Rotundine

Background: At present, the avoidance of drug shortages mainly relies on expert experience. This study aimed to establish an evaluation index system for the risk of drug shortages in medical institutions in China and to apply the system to guide the graded management of drugs in short supply. Methods: A two-round Delphi process was conducted to determine the indicators in the index system. The weight value of each indicator was calculated using analytic hierarchy process (AHP) methods. The data of drugs in short supply from January 1 to December 31, 2020 in Hunan province were collected and evaluated using this index system. The evaluation scores, which ranged from 0 to 100, were calculated. Results: A three-level index system with four first-level indicators, 11 second-level indicators, and 36 third-level indicators was constructed by the two rounds of the Delphi process. The expert authority coefficient (Cr) of the first and second rounds of consultation were 0.88 and 0.90, respectively. The Kendall’s coefficients of concordance (Kendall’s W) for the two rounds of consultation were 0.44 and 0.50, respectively (P<.05). For the first-level indicators ‘supply stability,’ ‘causes of shortage,’ ‘medicine availability in medical institution’ and ‘pharmaceutical properties,’ the weight values were 0.3253, 0.2489, 0.2398, and 0.1860, respectively. Based on the risk evaluation score, drugs (dosage strength) at high risk of shortage included sodium thiosulfate (0.64 g), posterior pituitary lobe hormones (1 mL:6 IU), protamine sulfate (5 mL:50 mg), thrombin (500 U), urokinase (10 WU), and rotundine sulfate (2 mL:60 mg). Conclusion: An indexed system for the risk assessment of drug shortages in China was established to guide the graded response to drug shortages in medical institutions and the implementation of differential management strategies to address these shortages.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by failure of spontaneous resolution of inflammation. The stem of Kadsura heteroclite (KHS) is a well-known anti-arthritic Tujia ethnomedicinal plant, which named Xuetong in folk, has long been used for the prevention and treatment of rheumatic and arthritic diseases.

The analgesic and anti-inflammatory effects and the potential mechanisms behind such effects of KHS would be investigated by using different animal models.

The abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid and the tail-flick response induced by radiant heat stimulation were used to evaluate the analgesic effect of KHS. The number of abdominal writhing episodes of mice and the latency of tail-flick in rats were measured and recorded. In acute inflammatory models, the ear edema of mice was induced by applying xylene on the ear surface, while the paw edema of male and female rats was induced by subcutaneous injection of carrageenan into the right hind paws of animals. The carrageenan-induced paw swelling in rats were selected as an anti-acute inflammatory mechanism of KHS. Serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) were measured by ELISA, and protein expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected by Western blot.

The maximal tolerated single dose of KHS was determined to be 26 g/kg in both sexes of mice. Pharmacological studies showed that KHS at the dose of 200 mg/kg significantly prolonged the reaction time of rats to radiant heat stimulation and suppressed abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid. KHS at the dose of 200, 400, and 800 mg/kg, showed dose-dependent inhibition of xylene-induced ear swelling in mice. KHS at the dose of 100, 200, 400, and 800 mg/kg demonstrated dose- and time-dependent suppression of paw edema induced by subcutaneous injection of carrageenan in both all rats. Mechanistic studies revealed that the anti-inflammatory effect of KHS was associated with inhibition of the production of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and effectively decreased the expression of COX and iNOS proteins in the carrageenan-injected rat serum, paw tissues and inflammatory exudates. The positive reference drug, rotundine at a dosage of 100 mg/kg and indomethacin at a dosage of 10 mg/kg were used in both mice and rat models.

These results suggested that KHS has significant effects on analgesia and anti-inflammation with decreasing the pro-inflammation cytokines of IL-1β, IL-6, and TNF-α and inhibiting the proteins expression of COX-2 and iNOS.