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The purpose of the present study was to establish a continuous hemofiltration model using porcine blood to compare filter life. Continuous hemofiltration (CHF) experiments were performed using an in vitro hemofilter evaluation system utilizing porcine blood containing trisodium citrate in addition to nafamostat mesilate as anticoagulants. The lifetime of the hemofilter was evaluated using the transmembrane pressure and the pressure drop across the hemofilter at varying trisodium citrate concentrations. The porcine blood used in this experiment was considered to be in a slightly hypercoagulable state because of the continuous contact with non-biological materials and calcium inflow from substitution fluid. Blood containing 7 or 8 mM of trisodium citrate and nafamostat mesilate could be effectively used to compare the lifetimes of hemofilters utilized under the same conditions. In this CHF model using porcine blood, the plugging of the hollow fibers occurred shortly after the plugging of the membrane pores. In conclusion, a CHF model using porcine blood can be established by adjusting the concentration of trisodium citrate added to the blood.

Background: Renal fibrosis is characterized by excessive production and deposition of extracellular matrix (ECM), which leads to progressive renal failure. Adenosine-monophosphate-activated protein kinase (AMPK) is a highly conserved kinase that plays a key role in Smad-3 signaling. Here, we examined the effect of a novel AMPK activator, HL156A, on the inhibition of renal fibrosis in in vivo and in vitro models., Methods: Unilateral ureteral obstruction (UUO) was induced in male Wistar rats. Rats with UUO were administered HL156A (20mg/kg/day), and then the kidneys were harvested 10 days after ligation for further analysis., Results: In the rat UUO model, HL156A attenuated ECM protein deposition. After HL156A treatment, expressions of TGF-β1, p-Smad3, α-SMA, fibronectin, and type IV collagen were suppressed, and E-cadherin expression was up-regulated. In the in vitro experiment, NRK52E cells were treated with HL156A before TGF-β1 stimulation. The inhibitory effects of HL156A upon the signaling pathways and markers of the epithelial-to-mesenchymal transition (EMT) were analyzed. In TGF-β1-treated NRK-52E cells, HL156A co-treatment inhibited the TGF-β1-induced Smad3 signaling pathway and EMT markers., Conclusion: Taken together, the above findings suggest that HL156A, a novel AMPK activator, ameliorates renal fibrosis in vivo and in vitro., Competing Interests: This research was funded by Hanall Biophama Co., Korea. No participating authors are employees, or consultants of the company. Besides, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

The aim of this study was to evaluate the efficacy of an insecticidal product in rabbits that combines the neonicotinoid dinotefuran with the pyrethroid permethrin plus the insect growth regulator pyriproxyfen. Adult New Zealand rabbits (n = 12) were infested with Ctenocephalides felis felis (50 males and 50 females per rabbit) at days -7, -2, +5, +12 and +19. The control group (n = 6) received no treatment and the treated group (n = 6) received the commercial formulation, indicated for use in dogs, which was applied topically on day 0. The animals were mechanically evaluated with combs (comb test), to assess pulicidal efficacy, on days -5, +2, +7, +14 and +21. All flea removals and counts were performed by region, following the order: head, ears, neck, forelegs, dorsum, abdomen, hind limbs and tail, in order to determine the preferred sites of parasitism by the C. felis felis flea in rabbits. The distribution of fleas prevailed in the head region (about 62%), followed by the neck and back (14 and 11%, respectively). The insecticidal efficacy was calculated using arithmetic means, showing effectiveness of 100% on days +2 and +7 and 82.2% and 81.6%, on days +14 and +21, respectively. Thus the present study has shown the combination to be a viable option in the treatment and control of rabbits infested by C. felis felis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Clostridium difficile infection (CDI) symptoms range from diarrhea to severe toxic megacolon and even death. Due to its rapid acquisition of resistance, C. difficile is listed as an urgent antibiotic-resistant threat, and has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common hospital-acquired infection in the USA. To combat this pathogen, a new structural class of pseudo-peptides that exhibit antimicrobial activities could play an important role. Herein we report a set of bis-cyclic guanidine compounds that show potent antibacterial activity against C. difficile with decent selectivity. Eight compounds showed high in vitro potency against C. difficile UK6 with MIC values of 1.0 μg mL -1 , and cytotoxic selectivity index (SI) values up to 37. Moreover, the most selective compound is also effective in the treatment of C. difficile-induced disease in a mouse model of CDI, and appears to be a very promising new candidate for the treatment of CDI., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The safety and clinical effectiveness data of peramivir in the real clinical field are limited. A prospective observational study was conducted based on the post-marketing surveillance data to evaluate the post-marketing safety and effectiveness of peramivir in Korean adults with seasonal influenza., Methods: Among adults aged 20 years or older who were diagnosed with influenza A or B, patients who started peramivir within 48 hours from the initial symptoms of influenza were enrolled. All adverse events (AEs) that occurred within 7 days after administration of peramivir were checked. For the evaluation of effectiveness, changes in the severity of influenza symptoms and daily living performance were examined before and 7 days after the administration of peramivir. The date on which influenza related symptoms disappeared was checked., Results: A total of 3,024 patients were enrolled for safety evaluation and 2,939 patients were for effectiveness evaluation. In the safety evaluation, 42 AEs were observed in 35 (1.16%) patients. The most common AE was fever. AEs were mostly rated as mild in severity. Serious AEs were observed in 10 patients and two of them died. However, both deaths were considered to be less relevant to peramivir. In the effectiveness evaluation, the severity of influenza symptoms decreased by 10.68 ± 4.01 points and daily living performance was improved 5.59 ± 2.16 points. Influenza related symptoms disappeared on average 3.02 ± 2.39 days after peramivir administration., Conclusion: Peramivir showed a tolerable safety profile and acceptable effectiveness in Korean adult patients with seasonal influenza., Competing Interests: Disclosure: The sponsor participated in the post-marketing study design, execution, and the data collections. Although the sponsor reviewed the draft, the opinions expressed by the sponsor may not necessarily be reflected. The results of this study were presented as a poster at the 5th ISIRV-AVG conference.

We herein report a case of a 31-year-old Japanese man who simultaneously had a positive influenza A virus antigen test result and Vogt-Koyanagi-Harada disease (VKHD), demonstrated by both diffuse multiple early hyperfluorescent points on fluorescein fundus photography and serous retinal detachments on optical coherence tomography. He had meningitis. It was difficult to determine whether the main cause of meningitis was influenza A or VKHD. After initial treatment with peramivir for influenza A and then methylprednisolone pulse with subsequent corticosteroid therapy for VKHD, his symptoms improved gradually. These findings suggest that influenza A virus infection contributes to the onset or exacerbation of VKHD.

Purpose: Therapeutic options for patients with malignant pheochromocytoma are currently limited, and therefore new treatment approaches are being sought. Targeted radionuclide therapy provides tumor-specific systemic treatments. The β-emitting radiopharmaceutical meta- 131 I-iodo-benzylguanidine ( 131 I-MIBG) provides limited survival benefits and has adverse effects. A new generation of radionuclides for therapy using α-particles including meta- 211 At-astato-benzylguanidine ( 211 At-MABG) are expected to have strong therapeutic effects with minimal side effects. However, this possibility has not been evaluated in an animal model of pheochromocytoma. We aimed to evaluate the therapeutic effects of the α-emitter 211 At-MABG in a pheochromocytoma model., Methods: We evaluated tumor volume-reducing effects of 211 At-MABG using rat pheochromocytoma cell line PC12 tumor-bearing mice. PC12 tumor-bearing mice received intravenous injections of 211 At-MABG (0.28, 0.56, 1.11, 1.85, 3.70 and 5.55 MBq; five mice per group). Tumor volumes were evaluated for 8 weeks after 211 At-MABG administration. The control group of ten mice received phosphate-buffered saline., Results: The 211 At-MABG-treated mice showed significantly lower relative tumor growth during the first 38 days than the control mice. The relative tumor volumes on day 21 were 509.2% ± 169.1% in the control mice and 9.6% ± 5.5% in the mice receiving 0.56 MBq (p < 0.01). In addition, the mice treated with 0.28, 0.56 and 1.11 MBq of 211 At-MABG showed only a temporary weight reduction, with recovery in weight by day 10., Conclusion: 211 At-MABG exhibited a strong tumor volume-reducing effect in a mouse model of pheochromocytoma without weight reduction. Therefore, 211 At-MABG might be an effective therapeutic agent for the treatment of malignant pheochromocytoma.

Background: Neuraminidase inhibitors are recommended for children hospitalized with influenza-related respiratory infections, and oseltamivir is the first choice of treatment in most situations. However, little is known regarding the recent trend in using neuraminidase inhibitors and their difference in health economy. The aim of this study was to reveal recent trends in neuraminidase inhibitor use and compare hospitalization costs across different treatment regimens., Methods: We retrospectively obtained the hospital discharge records of inpatients under 18 years of age with a diagnosis of influenza-related respiratory infections using a national inpatient database in Japan. We excluded patients with chronic medical conditions from the analyses. Multivariable mixed effects regression models were used to investigate the recent treatment trends and healthcare costs., Results: We identified 27 771 inpatients with influenza-related respiratory infections. The proportions of neuraminidase inhibitor use increased from 62.6% in 2010 to 71.8% in2014 (P trend  < 0.001). Correspondingly, the proportions of peramivir use showed an upward trend, ranging from 31.4% to 57.4% (P trend  < 0.001). In contrast, proportions of oseltamivir and zanamivir use decreased from 26.1% to 12.1% and from 4.9% to 1.5%, respectively (P trend  < 0.001). Laninamivir use did not change over the period. Total hospitalization costs were higher in the peramivir group than in the oseltamivir group (adjusted difference, $84.3; 95%CI, $70.7-$98.4)., Conclusions: We observed an increasing trend in peramivir use and decreasing trends in use of oseltamivir and zanamivir. Treatment with peramivir required higher hospitalization costs., (© 2018 Wiley Periodicals, Inc.)

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012)., (Copyright © 2018. Published by Elsevier Ltd.)

The efficacy of anthelmintic treatment at 1, 3, and 6 month intervals was evaluated in a prospective controlled field study with naturally exposed Lithuanian village dogs by monthly coproscopy during 1 year. A placebo-treated control group (C) (n = 202) and groups treated with two broad-spectrum anthelmintics, febantel/pyrantel-embonate/praziquantel (Drontal® Plus, Bayer) (D1, D3, D6; n = 113-117) and emodepside/praziquantel (Profender®, Bayer) (P1, P3, P6; n = 114-119), were included. At the beginning of the study, eggs of Toxocara canis (4.02%) and T. cati (0.44%) identified morphometrically and/or molecularly and eggs of taeniid- (0.78%) and Capillaria-like eggs (5.03%) were present in the feces without significant differences in prevalence between groups. Significant decreases in excretion of T. canis eggs was found 1 month after the treatment with Drontal® Plus in February (D1) and with Profender® in October (P1), November (P1), December (P3), February (P1), and March (P1, P3), as compared to controls in the same months. The incidence of egg excretion per dog at least once a year was significantly lower in group P1 for T. canis (4.24%; p < 0.01) and in groups D1, P1 for taeniid eggs (0%; p < 0.01 and p < 0.001), when compared to controls (16.96 and 6.70%, respectively). A critical analyses of factors possibly responsible for intestinal passage of canine helminth eggs revealed that chained dogs excreted T. canis eggs more frequently 1 month after treatment compared to dogs in pens, particularly from November to March (p = 0.01). The incidence of single detection of T. cati eggs was significantly increased in chained dogs (12.46%) as compared to fenced dogs (1.08%; p = 0.0001).

Aim: The present study was designed to investigate the effect of mercurius solubilis (merc sol) on scopolamine induced memory deficits and motor coordination in mice., Materials and Methods: Three different formulations of merc sol (30X, 200M, 1M) were screened for their in vitro antioxidant potential through DPPH (2, 2-diphenyl-1-picrylhydrazyl) and nitric oxide scavenging activity using response surface methodology. Memory impairment was induced by the administration of scopolamine (1mg/kg i.p.) for 3 days to mice and assessment of memory acquisition and retention was done using Morris water maze test, passive avoidance test, elevated plus maze test, light and dark box test, motor coordination was evaluated using rotarod test and inclined plan test. The involvement of ion channels and nitric oxide pathway in the observed effect of merc sol was elucidated by administration of veratrine (0.125 μg/kg, i.p.), A23187 (20 μg/kg, i.p.), L- arginine (40 mg/kg, i.p.), aminoguanidine (50 mg/kg, i.p.) 30 min prior to merc sol. Acute toxicity studies were performed in accordance with the OECD (Organisation for Economic Co-operation and Development) guidelines., Results: In vitro studies have revealed merc sol 30 X to have maximum free radical and nitric oxide scavenging activity. Administration of merc sol 30 X to mice significantly reduced scopolamine induced memory deficits and motor incoordination in all the performance tasks. The calcium ionophore, A23187 significantly altered the effect of merc sol in mice. No major signs of toxicity were observed., Conclusion: Merc sol has antiamnesic effect in scopolamine induced deficits and motor coordination in mice.

Objective: To evaluate nafamostat mesilate (NM) as an alternative anticoagulant agent for intermittent hemodialysis (IHD)., Design: Prospective randomized study., Setting: University teaching hospital., Animals: Eighteen healthy Beagle dogs., Interventions: In group 1 (n = 6), NM was administered at a dose of 0.5 mg/kg/h during IHD for 5 hours. In group 2 (n = 6), NM was administered at a low dose of 0.25 mg/kg/h during IHD. In group 3 (n = 6), which was the control group, unfractionated heparin (UFH) was administered during IHD. The evaluated parameters included: the amount of residual blood clots in the blood chamber and arterial side of the dialyzer; the levels of hemoglobin, hematocrit, and platelets; and the prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT)., Measurements and Main Results: Groups 1 and 2 successfully completed IHD without serious coagulation in the extracorporeal circulation. The residual blood clotting in the blood chamber and arterial side of the dialyzer did not significantly differ in groups 1 and 2 compared to group 3 (group 1 vs group 3, P = 1.000; and group 2 vs group 3, P = 1.000). No significant differences were observed between pre- and posttreatment PTs in groups 1 (P = 0.476) and 2 (P = 0.597), between pre- and posttreatment aPTTs in groups 1 (P = 0.983) and 2 (P = 0.977), and between pre- and posttreatment ACT in groups 1 (P = 0.282) and 2 (P = 0.401). In group 3, a significant elevation of ACT was observed at the posttest (P < 0.001)., Conclusions: The results of this study in healthy Beagle dogs suggest that NM at 0.25 mg/kg/h may be a valid alternative to UFH for IHD. Further studies are needed in patients at high risk of bleeding., (© Veterinary Emergency and Critical Care Society 2018.)

Background: Neuraminidase inhibitors (NAIs) reduce influenza symptoms but clear evidence of relationships between viral titer reduction and symptom alleviation is lacking. This open-label, randomized study evaluated differences in viral dynamics between NAIs, and relationships between viral dynamics and influenza symptoms (trial registration number: UMIN000012670)., Methods: Patients (n = 123) aged 4-12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir. Patients received regular viral assessments of nasal discharge, at least until rapid antigen tests were negative. Time to virus clearance, based on influenza virus titer, was the primary endpoint., Results: Peramivir recipients had a significantly shorter time to virus clearance than oseltamivir recipients (adjusted p = 0.035). Comparisons between the peramivir group and other NAI groups were not significant. There were no significant inter-group differences in other clinical efficacy endpoints (time to resolution of fever, time to alleviation of symptoms). However, the peramivir group showed a smaller numerical proportion of relapses with fever or positive virus than the other groups., Conclusions: The time to virus clearance was significantly shorter with peramivir than with oseltamivir. Although no clear relationship between virus dynamics and symptoms was observed, ongoing studies should clarify the situation.

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.

Background: A series of novel sulphonylureas/guanidine derivatives was designed, synthesized, and evaluated for the treatment of diabetes mellitus. In this study, the designed compounds were docked with AKR1C1 complexes by using glide docking program and docking calculations were performed to predict the binding affinity of the designed compounds with the binding pocket of protein 4YVP and QikProp program was used to predict the ADME/T properties of the analogues., Methods: All the targeted derivatives were synthesized and purified by recrystallization. Synthesized compounds were characterized by various physicochemical and various spectroscopic techniques like melting point, thin layer chromatography, infrared spectroscopy (KBr pellets), mass spectroscopy(m/z), 1H NMR (DMSO-d6), and 13C NMR. The synthesized compounds were further studied for biological evolution by alloxan (150 mg/dl, intraperitonial) induced diabetic rat model for in-vivo studies., Result: Among all the synthesized derivatives, 5c and 5d were most potent as per binding energy. Compound 5i have shown a better plasma glucose reduction compared to glibenclamide. Hence, it will be further used as a lead compound to develop a more such kind of agent., Conclusion: The docking study revealed that in all designed sulphonylureas/ guanidine series of compounds 5c and 5d were found to be most potent compounds as per the binding energy compared to glibenclamide. With the help of detailed study of in vivo biological activity, we observed that compound 5i gives better result compared to glibenclamide as standard., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Primary Objective: We aim to study the effects of chronic aminoguanidine (AG) administration on learning and memory impairment after TBI and explore the potential mechanism involved in this process., Research Design: Male C57BL/6J mice were divided into 6 groups: Control, TBI + Veh, TBI+ AG (50, 100, 200 and 400 mg/kg, i.p.)., Methods and Procedures: Then, we measured cyclicadenosine 3', 5'-monophosphate (cAMP) content, phosphorylated form of cAMP-response element binding protein (p-CREB) level, iNOS, brain-derived neurotrophic factor (BDNF) and postsynaptic density-93/95 (PSD-93/95) expression in hippocampus. The learning and memory abilities were assessed using Morris water maze and step-down test., Main Outcomes and Results: The results demonstrate that TBI induced down-regulation of BDNF, loss of PSD-93/95, learning and memory deficits with down-regulation of cAMP content and p-CREB/CREB ratio. Administration of AG (200 and 400 mg/kg) reversed TBI induced down-regulation of BDNF and PSD-93/95, up-regulated the cAMP content and p-CREB/CREB ratio, which resulted in improvement of learning and memory ability., Conclusions: We suspect that AG (200 and 400 mg/kg) might reverse TBI-induced selective loss of postsynaptic proteins and learning and memory deficits with the activation of cAMP/CREB/BDNF signalling pathway.

Background: Immune response after intravenous peramivir administration, which is approved for children with influenza infection in Japan, is unclear., Methods: Kinetics of viral load and serum cytokine levels before and after peramivir therapy were analysed in 17 and 8 hospitalized children infected with influenza A and B, respectively. Additionally, haemagglutination inhibition (HI) titre was measured. The first day of hospital admission was defined as day 0., Results: Serum interleukin (IL)-6 levels in influenza-A-infected children significantly decreased after peramivir administration, unlike in those with influenza B where a decrease on day 1 was followed by an increase on day 2. Serum IL-6 kinetics were similar to viral load kinetics in both influenza-A- and B-infected children between days 0 and 2. Serum IL-8 levels gradually decreased after peramivir therapy in influenza-A-infected children but increased between days 1 and 2 in influenza-B-infected children. Conversely, serum IL-10 levels gradually decreased over time. Serum interferon-γ and granulocyte macrophage colony-stimulating factor levels remained low until day 5. Day 0-4 serum HI titres were <4-fold in all children infected with influenza A or B. Additionally, day 5 HI titres were positive in 4 of 6 influenza A cases and all 3 influenza B cases., Conclusions: Our results suggest that viral load and inflammatory cytokine kinetics were associated with the antiviral therapy used and that second peramivir administration should be considered in influenza B. The results also highlight antiviral agents as key determinants of the clinical course of influenza virus infection in children.

Objective: Inducible nitric oxide synthase (iNOS) aggravates and endothelial nitric oxide synthase (eNOS) ameliorates fibrosis in the lung. Our previous study demonstrated that aminoguanidine (AG), a preferred iNOS inhibitor, prevents bleomycin-induced injury and fibrosis in the lung. The diethylenetriamine nitric oxide adduct (DETA/NO) is a slow-release NO donor. Here, to clarify the exact role of the nitric oxide (NO) molecule in the pathogenesis of pulmonary fibrosis in vivo, we observed the effects of inhalation of aerosolized DETA/NO on fibrosis in the lungs of bleomycin-exposed rats with AG treatment, including the effects on the myofibroblast number, collagen deposition, peroxynitrite anion (ONOO - ) formation, and injury in the lung., Design and Methods: Rats received a single intratracheal instillation of bleomycin or normal saline (NS) on day 0, followed by a daily intraperitoneal injection of AG or NS from day 1 to day 13. Each group was additionally given a daily inhalation of DETA/NO or placebo from day 1 to day 13. On day 14, half of the rats in each group was euthanized, and plasma nitrite and nitrate (NOx), myofibroblasts, type I collagen, ONOO - and injury in the lung were estimated by the Griess reaction, western blotting, immunohistochemical staining, sirius red staining, and hematoxylin and eosin (HE) staining, respectively. On day 28, the other half of the rats in each group was euthanized, and the total collagen of the lung was evaluated by hydroxyproline assay., Results: ① At the day 14 time point, AG reduced the plasma NOx level in bleomycin rats, while this drug had no significant effect on sham rats. Inhalation of aerosolized DETA/NO increased the plasma NOx level of bleomycin + AG rats, sham rats and sham + AG rats. However, due to large areas of airspace obliteration in the lungs of bleomycin rats, DETA/NO inhalation had no significant effect on the plasma NOx level in these rats. ② At the day 14 time point, AG reduced ONOO - formation (marked by nitrotyrosine, NT), injury, myofibroblast number, and type I collagen deposition in the lungs of bleomycin rats, while this drug had no significant impact on the above parameters in the lungs of sham rats. Interestingly, DETA/NO inhalation enhanced the preventive effects afforded by AG on myofibroblast number and type I collagen deposition, but had no significant impact on ONOO - and injury in lung. ③ At the day 28 time point, because rats were not exposed to DETA/NO after day 13, there was no significant difference of the plasma NOx level in sham rats, sham + AG rats, bleomycin rats, and bleomycin + AG rats between DETA/NO inhalation and placebo inhalation. Interestingly, rats administered both DETA/NO and AG still showed a reduction in total collagen of the entire lung compared to rats administered AG alone at this time point., Conclusions: Exogenous NO enhances the prophylactic effect afforded by AG on the myofibroblast number and collagen deposition in the lungs of bleomycin-treated rats in vivo. These results suggest that NO has a direct antifibrotic effect in lungs, except for the formation of ONOO - in the development of pulmonary fibrosis in vivo., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neuroinflammation is a key feature of cerebral complication which is associated with diabetes mellitus (DM). Inducible nitric oxide synthase (iNOS) is implicated in the pathogenesis of neuroinflammation. However, how iNOS facilitates the development of inflammation in brain is still unidentified. The aim of the present study was to investigate the association of iNOS and neuroinflammation in diabetic mice, and elucidate the potential mechanisms underlying aminoguanidine (AG), the selective inhibitor of iNOS, protected neurons against inflammation in diabetic mice. In present experiment, diabetic mice model were established by a single intraperitoneal injection of streptozotocin (STZ). AG was administered to diabetic mice for ten weeks after this disease induction. Then we measured iNOS activity in the serum and brain, detected the glial fibrillary acidic protein (GFAP) and ionised calcium binding adaptor molecule-1 (Iba-1) expressions in the brain. Moreover, nuclear factor-kappa B (NF-κB) in cytoplasm and nucleus were tested by IP and WB. Results revealed that high expression of iNOS in serum and brain could be reversed by AG treatment. Furthermore, AG could also inhibit GFAP and Iba-1 expressions, and NF-κB nuclear translocation by inhibiting it from binding to iNOS in cytoplasm. Our findings indicated that iNOS can combine with NF-κB in cytoplasm and promote its nuclear transfer in diabetic mice. Furthermore, AG decreased neuroinflammation through inhibiting iNOS activity and reducing NF-κB nuclear translocation by promoting its dissociation with iNOS in cytoplasm.

Background/purpose: Neuraminidase inhibitors (NAIs) including oseltamivir and peramivir are used for influenza treatment. A systemic corticosteroid is usually administrated for acute respiratory distress syndrome. The aim of this study was to investigate the effect of a systemic corticosteroid and its interaction with NAIs in patients with influenza infection and respiratory distress., Methods: A retrospective survey of hospitalized patients infected with influenza from January 2012 to May 2014 was conducted in a medical center in Taiwan., Results: Eighty-six patients were hospitalized during the study period. Forty-eight patients had respiratory distress and 39 of them (81.3%, 39/48) were supported by a mechanical ventilator. All patients with respiratory distress received oseltamivir; 60.4% (29/48) and 31.3% (15/48) of them received a corticosteroid and salvage intravenous peramivir, respectively. All-cause mortality was 29.1% (14/48), 20% (3/15), and 31% (9/29) in patients with respiratory distress, patients who received salvage peramivir, and patients who received a systemic corticosteroid, respectively. Salvage peramivir seemed to improve prognosis in patients with H1pdm09 or type B virus infection and respiratory distress (p = 0.05). Early initiating corticosteroid had a worse prognosis than initiation after 72 hours of NAI treatment (p = 0.024). In particular, a systemic corticosteroid seemed to lead to a shorter survival time in patients with chronic lung disease (p = 0.05)., Conclusion: Salvage peramivir provided a better prognosis than monotherapy with oseltamivir in patients who were infected with H1pdm09 or type B virus and who developed respiratory distress. A systemic corticosteroid should be administered after initiating NAI therapy, especially in patients with chronic lung disease., (Copyright © 2015. Published by Elsevier B.V.)

Background: The present study assessed the activity of a combination of dinotefuran and pyriproxyfen (Vectra® Felis) for long-term control (3 months) of allergic dermatitis (AD) in privately-owned cats under common household conditions in Ile-de-France region., Methods: This was an open pre-treatment vs post-treatment study. Twenty-eight client-owned cats with clinical signs of AD were enrolled in the study. They received topical application of the combination of dinotefuran and pyriproxyfen on days 0, 28, 56 and 84. Two parameters (clinical signs and pruritus severity) were used to assess the animals' condition on days 0, 28 and 84. Fleas were counted if they were observed., Results: Of the 28 cats initially enrolled, 26 were presented on day 28 and 20 for the final evaluation on day 84. A significant improvement in clinical signs and pruritus was observed in cats for which fleas and/or flea feces were detected on day 0. Globally, the post-treatment AD clinical scores on days 28 and 84 were different from that of the pre-treatment on day 0, with a reduction of 30% and 71%, respectively. For cats with fleas and/or flea feces, the reduction on days 28 and 84 was 33% and 85%, respectively. The improvement of clinical signs and pruritus was not significant in cats with no visible fleas and no flea feces at the beginning of the trial (n = 8)., Conclusions: The present study indicated that the treatment with a combination of dinotefuran and pyriproxyfen should be considered as useful in controlling fleas on cats without additional environmental treatment and useful for long-term control of clinical signs and pruritus in allergic cats.

The Na + /H + exchanger is responsible for maintaining the acidic tumor microenvironment through its promotion of the reabsorption of extracellular Na + and the extrusion of intracellular H + . The resultant increase in the extracellular acidity contributes to the chemoresistance of malignant tumors. In this study, the chemosensitizing effects of cariporide, a potent Na + /H + -exchange inhibitor, were evaluated in human malignant mesothelioma H-2452 cells preadapted with lactic acid. A higher basal level of phosphorylated (p)-AKT protein was found in the acid-tolerable H-2452AcT cells compared with their parental acid-sensitive H-2452 cells. When introduced in H-2452AcT cells with a concentration that shows only a slight toxicity in H-2452 cells, cariporide exhibited growth-suppressive and apoptosis-promoting activities, as demonstrated by an increase in the cells with pyknotic and fragmented nuclei, annexin V-PE(+) staining, a sub-G 0 /G 1 peak, and a G 2 /M phase-transition delay in the cell cycle. Preceding these changes, a cariporide-induced p-AKT down-regulation, a p53 up-regulation, an ROS accumulation, and the depolarization of the mitochondrial-membrane potential were observed. A pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 markedly augmented the DNA damage caused by the cariporide, as indicated by a much greater extent of comet tails and a tail moment with increased levels of the p-histone H2A.X, p-ATM Ser1981 , p-ATR Ser428 , p-CHK1 Ser345 , and p-CHK2 Thr68 , as well as a series of pro-apoptotic events. The data suggest that an inhibition of the PI3K/AKT signaling is necessary to enhance the cytotoxicity toward the acid-tolerable H-2452AcT cells, and it underlines the significance of proton-pump targeting as a potential therapeutic strategy to overcome the acidic-microenvironment-associated chemotherapeutic resistance.

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.

Objective: To explore the protective effect of sodium channels antagonists HOE642 on lung ischemia reperfusion and the role of the p38 mitogen activated protein kinase (p38MAPK) signaling pathway in this process.
 Methods: A total of 36 mice were randomly divided into a sham operation group (SHAM group), a lung ischemia reperfusion group (I/R group) and a lung ischemia reperfusion+HOE642 group (HOE group). The water content was detected by electronic scales, and the lung tissue pathological changes were observed under optical microscope. The inflammatory cytokines including IL-6 and TNF-α were examined by ELISA. The intracellular calcium fluorescence intensity was examined and observed under fluorescence microscope, and the protein expression of p38MAPK was detected by Western blot.
 Results: Lung water content in the HOE group was lower than that in the I/R group, but higher than that in the SHAM group (both P<0.05). Lung interstitial edema, hemorrhage, lung tissue inflammatory cells infiltration were significantly alleviated in the HOE group than those in the I/R group, while the injury in the HOE group was aggravated than those in the SHAM group (both P<0.05). The IL-6 and TNF-α in lung tissues in the HOE group were lower than those in the I/R group, but higher than those in the SHAM group (both P<0.05). Intracellular calcium fluorescence intensity in the HOE group was lower than that in the I/R group, but higher than that in the SHAM group (both P<0.05). The protein expression of p38MAPK in lung tissues in the HOE group was lower than that in the I/R group, but higher than that in the SHAM group (both P<0.05).
 Conclusion: HOE642 may exert protective effect on pulmonary I/R injury through regulation of the p38MAPK signaling pathway, resulting in reduction of intracellular calcium ion concentration and calcium overload, and decrease of inflammatory response.

Purpose: Peramivir is the first intravenously administered neuramidase inhibitor for immediate delivery of an effective single-dose treatment in patients with influenza. However, limited data are available on intravenous (IV) peramivir treatment compared to oral oseltamivir for these patients., Materials and Methods: With a systematic review and meta-analysis, we compared the efficacy of IV peramivir with oral oseltamivir for treatment of patients with seasonal influenza. MEDLINE, EMBASE, and Cochrane Central Register were searched for relevant clinical trials., Results: A total of seven trials [two randomized controlled trials (RCTs) and five non-randomized observational trials] involving 1676 patients were finally analyzed. The total number of peramivir- and oseltamivir-treated patients was 956 and 720, respectively. Overall, the time to alleviation of fever was lower in the peramivir-treated group compared with the oseltamivir-treated group [mean difference (MD), -7.17 hours; 95% confidence interval (CI) -11.00 to -3.34]. Especially, pooled analysis of observational studies (n=4) and studies of outpatients (n=4) demonstrated the superiority of the peramivir-treated group (MD, -7.83 hours; 95% CI -11.81 to -3.84 and MD, -7.71 hours; 95% CI -11.61 to -3.80, respectively). Mortality, length of hospital stay, change in virus titer 48 hours after admission, and the incidence of adverse events in these patients were not significantly different between the two groups., Conclusion: IV peramivir therapy might reduce the time to alleviation of fever in comparison with oral oseltamivir therapy in patients with influenza; however, we could not draw clear conclusions from a meta-analysis because of the few RCTs available and methodological limitations., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2017)

Background: Influenza viruses are a significant cause of morbidity and mortality in the United States. Given the wide range of symptoms, emergency physicians must maintain a broad differential diagnosis in the evaluation and treatment of patients presenting with influenza-like illnesses., Objective: This review addresses objective and subjective symptoms commonly associated with influenza and discusses important mimics of influenza viruses, while offering a practical approach to their clinical evaluation and treatment., Discussion: Influenza-like symptoms are common in the emergency department (ED), and influenza accounts for > 200,000 hospitalizations annually. The three predominant types are A, B, and C, and these viruses are commonly transmitted through aerosolized viral particles with a wide range of symptoms. The most reliable means of identifying influenza in the ED is rapid antigen detection, although consideration of local prevalence is required. High-risk populations include children younger than 4 years, adults older than 50 years, adults with immunosuppression or chronic comorbidities, pregnancy, obesity, residents of long-term care facilities, and several others. The Centers for Disease Control and Prevention recommends treatment with neuraminidase inhibitors in these populations. However, up to 70% of patients with these symptoms may have a mimic. These mimics include infectious and noninfectious sources. The emergency physician must be aware of life-threatening mimics and assess for these conditions while beginning resuscitation and treatment., Conclusions: The wide range of symptoms associated with influenza overlap with several life-threatening conditions. Emergency physicians must be able to rapidly identify patients at risk for complications and those who require immediate resuscitation., (Published by Elsevier Inc.)

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor β (PDGFR β ) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR β promoter-driven Cre system to delete α v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR β -Cre line to isolate and study renal fibroblasts ex vivo We found that renal fibroblasts express three α v integrins, namely α v β 1, α v β 3, and α v β 5. Blockade of α v β 1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF- β 1 and prevented activation of the latent TGF- β complex. Continuous administration of a recently described potent small molecule inhibitor of α v β 1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of α v β 1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis., (Copyright © 2017 by the American Society of Nephrology.)

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid metabolite which has been implicated in many diseases including cancer and inflammatory diseases. Recently, sphingosine kinase 1 (SK1), one of the isozymes which generates S1P, has been implicated in the development and progression of inflammatory bowel disease (IBD). Based on our previous work, we set out to determine the efficacy of a novel SK1 selective inhibitor, LCL351, in a murine model of IBD. LCL351 selectively inhibits SK1 both in vitro and in cells. LCL351, which accumulates in relevant tissues such as colon, did not have any adverse side effects in vivo. In mice challenged with dextran sodium sulfate (DSS), a murine model for IBD, LCL351 treatment protected from blood loss and splenomegaly. Additionally, LCL351 treatment reduced the expression of pro-inflammatory markers, and reduced neutrophil infiltration in colon tissue. Our results suggest inflammation associated with IBD can be targeted pharmacologically through the inhibition and degradation of SK1. Furthermore, our data also identifies desirable properties of SK1 inhibitors., (Published by Elsevier Inc.)

Transcription factors (TFs) are a major class of protein signaling molecules that play key cellular roles in cancers such as the highly lethal brain cancer-glioblastoma (GBM). However, the development of specific TF inhibitors has proved difficult owing to expansive protein-protein interfaces and the absence of hydrophobic pockets. We uniquely defined the dimerization surface as an expansive parental pharmacophore comprised of several regional daughter pharmacophores. We targeted the OLIG2 TF which is essential for GBM survival and growth, we hypothesized that small molecules able to fit each subpharmacophore would inhibit OLIG2 activation. The most active compound was OLIG2 selective, it entered the brain, and it exhibited potent anti-GBM activity in cell-based assays and in pre-clinical mouse orthotopic models. These data suggest that (1) our multiple pharmacophore approach warrants further investigation, and (2) our most potent compounds merit detailed pharmacodynamic, biophysical, and mechanistic characterization for potential preclinical development as GBM therapeutics.

Histopathological diagnosis was used to understand the pathological events associated with Heterophyes heterophyes (H. heterophyes) infection. CD3 and CD79α antibodies had been used as markers for both T and. B lymphocytes respectively. Immunohistochemical techniques had several advantages as remarkable sensitivity and specificity. This study aims to evaluate the roles-of praziquantel (PZQ) and aminoguanidine (AG) treatment in H heterophyes infected dogs pathologically and immunohisto-chemically. Study design included experimental infection of dogs with encysted metacercariae of H heterophyes followed by treatment with PZQ and AG. Tissue samples were taken from small intestinal, liver, heart and lung of all groups for histopathological and immunohistochemical studies. Pathological changes were detected in infected tissues by histopathological examination. There was different degree of CD79α+B lymphocytic & CD3+T lymphocytic infiltration detected in immuno-histochemical stained tissues. PZQ caused improvement of pathological changes in the small intestine. However the cellular inflammatory infiltration increased. There was reduction in inflammatory infiltration after intake of AG. Both PZQ and AG improved the pathological changes in the.liver, heart and lung, while the cellular inflammatory infiltration increased after PZQ and reduced by AG. Moreover in the lung AG improves pulmonary congestion and alveolar wall thickness.

Introduction: Respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, coronavirus, human metapneumovirus, and rhinovirus) represent the most common causes of respiratory viral infections in immunocompromised patients. Also, these infections may be more severe in immunocompromised patients than in the general population. Early diagnosis and treatment of viral infections continue to be of paramount importance in immunocompromised patients; because once viral replication and invasive infections are evident, prognosis can be grave. Areas covered: The purpose of this review is to provide an overview of the main antiviral agents used for the treatment of respiratory viral infections in immunocompromised patients and review of the new agents in the pipeline. Expert commentary: Over the past decade, important diagnostic advances, specifically, the use of rapid molecular testing has helped close the gap between clinical scenarios and pathogen identification and enhanced early diagnosis of viral infections and understanding of the role of prolonged shedding and viral loads. Advancements in novel antiviral therapeutics with high resistance thresholds and effective immunization for preventable infections in immunocompromised patients are needed.

High morbidity and mortality associated with human cases of highly pathogenic avian influenza (HPAI) viruses, including H5N1 influenza virus, have been reported. The purpose of the present study was to evaluate the antiviral effects of peramivir against HPAI viruses. In neuraminidase (NA) inhibition and virus replication inhibition assays, peramivir showed strong inhibitory activity against H5N1, H7N1 and H7N7 HPAI viruses with sub-nanomolar activity in enzyme assays. In H5N1 viruses containing the NA H275Y mutation, the antiviral activity of peramivir against the variant was lower than that against the wild-type. Evaluation of the in vivo antiviral activity showed that a single intravenous treatment of peramivir (10 mg/kg) prevented lethality in mice infected with wild-type H5N1 virus and also following infection with H5N1 virus with the H275Y mutation after a 5 day administration of peramivir (30 mg/kg). Furthermore, mice injected with peramivir showed low viral titers and low levels of proinflammatory cytokines in the lungs. These results suggest that peramivir has therapeutic activity against HPAI viruses even if the virus harbors the NA H275Y mutation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Methylmalonic acidemia (MMA) is the most common organic acidemia in childhood. Many "treated" patients continued to display various degrees of mental retardation and psychomotor delay, which could be caused by brain damage from elevated oxidative stress. Aminoguanidine (AG), a synthetic antioxidant, was tested in a MMA rat model for its potential therapeutic effects on memory impairment. The effects of AG on MMA-induced cognitive impairment in Wistar rats were evaluated with Morris Water Maze. The levels of nerve cell apoptosis and microglial activation were investigated to illustrate the mechanisms of the improvement of cognition with AG treatment in MMA rats. To further explore the mechanism of neuroprotection induced by AG, several biomarkers including free radicals and inflammatory cytokines in the hippocampus were quantified. The results showed that the rats treated with AG exhibited better neurological behavior performances than MMA model rats. The AG-treated rats had a decreased level of apoptosis of the hippocampal neurons, which could be the structural basis of the observed neural behavior protection. In addition, AG treatment significantly inhibited the activation of microglia. The AG-treated rats had decreased levels of IL-1β, IL-6, TNF-α, NO, malonaldehyde and iNOS activities in the hippocampus. The level of glutathione and superoxide dismutase activity in the hippocampus of the AG-treated rats increased significantly. In conclusion, AG could alleviate the MMA-induced cognitive impairment via down-regulating of oxidative stress and inflammatory reaction and provide a basis as a therapeutic potential against MMA-induced cognitive impairment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To investigate the lower urinary tract changes in mice treated with L-NAME, a non-selective competitive inhibitor of nitric oxide synthase (NOS), or aminoguanidine, a competitive inhibitor of inducible nitric oxide synthase (iNOS), after 5 weeks of partial bladder outlet obstruction (BOO), in order to evaluate the role of constitutive and non-constitutive NOS in the pathogenesis of this experimental condition., Materials and Methods: C57BL6 male mice were partially obstructed and randomly allocated into 6 groups: Sham, Sham + L-NAME, Sham + aminoguanidine, BOO, BOO + L-NAME and BOO + aminoguanidine. After 5 weeks, bladder weight was obtained and cystometry and tissue bath contractile studies were performed., Results: BOO animals showed increase of non-voiding contractions (NVC) and bladder capacity, and also less contractile response to Carbachol and Electric Field Stimulation. Inhibition of NOS isoforms improved bladder capacity and compliance in BOO animals. L-NAME caused more NVC, prevented bladder weight gain and leaded to augmented contractile responses at muscarinic and electric stimulation. Aminoguanidine diminished NVC, but did not avoid bladder weight gain in BOO animals and did not improve contractile responses., Conclusion: It can be hypothesized that chronic inhibition of three NOS isoforms in BOO animals leaded to worsening of bladder function, while selective inhibition of iNOS did not improve responses, what suggests that, in BOO animals, alterations are related to constitutive NOS., (Copyright® by the International Brazilian Journal of Urology.)

Intracerebroventricular (i.c.v.) injection of colchicine induces neurodegeneration, memory impairments and changes of some systemic immune responses in rats. Though the role of cox 2 in these colchicine induced changes have been evaluated, the influence of nitric oxide synthase (NOS) remains to be studied. The present study was designed to assess the role of NOS on the i.c.v. colchicine induced neurodegeneration, memory impairments and changes of some systemic immune responses by inhibiting its activity with aminoguanidine. In the present study the impairments of working and reference memories, neurodegeneration (chromatolysis and plaque formation) and changes of neuroinflammatory markers in the hippocampus (increased TNF α, IL 1β, ROS and nitrite) along with changes of serum inflammatory markers (TNF α, IL 1β, ROS and nitrite) and alteration of systemic immune responses (higher phagocytic activity of blood WBC and splenic PMN, higher cytotoxicity and lower leukocyte adhesion inhibition index of splenic MNC) were measured in the intracerebroventricular colchicine injected rats (ICIR). Administration of aminoguanidine (p.o. 30/50mg/kg body weight) to ICIR resulted in recovery of neuroinflammation and partial prevention of neurodegeneration which could be corroborated with the partial recovery of memory impairments in this model. The recovery of serum inflammatory markers and the systemic immune responses in ICIR was also observed after administration of aminoguanidine. Therefore, the present study shows that aminoguanidine can protect the colchicine induced neurodegeneration, memory impairments, and changes of systemic immune systemic responses in ICIR by inhibiting the iNOS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Giardia parasites cause gastrointestinal disease in humans, dogs, and many other animals worldwide. The treatment of dogs for giardiasis requires further investigation to ascertain levels of drug efficacy and the possibility of adverse side effects. Nitazoxanide (NTZ) has shown good clinical anti-Giardia activity in humans, yet it has not been evaluated for the treatment of giardiasis in dogs., Methods: Thirty-five dogs, naturally infected with Giardia were divided into five groups (n = 7): dogs in group NTZ1, NTZ2, and NTZ3 were treated with a single oral dose of 37.5 mg/kg, 75 mg/kg, and 150 mg/kg, respectively, of NTZ on days 0 and 14. The fourth group was treated with a commercially available regimen that includes a combination of pyrantel, praziquantel, and febantel (FEB) administered orally for three consecutive days. Additionally, an untreated control group was established. Giardia cysts from the stool of each dog were quantified on days -3, 0, 5, 7, 9, 11, 14, 18, 25, and 28. Biochemical parameters were evaluated in all dogs, before the first treatment and after concluding the experiment., Results: Shedding of Giardia cysts was reduced in all treated groups when compared to untreated controls (P < 0.01). However, NTZ2, NTZ3, and FEB had a lower risk during the study. Furthermore, NTZ was also effective against another protozoan, Cryptosporidium spp. at doses of 75 mg/kg and 150 mg/kg, in contrast to the combination of febantel + pyrantel + praziquantel. Biochemical parameters of treated animals, namely, aspartate transaminase and alanine transaminase enzymes, remained within physiological ranges., Conclusions: Based on these results, the implementation of NTZ as a treatment for giardiasis in dogs is proposed. The administration of a single dose is an important advantage of NTZ because it reduces workload, particularly in animals placed in shelters and kennels, where handling of large numbers of animals is required, and personnel is frequently scarce.

A 19-year-old man presented with a fever, convulsions, and loss of consciousness at our hospital. The patient had a Glasgow Coma Scale score of 12. Influenza B virus infection was diagnosed using the rapid test kit, and an eight-fold increase in the serum levels of anti-influenza B virus antibody was confirmed using the complement fixation test. Brain magnetic resonance imaging showed multifocal high-signal lesions, and an electroencephalogram showed diffuse slowing of the background activity, indicating acute encephalopathy. After treatment with peramivir and methylprednisolone for 3 days, the patient was discharged without any neurological impairment. This was a case of influenza B infection associated with acute encephalopathy in a healthy young man.

(2S,3S,4S,5R,6R)-6-(4-((4-guanidinobutoxy)carbonyl)-2,6-dihydroxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (ZYZ-488) was discovered as a novel inhibitor of apoptotic protease activating factor-1 (Apaf-1). In present work, a surface plasmon resonance (SPR) assay confirms the direct binding between ZYZ-488 and Apaf-1 and this interaction was found to be able to block the recruitment of procaspase-9 by Apaf-1. This study also shows that the treatment of MI (myocardial infarction) mice with this novel Apaf-1 inhibitor remarkably reduces the infarct size, improves cardiac functions, and attenuates the histopathology changes caused by MI. Meanwhile, here it is shown that ZYZ-488 decreases myocardial enzyme release, inhibits cardiomyocyte apoptosis, and suppresses the activation of the downstream cascade of caspases. Moreover, in silico prediction validated the drug-like properties of ZYZ-488. In conclusion, our findings present the first piece of evidence indicating the interaction between Apaf-1 and procaspase-9 as a novel therapeutic target in myocardial infarction and suggesting ZYZ-488 as a promising therapeutic option for myocardial infarction disease.

Background: The purpose of this study is to determine the maximum tolerated dose of a single intravitreal injection of aminoguanidine and 1400W, 2 inhibitors of inducible nitric oxide synthase, in rabbit eyes. Inhibition of inducible nitric oxide synthase has already been shown to be beneficial in various animal models of diabetic eye disease., Methods: Groups of 4 New Zealand white rabbits were injected with balanced salt solution in the right eye and a single dose of either aminoguanidine (5, 1, 0.25 mg) or 1400W (2 mg and 0.4 mg) in the left eye. Toxicity was assessed by slit-lamp and fundus examination, intraocular pressure and pachymetric measurements, and electrophysiologic and histologic analysis., Results: Eyes injected with high doses of aminoguanidine (5 mg) or 1400W (2 mg) demonstrated severe retinal vascular attenuation and infarction. Lower doses of intravitreal aminoguanidine (1 mg) and 1400W (0.4 mg) caused no significant toxic ocular effects in rabbit eyes., Conclusion: If the difference in vitreal volume between rabbit eyes and human eyes is taken into account, aminoguanidine (2.7 mg) and 1400W (1 mg) would be reasonable intravitreal doses to test for safety and efficacy in early clinical trials.

Background In Japan, four neuraminidase inhibitors (NAIs) are currently prescribed to patients with influenza A and B. To know the backgrounds and clinical courses of patients with influenza who were treated with NAIs is important in the selection of appropriate medications. Methods We conducted a multicenter observational study in Osaka with postcard questionnaires. Patients who were prescribed NAIs were provided postcard questionnaires containing questions on their backgrounds, body temperatures, and durations of other influenza symptoms. We analyzed the factors that were associated with early fever alleviation using a logistic regression model. Results The postcard response rate was 31% (326 of 1050), and 307 patients were enrolled in this study [150 patients who were under 10 years old (type A, 118; and type B, 32) and 157 patients who were 10 or older (type A, 114; and type B, 43)]. In the patients under 10, the multivariate analysis showed that influenza type (Type B vs Type A; Odds Ratio, 0.13; 95% Confidence Interval: 0.04-0.38) was associated with early fever alleviation. However, NAIs were not related to early fever alleviation. Laninamivir tended to contribute more to early fever alleviation compared to oseltamivir in patients under 10 (Odds Ratio, 2.50;$95% Confidence Interval: 0.90-7.80). Conclusions The types,of prescibed NAIs were not significantly related to early fever alleviation. However, the fever durations of the patients under 10 who were prescribed laninamivir were shorter than those of patients under 10 who were prescribed oseltamivir or zanamivir.

Background: Because of difficulties with early diagnosis, most patients with pancreatic cancer receive chemotherapy. The National Comprehensive Cancer Network guidelines (version 2.2015) suggest therapy with gemcitabine (GEM) plus nab-paclitaxel (nPTX) as a category 1 recommendation for metastatic pancreatic ductal adenocarcinoma. According to the results of many studies, the activation of chemotherapeutic agents-induced nuclear factor-κB (NF-κB) causes chemoresistance. Hence, we hypothesized that the addition of nafamostat mesilate (NM), a potent NF-κB inhibitor, to GEM/nPTX therapy could enhance the antitumor effect in the treatment of pancreatic ductal adenocarcinoma., Materials and Methods: In vitro, we assessed NF-κB activity and apoptosis under treatment with NM alone (80 μg/mL), with GEM/nPTX, or with a combination of NM and GEM/nPTX in human pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and AsPC-1). In vivo, orthotopic pancreatic cancer mice (BALBc nu/nu) were divided into four groups: control (n = 13), NM (n = 13), GEM/nPTX (n = 13), and triple combination (n = 13). NM (30 mg/kg) was delivered intraperitoneally three times a week, and GEM/nPTX was injected intravenously once a week to orthotopic pancreatic cancer model mice. In the triple combination group, mice received NM followed by GEM/nPTX on the first day to avoid GEM/nPTX-induced NF-κB activation., Results: In vitro and in vivo, NM inhibited GEM/nPTX-induced NF-κB activation, and a synergistic effect of apoptosis was observed in the triple combination group. Furthermore, tumor growth was significantly suppressed in the triple combination group compared with the other groups., Conclusions: NM enhances the antitumor effect of GEM/nPTX chemotherapy for orthotopic pancreatic cancer by inhibition of NF-κB activation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Peramivir, the only injectable anti-influenza neuraminidase inhibitor medically available in Japan at present, is considered first-line treatment in patients with high risk factors for influenza exacerbation. We conducted a drug-use investigation of peramivir in inpatients with high risk factors (old age, pregnancy, and underlying disease such as chronic respiratory disease) from January 2010 to March 2013. Data of 772 patients from 124 facilities across Japan were collected; peramivir's safety in 770 patients and effectiveness in 688 patients were examined. In total, 412 adverse events were observed in 219 patients (28.4%). Of these, 155 events were adverse drug reactions (ADRs) observed in 98 patients (12.7%). Major ADRs (≥2%) were increased aspartate aminotransferase (5.1%), increased alanine aminotransferase (3.8%) and decreased white blood cell count (2.5%). Fourteen serious ADRs were observed in 12 patients (1.6%). All serious ADRs were resolved or improved except for two events for which outcomes were unknown. Multivariate analyses revealed that ADR incidences were significantly associated with these four backgrounds of patients: medical history, no influenza vaccination, renal impairment and other infection(s). With regard to its effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration, which was the same as in other previous surveillance studies. This surveillance study indicated the safety of peramivir in the treatment of influenza inpatients with high risk factors under routine clinical settings., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This experimental study was designed to investigate both protective and therapeutic effects of aminoguanidine (AG), on radiotherapy (RT)-induced oxidative stress in kidney and testis. Forty rats were divided into five groups equally as follows: (i) control, (ii) RT, (iii) AG, (iv) AG+RT and (v) RT+AG group. Histopathological findings and biochemical evaluations, including tissue malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), total oxidant status (TOS), total antioxidant capacity, oxidative stress index (OSI), blood urea nitrogen (BUN), serum creatinine (Cr) and testosterone levels, were determined. MDA, TOS and OSI were significantly higher in RT-treated groups, whereas SOD, CAT, GPX and GSH were significantly lower in these groups when compared with the control rats in the kidney and testis tissue. AG treatment significantly decreased MDA, TOS and OSI levels and increased SOD, CAT, GPX and GSH levels, when compared to the RT-treated groups in both kidney and testis tissue. BUN and Cr levels did not change among the groups, whereas testosterone levels were found as reduced in the RT-treated rats. AG treatment significantly augmented these hazardous effects of RT on testis tissue. According to our results, AG has beneficial effects against RT-induced kidney and testis injury., (© 2015 Blackwell Verlag GmbH.)

Serine proteases, such as thrombin, are contributors to the disruption of the blood-brain barrier (BBB) and exacerbate brain damage during ischemic stroke, for which the current clinical therapy remains unsatisfactory. However, the effect of nafamostat mesilate (NM), a synthetic serine protease inhibitor, on BBB disruption following cerebral ischemia is unknown. Here, we investigated the in vivo effect of NM on BBB integrity in rats subjected to transient middle cerebral artery occlusion (MCAO) and explored the possible mechanism in an in vitro BBB model comprising rat brain microvascular endothelial cells and astrocytes after oxygen and glucose deprivation (OGD) in the presence of thrombin. The results showed that NM treatment remarkably attenuated transient MCAO-induced brain infarcts, brain oedema and motor dysfunction in addition to BBB disruption, which might be related to changes in tight junction protein expression and localization. Meanwhile, NM preserved BBB integrity and alleviated the changes in tight junction protein expression and localization and cytoskeleton rearrangement in rat brain microvascular endothelial cells via thrombin inhibition. Our findings suggest that NM treatment can preserve BBB integrity through the inhibition of thrombin, which might be correlated with the regulation of PKCα/RhoA/MLC2 pathway components., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Acute kidney injury is usually associated with distant organ dysfunction. The roles of inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) in this phenomenon were investigated following 2 h unilateral renal ischemia and 24 h reperfusion. There were 3 groups of rats subjected to either unilateral ischemia/reperfusion (UIR group), unilateral nephrectomy (UNX group), or sham operation. Two further groups were given α-tocopherol and aminoguanidine with UIR (treated-UIR group) and UNX (treated-UNX group). Plasma nitrite/nitrate and malondialdehyde were elevated only in the UIR group. Creatinine clearance and blood flow increased in non-ischemic kidney of the UIR, but not to the same extent as remnant kidney of the UNX group, while they had equal compensatory rises in absolute Na(+) and K(+) excretion and urine flow. Non-ischemic kidney of the treated-UIR group, but not remnant kidney of the treated-UNX group, showed more elevation in blood flow, whereas both kidneys had reductions in absolute Na(+) excretion and urine flow. Respiratory functional variable were not different between all groups. Therefore, 2 h unilateral renal ischemia and 24 h reperfusion did not affect lung but had distant effects on contralateral kidney partly mediated by ROS and NO-derived from iNOS to dampen compensatory increases in renal hemodynamics and to decrease tubular reabsorption.

Background: In patients with ST-elevation acute myocardial infarction (STEMI), reperfusion therapy limits infarct size, but can directly evoke myocardial reperfusion injury. Activation of the Na(+)/H(+) exchanger (NHE) plays an important role in reperfusion injury. TY-51924, a novel NHE inhibitor, significantly reduced infarct size in animal studies and was well tolerated in early-phase clinical trials. This study aim was to evaluate the efficacy and safety of TY-51924 in patients with STEMI., Methods: In this multicenter, randomized, double-blind, placebo-controlled Phase II trial, 105 patients with first anterior STEMI undergoing primary percutaneous coronary intervention (pPCI) were randomly assigned to receive an intravenous infusion of either TY-51924 or placebo. Primary endpoints were myocardial salvage index (MSI) as determined by single photon emission computed tomography (SPECT) 3-5 days after pPCI and safety up to 7 days., Results: Baseline characteristics were similar in the two groups. MSI 3-5 days after pPCI (0.200 vs. 0.290, p=0.56), 3 months after pPCI (0.470 vs. 0.500, p=0.76), and the incidences of side effects did not differ between the two groups as a whole. However, on post hoc analysis of 52 patients with a large area at risk (AAR) (≥38%) and no antegrade coronary flow, MSI by SPECT at 3 months after pPCI was significantly higher in TY-51924 group (0.450 vs. 0.320, p=0.03). TY-51924 did not adversely influence hemodynamics., Conclusions: TY-51924 did not improve MSI or increase side effects as a whole. However, TY-51924 is potentially cardioprotective in the presence of a large AAR and no antegrade coronary flow., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Since the novel H7N9 avian influenza outbreak occurred in China in 2013, neuraminidase inhibitors (NAIs) such as oseltamivir and peramivir have been used as first-line drugs to treat the influenza virus infection. This study aimed to compare the efficacy of oseltamivir-peramivir combination therapy versus oseltamivir monotherapy., Methods: A retrospective study of 82 H7N9 confirmed patients was conducted by reviewing medical charts at the First Affiliated Hospital of ZheJiang University in China from April 1, 2013 to Feb 28, 2014. The patients' clinical information was collected systematically, and we compared the virology and clinical data between oseltamivir monotherapy group (43 patients) and oseltamivir-peramivir combination group (39 patients)., Results: The median duration from NAIs administration to H7N9 virus-negative in oseltamivir monotherapy group and oseltamivir-peramivir combination group was 6.50 and 7.00 days (p >0.05), respectively. The median decline of Day 2 to Day 0 (initiation of NAIs therapy) viral load was 0.00 and 0.69 log10 copies/μl (p >0.05) respectively in the monotherapy vs. combination therapy groups. The incidence of new Acute Respiratory Distress Syndrome during NAI administration was 63.89 and 77.78 % (p >0.05); while the mortality rates were 25.58 and 43.59 % (p >0.05) in the oseltamivir group vs. oseltamivir-peramivir group., Conclusions: Our results suggest that in adults with H7N9 virus infection, the use of oseltamivir-peramivir combination therapy was not superior to oseltamivir monotherapy.

A variety of disorders erratically activate coagulation cascades. The disseminated intravascular coagulation (DIC) is caused by unbalanced activation between coagulation and fibrinolysis. Some of auxiliary treatments for DIC on top of main therapy against causative disease are beneficial in terms of better outcome. The anticoagulation therapy is indicated when an activation of coagulation dominates in DIC caused by sepsis. Whereas in DIC associated with trauma, since balance between coagulation and fibrinolysis collapses drastically in a short period, both anticoagulantion therapy and antifibrinolytic therapy can be utilized depending on clinical conditions. There are quite a few of anti DIC agents in Japan. It is imperative to choose appropriate agents to treat DIC taking their pharmacological properties into account.