Pharmacokinetics and pharmacodynamics of subcutaneous injection and intravenous infusion of recombinant human interleukin-12 and recombinant human interleukin-12 combined with hepatitis B surface antigen in cynomolgus monkeys.

BACKGROUND/AIMS: Interleukin-12 (IL-12) is a cytokine that plays an important role in cell-mediated immunity and shows great potential as a therapeutic agent for the treatment of tumors and infectious diseases. METHODS: We investigated the pharmacokinetics (PK) and pharmacodynamics of recombinant human IL-12 (rhIL-12) and rhIL-12 combined with hepatitis B surface antigen (HB(s)Ag) after administration by subcutaneous (s.c.) injection or intravenous infusion in cynomolgus monkeys. RESULTS: After s.c. injection of rhIL-12 at doses of 0.15-1.5 microg/kg, the monkey's metabolism showed linear kinetic characteristics. The intramuscular injection of HB(s)Ag vaccine did not affect the pharmacokinetic profile of rhIL-12. In monkeys administered rhIL-12 in a continuous dosing fashion, serum rhIL-12 was undetectable, probably due to the neutralizing effect of anti-rhIL-12 antibodies. In monkeys receiving high-dose s.c. injection of rhIL-12, the T(max) for serum rhIL-12 concentration was 4-8 h, and the T(max) for serum interferon-gamma (IFN-gamma) concentration was 24-72 h. However, in monkeys receiving continuous dosing of rhIL-12, serum IFN-gamma concentration was very low or even undetectable. CONCLUSION: We found that the PK of rhIL-12 was dose-dependent and its pharmacological effects appeared after T(max) and lasted much longer than mean retention time.

[Study on the prevention of postoperative intraperitoneal adhesion of rat with PLGA/PEG electrospun polymer membrane].

Objective: Adopting poly- L-lactic/glycolic acid (PLGA) and polyethylene glycol (PEG) as the material to fabricate PLGA/PEG electrospun polymer membrane by electrospinning technology. And to study its preventive effect on postoperative intraperitoneal adhesion of rat. Methods: PLGA and PEG were mixed at the ratio of 19∶1( M/M), then dissolved in organic solvent. The PLGA/PEG electrospun polymer membrane was prepared by electrospinning technology, and then the gross observation and scanning electron microscope observation were taken. Fifty-four Sprague Dawley rats (weighing, 180-200 g), were randomly divided into 3 groups. The rats in control group ( n=6) were left intact. The rats in model group ( n=24) and PLGA/PEG group ( n=24) were treated with the method of mechanical injury of the cecal serosa in order to establish the intraperitoneal adhesion models; then the PLGA/PEG electrospun polymer membrane was used to cover the wound in PLGA/PEG group, but was not in the model group. The intraperitoneal adhesion in PLGA/PEG group and model group were observed at 3 days, 1 week, 2 weeks, and 8 weeks after operation, and the adhesion degree was assessed according to the self-generated standard. The degradation of PLGA/PEG electrospun polymer membrane was also observed in PLGA/PEG group. At each time point, the rats were harvested for histological observation. All the above indexes were compared with the control group. Results: Using the electrospinning technology, PLGA/PEG electrospun polymer membrane was prepared successfully. PLGA/PEG electrospun polymer membrane was white and opaque, with soft texture. Scanning electron microscopy observation showed that PLGA/PEG electrospun polymer membrane was mainly composed of disorderly staggered fibers, with microporous structure. All rats survived to the end of the experiment. Gross observation showed that PLGA/PEG electrospun polymer membrane gradually degraded after implantation in vivo, and the adhesion degree in PLGA/PEG group was significantly lower than that in model group ( P<0.05), but it had not yet reached to the level of the control group ( P<0.05). Histological observation showed that the proliferation of cecal fibrous connective tissue was slower in PLGA/PEG group than in model group, and adhesion severity significantly decreased, only with a small amount of inflammatory cell infiltration. Nevertheless, it was not up to the level of the control group. Conclusion: PLGA/PEG electrospun polymer membrane can effectively prevent postoperative intraperitoneal adhesion of rat, and has good biodegradability.

Determination of piperphentonamine and metabolites M1 and M6 in human plasma and urine by LC/MS/MS and its application in a pharmacokinetics study in Chinese healthy volunteers.

Piperphentonamine hydrochloride (PPTA) is a new calcium sensitizer. A liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for determination of piperphentonamine and its metabolites M1 and M6 was developed for the first time and applied to a pharmacokinetics study. Protein precipitation was used for pre-treatment of plasma samples, and solid phase extraction method was used for pre-treatment of urine samples. The chromatographic separation was achieved on a C(18) column using gradient elution in this study: A: 1% acetic acid aqueous solution, and B: acetonitrile. The whole analysis lasted for 10.5min and the gradient flow rate was 0.25mL/min constantly. The detection was performed of a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via a positive electrospray ionization source. The results were that the m/z ratios of monitored precursor ions and product ions of PPTA, M1 and M6 were 354.0→191.8, 356.0→148.7 and 358.0→148.7, respectively. From the standard curve, the concentration ranges of both PPTA and M1 in blood and urine samples were 0.1-500ng/mL and 0.1-200ng/mL, respectively; the concentration ranges of M6 in blood sample and urine sample were 0.2-500ng/mL and 0.2-200ng/mL, respectively; and the correlation coefficient of standard curve was r>0.99. A total of 31 healthy Chinese subjects participated in the pharmacokinetic study of single bolus intravenous injection of piperphentonamine hydrochloride. They were divided into three dosage groups and given 0.2, 0.4 and 0.6mg/kg of PPTA. After drug administration, concentrations of PPTA, M1 and M6 in human plasma and urine samples were determined to evaluation the pharmacokinetic characteristics of PPTA and its metabolites M1 and M6.