DSC and NMR Study on the Inclusion Complex of Lappaconitine with b-Cyclodextrin

The inclusion complex of lappaconitine (Lap) with b-cyclodextrin (b-CD) has been studied by the differential scanning calorimetry (DSC) and 1H-NMR, 2D-NMR spectroscopy. The structure of the complex has been deduced.

Detection and Characterization of Non-covalent Complex between Lappaconitine and β-Cyclodextrin by Electrospray Ionization Tandem Mass Spectrometry

The non-covalent complexes between lappaconitine （LA） and β-cyclodextrin （β-CD） have been detected and characterized by electrospray ionization combined with ion trap tandem mass spectrometry （ESI-MSn）. The experimental results showed that only 1：1 non-covalent complex can be formed in different starting molar ratios of LA to β-CD. Furthermore, the diagnostic fragmentation of the β-CD-LA complex, with a significant contribution of covalent fragmentation of LA leaving the N-acetyl anthranoyl （AN） moiety inserted to β-CD, provided the convincing evidence for the formation of non-covalent complex between LA and β-CD and the cite of LA molecule included to cavity of β-CD assigned to AN residue.

NaIO_4-Catalyzed Bromination of the Aromatic Ring of Lappaconitine

Treatment of lappaconitine 1 with NaIO_4 and Br_2-HOAc at room temperature for 7 h afforded smoothly the bromine-containing derivative 4 in 71% yield.

Novel Product and Its Derivatives from the Reaction of Lappaconitine with HIO_4

Treatment of lappaconitine 1 with HIO4 at room temperature afforded 2 in 41% yield, to which Br2-HOAc solution was added and allowed to stand at room temperature for 2 days to give 3 (13%) and 4(31%).

Lappaconitine solid dispersion monolithic osmotic tablet and lappaconitine push-pull osmotic pump: preparation and comparison of their release performance in vitro

Lappaconitine is a water-insoluble drug, which was used as model drug in this study. Currently, two osmotically controlled delivery systems that are widely used for water-insoluble drug are monolithic osmotic tablet （MOT） and push-pull osmotic pump （PPOP）. In the present study, lappaconitine solid dispersion monolithic osmotic tablet （lappaconitine-SD-MOT） and lappaconitine-PPOP were developed. The prepared lappaconitine-PPOP was able to delivery drug at the rate of approximate zero-order （r = 0.9931）, and the cumulative release was above 95.0%. The lappaconitine-SD-MOT showed a comparatively poor linearity when the data were plotted according to the zero-order equation （r = 0.9798）, and the cumulative release was 84.69%. Lappaconitine-PPOP exhibited better controlled drug release （higher regression value） compared with lappaconitine-SD-MOT. The similarity index （f2） between lappaconitine-PPOP and lappaconitine-SD-MOT was 49.1 （〈50）. A clear difference of drug release characteristics between the lappaconitine-SD-MOT and lappaconitine-PPOP was revealed. It indicated that the drug release performance of lappaconitine-PPOP could gain favorable zero-order kinetics and higher cumulative release compared with lappaconitine-SD-MOT. Therefore, these results suggested that PPOP was still a very effective device for the delivery of poorly water-soluble drug with zero-order pattern.

Study of Analgesic and Anti-inflammatory Effects of Lappaconitine Gelata

Objective: To explore the analgesic and anti-inflammatory effects of lappaconitine gelata (LA). Methods: The writhing response induced by acetic acid, the pain response induced by formaldehyde and hot plate method in the mouse, and the paw edema induced by egg albumen in the rat and the ear edema induced by xylene in the mouse were used for investigation on the analgesic and anti-inflammatory effects of LA. Results: The writhing response induced by acetic acid, the pain response induced by formaldehyde and hot plate methods was significantly inhibited by LA. In addition, the paw edema induced by egg albumen in the rat and the ear edema induced by xylene in the mouse were all significantly suppressed by LA. Conclusion: LA has the analgesic and anti-inflammatory effects.

Synthesis, in vitro and in vivo biological evaluation of novel lappaconitine derivatives as potential anti-inflammatory agents

Lappaconitine(LA),a natural compound with a novel C18-diterpenoid alkaloid skeleton,displayed extensive biological profile.Recent research on LA is focused mainly on its anti-tumor and analgesic effects,and therefore we aimed to investigate its anti-inflammatory potential.A series of novel LA derivatives with various substituents on the 20-N position was designed and synthesized.In the initial screening of LA derivatives against NO production,all the target compounds,except compound E2,exhibited excellent inhibitory ability relative to that of LA.Particularly,compound A4 exhibited the most potent inhibition with IC50 of 12.91 mmol/L.The elementary structureeactivity relationships(SARs)of NO inhibitory activity indicated that replacement of the benzene ring with an electron donating group could improve the anti-inflammatory efficacy.Furthermore,compound A4 shows an anti-inflammatory mechanism by inhibiting NO,PGE2,and TNF-a generation via the suppression of NF-kB and MAPK signaling pathways.Notably,compound A4 could exert a significant therapeutic effect on LPS-induced acute lung injury(ALI)in vivo.Based on the above research,we further investigated the preliminary pharmacokinetic property of A4 in rats.Therefore,compound A4 could be a promising candidate for the development of anti-inflammatory agents in the future.

Quantitative Electrophysiological Evaluation of the Analgesic Efficacy of Two Lappaconitine Derivatives: A Window into Antinociceptive Drug Mechanisms

Quantitative evaluation of analgesic efficacy improves understanding of the antinociceptive mechanisms of new analgesics and provides important guidance for their development.Lappaconitine(LA),a potent analgesic drug extracted from the root of natural Aconitum species,has been clinically used for years because of its effective analgesic and non-addictive properties.However,being limited to ethological experiments,previous studies have mainly investigated the analgesic effect of LA at the behavioral level,and the associated antinociceptive mechanisms are still unclear.In this study,electrocorticogram(ECoG)technology was used to investigate the analgesic effects of two homologous derivatives of LA,Lappaconitine hydrobromide(LAH)and Lappaconitine trifluoroacetate(LAF),on Sprague-Dawley rats subjected to nociceptive laser stimuli,and to further explore their antinociceptive mechanisms.We found that both LAH and LAF were effective in reducing pain,as manifested in the remarkable reduction of nocifensive behaviors and laser-evoked potentials(LEPs)amplitudes(N2 and P2 waves,and gamma-band oscillations),and significantly prolonged latencies of the LEP-N2/P2.These changes in LEPs reflect the similar antinociceptive mechanism of LAF and LAH,i.e.,inhibition of the fast signaling pathways.In addition,there were no changes in the auditory-evoked potential(AEP-N1 component)before and after LAF or LAH treatment,suggesting that neither drug had a central anesthetic effect.Importantly,compared with LAH,LAF was superior in its effects on the magnitudes of gamma-band oscillations and the resting-state spectra,which may be associated with their differences in the octanol/water partition coefficient,degree of dissociation,toxicity,and glycine receptor regulation.Altogether,jointly applying nociceptive laser stimuli and ECoG recordings in rats,we provide solid neural evidence for the analgesic efficacy and antinociceptive mechanisms of derivatives of LA.

A Clinical Study in Epidural Injection with Lappaconitine Compound for Post-Operative Analgesia

Objective:The effect and side-effect of epidural injection with lappaconitine compound for post-operative analgesia was observed. Methods: One hundred and twenty patients were randomly divided into 4 groups. Lappaconitine compound (LB) consisted of 12 mg of lappaconitine and 22. 5 mg of bupivacaine, was used for the observed group, and lappaconitine 12 mg, bupivacaine 22. 5 mg and morphine 2 mg for the control group respectively, All were given by epidural injection with single blind method during post-operative pain of incision operation. Results: It was showed that the initiating of analgesia was earlier in LB and bupivacaine group than that in group B and D, and the efficacy was morphine group > LB > bupivacaine > lappaconitine.There was significant difference between group A and B in the above two parameters, P < 0. 01 and P < 0. 05. The analgesia maintenance time of a single injection was morphine > LB > lappaconitine > bupivacaine, that of group D was significantly longer than that of group A (P < 0. 01 ). Conclusions: It indicated that the epidural injection with LB was more rapid and potent than that with lappaconitine alone in post-operative analgesia. Besides, it had no side-effect and safer than morphine.

Clinical Study on Epidural Injected Lappaconitine for Post－operative Analgesia

This paper studied the effect and side-effect of epidural injected Lappaconitine (LC) for post-operative analgesia. 50 patients who were operated in the upper abdomen with epidural anesthesia, wererandomly divided into 5 groups. The general condition of each group was similar. Group A, B , C was given LC4mg, 8mg, 12mg respectively for observation. Group D, E was given 0.9% NS 6ml and morphine 2mg indi-vidually as control. When the operation was finished, LC was injected into the epidural space with singleblind method. The result showed the analgesia of LC and its effective time was: group E >C > B >A > D . Theanalgesic effect of group C was satistactory. The efficacy and the maintenance time of A, B, C groups weresignificantly different from that of group D ( P < 0. 05 , P < 0 . 01 ) . Although the effect ot group C was less po-tent than that of group E ( morphine injection) , there was no side-effect like that of morphine. It suggestedthat epidural injected LC for post-operative analgesia is effective and safe.

白喉乌头中的二萜生物碱成分

从白喉乌头Aconitumleucostomum的根中分得4个二萜生物碱，通过光谱分析分别鉴定为6，14－dimethoxyforesticine（Ⅰ）、lappaconitine（Ⅱ）、N－deacetyllappaconitine（Ⅲ）和anthranoyllycoctonine（Ⅳ）。其中Ⅰ系首次直接从植物中分得。

Pain management using Han’s acupoint nerve stimulator combined with patient-controlled analgesia following neurosurgery A randomized case control study

BACKGROUND： Han＇s acupoint nerve stimulator （HANS） has been frequently used to relieve pain by promoting the central nerve system＇s release of endogenous opioid peptides through electric stimulation to the body surface. OBJECTIVE： To investigate the pain-relieving effects of HANS, combined with patient-controlled analgesia, following neurosurgery, and to observe adverse reactions and effects. DESIGN, TIME AND SETTING： A randomized control observation was performed at the Department of Neurology in the First Affiliated Hospital of Gannan Medical College （Ganzhou, Jiangxi Province, China） from January 2005 to February 2006. PARTICIPANTS： Forty patients, who were selected for craniotomy and required pain relief following surgery at the Department of Neurology in the First Affiliated Hospital of Gannan Medical College （China）, were included in this study. METHODS： Forty patients underwent neurosurgery and were randomly divided into two groups： patient-controlled analgesia plus HANS （＋HANS, n = 20） and patient-controlled analgesia （-HANS, n = 20）. Both groups were well matched in baseline data. Automatic syringe infusion pump ZZB-150 was the product of Nantong Aipeng Medical Instruments Co., Ltd. （China）. Patient-controlled analgesia consisted of 100 mL 0.02% lappaconitine/0.02% metoclopramide. LH-402 HANS instrument was produced in Beijing （China）, with a serial number of 402183. The HANS instrumentation was used to stimulate the Hegu-Laogong acupoint on one side and Jiaogan, Shenmen penetrating Shen, Waifei, Naogan penetrating Pizhixia ear acupoints on the affected side for one hour, with 2-hour intervals. The disperse-dense wave was alternating, with a 2/100 Hz frequency of electrical stimulation. MAIN OUTCOME MEASURE： The scores of visual analogue scale and incidence of adverse reaction were observed in two groups following surgery. RESULTS： Compared with the HANS group, the visual analogue scale scores were remarkably lower in the ＋HANS group six hours after surgery （P 〈 0.01）, and the incidence rate of adverse reactions, such as nausea and vomiting, was also decreased （P 〈 0.05）.CONCLUSION： The application of HANS to induce body surface stimulation can enhance the effect of pain relief and reduce adverse reactions when used in combination with patient-controlled analgesia following neurosurgery. The effect of combined therapy is superior to patient-controlled analgesia alone.