Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Effects of Anisodine Hydrobromide on the Cardiovascular and Respiratory Functions in Conscious Dogs This article was published in the following Dove Press journal: Drug Design, Development and Therapy Yunlu Liu 1,2 Purpose: Anisodine hydrobromide (Ani) is isolated from the medicinal plant Anisodus Lin Wang1 tanguticus (Maxim.) Pascher for clinical use. Although considerable research regarding Feng Wan3 Ani has been reported, the safety profiles of Ani are currently unknown. This study Na Yang1 investigated the cardiorespiratory effects of Ani in conscious dogs to provide clinicians a detailed safety profile of Ani on the cardiorespiratory system. 1 Institute of Laboratory Animal Sciences, Materials and Methods: Using the Latin square design, the study was divided into six Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, phases, where in each phase, six telemetered beagle dogs received one dose of normal saline Chengdu, People’s Republic of China; or sotalol hydrochloride or Ani (0.1, 0.4, 1.6, or 6.4 mg/kg). Electrocardiogram, blood 2Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan pressure (BP) and respiratory parameters were collected before and after administration for Provincial People’s Hospital, Chengdu, 24 hours. Statistical comparisons were performed at scheduled time-points. People’s Republic of China; 3College of Results: The heart rate was significantly increased, PR and QTCV intervals were significantly Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, shortened in Ani 0.4, 1.6, 6.4 mg/kg treatment group after drug administration. Compared with People’s Republic of China the saline group, a significant increase in heart rate and shortening of PR, QTCV intervals were observed in the Ani 1.6, 6.4 mg/kg treatment groups from 5 min to 4 h time-points. Diastolic and mean BP were significantly increased in Ani 1.6, 6.4 mg/kg from 1 h to 2 h time-points compared to those of the saline control. Accelerated breathing was observed in the first 20 min after Ani 0.4, 1.6, and 6.4 mg/kg treatment, although not statistically significant.Furthermore, no significant differences were observed in any of the corresponding indexes of Ani 0.1 mg/kg treatment group at different time-points compared to those of the saline group. Conclusion: Ani may have adverse effects on the cardio-respiratory systems of dogs at doses above 0.4 mg/kg, whereas Ani 0.1 mg/kg was devoid of potentially deleterious effects on cardiorespiratory function. Keywords: anisodine hydrobromide, electrocardiogram, blood pressure, cardio-respiratory function, telemetered dogs, safety Introduction Anisodine, a tropane alkaloid extracted from the root of Anisodus tanguticus 1 Correspondence: Na Yang (Maxim.) Pascher in the family Solanaceae, has shown significant therapeutic Institute of Laboratory Animal Sciences, effects on various conditions, such as ocular diseases,2–5 motion sickness and Sichuan Academy of Medical Sciences & 6 7 8 Sichuan Provincial People’s Hospital, Ying migraine, acute circulatory shock, and organophosphorus pesticide poisoning. Long Community, Zhong he Street Office, In view of the unstable chemical properties of anisodine, researchers have devel­ High Tech Zone, Chengdu 610212, People’s Republic of China oped anisodine hydrobromide (Ani). Tel +86 13880145342 Ani acts as non-specific muscarinic cholinoceptor antagonist competing with Fax +86 2867087558 Email [email protected] acetylcholine for binding to the muscarinic cholinergic receptor to block the nerve submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 4263–4276 4263 DovePress © 2020 Liu et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php http://doi.org/10.2147/DDDT.S268113 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Liu et al Dovepress impulse and physiological functions associated with cho­ parameters were collected by a telemetry system using linergic neurotransmission.9 The autonomic receptors dis­ electrical impedance technology, a common detection tributed in the cardiac, vascular, and airway smooth method showing strong correlation with pneumotacho­ muscle are mainly muscarinic cholinoceptors.10–12 Thus, graph results in the clinic.26 the antimuscarinic activity of Ani could potentially lead to various physiological effects on the cardiorespiratory sys­ Materials and Methods tem. Early experimental and clinical studies have reported The study was reviewed and approved by the Welfare and that structurally-related tropane alkaloids (such as aniso­ Ethics of Experimental Animals Committee of Institute of damine, scopolamine, and atropine) have potential unde­ Laboratory Animal Science, Sichuan Academy of Medical sirable effects on the cardiovascular and respiratory Sciences & Sichuan Provincial People’s Hospital for com­ systems.13–18 Thus, it is necessary to investigate the effects pliance with Guide for the Care and Use of Laboratory of Ani on cardiorespiratory function systematically. Animals (No. Lunshen2018-016). It was conducted in Additionally, although some drugs, such as antibiotics, a research facility accredited by Sichuan Provincial tricyclic antidepressants, and antifungal agents do not act Laboratory Animal Management Committee. The flow­ on the cardiovascular system directly based on their chart of the study is detailed in Figure 1. mechanism of action, nonetheless they have been reported to lead to life-threatening adverse effects, and some patients have suffered serious heart damage after taking Animals and Surgical Preparation for these drugs in clinical practice.19–21 However, to the best Telemetry of our knowledge, no previous studies have extensively Six beagle dogs (three females and three males, 9–10 months assessed the cardiovascular and respiratory effects of Ani. old, 9–12 kg) were obtained from Marshal Biotechnology To this end, this study was designed to define the effects of (Beijing, China). All dogs were housed singly in stainless- Ani on the cardio-respiratory system by following the steel canine cages (1000×1000×2080 mm) for 80 days International Council for Harmonization (ICH) guidelines throughout the study, they were given 25 days to acclimate (S7A, S7B) and the China Food and Drug Administration to the housing environment and team members before the (CFDA) guidelines, to provide a comprehensive profile of implanted surgery started. All animals were fed the cardiorespiratory safety of Ani to the clinician. a maintenance diet. Filtered mains water was offered ad- Electrocardiogram (ECG), blood pressure, and respira­ libitum. Environmental controls were set to maintain the 12- tory indices were collected to describe the effects of Ani hour light-dark cycle (lights on 6:00 AM, off 6:00 PM), on the cardiorespiratory system. We especially focused on 20–25°C temperature and 40–70% humidity range. the prolongation of the QT interval of the ECG, which The animals were anesthetized with propofol (8–12 mg/ represents the cardiac repolarization disturbance that can kg intravascular), and maintained general effect by isoflurane cause torsade de pointes and sudden cardiac death.22 (1.5–5 volume % in oxygen) inhalation. With the sterile Furthermore, indicators of the PR interval and QRS dura­ surgical technique, telemetry transmitter (model number tion of the ECG were also used to evaluate atrioventricular TL11M3-D70-PCTR, Data Sciences International [DSI], and intraventricular conductivities. In order to validate and St. Paul, MN, USA) was implanted in the dogs. The respira­ define the sensitivity of the experimental system, sotalol tory electrodes were implanted subcutaneously on both sides hydrochloride (Sol), an antiarrhythmic agent, which is of the left and right seventh ribs. The ECG electrodes were known to prolong the PR interval and QT interval and implanted subcutaneously on the left side of the chest at the widen the QRS duration,23 was used as the positive control intersection of the last rib and the anterior axillary line and on drug. In addition, an implantable telemetry system the right side at the middle lower edge of the clavicle. The strongly recommended by ICH and CFDA in safety phar­ pressure catheter for blood pressure measurement was macology studies and has been used in the pharmaceutical implanted in the femoral artery, and the main implant body industry for safety evaluation,24 was applied in the present was fixedin the extra-abdominal oblique muscle. After post­ study. Beagle dogs were selected because of the stability operative care and recovery period were completed, animals of their genetic characteristics and completeness of genetic were assessed with indices for general physical conditions, background information, and feasibility of surgical opera­ including body weight, hematology, blood biochemistry, tion in telemetry experiments.25 In addition, respiratory