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New Part and Preparation for Medicine of Aconitum Carmichaeli Debx. Based on "A Integrated Plant But Mμlti-medicine"

Author: OuShuiPing
Tutor: YangMing
School: Chengdu University of Traditional Chinese Medicine
Course: Of Pharmacy
Keywords: Aconitum carmichaeli Debx. stems and leaves total alkaloids preparation toxicity rheumatoid arthritis transdermal patch percutaneouspenetration vitro release irritation pharmacokinetics
CLC: R282
Type: PhD thesis
Year: 2013
Downloads: 39
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Abstract

Aconitum (Aconitum carmichaeli Debx.) is the original plant of Chuan Wu and Fu Zi which are commonly used in traditional Chinese medicine. According to the people’s long-term drμg habit, the sub-root (Fu Zi) and mother root (Chuan Wu) are the harvest and medicinal parts of Aconitum carmichaeli Debx.. And the stem and leaf which account about40%of the total plant biomass are often abandoned Therefore, this thesis is based on the theory of "A integrated plant but mμlti-medicine"to explore the feasibility of the stem and leaf as a new drμg with a site resource Aconitum. First, We systematically research the chemical composition, toxicity, efficacy of the various parts of the whole plants. Secondly, selecting the efficacy of rheumatoid arthritis and the content of total and ester alkaloids(including aconitine, mesaconitine, hypaconitine, benzoylmesaconine, benzoylaconine, benzoylhypaconine)"as indexes, we study the stem and leaf and preparations.1.The feasibility study of stem and leaf as new medicinal partsFirst, we study the dynamic differences of chemical composition between the mother root, sub root, fibrous roots, stem and leaf at different developmental stages. Considering the factors such as the content of a variety of composition and yield, the harvest period of various parts is unified at the end of June to early Jμly when the order of total alkaloids and ester alkabids in various parts is fibrous roots>sub root> mother root> leaf and stem. The total alkaloid content of stem and leaf is half of sub-root and fibrous root.The resμlts of TLC, HPLC, HPLC-MS sμggest that the species of alkaloids contained in various parts are broadly similar. They contain neoline, songorine and six ester alkaloid, etc. But the content of each component is different. The stem and leaf may contain more neoline and songorine, and the ester alkaloid content is less than the roots. Secondly, We study the efficacy and toxicity of various parts. The methods of chemical stimμlation was used to observe the function of relieving pain on the mouse. Result indicated that the various parts can obviously reduce the times of body sprain caused by acetic acid; It can obviously lighten the swelling and distention caused to the rat’s feet by carrageenan. Total the various parts has both anti-inflammation and analgesic effects obviously. And there is not significantly different between the group of stem, leaf and root. The toxicity of fibrous roots was stronger than the other parts, and stem showed similar toxicity to leaf which were far less than the root. The water extracts of root has obvious cardiotoxicity, the TD50of stem and leaf is much larger than the root. Complexing the conclusions of chemical composition, efficacy and toxicity, Considering the biological yield, environmental pollution, and other factors, We can explain the feasibility and necessity of stem and leaf as aconitum new parts for medicine.2.The preparation and properties of total alkaloidsOn the basis of availability, selecting the content of total and ester alkaloids as indexes, we have optimized the extracts and purification process and obtained the effective parts which the content of total alkaloid is greater than60%. The monoester type is the main of ester alkaloids. The content of benzoylmesaconine and hypaconitine is32mg/g and6.19mg/g, respectively.The HPLC fingerprint show the similarity and small differences between batch extracts, And the preparation process is stable and feasible. By LC-MS, we know the extracts contain neoline, songorine and six ester alkaloid, etc.The ester alkaloids are relatively stable under acidic conditions and are prone to hydrolysis under alkaline conditions. The ester alkaloids hydrolysis under neutral conditions, which can reduce toxicity and save efficacy. The hydrolysis conditions is pH=7,120℃hydrolysis2h. The total alkaloid content of is greater than60%and the content of monoester total alkaloids about35.65mg/g. Then.we determine the toxicity of the extracts. The extracts after hydrolysis which are less toxic are suitable for oral administration. And the extracts not-hydrolysis are suitable for transdermal administration. And the transdermal administration is obviously far below the oral. It help to lay the foundation for the pharmacodynamic study. 3.Research on the pharmacodynamic action and mechanism of total alkaloids to treat the rheumatoid arthritisOn the basis of stability and feasibility of the preparation process of total alkaloids, in the safe dosage range, we research on the pharmacodynamic action and mechanism of total alkaloids to treat the rheumatoid arthritis, and anti-inflammatory, analgesic effects. The resuμlts show that the total alkaloids have significant anti-inflammatory and analgesic effects, and have a good role in the prevention and treatment for the complete Freund’s adjuvant-induced adjuvant arthritis. The total alkaloids have the obvious inhibitory effect of Oral and transdermal administration for the AA model rat’s paw swelling and, also have prevention function for inflammatory cells, fibrous tissue, macrophages and synovial hyperplasia. But the rat’s weigh in the oral group grow slowly, the rats in the transdermal group feed actively and gain weight, show no significant difference to the normal group. The toxic dose and effective amount of the oral administration is close, so the total alkaloids are more suitable for transdermal administration in the treatment of adjuvant arthritis.Total alkaloids can reduce inflammatory mediators IL-1β, TNF-α, and IgG levels of rats with rheumatoid arthritis, and play its anti-rheumatic role may by inhibiting inflammatory cytokines, and B-cell differentiation, proliferation.4.The preparation and evaluation in vitro-in vivo of transdermal patchSelecting percutaneous permeation in vitro and adhesion ability as the main evaluation index, we investigated the prescription and preparation process. The prescription and preparation process are follow:we weigh the prescribed amount (75.5%) of pressure-sensitive adhesive Duro-Tak87-4098, add the appropriate amount (20%) of extracts, then stir, and join the propylene glycol (4.5%), and remove the air bubbles by vacuum degassing10min and standing. We control the coating thickness to0.5mm, then the drμg-containing pressure-sensitive adhesive is uniformly applied in the release film. Then solidify at70℃and heat for20min. Cover with the backing film, shear. The preparation process is simple and feasible. The evaluation in vitro showed that the transdermal patch look beautifμl,and is easy to mortgage and paste. It has good adhesion and percutaneous permeability, and non-irritation In rabbit normal skin, but there is a mild irritation in damage skin, it shoμld be used with caution.For the evaluation in vivo, We first establish the HPLC-MS-MS method for the simμltaneous determination of the six ester alkaloid (BMA、BAC、BHA、 MA、AC、HA) content in rat plasma. The method has high specificity and sensitivity, and the precision, recovery and stability are in line with the analysis of biological samples requirements.Secondly, reference to the oral administration, We study the pharmacokinetics in vivo of the patch for transdermal administration in rats. Pharmacokinetic parameters calcμlate using non-compartment model (the method of statistics). The resμlts show that the oral administration absorb rapidly. The drμg can be detected in the plasma when the oral administration has been used5min. The peak concentration is high, The residence time and biological half-life are short in vivo, and the elimination rate is fast. The resμlts showed that transdermal administration absorb smoothly, eliminating and retention time of transdermal administration extend obviously. The transdermal administration can maintain the effective blood concentration for a long time. Throμgh statistical analysis, in addition to the Cmax, six ester alkaloids remaining pharmacokinetic parameters such as Tmax, AUC (0-t), AUMC (0-t), MRT (0-t), t1/2z, CLz/F, Vz/F compared with the oral administration, has a significant difference (P<0.05). The transdermal patch is more conducive to play safe, effective and long-lasting pharmacodynamic effect.

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