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2244 J. Med. Plants Res. Table 2. Pharmacokinetic parameters of senkyunolide A in rats after i.v., i.p. and p.o. administration (n =5, Mean ± S.D.). Pharmacokinetic parameter Route of administration i.v. i.p. p.o. Dose (mg/kg) 20 (pure) 7.65 (ext) † 50 100 100 Tmax (h) - - 0.04 ± 0.01 0.04 ± 0.01 0.21 ± 0.08*** Cmax (mg/L) 19.67 ± 3.48 4.86 ± 0.45 17.60 ± 3.35 31.01 ± 4.26 1.66 ± 0.23*** t1/2 (h) 0.65 ± 0.06 0.69 ± 0.31 0.67 ± 0.10 0.99 ± 0.23 0.52 ± 0.03 AUC0-∞ (mg·h/L) 2.81 ± 0.19 0.95 ± 0.16 5.29 ± 0.94 10.65 ± 0.98 1.11 6 ± 10*** Vd/F (l/kg) 6.74 ± 0.73 7.12 ± 2.16 9.98 ± 1.66 13.78 ± 3.30 68.97 ± 4.64*** CL/F (l/h/kg) 7.20 ± 0.48 9.17 ± 1.81 10.92 ± 2.10 9.72 ± 0.91 94.81 ± 12.06*** F (%) - 45.7 75.3 75.8 7.9*** ***P < 0.001 compared with the same intraperitoneal doses. † The herbal extract containing 7.65% of senkyunolide A was given at a doses of 100 mg/kg. al., 2007; Kuang et al., 2008). It was also pronounced that Z-Ligustilide has aprotective effect against H2O2induced cytotoxicity, at least partly through improving cellular antioxidant defense and inhibiting the mitochondrial apoptotic pathway (Yu et al., 2008). Antipyretic effects The activity of body temperature regulation was involved by central monoamine neurotransmitters. The theory of monoamine of body temperature recognized that the quantity dynamic balance of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) can keep a relative constancy of body temperature. The report showed that the essential oil of Chuanxiong Rhizoma have the ability of antipyretic effect and make the proportion of 5-HT and NE in hypothalamus have a significant change, so it was considered as one of the mechanism of Chuanxiong Rhizoma to antipyretic effect (Li et al., 2003b). Anti-trichophyton effects At present, trichophyton are frequently treated by oral administration of ketoconazole or the development drug. However, ketoconazole have unpleasant side effects and the other drug has relatively low bioavailability after oral administration and adverse effects. Ligustilide and butylidenephthalide, which are major oil components comprising of the volatile oil of Chuanxiong Rhizoma, have the synergistic anti-fungal effects in combination with antifungal drugs by checkerboard microtiter and microdilution tests. With this synergistic anti-fungal effect, the use of lower concentrations of ketoconazole may facilitate and minimize its potential side effects. The improvement of anti-trichophyton activity of itraconazole administered in combination with ligustilide or butylidenephthalide could provide alternative therapies to overcome current limitations in the use of itraconazole for treatment of trichophyton infections (Sim and Shin, 2008). PHARMACOKINETICS In recent years, with the development of analytical technique, many investigations have been reported the pharmacokinetics of Chuanxiong Rhizoma oil. However, these reports were concentrated on senkyunolide A, ligustilide and butylidenephthalide, the other compounds of essential oil of Chuanxiong Rhizoma are very limited. The main pharmacokinetics of these three active components is summarized as the following. Senkyunolide A The pharmacokinetic parameters of senkyunolide A after three different ways of administration, including intravenous (i.v.), intraperitoneal (i.p.) and per os (p.o.) are as shown in Table 2. After i.v. administration, senkyunolide A was extensively distributed [apparent volume of distribution based on the terminal phase (Vd/F): 6.74 ± 0.73 l/kg] and rapidly eliminated from the plasma [apparent plasma clearance (CL/F): 7.20 ± 0.48 l/h/kg and biological half life (t1/2): 0.65 ± 0.06 h]. Hepatic metabolism was suggested as the major route of senkyunolide A elimination as indicated by the results of in vitro S9 fraction study. After i.p. administration, senkyunolide A exhibited dose-independent pharmacokinetics. The absorption after i.p. administration was rapid [maximum concentration (Tmax): 0.04 ± 0.01 h], and the absolute bioavailability (F) was 75%. After p.o. administration, senkyunolide A was also absorbed rapidly (Tmax: 0.21 ± 0.08 h); however, its oral bioavailability was low (~8%). The contributing factors were determined to be instability in the gastrointestinal tract (accounting for 67% of the loss) and hepatic first-pass metabolism (accounting for another 25%). Pharmacokinetics of senkyunolide A were unaltered when Chuanxiong Rhizoma extract was administered, which suggests that components in the extract have insignificant effects on
Table 3. Pharmacokinetic parameters of ligustilide in rats after i.v., i.p. and p.o. administration (n=5, Mean ± S.D.). Pharmacokinetic parameter Route of administration Hou and He 2245 i.v. i.p. p.o. Dose (mg/kg) 15.6 14.9 a 26 52 500 Tmax (h) - - 0.05 ± 0.02 0.08 ± 0.01 0.36 ± 0.19 Cmax (mg/L) 13.19 ± 0.84 6.93 ± 0.60*** 7.48 ± 1.10*** 20.75 ± 2.55 ### 0.66 ± 0.23*** t1/2 (h) 0.31 ± 0.12 0.22 ± 0.07 0.36 ± 0.05 0.44 ± 0.08 # 3.43 ± 1.01*** AUC0-∞(mg·h/L) b 1.81 ± 0.24 0.79 ± 0.10** 0.93 ± 0.07* 1.77 ± 0.23 # 0.047 ± 0.012** Vd/F (l/kg) c 3.76 ± 1.23 5.62 ± 1.19 6.54 ± 1.56 6.32 ± 1.81 16 41.9 ± 121.6*** CL/F (l/h/kg) c 9.14 ± 1.27 20.35 ± 3.05** 16.9 ± 1.21** 9.26 ± 1. 04 ## 411.1 ± 145.7*** MRT (h) 0.3 ± 0.07 0.19 ± 0.03 0.3 ± 0.05 0.41 ± 0 .03 5.14 ± 1.56*** F (%) - 45.7d 51.7 97.7 2.6 *P < 0.05, **P < 0.01, ***P < 0.001, compared with i.v. dosing of the isolated ligustilide. # P < 0.05, ## P < 0.01, ### P < 0.001, compared with the lower i.p. dose of the isolated ligustilide. a Dose of ligustilide in 100 mg/kg of Chuanxiong Rhizoma extract. b Normalized with dose. c Data represent Vd and CL in the case of i.v. dosing of the isolated ligustilide. d Relative bioavailability compared with that of i.v. dosing of the isolated ligustilide. senkyunolide A pharmacokinetics (Yan et al., 2007). Ligustilide The pharmacokinetic parameters of ligustilide after three different administrations, including i.v., i.p. and p.o. are as shown in Table 3. After i.v. administration of pure ligustilide, it was distributed extensively (Vd/F: 3.76 ± 1.23 l/kg) and eliminated rapidly (t1/2: 0.31 ± 0.12 h). The i.v. CL/F of ligustilide after Chuanxiong extract administration was significantly higher than that dosed in its pure form [CL/F: 20.35 ± 3.05 versus 9.14 ± 1.27 l/h/kg, P Cspleen > Ckidney. The concentration of ligustilide in tissues in different time is as shown in Figure 4 (Qian et al., 2008). There is a difference in the metabolism of the main active constituent monomer and the active constituent group. High-performance liquid chromatography with diode array detection was used to analyze the metabolites in the urine, feces and bile of rats dosed with the essential oil or ligustilide. A clear difference in the metabolism of the essential oil and ligustilide indicating that the multiple components of essential oil influence the types of metabolites produced and the relative ratios of the main active components. The possible pathway for the metabolism of ligustilide in rats is as shown in Figure 5 (Ding et al., 2008). Butylidenephthalide Butylidenephthalide quickly permeate into peripheral circulation system without accumulation in the skin and then distribute into lung, liver, bile and kidney after dermal application by the whole body autoradiogram and liquid scintillation analysis, and excretion mainly into urine. In the case of i.v. administration, 80% of the administered butylidenephthalide was excreted into urine within 24 h, while only 5% was excreted into feces within 24 h. The metabolite in urine was determined to be a cysteine conjugate by LC-MS/MS method (Sekiya et al., 2000). TOXICITY STUDIES L. chuanxiong Hort., which is contained in China plant map database is one of the poisonous plant. The acute toxicity (LD50) was 328 mg/kg in mice when the essential oil of radix and stem of L. chuanxiong Hort. was administered by intraperitoneal injection resulting in death within 4 to 5 h. Using toxic effect method to detect pharmacokinetic parameter of Chuanxiong Rhizoma oil, LD50 was 517.51 ± 90.01 mg/kg and 2982.37 ± 345.12 mg/kg after the administration to mice by i.p. and i.g., respectively (Pan et al., 1999). CONCLUSION L. chuanxiong Hort., as one of the TCM herbs has been used clinically for thousands of years in China. In the
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Journal of Medicinal Plants Researc
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Table 2. MIC of a compound 1 from c
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Zirihi et al. 2301 Figure 2. Termin
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Figure 5. T. catappa Linn. (Combret
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Figure 8. A. fumigatus: Aspect of c
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Figure 12. Sensitivity of A. fumiga
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Noormi et al. 2311 Table 1. Callus
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Table 2. Contd. NoC=No callus. 4.0
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Figure 2. Contd. at 2.0 mg/L yellow
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Table 1. Biochemical parameters in
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Figure 3. Bcl-xL reactions in inter
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ACKNOWLEDGMENTS The authors would l
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Figure 1. The first page of the boo
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Figure 3. The most widely included
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Figure 4. Lithographic print “St.
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Table 1. List of plants included in
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Table 1. Contd. Nedelcheva 2333 Cin
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Table 1. Contd. Nedelcheva 2335 Rhe
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14 7 1 15 1 35 17 16 Imported plant
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Academy of Science Publishing House
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et al., 1996; van Wyk and Gericke,
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DPPH inhibition (%) DPPH % inhibiti
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% Mortality Concentration (µg/ml)
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information on plants used for the
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Table 1. Levels of independent vari
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Arbutin (mg/g) Co-solvent Figure 1.
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Arbutin (mg/g) Extraction pressure
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Table 3. Arbuitn content of Asian p
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Arbutin (mg/g) Extraction pressure
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Arbutin (mg/g) Extraction temperatu
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Table 1. Chemical composition of es
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Darjazi 2369 Table 2. Statistical a
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Table 3. Correlation matrix (number
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Table 1. Precision test. extraction
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Figure 2. Effect of different alcoh
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Table 6. Results of ANOVA. Nie et a
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Table 2. Plant data and MIC values
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exhibiting the polar extracts of P.
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Figure 1. Map of Ladakh region of I
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Warghat et al. 2391 Table 3. Summar
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Table 5. Inter-Population genetic i
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Excoffier L, Smouse PE, Quattro JM
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ice residue is an ideal raw materia
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DPPH• scavenging ratio(%) OD valu
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scavenging effect on free radical a
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our new CL system. Fenton reaction
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1 2 Time (s) Figure 2. Kinetic curv
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Wong et al., 2006). It can be seen
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Pan YM, Liang Y, Wang HS, Liang M (
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2422 J. Med. Plants Res. close cano
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2442 J. Med. Plants Res. Stability
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2524 J. Med. Plants Res. ACKNOWLEDG
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UPCOMING CONFERENCES 15th European
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