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Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.
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A chemical investigation on the aqueous extract of Corydalis yanhusuo tubers led to the isolation and structural elucidation of three pairs of trace enantiomeric hetero-dimeric alkaloids, (+)/(-)-yanhusamides A-C ( 1- 3), featuring an unprecedented 3,8-diazatricylco[5.2.2.02,6]undecane-8,10-diene bridged system. Their structures were exhaustively characterized by X-ray diffraction, comprehensive spectroscopic data analysis, and computational methods. Guided by the hypothetical biosynthetic pathway for 1- 3, a gram-scale biomimetic synthesis of (±)- 1 was achieved in 3 steps using photoenolization/Diels-Alder (PEDA) [4+2] cycloaddition. Compounds 1‒3 exhibited potent inhibition of NO production induced by LPS in RAW264.7 macrophages. The in vivo assay showed that oral administration of 30 mg/kg of (±)- 1 attenuated the severity of rat adjuvant-induced arthritis (AIA). Additionally, (±)- 1 induced a dose-dependent antinociceptive effect in the acetic acid-induced mice writhing assay.
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Background: Pain is the most common symptom in various pathological conditions requiring appropriate treatment with analgesics. Use of analgesics is limited by various adverse drug effects. The present study was aimed to evaluate the analgesic activity of hydroalcoholic extract of Costus pictus leaves in Wistar albino rats. Aim and Objective: The objective of this study is to evaluate the analgesic activity of hydroalcoholic extract of C. pictus leaves in Wistar albino rats. Materials and Methods: The study was conducted on 30 Wistar albino rats and was divided into five groups each of six rats. Group-I (Sterile water-equivalent volume/po), Group-II Morphine (5 mg/kg/ip), Group-III CPHAE (200 mg/kg/po), Group-IV CPHAE (400 mg/kg/po), and Group-V Diclofenac (12.5 mg/kg/po). All the rats were administered respective drugs before starting of 30 min of experiment. Central analgesic (Tail clip and hot plate) and peripheral analgesic (Writhing test) methods were used to evaluate the analgesic activity. The data were recorded and analyzed with SPSS software. Results: Group-II, III, IV and V showed significant analgesic activity compared to Group-I in both central and peripheral animal models. Group-II showed significant effect compared to Group-III and IV in the central analgesic activity. Group-V showed significant effect compared to Group-III and IV in peripheral analgesic activity. Group-IV showed significant effect compared to Group-III. Conclusion: High dose of (400 mg/kg) C. pictus plant extract showed significant analgesic activity in the central and peripheral animal models compared to low dose.
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Objective: To investigate the analgesic substances in the aerial part of Urtica fissa (Urticae Fissae Herba), commonly used for rheumatoid and rheumatism arthritis. Methods: The analgesic constituents were isolated with the active guidance of hot plate and acetic acid writhing models, and identified by comprehensive spectroscopic analysis. Results: Thirteen alkaloids (1–13), two lignans (14, 15), and three amides (16–18) were isolated from the active fractions. Among them, compound 1 was a new alkaloid, and compound 6 was a new natural product. The activity evaluation in vivo indicated that various pyrrole alkaloids (1, 3, 6, and 12) possessed significant analgesic activities, they could significantly inhibit the mice pain response induced by acetic acid and hot plate at the dosage of 2 mg/kg BW. Conclusion: The study revealed that the pyrrole alkaloids played important roles in the analgesic activities of Urticae Fissae Herba.
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Objective To explore the anti-inflammatory and analgesic mechanism of Yinlian Tongfeng granules by network pharmacology. Methods Three main active components of Yinlian Tongfeng granules were collected from TCMSP database to predict its effective targets. Based on the network information of active components and targets, the anti-inflammatory and analgesic related targets were established by using protein-protein interaction information. The enrichment analysis of KEGG biological pathway and go function enrichment were carried out to construct the active component-target-signal pathway network and explain the main mechanism of anti-inflammatory and analgesic. Results 37 targets were closely related to anti-inflammation and analgesic effects of Yinlian Tongfeng granules, mainly on Prostaglandin endoperoxide synthase 2(PTGS2), interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factors (TNF). The mechanism of action may relate to the regulation of nuclear transcription factor B signaling pathway(NF-κB). Conclusion The study predicted the anti-inflammatory and analgesic mechanism of Yinlian Tongfeng granules, and provided theoretical basis for further verification and interpretation of its mechanism.
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Background:Bixa orellanaLinn, (Family: Bixaceae) commonly known as “Lipstick tree” have been extensively used traditional medicine in India and others part of the world to cure laxative, cardiotonic, hypotensive,expectorant, antibiotic, antipyretic, aphrodisaic etc. It has been found that B. orellanacontains different phytochemical groups such as phenolic compounds, glycosides, tannins, steroids, alkaloids, saponins.The project work has been designed to investigate the phytochemical nature (group determination of plant constituents), analgesic and neuropharmacological activity of B.orellanaleaves extract. Methods:Analgesic activity of B. orellanawas determined by acetic acid induced writhing, hot plate, tail immersion and paw tickling test/formalin induced nociceptortest. Open field, hole cross, tail suspension and light/dark box test were employed for the assessment of neuropharmacological activity of B. orellana.Results:Phytochemical screening revealed the presence of reducing sugar, alkaloids, glycosides, gum,terpenoids, tannins, steroids and flavonoids. In analgesic activity test, the sample showed significant analgesic activity. The dose-dependent neuropharmacological activity is shown in neuropharmacological activity test.Conclusions:Our exploration suggests that B. orellanacontains bioactive compounds and it should be studied further for isolation and purification of such novel compounds
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Background: The objective of the study was to evaluate analgesic activity of ethanolic extract, methanol and benzene fraction of Myristica fragrans on wistar albino rats.Methods: The present study was carried out in the department of pharmacology JNMC AMU and F.H. Medical College, Agra. The analgesic activity was evaluated by employing the Eddy’s hot plate method and tail flick response method. In both the tests, Rats of either sex weighing 150-200 g were used. The total number of animals n=36 were allocated to six groups. Each group consist of six animals each. The response noted in animals that were tested by hot plate method was reaction time for licking/biting of both the paws before and after administration of control & test drugs. However in Tail flick test, the pain threshold response was recorded before and after administration of control & test drugs. The statistical analysis was done by using one-way ANOVA. The data is expressed as Mean±SEM. P<0.05 was considered to be statistically significant.Results: Ethanolic extracts and methanol fraction of M. fragrans showed statistically significant (p<0.001) increase in reaction time for licking/biting in hot plate method. On the contrary a significant increase in pain threshold was also recorded in tail flick response test. It is interesting to note that no significant degree of analgesia related to any dose of benzene fraction was observed.Conclusions: The present study reveals the dose dependent significant analgesic activity of the extracts of M. fragrans i.e. ethanolic extracts and methanol fraction in both the test. However, the degree of analgesia was recorded significantly higher in groups received higher doses of extracts of M. fragrans.
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Background: Levocetirizine, the R-enantiomer of Cetirizine has pharmacokinetically and pharmacodynamically favourable characteristics, with rapid onset of action, high bioavailability, high affinity for and occupancy of the H1-receptor, limited distribution, minimal hepatic metabolism together with minimal side effects. Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for many years for analgesic, anti-inflammatory, and more recently in the case of aspirin, antithrombotic purposes. Because of the significant side effect profiles of steroidal and NSAID medications, there is a greater interest in newer compounds such as antihistaminic drugs. This article will consider the potential or otherwise of the reported analgesic and anti-inflammatory effects of levocetirizine to enhance its effectiveness in the treatment of allergic disease with pain.Methods: Albino Wistar rats of either sex weighing 150-250 grams were used. For both Analgesic activity and Anti-inflammatory activity, 4 groups consisting of 6 animals per group were used. Group I: Control: 1% Gum acacia. 2ml/kg, Group II: Standard drug: Diclofenac sodium 4.5mg/kg; Group III: Test Drug 1: Levocetirizine 1mg/kg; Group IV: Test Drugs 2: Levocetirizine 1mg/kg+Diclofenac sodium 4.5mg/kg. Drugs were administered orally. For analgesic activity, Tail clip method and Hot plate method was used. For acute anti-inflammatory activity Carrageenan induced rat paw oedema method was used.Results: Levocetirizine, is found to have significant analgesic activity in rats (1 mg/kg dose) alone and in combination with Diclofenac Sodium in Haffner’s Tail Clip method and Eddy’s Hot Plate Method. Levocetirizine also has got prominent anti-inflammatory activity in acute models evidenced by percentage inhibition of acute rat paw oedema.Conclusions: Levocetirizine possess analgesic and acute anti-inflammatory activity alone and in combination with Diclofenac sodium.
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Background: Pain is one of the most frequent reasons for visiting a doctor. Large-scale studies in Western countries have shown that a fifth of the adult population suffer from chronic pain. Treatment of pain, still a major problem in clinical practice. Despite several available analgesics, unrelieved pain remains a major health care issue. Amitriptyline is a tricyclic antidepressant drug, which is regarded as adjuvant analgesic. There is a common consensus among the researchers on analgesic effect of amitriptyline which is mediated by central pathway but for the peripheral mechanism no conclusive evidence exists till now.Methods: To establish the analgesic mechanism of amitriptyline we tried to evaluate the analgesic activity on different mice models for central (Radiant heat tail flick test and Haffner’s tail clip method) and peripheral analgesia (Writhing test). We also compare the effects of amitriptyline with standard drugs for central and peripheral analgesia.Results: Both in Radiant heat tail flick test and Haffner’s tail clip method we found that the amitriptyline showed significant (p<0.05 to p<0.001) activity as compared to control and diclofenac group. But in comparison to pentazocin group amitriptyline didn’t show significant difference in the reaction time. In acetic acid induced writhing test amitriptyline group mice showed 41.09% reduction in number of writhes as compared to control group. While the standard control (Diclofenac) showed reduction of 65.17% as compared to control. So, amitriptyline showed comparable efficacy towards reduction in number of writhes with that of diclofenac.Conclusions: The results revealed that amitriptyline has significant analgesic activity which is mediated by modulation of both the central and peripheral pathways.
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OBJECTIVE: To study the chemical constituents and analgesic activity of the aerial parts of Skimmia multinervia. METHODS: The chemical constituents were isolated by column chromatography packed with MCI and silica gel, respectively, and the structures of the purified compounds were elucidated by NMR and MS analysis. The analgesic activities of the extract, fractions and selected compounds from the aerial parts of S. multinervia were evaluated by using acetic acid-induced writhing test in mice model. RESULTS: The structures of compounds 1-13 are identified as skimmin (1), imperatorin (2), auraptene (3), umbelliferon (4), scopoletin (5), limonin (6), limonexic acid (7), nomilin (8), citrusin (9), taraxerol (10), kanalpin (11), skimmianine (12), and methyl vanillate (13). The extract, ethyl acetate fraction, and alkaloid fraction could reduce the times of mice writhing induced by acetic acid, and the analgesic effect of compound 3, with inhibition rate of 88.18%, was much better than that of the positive control, aspirin. CONCLUSION: Compounds 1-13 are isolated from the plant for the first time, while 7, 9, 11, and 13 are firstly isolated from Skimmia genus. The analgesic activities of S. multinervia and compound 3 are reported for the first time.
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OBJECTIVE: To study the chemical constituents of Hypericum uralum were isolated and identified and test the analgesic activity and β-hematin formation inhibitory activity of some selected compounds. METHODS: The compounds were isolated and purified by column chromatography padded with the separating material including silica gel and Sephadex LH-20, and their structures were elucidated based on the analyses of modern spectrum technology. Analgesic and antimalarial activities of selected compounds from H. uralum were evaluated by acetic acid-induced writhing, hot water tail-flick test in mice, and β-hematin formation inhibition method, respectively. RESULTS: Thirteen compounds were isolated from ethyl acetate portion of 95% ethanol extract of H. uralum and identified as (-)-eriodictyol (1), 3,4,5-trihydroxyxanthone (2), 1,7-dihydroxyxanthone (3), 4-hydroxy-2,3-dimethoxyxanthone (4), toxyloxanthone B (5), 1,3,6,7-tetrahydroxyxanthone (6), 2,3-dimethoxyxanthone (7), 1,5,6-trihydroxy-3-methoxyxanthone (8), hyperielliptone HD (9), 3,3′,4,4′-tetrahydroxybiphenyl (10), shikimic acid (11), quercetin-3-O-(4″-methoxy)-α-L-rahmnopyranosyl (12), and proanthocyanidin A-2 (13). The analgesic activity test indicated that compounds 3 and 12 had certain peripheral analgesic activity, while compound 1 exhibited strong β-hematin formation inhibitory activity. CONCLUSION: All the compounds are obtained from this plant for the first time.The analgesic and antimalarial activities of H. uralum have corresponding material basis.
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Objective: The target of anti-inflammatory and analgesic active components of Qizhi Weitong Granules was predicted by network pharmacology method, and the effect of multi-component-multi-target-multi-pathways on TCM-complexation theory was analyzed. Methods: The main chemical constituents of six Chinese medicines in Qizhi Weitong Granules were collected based on the TCMSP Chinese Medicine System Biological Analysis Database and analyzed by LC-MS. The main target of each component was predicted by TCMSP search and Pharmmapper software. The relationship between drug, target and inflammatory pain target was established by DIP database and protein interaction information. In order to elucidate the main mechanism of anti-inflammatory and analgesic effects of Qizhi Weitong Granules, the network of “drug-target-disease” was constructed and the target of anti-inflammatory and analgesic effects of Qizhi Weitong Granules were analyzed by network characteristics. Results: Through the network analysis, a total of 44 inflammatory targets were closely related to Qizhi Weitong Granules, of which 20 were directly targeted, mainly for the action of proteases such as COX-2 and iNOS. The mechanism may be related to the regulation of TNF signaling pathway, NOD-like receptor signaling pathways, VEGF signaling pathways and other signaling pathways closely related to inflammation. Conclusion: The anti-inflammatory and analgesic effects of Qizhi Weitong Granules reflect the multi-component, multi-target and multi-pathway characteristics of traditional Chinese medicine. This study provides a scientific basis for further understanding the anti-inflammatory and analgesic mechanism of Qizhi Weitong Granules and explains the scientificity of the traditional Chinese medicine compatibility theory.
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Objective Traditional raw pangolin products are not used as medicine, which can only be used as medicine after processing. Therefore, the processing mechanism of high temperature sand-fried pangolin was studied. Methods The changes of liposolubility and protein composition of pangolin before and after processing were analyzed by TLC and Nano LC-Q Exactive Orbitrap MS. Meanwhile, the simulation processing of cyclic dipeptides, which were significantly increased during processing, was performed. The activity of L-serine-L-tyrosine cyclic dipeptide was screened. Results The results showed that there was no significant change in fat-soluble components, significant decrease in polypeptides and significant increase in cyclic dipeptides after the sand-fried processing of pangolin. The formation of cyclic dipeptides was mainly related to the heating of the processing. At low temperature, the N-terminal of the linear peptide could be cycled to form L-shaped cyclic dipeptides. At high temperature, the N-terminal and C-terminal of the linear peptide could be rapidly cycled to form cyclic dipeptides. L-serine-L-tyrosine cyclic dipeptide could prolong coagulation time and increase the proliferation rate of mammary epithelial cells and the expression of genes related to milk protein synthesis in dairy cows. It also had significant analgesic activity, which was consistent with the traditional efficacy of pangolin. Conclusion These results suggested that large amounts of L-serine-L-tyrosine cyclic dipeptide produced by the processing of pangolin may be one of the material bases for enhancing the processing efficiency of pangolin. It was of great significance for revealing the material basis of pharmacodynamics of pangolin, searching for alternative resources and protecting pangolin.
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Background: Pain and inflammation are the basic processes involved in the pathogenesis of many diseases. Non-steroidal anti-inflammatory drugs are often used to treat rheumatic diseases. The study compound N-Benzoyl Isoserine Methyl Ester (N-bime) is a newly synthesized propionic acid derivative by National Chemical Laboratory, Pune. Since the biological data of this compound is not available, the present study has been planned to screen this compound for anti-inflammatory, analgesic activity and its toxicity profile in animals.Methods: Single dose toxicity study was carried out in rats. Anti-inflammatory activity was tested by Rat Hind Paw Oedema and Cotton Pellet Implantation method. For Analgesic activity, Acetic acid induced writhing and Tail Pinch method was used. Yeast induced Pyrexia was used for evaluation of anti-pyretic activity. Ibuprofen was the positive control. Data are presented as mean±SEM. Statistical analysis was performed by analysis of variance and students unpaired‘t’ test.Results: The test compound N-bime did not show any apparent adverse effects or mortality in the dose range 1mg - 500mg / 100gm body weight in animals. It showed better anti-inflammatory actions in higher doses as compared to Ibuprofen (p? 0.05). In acetic acid induced writhing test N-bime offered better protection against writhes, than Ibuprofen. But, both failed to demonstrate analgesic activity in the Tail Pinch method. N-bime showed a gradual decrease in temperature in the anti-pyretic test (P<0.001).Conclusions: The present study indicates that N-bime does possess anti-inflammatory, analgesic and weak anti-pyretic properties like the NSAIDs. It has proved to be safe in the dose range of 1mg - 500mg / 100gm body weight in rats and mice.
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Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC 120 nmol·L) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.
Sujet(s)
Animaux , Femelle , Humains , Mâle , Souris , Analgésiques , Chimie , Douleur chronique , Traitement médicamenteux , Abiétanes , Chimie , Évaluation préclinique de médicament , Antienzymes , Chimie , Souris de lignée ICR , Acylglycerol lipase , Métabolisme , Relation structure-activitéRÉSUMÉ
Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC 120 nmol·L) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.
Sujet(s)
Animaux , Femelle , Humains , Mâle , Souris , Abiétanes , Chimie , Analgésiques , Chimie , Douleur chronique , Traitement médicamenteux , Évaluation préclinique de médicament , Antienzymes , Chimie , Souris de lignée ICR , Acylglycerol lipase , Métabolisme , Relation structure-activitéRÉSUMÉ
By the means of chromatographic methods and spectroscopic evidences, 7 diterpenoids were isolated and identified from the roots of Pieris formosa. These known compounds are elucidated as secorhodomollolide C(1), pierisoid B (2), secorhodomollolide B (3), secorhodomollolide A (4), pierisformotoxin G (5), pierisformotoxin B (6) and pierisformotoxin A (7). Compounds 3, 4 were obtained from this plant for the first time. The analgesic activities of compounds 1-7 were evaluated using an acetic acidinduced writhing test in mice. Compounds 3, 4, 6, and 7 exhibited significant analgesic activity at 5 mg·kg;⁻ (ip) compared to vehicle-injected mice (<0.05). The writhe inhibition rates of compounds 3, 4, 6 and 7 at 5 mg·kg⁻¹ (ip) were 41.3%, 39.4%, 38.6% and 37.5%, respectively.
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Buthus martensii is a precious Chinese materia medica, which has been extensively studied due to its various pharmacological effects such as anti-microbial activity, anti-tumor activity, analgesic activity, etc. This paper reviews domestic and foreign researches about the pharmacological activities of peptides from B. martensii, which will provide references for the utilization of these active medicinal peptides in B. martensii.
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Objective To study the overall similarity of composition-activity of different kinds of Paridis Rhizoma, and establish a new method for selecting alternative resources. Methods The HPLC method was used to detect the content of polyphyllin I, II, VI, and VII, and pharmacological model of analgesic and hemostatic were used to detect the efficacy. The data were standardized using standard deviation method. Using polyphyllin I, II, VI, and VII at minimum 0.6%, aspirin and Yunnan Baiyao Group analgesic and hemostatic efficacy data as standard controls, we also established component and activity indexes. SPSS 20.0 Software was used to analyze the principal component analysis (PCA) and hierarchical cluster analysis (HCA) of these seven medicinal plants. Results The total content of the main saponins in seven medicinal plants of Paris genus ranged from 0.125% to 1.649%, and the maximum content (1.649%) was found in the P. forrestii while the minimum content (0.125%) was found in P. daliensis. The study also disclosed that P. polyphylla var. yunnanensis has the most active analgesic activity, and the time of bleeding (BT) in mice and the time of coagulation (CT) in mice were the shortest in P. polyphylla. The shortest mice activated partial thrombin time (APTT) was P. forrestii and the longest was P. thibetica. The shortest prothrombin time (PT) in mice was P. vietnamensis. The longest BT in mice was P. daliensis. The longest CT and PT in mice was P. polyphylla. PCA and HCA results showed that P. polyphylla var. yunnanensis, P. vietnamensis and P. thibetica were in the same class, while P. pubescens, P. daliensis, P. polyphylla, and P. forrestii were in another class. It is indicated that the overall similarity of component-activity of P. vietnamensis, P. thibetica, and P. polyphylla var. yunnanensis was higher, thus they can be considered as alternative sources. Conclusion The quality relations of different kinds of Paris genus were evaluated by the overall similarity of the component and activity index, which provides ideas and methods for the search of the replacement resources of the endangered plants.
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Ipomoea pes-caprae, the plant of Ipomoea (Convolvulaceae), is the marine medicine growing in the intertidal zone of coasts. It is not only the Jing nationality medicine in the southern coastal areas of China, but also the folk medicine in the tropical and subtropical countries such as Australia, Mexico, Thailand, Brazil, and Pakistan. It is resource-rich and widely used. The main compounds contain resin glycosides, terpenoids, phenolic acid, flavonoids, volatile oils, and steroids. Pharmacological studies have been reported that I. pes-caprae has a variety of pharmacological activities, such as antitumor, antibiosis, anti-inflammatory and analgesic, anticollagenase, anti-oxidation, immun regulation, and other activities. The recent study on chemical composition and pharmacological activities of I. pes-caprae are summarized in this paper to provide reference for the clinical application, quality control and product development of the marine medicine.