Effect of Enzymes in Buccal Mucous Membrane on Buccal Absorption of Insulin

To evaluate the effect of proteolytic enzymes on the absorption of insulin in the buccal mucosa, the trichloroacetic acid (TCA) method was used to estimate the degradation of insulin under different conditions in the buccal mucosal homogenates. In vivo experiments estimating the enhancement of hypoglycaemic effect by enzyme inhibitors were also conducted. The results showed that proteolytic enzymes in the buccal mucosa were less active than in the intestine. Bacitracin, aprotinin and sodium deoxycholate could inhibit the degradation of insulin in the buccal mucosal homogenates. The degradation of insulin in buccal mucosal homogenates of normal hamsters was smaller than that of diabetic hamsters. In vivo experiments of hypoglycaemia supported the in vitro results. When given buccally, bacitracin, aprotinin and sodium deoxycholate could increase the relative pharmacological bioavailability of insulin. When co-administered with aprotinin(0.1%), bacitracin(0.5%) and sodium deoxycholate(5%), the relative pharmacological bioavailabilities of insulin were 4.84%, 6.60% and 14.95% respectively. The in vitro and in vivo results suggest that proteolytic enzymes are present in the buccal mucosa, which limit absorption of insulin. Co-administration with some enzyme inhibitors can improve the bioavailability of insulin via buccal delivery and sodium deoxycholte is more efficient than some enzyme inhibitors used for improving buccal absorption.

The Topical Use of Aprotinin in Cardiac Surgery with Cardiopulmonary Bypass

Objective To investigate the effects of the topical use of aprotinin on thebasis of comprehensive blood conservations in cardiopulmonary bypass (CPB). Methods In a prospectiveclinical trial, 20 patients were randomly divided into 2 groups. Control group: placebo was usedtopically. Aprotinin group: aprotinin was poured into the pericardial cavity before closure of thesternotomy. Before and 24h after surgery, hemoglobin (Hb), hematocrit (Hct), bleeding time (BT),clotting time (CT) and prothrombin time (PT) were measured. Meanwhile, amounts of the mediastinaldrainage and the hemoglobin loss were observed at 0, 2, 6 and 24h after operation. The samples fromthe mediastinal drainage were also collected to measure D-Dimer (D-D), tissue type plasminogenactivator (t-PA) activity, plasminogen activator inhibitor (PAI) activity and protein C (PC).Results In Aprotinin group, D-D, t-PA activity and PC were significantly reduced, compared withthose in Control group (P<0.05, P<0.05, P<0.01). On the contrary, PAI activity was significantlyincreased, compared with that in Control group. Amounts of the mediastinal drainage and thehemoglobin loss were decreased by 43% and 52%, compared with those in Control group. Conclusion Ourresults suggest that the topical use of aprotinin can have better effects on the basis ofcomprehensive moderate blood conservation.

丝氨酸蛋白酶抑制剂可抑制昆虫细胞表达的蛋白质降解(英文)

干细胞因子是一种多功能细胞因子,能在多级造血水平与其他细胞因子协同作用促进造血干/祖细胞及各种血细胞的存活、增殖和分化。重组人二连体干细胞因子具有比干细胞因子单体更高的比活,可以避免副反应。重组人二连体干细胞因子在Sf9细胞和大肠杆菌中表达时,发现有特异性降解。片段缺 失实验证实切割位点位于重组人二连体干细胞因子的145位到165位氨基酸之间。丝氨酸蛋白酶抑制剂aprotinin和PMSF能抑制这种特异性降解。试验了不同浓度的aprotinin和PMSF对Sf9细胞存活和重组人二连体干细胞因子产量的影响,显示当aprotinin的浓度为 1.0μg/mL时,重组人二连体干细胞因子的产量是没有加aprotinin时产量的2倍,而且aprotinin可以完全抑制这种特异性降解。

Requirements for transfusion and postoperative outcomes in orthotopic liver transplantation:A meta-analysis on aprotinin

AIM:To study the effect of aprotinin used in orthotopic liver transplantation (OLT) on the intraoperative requirement for blood products and on the incidence of laparotomy for bleeding, thrombotic events and mortality. METHODS: A systematic review of the literature in the electronic database Medline and the Clinic Trials Registry Database was performed. Literature that did not fit our study were excluded. Patients in the reviewed studies were divided into two groups; one group used aprotinin (aprotinin group) while the other did not (control group). The data in the literature that fit our requirements were recorded. Weighted mean differences (WMD) in the requirements for blood products between the aprotinin group and the control group were tested using a fixed effect model. A Z test was performed to examine their reliability; the Fleiss method of fixed effect model was used to analyze data on postoperative events, and odds ratios (ORs) were tested and merged. RESULTS: Seven citations were examined in our study. Among them, a requirement for blood products was reported in 4 studies including 321 patients, while postoperative events were reported in 5 studies including 477 patients. The requirement for red blood cells and fresh frozen plasma in the aprotinin group was statistically lower than that in the control group (WMD=-1.80 units, 95% CI,-3.38 to-0.22; WMD=-3.99 units, 95% CI,-6.47 to-1.50, respectively). However, no significant difference was indicated in the incidence of laparotomy for bleeding, thrombotic events and mortality between the two groups. Analysis on blood loss, anaphylactic reactions and renal function was not performed in this study due to a lack of sufficient information.CONCLUSION: Aprotinin can reduce the intraoperative requirement for blood products in OLT, and has no significant effect on the incidence of laparotomy for bleeding, thrombotic events and mortality.

Platelet activation and the protective effect of aprotinin in hepatolithiasis patients

OBJECTIVE: To explore platelet activation and the protective effect of aprotinin in patients with hepatolithiasis. METHODS: The count of plaletets and levels of CD_(62P) and CD_(63) were measured by flow cytometry in 38 patients with hepatolithiasis. Several measurements were carried out after treatment with aprotinin. RESULTS: The levels of CD_(62P), CD_(63) in patients with hepalolithiasis were higher than those in patients with cholecystolithiasis (P<0.05), but the count of platelets was lower (P<0.05). After operation, the levels of CD_(62P), CD_(63) were significantly increased in patients with hepatolithiasis, but the count of platelets was lower (P<0.05). Postoperative levels of CD_(62P), CD_(63) were significantly lower in patients treated with aprotinin than in normal controls (P<0.05); but there was no significant change in the count of platelets in the two groups. CONCLUSION: Platelet activation occurs in patients with hepatolithiasis, and may be inhibited by aprotinin.

Effects of Aprotinin on Serum Interleukin-2 and Soluble Interleukin-2 Receptor during Cardiopulmonary Bypass

Interleukin-2 and its receptor are of importance in regulating immunity responses. The changes of interleukin-2 (IL-2) and soluble interleukin-2 receptor (IL-2R) during heart valve (s) replacement operation and effects of aprotinin on them were observed. Twenty patients undergoing heart valve (s) replacement were randomly divided into two groups: control group (n=10) and apro- tinin group (n=10). In aprotinin group, 1 000 000 KIU aprotinin was given by vein injection and then 2 000 000 KIU was given as a bolus in prime. Blood samples were collected before CPB, right after CPB and on the 1st, 3rd and 7th postoperative day (POD) for serum IL-2 and sIL-2R determination. Results showed that after CPB, IL-2 was reduced and slL-2R increased. Meanwhile, serum IL-2R was lower in aprotinin group than that of control. It is concluded that the immunity depression after CPB is associated with low level of IL-2 and high level of sIL-2R and aprotinin can ameliorate the situation.

A clinical study of aprotinin blood anesthesia used in the surgery of liver cancer

Objective: To investigate the role of aprotinin blood anesthesia used in hepatotomy. Methods: Patients with liver cancer undergoing hepatotomy were divided into two groups. In experimental group (40 patients) a loading dose with 1112 EPU aprotinin and maintained by 278 EPU/h was used until 2 h after operation. The control group (42 patients) was treated with 0.9% normal saline. The venous blood was withdrew for blood routine, thrombelastography and coagulable test at the time of preinduced, 1 h, 2 h and 4 h following the operation beginning, 6 h and 12 h after operation. The change of TEG and coagulable profile were monitored during the whole surgery. The volume of blood transfusion and hemorrhage between two groups were compared. Results: After the usage of aprotinin, the preoperative hypercoagulability of the experimental group was remitted and the coagulative state was kept relatively stable during the operation. However, hypercoagulability of the control group aggravated following the operation beginning and some of them switched to hypocoagulability. The volumes and rates of hemorrhage and transfusion were smaller in the experimental group than in the control group. Conclusion: Aprotinin can stabilize the coagulable state, reduce the volumes and rates of hemorrhage and transfusion, and is worth using in the surgery of operations of liver cancer.

Experimental Study on the Effects of Aprotinin on Myocardial Ischemia and Reperfusion

Direct effects of a high-dose aprotinin on the normally perfused hearts and the myocardial protection after ischemia and reperfusion were investigated in an isolated working rat heart model. In trial I, hearts had no ischemia and were perfused with either K-H solution or the K-H solution containing aprotinin (200KIU/ml) for 55 min. No statistically significant difference was observed in hemodynamics betweem the two groups. In trial Ⅱ, hearts were exposed to 150 minperiod of global ischemia at 15℃ with 4℃ multidose St. Thomas'Ⅱ solution (STS). The control group I received norma1 K-H solution; the group Ⅱ was treated with the solution with aprotinin added. The group, was similar to the group Ⅰ and received the STS enriched with aprotinin. On reperfusion, the recovery of hearts in group, was significantly better than those of the group Ⅰand Ⅱ, as reflected by better hemodynamics and myocardial oxygen consumption,lower level myocardial enzymes, higher myocardial ATP levels and milder myocardial ultrastructural injury. There was no difference between the group Ⅰand Ⅱ. These results suggest that the aprotinin at a dose of 200 KIU/ml has no harmful effects on normally perfused hearts and has a marked myocardial protective effect on the prolonged myocardial ischemia when used in cold crystalloid cardioplegia.

MECHANISM OF PRESERVING EFFECT OF APROTININ ON PLATELET FUNCTION DURING CARDIOPULMONARY BYPASS

The deficiency of platelet function is the main defect of hemostatic mechanism during cardiopulmonary bypass (CPB), which attributed to the postoperative bleeding complication to a great extent. The proteinase inhibitor aprotinin was reported to have preserving effect on platelet adhesion during CPB. In this clinical reserch we found that CPB caused plasma alpha 2-antiplasmin decreasing, indicating the fibrinolytic system activation. Meanwhile, the ristocetin-induced aggregation declined to 39.6% and platelet GPIb decreased to 50% of preoperative value. However, by treatment with aprotinin, the plasma alpha 2-antiplasmin during CPB did not change, platelet aggregation was improved and platelet GPIb was preserved, and consequently resulted in a 46% lower blood loss postoperatively. These results confirmed that aprotinin could inhibit the fibrinolysis during CPB, and thus relieve the platelet damage and improve the postoperative hemostatic mechanism.

THE IMPAIRMENT OF PLATELET FUNCTION IN FIBRINOLYSIS AND PRESERVING EFFECT OF APROTININ

Platelet adhesion depends on the platelet membrane glycoprotein Ib (GPIb) and plasma von Willebrand Factor (vWF), which can be reflected by ristocetin-induced aggregation. Here we report damage effect of fibrinolysis and preserving effect of aprotinin on platelet function. Addition of 40 U/ml urokinase and 0.3 U/ml plasmin to PRP or washed platelets made the ristocetin-induced aggregation decline to 31.6% and 38.5% of control value respectively. The extent of declining was positively correlated with the concentration of urokinase and plasmin. Meanwhile, the platelet GPIb decreased to 76.4% of control value. The results showed that the fibrinolysis impaired the platelet function and this effect may be associated with the hydrolysis of GPIb. Further research found that by adding the same dose of urokinase or plasmin to aprotinin-pretreated PRP or washed platelets, the aggregation did not change statistically and decrement of GPIb is much less marked. We concluded that the aprotinin could relieve the platelet dsfunction effectively by its inhibitory effect on fibrinolytic activity.

Redo Cardiac Surgery: Bleeding Control

Redo cardiac surgery increases?mortality and morbidity. The aim of this study was to determine if aprotinin was superior to tranexamic acid concerning control bleeding loss after redo valve surgery. A retrospective study was conducted from January 1994 until December 2014. 221 patients underwent redo cardiac valve surgery and separated into two groups: aprotinin group (n?=?85) and tranexamic acid group (n?=?136). Univariate tests were applied for data analysis. A total of 221 patients were enrolled in this study. This cohort was separated into two groups: aprotinin group (n?=?85) and tranexamic acid group (n?=?136). Euroscore in tranexamic acid group was higher: 5.96 ± 3.04 vs.?5.17 ± 2.83 in aprotinin group?(p?=?0.055). There was no statistical difference in postoperative mortality between the two groups (p?= 0.153). No statistical differences were reported concerning: total blood loss (p?= 0.51), red blood cells transfusion (p?= 0.215), reexploration for bleeding (p?= 0.537) and postoperative renal failure (p?= 0.79). There were statistical differences concerning mechanical ventilation time, which is longer in tranexamic acid group (p?= 0.008) and the use of inotropic drug support, which is more frequent in the tranexamic acid group (p?= 0.001). Our results demonstrated that tranexamic acid and aprotinin reduce transfusion requirement and blood loss. Due to financial reason, we chose tranexamic acid in preventing blood loss in redo valve surgery.

Death as a Drug Side Effect in FAERS: Is Glyphosate Contamination a Factor?

An analysis of selected datasets from the FDA’s drug Adverse Event Reporting System (FAERS) leads us to hypothesize that glyphosate contamination in both food and drugs is a major contributor to chronic and acute kidney failure respectively. In chronic kidney failure, glyphosate-induced pancreatitis results in the release of trypsin, causing a leaky vasculature. The albumin-bound glyphosate escapes into the tissues, protecting the circulatory system and kidneys but resulting in multiple symptoms related to skin, gut, brain, bones, lungs, etc. The rare and poorly understood acute kidney failure response reported for protamine sulfate and Trasylol? is strikingly similar to that associated with glyphosate poisoning. Both drugs are derived from biological tissues that are plausibly contaminated with glyphosate. These drugs protect from haemorrhage, which leads to retention of glyphosate in the vasculature, are followed by circulatory collapse and a high likelihood of death as an outcome. We support our argument by comparing symptom profiles of selected subsets of FAERS with those related to glyphosate poisoning, anomalous reactions to protamine sulfate, and conditions showing strong statistical time-trend correlations with glyphosate.

The influence of aprotinin on the mRNA expression of P-selectin and ICAM-1 in the in situ lung tissue after ischemic cold storage and reperfusion

To explore the influence of aprotinin on the mRNA expression of P-selectin and ICAM-1 in lung tissue after ischemic reperfusion.Methods Thirty New Zealand white rabbits were randomly divided into 3 groups:control group,LPD group and aprotinin group.In situ rabbit lung preservation model was established.In control group,the left lower lung lobe was stored at 10℃ in a specially made lung preservation container for 2 hours and reperfused for another 2 hours.In LPD group and aprotinin group,the left lower lobe was perfused with LPD solution or aprotinin containing LPD solution,respectively,after left lung hilus was clamped.The other procedures were the same as those in control group.The lung tissue was harvested at different time intervals including preclamping lung hilus,2 hours after clamping and 2 hours after reperfusion.The mRNA expression of ICAM-1 and P-selectin in the lung tissue was detected with RT-PCR technique.Results The contents of mRNA of P-selectin at 2 hours after reperfusion in control group and LPD group were significant higher than pre-ischemia and 2 hours after champing the left lung hilus.There was no such significant difference in aprotinin group.The mRNA expression of P-selectin in aprotinin group at 2 hours after reperfusion was significantly lower than that in control group and LPD group.The ICAM-1 mRNA expression at 2 hours after Ischemia and 2 hours after reperfusion in control group and LPD group was significantly higher than the pre-ischemia and its was significantly higher than that in aprotinin group.Conclusion Aprotinin can inhibit the upregulation of the mRNA expression of P selectin and ICAM-1 after ischemia reperfusion in the lung tissue,so the addition of aprotinin in LPD solution may reduce the ischemia reperfusion injury in lung tissue.5 refs,1 tab.

Multi-organ protection during open heart surgery

PURPOSE AND METHODS: Open-heart surgery with the use of cardiopulmonary bypass (CPB) is associated with an inflammatory cascade which contributes to the development of postoperative complications including multiple organ failure. To provide an update on the subject, we briefly review the recent English-language literature. RESULTS: During CPB, various factors have been recognized to induce a complex inflammatory response. Based on an enhanced understanding of the underlying mechanisms, therapeutic strategies have been developed to reduce this inflammatory reaction and its subsequent damaging effects. Off-pump coronary artery bypass grafting may result in less inflammatory injury as compared with the conventional maneuver, which can in turn, diminish the incidence of cardiac, renal, or neurological dysfunction. It is also clear that improving the biocompatibility of CPB materials can lead to a better patient recovery. Inasmuch as the pathophysiology involved appears to be multifactorial, it is unlikely that a single intervention could achieve the desired goal. Both pharmacologic strategies, such as steroid pretreatment, and modification of mechanical devices, such as the use of heparin-coated CPB circuits, could have important clinical implications. The balance pro- and anti-inflammatory responses may be crucial in limiting the extent of inflammatory injury. CONCLUSIONS: To date, the concept of organ protection should no longer be limited to the individual organ. Instead, investigations must be extended to focus on a systemic level.