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The “eighteen incompatible medicaments” is an important content of Chinese materia medica (CMM) compatibility contraindication, involving the key basic problem of safe and effective clinical use of CMM. Based on the rule of the automatic action of supramolecular “imprinting template” previously proposed, the current research basis of “eighteen incompatible medicaments” were integrated and analyzed. Firstly, the history of “eighteen incompatible medicaments” were summarized, then the theory of Chinese materia medica (CMM) compatibility was interpreted by supramolecular “imprinting template”: the compatibility of CMM are that two or more than two kinds of CMM effective components group of molecules (object) are combined by non-covalent bonds, and the new formed supramolecular system and the human body (subject) are interacted with each other according to “imprinting template”, and then the toxicity and efficacy were generated, while the compatibility law of CMM is displayed macroscopically. Based on this, three groups of “eighteen incompatible medicaments” were discussed from the perspective of supramolecular chemistry, and the supramolecular method integrating toxicity with efficacy was put forward, including “chemicalkinetics”, “network kinetics” and “spectrum toxicity and efficacy kinetics” methods, thereby providing the ideas and reference for the research on the mechanism of “eighteen incompatible medicaments” and providing reference for clinical application.
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“Incompatibility” is the focus of the “Eighteen Incompatible Medicaments” in Chinese materia medica. At present, most experts in traditional Chinese medicine supported that “incompatibility” is relative, that is, the conversion between incompatibility and appropriate compatibility can occur under certain conditions. Genkwa Flos and Glycyrrhizae Radix et Rhizoma are one of the representative of incompatible pairs in “Eighteen Incompatible Medicaments”, which had been well studied. This paper summarized the research progress of the incompatible pairs of Genkwa Flos and Glycyrrhizae Radix et Rhizoma from seven aspects of material basis, pharmacological toxicology, drug metabolism and metabolomics, incompatibility mechanism, gut microbiota, clinical application and compatibility conditions. Combined with the author’s previous systematic study on the chemical components of Daphne genkwa, the connotation of the material base of Genkwa Flos and Glycyrrhizae Radix et Rhizoma was discussed from the perspective of the weak bond between the active components in this paper, so as to provide reference for further research of the incompatible pair.
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OBJECTIVE： To investigate the historical evolution and clinical application of “eighteen incompatible medicaments” and “nineteen medicaments of mutual restraint” of TCM， and to provide reference for enriching the contents of rational use of TCM. METHODS： Through the methods of literature mining， using “eighteen incompatible medicaments” “nineteen medicaments of mutual restraint” “incompatible medicaments” “clinical use” “ADR” “ADE” as keywords， retrieved from CNKI， Wanfang， VIP database （from the date of database establishment to August 2018） and library of Henan University of TCM， related literatures about “eighteen incompatible medicaments” and “nineteen medicaments of mutual restraint” were extracted and combed， and the history and clinical application of them were summarized and analyzed. RESULTS & CONCLUSIONS： “Eighteen incompatible medicaments” is one of the main contents of TCM basic theory. The word is first published in Shubencao， which is the concrete embodiment of the “opposite” in the “seven compatibility regularities” of TCM， and the number of “eighteen incompatible medicaments” of TCM recorded in the medical books of TCM is different from each other in the past dynasties. “Nineteen medicaments of mutual restraint” is one of the taboos of TCM compatibility， which is first found in Shennong’s Herbal. There are mixed use of “mutual inhibition” “incompatible” and “mutual restraint” in all dynasties， and there is still controversy about the attribution of “seven compatibility regularities” of “nineteen medicaments of mutual restraint” among physicians. Regardless of ancient medical books， modern medical books， various editions of Chinese Pharmacopeia， literature reports and clinical applications， there are compatibility usage of drug pairs of “eighteen incompatible medicaments” and “nineteen medicaments of mutual restraint”. Among them， 8 kinds of set prescription preparations containing drug pair of “eighteen incompatible medicaments” were involved in 2015 edition of Chinese Pharmacopoeia （part Ⅰ）， most of which were Aconitum carmichaelii/Aconitum kusnezoffii-Bletilla striata/Ampelopsis japonica； 9 kinds of set prescription preparations containing drug pair of “nineteen medicaments of mutual restraint” were also involved， most of which were Syringa oblate-Curcuma rcenyujin， Cinnamomum cassia-Halloysitum rubrum. Although there are medical records or literature pointing out that it can be used to treat critical and difficult diseases， and some studies have preliminarily confirmed the compatibility rationality of individual incompatibility medicaments/medicaments of mutual restraint， the conclusions of relevant studies are not entirely consistent， and the intensity of research evidence is not high， and the research evidence is insufficient. Basic researches should be strengthened and large-scle， multiple-center and high-quality clinical studies are needed to confirm this conclusion so as to guaratetee the rationality and safety of drug use in clinic.
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Currently,the toxicity study of traditional Chinese medicine is faced with the following problems. Firstly,the evaluation in vitro cannot fully reflect the true state of the body. Secondly,the traditional method is not sensitive enough to the early toxicity. Lastly,the toxicity evaluation indexes cannot determine whether the compatibility of traditional Chinese medicine produces toxicity or increases toxicity systematically. The paper proposed a synthesized early evaluation research method for target organ toxicity induced by traditional Chinese medicine:screening,validation,optimization and application. This method mainly inoolves early target organ toxicity biomarkers in screening,optimi?zation,validation,biological significance explanation,and application to the traditional Chinese medicine incompatibility based on the metabolic dynamic fingerprint spectrum in order to obtain biomarkers of target organ toxicity that are sensitive and precede conventional biochemical indices for early evaluation . We attempted to analyze the pattern of chang of the biomarkers for animals acted by″18 incompatible medicaments″compatibility combination. We found that Radix Aconiti Lateralis Preparata with cardiotoxicity were compatible with Rhizoma Pinelliae,and that Trichosanthes kirilowii Maxim,Fritillaria,Ampelopsis Radix and Bletilla striata without non-cardiotoxicity produced and increased cardiotoxicity systematically.
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Objective To compare the potential cytotoxicity induced by Veratrum nigrum coadministered with Panax ginseng, and to provide experimental evidence on the mode of herb-herb interaction based on human liver drug metabolizing enzymes.Methods The effect of V.nigrum and coadministration on cultured human hepatoma (HepG2) cells was investi-gated by detecting morphological changes , cell viability , cytomembrane integrity and apoptosis after the cells were treated for 24 h.The mRNA expression levels of drug metabolizing enzymes influenced by P.ginseng were determined by real-time quantitative reverse-transcriptase polymerase chain reaction .Results V.nigrum coadministered with P.ginseng had a better inhibitive effect on the growth of HepG2 cells at the IC50value of (15.18 ±1.03) mg/ml than at the value of IC50 (21.46 ±1.10) mg/ml of V.nigrum.Coadministration more significantly raised the LDH level in cell culture medium than at the same dose of V.nigrum.Moreover, in coadministration group, compared with the same dose of V.nigrum,the total apoptosis and necrosis of HepG2 cells were significantly increased .P.ginseng had effect on the expression of CYP3A4, CYP1A1, CYP1A2, CYP2B6 and CYP2E1 mRNA.Conclution Compatibility of medicines in a prescription also has herb-herb interactions based on drug metabolizing enzymes .The interaction mode is that the P.ginseng inhibits and induces CYPs and the modulated CYP isozymes ,inturn,have an impact on the metabolism of constituens in coadministered herbs causing herb-herb interaction .
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Objective To investigate the damage of mice liver and kidney with the compatibility application of Paeoniae radix rubra and Veratrum nigrum, and explore its mechanism. Methods We examined the alanine aminotransferase, aspartate aminotransferase (AST), lactic dehydrogenase, creatinine and urea nitrogen from serum, and glutathion peroxidase (GSH-Px) and malondialdehyde (MDA) from liver and kidney tissue after intragastric administration of different ratio (4∶1, 2∶1, 1∶1, 1∶2, 1∶4) of Paeoniae radix rubra and Veratrum nigrum in mice for 22 d. Results Paeoniae radix rubra used with Veratrum nigrum did not induce the obvious damage to liver with AST increase, but induced the obvious damage to kidney. At the same time, the depressed GSH-Px activity and the increased MDA content were observed in kidney tissue. When Paeoniae radix rubra and Veratrum nigrum is on a ratio of 2∶1, the kidney injury was the most obvious. Conclusion Paeoniae radix rubra used with Veratrum nigrum in varying proportions could induce the kidney injury in mice which is related to the oxidation-antioxidation balance disturbance.
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The eighteen incompatible medicaments is the incompatibilities in traditional Chinese medicine (TCM). However, in some special occasion, the incompatible medicaments can also be used in one prescription in the clinical applications. In order to reveal the theoretical basis for applications of incompatible medicaments in prescriptions, we analyzed ancient prescriptions and found that there are contrary Chinese herbal nature combina-tions (CHNCs) which have the same meridian tropism as well as the opposite nature and taste in prescriptions. In clinical applications, one of the non-contrary CHNCs was selected as the main response to syndrome differentia-tion. The contrary CHNCs in the same meridian tropism were used to restrict each other and therefore have the protective effects. The features found in this paper will be beneficial to further research on the rational applica-tion of incompatible medicaments.