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Objective: Nafamostat mesilate (NM), a synthetic broad-spectrum serine protease inhibitor, has been commonly used for treating acute pancreatitis (AP) and other inflammatory-associated diseases in some East Asia countries. Although the potent inhibitory activity against inflammation-related proteases (such as thrombin, trypsin, kallikrein, plasmin, coagulation factors, and complement factors) is generally believed to be responsible for the anti-inflammatory effects of NM, the precise target and molecular mechanism underlying its anti-inflammatory activity in AP treatment remain largely unknown. Methods: The protection of NM against pancreatic injury and inhibitory effect on the NOD-like receptor protein 3 (NLRP3) inflammasome activation were investigated in an experimental mouse model of AP. To decipher the molecular mechanism of NM, the effects of NM on nuclear factor kappa B (NF-κB) activity and NF-κB mediated NLRP3 inflammasome priming were examined in lipopolysaccharide (LPS)-primed THP-1 cells. Additionally, the potential of NM to block the activity of histone deacetylase 6 (HDAC6) and disrupt the association between HDAC6 and NLRP3 was also evaluated. Results: NM significantly suppressed NLRP3 inflammasome activation in the pancreas, leading to a reduction in pancreatic inflammation and prevention of pancreatic injury during AP. NM was found to interact with HDAC6 and effectively inhibit its function. This property allowed NM to influence HDAC6-dependent NF-κB transcriptional activity, thereby blocking NF-κB-driven transcriptional priming of the NLRP3 inflammasome. Furthermore, NM exhibited the potential to interfere the association between HDAC6 and NLRP3, impeding HDAC6-mediated intracellular transport of NLRP3 and ultimately preventing NLRP3 inflammasome activation. Conclusions: Our current work has provided valuable insight into the molecular mechanism underlying the immunomodulatory effect of NM in the treatment of AP, highlighting its promising application in the prevention of NLRP3 inflammasome-associated inflammatory pathological damage. [ABSTRACT FROM AUTHOR]

Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration–response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10−10 to 10−5 M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration–response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (− logEC50: − 5.73 ± 0.25 vs. − 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (− logEC50: − 6.62 ± 0.21 vs. − 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r2 = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS. [ABSTRACT FROM AUTHOR]

Background: Regional citrate anticoagulation (RCA) is the preferred continuous kidney replacement therapy (CKRT) anticoagulation strategy for children in the USA. Nafamostat mesilate (NM), a synthetic serine protease, is used widely for CKRT anticoagulation in Japan and Korea. We compared the safety and efficacy of NM to RCA for pediatric CKRT. Methods: Starting June 2019, the most recent 100 medical records of children receiving CKRT with either RCA or NM were reviewed retrospectively, at one children's hospital in Japan (NM) and one in the USA (RCA). The number of hours a single CKRT filter was in use, was the primary outcome. Safety was assessed by bleeding complications for the NM group and citrate toxicity leading to RCA discontinuation or electrolyte imbalance in the RCA group. Results: Eighty patients received NM and 78 patients received RCA. Median filter life was longer for the NM group (NM: 38 [22, 74] vs. RCA: 36 [17, 66] h, p = 0.02). When filter life was censored for discontinuation other than clotting, the 60-h survival rate was higher for RCA (71% vs. 54%). The hazard ratio comparing NM over RCA varied over time (HR 0.7; 0.2–1.5, p = 0.33 at 0 h to HR 5.5; 1.3–23.7, p = 0.334 at 72 h). The lack of difference in filter survival persisted controlling for filter surface area, catheter diameter, and pre-CKRT platelet count. Major bleeding rates did not differ between groups (NM: 5% vs. RCA: 9%). Conclusions: RCA and NM provide satisfactory anticoagulation for CKRT in children with no difference in major bleeding rates. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

Background: Heparin-induced thrombocytopenia type II (HIT II) is a rare, immune-mediated complication of heparin therapy and can cause life-threatening thromboembolism. However, perioperative anticoagulation therapy for patients with a complication of HIT II has not been established. Case presentation: A 6-year-old boy with tetralogy of Fallot underwent radical intracardiac repair with administration of argatroban at 1 year old due to positive HIT antibody. Reoperation was scheduled for pulmonary valve insufficiency, using argatroban and nafamostat mesilate as anticoagulants. Argatroban has a long onset time and the activated coagulation time (ACT) requires 7–26 h to return to the preadministration level, making hemorrhage control difficult, while half-life of nafamostat mesilate is shorter than that of argatroban. Celite ACT reflects the effects of both argatroban and nafamostat mesilate, but kaolin ACT reflects only the effect of argatroban. Due to the early termination of argatroban administration based on Celite and kaolin ACTs, ACT recovered to ≤ 200 s at 5 h after the end of argatroban administration. Conclusion: Celite and kaolin ACTs can be used as markers to obtain close control of the required dose of argatroban in combination with nafamostat mesilate for the management of HIT II patients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine the potential efficacy of camostat mesilate, a protease inhibitor, against dyspepsia associated with non-alcoholic mild pancreatic disease. Patients with upper abdominal pain suggesting pancreatic disease (persistent over hours, pain aggravated by ingestion of food, epigastric pain radiating to the back), without a history of alcohol consumption and who exhibited no abnormalities regarding serum amylase and lipase, ultrasonography, CT and upper gastrointestinal endoscopy, were prescribed 200 mg camostat mesilate three times daily for 2 weeks. The patients were subjected to endoscopic ultrasonography (EUS) while under treatment and were distributed into those who had 4 or more suggestive findings of chronic pancreatitis (suspected pancreatic disease group), 2 or 3 (equivalent group) and those with 1 or no findings (control group). Symptom severity was recorded before and after treatment using a 10-cm visual analog scale (VAS). Among 95 patients, 40 were in the suspected pancreatic disease group, 30 were in the equivalent group and 25 served as controls. A significant intra- and intergroup improvement of symptoms was observed not only in the suspected pancreatic disease group but also in the equivalent group. Camostat mesilate may serve as a therapeutic agent for patients with dyspepsia associated with mild pancreatic disease, who do not habitually drink alcohol. [ABSTRACT FROM AUTHOR]

The effects of camostat mesilate (CM), a derivative of gabexate mesilate developed for oral use, on primary glomerulonephritis (GN) and chance hematuria and/or proteinuria were evaluated. Fourteen patients (6 males, 8 females) with a mean age of 11 years and 3 months (range 4–16 years) were enrolled. Histological and clinical diagnoses of the 14 patients were as follows: IgA nephropathy 3, non-IgA GN 2, and asymptomatic significant microscopic hematuria [more than 100 red blood cells per high-power field (x400)] with or without proteinuria 9. They were consecutively treated with oral CM (100 mg twice a day) when they were confirmed to have continuous significant microscopic hematuria and/or proteinuria after a few months of observational follow-up. Urinary findings were normalized in 10 of the 14 patients (85.7%) between 1 month 1 week and 10 months (mean 4 months) after administration of CM. Hematuria cleared in 11 of 13 patients, and proteinuria disappeared in 4 of 5 patients. The mean duration of CM administration was 21.7±9.1 months (range 4–37 months). At present, 3–12 years after discontinuation of CM therapy, their urinary findings remain normal at 9 years 10 months to 26 years 6 months of age. In conclusion, there appears to be an association between the oral use of CM and reduction in significant microscopic hematuria and/or proteinuria. Oral CM therapy could represent a practical primary care approach to chance hematuria and/or proteinuria in children. [ABSTRACT FROM AUTHOR]

The purpose of the present study is to characterize polymorphic forms and intermolecular interactions of freeze-dried pharmaceuticals containing additives by terahertz (THz) spectroscopy as a, process analytical technology tool in the pharmaceutical industry. Freeze-dried gabexate mesilate/D-mannitol products containing 17-75 mol% gabexate mesilate were obtained using a conventional freeze-dryer. Freeze-dried products and physical mixtures of gabexate mesilate and mannitol with various drug contents were characterized by X-ray powder diffraction (XRD) analysis, differential scanning calorimetry (DSC) and THz. The XRD and DSC results indicated that freeze-dried mannitol was obtained as a mixture of β and δ forms of mannitol from a plain solution, but the freeze-dried product of the gabexate mesilate/mannitol mixture consisted of crystalline gabexate mesilate and the pure δ form of mannitol. Similar to the results of XRD and DSC, THz before the freeze-drying of gabexate mesilate was almost the same as that after. In contrast, the THz of mannitol before freeze-drying had specific peaks due to the β form, but that after had peaks due to δ and β forms. To clarify the polymorphic forms of the freeze-dried products, the THz were analyzed by least squares regression. The calibration models used to predict the amounts of gabexate mesilate and mannitol had sufficient accuracy and linearity, respectively. Two decomposed THz in FGMs had specific peaks due to the δ form of mannitol or gabexate mesilate. [ABSTRACT FROM AUTHOR]

The hepatic metabolism and biliary and pancreatic excretion of the serine protease inhibitor camostat mesilate and its metabolites FOY-251 and GBA were studied in rats in vivo and in in situ liver-perfusion experiments. After oral feeding (100 mg/kg) and iv infusion (5 mg/kg-h) of camostat mesilate, the original compound and both metabolites appeared in bile, but could not be detected in pancreatic juice. In plasma, only FOY-251 and GBA were detected. In the perfused rat liver, camostat mesilate (10 μM) was eliminated by 33.8% and its molar rate of degradation to FOY-251 was 25.1%. During the study period about 0.1% of camostat mesilate and FOY-251 appeared in bile. The liver perfusion of FOY-251 or GBA revealed very low hepatic extraction rates of 10.3 and 2.4%, respectively. In conclusion, the low hepatic extraction rate of camostat mesilate and its metabolites leads to high concentrations of the active metabolite FOY-251 in plasma. Camostat mesilate and its metabolites are effectively excreted into bile, but not in rat pancreatic juice. [ABSTRACT FROM AUTHOR]

We evaluated clinical outcomes of disseminated intravascular coagulation (DIC) in patients with hematological malignancies treated with synthetic protease inhibitors (SPIs) and compared the effects of gabexate mesilate (FOY) and nafamostat mesilate (FUT). We retrospectively examined 127 patients [acute myeloid leukemia (n = 48), acute lymphoblastic leukemia (n = 25), and non-Hodgkin lymphoma (n = 54)] with DIC, who were diagnosed according to Japanese Ministry of Health, Labour and Welfare criteria and treated with SPIs [FOY (n = 55) and FUT (n = 72)] at our hospital from 2006 to 2015. The DIC resolution rates on days 7 and 14 were 42.6% and 62.4%, respectively. No significant differences were observed in DIC resolution rates between the FUT and FOY groups [40.3% vs. 45.5% (day 7), P = 0.586; 56.3% vs. 69.8% (day 14), P = 0.179, respectively]. Multivariate analysis revealed that response to chemotherapy was the only independent predictor of DIC resolution on days 7 and 14 (ORR 2.81, 95% CI 1.32-5.98, P = 0.007; ORR 2.51, 95% CI 1.12-5.65, P = 0.026). Resolution of DIC was correlated with improvement of background hematological malignancies, and no significant differences were observed between the two SPIs. [ABSTRACT FROM AUTHOR]

Evidence suggests that thrombin, a blood coagulation serine protease, mediates neuronal injury in experimental cerebral ischemia. Here, we test the hypothesis that nafamostat mesilate, a serine protease inhibitor, may ameliorate ischemia-induced neuronal damage through thrombin inhibition after ischemic stroke. Focal ischemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery for 2 hours followed by 22 hours of reperfusion. The administration of nafamostat mesilate during ischemia and reperfusion reduced the brain infarct volume, edema volume and neurological deficit. Thrombin expression and activity in the ipsilateral striatum were increased after ischemia, whereas the administration of nafamostat mesilate significantly inhibited thrombin expression and activity. Immunostaining showed that the majority of thrombin was expressed in neurons. TUNEL staining showed that nafamostat mesilate reduced the number of dying cells during ischemia. A rat behavioral test showed that nafamostat mesilate treatment significantly improved the learning ability of ischemic rats. These results suggest that nafamostat mesilate may have a potential therapeutic role for neuroprotection against focal cerebral ischemia through thrombin inhibition. [ABSTRACT FROM AUTHOR]

An advanced quantification method was developed with solid-phase extraction (SPE) and mass spectrometry (MS) determination for nafamostat, an unstable and highly polar drug, in human plasma. For unstable drugs with an ester group, the main analytical challenge is how to avoid the ester hydrolysis, and strong acid or alkaline conditions should be excluded during sample preparation. Considering that, we developed a relatively mild method with SPE for sample preparation without strong acid and alkaline treatment, which was optimized with different pHs and salt concentrations in phosphate-buffered saline treatment. The results indicated that pH 5 gave the most efficient extraction and 0.1 M salt concentration enhanced the extraction the most, with a minor effect on MS monitoring. The extraction method effectively avoided drug hydrolysis and achieved good drug enrichment over 82.2%. The linear range of quantification was 1.25–160 ng mL−1. The stability of the drug in sample treatment was fully validated according to the sample processing procedure, including the stability in fresh blood, mobile phase, plasma and acidic methanol, and the results indicated that the drug remained stable during the whole sample preparation. Compared with a previous isotope-labeling method, more accurate and specific quantification of plasma concentration was achieved with liquid chromatography–electrospray ionization MS determination. With use of our method, nafamostat mesilate pharmacokinetics in 30 Chinese healthy volunteers was investigated with three doses via intravenous-drip infusion. The pharmacokinetic parameters were also estimated and compared with those of Japanese volunteers (slightly lower plasma concentration and longer terminal elimination half-life for Chinese volunteers). The difference in the pharmacokinetics may be ascribed to the quantification method, because previous isotope labeling may have overestimated the parent drug. [ABSTRACT FROM AUTHOR]

Background:Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin's effects on the balance between epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) in human breast cancer cells were investigated.Methods:Triple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER−)/progesterone receptor (PR−)/human epithelial growth receptor 2 (HER2−) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF-β/Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo, the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting.Results:Treatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF-β induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model.Conclusions:Eribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo, consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo. These preclinical findings may provide a plausible scientific basis for clinical observations of prolonged OS by suppression of further spread of metastasis in breast cancer patients treated with eribulin. [ABSTRACT FROM AUTHOR]

A 4-year-old Japanese girl received a continuous infusion of gabexate mesilate (200 mg/25 ml 5% glucose) for 6 days via a peripheral vein for the treatment of hemolytic uremic syndrome. After administration, pigmentation was seen at the needle entry point on her right hand. Six years later, an elastic, hard subcutaneous mass was noted around this pigmentation. The tumor was encapsulated and partially adherent to the tendon of the extensor digitorum muscle. Histological examination revealed a membranous structure consisting of fibrous tissue containing many inflammatory cells. This was considered to be a side effect of gabexate mesilate. [ABSTRACT FROM AUTHOR]

This randomized, double-blind, placebo-controlled study was conducted to examine the preventive effect of nafamostat mesilate, a kallikrein inhibitor, on the withdrawal response associated with rocuronium injection. Ninety American Society of Anesthesiology (ASA) physical status I or II patients, aged 18–65 years, were randomly divided into two groups that received either a 1.5-ml solution containing 1.5 mg nafamostat mesilate diluted in a 5% glucose solution or a 1.5-ml 5% glucose solution. Anesthesia was induced by 5 mg/kg 2.5% thiopental. After confirming loss of consciousness, a tourniquet was applied to the mid forearm and tightened to block venous flow. The test solution was then administered, 1 min after which the tourniquet was removed and 0.6 mg/kg rocuronium was administered. Each patient’s response to rocuronium injection was graded on a four-point scale in a double-blind manner. Activated coagulation time and plasma potassium concentration were measured before and 5 and 10 min after nafamostat administration. The incidence of withdrawal response was 68.9% in the control group and 24.4% in the nafamostat group ( P < 0.001). The number of patients showing generalized movement (response 4) with the rocuronium injection was significantly lower in nafamostat group [1 (2.2%)] than the control group [15 (33.3%)], P < 0.001. Five and 10 min after nafamostat administration, measured potassium and activated coagulation time were similar to baseline values. Pretreatment with 1.5 mg nafamostat mesilate decreased withdrawal response associated with rocuronium injection. [ABSTRACT FROM AUTHOR]

The present investigation was carried out to screen compatibility of some diluents with pefloxacin mesilate using differential scanning calorimetry (DSC), isothermal stability studies, along with stability studies in liquid state and to assign relative ranking to diluents. Compatibility was predicted with MCC101, MCC102, DCP anhydrous, Emcompress, while melting endotherm of drug was lost in admixtures of dextrose anhydrous, Pearlitol, Lactopress spray dried, Lactochem fine powder and Lycatab indicating possibility of interaction. Enthalpy changes were used for relative ranking of diluents. [ABSTRACT FROM AUTHOR]

Prof. Setsuro Fujii achieved significant results in the field of drug discovery research in Japan. He developed nine well-known drugs: FT, UFT, S-1 and FTD/TPI are anticancer drugs, while cetraxate hydrochloride, camostat mesilate, nafamostat mesilate, gabexate mesilate and pravastatin sodium are therapeutic drugs for various other diseases. He delivered hope to patients with various diseases across the world to improve their condition. Even now, drug discovery research based on Dr. Fujii's ideas is continuing. [ABSTRACT FROM AUTHOR]

Cerebellar syndrome is one of the most disabling developments in multiple sclerosis (MS). In neurodegenerative disorders, cerebellar syndrome is thought to be related to a neurochemical deficit of 5-hydroxytryptamine (5-HT). Previous studies found that a levorotatory form of 5-hydroxytryptophan, a 5-HT precursor, and ondansetron, a 5-HT 3 receptor antagonist, decreased cerebellar symptoms in Friedreich?s ataxia and MS. We studied the effect of another 5-HT 3 receptor antagonist, dolasetron mesilate, on cerebellar syndrome in MS patients. Thirty-four MS patients were included in a placebo-controlled double-blind crossover study. They received a single dose of intravenous dolasetron mesilate or placebo. A quantitative evaluation of cerebellar syndrome using the nine-hole peg test and an ataxia score comprising static and kinetic parameters were performed before and after each treatment. No statistical difference was observed in the dolasetron mesilate group, compared with the placebo group. There was, however, inter-individual variability in the treatment response. This double-blind study on cerebellar syndrome in MS patients did not confirm the positive effect of dolasetron mesilate suggested by previous studies. [ABSTRACT FROM AUTHOR]

Children with acute pancreatitis have been treated by fasting and parenteral nutritional support, and to date, the efficacy of drugs for acute pancreatitis in children is unclear. Gabexate mesilate is a synthetic serine protease inhibitor used to prevent or treat acute pancreatitis in adult patients. The purpose of this study was to evaluate the clinical efficacy of gabexate for acute pancreatitis in children. Fifty-three children hospitalized with acute pancreatitis between 2004 and 2012 were divided between a gabexate-treated group ( n = 26) and a control group without gabexate infusion ( n = 27). The severity of acute pancreatitis was graded according to Balthazar scoring of computed tomography images. All subjects had a Balthazar score of <4 without pancreatic necrosis or organ failure. The median age of the patients was 11.8 years (range, 18 months-17 years). The durations of hospitalization, abdominal pain, and parenteral nutrition in the gabexate-treated group were significantly shorter than in control subjects ( P = 0.032, P = 0.000, and P = 0.016, respectively). Serum levels of amylase and lipase were significantly lower in gabexate-infused children than in control subjects on day 7 (median amylase, 81 vs. 137 IU/L, P = 0.001; median lipase, 273 vs. 523 IU/L, P = 0.031). Conclusion: The present study showed that gabexate infusion has some clinical benefits for acute pancreatitis in children. The clinical application of gabexate for managing acute pancreatitis in children may be appropriate beyond conventional therapy. [ABSTRACT FROM AUTHOR]

Objective: Nafamostat mesilate, a potent protease inhibitor, is widely used for the treatment of pancreatitis, disseminated intravascular coagulation and as an anticoagulant in haemodialysis. However, hyperkalaemia associated with nafamostat mesilate has been reported. It is thought to be due to decreased urinary potassium excretion, of the drug suppression of aldosterone secretion, and a direct inhibitory action on the apical Na conductance in collecting ducts. We have seen two cases of nafamostat mesilate associated-hyperkalaemia, which indicated that extrarenal potassium imbalance might play a role in inducing hyperkalaemia. Methods: To examine the effect of nafamostat mesilate on potassium transport in erythrocytes in vitro, RbCl uptake was measured in red blood cells from eight healthy volunteers. Results: Nafamostat mesilate and a metabolite, 6-amidino-2-naphthol, at concentrations of 10 and 10M, respectively, significantly, suppressed potassium influx whilst another metabolite, p-guanidinobenzoic acid, had no effect. The inhibitory action of nafamostat mesilate was not affected by various inhibitors. Conclusion: Nafamostat mesilate and its metabolite, 6-amidino-2-naphthol, suppressed potassium influx in erythrocytes by inhibition of a Na-K ATPase dependent pathway, which was not inhibited by amiloride, barium, nor by frusemide (furosemide). [ABSTRACT FROM AUTHOR]

We investigated the effect of gabexate mesilate on the catalytic activity of phospholipase A in homogenized porcine pancreatic tissue. Gabexate mesilate is a potent inhibitor of serine proteases. There is no direct inhibition of phospholipase A catalytic activity in concentrations up to 6 mmol/l. Preincubation of homogenized pancreatic tissue with gabexate mesilate leads to a reduction of phospholipase A activity even in concentrations as low as 6 µmol/l. The activation of purified porcine prophospholipase A added to pancreatic tissue can be completely inhibited. Thus, gabexate mesilate might influence the activation of phospholipase A administered in therapeutic concentrations in inflamed pancreatic tissue. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) lacking of oestrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2 is a highly malignant disease which results in a poor prognosis and rare treatment options. Despite the use of conventional chemotherapy for TNBC tumours, resistance and short duration responses limit the treatment efficacy. Therefore, a need exists to develop a new chemotherapy for TNBC. The aim of this study was to examine the anti-cancer effects of nafamostat mesilate (NM), a previously known serine protease inhibitor and highly safe drug on breast cancer cells. Here, we showed that NM significantly inhibits proliferation, migration, and invasion in MDA-MB231 cells, induces G2/M phase cell-cycle arrest, and inhibits the expression of cyclin-dependent kinase 1 (CDK1). Exposure of MDA-MB231 cells to NM also resulted in decreased transcription factor activities accompanied by the regulated phosphorylation of signalling molecules and a decrease in metalloproteinases, the principal modulators of the extracellular environment during cancer progression. Especially, inhibition of TGFβ-stimulated Smad2 phosphorylation and subsequent metastasis-related gene expression, and downregulation of ERK activity may be pivotal mechanisms underlying inhibitory effects of NM on NM inhibits lung metastasis of breast cancer cells and growth of colonized tumours in mice. Taken together, our data revealed that NM inhibits cell growth and metastasis of TNBC cells and indicated that NM is a multi-targeted drug that could be an adjunct therapy for TNBC treatment. [ABSTRACT FROM AUTHOR]

Previous reports have demonstrated increased tryptase-like proteolytic activity in the crevicular fluid of patients with periodontal disease. In the present study, we have investigated the effect of tryptase inhibition with nafamostat mesilate (NM, 6-amino-2-naphtlyl p-guanidinobenzoate dimethansulfonate) on the development of experimental periodontitis in rats. Eighty (80) male Wistar rats were randomly separated into four groups: Control group, NM group (daily 0.1 mg/kg body weight of NM, i.p.), Ligature group (ligature placed at lower right first molars), and NM+Ligature group. The amount of alveolar bone loss (ABL) around the mesial root surface of the first mandibulary molar, as well as the myeloperoxidase (MPO) activity, and total proteolytic activity [ N-benzoyl- l-arginine- p-nitroanilide (BApNA) substrate] were determined at 7 and 14 days. NM led to significantly ( p < 0.05) decreased ABL in animals subjected to ligature-induced periodontitis. Tryptase inhibition prevented the onset of significant ABL at 7 days of experiment (0.44 ± 0.16 and 0.60 ± 0.22, p > 0.05, NM+Ligature and Control, respectively) and significantly decreased the ABL at 14 days (0.97 ± 0.17 versus 1.82 ± 0.26, p < 0.001, NM+Ligature versus Ligature, respectively). In addition, NM significantly decreased MPO and total proteolytic activity at 14 days ( p < 0.05). These data provided evidence that tryptase inhibition with NM attenuates gingival granulocyte infiltration and ABL in an experimental model of periodontitis in rats. [ABSTRACT FROM AUTHOR]

Abstract  Gabexate mesilate (GM), a synthetic serine protease inhibitor, suppresses nuclear factor-κB (NF-κB) activity in human monocytes or human umbilical vein endothelial cells (HUVECs). In this study we examine whether GM also suppresses NF-κB activation and induces apoptosis in human pancreatic cancer cell lines. The addition of tumor necrosis factor α (TNF-α) did not change the rates of growth of BxPC-3 and MIA PaCa-2. However, in the presence of GM and TNF-α, proliferation decreased in a dose-dependent manner. GM- and TNF-α-treated cells exhibited morphologic changes indicative of apoptosis, including chromatin condensation and nuclear fragmentation. The NF-κB activity of both cell lines was increased by the addition of TNF-α, while TNF-α-induced NF-κB activity was suppressed by prestimulation with GM in a dose-dependent manner. Caspase 3 and 7 activity was significantly increased by TNF-α with GM stimulation. Furthermore, GM also suppressed the invasive potential of both cell lines. These results indicate that GM inhibits TNF-α-induced NF-κB activation and enhances apoptosis in human pancreatic cancer cell lines. [ABSTRACT FROM AUTHOR]

A novel molecularly imprinted polymer solid-phase extraction (MISPE) with flow-injection chemiluminescence (CL) was developed for the determination of pazufloxacin mesilate (PZFX). The molecularly imprinted polymer (MIP) was synthesized by using PZFX as the imprinting molecule. A glass tube packed the particles of the MIP was employed as MISPE micro-column, which was connected into the sampling loop of the eight-way injection valve for on-line selective preconcentration and extraction of PZFX. The eluent of acetonitrile:acetic acid (9:1, v:v) was used as carrier for eluting the adsorbed PZFX to react with the mixture of cerium(IV) and sodium sulfite in the flow cell to produce strong CL. The relative intensity of CL was linear to PZFX concentration in the range from 2.5 × 10−9 to 2.5 × 10−7 g mL−1. The limit of detection was 7 × 10−10 g mL−1 (3 σ) and the relative standard deviation for 5 × 10−8 g mL−1of PZFX solution was 3.7% ( n = 7). This method has been applied to the determination of PZFX in human urine. [ABSTRACT FROM AUTHOR]

High mobility group box 1 (HMGB1) protein has recently been shown to be an important late mediator of acute lung injury and a promising therapeutic target. Nafamostat mesilate (NM) is a broad-range synthetic protease inhibitor with some anti-inflammatory action. The purpose of this study was to evaluate the effect of NM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats. Male Wistar rats were given either saline (LPS group) or NM (NM+LPS group) 30 min before the intravenous injection of a bolus of LPS (5 mg·kg−1). After the administration of LPS, injury to the lung and the expression of HMGB1, tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1) were examined. Histological examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the NM+LPS group compared to the LPS group. Furthermore, the LPS-induced increases in PAI-1 activity and in plasma TNF-α concentrations were also lower in the rats given both NM and LPS than in the rats given LPS alone. The anticoagulatory activity of NM may have inhibited PAI-1, while its anti-inflammatory activity blockaded TNF-α, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. These findings indicate that NM can inhibit the lung injury induced by LPS in rats. NM is an excellent candidate for use in new therapeutic strategies to prevent or minimize lung injury. [ABSTRACT FROM AUTHOR]

Imatinib mesilate (Glivec®, Novartis Pharmaceuticals) is a novel therapy for the treatment of chronic myeloid leukaemia (CML). We evaluated the cost-effectiveness of imatinib (600?mg daily) when used for the treatment of patients in advanced stages of CML (accelerated phase and blast crisis) against conventional therapies of combination chemotherapy (DAT) and palliative care in hospital or at home. A Markov model simulated the transitions of hypothetical patient cohorts and outcomes were modelled for 5 years from the start of treatment. Costs were estimated from the perspective of the UK National Health Service. Over 5 years, a patient in accelerated phase will, on average, accrue an additional 2.09 QALYs with imatinib compared to conventional therapies, while patients in blast crisis will accrue an additional 0.58 quality-adjusted life-years (QALYs) with imatinib compared to conventional therapies. The costs per additional QALY gained from treatment with imatinib compared with conventional therapies were £29?344 (accelerated phase) and £42?239 (blast crisis). The results were particularly sensitive to the price of imatinib, improvements in quality of life, and the duration of haematological responses. We conclude that treatment of CML with imatinib confers considerably greater survival and quality of life than conventional treatments but at a cost.British Journal of Cancer (2003) 89, 634-640. doi:10.1038/sj.bjc.6601151 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Background: Continuous regional arterial infusion (CRAI) of protease inhibitor nafamostat mesilate (NM) is used in the context of predicted severe acute pancreatitis (SAP) to prevent the development of pancreatic necrosis. Although this therapy is well known in Japan, its efficacy and safety remain unclear.Methods: This investigator-initiated and -driven, multicenter, open-label, randomized, controlled trial (UMIN000020868) enrolled 39 patients with predicted SAP and low enhancement of the pancreatic parenchyma on computed tomography (CT). Twenty patients were assigned to the CRAI group, while 19 served as controls and were administered NM at the same dose intravenously (IV group). The primary endpoint was the development of pancreatic necrosis as determined by CT on Day 14, judged by blinded central review.Results: There was no difference between the CRAI and IV groups regarding the percentages of participants who developed pancreatic necrosis (more than 1/3 of the pancreas: 25.0%, range 8.7-49.1% vs. 15.8%, range 3.4-39.6%, respectively, P = 0.694; more than 2/3 of the pancreas: 20%, range 5.7-43.7% vs. 5.3%, range 0.1-26.0%, respectively, P = 0.341). The early analgesic effect was evaluated based on 24-h cumulative fentanyl consumption and additional administration by intravenous patient-controlled analgesia. The results showed that the CRAI group used significantly less analgesic. There were two adverse events related to CRAI, namely bleeding and splenic infarction.Conclusions: CRAI with NM did not inhibit the development of pancreatic necrosis although early analgesic effect of CRAI was superior to that of IV. Less-invasive IV therapy can be considered a viable alternative to CRAI therapy. [ABSTRACT FROM AUTHOR]

The effects of the anti-inflammatory serine esterase inhibitor, gabexate mesilate (Foy) were studied, on locomotion, autoaggregation and adhesion of polymorphonuclear leukocytes stimulated with the complement peptide C5a-desArg. The drug inhibited aggregation as well as spontaneous and directed migration of human leukocytes at concentrations of about 10 M. Adhesion of peritpneal guinea-pig leukocytes to autologous aortic strips was reduced at about 20 times lower drug concentrations. The inhibitory drug effects were highly time- and temperature-dependent. Experiments with the two major drug metabolites, pHB and εGC, indicate that gabexate mesilate is not active by itself but rather by its hydrolytic aromatic metabolite pHB. The results further suggest that the inhibitory effects on leukocyte activities observed are not related to the anti-inflammatory effects of gabexate mesilate. [ABSTRACT FROM AUTHOR]

Gabexate mesilate (FOY, ethyl- p-(6-guanidino-hexanoyl-oxy)-benzoate-methansulfonate), camostate ( N,N-dimethyl-carb-amoylmethyl-4-(guanidinobenzoyloxy)-phenyl-acetate) methansulfonate and aprotinine (Trasylol) were tested for possible inhibition of phospholipase A. Gabexate mesilate at a concentration of 5×10 mol/l and camostate at a concentration of 10 mol/l caused a 50% reduction in enzyme activity. There was almost no inhibition by aprotinine at clinical doses; 40 million KIU/l were necessary to reduce phospholipase A activity by 20%. From the therapeutic dose (4,000 mg/day per i.v. infusion) and the half-life of gabexate mesilate in blood circulation (1 min) it can be calculated that the in vitro concentration of gabexate mesilate is only 10 to 10 mol/l. Under these conditions gabexate mesilate cannot diminish the in vivo enzyme activity of phospholipase A. [ABSTRACT FROM AUTHOR]

A liquid chromatographic method for analysis of pazufloxacin mesilate in human plasma and urine has been developed and validated for selectivity, sensitivity, accuracy, precision, and stability in pharmacokinetic analysis. The sensitivity of the method was 0.02 μg mL−1 in plasma and 0.5 μg mL−1 in urine, with overall intra-day and inter-day precision (RSD < 10%) and accuracy (90–120%) acceptable for clinical pharmacokinetic analysis. Recovery from plasma and urine was 80–110% for both pazufloxacin mesilate and enoxacin, the internal standard. Pazufloxacin was stable in both plasma and urine, with no significant degradation under four different conditions. The method was successfully used in a preliminary study of the bioavailability of pazufloxacin mesilate in healthy human volunteers after intravenous administration of 300 and 500 mg. [ABSTRACT FROM AUTHOR]

Background: Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities.Methods: In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1-14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics.Results: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy.Conclusions: The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC. [ABSTRACT FROM AUTHOR]

This post hoc subgroup analysis of a large phase 3 study compared the efficacy and safety of eribulin versus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who received second-line treatment. In the phase 3 study, women with advanced/metastatic breast cancer and ≤ 3 prior chemotherapies were randomized 1:1 to eribulin mesilate 1.4 mg/m2 intravenously on days 1 and 8, or twice-daily oral capecitabine 1.25 g/m2 on days 1-14 (21-day cycles). This analysis included 392 patients. Median overall survival was longer in patients receiving eribulin compared with capecitabine (16.1 vs 13.5 months, respectively; HR 0.77, P = 0.026). Median progression-free survival and response rates were similar between arms. Both treatments had manageable safety profiles. [ABSTRACT FROM AUTHOR]

We previously experienced severe clot formation in a polyester-polymer alloy (PEPA) dialyzer and hemodialysis (HD) circuit with nafamostat mesilate (NM) as an anticoagulant. The possibility of NM adsorption to the PEPA membrane was taken into consideration, but there was not enough information. In the present study, we evaluated differences in the adsorption of NM between a PEPA membrane (FDX-120 GW, Nikkiso, Tokyo, Japan) and two different polysulfone membranes (FX-140, Fresenius Medical Care, Tokyo, Japan; NV-15U, Toray Medical, Tokyo, Japan). We calculated the NM concentration by measuring absorbance at 241 nm using a spectrometer. NM adsorption was evaluated in three ways. First, we evaluated NM adsorption to hollow fibers. Then, we passed an NM solution through dialyzers and evaluated its adsorption in a single-pass examination. Finally, we circulated an NM solution in an HD circuit using a blood pump and evaluated NM adsorption. In all the experiments, NM adsorption to the PEPA membrane was greater than that to the polysulfone membranes examined. In the blood pump experiment, the estimated adsorption quantities of NM to the PEPA membrane and the FX-140 and NV-15U polysulfone membranes were 12.0 ± 0.1, 1.0 ± 0.1, and 4.1 ± 0.4 mg/m, respectively. NM adsorption was confirmed, especially in the early phase, and the PEPA membrane adsorbed greater amounts of NM than the polysulfone membranes. We should pay attention to the choice of dialyzer as well as the appropriate dose of NM administration during the preparation of HD circuits. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to evaluate the efficacy and safety of oral dolasetron mesilate in the prevention of nausea and vomiting that might otherwise be induced by total-body irradiation (TBI) and high-dose cyclophosphamide. In an open non-comparative study 20 patients who received TBI for 3 days and high-dose cyclophosphamide chemotherapy for 2 days as part of their preparation for bone marrow transplantation were given oral dolasetron mesilate at dosages ranging from 50 to 200 mg 1 h before each fraction of radiotherapy and cyclophosphamide administration. Initial rescue therapy consisted of intravenous dolasetron mesilate. If nausea and vomiting remained uncontrolled, standard antiemetics were to be used. Of the 20 patients, 13 had only two emetic episodes or fewer in the 3-day TBI period. On days 1 and 2 of cyclophosphamide administration, 11 and 6 patients had fewer than two emetic episodes. From day 1 to day 3, 15 patients experienced no nausea or only mild nausea, and on the days of chemotherapy 8 and 7 patients had mild nausea or none at all. Rescue with i.v. dolasetron mesilate was needed by 3 and 6 patients during the TBI and the chemotherapy periods respectively. In 2 patients additional antiemetics were used on days 2–3 and 4–5. Mild to moderate headache was reported in 6 patients. No unexpected abnormalities were observed in haematology, biochemistry or urinalysis, and vital signs were unaffected throughout the study period. The data suggest that oral dolasetron mesilate is effective and safe for the prevention of nausea and vomiting during TBI and cyclophosphamide chemotherapy prior to bone marrow transplantation. Future controlled studies should evaluate combination antiemetic therapy with dolasetron mesilate for this indication. [ABSTRACT FROM AUTHOR]

Disability including deficiency in sensorimotor and cognition functions is a dominant consequence after stroke. Evidence suggests that serine proteases play an important role in the physiology and pathology of the brain. Previous studies reported that nafamostat mesilate (NM), a synthetic serine protease inhibitor, attenuates neuronal damage in the acute phase after stroke. However, its efficacy in the chronic phase and the mechanism underlying its beneficial effect are not fully known. Here, we have studied whether NM improves long-term functional recovery after ischemic stroke. Experimental ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO). NM treatment attenuated the brain infarct volume and the loss of body weight and improved the recovery of sensorimotor and cognitive functions. One month after tMCAO, neuronal axons and dendrites were preserved in the NM group, accompanied by increasedsynaptic proteins and structures in the ipsilateral hippocampus. The expression of brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3 was increased in the contralateral sensorimotor cortex and ipsilateral hippocampus by the administration of NM. Furthermore, NM activated tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinas1/2(ERK1/2) and cAMP-response element binding protein (CREB) and inhibited the activity of Cyclin-dependent Kinase 5 (Cdk5) in the contralateral sensorimotor cortex and ipsilateral hippocampus. These results demonstrated that NM treatment could improve neurological outcome and axonal regeneration, which might be correlated with down-regulating Cdk5 activity and up-regulating TrkB-ERK1/2-CREB pathway. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the effects of a synthetic serine protease inhibitor, gabexate mesilate (GM), in rats with ischemia-reperfusion (I-R) damage due to unilateral testicular torsion. Thirty male Sprague-Dawley rats were separated into three groups, each containing ten rats. A sham operation was performed in group 1 (control). In group 2 (I-R/untreated), 1 h detorsion of the testis was performed after 6 h of unilateral testicular torsion. In group 3 (I-R/GM), after performing the same surgical procedures as in group II, gabexate mesilate was given intravenously. In all experimental rats, ipsilateral orchiectomies were performed for histological examination and measuring the tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). MDA values and the testicular injury score decreased and SOD, CAT and GSH-Px values increased in the GM-treated group compared to the I-R/untreated group. The Tc-99m pertechnetate uptake ratio and the perfusion index were significantly decreased in the group 2 compared to the group 1 and 3 rats. In group 3, these values were significantly increased compared to group 2. Most of the specimens in the GM-treated group showed grade-I testicular injury. However, the injuries in the I-R/untreated rats varied between grade-III and grade-IV. The results of this study show that GM may play a role in reducing the injury caused by I-R. [ABSTRACT FROM AUTHOR]

Background: Gabexate mesilate, a synthetic protease inhibitor, is used to treat acute pancreatitis and disseminated intravascular coagulation because it inhibits various serine proteases; however, whether gabexate mesilate prevents acute liver failure has not yet been studied. The aim of the present study was to investigate the effect of gabexate mesilate in carbon tetrachloride (CCl4)-induced liver injury in rats. Methods: Acute hepatic failure was induced by administration of CCl4 intragastrically to male Sprague-Dawley rats. The effects of gabexate mesilate were examined in terms of serum transaminase levels, liver histology, and the prognosis of rats. Results: Gabexate mesilate treatment significantly decreased the elevation of serum transaminase levels and improved liver histology 24 h after the administration of CCl4 (0.2 ml/100 g rat weight). Plasma tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) decreased significantly in the gabexate mesilate-treated rats compared with saline-treated rats. Gabexate mesilate treatment also significantly improved survival rate after a lethal dose of CCl4 (0.5 ml/100 g rat weight) from 0% to 20%. Conclusions: Gabexate mesilate treatment attenuated CCl4-induced liver injury via a suppression of proinflammatory cytokine production. In addition, these investigations suggest that gabexate mesilate treatment may provide therapeutic strategies for human acute liver failure. [ABSTRACT FROM AUTHOR]

Background: Andexanet alfa, an anti-Xa inhibitor antagonist, induces heparin resistance. Here, we report a case of successful management of cardiopulmonary bypass with andexanet alfa-induced heparin resistance using nafamostat mesylate. Case presentation: An 84-year-old female, with Stanford type A acute aortic dissection, underwent an emergency surgery for total aortic arch replacement. Andexanet alfa 400 mg was administered preoperatively to antagonize edoxaban, an oral Xa inhibitor. Heparin 300 IU/kg was administered before cardiopulmonary bypass, and the activated clotting time (ACT) was 291 s. The ACT was 361 s after another administration of heparin 200 IU/kg. According to our routine therapy for heparin resistance, an initial dose of nafamostat mesylate 10 mg was administered intravenously, followed by a continuous infusion of 20–30 mg/h. The ACT was prolonged to 500 s, and cardiopulmonary bypass was successfully established thereafter. Conclusions: This case report presents the successful management of cardiopulmonary bypass with andexanet alfa-induced heparin resistance using nafamostat mesilate. This report presents the successful management of cardiopulmonary bypass with andexanet alfa-induced heparin resistance using nafamostat mesilate. [ABSTRACT FROM AUTHOR]

The potent serotonin receptor (5-HT3) antagonists are new highly selective agents for the prevention and control of chemotherapy-induced nausea and vomiting that have been shown to be comparable to or more effective than traditional metoclopramide regimens. This study was designed to compare the antiemetic efficacy of dolasetron and metoclopramide in chemotherapy-naive and non-naive cancer patients receiving high-dose cisplatin-containing chemotherapy. This multicentre, double-blind, randomized trial compared the efficacy and safety of single i.v. doses of dolasetron mesilate salt (1.2 or 1.8 mg/kg) and metoclopramide (7 mg/kg) in 226 patients for the prevention of acute emesis and nausea associated with the administration of high-dose (≥80 mg/m2) cisplatin. Efficacy and safety were evaluated for 24 h. Complete responses were achieved by 57%, 48%, and 35% of patients given dolasetron mesilate 1.8 mg/kg ( P=0.0009 vs metoclopramide), dolasetron mesilate 1.2 mg/kg ( P=0.0058 vs metoclopramide), and metoclopramide, respectively. Overall, dolasetron was significantly more effective than metoclopramide for time to first emetic episode, nausea, patient satisfaction, and investigator global assessment of efficacy. Males, chemotherapy-naive patients, and alcoholics had higher response rates. Dolasetron was well tolerated, with mild-to-moderate headache most commonly reported. Twelve percent of patients receiving metoclopramide reported extrapyramidal symptoms compared with 0% of patients receiving dolasetron. In conclusion, dolasetron mesilate was effective for the prevention of CINV with high-dose cisplatin. Single i.v. doses of dolasetron mesilate were more effective than 7 mg/kg metoclopramide in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, 1.8 mg/kg dolasetron mesilate consistently produced the highest response rates and appears to be the most effective dose for further clinical development. [ABSTRACT FROM AUTHOR]

Introduction: Seglor capsules, a unique modified-release formulation of dihydroergotamine mesilate, have long been in clinical use in France for migraine prophylaxis. The aim of the PROMISE (PROphylaxis of MIgraine with SEglor) study was to establish the efficacy and tolerability of Seglor in the prevention of migraine in a general practice setting.Methods: The PROMISE study was a double blind, placebo-controlled, parallel-group study carried out in primary care practice. It included 363 migraine patients treated with Seglor or placebo for 5 months after a 1-month placebo run-in phase.Results: Migraine attack frequency (primary efficacy criterion) decreased markedly in the two treatment groups so that the difference in favour of Seglor did not reach statistical significance. However, most secondary outcome measures (duration of single attack, total duration of attacks over 1 month, consumption of mild opiate analgesics, subjective improvement) improved to a significantly greater degree in patients receiving Seglor than in those receiving placebo. In the 84.5% of patients who had impaired quality of life at entry, the percentage of reduction in attack frequency and most other efficacy measures showed significant improvement with Seglor. The safety profile for Seglor was comparable to that of placebo.Conclusion: These results support the effectiveness of Seglor in patients with migraine-related quality-of-life impairment. The findings of the PROMISE study also suggest that patients' quality of life should be assessed systematically before initiating a preventive treatment for migraine. [ABSTRACT FROM AUTHOR]

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Abstract The precise inhibitory action of gabexate mesilate (GM) on the various pancreatic enzymes remains unclear. We designed this study to investigate the enzyme inhibitory action of GM in the serum and directly in the pancreatic juice. We observed 16 cases with postoperative pancreatic drainage. Patients were randomly assigned to one of two groups, to receive GM at a dose of 600 mg/24 hr (treated group: 8 patients) or a physiological solution (control group: 8 patients) by continuous intravenous infusion. In both groups pancreatic juice and serum were sampled three times: before infusion began (T0) and at 12 hr (T1) and 24 hr after infusion ended (T2). At the end of the study, seven patients received octreotide and the volume of pancreatic secretion was determined. No statistical difference was observed in serum amylase and phospholipase A2 activity in the treated and control groups. On the contrary, amylase and phospholipase A2 activity in the pancreatic juice diminished significantly only in the treated group, and in these patients a GM metabolite was also detectable in the pancreatic secretion. The volume of pancreatic secretion decreased only after infusion of octreotide. The enzyme inhibition in the pancreatic gland itself and the central role of inhibition of phospholipase A2 in the enzyme cascade responsible for activating other proteases, confirm the therapeutic use of GM in acute pancreatitis. An association of GM and octreotide during acute pancreatitis should be useful because of their different mechanisms. [ABSTRACT FROM AUTHOR]

The authors report the results of a randomized, double-blind multicenter clinical trial on the use of gabexate mesilate vs aprotinin in the therapy of acute pancreatitis. The size of the study sample and the end points chosen for evaluation of the early systemic complications of the pancreatitis-carefully selected targets for reliable assessment of the efficacy of any protease inhibitor-lead to the conclusion that gabexate mesilate is more efficacious than aprotinin in reducing the early complications of necrotizing acute pancreatitis, if administered within 72 h of onset of symptoms. Its good tolerability means that it can be used safely even at the dose of 3 g/24 h. [ABSTRACT FROM AUTHOR]

A novel capacitive sensor for pazufloxacin mesilate (pazufloxacin) determination was developed by electropolymerizing p-aminobenzene sulfonic ( p-ABSA) and molecularly imprinted polymers (MPs), which was synthesized through thermal radical copolymerization of metharylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) in the presence of pazufloxacin template molecules, on the gold electrode surface. Furthermore, 1-dedecanethiol was used to insulate the modified electrode. Alternating current (ac) impedance experiments were carried out with a Model IM6e to obtain the capacitance responses. Under the optimum conditions, the sensor showed linear capacitance response to pazufloxacin in the range of 5 ng·mL−1 to 5 μg·mL−1 with a relative standard deviation (RSD) 5.3% ( n=7) and a detection limit of 1.8 ng·mL−1. The recoveries for different concentration levels of pazufloxacin samples varied from 94.0% to 102.0%. Electrochemical experiments indicated the capacitive sensor exhibited good sensitivity and selectivity and showed excellent parameters of regeneration and stability. [ABSTRACT FROM AUTHOR]

We report here a case of culture-proven Legionnaires’ disease successfully treated with intravenous injection of pazufloxacin mesilate (PZFX), a fluoroquinolone newly approved in Japan. The patient was a 51-year-old man hospitalized after a diagnosis of community-acquired pneumonia. Legionella pneumophila SG1 was isolated from the patient’s bronchoalveolar lavage (BAL) fluid, and the soluble antigen of the bacterium was detected in the fluid as well. Subsequently, intravenous PZFX was administered for a week and proved markedly effective. An in vitro study confirmed that PZFX had excellent extracellular and intracellular activity against the isolate from the patient. This case suggests that PZFX is an option for treating Legionnaires’ disease. [ABSTRACT FROM AUTHOR]

Gabexate mesilate is an antiprotease drug, which reduced the severity of pancreatitis and frequency of post-ERCP pancreatitis. In dogs gabexate inhibits sphincter of Oddi motility but no data are available in humans. The aim of this study was to verify by manometry the action of gabexate on human sphincter of Oddi motility. We enrolled 12 patients with idiopathic recurrent pancreatitis (eight males, five females, mean age 46 ± 8 years). Standard preendoscopic sphincter of Oddi manometry was done in basal conditions and during infusion of gabexate 20 mg/min: basal pressure, amplitude and frequency of phasic contractions, and motility index (amplitude per frequency) were calculated before and after gabexate injection. Statistical analysis was performed by using Wilcoxon rank test for paired data. Six patients had a manometric diagnosis of stenosis (basal pressure greater than 40 mm Hg); six had normal findings. Phasic activity was not evaluable in five patients with stenosis. Basal pressure was unaffected by drug infusion, while gabexate caused a significant reduction of phasic activity, both in terms of frequency (4.5 ± 1 vs 3.6 ± 1; P < 0.05) and amplitude (157.4 ± 44 vs 80.0 ± 32; P < 0.05) of contractions. Motility index was reduced on average by 49%. In conclusion, this pilot study confirms, in patients with acute recurrent pancreatitis, the inhibitory action of gabexate on sphincter of Oddi motility already described in dogs. This action needs to be revaluated at therapeutic dosages. On the other hand, prophylactic use of the drug should be avoided during sphincter of Oddi manometry, in order to avoid false negative results. [ABSTRACT FROM AUTHOR]