Telitacicept, an injectable recombinant human B‐lymphocyte stimulating factor receptor‐antibody fusion protein, is a new dual B lymphocyte stimulator (BLyS)/APRIL (a proliferation‐inducing ligand) inhibitor that effectively blocks proliferation of B lymphocytes. This study evaluates the pharmacokinetic characteristics, tolerability, and safety of a single subcutaneous injection of various doses (80, 160, and 240 mg) of telitacicept in healthy Chinese subjects. This trial is a single‐center, randomized, open‐label phase I clinical study that includes three dose groups (80, 160, and 240 mg) with 12 subjects in each dose group. The subjects were randomly assigned to different dose groups in a 1:1:1 ratio for a single subcutaneous administration trial. After a single dose, the maximum serum concentration (Cmax) of total and free telitacicept was reached within 0.5‐1 days. The elimination half‐lives of total and free telitacicept at doses of 80–240 mg were 10.9–11.9 days and 11–12.5 days, respectively. The formation and elimination of the BLyS‐telitacicept complex were much slower; the median time to Cmax was 15–57 days and was significantly prolonged with increasing dose. Only two of the 36 healthy subjects had positive antidrug antibodies with antibody titers of 1:15. The severity of adverse events was mild or moderate, and no higher treatment‐emergent adverse events were reported. In conclusion, total telitacicept within a dose range of 80–240 mg and free telitacicept within a dose range of 160–240 mg had linear pharmacokinetic characteristics.
Paraquat (methyl viologen, PQ) is highly toxic to humans. Pulmonary fibrosis is the most common cause of death after PQ poisoning. However, no effective therapy is available. The current treatment dilemma and pathology suggest that we should reconsider how to treat the poisoning using other methods, such as immunization. Some clues indicate that immune mechanisms may play important roles in the pathology of PQ poisoning. We implemented a simple experiment to test the hypothesis that activated innate immunity was involved in acute lung injury induced by PQ. Six rats were randomly distributed to two groups: PQ poisoning group and Immunosuppression group (cyclophosphamide pretreatment). Forty-eight hours after PQ administration, rats were anesthetized. The right lungs were excised for histopathology. The experimental results confirmed that in the set of immune deficiency, the inflammatory response in Immunosuppression group could not be effectively triggered so the lung pathology was much better than PQ poisoning group. The immunopathogenic mechanism of PQ poisoning may be essentially a sterile inflammation triggered and amplified by damage-associated molecular patterns (DAMPs). If the hypothesis is established, it may change the therapeutic regimen of PQ poisoning and the prognosis of patients.
Background
The most common cause of death in sepsis is MODS. We hope that miR-126 can regulate the differentiation of Th17/Treg, reduce the infiltration of inflammatory factors in peripheral blood and various organs and tissues, and improve organ function and prognosis in sepsis.
Methods and results
Septic rat model was established by cecal perforation and ligation. miR-126 mimic and inhibitor were used to intervene sepsis. The experimental results showed that miR-126 mimic reduced the differentiation of Th17 and increased the differentiation of Treg in septic rats, resulting in the TNF-α, IL-6 and IL-17 were decreased in peripheral blood, the infiltration levels of TNF-α, IL-6 and IL-17 were decreased in lung, liver and kidney, the tissue damage degree of lung, liver and kidney were weakened, and the corresponding histopathological score decreased. Finally, the survival rate of septic rats was increased. However, after using miR-126 inhibitor, the levels of inflammatory factors and the degree of multiple organ injury in septic rats increased in varying degrees, and the prognosis of septic rats was worse.
Conclusion
This study confirmed that miR-126 can regulate the differentiation of Th17/Treg, change the infiltration of inflammatory factors in peripheral blood, lung, liver and kidney of septic rats, alleviate MODS, and improve the organ function and prognosis of septic rats.
In order to provide an idea dose of polymyxin B in Chinese patients with renal impairment, the present study collected the clinical data of all patients with renal impairment who received polymyxin B therapy in the intensive care unit (ICU) of The First Affiliated Hospital of Bengbu Medical College (Bengbu, China). The clinical data of six patients treated in the ICU between February 2018 and May 2019 were retrospectively analyzed. All patients had renal impairment and were treated with polymyxin B combination therapy. The patients in the current study received polymyxin B and carbapenem, or polymyxin, carbapenem, cefoperazon and sulbactam, or polymyxin B, carbapenems and aminoglycoside treatment. One patient discontinued treatment. The other five patients received polymyxin B at a dosage of 50 mg every 12 h (100 mg/day) through an intravenous drip. During treatment, four of the five patients had deteriorating renal function to varying degrees, and continuous renal replacement therapy (CRRT) was initiated. Polymyxin B was discontinued in all patients when the infection was controlled. After treatment, four of five patients showed improvement in renal function, and had normal kidney function at the 1-month follow-up evaluation, whereas one patient had chronic renal disease. During hospitalization, one patient experienced neurotoxicity, showing decreased limb muscle strength and cognitive impairment, which might have been caused by polymyxin B, according to the Naranjo adverse drug reactions probability scale (also known as the Naranjo algorithm) score. The present report demonstrated that the administration of 100 mg daily dosage of polymyxin B to the five patients weighing between 50 and 75 kg, could control pulmonary infection during the course of treatment of Chinese patients with renal impairment, however, further research is needed to verify this result. Risk factors for nephrotoxicity and neurotoxicity need to be fully assessed before initiating polymyxin B therapy in patients with renal impairment.
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