Safety assessment of Wuzhuyu decoction extract: acute and subacute oral toxicity studies in rats.

Wuzhuyu decoction (WZYD) is a well-known classic traditional Chinese medicine prescription and has been widely used to treat headache, nausea, vomiting, insomnia, etc. However, little published information is available about its safety. Our aim was to investigate the acute and subacute oral toxicity of WZYD extract in rats following the technical guidelines from China's National Medical Products Administration (NMPA) for single and repeated doses toxicity studies of drugs. Acute oral toxicity was assessed in rats via oral administration of WZYD extract at 4 g/kg three times within a day followed by a 14-day observation period. To evaluate the subacute toxicity, rats were orally administered with WZYD extract at doses of 0, 0.44, 1.33, and 4 g/kg for 28 days. The items examined included clinical signs, body weight, food consumption, hematological and biochemical parameters, bone marrow smear, organ index, and histopathology. After the rats were administered with 12 g/kg (3 × 4 g/kg) WZYD extract, no mortality and toxic effects were observed during the observation period. In the subacute toxicity study, WZYD extract did not cause any significant treatment-related abnormality in each examined item of rats, so the no observed adverse effect level (NOAEL) of WZYD extract for 28 days orally administered to rats is considered to be 4 g/kg, which is approximately 80-fold of its clinical proposed dosage.

Network pharmacology-based predictions of active components and pharmacological mechanisms of Artemisia annua L. for the treatment of the novel Corona virus disease 2019 (COVID-19).

BACKGROUND: Novel Corona Virus Disease 2019 (COVID-19) is closely associated with cytokines storms. The Chinese medicinal herb Artemisia annua L. (A. annua) has been traditionally used to control many inflammatory diseases, such as malaria and rheumatoid arthritis. We performed network analysis and employed molecular docking and network analysis to elucidate active components or targets and the underlying mechanisms of A. annua for the treatment of COVID-19. METHODS: Active components of A. annua were identified through the TCMSP database according to their oral bioavailability (OB) and drug-likeness (DL). Moreover, target genes associated with COVID-19 were mined from GeneCards, OMIM, and TTD. A compound-target (C-T) network was constructed to predict the relationship of active components with the targets. A Compound-disease-target (C-D-T) network has been built to reveal the direct therapeutic target for COVID-19. Molecular docking, molecular dynamics simulation studies (MD), and MM-GBSA binding free energy calculations were used to the closest molecules and targets between A. annua and COVID-19. RESULTS: In our network, GO, and KEGG analysis indicated that A. annua acted in response to COVID-19 by regulating inflammatory response, proliferation, differentiation, and apoptosis. The molecular docking results manifested excellent results to verify the binding capacity between the hub components and hub targets in COVID-19. MD and MM-GBSA data showed quercetin to be the more effective candidate against the virus by target MAPK1, and kaempferol to be the other more effective candidate against the virus by target TP53. We identified A. annua's potentially active compounds and targets associated with them that act against COVID-19. CONCLUSIONS: These findings suggest that A. annua may prevent and inhibit the inflammatory processes related to COVID-19.

Acute and subacute oral toxicity assessment of Gancao Xiexin decoction in Sprague-Dawley rats.

Gancao Xiexin decoction (GCXXD), a well-known classic traditional Chinese medicine prescription, is used to treat various oral ulcers, Behcet disease, gastrointestinal ulcers, etc. However, there is very little information on its safety. This study aimed to investigate the acute and subacute oral toxicity of GCXXD in Sprague-Dawley rats. In the acute toxicity study, rats were orally administered 10 g/kg GCXXD three times a day. Clinical signs of abnormality and mortality were observed daily for 14 days. In the subacute toxicity study, rats were orally administered 0, 1.47, 3.83, or 10 g/kg GCXXD for 28 days. The rats' clinical signs, body weight, food consumption, hematological and biochemical parameters, bone marrow smear, organ index, and pathological morphology were analyzed. The acute toxicity study showed that GCXXD is safe in rats without any obvious toxicity via an oral dose of 30 g/kg/day (3 × 10 g/kg). After 28 days of administration, slightly decreased RBC, HGB, and HCT were observed in female rats at 10 g/kg, suggesting that repeated doses of high-dose GCXXD may cause mild anemia in female rats. The no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of oral administration of GCXXD for 28 days in rats are considered to be 3.83 g/kg and 10 g/kg, respectively. Long-term toxicity studies are recommended to strengthen the findings.

Pharmacokinetics and Toxicokinetics of Artemisinin-Hydroxychloroquine Sulfate Tablets in Rats and Dogs.

Artemisinin-hydroxychloroquine sulfate tablets (AH) are relatively inexpensive and a novel combination therapy for the treatment of all forms of malaria, especially aminoquinine drug-resistant strains of P. falciparum. Our aim was to assess the pharmacokinetics (PK) and toxicokinetics (TK) of AH following oral administration in Sprague Dawley rats and Beagle dogs by using the liquid chromatography tandem mass spectrometry methods (LC-MS/MS). The PK studies were carried out in eighteen rats at three doses and six dogs at three rounds of three doses after a single oral administration of AH. The TK studies in rats and dogs were accompanied by the 14-day repeated dosing studies. The PK results revealed that artemisinin was absorbed and cleared rapidly in rats with obvious gender difference and interindividual variability, and the systemic exposure with regard to AUC was positively correlated with the dosage in female rats. However, the kinetics parameters of artemisinin in dogs were not obtained because the plasma concentration was undetectable. The absorption and elimination of hydroxychloroquine in dogs and rats were relatively slow, and no gender difference was observed. The AUC of hydroxychloroquine showed a linear correlation with the dosage, but C max varied significantly among individuals. After 14-day repeated oral administration of AH, hydroxychloroquine shows an increase in systemic exposure and accumulation in rats and dogs, whereas the AUC and C max of artemisinin remarkably decreased in female rats due to its autoinduction metabolism. The TK results were basically consistent with the dose- and time-dependent toxic reaction in 14-day repeated dosing studies of AH in rats and dogs. The information from our studies could be helpful for further pharmacological and toxicological research and clinical application of AH.

Colloidal Manganese Salt Improves the Efficacy of Rabies Vaccines in Mice, Cats, and Dogs.

Rabies, caused by rabies virus (RABV), remains a serious threat to public health in most countries worldwide. At present, the administration of rabies vaccines has been the most effective strategy to control rabies. Herein, we evaluate the effect of colloidal manganese salt (Mn jelly [MnJ]) as an adjuvant of rabies vaccine in mice, cats, and dogs. The results showed that MnJ promoted type I interferon (IFN-I) and cytokine production in vitro and the maturation of dendritic cells (DCs) in vitro and in vivo. Besides, MnJ serving as an adjuvant for rabies vaccines could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, plasma cells (PCs), and RABV-specific antibody-secreting cells (ASCs), consequently improve the immunogenicity of rabies vaccines, and provide better protection against virulent RABV challenge. Similarly, MnJ enhanced the humoral immune response in cats and dogs as well. Collectively, our results suggest that MnJ can facilitate the maturation of DCs during rabies vaccination, which can be a promising adjuvant candidate for rabies vaccines. IMPORTANCE Extending the humoral immune response by using adjuvants is an important strategy for vaccine development. In this study, a novel adjuvant, MnJ, supplemented in rabies vaccines was evaluated in mice, cats, and dogs. Our results in the mouse model revealed that MnJ increased the numbers of mature DCs, Tfh cells, GC B cells, PCs, and RABV-specific ASCs, resulting in enhanced immunogenicity and protection rate of rabies vaccines. We further found that MnJ had the same stimulative effect in cats and dogs. Our study provides the first evidence that MnJ serving as a novel adjuvant of rabies vaccines can boost the immune response in both a mouse and pet model.