Influence of nimodipine combined with ulinastatin on neurological function and inflammatory reaction in patients with cerebral vasospasm after subarachnoid hemorrhage.

OBJECTIVE: This study aimed to discuss the influence of nimodipine+ulinastatin on the neurological function and inflammatory reaction in patients with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). METHODS: Overall, 90 patients with CVS after SAH who were admitted to our hospital were enrolled in this study and randomly divided into research and control groups (n = 45 for both groups). On the basis of conventional therapy, patients in the control group were injected with ulinastatin and those in the research group were injected with ulinastatin+nimodipine through an intravenous drip for 7 days with the others the same as those of the control group. RESULTS: Blood flow velocity in all cerebral arteries was lower in the research group than in the control group after treatment (P < 0.05). Calcitonin gene-related peptide and nitric oxide levels were higher in the research group than in the control group after treatment (P < 0.05). Endothelin levels were lower in the research group than in the control group (P < 0.05). The total effective rate was higher in the research group than in the control group (P < 0.05). Glasgow Coma Scale scores were higher in the research group than in the control group (P < 0.05). CONCLUSION: The drug combination of nimodipine and ulinastatin improved blood flow and neurological function in patients with CVS after SAH and enhanced the therapeutic efficacy; the underlying mechanism may be associated with the regulation of vascular endothelial dilatation function and the inhibition of relevant inflammatory factors' expression.

Traditional Chinese medicine for septic patients undergoing ulinastatin therapy: A meta-analysis.

PURPOSE: This study aimed to assess the efficacy of traditional Chinese medicine (TCM) in septic patients treated with ulinastatin. METHODS: PubMed, EmBase, and the Cochrane library were searched up to January 2021 to identify randomized controlled trials. The weight mean difference (WMD) and relative risk (RR) with 95% confidence intervals were used with the random-effects model. RESULTS: Twenty-three randomized controlled trials with 1903 septic patients were included. TCM significantly reduced the APACHE II score (WMD: -5.18; P < .001), interleukin-6 (WMD: -63.00; P < .001), tumor necrosis factor-α (WMD: -8.86; P < .001), c-reactive protein (WMD: -9.47; P < .001), mechanical ventilation duration (WMD: -3.98; P < .001), intensive care unit stay (WMD: -4.18; P < .001), procalcitonin (WMD: -0.53; P < .001), lipopolysaccharide (WMD: -9.69; P < .001), B-type natriuretic peptide (WMD: -159.87; P < .001), creatine kinase isoenzyme MB (WMD: -45.67; P < .001), cardiac troponin I (WMD: -0.66; P < .001), and all-cause mortality risk (RR: 0.55; P < .001). CONCLUSIONS: TCM lowers inflammation levels and reduces the risk of all-cause mortality for septic patients.

Antitumor activity of Moringa oleifera (drumstick tree) flower trypsin inhibitor (MoFTI) in sarcoma 180-bearing mice.

The plant Moringa oleifera is used as food and medicine. M. oleifera flowers are source of protein, fiber, and antioxidants, and are used to treat inflammation and tumors. This work evaluated the antitumor activity of the M. oleifera flower trypsin inhibitor (MoFTI) in sarcoma 180-bearing mice. Swiss female mice were inoculated with sarcoma 180 cells. Seven days later, the animals were treated intraperitoneally for 1 week with daily doses of PBS (control) or MoFTI (15 or 30 mg/kg). For toxicity assessment, water and food consumption, body and organ weights, histological alterations, and blood hematological and biochemical parameters were measured. Treatment with MoFTI caused pronounced reduction (90.1%-97.9%) in tumor weight. The tumors of treated animals had a reduced number of secondary vessels and lower gauge of the primary vessels compared to the control. No significant changes were observed in water and food consumption or in body and organ weights. Histopathological analysis did not indicate damage to the liver, kidneys, and spleen. In conclusion, MoFTI showed antitumor potential, with no clear evidence of toxicity.

Protective effect of rhubarb combined with ulinastatin for patients with sepsis.

BACKGROUND: Sepsis is the leading cause of death in critically ill patients. Ulinastatin (UTI), a protease inhibitor, and rhubarb, used as a traditional Chinese medication, are proved to be effective in treating sepsis, but the effect of the combination therapy of these two drugs on sepsis remains unclear. This study aimed to investigate the effect of the combination treatment of UTI and rhubarb on sepsis patients. METHODS: A total of 75 septic patients were randomly divided into control group, UTI group, Rhubarb group, and UTI plus Rhubarb group. Clinical data and score of Acute Physiology and Chronic Health Evaluation II (APACHE II) were collected; lymphocyte subtypes in the peripheral blood were analyzed before and after the 5-day treatment in the Intensive Care Unit. RESULTS: All the therapeutic interventions (UTI alone, rhubarb alone, or UTI plus rhubarb) significantly reduced the levels of C-Reactive protein, white blood cell density, lactic acid, and APACH II scores, and elevated the levels of CD4/CD8, but only UTI plus rhubarb treatment obviously decreased the level of procalcitonin. CONCLUSION: This study suggested that the combination of UTI and rhubarb may be a promising therapeutic scheme to ameliorate sepsis.

Tamarind Trypsin Inhibitor in Chitosan-Whey Protein Nanoparticles Reduces Fasting Blood Glucose Levels without Compromising Insulinemia: A Preclinical Study.

In vivo studies show the benefits of the trypsin inhibitor isolated from tamarind (Tamarindusindica L.) (TTI) seeds in satiety and obesity. In the present study, TTI nanoencapsulation (ECW) was performed to potentialize the effect of TTI and allow a controlled release in the stomach. The impact on glycemia, insulin, and lipid profile was evaluated in Wistar rats overfed with a high glycemic index diet (HGLI). Characterization of the nanoparticles and in vitro stability in simulated gastrointestinal conditions, monitored by antitrypsin activity and HPLC, was performed. ECW and empty nanoparticles (CW) were administered by gavage, using 12.5 and 10.0 mg/kg, respectively. Both nanoformulations presented a spherical shape and smooth surface, with an average diameter of 117.4 nm (24.1) for ECW and 123.9 nm (11.3) for CW. ECW maintained the antitrypsin activity (95.5%) in the gastric phase, while TTI was completely hydrolyzed. In Wistar rats, the nanoformulations significantly reduced glycemia and HOMA IR, and ECW increased HDL-c compared to CW (p < 0.05).Pancreas histopathology of animals treated with ECW suggested an onset of tissue repair. Thenanoencapsulation provided TTI protection, gradual release in the desired condition, and improvement of biochemical parameters related to carbohydrate metabolism disorders,without compromising insulinemia.

Curative efficacy and safety of traditional Chinese medicine xuebijing injections combined with ulinastatin for treating sepsis in the Chinese population: A meta-analysis.

BACKGROUND: Sepsis is a clinically critical disease. However, it is still controversial whether the combined use of traditional Chinese medicine Xuebijing injections (XBJI) and western medicine can enhance curative efficacy and ensure safety compared with western medicine alone. Thus, this research consisted of a systematic review of the curative efficacy and safety of traditional Chinese medicine XBJI combined with ulinastatin for treating sepsis in the Chinese population. METHODS: A total of 8 databases were retrieved: 4 foreign databases, namely, PubMed, The Cochrane Library, Embase, and Web of Science; and 4 Chinese databases, namely, Sino Med, China National Knowledge Infrastructure (CNKI), VIP, and Wangfang Data. The time span of retrieval began from the establishment of each database and ended on August 1, 2017. Published randomized controlled trials about the combined use of traditional Chinese medicine XBJI and western medicine were included, regardless of language. Stata12.0 software was used for statistical analysis. RESULTS: Finally, 16 papers involving 1335 cases were included. The result of meta-analysis showed that compared with the single use of ulinastatin, traditional Chinese medicine XBJI combined with ulinastatin could reduce the time of mechanical ventilation, shorten the length of intensive care unit (ICU) stay, improve the 28-day survival rate, and decrease the occurrence rate of multiple organ dysfunction syndrome, case fatality rate, procalcitonin (PCT) content, APACKEII score, tumor necrosis factor (TNF)-α level, and interleukin (IL)-6 level. CONCLUSION: On the basis of the common basic therapeutic regimen, the combined use of traditional Chinese medicine XBJI and ulinastatin was compared with the use of ulinastatin alone for treating sepsis in the Chinese population. It was found that the number of adverse events of combination therapy is not significantly increased, and its clinical safety is well within the permitted range. However, considering the limitations of this conclusion due to the low-quality articles included in the present research, it is necessary to conduct high-quality randomized controlled trials.

Xuebijing combined with ulinastation benefits patients with sepsis: A meta-analysis.

BACKGROUND: The potential benefits and possible risks associated with Xuebijing when combined with ulinastatin for sepsis treatment are not fully understood. METHODS: Databases, such as PubMed, Web of Science, CNKI, WanFang and VIP, were searched to collect randomized, controlled trials. Studies were screened, data were extracted, and the methodological quality was assessed by two reviewers independently. A meta-analysis was carried out with Stata 11.0 software. RESULTS: A total of 16 studies involving 1192 participants were enrolled for meta-analysis based on the inclusion and exclusion criteria. The results showed that compared with the group using routine therapies and the group using a single administration of either ulinastatin or Xuebijing, the trial group using Xuebijing combined with ulinastatin was significantly superior in the following aspects: mortality (RR = 0. 54,95% CI (0. 41, 0. 70, P = .000), 7 d APACHE II (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), duration of mechanical ventilation (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), average length of time in the intensive care unit (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), incidence of multiple organ dysfunction syndromes (RR = 0. 54, 95% CI (0.41, 0. 70, P = .000), interleukin-6 (SMD = -1.36,95%CI (-2.46, -0.27), P = .000), lipopolysaccharide (SMD = -9.92, 95%CI (-11.7, -7.90), P = .006), and procalcitonin (SMD = -0.30, 95%CI (-0.34, -0.26), P = .012). CONCLUSIONS: Our results found that Xuebijing when combined with ulinastatin was superior to both routine therapies and the single administration of either ulinastatin or Xuebijing. This finding provides a new therapeutic option for the treatment of sepsis.

Supplementation with a new trypsin inhibitor from peanut is associated with reduced fasting glucose, weight control, and increased plasma CCK secretion in an animal model.

Ingestion of peanuts may have a beneficial effect on weight control, possibly due to the satietogenic action of trypsin inhibitors. The aim of this study was to isolate a new trypsin inhibitor in a typical Brazilian peanut sweet (paçoca) and evaluate its effect in biochemical parameters, weight gain and food intake in male Wistar rats. The trypsin inhibitor in peanut paçoca (AHTI) was isolated. Experimental diets were prepared with AIN-93G supplemented with AHTI. Animals had their weight and food intake monitored. Animals were anesthetized, euthanized, and their bloods collected by cardiac puncture for dosage of cholecystokinin (CCK) and other biochemical parameters. Supplementation with AHTI significantly decreased fasting glucose, body weight gain, and food intake. These effects may be attributed to increased satiety, once supplemented animals showed no evidence of impaired nutritional status and also because AHTI increased CCK production. Thus, our results indicate that AHTI, besides reducing fasting glucose, can reduce weight gain via food intake reduction.

Ulinastatin prevents acute lung injury led by liver transplantation.

BACKGROUND: Little is known regarding the effect of ulinastatin (UTI) on acute lung injury (ALI) induced by orthotopic liver transplantation. This study aims to investigate the protective effect of UTI on ALI induced by orthotopic autologous liver transplantation (OALT) in a rat model and to explore the potential underlying mechanism. MATERIALS AND METHODS: Rats were randomly allocated into the following four groups (n = 8 each): (i) sham control group (group sham); (ii) model group (underwent OALT) (group model); (iii) low-dose UTI-treated group (group u1), with UTI (50 U/g) administered intravenously both before the portal vein was occluded and after liver reperfusion started; and (iv) high-dose UTI-treated group (group uh), with UTI (100 U/g) given in the same way as group ul. The lung pathologic parameters, lung water content, and levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, malondialdehyde (MDA), superoxide dismutase (SOD) activity, RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1), and peroxiredoxin-2 (Prx-2) were assessed 8 h after OALT was performed. RESULTS: According to histology, there was severe damage in the lung of group model accompanied by increases in the TNF-α, IL-1ß, IL-6, and MDA levels and decreases in SOD activity and the expression of RBCK1 and Prx-2. UTI treatment significantly reduced the pathologic scores, lung water content, and TNF-α, IL-1ß, IL-6, and MDA levels while restoring the SOD activity and expression of RBCK1 and Prx-2. Furthermore, compared with group u1, treatment with a high dose of UTI resulted in a better protective effect on the lung when assessed by the TNF-α, IL-1ß, IL-6, and MDA levels and SOD activity. CONCLUSIONS: UTI dose-dependently attenuates ALI that is induced by OALT in this rat model, which is mainly due to the suppression of the inflammatory response and oxidant stress, which may, in turn, be mediated by the upregulation of RBCK1 and Prx-2 expression.

Potato protease inhibitors inhibit food intake and increase circulating cholecystokinin levels by a trypsin-dependent mechanism.

OBJECTIVE: To investigate the mechanisms underlying the satiety-promoting effects of a novel protease inhibitor concentrate derived from potato (PPIC). METHODS: The acute and prolonged effects of oral PPIC administration (100 mg kg(-1) per day) on food intake, body weight and gastric emptying were evaluated in healthy rats. Parameters of body weight, food intake, plasma glucose, insulin and cholecystokinin (CCK) were measured. Duodenal proteolytic activity and CCK expression were determined in tissue extracts. Intestinal STC-1 cell culture model was used to investigate the direct effect of PPIC on CCK transcript level and secretion. RESULTS: Acute oral administration of PPIC reduced immediate food intake during the first 2 h following the treatment, delayed gastric emptying and decreased proteolytic activity in the duodenum. Repeated oral ingestion of PPIC reduced weight gain in male rats and significantly elevated the plasma CCK levels. Although duodenal mucosal CCK mRNA levels increased in response to PPIC administration, the concentrate failed to elevate CCK expression or release in STC-1 cells. The 14-day ascending dose range study (33-266 mg kg(-1) PPIC per day) showed no adverse side effects associated with PPIC administration. CONCLUSION: These findings provided evidence that PPIC is effective in reducing food intake and body weight gain in healthy rats when administered orally by increasing circulating CCK levels through a trypsin-dependent mechanism.

Effect of hyperbaric oxygen and ulinastatin on plasma endotoxin, soluble CD14, endotoxin-neutralizing capacity and cytokines in acute necrotizing pancreatitis.

BACKGROUND: We sought to study the effect of a combination therapy comprised of hyperbaric oxygen (HBO) and ulinastatin on the plasma levels of endotoxin, soluble CD14 (sCD14), endotoxin neutralizing capacity (ENC) and cytokines in acute necrotizing pancreatitis (ANP) in rats. METHODS: We randomly allocated 90 Sprague-Dawley rats into 6 groups: group 1 (ordinary control), group 2 (sham operation), group 3 (ANP), group 4 (ANP with HBO), group 5 (ANP with ulinastatin) and group 6 (ANP with HBO and ulinastatin). We induced ANP by retrograde injection of 3.5% sodium taurocholate (2.5 mL/kg) via the pancreatic duct. Five minutes after induction, animals in groups 5 and 6 were infused with ulinastatin (20 000 U/kg) via the portal vein. Thirty minutes after induction, animals in groups 4 and 6 received HBO therapy. We collected samples 3, 6 and 10 hours after induction of ANP. RESULTS: We found that the plasma level of endotoxin in group 3 was significantly higher than in group 4 (3, 6 h, both p < 0.001), group 5 (3 h, p < 0.001; 6 h, p = 0.014) and group 6 (both p < 0.001). The level of plasma sCD14 in group 3 was significantly higher than in group 4 (3, 6 h, both p < 0.001), group 5 (3, 6 h, both p = 0.001) and group 6 (3 h, p < 0.001; 6 h, p = 0.001). The plasma endotoxin and sCD14 levels in group 6 were significantly lower than in groups 4 and 5. The plasma ENC level in group 6 was significantly higher than in groups 3, 4 and 5 (p < 0.001). The ENC level in groups 4 and 5 were higher than in group 3, but there was no significant difference. The plasma level of tumour necrosis factor-alpha (TNF-alpha) and IL-6 in group 6 were significantly lower than in groups 3, 4 and 5 (p < 0.001). The TNF-alpha and IL-6 levels in groups 4 and 5 were lower than in group 3, but there was no significant difference. CONCLUSION: The use of an early combination therapy of HBO and ulinastatin was more effective than either therapy alone in the treatment of ANP.

Carboxymethyl-starch excipients for gastrointestinal stable oral protein formulations containing protease inhibitors.

PURPOSE: The aim of this study was to develop a formulation for bioactive compounds using Carboxymethyl Starch (CMS) as excipient containing protease inhibitors. This formulation provided gastro protection and enhanced stability against pancreatic enzymes. Such stability is needed for formulation of oral vaccines with specific antigens. METHODS: CMS was synthesized by treatment of starch with monochloroacetic acid in conditions leading to a substitution degree of about 1 meq/g and used as excipient for monolithic devices (300 mg tablets). Pefabloc SC and Aprotinin inhibitors were tested in dissolution media and in formulation to prevent the degradation of released bioactive materials. To evaluate the structural integrity and biological stability of plant proteins in the CMS formulation, albumin and lipase were added to the plant protein extract as protein and respectively as enzyme markers. The amounts of released and recovered proteins were evaluated by SDS-PAGE and densitometric analysis. RESULTS: It was found that 1.6 % (w/w) of Pefabloc SC provides 98 % protection of the released plant proteins for formulations of 30 % alfalfa protein extract (APE) with CMS. In addition, when bovine serum albumin (BSA) added to the plant protein extract as a marker, 90 % protection of the released BSA was observed. Furthermore, a much higher lipase activity was found in the releasing media when the formulations contained Pefabloc SC. CONCLUSION: Formulations with CM-Starch excipients and containing protease inhibitors prevent protein degradation and protect lipase activity, showing a marked potential to use for orally administered bioactive peptides and therapeutic enzymes.

Antitrypsin activity of extracts from Ecballium elaterium seeds.

The antitrypsin activity of extracts obtained from two different seed types of Ecballium elaterium, was tested in vitro. The presence of trypsin inhibitors in three chromatographed samples for each extract, showed a strong and specific antitrypsin activity.

A trypsin inhibitor from Cassia obtusifolia seeds: isolation, characterization and activity against Pieris rapae.

A trypsin inhibitor was isolated from Cassia obtusifolia by ammonium sulfate precipitation, Sepharose 4B-trypsin affinity and Sephadex G-75 chromatography. The inhibitor consisted of a single polypeptide chain with a molecular mass of 19, 812.55 Da. It was stable from pH 2 to 12 for 24 h, whereas it was unstable either above 70 degrees C for 10 min or under reduced conditions. The inhibitor, which inhibited trypsin activity with an apparent Ki of 0.3 microM, had one reactive site involving a lysine residue. The native inhibitor was resistant to pepsin digestion, whereas the heated inhibitor produced 40% degree of susceptibility. The disulfide linkage and lysine residue were important in maintaining its conformation. Partial amino acid sequence of the purified protein showed a high degree of homology with various members of the Kunitz inhibitor family. Moreover, the inhibitor showed significant inhibitory activity against trypsin-like proteases present in the larval midgut on Pieris rapae and could suppress the growth of larvae.

Evaluation of a colostrum supplement, with or without trypsin inhibitor, and an egg protein milk replacer for dairy calves.

Forty-eight Holstein bull calves were assigned to a 2 x 2 x 2 factorial arrangement in a completely randomized block design. Main effects were colostrum versus a serum-derived colostrum supplement, 0 versus 1 g of trypsin inhibitor added at the initial 2 feedings, and milk replacer containing 0 or 50% CP from whole egg. Calves were bled at 0, 6, 12, 18, and 24 h after birth for determination of serum immunoglobulin (Ig). G. Serum IgG concentrations were lower in calves consuming the colostrum supplement compared with calves consuming colostrum. Apparent efficiency of absorption of IgG was similar. Trypsin inhibitor did not affect IgG concentrations or absorption of IgG. Calves were fed either milk replacer for 28 to 35 d (preweaning phase) and weaned when they consumed 0.7 kg of starter grain for 2 consecutive days. The postweaning phase was from weaning to d 56. Feeding colostrum supplement resulted in higher fecal scores postweaning (1.90 vs. 1.58) and overall (1.85 vs. 1.65) and fewer days medicated preweaning (5.1 vs. 2.2 d) and postweaning (3.9 vs. 1.9 d) and overall (9.0 vs. 4.2 d). Calves were treated for upper respiratory tract infections and diarrhea. Dry matter intake and weaning age were not affected by treatment. Postweaning (1.69 vs. 1.2 kg) and overall (1.22 vs. 1.0 kg), calves that received colostrum and egg milk replacer consumed more dry matter and starter. Postweaning, calves fed colostrum and egg milk replacer had similar or greater body weight and gains compared with calves fed colostrum and milk protein milk replacer. Preweaning, feed efficiency was greater for calves fed colostrum (0.44 vs. 0.34), trypsin inhibitor (0.42 vs. 0.36), and milk protein milk replacer (0.48 vs. 0.30) compared with calves fed colostrum supplement, no trypsin inhibitor, and egg milk replacer, respectively. Trypsin inhibitor increased feed efficiency postweaning. Calves fed trypsin inhibitor and milk protein milk replacer were more efficient preweaning and overall than calves fed trypsin inhibitor and egg milk replacer. Results indicate that the blood derived colostrum supplement did not provide as much IgG as colostrum (4.55 g/L vs. 14.6 g/L, respectively), that feeding 1.0 g of trypsin inhibitor did not enhance serum IgG concentrations, and that the egg milk replacer-fed calves fed colostrum performed nearly as well as calves fed colostrum and the milk protein milk replacer.

Zeamatin, clotrimazole and nikkomycin Z in therapy of a Candida vaginitis model.

OBJECTIVE: To study the interaction of antifungal drugs in topical therapy. MATERIALS AND METHODS: Local therapy of Candida vaginitis with drugs alone and in combination was examined in a murine model. Zeamatin, a natural plant-derived antifungal protein, was tested alone and in combination with an azole, clotrimazole or nikkomycin Z, a chitin synthase inhibitor. RESULTS: Whereas alone, zeamatin was ineffective, nikkomycin Z was effective only when dosed multiple times per day, and clotrimazole efficacy was variable when administered in experimental vehicles (unlike the complex and undefined commercial preparation), zeamatin enhanced the efficacy of either of the other two drugs when they were given in combination. CONCLUSION: Drug interactions between novel drugs with unique mechanisms of action should be explored further, and may lead to more potent regimens.

Treatment of septic shock with a protease inhibitor in a canine model: a prospective, randomized, controlled trial.

OBJECTIVES: To evaluate the efficacy and mechanism of action of a protease inhibitor (ulinastatin) in septic shock. DESIGN: Prospective, randomized, controlled trial. SETTING: A university laboratory. SUBJECTS: Twelve mongrel dogs. INTERVENTIONS: One of the protease inhibitors, ulinastatin, a glycoprotein (molecular weight 67,000 daltons) detected in human urine was estimated. We used Escherichia coli to obtain a model of septic shock in dogs in vivo study. Human neutrophils were used as an activating target in vitro. MEASUREMENTS AND MAIN RESULTS: The final concentration of E. coli was 1.9 x 10(6) colony-forming units/mL. There was no significant difference in E. coli concentration between ulinastatin-treated and control groups. Human neutrophils treated with 100 U/mL of ulinastatin showed 70.5% to 78.7% of the superoxide production or untreated neutrophils. Phagocytic activity was enhanced in a dose-dependently manner by ulinastatin. At a ulinastatin concentration of 100 U/mL, an approximate two-fold increase in activation was found. In the ulinastatin-treated group, cardiac index, blood pressure, lactic acid, blood glucose, and blood base values significantly improved 60 mins after ulinastatin administration, and the bacterial count was significantly decreased, while the endotoxin concentration in the control group showed a continuous increase of endotoxin concentration. The improvement in the monitored factors observed 60 mins after initiation of treatment persisted after the end of treatment. The survival rate after 1 wk in the ulinastatin-treated group was 84% (five of six dogs survived), while it was 16% (one of six dogs survived) in the control group (p = .04). CONCLUSIONS: Ulinastatin does not have antimicrobial activity, and it does not sufficiently activate phagocytes. It is suggested that the efficacy of this agent in experimental septic shock is due to a mechanism that activates the reticuloendothelial system and septic reactions.

Effect of urinary trypsin inhibitor on pancreatic cellular and lysosomal fragility in cerulein-induced acute pancreatitis in rats.

We evaluated the protective effect and the mechanism of action of the trypsin inhibitor, urinastatin, extracted from human urine, in experimental acute pancreatitis induced by a supramaximal dose of cerulein (5 micrograms/kg/hr for 3.5 hr). Urinastatin in a dose of 10,000 units/kg/hr was given by three different methods of continuous infusion: (1) 2 hr before and during cerulein infusion, (2) only during cerulein infusion, and (3) starting 1 hr after the beginning of cerulein infusion and continued for 3.5 hr. In protocol 1 and 2 urinastatin was significantly more protective than in 3. In protocol 1 urinastatin was very protective in all parameters tested (serum amylase level, pancreatic water and amylase content, distribution of lysosomal enzymes, cellular and lysosomal fragility). These results suggest that the administration of urinastatin before and during cerulein infusion may suppress the pathogenesis and evolution of pancreatitis by inhibiting the chain reaction of pancreatic enzyme activation closely related to redistribution of lysosomal enzyme and lysosomal fragility.

Cytotoxic effects of cyclosporin A on the exocrine pancreas in rats.

The current study was done to evaluate the subacute toxic effects of cyclosporin A (CS) on the exocrine pancreas and the protective effect of potent protease inhibitor camostate (FOY-305). CS administration (15 milligrams, twice a day) for 14 days caused a significant increase in serum amylase levels, pancreatic amylase and cathepsin B content and mild acinar cell vacuolization and interstitial edema. CS also caused the redistribution of cathepsin B activity from the lysosomal fraction to the zymogen fraction, indicating colocalization of lysosomal enzyme with pancreatic digestive enzymes. The administration of camostate (150 milligrams per kilogram, twice a day for 14 days) almost completely prevented the toxic changes induced by CS. These results indicate that CS induces exocrine pancreatic injury and that lysosomal enzymes play important roles in the pathogenesis of the injury. The results also suggest the usefulness of camostate in protecting the exocrine pancreas in patients treated with CS after organ transplantation, because it can inhibit some proteases that are closely involved in the fragility of the subcellular organelles.

Nutritional evaluation of the trypsin (EC 3.4.21.4) inhibitor from cowpea (Vigna unguiculata Walp.).

The effect of feeding rats purified cowpea (Vigna unguiculata Walp.) trypsin (EC 3.4.21.4) inhibitor in a semi-synthetic high-quality diet based on lactalbumin (10 g inhibitor/kg) for 10 d was a moderate reduction in the weight gain of rats in comparison with controls, despite an identical food intake in the two groups. The reduction in the growth rate was about 20% on a live weight basis. However, the corresponding value calculated from the weight of dry carcasses was less, only about 7%, probably because the water content of the body of the two groups of rats was different. Although most of the cowpea trypsin inhibitor (CpTI) was rapidly broken down in the digestive tract, its inclusion in the diet led to a slight, though significant, increase in the nitrogen content of faeces but not of urine. Accordingly, the net protein utilization of rats fed on inhibitor-containing diets was also slightly depressed while their energy expenditure was elevated. In agreement with results obtained for the protease inhibitors of soya bean, the slight anti-nutritional effects of CpTI were probably due mainly to the stimulation of the growth and metabolism of the pancreas. Thus, the nutritional penalty for increased insect-resistance after the transfer of the cowpea trypsin inhibitor gene into food plants is slight in the short-term.