TABLE 2.
Characteristics of included studies.
| Intervention | Type of the study | Country | Participants | Benefit in humans | Adverse drug reactions | References | The offending drug(s) | Criteria for DILI/drug induced toxic hepatitis diagnosis |
|---|---|---|---|---|---|---|---|---|
| Bicyclol | Randomized, double blind, positive controlled, multicenter phase II study | China | 244 | Results not published; Primary outcome measure: ALT decline range | Not applicable (NA) | NCT02944552 (2016) | NA | Acute DILI clinical diagnosis, patients with ALT 3–-20× ULN, TBL ≤2× ULN, liver biochemical abnormalities duration ˂90 days were included in the study |
| Bicyclol | Randomized, positive controlled, multicenter study | China | 168 | The ALT levels in the bicyclol group significantly lower vs. control group | No SAEs, no statistically significant differences between the two groups in AEs | Naiqiong et al. (2017) | Statins | Acute DILI clinical diagnosis, patients with ALT ≥ 2–5× ULN, TBL ≤2× ULN, liver biochemical abnormalities duration ˂3 months were included in the study |
| Calmangafodipir | Randomized open-label, rising-dose phase I study | United Kingdom | 24 | Good safety profile and reduced biomarkers of paracetamol toxicity (ALT, INR) | No AEs or SAEs were probably or definitely calmangafodipir-related | Morrison et al. (2019); The POP Trial Investigators and Dear (2019) | Paracetamol | No official definition, but hepatotoxicity was assessed using ALT and INR. |
| Cytisin amidophosphate | Randomized, double blind, positive controlled, single-center study | Kazakhstan | 142 | Normalization of hepatic inflammatory markers, increase activity of antioxidant enzymes | Tachycardia and hypertension related to high doses of cytisin amidophosphate | Zhumadilov et al. (2012) | Ethyl alcohol, alcohol surrogates, reserpine, paracetamol | No official definition, but patients with diagnosis of acute toxic hepatitis based on history, ultrasound and biochemical tests (ALT, AST, TBL) were included in the study |
| Fomepizole | Randomized, double-blind, cross-over, single centre, study | United States | 5 | Reduced oxidative metabolism and NAPQI production after paracetamol overdose | NA | Kang et al. (2020) | Paracetamol | DILI was not considered, but paracetamol and its metabolites |
| Fomepizole | Case report, case series | United States | 8 | ALT, AST and INR normalisation and/or significant decrease of paracetamol plasma concentration | Not reported | Zell-Kanter et al. (2013); Rampon et al. (2020); Shah and Beuhler (2020) | paracetamol, ethanol, benzodiazepine, diphenhydramine, salicylate, ibuprofen, loperamide | No official definition, but patients with increased AST and ALT levels and/or elevated paracetamol plasma concentration |
| Livina a | Randomized, single blind, placebo controlled study | India | 42 | AST, ALT significantly lower in the Livina vs. placebo group | None related to the Livina treatment | Gulati et al. (2010) | Antituberculotic drugs: rifampicin, Isoniazid, ethambutol, pyrazinamide | No official definition, but efficacy of the Livina or placebo was assessed by performing liver function tests (serum bilirubin, AST, ALT and ALP) |
| Magnesium Isoglycyrrhizinate (MgIG) | Randomized, double-blind, active controlled, multidose, multicentre phase II study | China | 174 | ALT normalization in MgIG groups (either dose) significantly greater vs. active control group | No significant difference in safety | Wang et al. (2019) | Antituberculotic drugs, antitumor, traditional Chinese medicine, antibiotics, cardiovascular,anti-inflammatory, hormone | No official definition, but patients with ALT ≥ 2× ULN, TBL ≤ 3× ULN, liver biochemical abnormalities duration ≤3 months were included in the study |
| MgIG | Randomized, single-blind, controlled, multicentre phase IV study | China | 73 | Results not published; Primary Outcome Measure: ALT normalization rate | NA | NCT04595916 (2020) | NA | Acute DILI clinical diagnosis, patients with ALT ≥ 3× ULN, TBL ≤5× ULN, duration of current liver injury ˂6 months were included in the study |
| S-adenosylmethionine | Retrospective study | Italy | 233 | Reduction of AST, ALT, LDH, and TBL, AP, GGT, liver toxicity grade, minimal number of chemotherapy dose reductions or administration delays | Not reported | Vincenzi et al. (2011); Vincenzi et al. (2012) | Chemotherapy regimens b (FOLFIRI, CMF, FOLFOX, Bevacizumab+XELOX) | No official definition, but patients with AST or/and ALT ≥ 2.5× ULN, were included in the study |
| Prospective study | Santini et al. (2003) | Liver toxicity was assessed according to NCI-CTCAE c (version 3), course delays, discontinuations and dose reductions due to liver toxicity were recorded | ||||||
| Picroliv | Randomized, placebo controlled study | India | 260 in protocol, but 182 in abstract | Protocol is available online, results in abstract form only—inconsistent | NA | Gaur and Bhosale, (2002); Bhosale et al. (2013) | Antituberculotic drugs | No official definition |
| Plasma exchange (TPE) | Retrospective study | India | 10 | Significant improvement in aminotransferases, TBL, direct bilirubin, INR | None related to the TPE. | Sachan et al. (2017); Jothimani et al. (2018) | Antituberculotic drugs, antimalarial drugs with paracetamol overdose, native medication for skin and rheumatic disorders, stanazol, carbamazepine, Augmentin | No official definition, but patients with bilirubin >15 mg/dl and diagnosed as DILI with history of recent drug intake were included in study |
| TPE | Case reports, case series, Letter to the editor | Turkey, Germany, India, Spain, China | 19 | Pathological, laboratory and clinical markers of liver function have been improved | None reported and related to TPE | Aydemir et al. (2005); Bilgir et al. (2013); Liu et al. (2013); Göpel et al. (2016); Philips et al. (2017); Riveiro-Barciela et al. (2019); Rong et al. (2020) | Propylthiouracil, L-asapaginase, PEG-asparaginase, metoprolol, ipilimumab, complementarymedication containing Fructus Psoraleae | Liver scintigraphy, liver function tests, liver biopsy, NA |
| TPE | Randomized controlled trial | India | 30 | Significant reduction in bilirubin, bile acid levels, INR and IL-6/TNF-α/IL-1β | Hypocalcaemia (59.2%) and alkalosis (42.9%) were the major adverse events; one patient had TRALI during TPE | Sinha et al. (2020) | Complementary and alternative medicines, not known for all participants | Diagnosis of severe DILI, based on history and liver biopsy and graded for the severity as by DILIN |
| Radix Paeoniae Rubra (RPR) | Prospective study | China | 14 | The levels of ALT, AST, TBL, direct bilirubin, total bile acid, Child-Pugh and MELD d scores significantly decreased; the levels of albumin and cholinesterase statistically significantly elevated. Improved jaundice, fatigue | Diarrhea in six cases, but spontaneously disappeared after the RPR discontinuation | Jing et al. (2017) | Different spectra of drugs, including antibiotics, paracetamol, alternative medications | No DILI definition, no data about causality assessment |
a
Polyherbal preparation of 50 mg each of Picrorhizha kurroa (kutaki), Phyllanthus niruri (bhuyamalaki), Andrographis paniculata (kalmegh), Cichorium invitybus (kasni), Tephrosia purpurea (sharphaunka), Solanum dulcamara (kakamarchi), Crenum aciaticum (macchaka), Astonia seholanis (saptaparna), and 25 mg each of Holarrhave ntidysentric (indriyava), Tinospora cordifolia (guduchi), Terminala chebula (Haritaki), Asteracantha longifolia (kakilakshya).
b
FOLFIRI regimen, Raltitrexed, Oxaliplatin, Irinotecan, 5-Fluorouracil (5-FU), Folinic Acid (FA); CMF regimen, Cyclophosphamide (CTX), Methotrexate (MTX) plus 5-FU; FOLFOX regimen: Oxaliplatin, FA, 5-FU; Bevacizumab + XELOX regimen: Bevacizumab, Oxaliplatin, Capecitabine.
c
NCI-CTCAE: National Cancer Institute—The NCI Common Terminology Criteria for Adverse Events.
d
MELD: model for end-stage liver disease.