Nonclinical Safety Pharmacology Study of the Herbal Product HAD-B1

HAD-B1 is a Korean herbal formula designed to treat solid tumors, and through cell experiments, it has proven to have an anticancer effect. The current study aims to test the safety of HAD-B1. This experiment is under the regulation of ICH. In order to find if HAD-B1 has any effect on the CNS, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally administered to male and female rats once. To discover any effect on the respiratory system, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally given to male rats followed by measuring the respiratory rate, tidal volume, and minute respiratory volume. To assess the possibility of a delayed QT period as a result of the drug administration, hERG analysis was conducted at 0, 0.1, 0.3, and 1 μg/ml. To assess any effect on the cardiovascular system, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally given to male beagle dogs once followed by temperature, blood pressure, ECG, and heart rate analyses. There were no clinically significant changes in both male and female rats on assessing any effects on the CNS. There were no clinically significant changes in male rats’ respiratory assessment. There were no clinically significant changes in hERG analysis results. There were no clinically significant changes in the cardiovascular system of male beagle dogs. Our results demonstrate that HAD-B1 is a safe herbal formula that does not have a clinically significant effect on the CNS, respiratory, and cardiovascular systems.

Safety assessment of subtilisin QK in rats

Background Subtilisin QK is a serine protease in the subtilisin family, and is fermented by Bacillus subtilis QK02. The fibrinolytic activity of subtilisin QK was measured by detecting low molecular weight degradation products using a spectrophotometric method developed by Japan Bio Science Laboratory Co., Ltd. Subtilisin QK powder can maintain its fibrinolytic activity for more than 24 months when it is stored at room temperature and protected from light. Our previous results showed that subtlisin QK directly degraded cross-linked fibrins in the fibrin plate assay and effectively inhibited thrombosis in the mouse thrombus model. The aim of this study was to determine the acute toxicity, potential subchronic toxicity, and safety pharmacology of subtilisin QK in Sprague–Dawley (SD) rats. Methods In the acute toxicity study, a single oral dose of 100,000 FU/kg was administered to 10 female and 10 male SD rats. In the 28-day subchronic toxicity, 60 female and 60 male SD rats were randomly assigned to four experimental groups (daily oral dose of 0, 2500, 7500 and 25,000 FU/kg). In the safety pharmacology study, 20 female and 20 male SD rats were randomly assigned to four experimental groups (single oral dose of 0, 500, 1500 and 5000 FU/kg). Results No death occurred and no adverse effects were observed in the acute toxicity study at a dose of 100,000 FU/kg. In the 28-day subchronic toxicity study, several hematological and blood biochemical parameters showed increases or decreases; however, due to the lack of a dose–response relationship, these differences were considered unrelated to treatment. In the safety pharmacology study, no adverse effects were observed on the central nervous of SD rats post-administration up to a dose of 5000 FU/kg subtilisin QK. Conclusion The results showed that oral consumption of subtilisin QK is of low toxicological concern. No adverse effects were observed at doses of 2500, 7500, and 25,000 FU/kg in the 28-day subchronic toxicity, and the no-observed-adverse-effect level (NOAEL) of subtilisin QK was 25,000 FU/kg.

Safety Pharmacology Study of Medicines Used for Febrile Syndrome Management in Children

Summary. Safety pharmacology studies of paediatric medicines are an important stage in the life cycle of drugs.The purpose of the study was to analyse and compare the safety pharmacology profiles of the recommended paediatric dosage regimens of a fixed ibuprofen (IBU)/paracetamol (PAR) combination and of IBU and PAR monopreparations following repeated oral administration of these products to juvenile rats. Material and methods: safety pharmacology was assessed in both male and female outbred juvenile rats. Two dose levels were used in the study—the highest treatment dose (HTD) equivalent for juvenile rats, and the three-times-equivalent therapeutic dose (3 HTD). The animals were given the fixed IBU/PAR combination in the form of suspension from dispersible tablets (100 mg IBU + 120 mg PAR), IBU in the form of oral suspension (100 mg/5 mL), and PAR in the form of oral suspension (120 mg/5 mL). Statistical processing was performed using Statistica 10.0 software. Results: unlike monopreparations, the fixed IBU/PAR combination did not have clinically significant hepatotoxic or nephrotoxic effects when administered to juvenile rats. Administration of IBU alone resulted in an increase in blood urea nitrogen concentration in female rats (HTD) and male rats (3 HTD), and a small amount of leucocytes in the urine of female rats. Administration of PAR resulted in an increase in the amount of red blood cells in the urine of male rats. Administration of the monopreparations at the HTD dose led to a decrease in the locomotor activity of the animals. No significant effect on the cardiovascular or respiratory systems was observed for any of the products.Conclusions: the safety pharmacology profile of the fixed IBU/PAR combination after repeated oral administration to juvenile rats did not differ much from those of IBU and PAR used alone, and in some cases was even better.