Safety reassessment of cinobufotalin injection: new findings into cardiotoxicity.

Cinobufotalin injection, a traditional Chinese medicine preparation, successfully used for several years, might induce cardiotoxicity. The aim of the study was to evaluate the cardiotoxicity of cinobufotalin injection and the cardiotoxicity-preventive effect of sodium phenytoin in vivo. According to the 4 × 4 Latin square design, four Beagle dogs were allocated into four dose levels of 0, 0.3, 1, and 3 g/kg in treatment phases I-IV (cinobufotalin injection) and 3 g/kg in treatment phase V (cardiotoxicity antidote). The following parameters and endpoints were assessed: clinical observations, body weight, indicators of myocardial injury, and electrocardiogram (ECG) parameters. The cinobufotalin injection-related changes were observed in clinical observations (rapid breathing pattern), indicators of myocardial injury (increased cardiac troponin I, creatine kinase isoenzymes, and aspartate aminotransferase), and ECG graphics (arrhythmia) at 3 g/kg concentration in treatment phases I-IV. The cardiotoxicity of cinobufotalin injection was attenuated by sodium phenytoin in treatment phase V. The results confirmed the cardiotoxicity of cinobufotalin injection, and they might bring information about the appropriate monitoring time points and cardiotoxicity parameters in clinical practices and shed light on the treatment of cardiovascular adverse reactions.

Bufalin-induced cardiotoxicity: new findings into mechanisms.

Bufalin is one of the main pharmacological and toxicological components of Venenum Bufonis and many traditional Chinese medicine preparations. The cardiotoxicity clearly limits its application to patients living in countries. Hence, an investigation of its toxicological mechanism is helpful for new drug development and treatment of the related clinical adverse reactions. We investigate the cardiotoxicity of bufalin using human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) (0.003-0.1 µmol·L-1), human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) (0.03-0.3 µmol·L-1) and eight human cardiac ion channel currents (0.01-100 µmol·L-1) combined with an impedance-based bioanalytical and patch clamp method. Biphasic effect of bufalin on the contractility in hiPSC-CMs, which has been shown to strengthen myocardial contractility, accelerate conduction, and increase beating rate at the earlier stage of administration, whereas weakened myocardial contractility, abolished conduction, and ceased beating rate at the later stage of administration. Bufalin decreased the action potential duration (Action potential duration at 30%, 50% and 90% repolarization), cardiac action potential amplitude, and maximal depolarization rate and depolarized the resting membrane potential of hiPSC-CMs. Spontaneous beating rates of hiPSC-CMs were markedly increased at 0.03 µmol·L-1, while were weakened at 0.3 µmol·L-1 after application. Bufalin blocks INav1.5 in a concentration-dependent manner with half maximal inhibitory concentration of 74.5 µmol·L-1. Bufalin respectively increased the late sodium current and Na+-Ca2+ exchange current with a concentration for 50% of maximal effect of 2.48 and 66.06 µmol·L-1 in hiPSC-CMs. Whereas, bufalin showed no significant effects on other cardiac ion channel currents. The enhancement of the late sodium current is one of the main mechanism for cardiotoxicity of bufalin.

Combined oral administration of bovine collagen peptides with calcium citrate inhibits bone loss in ovariectomized rats.

PURPOSE: Collagen peptides (CPs) and calcium citrate are commonly used as bone health supplements for treating osteoporosis. However, it remains unknown whether the combination of oral bovine CPs with calcium citrate is more effective than administration of either agent alone. METHODS: Forty 12-week-old Sprague-Dawley rats were randomly divided into five groups (n = 8) for once-daily intragastric administration of different treatments for 3 months at 3 months after ovariectomy (OVX) as follows: sham + vehicle; OVX + vehicle; OVX + 750 mg/kg CP; OVX + CP-calcium citrate (75 mg/kg); OVX + calcium citrate (75 mg/kg). After euthanasia, the femurs were removed and analyzed by dual energy X-ray absorptiometry and micro-computed tomography, and serum samples were analyzed for bone metabolic markers. RESULTS: OVX rats supplemented with CPs or CP-calcium citrate showed osteoprotective effects, with reductions in the OVX-induced decreases in their femoral bone mineral density. Moreover, CP-calcium citrate prevented trabecular bone loss, improved the microarchitecture of the distal femur, and significantly inhibited bone loss with increased bone volume, connectivity density, and trabecular number compared with OVX control rats. CP or CP-calcium citrate administration significantly increased serum procollagen type I N-terminal propeptide levels and reduced serum bone-specific alkaline phosphatase, osteocalcin, and C-telopeptide of type I collagen levels. CONCLUSIONS: Our data indicate that combined oral administration of bovine CPs with calcium citrate inhibits bone loss in OVX rats. The present findings suggest that combined oral administration of bovine CPs with calcium citrate is a promising alternative for reducing bone loss in osteopenic postmenopausal women.

Pharmacological effect of deoxypodophyllotoxin: a medicinal agent of plant origin, on mammalian neurons.

Deoxypodophyllotoxin (DOP) is a natural product that can be isolated from a variety of medicinal herb plants. It is well known for its antitumor, antiviral, and anti-inflammatory activities. However, there are few investigations that address neurotoxic effect of DOP in animal nervous system. In this study, whole-cell patch clamp and calcium imaging techniques were employed to investigate effects of DOP on electrophysiological properties and calcium regulation of rat dorsal root ganglion (DRG) neurons. DOP inhibited both TTX-S (tetrodotoxin-sensitive) and TTX-R (tetrodotoxin-resistant) sodium currents in voltage clamp recording and caused a decrease in the number of action potentials (APs) in current clamp experiment. Suppressive and unfavorable effects of DOP on the kinetics of sodium currents in terms of excitability of DRG neurons may greatly contribute to its antitumor and anti-inflammatory activities. Moreover, DOP evoked increase of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in DRG neurons, and this effect may lead to neuronal cytotoxicity.