[Self-assembly and in vitro and in vivo evaluation of spherical crystallized interferon for sustained delivery].

It is a challenging and important project to prolong the in vivo half life of protein and peptide drugs by physicochemical methods without new molecular entities generation. Protein crystallization provides a new strategy for improving the stability and in vivo delivery of these drugs. We show here that recombinant human interferon-alpha (rhIFN) can form spherical crystals. The physical and chemical features of the crystals were characterized, and drug dissolution was determined in vitro. The pharmacokinetics of crystallized interferon after sc injection in rabbit at 1.5 x 10(7) U x kg(-1) was compared to that of soluble form. The crystals were characterized as mono-dispersed spheres, with yield of > 80%, mean diameter size of about 16 microm and crystallinity of 23.2%. The in vitro dissolution behavior of crystallized rhIFN was featured as low initial burst release (21% within the first 2 h) and prolonged cumulative dissolution time up to 72 h without biological potency lost. After sc administration of soluble and crystallized interferon in rabbits, the peak time (T(max)) and half life (t1/2) were prolonged from (1.80 +/- 0.45) h and (1.35 +/- 0.35) h to (13.20 +/- 2.68) h and (10.68 +/- 1.97) h, respectively. The corresponding peak concentration decreased from (1 411.10 +/- 575.28) U x mL(-1) to (721.37 +/- 206.55) U x mL(-1). PK/PD analysis indicated that (96.87 +/- 20.30) % of relative bioavailability was obtained. The research results of this work will provide important academic value and application prospect for improving clinical therapeutic effect and development of biomacromolecules delivery system for protein and peptide drugs.

[Progress in the development of crystallized proteins as drug delivery system].

Crystallization has been widely applied in pharmaceutical formulations as an effective approach to improve the stability and efficacy of small agents. However protein crystals are suffered from limitation in the drug delivery system due to their complex crystallization behaviors. With development of crystallization technologies and their industrial application, protein crystals are receiving more and more attentions as a novel delivery system for biomacromolecules. Crystals with thermodynamic stable structure can improve the physical and chemical stability of protein drugs and present a sustained release behavior. On the basis of pertinent literatures, this review introduces the recent research situation and development process of protein crystals as drug delivery system. Moreover, the crystallization process of proteins, as well as the preparation and potential application are discussed systematically.

[Effect of esmolol on propofol dose requirement for anesthesia in thyroidectomy].

OBJECTIVE: To observe the effect of esmolol application before and during operation on propofol dose required for anesthesia induction and maintenance. METHODS: Forty patients (ASA physical status I or II) undergoing general anesthesia for thyroidectomy were randomized equally into esmolol and control groups. Patients in esmolol group received a loading dose of esmolol at 0.5 mg/kg in 30 ml normal saline over a period of 5 min followed by an intravenous infusion of esmolol at 50 microg.kg(-1).min(-1) until the end of surgery, while patients in the control group were given normal saline in the same manner, in addition to anesthesia with protofol. Perioperative hemodynamic parameters and BIS were measured, and the duration of anesthesia, operation and recovery time from anesthesia were recorded. RESULTS: There were significant differences between the two groups in propofol dose required for anesthesia induction and recovery time from anesthesia, but not in maintenance propofol dose. Patients in esmolol group had significantly lower HR and BIS during tracheal intubation than those in the control group , and no significant differences were found in HR, BP and BIS during operation between the two groups. The hemodynamic parameters during extubation showed less fluctuation in esmolol group. CONCLUSION: Perioperative esmolol administration during anesthesia reduces propofol dose required for anesthesia induction and recovery time from anesthesia, and decreases HR and BIS variation during tracheal intubation and hemodynamic response during extubation without affecting the maintenance propofol dose.

[Effects of ulinastatin on interleukin-8 during one-lung ventilation in surgery].

BACKGROUND & OBJECTIVE: Ulinastatin is a kind of broad- spectrum hydrolase inhibitors purified from urine of healthy males.There was no data showing whether ulinastatin could affect alveolar inflammatory reactions.This study was designed to investigate the changes of pulmonary alveolar interleukin-8 during one lung ventilation (OLV) in surgery and the effects of ulinastatin on alveolar IL-8. METHODS: Sixty patients,ASA II- III,who underwent lobectomy, were randomly divided into two groups [30 patients in each group,surgery group(II) and control group (I)].Patients in surgery group were treated with ulinastatin 5,000 u/kg preoperatively. Alveolar IL-8 was harvested by bronchoalveolar lavage at 0, 1, and 2 hours after one lung ventilation and at the end of surgery. The changes of concentration of IL-8 in bronchoalveolar lavage fluid were analyzed statistically. RESULTS: (1)Alveolar interleukin 8 was significantly higher at 2 hours after OLV [(160.85+/-46.58)ng/L] than before OLV [(128.26+/-35.35)ng/L] in control group. The results indicated that OLV and/or the stimulation of surgery could induce the pulmonary inflammatory reaction. (2)The concentrations of alveolar IL-8 at 2 hours [(140.32+/-41.25)ng/L] after OLV and at the end of surgery [ (156.74+/-43.58) ng/L] were significantly lower in surgery group than those in control group [(160.85+/-46.58)ng/L and (172.41+/-52.60)ng/L] respectively(P< 0.05). CONCLUSION: Ulinastatin could alleviate the pulmonary alveolar inflammatory reactions in OLV.

[Influence of different doses of fentanyl on T-lymphocyte subpopulations and natural killer cells of patients with esophageal tumor during preoperation and postoperation].

BACKGROUND & OBJECTIVE: Morphine has been proved to inhibit human immune system, and large dose of fentanyl also decrease the activation of natural killer cells. This study was designed to investigate the effects of different doses of fentanyl on T-lymphocyte subpopulations and natural killer cells during esophageal cancer surgery under general anesthesia. METHODS: Forty-five patients with esophageal cancer were randomly divided into 3 groups (I, II,III) with 15 cases in each group respectively. The doses of fentanyl in three groups were 5, 10, and 20 microg/kg, respectively. Central venous blood samples (6 ml) were collected before anesthesia, 24 hours and 48 hours after the operation, respectively. Monoclonal antibodies assay was used to identify T cells and NK cells. RESULTS: The counts of CD3(+) (T%) (Group I 50.30+/-8.42, Group II 48.53+/-9.62, GroupIII 46.58+/-8.56), CD4(+) (T%) (Group I 30.04+/-7.24, Group II 28.67+/-7.52, Group III 26.65+/-6.55),and NK cells (Group I 3.26+/-1.62, Group II 3.01+1.56, GroupIII 3.01+/-1.54) in three groups decreased significantly at 24 hours after surgery (P< 0.01). The decrease at 48 hours after surgery were more significant in groupIII (CD3(+) 48.89+/-9.82, CD4(+) 22.64+/-6.02, NK Cells 3.41+/-1.88) than in group I(CD3(+) 57.32+/-9.13, CD4(+) 35.62+/-5.98, NK cells 5.96+/-1.08) and group II(CD3(+) 55.62+/-10.21, CD4(+) 34.24+/-6.85, NK cells 6.04+/-1.09) (P< 0.05). There was no statistical significance in the counts of CD3(+), CD4(+), and NK cells between the time of 48 hours after the operation and preoperation in group I and group II. CONCLUSION: Fentanyl, as a kind of opiate drug, could contribute to the immunosuppression, and large-dose fentanyl administration would be more effective in suppression of immunity function than small dose fentanyl.