Research progress in pharmacology and toxicology of evodiamine / 中国中药杂志

Evodiamine, a bioactive indole alkaloid from Evodia rutaecarpa, E. rutaecarpa var. officinalis, or E. rutaecarpa var. bodinieri, has been extensively investigated due to its pharmacological activities in recent years. At present, evodiamine is proved to significantly suppress the proliferation of a variety of cancer cells and mediate cell processes such as cell cycle arrest and cell migration. In addition, evodiamine displays significant pharmacological activities against cardiovascular diseases(hyperlipidemia, etc.), and tinea manus and pedis. Recently, evodiamine has been found to have potential toxic effects, such as hepatotoxicity, nephrotoxicity, and cardiotoxicity. However, the pharmacological and toxicological mechanism of evodiamine is not clear, and its toxicity in vitro and in vivo has been rarely reported. Therefore, this study reviewed the pharmacological and toxicological articles of evodiamine in recent years, aiming at providing new ideas and references for future research.

Evodiamine Reduces Caffeine-Induced Sleep Disturbances and Excitation in Mice

Worldwide, caffeine is among the most commonly used stimulatory substances. Unfortunately, significant caffeine consumption is associated with several adverse effects, ranging from sleep disturbances (including insomnia) to cardiovascular problems. This study investigates whether treatment with the Evodia rutaecarpa aqueous extract (ERAE) from berries and its major molecular component, evodiamine, can reduce the adverse caffeine-induced sleep-related and excitation effects. We combined measurements from the pentobarbital-induced sleep test, the open field test, and the locomotor activity test in mice that had been dosed with caffeine. We found that ERAE and evodiamine administration reduced the degree of caffeine-induced sleep disruption during the sleep test. Additionally, we found that evodiamine significantly inhibits caffeine-induced excitation during the open field test, as well as decreasing hyperlocomotion in the locomotor activity test. Additional in vitro experiments showed that caffeine administration decreased the expression of γ-aminobutyric acid (GABA)(A) receptor subunits in the mouse hypothalamus. However, evodiamine treatment significantly reversed this expression reduction. Taken together, our results demonstrate that ERAE and its major compound, evodiamine, provide an excellent candidate for the treatment or prevention of caffeine-induced sleep disturbances and excitatory states, and that the mechanism of these beneficial effects acts, at least in part, through the GABA(A)-ergic system.

Molecular diversity analysis of Tetradium ruticarpum (WuZhuYu) in China based on inter-primer binding site (iPBS) markers and inter-simple sequence repeat (ISSR) markers / 中国天然药物

"Wu zhu yu", which is obtained from the dried unripe fruits of Tetradium ruticarpum (A. Jussieu) T. G. Hartley, has been used as a traditional Chinese medicine for treatment of headaches, abdominal colic, and hypertension for thousands of years. The present study was designed to assess the molecular genetic diversity among 25 collected accessions of T. ruticarpum (Wu zhu yu in Chinese) from different areas of China, based on inter-primer binding site (iPBS) markers and inter-simple sequence repeat (ISSR) markers. Thirteen ISSR primers generated 151 amplification bands, of which 130 were polymorphic. Out of 165 bands that were amplified using 10 iPBS primers, 152 were polymorphic. The iPBS markers displayed a higher proportion of polymorphic loci (PPL = 92.5%) than the ISSR markers (PPL = 84.9%). The results showed that T. ruticarpum possessed high loci polymorphism and genetic differentiation occurred in this plant. The combined data of iPBS and ISSR markers scored on 25 accessions produced five clusters that approximately matched the geographic distribution of the species. The results indicated that both iPBS and ISSR markers were reliable and effective tools for analyzing the genetic diversity in T. ruticarpum.

Molecular diversity analysis of Tetradium ruticarpum (WuZhuYu) in China based on inter-primer binding site (iPBS) markers and inter-simple sequence repeat (ISSR) markers / 中国天然药物

"Wu zhu yu", which is obtained from the dried unripe fruits of Tetradium ruticarpum (A. Jussieu) T. G. Hartley, has been used as a traditional Chinese medicine for treatment of headaches, abdominal colic, and hypertension for thousands of years. The present study was designed to assess the molecular genetic diversity among 25 collected accessions of T. ruticarpum (Wu zhu yu in Chinese) from different areas of China, based on inter-primer binding site (iPBS) markers and inter-simple sequence repeat (ISSR) markers. Thirteen ISSR primers generated 151 amplification bands, of which 130 were polymorphic. Out of 165 bands that were amplified using 10 iPBS primers, 152 were polymorphic. The iPBS markers displayed a higher proportion of polymorphic loci (PPL = 92.5%) than the ISSR markers (PPL = 84.9%). The results showed that T. ruticarpum possessed high loci polymorphism and genetic differentiation occurred in this plant. The combined data of iPBS and ISSR markers scored on 25 accessions produced five clusters that approximately matched the geographic distribution of the species. The results indicated that both iPBS and ISSR markers were reliable and effective tools for analyzing the genetic diversity in T. ruticarpum.

Composition of essential oils from Euodia lepta (Spreng.) Merr and Euodia calophylla Guill., grown in Vietnam / Composición de los aceites esenciales de Euodia lepta (Spreng.) Merr y Euodia calophylla Guill., crecidas en Vietnam

The chemical compositions of essential oils obtained by hydrodistillation of the leaves, stems and flowers of Euodia lepta and Euodia callophylla grown in Vietnam and then analysed by gas chromatography-flame ionization detector (GC-FID) and gas chromatography/mass spectrometry (GC-MS) were being reported. The main compounds of the leaves oil of E. lepta were (E)-beta-ocimene (24.4 percent), alpha-pinene (9.8 percent), (Z)-beta-ocimene (6.3 percent) and delta-cadinene (5.2 percent), while the stems oil comprised of spathulenol (26.0 percent), (E)-beta- ocimene (9.9 percent) and (Z)-9-octadecenamide (7.7 percent). However, ciscarane (19.2 percent), alpha-cadinol (10.8 percent), alpha-pinene (10.5 percent) and (E)-beta-ocimene (9.0 percent) were present in the flowers oil of E. lepta. On the other hand, alpha-pinene (8.3 percent), trans-alpha-bergamotene (7.5 percent), (E)-beta-ocimene (7.0 percent) and (E)-nerolidol (6.6 percent) were the major constituents of the leaves oil of E. calophylla. The quantitatively significant compounds of the stems oil were (E,E)-alpha-farnesene (11.9 percent), alpha-terpinolene (11.3 percent) and alpha-pinene (8.2 percent), while alpha-pinene (21.6 percent), limonene (19.0 percent) and sabinene (15.5 percent) were obtained from the flowers oil...

La composición químicas de los aceites esenciales obtenidos por hidrodestilación de las hojas, tallos y flores de Euodia lepta y Euodia callophylla cultivadas en Vietnam, fueron analizados por cromatografía de gases-detector de ionización de llama (GC-FID) y la cromatografía de gases/espectrometría de masas (GC-MS). Los principales compuestos del aceite de hojas de E. lepta fueron (E) -beta-ocimeno (24,4 por ciento), alfa-pineno (9,8 por ciento), (Z)-beta- ocimeno (6,3 por ciento) y delta-cadineno (5.2 por ciento), mientras que los tallos de aceite estaban compuestos de spatulenol (26,0 por ciento), (E) -beta-ocimeno (9,9 por ciento) y (Z) -9- octadecenamida (7,7 por ciento). Sin embargo, cis-carano (19,2 por ciento), alfa-cadinol (10,8 por ciento), alfa-pineno (10,5 por ciento) y (E) -beta-ocimeno (9,0 por ciento) estaban presentes en el aceite de flores de E. lepta. Por otro lado, alfa-pineno (8,3 por ciento), trans-alfa-bergamoteno (7,5 por ciento), (E) - beta-ocimeno (7,0 por ciento) y (E) -nerolidol (6,6 por ciento) fueron los principales constituyentes del aceite de las hojas de E. calophylla. Los compuestos cuantitativamente significativos del aceite de los tallos fueron (E, E)-farneseno -alfa (11,9 por ciento), alfa-terpinoleno (11,3 por ciento) y alfa-pineno (8,2 por ciento), mientras que alfa-pineno (21,6 por ciento), limoneno (19,0 por ciento) y sabineno (15,5 por ciento) se obtuvieron del aceite de las flores...

Study on efficacy accompanied by side effects of water extraction components of Evodiae Fructus based on syndrome model / 中国中药杂志

The range of effective dose and mechanism of abirritation about water extraction components of Evodiae Fructus on the stomach cold syndrome model in mice were preliminary studied. The method of stomach cold-syndrome model in mice was built, which were administrated with different doses water extraction components of Evodiae Fructus, observing abirritation and toxicity by the classical hot plate method, detecting the level of ALT, AST, PGE2, NO, NOS, MDA, SOD, GSH, GSH-Px, BUN, CR in serum and ALT, AST in hepatic tissue, and recording toxicity symptoms in mice according to the list of relevant toxicity reaction. The water extraction component of Evodiae Fructus has obvious analgesic action after administration 30 min, arriving peak effect after administration 60 min, showing certain "dose-time-toxicity" relationship. ALT and AST levels in mice serum and liver tissue enhanced; PGE2, MDA, NO, NOS enhanced in mice serum; SOD, GSH, GSH-Px reduced; the BUN, CR levels was no significant alteration; liver weight/ body weight enhanced; kidney weight/body weight was no significant alteration. The a irritation mechanism of volatile oil of Evodiae Fructus was connected with suppressing pain transmitters release, per oxidative damage mechanism and NO damage, which also induced hepatotoxicity and the mechanism of hepatotoxicity is main lyoxidative damage, showing certain "dose-time-toxicity" relationship in accordance to hepato-toxicity injury.

Study on efficacy and accompanying toxic and side effects of volatile oil of Evodia Fructus based on stomach cold syndrome model / 中国中药杂志

<p><b>OBJECTIVE</b>To preliminarily study the effective dosage range and mechanism of the abirritation of volatile oil of Evodia Fructus on the stomach cold syndrome model in mice, and discuss the correlation between its accompanying toxicity and oxidative damage mechanism, in order to provide the experimental basis for explaining the efficacy-syndrome-toxicity correlation.</p><p><b>METHOD</b>The stomach cold-syndrome model in mice was induced by the classic hot plate test by orally administrating with different doses of volatile oil of Evodia Fructus, in order to observe its abirritation and companying toxic and side effects and detect serum ALT, AST, PGE2, NO, NOS, MDA, SOD, GSH, GSH-Px, BUN, CR and hepatic ALT, AST. The companying toxic symptoms in mice were recorded in toxic reaction integral table.</p><p><b>RESULT</b>Volatile oil of Evodia Fructus had an obvious analgesic effect at 30 min after the oral administration and reached the peak effect at 60 min, with certain "dose-effect" and "time-effect" relations, rises in serum and hepatic ALT and AST levels, serum PGE2, MDA, NO and NOS and hepatic indexes, decreases in SOD, GSH and GSH-Px and no notable change in BUN, CR levels and kidney weight/body ratio. Conclusion: The abirritation mechanism of volatile oil of Evodia Fructus was related to the inhibition of pain transmitter release, peroxidative damage and NO damage, which is accompanied by certain hepatotoxicity, mainly mainly oxidative damage, with a concurrent "dose-time-toxicity" relationship.</p>

Advance in modern studies on compatibility of Coptidis Rhizoma and Evodiae Fructus / 中国中药杂志

In traditional clinical application, Coptidis Rhizome and Evodiae Fructus have been combined to treat various stomach heat and cold syndromes, gastritis, gastric ulcer and the like. With the application of modem instruments and the development of molecular pharmacologic theory, their chemical constituents and pharmacological effects have been sufficiently studied. In this paper, literatures from Pubmed were adopted, with particular emphasis on findings of international counterparts and studies on compatibility of main chemical components in Coptidis Rhizoma and Evodiae Fructus, in order to elaborate on the scientific comparability of Coptidis Rhizoma and Evodiae Fructus through chemical analysis, and pharmacological and biopharmaceutics studies and introduce the future development trend of the studies.

Euodia sutchuenensis Dode extract stimulates osteoblast differentiation via Wnt/beta-catenin pathway activation

The Wnt/beta-catenin pathway has a role in osteoblast differentiation and bone formation. We screened 100 plant extracts and identified an extract from Euodia sutchuenensis Dode (ESD) leaf and young branch as an effective activator of the Wnt/beta-catenin pathway. ESD extract increased beta-catenin levels and beta-catenin nuclear accumulation in murine primary osteoblasts. The ESD extract also increased mRNA levels of osteoblast markers, including RUNX2, BMP2 and COL1A1, and enhanced alkaline phosphatase (ALP) activity in murine primary osteoblasts. Both ESD extract-induced beta-catenin increment and ALP activation were abolished by beta-catenin knockdown, confirming that the Wnt/beta-catenin pathway functions in osteoblast differentiation. ESD extract enhanced terminal osteoblast differentiation as shown by staining with Alizarin Red S and significantly increased murine calvarial bone thickness. This study shows that ESD extract stimulates osteoblast differentiation via the Wnt/beta-catenin pathway and enhances murine calvarial bone formation ex vivo.

Study on molecular mechanism of Euodiae Fructus on liver toxicity in MICE / 中国中药杂志

<p><b>OBJECTIVE</b>To study the molecular mechanism of extracts from Euodia rutaecarpa on hepatotoxicity in mice.</p><p><b>METHOD</b>Totally 30 KM mice were divided into 3 groups and orally administrated extracts from E. rutaecarpa for consecutively 15 days. The expressions of Erkl/2, CDK8, CK1e, Stat3 and Src were detected by Western blotting method.</p><p><b>RESULT</b>The extracts from E. rutaecarpa could up-regulated Erkl/2, CDK8 and CK1e expressions (P <0.01) and down-regulate Stat3 and Src (P <0.01).</p><p><b>CONCLUSION</b>The molecular mechanism of E. rutaecarpa on hepatotoxicity may be correlated with Erkl/2, CDK8, CKle, Stat3 and Src signal molecules.</p>

Simultaneous determination of seven constituents in Euodiae Fructus and two related species by HPLC / 中国中药杂志

This study is to develop a HPLC method for quality evaluation of Euodiae Fructus and related species by simultaneous determination limonin, indole alkaloids (14-fomyldihydroxyrutaecarpine, evodiamine, rutaecarpine), and quinolone alkaloids [1-methyl-2-undecyl-4 (1H)-quinolone, evocarpine, dihydroevocarpine] in the fruits of five Evodia species. Samples were analyzed on a YMC C18 column (4.6 mm x 250 mm, 5 microm) eluted with mobile phases of acetonitrile (A), tetrahydrofuran (B), and a buffer solution of 5 mmol x L(-1) ammonium acetate (pH 3.8) (C) in a linear gradient mode. The column temperature was 30 degrees C and the flow rate was 1.0 mL x min(-1). The PDA detector wavelengths were set at 220 and 250 nm. The seven compounds were well separated and showed good linearity (r = 0.999 9) within the concentration ranges tested. The mean recoveries were between 96.7%-102.4% (RSD 1.4%-3.1%). Through the validation, the method was proved to be accurate and repeatable. All the seven constituents were detected in the fruits of five species, but the contents of them varied widely in different samples. The total contents of seven constituents in 16 batches of Euodiae Fructus were 9.46-69.9 mg x g(-1), and the mean content was 28.2 mg x g(-1). The total content of seven constituents in E. compacta and E. fargesii was 25.8, 7.69 mg x g(-1), respectively.

Study on metabolism of Coptis chinensis alkaloids from different compatibility of Wuji Wan in human intestinal flora / 中国中药杂志

<p><b>OBJECTIVE</b>To study the metabolism of berberine and palmatine in prescription compatibility of Wuji Wan in human intestinal flora.</p><p><b>METHOD</b>The L9 (3(4)) orthogonal design was adopted to compare prescription compatibility of nine groups of Wuji Wan composed of Coptis chinensis, Evodiae and fried Radix paeoniae alba into and single ingredient of C. chinensis. They were cultivated with fresh human excrements under anaerobic conditions for 24 h. A HPLC-UV method was adopted for determining berberine and palmatine in bacteria culture medium, in order to compare the metabolism of the two components in different prescription compatibility.</p><p><b>RESULT</b>Metabolism of berberine was positively correlated with doses, whereas metabolism of palmatine was negatively correlated with doses in extracts from C. chinensis. Compound compatibility speeded up the metabolism of berberine in low dose, which was positively related to the doses of Evodiae and fried Paeoniae Alba Radix; meanwhile Compound compatibility slowed down the metabolism of berberine in high dose, which was negatively related to the dose of Evodiae. Compound compatibility speeded up the metabolism of palmatine in high dose, which was negatively related to the doses of Evodiae and fried Paeoniae Alba Radix.</p><p><b>CONCLUSION</b>The metabolism of the compatibility of Wuji Wan speeds up, when Coptis chinensis components metabolite rapidly in intestinal flora; while the metabolism of the compatibility of Wuji Wan slows down, when C. chinensis components metabolite slowly in intestinal flora. Therefore, they show a balanced effect. Additionally, different proportion of C. chinensis, Evodiae and fried Paeoniae Alba Radix cause difference in metabolism speed of berberine and palmatine to some extent.</p>

Research on Chinese medicine pairs (VI)--Coptidis Rhizoma-Euodiae fructus / 中国中药杂志

Coptidis Rhizoma-Euodiae Fructus has been widely used for the treatment of digestive diseases since Song Dynasty, and therapeutic efficacy is very obvious. Modern research found that alkaloids are the main bio-active constituents, and some of their contents have striking difference after compatibility of the two herbs. The Chinese medicine pair (CMP) has extensive biological activities, such as the effect of gastrointestinal effect, anti-tumor, lowering the blood pressure and blood fat and so on. And some action mechanism of CMP also got partial demonstration. This paper mainly summarized the bio-active constituents, compatibility effects, action mechanism and clinical applications of the CMP, which can provide a basis for further research and development of the CMP.

Effect of euodiae fructus on hepatic energy metabolism-related mechanisms of reserpine-induced asthenia cold syndrome rats / 中国中药杂志

<p><b>OBJECTIVE</b>To discuss the effect of Euodiae Fructus on hepatic energy metabolism-related mechanisms of mitochondria of hepatic tissues of asthenia cold syndrome rats.</p><p><b>METHOD</b>Rats were subcutaneously injected with Reserpine to establish the model. After the oral administration with Euodiae Fructus for 12 d, the oxygen electrode method was adopted to determine the respiration efficiency. The expressions of Cox4, Atp5b, Ucp2,Pgc-1alpha, Nrf1, Tfam mRNA were assayed by using RT-PCR method.</p><p><b>RESULT</b>Euodiae Fructus 4.2 g x kg(-1) could obviously increase ST3 and RCR of asthenia cold syndrome rats, and expressions of Cox4, Ucp2 Nrf1 mRNA. It could also increase expressions of Atp5b and Pgc-1alpha mRNA, but with no statistical significance. No obvious change was observed in Tfam mRNA expression. Euodiae Fructus 4.2 g x kg(-1) could significantly increase ST3 and RCR of asthenia cold syndrome rats and Pgc-1alpha mRNA and Nrf1 mRNA expressions, and significantly decrease P/O, with no obvious impact on Cox4, AtpSb, Ucp2, Tfam mRNA expressions.</p><p><b>CONCLUSION</b>Euodiae Fructus can promote mitochondrial respiratory function and oxidative phosphorylation efficiency by improving Pgc-1alpha mRNA and Nrf1 mRNA expressions and regulating Cox4 and Atp5b mRNA in mitochondrial respiratory chain. It can also strengthen mitochondrial uncoupling respiration and add heat production by activating Ucp2 mRNA expression in liver.</p>

Chemical constituents from leaves of Evodia lepta / 中国中药杂志

To explore the alternative material for the stems of Evodia lepta used in clinic, the leaves extract of E. lepta was chemically investigated by silica gel, Sephadex LH-20, ODS column chromatographies, and preparative HPLC and the structures of the compounds were identified mainly by spectroscopic methods. Ten known compounds 4-hydroxy-4, 7-dimethyl-1-tetralone (1), (6R, 7E) -4, 7-megastigmadien-3, 9-dione (2), 4-megastigmen-3, 9-dione (3), formononetin (4), daidzein (5), oroxylin A (6), wogonin (7), 5, 7-dihydroxy-3, 4'-dimethoxyflavone (8), N-trans-coumaroyltyranine (9) and (E) -p-hydroxycinnamic acid (10), have been obtained and identified. All these compounds were isolated from this species for the first time. The results revealed that there is a considerate chemical difference between the stems and leaves of E. lepta.

Study on analgesic and accompanying toxic and side effects of euodiae fructus based on clinical efficacy dose / 中国中药杂志

<p><b>OBJECTIVE</b>To observe and study the toxic and side effects of water extracts from Euodiae Fructus accompanied with its efficacy analgesic dose and its mechanism, in order to provide experimental basis for the correlation between its "efficacy-toxicity".</p><p><b>METHOD</b>Mice were randomly divided into 5 groups according to weight, namely the normal group, the voltaren group, and Euodiae Fructus water extracts high, middle and low dose groups. Mice were administered with drugs for consecutively seven days, abdominally injected with acetic acid at 90 min and treated with hot plates after the last administration to establish the pain model, in order to the toxic and side effects accompanied with the efficacy. Besides toxic symptoms in mice, activities of ALT and AST, and content of BUN and Cr in serum were detected to calculate indexes in livers and kidneys. The other part of serum was collected to detect the content and activities of PGE2, MDA, SOD, NO, NOS, GSH and GSH-PX in serum.</p><p><b>RESULT</b>Continuous oral administration of water extracts from Euodiae Fructus of efficacy dose could significantly decrease the frequency of writhe in mice and increase the hot plate pain threshold, with good dose-efficacy relationship. During the administration, mice showed such toxic symptoms as diarrhoea, idle move, dysphoria and slow growth of weight. The activities of both ALT and AST in serum and hepatic tissues were remarkably increased and the liver size remarkably increased, without notable chance in content of BUN and CR in serum. Kidney size increased in only the high dose group. The content and activities of PGE2, SOD, GSH, GSH-PX in serum notably decreased, where the content and activities of MDA, NO, NOS in serum increased. The above-mentioned changes gradually aggravated with the rise in dose. There was significant difference compared with the model group, showing 'dose-toxicity' relationship to certain extent.</p><p><b>CONCLUSION</b>Continuous oral administration of certain dose of water extracts from Euodiae Fructus to mice can generate the toxic and side effects in liver accompanying with the analgesic effect, and show dose-dependence relationship to some extent. Its analgesic mechanism is related to the reduction of PGE, content in blood, while its toxic mechanism is related to oxidative injury to some extent.</p>

Pharmacokinetics, Pharmacodynamics and Safety of JES9501 after Single and Multiple Oral Administration in Healthy Subjects

BACKGROUND: JES9501 is dehydroevodiamine, the extract of Evodia rutaecarpa, expected to be a new therapeutic for Alzheimer disease. This study aims to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of JES9501 after single or multiple dosing. METHODS: A double-blind, randomized, placebo-controlled, dose ascending, parallel study was conducted in healthy subjects. A single dose of JES9501 50.100.200.400 or 800 mg and multiple doses of JES9501 100.200 or 400 mg once-daily for 7days was administered. Serial blood and urine samples for PK evaluation were collected. Acetylcholinesterase (AChE) activity was measured for PD evaluation in multiple dose group. RESULTS: In the single dose study, means of dose-normalized peak concentration (Cmax) of 100.200.400 and 800 mg dose group are comparable except 50 mg dose group. Means of dose-normalized area under the plasma concentration-time curve (AUC) from dosing to the last quantifiable concentration of corresponding dose group were similar. At steady state in the multiple dose study, means of dose-normalized Cmax and AUC for dosing interval of 100.200 and 400 mg dose group decreased as the dose increased, however those were not relevant. There was no significant difference of AChE activity between three dosage groups and placebo group. Adverse events related to study drug were all mild and there were no remarkable findings. CONCLUSION: JES9501 was safe and well-tolerated after single or multiple doses in healthy male subjects. Further studies are warranted to evaluate the PK of optimized dosage form and to prove the drug effect in clinical trials for Alzheimer disease patients.

Impact on absorption of berberine and palmatine in different compatibilities of Wuji pill / 中国中药杂志

<p><b>OBJECTIVE</b>To observe the impact on absorption of berberine and palmatine in different compatibilities of Wuji pill by the perfused rat intestine-liver preparation.</p><p><b>METHOD</b>Use L9 (3(4)) orthogonal design table, establish the perfused rat intestine-liver preparation, the twelve Wuji pill compatibilities duodenal administrated, collect the perfusate at different times points for LC-MS detection, calculate the absorbed score, Ka.</p><p><b>RESULT</b>Evodiae Fructus and the absorption score, Ka of berberine and palmatine are inverse correlated. The most superior portion which promote the absorption is Coptidis Rhizoma-Evodiae Fructus-Paeoniae Radix Alba 3:1:3.</p><p><b>CONCLUSION</b>Evodiae Fructus suppressed the absorption of berberine and palmatine. With the different portion the absorption also have big different.</p>

Research on toxicity characteristics in Evodia Fructus of different orgins and producing areas / 中国中药杂志

<p><b>OBJECTIVE</b>To study the toxicity of water extracts from the fruits of Evodia Fructus in different producing areas.</p><p><b>METHOD</b>Compare the toxicity of the extracts from different Evodia Fructus on mice by the methods of acute and subacute toxicity test. The mice were given the extracts for 1 d to test the maximal tolerance dose (MTD) or maximal dose and observe the acute toxic symptoms; The mice were given the extracts for 15 d and then detected the level of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG). The liver index was calculated, and the liver histological changes were investigated.</p><p><b>RESULT</b>The MTD of water extracts from the fruits of Evodia Fructus is 62, 44.8, 35.84 g x kg(-1); the MTD of Evodia Fructus is 56, 44. 8, 35.84 g x kg(-1); the maximal dose of Evodia Fructus is 60, 54, 45 g x kg(-1). The toxic symptoms of the mice which had been given the nine samples were almost consistent. Compared with the control group in subacute toxicity test, the level of serum ALT and the liver index were all increased. The liver histological were changed.</p><p><b>CONCLUSION</b>When water extracts from the fruits of Evodia Fructus are given to mice one or more times. It may be toxic and induce liver damage. There is no significant correlation between the toxicity and Evodia orgins, while the toxicity seems to be more closely related to the producing area.</p>

"Dose-time-toxicity" relationship study on hepatotoxicity caused by multiple dose water extraction components of Evodiae Fructus to mice / 中国中药杂志

<p><b>OBJECTIVE</b>To study on the time-toxicity and dose-toxicity relationships caused by multiple dose water extraction components of Evodia Fructus to mice.</p><p><b>METHOD</b>Mice were grouped according to different time or dose points, to observe the death condition and toxicity of mice. The changes of the activity of ALT, AST and liver, kidney index were detected, and the morphological changes of liver tissue were observed under light microscope.</p><p><b>RESULT</b>On the first day after administration the hepatotoxicity which displayed with obvious increase of ALT, AST activity in serum and liver tissue and hepatic injury appeared. On the third day the hepatotoxicity kept a higher level that the active units in serum ALT, AST were significantly higher than the normal group. On the 7th day after administration ALT, AST level in serum are restored near normality. Compared with the normal group, within 7 days after the administration, water extracted components in 0.63-5.0 g x kg(-1) dose scope could cause significant damage to liver, the activity of ALT, AST, AKP, TBI elevated, while ALB reduced, and liver ratio increased, and under light microscope, the different doses' liver tissue of mice all had different degree's edema, fatty degeneration in liver cells and interstitial congestion. There were certain time-toxicity and dose-toxicity relationships. The above-mentioned change gradually aggravated with dose increasing, and it was the obvious discrepancy compared with distilled water control group.</p><p><b>CONCLUSION</b>Multiple intragastric administrations of water extracted components of Evodia Fructus with certain dosage may induce acute hepatotoxical injury in mice and show certain "dosage-time-toxicity" relationship.</p>