness, improvement in overall condition (global response), oral discomfort, difficulty in speaking, chewing and swallowing, denture wearing, and usage of artificial saliva. Evaluations were conducted at baseline, and weeks 4, 8, and 12.
There were statistically significant improvements in salivary flow in pilocarpine treatment groups vs. placebo. There was a significant improvement in the overall "global" condition of xerostomia associated with the use of pilocarpine in both studies. In the fixed-dose study, there were significant improvements in oral dryness, mouth comfort, ability to speak, and reduction in the use of oral comfort agents. The dose-titration study showed improvements in dryness that approached significance (p = 0.057) and a decreased use of oral comfort agents (p = 0.045). All pilocarpine dosages (2.5, 5.0, and 10.0 mg three times a day) were judged to be safe. Adverse experiences were those expected for a cholinergic agonist, with the most common being mild to moderate sweating. The incidence of these events increased by dose.
It is concluded that in these studies pilocarpine produced clinically significant benefits with acceptable side effects and risks for the treatment of symptomatic postradiation xerostomia. The incidence of most adverse events increased with dose. Best results may require continuous treatment for more than 8 weeks with doses greater than 2.5 mg three times a day. A 5.0 mg thrice daily regimen produced the best clinical results when both efficacy and side effects were taken into consideration. There may be some patients who would experience some additional benefit by increasing the dose to 10 mg thrice daily.
评估按固定剂量或剂量滴定方案每日三次服用盐酸毛果芸香碱12周，缓解放射性口干症状及增加唾液分泌的能力。这些研究为随机、双盲、安慰剂对照的多中心临床试验。两项研究共纳入369例头颈部接受至少40 Gy放疗且有临床显著口干症状的患者。在剂量滴定研究中，纳入162例患者，在为期12周的研究中，他们在前4周每日服用三次2.5 mg片剂，中间4周每日服用三次5.0 mg片剂，最后4周每日服用三次10.0 mg片剂。滴定研究中的患者在至少一次剂量增加后，若出现令人困扰的副作用，可降低剂量。在固定剂量研究中，207例患者每日三次服用安慰剂、5.0 mg或10.0 mg片剂，持续12周。
通过视觉模拟量表和分类问题问卷评估患者的症状缓解情况；通过唾液流量测定评估唾液分泌情况。问卷测量口腔内干燥缓解情况、整体状况改善（总体反应）、口腔不适、说话、咀嚼和吞咽困难、佩戴假牙情况以及人工唾液使用情况。在基线、第4、8和12周进行评估。
与安慰剂相比，毛果芸香碱治疗组的唾液流量有统计学显著改善。在两项研究中，使用毛果芸香碱均使口干的整体“总体”状况有显著改善。在固定剂量研究中，口腔干燥、口腔舒适度、说话能力均有显著改善，口腔舒适剂使用减少。剂量滴定研究显示口干改善接近显著水平（p = 0.057），口腔舒适剂使用减少（p = 0.045）。所有毛果芸香碱剂量（每日三次2.5、5.0和10.0 mg）均被判定为安全。不良事件为胆碱能激动剂常见的不良反应，最常见的是轻度至中度出汗。这些事件的发生率随剂量增加。
得出结论，在这些研究中，毛果芸香碱对放射性口干症状的治疗产生了具有临床意义的益处，且副作用和风险可接受。大多数不良事件的发生率随剂量增加。最佳结果可能需要每日三次服用剂量大于2.5 mg持续治疗8周以上。综合疗效和副作用考虑，每日三次5.0 mg的治疗方案产生了最佳临床效果。可能有部分患者将剂量增加至每日三次10 mg会有更多益处。
