BACKGROUND: Significant blood loss is still one of the most frequent complications in spinal surgery, which often necessitates blood transfusion. Massive perioperative blood loss and blood transfusion can create additional risks. Aprotinin, tranexamic acid (TXA), and epsilon-aminocaproic acid (EACA) are antifibrinolytics currently offered as prophylactic agents to reduce surgery-associated blood loss. The aim of this study was to evaluate the efficacy and safety of aprotinin, EACA, and low/high doses of TXA in spinal surgery, and assess the use of which agent is the most optimal intervention using the network meta-analysis (NMA) method. METHODS: Five electronic databases were searched, including PubMed, Cochrane Library, ScienceDirect, Embase, and Web of Science, from the inception to March 1, 2018. Trials that were randomized and compared results between TXA, EACA, and placebo were identified. The NMA was conducted with software R 3.3.2 and STATA 14.0. RESULTS: Thirty randomized controlled trial (RCT) studies were analyzed. Aprotinin (standardized mean difference [SMD]=-0.65, 95% credibility intervals [CrI;-1.25, -0.06]), low-dose TXA (SMD = -0.58, 95% CrI [-0.92, -0.25]), and high-dose TXA (SMD = -0.70, 95% CrI [-1.04, -0.36]) were more effective than the respective placebos in reducing intraoperative blood loss. Low-dose TXA (SMD = -1.90, 95% CrI [-3.32, -0.48]) and high-dose TXA (SMD = -2.31, 95% CrI [-3.75, -0.87]) had less postoperative blood loss. Low-dose TXA (SMD = -1.07, 95% CrI [-1.82, -0.31]) and high-dose TXA (SMD = -1.07, 95% CrI [-1.82, -0.31]) significantly reduced total blood loss. However, only high-dose TXA (SMD = -2.07, 95% CrI [-3.26, -0.87]) was more effective in reducing the amount of transfusion, and was significantly superior to low-dose TXA in this regard (SMD = -1.67, 95% CrI [-3.20, -0.13]). Furthermore, aprotinin (odds ratio [OR] = 0.16, 95% CrI [0.05, 0.54]), EACA (OR = 0.46, 95% CrI [0.22, 0.97]) and high dose of TXA (OR = 0.34, 95% CrI [0.19, 0.58]) had a significant reduction in transfusion rates. Antifibrinolytics did not show a significantly increased risk of postoperative thrombosis. Results of ranking probabilities indicated that high-dose TXA had the greatest efficacy and a relatively high safety level. CONCLUSIONS The antifibrinolytic agents are able to reduce perioperative blood loss and transfusion requirement during spine surgery. And the high-dose TXA administration might be used as the optimal treatment to reduce blood loss and transfusion.
Aminocaproic Acid ; therapeutic use ; Antifibrinolytic Agents ; therapeutic use ; Aprotinin ; therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; Spine ; surgery ; Tranexamic Acid ; therapeutic use

BACKGROUND: Previous studies have reported that glypican-4 (GPC4) regulates insulin signaling by interacting with insulin receptor and through adipocyte differentiation. However, GPC4 has not been studied with regard to its effects on clinical factors in patients with type 2 diabetes mellitus (T2DM). We aimed to identify factors associated with GPC4 level in T2DM. METHODS: Between January 2010 and December 2013, we selected 152 subjects with T2DM and collected serum and plasma into tubes pretreated with aprotinin and dipeptidyl peptidase-4 inhibitor to preserve active gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). GPC4, active GLP-1, active GIP, and other factors were measured in these plasma samples. We performed a linear regression analysis to identify factors associated with GPC4 level. RESULTS: The subjects had a mean age of 58.1 years, were mildly obese (mean body mass index [BMI], 26.1 kg/m2), had T2DM of long-duration (mean, 101.3 months), glycated hemoglobin 7.5%, low insulin secretion, and low insulin resistance (mean homeostatic model assessment of insulin resistance [HOMA-IR], 1.2). Their mean GPC4 was 2.0±0.2 ng/mL. In multivariate analysis, GPC4 was independently associated with age (β=0.224, P=0.009), and levels of active GLP-1 (β=0.171, P=0.049) and aspartate aminotransferase (AST; β=–0.176, P=0.043) after being adjusted for other clinical factors. CONCLUSION: GPC4 was independently associated with age, active GLP-1, and AST in T2DM patients, but was not associated with HOMA-IR and BMI, which are well known factors related to GPC4. Further study is needed to identify the mechanisms of the association between GPC4 and basal active GLP-1 levels.
Adipocytes ; Aprotinin ; Aspartate Aminotransferases ; Body Mass Index ; Diabetes Mellitus ; Diabetes Mellitus, Type 2* ; Gastric Inhibitory Polypeptide ; Glucagon-Like Peptide 1* ; Glypicans* ; Hemoglobin A, Glycosylated ; Humans ; Insulin ; Insulin Resistance ; Linear Models ; Multivariate Analysis ; Plasma ; Receptor, Insulin

The causes and attributing factors of drug-induced liver injury (DILI) remain unclear as a result of exclusion-based diagnosis and low incidence. The aim of this study was to explore and evaluate potential drug-related causes and factors associated with DILI. Using electronic medical records (EMR) from the Seoul National University Bundang Hospital from 2003 to 2014, patients with DILI events were identified based on liver function test results. All patients with hepatic or biliary diseases were excluded. Patient characteristics, including demographics, clinical patterns, and severity of DILI were summarized and their associations were evaluated. Drugs frequently prescribed to patients exhibiting DILI within the month before their first DILI event compared to the total patient population were identified and the probabilities of hepatotoxicity associated with their use were assessed through examination of available reports. Among the 1,835 patients with laboratory test results, 1,023 were male and 1,053 were 65 years of age or older. Moderate DILI was dominant in older or male patients and cholestatic DILI tended to be more frequently identified in older patients of either sex. Cytarabine was the most frequently prescribed drug in DILI patients, followed by aprotinin and dopamine. Among the 30 most frequently prescribed drugs in DILI patients, 15 (50%) were identified as known hepatotoxic agents. In conclusion, this study evaluated differences in features of DILI among groups based on demographics and explored candidate drugs with possible associations with DILI, which has potential value reflecting real-world clinical practice.
Aprotinin ; Cytarabine ; Demography ; Diagnosis ; Dopamine ; Drug-Induced Liver Injury* ; Electronic Health Records* ; Humans ; Incidence ; Liver Function Tests ; Male ; Seoul

PURPOSE: In accordance to an increased interest in facial appearance and the popularization of computed tomography scanning, the number of diagnosis and treatment of blowout fractures has been increased. The purpose of this article is to review pure blowout fracture surgery through transconjunctival incision focusing on complications and their management. METHODS: In this retrospective study, 583 patients, who had been treated for pure blowout fracture through transconjunctival incision from 2000 to 2009, were evaluated. Their hospital records were reviewed according to their sex, age, fracture site, preoperative presentations, time interval between trauma and surgery, and postoperative complications. RESULTS: According to postoperative follow-up results, there were early complications that included wound dehiscence and infection (0.2%), hematoma (insomuch as extraocular movement is limited) (0.7%), lacriminal duct injury (0.5%), and periorbital nerve injury (0.7%). In addition, there were late complications that lasted more than 6 months, that included persistent diplopia (1.7%), extraocular movement limitation (0.9%), enophthalmos (1.0%), periorbital sensation abnormalities (1.0%), and entropion (0.5%). CONCLUSION: We propose the following guidelines for prevention of postoperative complications: layer by layer closure; bleeding control with the epinephrine gauzes, Tachocomb, and Tisseel; conjunctival incision 2 to 3 mm away from punctum; avoidance of excessive traction; performing surgical decompression and high dose corticosteroid therapy upon confirmation of nerve injury; atraumatic dissection and insertion of Medpor Barrier implant after securing a clear view of posterior ledge; using Medpor block stacking technique and BioSorb FX screw fixation; performing a complete resection of the anterior ethmoidal nerve during medial wall dissection; and making an incision 2 to 3 mm below the tarsal plate.
Aprotinin ; Conjunctiva ; Decompression, Surgical ; Diplopia ; Drug Combinations ; Enophthalmos ; Entropion ; Epinephrine ; Fibrinogen ; Follow-Up Studies ; Hematoma ; Hemorrhage ; Hospital Records ; Humans ; Orbital Fractures ; Polyethylenes ; Retrospective Studies ; Sensation ; Thrombin

PURPOSE: In accordance to an increased interest in facial appearance and the popularization of computed tomography scanning, the number of diagnosis and treatment of blowout fractures has been increased. The purpose of this article is to review pure blowout fracture surgery through transconjunctival incision focusing on complications and their management. METHODS: In this retrospective study, 583 patients, who had been treated for pure blowout fracture through transconjunctival incision from 2000 to 2009, were evaluated. Their hospital records were reviewed according to their sex, age, fracture site, preoperative presentations, time interval between trauma and surgery, and postoperative complications. RESULTS: According to postoperative follow-up results, there were early complications that included wound dehiscence and infection (0.2%), hematoma (insomuch as extraocular movement is limited) (0.7%), lacriminal duct injury (0.5%), and periorbital nerve injury (0.7%). In addition, there were late complications that lasted more than 6 months, that included persistent diplopia (1.7%), extraocular movement limitation (0.9%), enophthalmos (1.0%), periorbital sensation abnormalities (1.0%), and entropion (0.5%). CONCLUSION: We propose the following guidelines for prevention of postoperative complications: layer by layer closure; bleeding control with the epinephrine gauzes, Tachocomb, and Tisseel; conjunctival incision 2 to 3 mm away from punctum; avoidance of excessive traction; performing surgical decompression and high dose corticosteroid therapy upon confirmation of nerve injury; atraumatic dissection and insertion of Medpor Barrier implant after securing a clear view of posterior ledge; using Medpor block stacking technique and BioSorb FX screw fixation; performing a complete resection of the anterior ethmoidal nerve during medial wall dissection; and making an incision 2 to 3 mm below the tarsal plate.
Aprotinin ; Conjunctiva ; Decompression, Surgical ; Diplopia ; Drug Combinations ; Enophthalmos ; Entropion ; Epinephrine ; Fibrinogen ; Follow-Up Studies ; Hematoma ; Hemorrhage ; Hospital Records ; Humans ; Orbital Fractures ; Polyethylenes ; Retrospective Studies ; Sensation ; Thrombin

BACKGROUNDThe over increase of sympathetic drive in chronic heart failure (CHF) is with main responsibility for the deterioration and mortality of the disease. Myocardial (123)I-metaiodobenzylganidine (MIBG) scintigraphy is a non-invasive convenient method to assess sympathetic dysfunction in patients with CHF. The aim of the study was to detect if sympathetic antidrive analysed through myocardial MIBG scintigraphy plays a crucial role in long-term prognosis in CHF.

METHODSSixty-four enrolled patients underwent myocardial MIBG scintigraphy, and their plasma concentration of brain natriuretic peptide (BNP), myocardial contractile reserve (MCR), rest left ventricular ejection fraction (rest LVEF) and New York Heart Association (NYHA) function class were assessed. They were separated into groups according to median of above parameters. Endpoint was cardiac death and it was recorded in each group during average 54 months' follow-up.

RESULTSAt the end of follow-up, group with lower ratio of heart/mediastinum (H/M) had more death events (P = 0.001), and its BNP level was higher and MCR level was lower (P = 0.003 and 0.001, respectively); but its rest LVEF and NYHA function class were not significantly different. H/M, MCR and BNP correlated closely with death (P = 0.000, 0.000 and 0.001, respectively). Among the three indicators the death risk ratio (RR) of H/M was 4.66, more than MCR and BNP (1.88 and 2.56, respectively). However, rest LVEF and NYHA function class did not correlate with death (P = 0.652 and 0.384, respectively). The group with lower H/M and MCR, higher BNP had much more death than that with higher H/M and MCR, lower BNP, the RR being 12.8.

CONCLUSIONSMyocardial MIBG scintigraphy is a long-term prognostic marker in CHF. BNP, MCR are also excellent predictors of long-term prognosis in CHF, but not stronger than myocardial MIBG scintigraphy. If the three indicators were joined together, the prediction would become most powerful. Rest LVEF and NYHA have no significance in long-term prediction of CHF.

3-Iodobenzylguanidine ; Adult ; Aged ; Aprotinin ; chemistry ; Brain ; metabolism ; Echocardiography ; Edetic Acid ; chemistry ; Female ; Heart Failure ; metabolism ; pathology ; Humans ; Male ; Middle Aged ; Myocardial Perfusion Imaging ; methods ; Natriuretic Peptides ; metabolism ; Prognosis ; Prospective Studies

BACKGROUNDInflammation and coagulation are two intimately cross-linked defense mechanisms of most, if not all organisms to injuries. During cardiopulmonary bypass (CPB), these two processes are activated and interact with each other through several common pathways, which may result in subsequent organ dysfunction. In the present study, we hypothesized that the addition of nitric oxide, prostaglandin E1 (PGE1), and aprotinin to the systemic circulation, hereby referred to as blood hibernation, would attenuate the inflammation and coagulation induced by CPB.

METHODSThirty adult mongrel dogs were equally divided into five groups, anesthetized and placed on hypothermic CPB (32 degrees C). Each group received respectively the following treatments: (1) inhalation of 40 ppm nitric oxide; (2) intravenous infusion of 20 ng x kg(-1) x min(-1) of PGE1; (3) 80,000 kallikrein inhibitor units (KIU)/kg of aprotinin; (4) the combination of all three agents (blood hibernation group); and (5) no treatment (control group) during CPB. Activation of leukocyte, platelet, endothelial cell, and formation of thrombin were assessed after CPB.

RESULTSAs compared with the other four groups, leukocyte counts were higher, while plasma elastase, interleukin-8, CD11b mRNA expression, myeloperoxidase activities and lung tissue leukocyte counts were lower in the blood hibernation group (P < 0.05 versus other four groups after CPB). Plasma prothrombin fragment (PTF)1+2, and platelet activation factors were lower, while platelet counts were higher in the blood hibernation group (P < 0.05 versus other four groups at 6 and 12 hours after CPB). Electron microscopy showed endothelial pseudopods protrusion, with cell adherence in all four groups except the blood hibernation group where endothelial cells remained intact.

CONCLUSIONBlood hibernation, effected by the addition of nitric oxide, PGE1 and aprotinin to the circulating blood during extra-corporeal circulation, was observed to attenuate the inflammation and coagulation induced by cardiopulmonary bypass, most likely by inhibiting the important common intermediates between the two cross-linked processes.

Alprostadil ; pharmacology ; therapeutic use ; Animals ; Aprotinin ; pharmacology ; therapeutic use ; Blood Coagulation ; drug effects ; CD11b Antigen ; genetics ; Cardiopulmonary Bypass ; adverse effects ; Dogs ; Inflammation ; drug therapy ; etiology ; Male ; Nitric Oxide ; pharmacology ; therapeutic use ; Reverse Transcriptase Polymerase Chain Reaction

BACKGROUND: The objective of this study was to evaluate the role of proteases on the degradation of parathyroid hormone (PTH) in blood samples. METHODS: Protease inhibitors with specificity against serine proteases (aprotinin), cysteine proteases (E-64), serine and cysteine proteases (leupeptin), metalloproteases (EDTA), or a protease inhibitor cocktail with a broad spectrum of inhibitory activity were added to blood samples. After storage at room temperature (0-48 hr), PTH levels were measured. RESULTS: PTH levels in samples with the protease inhibitor cocktail did not change significantly after 48 hr of storage at room temperature, but the average PTH levels decreased by 40.7% and 20.1%, in samples stored at room temperature and stored at 4degrees C without protease inhibitors, respectively. PTH levels in samples with leupeptin were stable for up to 24 hr. After 48 hr, the mean PTH levels decreased by 17.1%, 16.0%, 26.2%, and 32.1%, with 500 KIU/mL aprotinin, 100 micro mol/L leupeptin, 10 micro mol/L E-64, and 10 micro mol/L EDTA, respectively, in the samples stored at room temperature. CONCLUSIONS: The decrease in PTH levels in blood samples seemed to be due to the degradation of PTH by proteases. Various proteases, including especially serine proteases, would act together to degrade PTH in blood specimen. The PTH degradation may be inhibited in blood specimen with protease inhibitor cocktail.
Aprotinin/pharmacology ; Blood Specimen Collection ; Edetic Acid/pharmacology ; Female ; Humans ; Leucine/analogs & derivatives/pharmacology ; Leupeptins/pharmacology ; Male ; Parathyroid Hormone/*blood/metabolism ; Protease Inhibitors/*pharmacology ; Time Factors

Spontaneous hypertensive rats (SHR) are an established model of genetic hypertension. Vascular smooth muscle cells (VSMC) from SHR proliferate faster than those of control rats (Wistar-Kyoto rats; WKY). We tested the hypothesis that induction of heme oxygenase (HO)-1 induced by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats. Aprotinin treatment inhibited VSMC proliferation in SHR more than in normotensive rats. These inhibitory effects were associated with cell cycle arrest in the G1 phase. Tin protoporphyrin IX (SnPPIX) reversed the anti-proliferative effect of aprotinin in VSMC from SHR. The level of cyclin D was higher in VSMC of SHR than those of WKY. Aprotinin treatment downregulated the cell cycle regulator, cyclin D, but upregulated the cyclin-dependent kinase inhibitor, p21, in VSMC of SHR. Aprotinin induced HO-1 in VSMC of SHR, but not in those of control rats. Furthermore, aprotinin-induced HO-1 inhibited VSMC proliferation of SHR. Consistently, VSMC proliferation in SHR was significantly inhibited by transfection with the HO-1 gene. These results indicate that induction of HO-1 by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats.
Animals ; Aprotinin ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Proliferation ; Cyclin D ; G1 Phase ; Heme ; Heme Oxygenase (Decyclizing) ; Heme Oxygenase-1 ; Hypertension ; Metalloporphyrins ; Muscle, Smooth, Vascular ; Phosphotransferases ; Protoporphyrins ; Rats ; Tin ; Transfection

Aprotinin is used clinically in cardiopulmonary bypass surgery to reduce transfusion requirements and the inflammatory response. The mechanism of action for the anti-inflammatory effects of aprotinin is still unclear. We examined our hypothesis whether inhibitory effects of aprotinin on cytokine-induced inducible nitric oxide synthase (iNOS) expression (IL-1beta plus TNF-alpha), reactive oxygen species (ROS) generation, and vascular smooth muscle cell (VSMC) proliferation were due to HO-1 induction in rat VSMCs. Aprotinin induced HO-1 protein expression in a dose-dependent manner, which was potentiated during inflammatory condition. Aprotinin reduced cytokine mixture (CM)-induced iNOS expression in a dose dependent manner. Furthermore, aprotinin reduced CM-induced ROS generation, cell proliferation, and phosphorylation of JNK but not of P38 and ERK1/2 kinases. Aprotinin effects were reversed by pre-treatment with the HO-1 inhibitor, tin protoporphyrin IX (SnPPIX). HO-1 is therefore closely involved in inflammatory-stimulated VSMC proliferation through the regulation of ROS generation and JNK phosphorylation. Our results suggest a new molecular basis for aprotinin anti-inflammatory properties.
Animals ; Aprotinin ; Cardiopulmonary Bypass ; Cell Proliferation ; Inflammation ; Metalloporphyrins ; Muscle, Smooth, Vascular ; Nitric Oxide Synthase Type II ; Phosphorylation ; Phosphotransferases ; Protoporphyrins ; Rats ; Reactive Oxygen Species ; Tin