Analysis of epidemiological characteristics of drug induced liver injury associated with Baixianpi Preparations / 中国中药杂志

A retrospective study was performed in drug-induced liver injury(DILI) cases associated with Dictamni Cortex(Baixianpi,BXP) Preparations,which were treated at grade Ⅲ class A liver disease hospitals from 2008 to 2016 and spontaneously reported for adverse reactions between 2012 and 2016 at HILI Cloud(hilicloud.net). The results showed 25 DLII cases associated with BXP Preparations treated at grade Ⅲ class A liver disease hospitals during the 9 years,including only 14 cases in line with the clinical diagnostic criteria of Guidelines for the Diagnosis and Treatment of Herb-Induced Liver Injury. And 74 DILI cases associated with BXP Preparations spontaneously reports adverse reactions,and 18. 92% of them had unreasonable medication,including polypharmacy(21. 43%),overdose(28. 57%) and repeated dosage(50%). And 47 DILI cases used BXP Preparations to treat psoriasis and vitiligo(a total of59. 57%). The time range of taking BXP Preparations until liver injury occurred was 1-366 d,with the median of 18 d. The dose of BXP Preparations was estimated to be 0. 09-12 g·d-1. And the cumulative dosage of taking drugs until liver injury occurred was 1. 1-336 g. Obvious associations with time-toxicity as well as quantity-toxicity could not be found based on the wide range of time-toxicity relations and quantity-toxicity relations. On the basis of the study,we found that DILI cases associated with BXP Preparations commonly occurred in patients with immune diseases,such as psoriasis and vitiligo,indicating specific individual differences. The results suggested that DILI cases associated with BXP Preparations would be correlated with the property of idiosyncratic drug-induced liver injury. In conclusion,the risk of liver injury clinically caused by BXP Preparations should be paid more attention,and the studies on the mechanism of idiosyncratic drug-induced liver injury must be enhanced,and those on risk factors,like irrational drug use,should be strengthened. Moreover,the evaluation of the risk-to-benefit ratio is supposed to be performed for the sake of improving the risk prevention and control standards for BXP preparations,and ensuring safe and rational clinical application of BXP Preparations.

Mass spectrometry guided strategy based on feature fragment ions for guided-separation on quinoline alkaloids from root barks of Dictamnus dasycarpus / 中国中药杂志

The root bark of Dictamnus dasycarpus is one of common traditional Chinese medicines (TCMs). Quinoline alkaloids are one of the main active substances in this TCM and possess many biological activities including anti-titumor, anti-inflammation, anti-bacteria, anti-oxidation, and anti-platelet aggregation activities. In this study, eight quinoline alkaloids 1-8 were firstly separated from the root barks of D. dasycarpus. It was difficult to isolate more quinoline alkaloids from the remaining fraction 8 in D. dasycarpus by this conventional chemical separation, so the target analysis method combined LC-MS guided-separation of quinoline alkaloids from fraction 8 was established. MS/MS fragmentation patterns of eight quinoline alkaloids reference standard compounds 1-8 were studied by ultra-performance liquid chromatography-electrospary ionization-mass spectrometry (UPLC-ESI-MS/MS). Based on the feature fragment ion 200, the parent ion scan mode was established for the target analysis of quinoline alkaloids in fraction 8. Finally, 8-methoxyflindersine (9) and N-metilatanina (10) were discovered and isolated quickly from fraction 8 guided by LC-MS, and their structures were identified by NMR and MS. Among them, compound 10 was isolated from the genus Dictamnus for the first time. These results indicated that this method is not only quick and sensitive for analyzing the quinoline alkaloids, but also to effectively guided-separate this kind of alkaloids in the root barks of D. dasycarpus.

Chemical constituents from root barks of Dictamnus dasycarpus and their cytotoxic activities / 中国中药杂志

Nineteen compounds, including kihadanin D (1), obacunone (2), kihadanin A (3), kihadanin B (4), kihadanin C (5), limonin (6), evodol (7), fraxinellone (8), furo[2,3-b]quinolin-4-ol (9), preskimmianine (10), ifflaiamine (11), dictamnol (12), naringenin (13), diosmetin (14), wogonin (15), scopoletin (16), cleomiscosin A (17), apocynin (18), and methyl pyroglutamate (19), were isolated from the methanol extract of the root barks of Dictamnus dasycarpus by using various column chromatographies. Their chemical structures were extensively determined on basis of UV, IR, NMR, MS, and CD spectroscopic data analyses. Among them, 1 is a new limonoid, 9 was isolated from plant kingdom for the first time, 11, 13-14 and 17-19 were obtained from the genus Dictamnnus for the first time. Cytotoxicities of compounds 1-18 were tested, and the results indicated that 1 exhibited cytotoxicities against three human cancer cell lines MDA-MB-231, A549 and HT29 with IC₅₈ values of 16.22, 21.72 and 31.06 μmol·L⁻¹, respectively.

Identification of antioxidant activity of two new aromatic ring butyrolactone derivatives from Dictamnus dasycarpus Turcz / 中国天然药物

The present study carried out a phytochemical investigation on the root barks of Dictamnus dasycarpus Turcz, leading to the isolation and characterization of two new aromatic ring butyrolactone derivatives, dasycarpusphenol acid A (1) and dasycarpusphenol acid B (2). Their structures were elucidated by using spectroscopic techniques and HR-FAB-MS. Compounds 1 and 2 exhibited antioxidant activity, with their IC values being 28.95 and 41.76 mg·mL, respectively.

A new quinoline alkaloid from the roots of Dictamnus angustifolius / 中国天然药物

AIM@#To investigate the quinoline alkaloids from the roots of Dictamnus angustifolius G.Don ex Sweet (Rutaceae).@*METHOD@#The quinoline alkaloids were isolated by various column chromatographic methods and their structures were elucidated on the basis of spectral analysis.@*RESULTS@#A new quinoline alkaloid, 5-methoxylrobustine (1), along with five known quinoline alkaloids were obtained, and their structures were identified as dictamnine (2), robustine (3), isopteleine (4), γ-fagarine (5), and skimmianine (6). Cytotoxicity testing of these alkaloids showed that all of them had weak cytotoxic activities against human breast cancer cells (MCF7).@*CONCLUSION@#Compound 1 is a new quinoline alkaloid. Alkaloid 3 showed stronger anti-proliferation effect than the other alkaloids.

Anticoccidial effects of the root bark of Dictamnus dasycarpus Turcz extract on experimental Eimeria tenella infection / 한국실험동물학회지

Anticoccidial effects of the root bark of Dictamnus dasycarpus Turcz (Rutaceae) extract (DDE) were evaluated in chickens following oral infection with Eimeria (E.) tenella. Three-day-old chickens (n=30) were assigned to three groups (control, untreated, and DDE 0.1% treated). Chickens were fed a standard diet supplemented with or without DDE for 1 week prior to infection with E. tenella (10,000 sporulated oocysts per chicken). The effects of DDE on E. tenella infection were assessed by two parameters; fecal oocysts shedding and body weights gain. The DDE-fed chickens produced significantly reduced fecal oocysts (P<0.05) when compared to the E. tenella-infected group fed standard diet. Also, DDE-based diet, improved body weight loss caused by E. tenella infection. Our data demonstrated that DDE had remarkable anticoccidial activities against E. tenella. This finding might have implications for the development of anticoccidial drug. This study is the first to demonstrate anticoccidial effect of DDE on Eimeria parasites.

Anti-toxoplasmosis effect of Dictamnus dasycarpus extract against Toxoplasma Gondii / 동물의과학연구지

Toxoplasma gondii (T. gondii) causes a life-threatening opportunistic infection. Despite its clinical importance, very few therapeutic drugs against T. gondii are available. Furthermore, these therapeutic regimens are not always suitable for prolonged treatment due to adverse side effects as well as the potential of clinical failure by selecting drug-resistant parasite variants. Dictamnus dasycarpus is known to have many medicinal properties, including anti-inflammatory, anti-fever, and anti-rheumatic activities. In this study, 70% ethanol extract of Dictamnus dasycarpus showed anti-T. gondii effects. Ethanolic extracts of Dictamnus dasycarpus used to treat T. gondii were tested in vitro for their anti-T. gondii activity and cytotoxicity. The selectivity of Dictamnus dasycarpus extract was 7.52, which was higher than that of Sulfadiazine (2.08). We conducted an in vivo animal test to evaluate the anti-T. gondii activity of Dictamnus dasycarpus extract as compared with that of Sulfadiazine. In T. gondii-infected mice, the inhibition rate of Dictamnus dasycarpus extract was high, similar to that of Sulfadiazine. This indicates that Dictamnus dasycarpus extract may be a source of new anti-T. gondii compounds.

Clinical features of 28 acutely toxic hepatitis patients who ingested Dictamnus dasycarpus: A single center clinical experience / 대한내과학회지

BACKGROUND/AIMS: The aim of this study was to investigate the clinical features of acutely toxic hepatitis associated with ingesting Dictamnus dasycarpus (D. dasycarpus). METHODS: Between January 2004 and July 2009, 28 patients were enrolled in this study. We reviewed the medical records retrospectively. Acutely toxic hepatitis associated with D. dasycarpus was diagnosed by a Roussel Uclaf Causality Assessment Method Values (RUCAM) score of 6 or above. All patients were tested for viral hepatitis A, B, C, cytomegalovirus, and Epstein-Barr virus. Other tests included anti-nuclear antibody, anti-mitochondrial antibody, and anti-smooth muscle antibody. Abdominal pelvic computed tomography was performed. RESULTS: The incidence was female predominant (64% vs. 36%). The mean patient age was 53.0+/-11 years. The symptoms were jaundice (68%), fatigue (57%), nausea (43%), anorexia (43%), and abdominal pain (24%). The mean RUCAM score was 7.0+/-0.8. The biochemical patterns of hepatotoxicity were hepatocellular (n=23, 82%) and mixed types (n=5, 18%). Radiologic findings were as follows: normal findings (29%), lymphadenopathy (50%), edema of the gall bladder wall (46%), periportal edema (43%), splenomegaly (11%), fatty liver (11%), and ascites (7%). The mean hospitalization period was 21.6+/-11.6 days. The mean duration of recovery from hepatitis was 56.6+/-30.4 days, and all patients recovered completely from the toxic hepatitis. One patient who had severe jaundice developed a complication of pure red cell aplasia during the hospitalization period. CONCLUSIONS: The biochemical pattern of liver injury was hepatocellular predominant. Although the initial manifestations and clinical course were variable, all patients completely recovered with supportive care or steroid treatment. Toxic hepatitis was accompanied by pure red cell aplasia in one patient.

One case of fulminant hepatic failure related to Dictamnus dasycarpus / 대한내과학회지

We report a case of fulminant hepatic failure related to ingesting Dictamnus dasycarpus. The patient had taken D. dasycarpus for 8 weeks after boiling down the root of D. dasycarpus in water, to promote health. The main symptoms and signs were general weakness and jaundice. Serology found no evidence of hepatitis A, B, or C infections. Imaging studies, including abdominal ultrasonography and abdominal computed tomography, did not reveal any bile duct structural abnormalities. Based on the RUCAM score (8 points), D. dasycarpus was the probable cause for the drug-induced liver injury. Despite meticulous monitoring and supportive care, the patient died by a progression to fulminant hepatic failure. This case indicates that D. dasycarpus can cause lethal outcomes by fulminant hepatic failure.

Simultaneous determination of three active compounds in root barks of Dictamnus dasycarpus by RP-HPLC / 中国中药杂志

<p><b>OBJECTIVE</b>To develop a RP-HPLC method for simultaneous determination of three active compounds, dictamnine, obacunone and fraxinellone in root bark of Dictamnus dasycarpus and supply a reference for the establishment of the quality standard of D. dasycarpus.</p><p><b>METHOD</b>A Kromasil C18 column was used with methanol-water (60:40) as the mobile phase, at the flow rate of 1 mL x min(-1). 236 nm was selected as the detected wavelength.</p><p><b>RESULT</b>The determined three compounds were well separated with a linear range of 0.0021-0.1060, 0.0201-0.9200 and 0.0102-1.020 g x L(-1), respectively. The recoveries of them were 100.5%, 99.2% and 100.2%, respectively.</p><p><b>CONCLUSION</b>This method is simple, rapid and accurate, particularly suitable for the quality control of D. dasycarpus.</p>

A case of acute hepatitis caused by ingesting Dictamnus dasycarpus / 대한내과학회지

Few cases of hepatitis related to Chinese medicine have been reported in Korea. In such instances, since herbal medicines contain many ingredients, the component that causes the hepatitis to develop is unclear. A 55-year-old man was admitted with sudden-onset jaundice after taking the herbal medicine Dictamnus dasycarpus. The patient had consumed 70 g of alcohol daily and stopped drinking about a month earlier. The physical examination revealed no abnormalities other than scleral icterus. The patient's blood chemistry showed a total bilirubin of 16.0 mg/dL, an ALP of 288 IU/mL, an AST of 1,369 IU/L, and an ALT of 1,660 IU/L. The viral studies were all negative. A liver biopsy showed acute cholestatic hepatitis superimposed on chronic alcoholic fibrosis. This case suggests the development of hepatitis due to an herbal medicine (Dictamnus dasycarpus). Moreover, we recently experienced a case of acute hepatitis that developed after the consumption of Dictamnus dasycarpus.

Liver Transplantation for Acute Toxic Hepatitis due to Herbal Medicines and Preparations

PURPOSE: Acute toxic hepatitis is a common cause of acute liver failure (ALF). We investigated the causes, clinical manifestation, and outcomes of ALF patients who underwent liver transplantation due to acute toxic hepatitis caused by herbal medicines and preparations. METHODS: Between January 1992 and May 2008, we retrospectively reviewed the medical records of 24 patients who were transplanted due to acute toxic hepatitis caused by herbal medicines and preparations. We applied the RUCAM score to patients with acute toxic hepatitis and assessed the relationship between herbal preparations and liver injury. We studied the patients' medication history, liver function tests, and clinical outcomes. RESULTS: The type of liver injury was divided into three groups: hepatocellular type, 14 patients (58.3%); cholestatic type, 4 patients (16.7%); and mixed type, 6 patients (25%). Polygonum multiflorum Thunberg (3 cases) was the most common cause of acute toxic hepatitis, followed by Acanthopanax senticosus (2 cases), pumpkin juice (2 cases), Dictamnus dasycarpus Turcz (2 cases), Hovenia dulcis (1 case), Phellinus linteus (1 case), and Artemisia capillaries (1 case). One year survival after liver transplantation was 76%. CONCLUSION: We identified the herbal preparations leading to acute liver failure. Many patients consider herbal remedies to be completely free of unwanted side effects. However, we found that many herbal products have biological activities that can lead to severe hepatotoxicity.

Four cases of toxic liver injury associated with Dictamnus dasycarpus / 대한간학회지

We report four cases of toxic hepatitis that occurred after taking a decoction made by boiling down the root of Dictamnus dasycarpus. The four patients had a median age of 60 years, common symptoms of jaundice and general weakness, and stated that they had not consumed alcohol for at least 5 years. The markers of hepatitis A, B, and C were all negative in the patients. Abdominal ultrasonography revealed common bile ducts with normal diameters. Two of the cases were a mother and daughter, and the other two were sporadic. All of them had consumed a decoction made by boiling down the root of Dictamnus dasycarpus five or six times daily until several days before admission. Dictamnus dasycarpus induced liver injury presenting with a benign course lasting less than 1 month after cessation of the causative agent. We suggest that this natural product can cause acute hepatitis in rural areas.

Determination of fraxinellone in root bark of Dictamnus dasycarpus by RP-HPLC / 中国中药杂志

<p><b>OBJECTIVE</b>To develop a RP-HPLC method for determination of fraxinellone in Dictamnus dasycarpus.</p><p><b>METHOD</b>RP-HPLC conditions were as follows: AT-LICHROM C18(4.6 mm x 250 mm) column, MeOH-H2O (70:30) as a mobile phase, detection wavelength 240 nm, column temperature 25 degrees C, Flow velocity 0.5 mL x min(-1).</p><p><b>RESULT</b>Linear relationship is very good (r = 0.9999) in 0.018-0.18 mg x mL(-1). The average recovery is 98.9%, RSD is 1.2% (n = 4).</p><p><b>CONCLUSION</b>The method is simple and repeatable and can be used for quantitative analysis of fraxinellone in root bark of D. dasycarpus.</p>

Studies on chemical constituents in bark of dictamnus dasycarpus / 中国中药杂志

<p><b>OBJECTIVE</b>To study the chemical constituents in bark of Dictamnus dasycarpus.</p><p><b>METHOD</b>Isolation and purification were carried out on silica gel column chromatography, prepared thin layer chromatography and sephadex LH - 20, et al. The structures were identified by spectral analysis.</p><p><b>RESULT</b>Twelve compounds were obtained from bark of D. dasycarpus and the structures were determined as dictamnine (I), fraxinellone (II), skimmianine (III), gamma-fagarine (IV ), beta-sitosterol (V), obacunone (VI), limonin disophenol (VII), fraxinellonone (VIII), wogonin (IX), rutevin (X), kihadinin B (XI), dasycarine (XII).</p><p><b>CONCLUSION</b>Compounds IX and XI were isolated from genus Dictamnus for the first time, and compound VIII was isolated from the species for the first time.</p>

Preliminary attempt at the speciation of 25-elements in the Chinese medicinal herbs / 中国中药杂志

<p><b>OBJECTIVE</b>To make an attempt at the multi-element speciation in the Chinese medicinal herbs by determining the concentrations of 25 elements in different extraction solutions.</p><p><b>METHOD</b>Firstly, five Chinese medicinal herbs (Buddleja officinalis, Dictamnus dasycarpus, Myristica fragrans, Albizia judibrissin and Inula japonica) from the same region of China were treated to obtain water-soluble phase, lipid-soluble phase and non-soluble phase by water extraction, organic solvent extraction and acid digestion, respectively. Secondly, Phytolacca acinosa, a Chinese medicinal herb collected from 9 regions of China, was extracted by 0% EtOH, 50% EtOH, 75% EtOH, 95% EtOH, respectively, referring the Chinese Pharmacopoeia. Finally, the concentrations of 25 elements, such as Be, Cr, Cu, Zn, Ge, Sr, Y, Mo, Cd, Tl, Pb and REEs, in the above three phases were determined by ICP-MS.</p><p><b>RESULT</b>Under the optimal conditions, all the 25 elements could be determined with detection limits ranged from 0.003 to 0.71 ng x g(-1). The average recoveries of the elements in P. acinosa were 88% approximately 119%, with the relative standard deviations 1.7% approximately 13.3%. It was observed that the determined 25 elements distributed in all the water-soluble, lipid-soluble and non-soluble phases, indicating that the inorganic species, organicspecies, as well as the protein bound species were coexisted in the herbs. Big differences of the element extraction rates could be found by using different ethanol solutions.</p><p><b>CONCLUSION</b>With the aid of the obtained results, we may increase the extraction of necessary elements while decrease that of the toxic elements from the herbs by choosing a suitable solvent during the drug production.</p>