Aconitine - A promising candidate for treating cold and mechanical allodynia in cancer induced bone pain.

BACKGROUND AND AIMS: Patients suffering from cancer induced bone pain (CIBP) have a poor quality of life that is exacerbated by the lack of effective therapeutic drugs. Monkshood is a flowering plant that has been used in traditional Chinese medicine where it has been used to relieve cold pain. Aconitine is the active component of monkshood, but the molecular mechanism for how this compound reduces pain is unclear. METHODS AND RESULTS: In this study, we employed molecular and behavioral experiments to explore the analgesic effect of aconitine. We observed aconitine alleviated cold hyperalgesia and AITC (allyl-isothiocyanate, TRPA1 agonist) induced pain. Interestingly, we found aconitine directly inhibits TRPA1 activity in calcium imaging studies. More importantly, we found aconitine alleviated cold and mechanical allodynia in CIBP mice. Both the activity and expression of TRPA1 in L4 and L5 DRG (Dorsal Root Ganglion) neurons were reduced with the treatment of aconitine in the CIBP model. Moreover, we observed aconiti radix (AR) and aconiti kusnezoffii radix (AKR), both components of monkshood that contain aconitine, alleviated cold hyperalgesia and AITC induced pain. Furthermore, both AR and AKR alleviated CIBP induced cold allodynia and mechanical allodynia. CONCLUSIONS: Taken together, aconitine alleviates both cold and mechanical allodynia in cancer induced bone pain via the regulation of TRPA1. This research on the analgesic effect of aconitine in cancer induced bone pain highlights a component of a traditional Chinese medicine may have clinical applications for pain.

The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α1-Adrenolytic Properties.

Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α1-adrenoceptors could restore normal heart rhythm in arrhythmia. In this study, we aimed to assess the antiarrhythmic potential of S-61 and S-73, two novel pyrrolidin-2-one derivatives with high affinity for α1-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with ß1-adrenoceptors. Next, we assessed whether S-61 and S-73 could protect rats against arrhythmia in adrenaline-, calcium chloride- and aconitine-induced arrhythmia models. Both compounds showed potent prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia model, but the effect of S-61 was more pronounced. None of the compounds displayed antiarrhythmic effects in calcium chloride- or aconitine-induced arrhythmia models. Interestingly, both derivatives revealed therapeutic antiarrhythmic activity in the adrenaline-induced arrhythmia, diminishing heart rhythm irregularities. Neither S-61 nor S-73 showed proarrhythmic potential in rats. Finally, the compounds decreased blood pressure in rodents. The hypotensive effects were not observed after coadministration with methoxamine, which suggests the α1-adrenolytic properties of both compounds. Our results confirm that pyrrolidin-2-one derivatives possess potent antiarrhythmic properties. Given the promising results of our experiments, further studies on pyrrolidin-2-one derivatives might result in the development of a new class of antiarrhythmic drugs.

The Effects of Lipopolysaccharide Derivatives in Rodent Models of Cardiac Arrhythmia.

BACKGROUND: Several previous studies have suggested that sublethal doses of Escherichia coli lipopolysaccharide (endotoxin) and monophosphoryl lipid A Re595, a nonpyrogenic derivative of Salmonella minnesota lipopolysaccharide, exhibit antiarrhythmic effects in the rat model of ischemia-reperfusion arrhythmias. METHODS: In this study, the protective effect of lipopolysaccharide derivatives was also further investigated in drug (aconitine or ouabain)-induced arrhythmia models, and conclusions were drawn with particular emphasis on the molecular characteristics of different types of lipopolysaccharide. RESULTS: The importance of the molecular structure for the antiarrhythmic effect of monophosphoryl lipid A and E. coli lipopolysaccharide was tested in the ischemia-reperfusion arrhythmia model. In contrast to monophosphoryl lipid A from Salmonella typhimurium SL 684 which has only monophosphoryl residue in its structure, monophosphoryl lipid A Re595, obtained from S. minnesota, and E. coli lipopolysaccharide which have both mono and diphosphoryl residue reduced the duration of ventricular tachycardia (e.g., during reperfusion: vehicle: 176 ± 22.8; monophosphoryl lipid A Re595: 132.83 ± 12.1, as second, n=8-10, P < .05) and the incidence of ventricular fibrillation. The antiarrhythmic effects of E. coli lipopolysaccharide and monophosphoryl lipid A Re595 in ischemia-reperfusion arrhythmia model were absent in either aconitine- (e.g., onset time for ventricular ectopic beats: saline 25.3 5.0, E. coli lipopolysaccharide 24.3 ± 7.1; vehicle: 24.0 ± 4.5, monophosphoryl lipid A SL684 23.8 ± 4.3, as second, n=6, P > .05) or ouabain-induced arrhythmia models in mice. CONCLUSION: Therefore, we conclude that lipopolysaccharide derivatives exhibit antiarrhythmic effect only in ischemia-reperfusion arrhythmias, and lipopolysaccharide should possess diphosphoryl groups in its subcomponent composition for this antiarrhythmic effect.

A New Strategy for the Rapid Identification and Validation of the Direct Targets of Aconitine-Induced Cardiotoxicity.

BACKGROUND: The interaction of small molecules with direct targets constitutes the molecular initiation events of drug efficacy and toxicity. Aconitine, an active compound of the Aconitum species, has various pharmacological effects but is strongly toxic to the heart. The direct targets of aconitine-induced cardiotoxicity remain unclear. METHODS: We predicted the toxic targets of aconitine based on network pharmacology and followed a novel proteomic approach based on the "drug affinity responsive target stability" technology combined with LC-MS/MS to identify the direct targets of aconitine. The identified targets were analysed from the perspective of multilevel and multidimensional bioinformatics through a network integration method. The binding sites were investigated via molecular docking to explore the toxicity mechanism and predict the direct targets of aconitine. Finally, atomic force microscopy (AFM) imaging was performed to verify the affinity of aconitine to the direct targets. RESULTS: PTGS2, predicted by network pharmacology as a toxic target, encodes cyclooxygenase 2 (COX-2), which is closely related to myocardial injury. Furthermore, cytosolic phospholipase A2 (cPLA2) is the upstream signal protein of PTGS2, and it is a key enzyme in the metabolism of arachidonic acid during an inflammatory response. We determined cPLA2 as a direct target, and AFM imaging verified that aconitine could bind to cPLA2 well; thus, aconitine may cause the expression of PTGS2/COX-2 and release inflammatory factors, thereby promoting myocardial injury and dysfunction. CONCLUSION: We developed a complete set of methods to predict and verify the direct targets of aconitine, and cPLA2 was identified as one. Overall, the novel strategy provides new insights into the discovery of direct targets and the molecular mechanism of toxic components that are found in traditional Chinese medicine.

Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison.

Aconitine (AC) is well-known as the main toxic ingredient and active compound of Aconitum species, of which several aconites are essential herbal medicines of Traditional Chinese Medicine (TCM) and widely applied to treat diverse diseases for their excellent anti-inflammatory, analgesic, and cardiotonic effects. However, the cardiotoxicity and neurotoxicity of AC attracted a lot of attention and made it a favorite botanic poison in history. Nowadays, the narrow therapeutic window of AC limits the clinical application of AC-containing herbal medicines; overdosing on AC always induces ventricular tachyarrhythmia and heart arrest, both of which are potentially lethal. But the underlying cardiotoxic mechanisms remained chaos. Recently, beyond its cardiotoxic effects, emerging evidence shows that low doses of AC or its metabolites could generate cardioprotective effects and are necessary to aconite's clinical efficacy. Consistent with TCM's theory that even toxic substances are powerful medicines, AC thus could not be simply identified as a toxicant or a drug. To prevent cardiotoxicity while digging the unique value of AC in cardiac pharmacology, there exists a huge urge to better know the characteristic of AC being a cardiotoxic agent or a potential heart drug. Here, this article reviews the advances of AC metabolism and focuses on the latest mechanistic findings of cardiac efficacy and toxicity of this aconite alkaloid or its metabolites. We also discuss how to prevent AC-related cardiotoxicity, as well as the issues before the development of AC-based medicines that should be solved, to provide new insight into the paradoxical nature of this ancient poison.

Ginsenoside Rb1 ameliorates cardiotoxicity triggered by aconitine via inhibiting calcium overload and pyroptosis.

BACKGROUND: Aconitine-induced cardiotoxicity limits the clinical treatment of cardiotonic, cancers and immune-related diseases. Ginsenoside Rb1 (Rb1) is an active ingredient of traditional Chinese medicine with cardioprotective effect. PURPOSE: This study aims to study the mechanism of aconitine cardiotoxicity and the detoxification mechanism of Rb1. STUDY DESIGN: METHODS: The regulatory effect of Rb1 on aconitine was evaluated in vitro and in vivo by myocardial enzyme indicators, pathological analysis, CardioECR detection, calcium transient analysis, western blotting and immunohistochemistry. RESULTS: Rb1 (10, 20, 40 mg/kg) alleviated apoptotic myocardial damage caused by aconitine in rats. Furthermore, Rb1 (25, 50, 100 µM) restored the contractile function and field potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) by regulating calcium channels and reduced myocardial cell damage by inhibiting the calcium transients of adult rat ventricular myocytes (ARVMs). Rb1 significantly reduced calcium levels in hiPSC-CMs, directly indicating that aconitine-induced calcium overload was alleviated by Rb1. Further, aconitine caused calcium overload by changing the expression of calcium pathway proteins, while Rb1 effectively restored calcium homeostasis. In addition, Rb1 also had a cardioprotective role by inhibiting cell pyroptosis. These results suggested that the maintenance of calcium homeostasis helped to suppress the inflammatory response related to pyroptosis of the heart. CONCLUSION: Aconitine-induced cardiotoxicity can be alleviated by Rb1 via restoring calcium homeostasis and inhibiting apoptosis and pyroptosis.

Paeoniflorin reduced the cardiotoxicity of aconitine in h9c2 cells.

Aconitine (ACO), the main active component in Aconitum carmichaelii Debeaux (family: Ranunculaceae), has high cardiotoxicity, however the mechanisms of this effect remain unclear. Paeoniflorin (PF), the main chemical ingredient in herbaceous peony, can protect the heart from damage through antioxidant, vasodilatory and other effects. In this study, we focused on the mechanism by which PF reduces ACO cardiotoxicity. We selected H9c2 cells as the experimental model. MTT assay, Western blot analysis and real-time PCR were used to measure cell proliferation, apoptosis, ion channels and oxidative stress. Cell proliferation was significantly increased, the Bcl-2/Bax ratio and p53 level were upregulated, and Caspase-3 was slightly reduced in the ACO+PF group compared with the ACO group. SCN5A mRNA expression was significantly increased in the ACO+PF group compared with the ACO group, while RyR2 and Cx43 mRNA expression was decreased. Compared with the ACO group, the ACO+PF group showed marked decreases in extracellular lactate dehydrogenase (LDH) and intracellular malondialdehyde (MDA), while there was no difference in intracellular superoxide dismutase (SOD). The above data demonstrate that the cardiotoxicity of ACO in H9c2 cells was significantly decreased by PF.

[Establishment and verification of risk assessment scale for clinical safety medication of aconitine].

Chinese patent medicine containing aconitine is the key in clinical rational drug use. These drugs contain Chuanwu, Caowu or Fuzi, and Aconitum brachypodum with functions of expelling wind-dampness or tonifying Yang, all of which shall be used by strictly following the indications and dosage. However, there are many kinds of such drugs. Not only the unfamiliar knowledge of some Chinese and Western physicians about the characteristics of them, but also the combination of multiple drugs from different clinical departments, would increase the risk of aconitine poisoning. Based on the previous research, this paper proposed three core elements "syndrome differentiation-dosage differentiation-toxicity differentiation" from the prescription review and pharmacy consulting work, and objective and standardized evaluation was used to build a risk assessment scale containing 3 categories, 9 items and 36 indicators with Hulisan Jiaonang and Qufeng Zhitong Jiaonang as the example. This scale was used to evaluate the risk of a therapeutic regimen before and after the implementation. According to the verification of the existing adverse reaction cases, the risk assessment scale can be used to indicate the risk of drug treatment program and identify the risk level of drug treatment status. This paper tried to provide a methodological paradigm for scientific and objective evaluation on the safety of Chinese patent medicines, and help to identify the key links and risk prevention in the rational use by Chinese medicine physicians and pharmacists.

Assessment of in vitro cardiotoxicity of extract fractions and diterpene alkaloids from Aconitum leucostomum Worosch: A short communication.

Aconitum leucostomum Worosch is a traditional Chinese medicine (TCM) and has a broad spectrum of health effects, but with a narrow therapeutic window. It is important to identify both the therapeutic ingredients and the toxic components to better utilize this TCM. The present study investigated the cardiotoxicity of the selected compounds in Aconitum leucostomum Worosch. The effects of extract of A. leucostomum Worosch and the isolated compounds on cardiocardiomyocytes were evaluated in vitro. Five known compounds in this TCM, including three C18-diterpene alkaloids, lappaconitine (2), N-deacetyllappaconitine (3), and ranaconitine (5), and two C19-diterpene alkaloids, delvestidine (1) and anthranoyllycoctonine (4), were isolated from A. leucostomum Worosch. The cardiotoxicity of these components and extract fractions, as measured by lactate dehydrogenase release and apoptosis, was ranked as follows, in descending order: delvestidine>anthranoyllycoctonine>pH 4 fraction>pH 8 fraction>aconitine>N-deacetyllappaconitine>ranaconitine>lappaconitine. The cytotoxicity of these compounds was shown to be dose-dependent, with delvestidine (1) and anthranoyllycoctonine (4) being the two most toxic compounds to cardiomyocytes in our assays. These results provide a basis for future rational use of this TCM, reducing side effects while retaining therapeutic effects.

A conscious rat model involving bradycardia and hypotension after oral administration: a toxicokinetical study of aconitine.

1. A model of aconitine-induced bradycardia and hypotension, which is similar to aconitine poisoning in humans, was constructed in conscious rats by oral administration. 2. Blood pressure (BP) and heart rate (HR) of Sprague-Dawley rats were measured using a volume pressure recording (VPR) system. The pharmacokinetics of toxic doses of aconitine and its metabolites were analyzed using UPLC-MS/MS. 3. The HR was significantly decreased by 29% at 2 h after oral administration of 200 µg/kg aconitine. When the dose was increased to 400 µg/kg, systolic BP and diastolic BP were significantly decreased by 11% and 12% at 2 h after the administration, except when bradycardia occurred at 2 h and 4 h. The drug concentration-time curve showed a double-peak phenomenon in rats administered a 400 µg/kg dose. The AUC0-12 h value in the 400 µg/kg group significantly increased 0.8-fold compared to the 200 µg/kg group. Moreover, a high plasma concentration of 16-O-demethyaconitine was found in the rats that received two toxic doses. 4. In conclusion, bradycardia and hypotension are induced in conscious rats by a toxic dose of aconitine (400 µg/kg), and there was no significant difference in dose-normalized AUC0-12 h values between oral administrations of 200 µg/kg and that of 400 µg/kg. However, the dose-normalized Cmax and AUC0-12 h values in 200 µg/kg and 400 µg/kg groups were significantly smaller than those in 100 µg/kg group. The metabolites of aconitine, 16-O-demethyaconitine, and benzoylaconitine may also contribute to the hypotensive response.

Termination of aconitine-induced atrial fibrillation by the KACh-channel blocker tertiapin: underlying electrophysiological mechanism.

The acetylcholine receptor-operated K(+) (KACh) channel may be a novel target for atrial-specific antiarrhythmic therapy. Recently it has been demonstrated that tertiapin, a selective blocker of KACh channel, suppressed aconitine-induced atrial fibrillation (AF) in dogs. However, the precise mechanism by which the KACh-channel blocker inhibits the aconitine-induced AF remains unknown. This study was undertaken to determine the role of KACh channel in aconitine-induced AF in guinea pigs. Tertiapin terminated the aconitine-induced AF in anesthetized guinea pigs. The results of an in vitro electrophysiological experiment using atrial cells and atrial preparations suggest that aconitine might activate KACh channels in atrial cells, probably by intracellular Na(+) accumulation, and inhibition of KACh channels by tertiapin might suppress AF by producing conduction block, probably due to further decrease in the resting membrane potential. Since it has been reported that constitutively active KACh channels can be observed in atrial cells of patients with chronic AF, aconitine-induced AF may be used as an experimental model for evaluation of drug effect on chronic AF.

[Comparative study of the toxicity and antiarrhythmic activity of some organic derivatives of dimethylacetamide].

A comparative study of the acute toxicity and antiarrhythmic activity of new domestic derivatives of dimethylacetamide showed that the introduction of amino and carboxylic acid residues into the structure of compounds is accompanied by reduction of the toxic properties of new substances on the average 2.73 times (p = 0.002) upon intraperitoneal introduction to animals. It has been established that the derivatives are able to prevent the formation of aconitine induced arrhythmias and eliminate the arrhythmia that occurs on the second day of myocardial infarction in dogs. Original derivatives of dimethylacetamide exhibit antiarrhythmic properties and their activity increases in proportion to the acute toxicity (r = 0.83, p = 0.0043).

[Efficacy and safety of allapinine and quinidine bisulphate in the treatment of patients with persistent atrial fibrillation after cardioversion].

OBJECTIVE: To assess and compare the safety and efficacy of allapinine and quinidine bisulphate in the treatment of patients with persistent atrial fibrillation after cardioversion. Design--Prospective, randomised, open study. Patients--73 consecutive patients (men only, mean age 44 ± 11 years) with persisnent atrial fibrillation and flutter. Interventions--37 patients were randomised to allapinine (ALP) (1.5 mg/kg/d), 36 to quinidine bisulphate (QUIN) (15 mg/kg/d) with subsequent successful pharmacological or electrical cardioversion. Main outcome measures--Recurrence of atrial fibrillation or side effects. RESULTS: In the ALP group 15 of the 37 patients developed atrial fibrillation up to 12 month of follow-up, while in the QUIN group 20 patients developed atrial fibrillation and 5 experienced significant side effects. Relative risk (RR) (ALP vs QUIN) 0.58 (95% CI 0.37-0.91, p < 0.02). The number needed to treat (NNT) was (-3.48) (14.2-1.97 harm). When 5 patients with significant side effects were excluded from the analysis RR was 0.62 (95% CI 0.39-1.0, p = 0.052) and NNT--(-4.1) (122.7-2.1 harm) but power of the study was too low--67%. CONCLUSION: Allapinine is as effective as quinidine bisulphate in the long term treatment of patients with persistent atrial fibrillation after successful cardioversion but causes significantly less side effects.

[Search for new drugs with antiarrhythmic properties among derivatives of adamant-2-ylamides of alkylamidocarbonic acids].

The experiments on white outbred awaken male rats have shown that derivatives of adamant-2-ylamides of alkylamidocarbonic acids exhibit prominent antiarrhythmic (antifibrillatory) effect on the model of calcium chloride arrhythmia. The most pronounced effect was demonstrated by N-[2(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide. This compound was also active on the model of aconitine arrhythmia, which is characteristic of class-I antiarrhythmic agents. It is established that N-[2-(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide has prominent antiarrhythmic activity and is more safe than other antiarrhythmic drugs of class I (lidocaine, ethmosine, novocainamide), class IV (verapamil), and class III (cardiocyclide).

[Prophylactic use of VFS in patients with coronary artery disease in the perioperative coronary artery bypass grafting].

Tachyarrhythmias (TA) - dangerous postoperative complications of coronary artery bypass grafting, threatening the lives of patients and found, according to different authors, in 13-40% of cases. VFS - an antiarrhythmic drug that belongs to a class 1C, is effective in the treatment and prevention of a variety of cardiac arrhythmias. The aim of the work was to study the clinical efficacy of VFS CHD patients with a history of tachyarrhythmias during the perioperative period of coronary bypass surgery, as well as its comparison with other antiarrhythmic drug (amiodarone). Clinical efficacy was evaluated in 218 patients with coronary heart disease at baseline with a history of tachyarrhythmia (paroxysmal atrial fibrillation or premature ventricular high grade (IV and V class on classification of Lown B. and Wolf M. in the modification of Ryan M.). Shown that the VFS is more effective than amiodarone, both in paroxysmal atrial fibrillation and ventricular arrhythmias when high gradation.

Observation on effects of aconitine via acupoint injection in rabbits.

OBJECTIVE: To investigate the ability of the pericardium meridian (PM) to mitigate or enhance the cardiotoxic effects of aconitine injected at specific acupoint and non-acupoint sites in rabbits. METHODS: This study consisted of 3 experiments that were designed to test the effects of injection of 30 µg/kg of aconitine at acupoints on the PM (Test 1), at non-acupoint sites on the PM (Test 2), and at acupoints on other meridians and non-meridian sites (Test 3). In Test 1, 24 rabbits were randomly assigned to receive injections at Quze (PC3), Tianquan (PC2), or intramuscularly. In Test 2, 24 rabbits were randomly assigned to receive injections of aconitine at non-acupoint I, non-acupoint II, or intramuscularly. In Test 3, 48 rabbits were randomly assigned to receive injections at Neiguan (PC6), Sanyinjiao (SP6), Yangjiao (GB35), a non-meridian and non-acupoint site (NMNA), intravenously, and intramuscularly. Electrocardiographs of the rabbits were performed before, during and after injection to determine the incidence of arrhythmia, latency of ventricular rhythm, and recovery rate after aconitine injection. The recovery time index and extent of arrhythmia scores were calculated. RESULTS: In all groups the incidence of arrhythmia was 100%, and the latency of ventricular rhythm was less than 30 min. In Tests 1 and 2, the recovery rates of the Quze and non-acupoint II groups were significantly higher than those of the muscular group (P < 0.05). In Test 3, the recovery time index and extent of arrhythmia scores of the Neiguan group were low. There were no significant differences between the other acupoint groups, or the NMNA group, when compared with the group receiving aconitine intramuscularly. CONCLUSIONS: Acupoints or non-acupoints along the PM could reduce the severity of the arrhythmia induced by aconitine in healthy rabbits. Meridians play an important role in protecting body functions.

[Antiarrhythmic therapy of paroxysmal tachycardias and extrasystoles in patients with sinus node dysfunction].

Antiarrhythmic therapy of patients with disturbed automatism of the sinus node and impaired atrioventricular conductance may be complicated by hemodynamically significant bradycardias and contraindications for implantation of a cardiac electrical stimulator This study aimed at estimating effect of antiarrhythmic therapy with allapinin on the function of sinus and atrioventricular nodes. It included 20 patients (mean age 37.5+-2.3 years) with disturbed cardiac rhythm and sinus node dysfunction treated with allapinin (37.5 - 50 mg/d per os). This therapy had well apparent antiarrhythmic effect manifest as improvement of supraventricular and ventricular ectopic activities in the absence of negative influence on the function of sinus and atrioventricular nodes.

Activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice.

In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective α7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.

Pharmacokinetics of aconitine in rat skin after oral and transdermal gel administrations.

The purpose of this study was to evaluate percutaneous penetration and arrhythmogenic effects of aconitine after transdermal administration, compared with the oral route. Skin penetration of aconitine was tested by a microdialysis technique in rats and in vivo recovery was determined by retrodialysis. After oral and transdermal administration of aconitine, dialysate was sampled at 20 min intervals until the end of the experiment for the determination of concentration of aconitine in skin. Blood samples were collected and analyzed using a validated HPLC-MS/MS method. In addition, we concurrently recorded the electrocardiogram (ECG). The in vivo recovery of aconitine in the skin was calculated to be 39.59%. The C(max) values for aconitine absorbed into the skin after oral and transdermal administration were 1.51 ± 0.53 and 2723.8 ± 848.8 ng/mL, respectively, and within the plasma, 215.86 ± 79.29 and 20.92 ± 3.15 ng/mL. The C(max) value for the plasma concentration of aconitine after oral administration was approximately 10 times higher than with the transdermal route. For oral administration, the ECG revealed various types of arrhythmias at a period of T(max) , which is normal in transdermal gel administration. These results indicate that transdermal aconitine gel is a safe formulation that can deliver the drug in sufficient amounts and safe concentrations to produce therapeutic action in rats.