Anderson Nora, Borlak Jürgen
Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
J Clin Med. 2019 May 10;8(5):652. doi: 10.3390/jcm8050652.
Petadolex, a defined butterbur extract has clinically proven efficacy against migraine attacks. However, spontaneous reports indicate cases of herbal induced liver injury (HILI). While most HILI patients presented mild serum biochemistry changes (<3 ULN, dose range 50 to 225 mg/day; treatment duration 4-730 days) nine developed severe HILI (average time-to-onset 103 days, ALT-range 3-153; AST 2-104-fold ULN). HILI cases resolved after medication withdrawal though two patients required liver transplantation. Liver biopsies revealed an inconsistent injury pattern, i.e. necrosis, macrovesicular steatosis, inflammation, cholestasis, and bile duct proliferation. Causality assessment rated 3 cases likely, 13 possible, 8 unlikely and 24 as unclassifiable/unclassified. Note, 22 patients reported hepatotoxic co-medications especially during periods of pain. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At >45 and 90-fold MCD bile duct hyperplasia was observed but could not be confirmed in an explorative minipig study at 218-fold MCD. Human hepatocyte studies at 49-fold C serum petasins (=active ingredient) and therapeutic Ibuprofen, Paracetamol and Naratriptan concentrations evidenced liver transaminase and CYP-monooxygenase changes. Collectively, Petadolex HILI cases are rare, idiosyncratic and frequently confounded by co-medications. A physician-supervised self-medication plan with herbs and pain relief medication is needed to minimize risk for HILI.
倍他朵力克（Petadolex）是一种经过提纯的白藜芦醇提取物，已被临床证明对偏头痛发作有效。然而，自发报告显示存在草药性肝损伤（HILI）病例。虽然大多数HILI患者的血清生化指标仅有轻度变化（<3倍正常上限值，剂量范围为50至225毫克/天；治疗持续时间为4至730天），但有9例发展为严重HILI（平均发病时间为103天，谷丙转氨酶（ALT）范围为3至153；谷草转氨酶（AST）为正常上限值的2至104倍）。停药后HILI病例病情得到缓解，不过有两名患者需要进行肝移植。肝活检显示损伤模式不一致，即坏死、大泡性脂肪变性、炎症、胆汁淤积和胆管增生。因果关系评估将3例评定为可能相关，13例为可能相关，8例为不太可能相关，24例为无法分类/未分类。注意，22例患者报告了肝毒性合并用药情况，尤其是在疼痛发作期间。在大鼠中确定了最大临床剂量（MCD，3毫克/千克/天）15倍时的无可见不良反应水平。在45倍和90倍MCD时观察到胆管增生，但在一项探索性小型猪研究中，在218倍MCD时未得到证实。在49倍C血清中的活性成分（白藜芦醇）以及治疗剂量的布洛芬、对乙酰氨基酚和那拉曲坦浓度下进行的人肝细胞研究证明了肝转氨酶和细胞色素P450单加氧酶的变化。总体而言，倍他朵力克导致的HILI病例罕见、具有特异性，并且经常因合并用药而混淆。需要医生监督的草药和止痛药物自我用药计划，以将HILI风险降至最低。
