Journal articles: 'Septic shock; Inhibitors'

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Orlicek, Shari L. "Cytokine inhibitors for sepsis and septic shock." Seminars in Pediatric Infectious Diseases 12, no. 1 (January 2001): 24–29. http://dx.doi.org/10.1053/spid.2001.19232.

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Cohen, J., and A. Silva. "NO inhibitors and septic shock." Lancet 339, no. 8795 (March 1992): 751. http://dx.doi.org/10.1016/0140-6736(92)90657-o.

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Strukov, Danila Viktorovich, Andrey Glebovich Vasiliev, and Yuriy Stanislavovich Alexandrovich. "No inducible synthase inhibitors produce a positive effect on indexes of central hemodynamics in rats with septic shock." Pediatrician (St. Petersburg) 6, no. 4 (December 15, 2015): 45–50. http://dx.doi.org/10.17816/ped6445-50.

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The purpose of the study was to evaluate the efficacy of NO inducible synthase (iNOS) inhibitors involved in simulation of septic shock in rats. Model of septic shock (SS) was obtained in rats by intravenous administration of live Bifidobacteria culture. Aminoguanidine was used as a selective inhibitor of iNOS. Indexes of central hemodynamics measured by direct method where analyzed. Vascular endothelial function was rated by determination of nitric oxide (II) (NO), vascular endothelial growth factor A (VEGF-A) and tissue plasminogen activator (tPA) in plasma. Hemostatic parameters were evaluated by the level of soluble fibrin monomer complexes (RKMF). Intravenous administration of live Bifidobacteria culture in rats proved to cause an adequate and effective septic shock model with characteristic changes of hemodynamics in laboratory animals, development of endothelial dysfunction and hemostasis system activation in response to bacteremia. INOS inhibitors have a positive impact on hemodynamics in septic shock. NO is not the only factor in the development of hypotension in septic shock. INOS inhibitors appear to affect the extent of vasopressor dose utilized in the therapy of septic shock contributing to improvement of microcirculation and tissue oxygenation.

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Martínez-Brotóns, F., J. R. Oncins, J. Mestres, V. Amargós, and C. Reynaldo. "Plasma Kallikrein-Kinin System in Patients with Uncomplicated Sepsis and Septic Shock-Comparison with Cardiogenic Shock." Thrombosis and Haemostasis 58, no. 02 (1987): 709–13. http://dx.doi.org/10.1055/s-0038-1645960.

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SummaryAlterations of the kallikrein-kinin system consistent with activation and increased consumption have been re2ported in septic patients and it has been suggested that this activation could contribute to the development of septic shock.The aim of this work was to confirm these alterations in septic patients and to investigate the possible existence of similar changes in subjects developing cardiogenic shock secondary to myocardial infarction as a model of non septic shock.Patients with septic shock, especially in fatal cases, showed a highly significant decrease in levels of factor XII, prekallikrein, high molecular weight kininogen (HMW-kininogen), α2-macro-globulin (α2-M) and antithrombin III (AT-III). C1-esterase inhibitor (C1-INH) activity was increased in uncomplicated sepsis but came back to normal or was slightly decreased in septic shock.Components and inhibitors of the kallikrein-kinin system were within normal limits in patients with cardiogenic shock.Our findings support the idea of a contribution of the kallikrein-kinin system to the development of septic shock though this system does not seem to play a significant role in the pathogenesis of cardiogenic shock or seem to be altered as a consequence of it.

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Wearden, Mary E. "Nitric oxide synthase inhibitors for septic shock." Seminars in Pediatric Infectious Diseases 12, no. 1 (January 2001): 42–45. http://dx.doi.org/10.1053/spid.2001.19234.

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Strukov, Danila Viktorovich, Yuriy Stanislavovich Alexandrovich, and Andrey Glebovich Vasiliev. "Actual aspects of sepsis and septic shock." Pediatrician (St. Petersburg) 5, no. 2 (June 15, 2014): 81–87. http://dx.doi.org/10.17816/ped5281-87.

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He review presents an analysis of up-to-date views on sepsis and septic shock. Results of consenting conferences are given with classification of sepsis in adults and children. Mortality indexes are presented in patients’ group with sepsis. Basic pathogenesis links are examined i.e. bacteriemia, microbe toxemia, endo(auto)toxicosis, systemic destructive vasculitis, growing hypercoagulation transforming into coagulopathia, consumption trombocytopenia with trombohemorrhagic syndrome and severe immunesuppression. Pathogenesis of septic shock is divided into processes developing in various organs and tissues as well as into intracellular ones: such as oxidative stress and mitochondrial insufficiency. The role of pathogen-associated molecular images - patterns is portrayed in the development of generalized acyclic infection process. A scheme of up-to-date septic shock therapy is presented. An important role of nitrogen oxide in the development of stabile hypotonia resistant to vasopressin therapy is proven. The potency of nitrogen oxide to produce free-radical peroxinitrite inducing lipids peroxide oxidation in membranes is reflected. Its ability to react with non-hem iron- and zink- containing proteins is mentioned. Key factors contributing to activation of genes responsible for inducible nitrogen oxide synthase operation are revealed. Extremely severe sepsis and septic shock are believed to be the most serious problem of contemporary medicine thus necessitating to produce new medicines affecting the most drug-resistant links of its pathogenesis. In many a countries trials are continuing to introduce new medicines like nitrogen oxide synthase inhibitors for the treatment of patients with septic shock.

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Haj, Montaser A., Linda A. Robbie, Gillian D. Adey, and Bruce Bennett. "Inhibitors of Plasminogen Activator in Neutrophils and Mononuclear Cells from Septic Patients." Thrombosis and Haemostasis 74, no. 06 (1995): 1528–32. http://dx.doi.org/10.1055/s-0038-1649977.

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SummaryLeucocytes, both polymorphs and mononuclear cells, play a variety of roles in the evolution of human response to sepsis, both local and generalised. In this study, inhibitors of plasminogen activator were measured in leucocytes from normal and septic patients. Plasminogen activator inhibitor-1 (PAI-1) was identified in polymorphs from normal individuals and levels rose significantly in polymorphs from septic patients: neutrophils from normal subjects did not contain PAI-2 but this protein was detectable in significant quantities in polymorph preparations from septic patients. In contrast, mononuclear cells from normal and septic patients contained no detectable quantities of PAI-1. Significant amounts of PAI-2 were present in normal mononuclear cells, and the levels rose significantly in monocytes from septic patients. PAI-2 is thus here identified in human subjects, distinct from those with pregnancy or malignancy, as playing a role in a pathological process. The increased levels of both inhibitors produced by leucocytes may clearly contribute directly to the persistence of fibrin, a characteristic feature of the response to infection, local or general; they may thus participate in successful localisation of infections (abscess formation etc.) and in the evolution of the major systemic complications of disseminated sepsis characterised by microvascular occlusion by fibrin such as renal failure, shock lung or digital ischaemia.

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Mesters, RM, PM Mannucci, R. Coppola, T. Keller, H. Ostermann, and J. Kienast. "Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients." Blood 88, no. 3 (August 1, 1996): 881–86. http://dx.doi.org/10.1182/blood.v88.3.881.881.

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Abstract Septic shock and multiple organ failure may be associated with coagulation activation, disseminated fibrin formation, and consumption of coagulation inhibitors such as antithrombin III. We have evaluated prospectively coagulation measurements in patients with severe chemotherapy-induced neutropenia. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective coagulation testing before and during evolving sepsis or septic shock. Sixty-two patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and 13 additional patients to septic shock as defined according to standard diagnostic criteria. At the onset of fever, factor (F) VIIa activity, FVII antigen and antithrombin III (AT III) activity decreased from normal baseline levels and were significantly lower in the group of patients who progressed to septic shock compared with those that developed severe sepsis (medians: 0.3 v 1.4 ng/mL, 21 v 86 U/dL and 45% v 95%; P < .001). The decrease of these measurements in septic shock was accompanied by an increase in prothrombin fragment 1+2 (median: 3.6 v 1.4 nmol/L; P = .05), a marker of thrombin generation. These differences were sustained throughout the septic episode (P < .0001). FVIIa and AT III levels of < 0.8 ng/mL and < 70%, respectively, at onset of fever predicted a lethal outcome with a sensitivity of 100% and 85%, and a specificity of 75% and 85%, respectively. In contrast, FXIIa-alpha antigen levels were not different between groups at onset of fever but increased modestly during the course of septic shock (P = .001). Thus, septic shock in neutropenic patients is associated with increased thrombin generation. Furthermore, both FVIIa and AT III measurements are sensitive markers of an unfavorable prognosis.

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Mesters, RM, PM Mannucci, R. Coppola, T. Keller, H. Ostermann, and J. Kienast. "Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients." Blood 88, no. 3 (August 1, 1996): 881–86. http://dx.doi.org/10.1182/blood.v88.3.881.bloodjournal883881.

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Septic shock and multiple organ failure may be associated with coagulation activation, disseminated fibrin formation, and consumption of coagulation inhibitors such as antithrombin III. We have evaluated prospectively coagulation measurements in patients with severe chemotherapy-induced neutropenia. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective coagulation testing before and during evolving sepsis or septic shock. Sixty-two patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and 13 additional patients to septic shock as defined according to standard diagnostic criteria. At the onset of fever, factor (F) VIIa activity, FVII antigen and antithrombin III (AT III) activity decreased from normal baseline levels and were significantly lower in the group of patients who progressed to septic shock compared with those that developed severe sepsis (medians: 0.3 v 1.4 ng/mL, 21 v 86 U/dL and 45% v 95%; P < .001). The decrease of these measurements in septic shock was accompanied by an increase in prothrombin fragment 1+2 (median: 3.6 v 1.4 nmol/L; P = .05), a marker of thrombin generation. These differences were sustained throughout the septic episode (P < .0001). FVIIa and AT III levels of < 0.8 ng/mL and < 70%, respectively, at onset of fever predicted a lethal outcome with a sensitivity of 100% and 85%, and a specificity of 75% and 85%, respectively. In contrast, FXIIa-alpha antigen levels were not different between groups at onset of fever but increased modestly during the course of septic shock (P = .001). Thus, septic shock in neutropenic patients is associated with increased thrombin generation. Furthermore, both FVIIa and AT III measurements are sensitive markers of an unfavorable prognosis.

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DeMott, Joshua M., Gourang Patel, and Ishaq Lat. "Effects of Chronic Antihypertensives on Vasopressor Dosing in Septic Shock." Annals of Pharmacotherapy 52, no. 1 (August 11, 2017): 40–47. http://dx.doi.org/10.1177/1060028017726552.

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Background: In septic shock, chronic antihypertensive medications are held acutely. Vasopressors are often required to maintain blood pressure. The effect of chronic exposure to antihypertensive therapies on vasopressor dosing in septic shock is not known. Objective: To determine the effects of chronic exposure to antihypertensive therapies, specifically β-blockers and angiotensin-converting enzyme (ACE) inhibitors, on cumulative vasopressor dosing in septic shock. Methods: This was a retrospective cohort review, with data collected from routine care. Patients admitted to the medical intensive care unit with septic shock and vasopressor use were included and divided into 4 groups based on chronic medication use: (1) no β-blocker or ACE inhibitor, (2) β-blocker only, (3) ACE inhibitor only, and (4) β-blocker and ACE inhibitor. Cumulative vasopressor dose at 48 hours was assessed. Demographics, comorbid conditions, suspected site of infection, disease severity, mortality, and concomitant therapies were evaluated between groups. Results: A total of 133 patients with septic shock treated with vasopressors were included. No difference in cumulative vasopressor dose at 48 hours was detected between the 4 groups, respectively (median norepinephrine milligram equivalents [interquartile range (IQR)]: no β-blocker or ACE inhibitor, 13.7 mg [6.0-35.7]; β-blocker only, 13.1 mg [5.4-23.9]; ACE inhibitor only, 13.2 mg [1.2-36.7]; β-blocker and ACE inhibitor, 11.3 mg [4.7-42.9]; P = 0.669). Total time on vasopressors differed between groups (median hours [IQR]: no β-blocker or ACE inhibitor, 30h [17-60]; β-blocker only, 24h [10-69]; ACE inhibitor only, 19h [6-25]; β-blocker and ACE inhibitor, 30h [15-58]; P = 0.031). Comorbid conditions, suspected infection sites, disease severity, mortality, and concomitant therapies were similar. Conclusions: Chronic β-blocker, ACE inhibitor use, or the combination of both did not affect cumulative vasopressor dose at 48 hours in septic shock. However, prior-to-admission medications may affect total time of vasopressor use.

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Mink, Steven N., Krika Kasian, Luis E. Santos Martinez, Hans Jacobs, Ratna Bose, Zhao-Qin Cheng, and R. Bruce Light. "Lysozyme, a mediator of sepsis that produces vasodilation by hydrogen peroxide signaling in an arterial preparation." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 4 (April 2008): H1724—H1735. http://dx.doi.org/10.1152/ajpheart.01072.2007.

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In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium, resulting in the production of nitric oxide (NO), which, in turn, activates the myocardial soluble guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. In a phenylephrine-contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of NO synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented the vasodilatory activity of Lzm-S. In addition, Aspergillus niger catalase, which breaks down H2O2, as well as hydroxyl radical scavengers, which included hydroquinone and mannitol, prevented the effect of Lzm-S. Electrochemical sensors corroborated that Lzm-S caused H2O2 release from the carotid artery preparation. In conclusion, these results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of H2O2, which, in turn, activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock.

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Vanlaere, Ineke, and Claude Libert. "Matrix Metalloproteinases as Drug Targets in Infections Caused by Gram-Negative Bacteria and in Septic Shock." Clinical Microbiology Reviews 22, no. 2 (April 2009): 224–39. http://dx.doi.org/10.1128/cmr.00047-08.

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SUMMARY The mammalian immune system is optimized to cope effectively with the constant threat of pathogens. However, when the immune system overreacts, sepsis, severe sepsis, or septic shock can develop. Despite extensive research, these conditions remain the leading cause of death in intensive care units. The matrix metalloproteinases (MMPs) constitute a family of proteases that are expressed in developmental, physiological, and pathological processes and also in response to infections. Studies using MMP inhibitors and MMP knockout mice indicate that MMPs play essential roles in infection and in the host defense against infection. This review provides a brief introduction to some basic concepts of infections caused by gram-negative bacteria and reviews reports describing MMP expression and inhibition, as well as studies with MMP-deficient mice in models of infection caused by gram-negative bacteria and of septic shock. We discuss whether MMPs should be considered novel drug targets in infection and septic shock.

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Géloën, A., C. Pichot, S. Leroy, C. Julien, M. Ghignone, C. N. May, and L. Quintin. "Pressor Response to Noradrenaline in the Setting of Septic Shock: Anything New under the Sun—Dexmedetomidine, Clonidine? A Minireview." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/863715.

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Progress over the last 50 years has led to a decline in mortality from ≈70% to ≈20% in the best series of patients with septic shock. Nevertheless, refractory septic shock still carries a mortality close to 100%. In the best series, the mortality appears related to multiple organ failure linked to comorbidities and/or an intense inflammatory response: shortening the period that the subject is exposed to circulatory instability may further lower mortality. Treatment aims at reestablishing circulation within a “central” compartment (i.e., brain, heart, and lung) but fails to reestablish a disorganized microcirculation or an adequate response to noradrenaline, the most widely used vasopressor. Indeed, steroids, nitric oxide synthase inhibitors, or donors have not achieved overwhelming acceptance in the setting of septic shock.Counterintuitively,α2-adrenoceptor agonists were shown to reduce noradrenaline requirements in two cases of human septic shock. This has been replicated in rat and sheep models of sepsis. In addition, some data show thatα2-adrenoceptor agonists lead to an improvement in the microcirculation. Evidence-based documentation of the effects of alpha-2 agonists is needed in the setting of human septic shock.

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Vallance, P. "Use of Nitric Oxide Synthase Inhibitors in Septic Shock." Vascular Medicine Review vmr-5, no. 3 (August 1994): 185–89. http://dx.doi.org/10.1177/1358863x9400500301.

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Cobb, J. Perren. "Use of nitric oxide synthase inhibitors to treat septic shock." Critical Care Medicine 27, no. 5 (May 1999): 855–56. http://dx.doi.org/10.1097/00003246-199905000-00002.

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Watson, C., D. Rees, and R. Grover. "EXPERIENCE WITH NITRIC OXIDE INHIBITORS IN PATIENTS WITH SEPTIC SHOCK." Shock 7, Supplement (March 1997): 67. http://dx.doi.org/10.1097/00024382-199703001-00269.

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Lavranou, Georgia-Athanasia, Spyros Mentzelopoulos, Paraskevi Katsaounou, Ilias Siempos, Ioannis Kalomenidis, Aikaterini Geranaki, Christina Routsi, and Spyros Zakynthinos. "Can Coagulation System Disorders and Cytokine and Inflammatory Marker Levels Predict the Temporary Clinical Deterioration or Improvement of Septic Patients on ICU Admission?" Journal of Clinical Medicine 10, no. 8 (April 7, 2021): 1548. http://dx.doi.org/10.3390/jcm10081548.

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Although coagulation disorders and immune/inflammatory response have been associated with the final outcome of patients with sepsis, their link with thetemporaryclinical deterioration or improvement of patients is unknown. We aimed to investigate this link. We prospectively included consecutive patients admitted to the intensive care unit (ICU) with a suspected diagnosis of infection and evaluated within the first 24 h from admission. Blood levels of many cytokines and inflammatory and coagulation factors were measured and their predictive value was assessed by calculating the Area Under the Receiver Operating Characteristic (AUROC) curves. Patients (n = 102) were allocated in five groups, i.e., sepsis (n = 14), severe sepsis (n = 17), septic shock (n = 28), Systemic Inflammatory Response Syndrome (SIRS) without infection (n = 17), and trauma/surgery without SIRS or infection (n = 26). In septic shock, coagulation factors FVII and FIX and Protein C had AUROCs 0.67–0.78. In severe sepsis, Antithrombin III, Protein C, C-reactive protein, Procalcitonin and Thrombopoietin had AUROCs 0.73–0.75. In sepsis, Tumor Necrosis Factor a, and Interleukins 1β and 10 had AUROCs 0.66–0.72. In patients admitted to the ICU with a suspected diagnosis of infection, coagulation factors and inhibitors, as well as cytokine and inflammatory marker levels, have substantial predictive value in distinct groups of septic patients.

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Kilbourn, Robert. "Nitric oxide synthase inhibitors - A mechanism-based treatment of septic shock." Critical Care Medicine 27, no. 5 (May 1999): 857–58. http://dx.doi.org/10.1097/00003246-199905000-00003.

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Cobb, J. P., C. Natanson, W. D. Hoffman, R. F. Lodato, S. Banks, C. A. Koev, M. A. Solomon, R. J. Elin, J. M. Hosseini, and R. L. Danner. "N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin." Journal of Experimental Medicine 176, no. 4 (October 1, 1992): 1175–82. http://dx.doi.org/10.1084/jem.176.4.1175.

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Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.

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Wang, Jianxun, Kaoru Saijo, Dylan Skola, Chunyu Jin, Qi Ma, Daria Merkurjev, Christopher K. Glass, and Michael G. Rosenfeld. "Histone demethylase LSD1 regulates hematopoietic stem cells homeostasis and protects from death by endotoxic shock." Proceedings of the National Academy of Sciences 115, no. 2 (December 20, 2017): E244—E252. http://dx.doi.org/10.1073/pnas.1718759114.

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Hematopoietic stem cells (HSCs) maintain a quiescent state during homeostasis, but with acute infection, they exit the quiescent state to increase the output of immune cells, the so-called “emergency hematopoiesis.” However, HSCs’ response to severe infection during septic shock and the pathological impact remain poorly elucidated. Here, we report that the histone demethylase KDM1A/LSD1, serving as a critical regulator of mammalian hematopoiesis, is a negative regulator of the response to inflammation in HSCs during endotoxic shock typically observed during acute bacterial or viral infection. Inflammation-induced LSD1 deficiency results in an acute expansion of a pathological population of hyperproliferative and hyperinflammatory myeloid progenitors, resulting in a septic shock phenotype and acute death. Unexpectedly, in vivo administration of bacterial lipopolysaccharide (LPS) to wild-type mice results in acute suppression of LSD1 in HSCs with a septic shock phenotype that resembles that observed following induced deletion of LSD1. The suppression of LSD1 in HSCs is caused, at least in large part, by a cohort of inflammation-induced microRNAs. Significantly, reconstitution of mice with bone marrow progenitor cells expressing inhibitors of these inflammation-induced microRNAs blocked the suppression of LSD1 in vivo following acute LPS administration and prevented mortality from endotoxic shock. Our results indicate that LSD1 activators or miRNA antagonists could serve as a therapeutic approach for life-threatening septic shock characterized by dysfunction of HSCs.

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Ejaz, Areeba, Meher B. Ali, Fatima Siddiqui, Mashal B. Ali, and Ammarah Jamal. "Pierson Syndrome Associated with Hypothyroidism and Septic Shock." Sultan Qaboos University Medical Journal [SQUMJ] 20, no. 4 (December 28, 2020): e385-389. http://dx.doi.org/10.18295/squmj.2020.20.04.017.

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Pierson syndrome is caused by mutations in the laminin β2 gene causing absent β2 laminin, which is a normal component of the basement membranes of the mature glomerulus, structures in the anterior eye and neuromuscular junctions. The mutations manifest as congenital nephrotic syndrome and microcoria which are characteristic ocular features of this disease. These mutations may also result in neurological abnormalities such as hypotonia and psychomotor retardation. We report a two-month old boy who presented to the Pediatrics Department of Dr. Ruth K. M. Pfau Civil Hospital, Karachi, Pakistan, in 2015, with the typical features of microcoria and congenital nephrotic syndrome. The hypocalcaemia, hypoproteinaemia and probable immunocompromised state consequent to nephrotic syndrome resulted in seizures, hypothyroidism and urosepsis. Despite being treated aggressively with high dose antibiotics, ionotropic support, angiotensin-converting enzyme inhibitors, thyroxine replacement and nutritional support, the infant died due to significant multiorgan disease including renal failure and septic shock. Keywords: Pierson Syndrome; Microcoria and Congenital Nephrotic Syndrome; Congenital Microcoria; Hypothyroidism; Septic Shock; Case Report; Pakistan.

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Yang, Ni, Xiao-Lu Shi, Bing-Lun Zhang, Jian Rong, Tie-Ning Zhang, Wei Xu, and Chun-Feng Liu. "The Trend of β3-Adrenergic Receptor in the Development of Septic Myocardial Depression: A Lipopolysaccharide-Induced Rat Septic Shock Model." Cardiology 139, no. 4 (2018): 234–44. http://dx.doi.org/10.1159/000487126.

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Septic shock with low cardiac output is very common in children. However, the mechanism underlying myocardial depression is unclear. The role of β3-AR in the development of myocardial depression in sepsis is unknown. In the present study, we generated an adolescent rat model of hypodynamic septic shock induced by lipopolysaccharide (LPS). Neonatal cardiomyocytes were also treated with LPS to mimic myocardial depression in sepsis, which was confirmed via an in vivo left ventricular hemodynamic study, and measurements of contractility and the Ca2+ transient in isolated adolescent and neonatal cardiomyocytes. After 16 h of LPS treatment, cultured neonatal cardiomyocytes showed a diminished Ca2+ transient amplitude associated with an increase in the β3-AR level. With the addition of a β3-AR agonist, the Ca2+ transient in LPS-treated neonatal rat cardiomyocytes gradually decreased over time; such a change was absent in cells treated with nitric oxide synthase (NOS) inhibitors prior to treatment with a β3-AR agonist. In adolescent rats with septic myocardial depression, cardiac function declined as indicated by decreased MAP, dP/dtmax, and dP/dtmix for 6 h after LPS injection; however, the β3-AR level first increased 2 h after LPS treatment and then decreased 6 h after LPS treatment in the absence of exogenous catecholamines. The results indicate that, in vitro, at the cellular level β3-AR may be involved in the development of myocardial depression (Ca2+ transient depression) in sepsis through NOS signaling pathways; however, in vivo, a complicated mechanism for modulating β3-AR may exist.

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Vadas, P., E. Stefanski, and W. Pruzanski. "Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock." Agents and Actions 19, no. 3-4 (November 1986): 194–202. http://dx.doi.org/10.1007/bf01966206.

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Mitaka, C., Y. Hirata, K. Ichikawa, T. Uchida, K. Yokoyama, T. Nagura, Y. Tsunoda, and K. Amaha. "Effects of nitric oxide synthase inhibitor on hemodynamic change and O2 delivery in septic dogs." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 5 (May 1, 1995): H2017—H2023. http://dx.doi.org/10.1152/ajpheart.1995.268.5.h2017.

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To elucidate the role of nitric oxide (NO) in septic shock, we measured hemodynamic and pulmonary gas changes in anesthetized dogs after intravenous administration of bacterial lipopolysaccharide (LPS) with or without NO synthase inhibitor, NG-nitro-L-arginine (L-NNA). Infusion of LPS (250 ng.kg-1.min-1) for 2 h decreased mean arterial pressure over 1-4 h. Although L-NNA (10 mg/kg) blocked LPS-induced hypotension, it decreased cardiac index, oxygen delivery index, arterial pH, and arterial PO2 and increased systemic vascular resistance index in the presence or absence of LPS. Administration of NG-nitro-D-arginine (D-NNA, 10 mg/kg) alone caused fewer hemodynamic effects (increased systemic vascular resistance index and decreased cardiac index) than L-NNA alone. Our study provides evidence that L-NNA prevents endotoxin-induced hypotension but decreases cardiac output and oxygen delivery, effects that may, in part, be due to a nonspecific NO synthase-independent event. Thus clinical use of NO synthase inhibitors for the treatment of septic shock should be cautiously considered.

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Wolfe, Thomas A., and Joseph F. Dasta. "Use of Nitric Oxide Synthase Inhibitors as a Novel Treatment for Septic Shock." Annals of Pharmacotherapy 29, no. 1 (January 1995): 36–46. http://dx.doi.org/10.1177/106002809502900108.

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Erwin, Beth, Michael Denaburg, Andrew Barker, Philip McArdle, and Sam Windham. "1412: EVALUATION OF VASOPRESSIN FOR SEPTIC SHOCK IN PATIENTS ON CHRONIC RAAS INHIBITORS." Critical Care Medicine 44, no. 12 (December 2016): 428. http://dx.doi.org/10.1097/01.ccm.0000510086.19527.0f.

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Petros, A., D. Bennett, and P. Vallance. "Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock." Lancet 338, no. 8782-8783 (December 1991): 1557–58. http://dx.doi.org/10.1016/0140-6736(91)92376-d.

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Hawiger, Jacek, Ruth Ann Veach, Xue-Yan Liu, Sheila Timmons, and Dean W. Ballard. "IκB Kinase Complex Is an Intracellular Target for Endotoxic Lipopolysaccharide in Human Monocytic Cells." Blood 94, no. 5 (September 1, 1999): 1711–16. http://dx.doi.org/10.1182/blood.v94.5.1711.

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Abstract Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-κB. This transcription factor is regulated by a family of structurally related inhibitors including IκB, IκBβ, and IκBɛ, which trap NF-κB in the cytoplasm. In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IκB kinases containing catalytic subunits termed IKK (IKK1) and IKKβ (IKK2). The kinetics of IKK and IKKβ activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-κB: IκB, IκBβ, and IκBɛ. Moreover, LPS activates IKKβ preferentially, relative to IKK. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-κB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock.

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Hawiger, Jacek, Ruth Ann Veach, Xue-Yan Liu, Sheila Timmons, and Dean W. Ballard. "IκB Kinase Complex Is an Intracellular Target for Endotoxic Lipopolysaccharide in Human Monocytic Cells." Blood 94, no. 5 (September 1, 1999): 1711–16. http://dx.doi.org/10.1182/blood.v94.5.1711.417k20_1711_1716.

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Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-κB. This transcription factor is regulated by a family of structurally related inhibitors including IκB, IκBβ, and IκBɛ, which trap NF-κB in the cytoplasm. In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IκB kinases containing catalytic subunits termed IKK (IKK1) and IKKβ (IKK2). The kinetics of IKK and IKKβ activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-κB: IκB, IκBβ, and IκBɛ. Moreover, LPS activates IKKβ preferentially, relative to IKK. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-κB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock.

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Li, Yongqing, and Hasan B. Alam. "Modulation of Acetylation: Creating a Pro-survival and Anti-Inflammatory Phenotype in Lethal Hemorrhagic and Septic Shock." Journal of Biomedicine and Biotechnology 2011 (2011): 1–15. http://dx.doi.org/10.1155/2011/523481.

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Histone deacetylases (HDACs) play a key role in homeostasis of protein acetylation in histone and nonhistone proteins and in regulating fundamental cellular activities. In this paper we review and discuss intriguing recent developments in the use of histone deacetylase inhibitors (HDACIs) to combat some critical conditions in an animal model of hemorrhagic and septic shock. HDACIs have neuroprotective, cardioprotective, renal-protective, and anti-inflammatory properties; survival improvements have been significantly shown in these models. We discuss the targets and mechanisms underlying these effects of HDACIs and comment on the potential new clinical applications for these agents in the future. This paper highlights the emerging roles of HDACIs as acetylation modulators in models of hemorrhagic and septic shock and explains some contradictions encountered in previous studies.

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Aronoff, David M. "Cyclooxygenase Inhibition in Sepsis: Is There Life after Death?" Mediators of Inflammation 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/696897.

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Prostaglandins are important mediators and modulators of the inflammatory response to infection. The prostaglandins participate in the pathogenesis of hemodynamic collapse, organ failure, and overwhelming inflammation that characterize severe sepsis and shock. In light of this, cyclooxygenase (COX) inhibiting pharmacological agents have been extensively studied for their capacity to ameliorate the aberrant physiological and immune responses during severe sepsis. Animal models of sepsis, using the systemic administration of pathogen-associated molecular patterns (PAMPs) or live pathogens, have been used to examine the effectiveness of COX inhibition as a treatment for severe sepsis. These studies have largely shown beneficial effects on mortality. However, human studies have failed to show clinical utility of COX inhibitor treatment in severely septic patients. Why this approach “worked” in animals but not in humans might reflect differences in the controlled nature of animal investigations compared to human studies. This paper contrasts the impact of COX inhibitors on mortality in animal models of sepsis and human studies of sepsis and examines potential reasons for differences between these two settings.

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Ramos, Maria Fátima de Paula, Alceni do Carmo Morais Monteiro de Barros, Clara Versolato Razvickas, Fernanda T. Borges, and Nestor Schor. "Xanthine oxidase inhibitors and sepsis." International Journal of Immunopathology and Pharmacology 32 (January 1, 2018): 205873841877221. http://dx.doi.org/10.1177/2058738418772210.

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Xanthine oxidase activation occurs in sepsis and results in the generation of uric acid (UrAc) and reactive oxygen species (ROS). We aimed to evaluate the effect of xanthine oxidase inhibitors (XOis) in rats stimulated with lipopolysaccharide (LPS). LPS (10 mg/kg) was administered intraperitoneally (i.p.) immediately after allopurinol (Alo, 2 mg/kg) or febuxostat (Feb, 1 mg/kg) every 24 h for 3 days. To increase UrAc levels, oxonic acid (Oxo) was administered by gavage (750 mg/kg per day) for 5 days. Animals were divided into the following 10 groups (n = 6 each): (1) Control, (2) Alo, (3) Feb, (4) LPS, (5) LPSAlo, (6) LPSFeb, (7) Oxo, (8) OxoLPS, (9) OxoLPSAlo, and (10) OxoLPSFeb. Feb with or without Oxo did not aggravate sepsis. LPS administration (with or without Oxo) significantly decreased the creatinine clearance (ClCr) in LPSAlo (60%, P < 0.01) versus LPS (44%, P < 0.05) and LPSFeb (35%, P < 0.05). Furthermore, a significant increase in mortality was observed with LPSAlo (28/34, 82%) compared to LPS treatment alone (10/16, 63%) and LPSFeb (11/17, 65%, P < 0.05). In addition, increased levels of thiobarbituric acid reactive substances (TBARS), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were observed at 72 h compared to the groups that received LPS and LPSFeb with or without Oxo. In this study, coadministration of Alo in LPS-induced experimental sepsis aggravated septic shock, leading to mortality, renal function impairment, and high ROS and proinflammatory IL levels. In contrast, administration of Feb did not potentiate sepsis, probably because it did not interfere with other metabolic events.

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Rossi, Antonietta, Carlo Pergola, Salvatore Cuzzocrea, and Lidia Sautebin. "The Role of 5-Lipoxygenase and Leukotrienes in Shock and Ischemia-Reperfusion Injury." Scientific World JOURNAL 7 (2007): 56–74. http://dx.doi.org/10.1100/tsw.2007.34.

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The leukotrienes (LTs) are metabolic products of arachidonic acid via the 5-lipoxygenase (5-LO) pathway. The biological activities of LTs suggest that they are mediators of acute inflammatory and immediate hypersensitivity responses. In particular, the 5-LO activation has been proposed to be an important regulator for pathogenesis in multicellular organisms. The role of LTs in tissue damage, associated with septic and nonseptic shock and ischemia-reperfusion, has been extensively studied by the use of 5-LO inhibitors, receptor antagonists, and mice with a targeted disruption of the 5-LO gene (5-LOKO). In particular, several data indicate that LTs regulate neutrophil trafficking in damaged tissue in shock and ischemia-reperfusion, mainly through the modulation of adhesion molecule expression. This concept may provide new insights into the interpretation of the protective effect of 5-LO inhibition, which may be useful in the therapy of pathological conditions associated with septic and nonseptic shock and ischemia-reperfusion injury.

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Reis, Julia, Xiaoyu Tan, Rongjie Yang, Cheryl E. Rockwell, Christopher J. Papasian, Stefanie N. Vogel, David C. Morrison, Asaf A. Qureshi, and Nilofer Qureshi. "A combination of proteasome inhibitors and antibiotics prevents lethality in a septic shock model." Innate Immunity 14, no. 5 (October 2008): 319–29. http://dx.doi.org/10.1177/1753425908096855.

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Mansart, Arnaud, Pierre-Edouard Bollaert, Philippe Giummelly, Christine Capdeville-Atkinson, and Jeffrey Atkinson. "Effects of dexamethasone and l-canavanine on the intracellular calcium-contraction relation of the rat tail artery during septic shock." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 3 (September 2006): H1177—H1182. http://dx.doi.org/10.1152/ajpheart.00997.2005.

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The intracellular mechanism by which sepsis lowers vascular reactivity and the subsequent reversal by dexamethasone or nitric oxide synthase (NOS) inhibitors remain unclear. We measured the sensitivity of contraction of the rat tail artery to intracellular Ca2+ in a model of polymicrobial septic shock. At 22 h after cecal ligation and puncture (CLP), rats were treated with an anti-inflammatory glucocorticoid (dexamethasone, 1 mg/kg ip), an inducible NOS inhibitor (l-canavanine, 100 mg/kg ip), or saline. At 24 h after CLP, endothelium-denuded, perfused segments of tail artery were loaded with the intracellular Ca2+-sensitive dye fura 2 in vitro. Intracellular Ca2+ concentration and perfusion pressure were measured simultaneously. The rightward shift of the perfusion pressure-intracellular Ca2+ mobilization curve after norepinephrine stimulation subsequent to CLP indicates decreased intracellular Ca2+ sensitivity of contraction. The relation was restored by dexamethasone (which also restored in vivo blood pressure and flow), but not by l-canavanine (which restored perfusion pressure by further mobilization of intracellular Ca2+). We conclude that CLP lowers vasomotion by lowering intracellular Ca2+ sensitivity, which can be restored with glucocorticoid treatment. The involvement of inducible NOS does not solely account for the sepsis-induced reduction in Ca2+ sensitivity of contraction.

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Mavrommatis, Antonis C., Thodoris Theodoridis, Michael Economou, Anastasia Kotanidou, Mahmoud El Ali, Vana Christopoulou-Kokkinou, and Spyros G. Zakynthinos. "Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock." Intensive Care Medicine 27, no. 12 (November 10, 2001): 1853–59. http://dx.doi.org/10.1007/s00134-001-1139-8.

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Serebryanaya, N. B., and P. P. Yakutseni. "Blood platelets in the development of sepsis, septic shock and multiple organ failure syndrome." Medical Immunology (Russia) 22, no. 6 (January 10, 2021): 1085–96. http://dx.doi.org/10.15789/1563-0625-bpi-2090.

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Participation of blood platelets in the development of sepsis is clearly illustrated by hemocoagulation disorders and frequently observed thrombocytopenia. In the patients with sepsis, thrombocytopenia develops rapidly, with minimal platelet counts registered on the fourth day of observation, after which the platelet counts usually rise. Continuous thrombocytopenia and absence of a relative increase in platelets are considered predictors of patient death. The mechanisms of thrombocytopenia developing in sepsis are quite diverse, but the processes in periphery are prevailing, e.g., the so-called “platelet consumption” which is determined by their activation, chemotaxis and isolation in the microvasculature. Recently, a mechanism has been identified for the accelerated removal of platelets with desialized surface glycoproteins from the circulation. Sialidases, also known as neuraminidases, are widely present in viruses and bacteria, and pharmacological inhibition of sialidases is able to withstand thrombocytopenia in the infectious process. The key role of platelets in the development of septic shock was revealed. Sequestration of platelets in the microvessels of the lungs and brain (manifesting as thrombocytopenia) is accompanied by rapid serotonin release, thus underlying the main clinical manifestations, e.g., decreased blood pressure, heart rate and increased capillary permeability. To counteract sharp release of this mediator, pharmacological attempts are made to inhibit the SERT transporter by means of selective serotonin reuptake inhibitors. Blood platelets are key participants in the pathogenesis of multiple organ failure syndromes, such as acute renal damage, acute respiratory distress syndrome, myocardial dysfunction, and sepsis-associated encephalopathy. To restore impaired vascular permeability in these conditions, in particular, sepsis-associated encephalopathy, a pharmacological S1P receptor mimetic is under study. The review specifies possible pathogenetically significant targets that can be used to perform pharmacological correction of conditions associated with sepsis and concomitant thrombocytopenia.

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Kumar, Anand, Rupinder Brar, Peter Wang, Linda Dee, Greg Skorupa, Fadi Khadour, Richard Schulz, and Joseph E. Parrillo. "Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 276, no. 1 (January 1, 1999): R265—R276. http://dx.doi.org/10.1152/ajpregu.1999.276.1.r265.

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Previous studies have demonstrated the existence of a circulating myocardial depressant substance during human septic shock. We have recently identified this substance as a synergistic combination of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study utilized an in vitro cardiac myocyte assay to evaluate the potential mechanistic role of nitric oxide (NO) and cGMP in depression of myocyte contractility induced by TNF-α, IL-1β, TNF-α + IL-1β (at low concentrations), and human septic shock serum (HSS). TNF-α, IL-1β, TNF-α + IL-1β, and each of 5 sera from patients with acute septic shock caused depression of both maximum extent and peak velocity of cardiac myocyte shortening and an increase in intracellular cGMP concentration during 30 min of exposure (minimum P < 0.01). NO synthetase (NOS) and guanylate cyclase inhibitors such as N-methyl-l-arginine (l-NMA) and methylene blue prevented these effects; an excess ofl-arginine withl-NMA restored them (minimum P < 0.01). In contrast,d-arginine failed to reestablish cytokine-induced myocyte depression and cGMP accumulation prevented byl-NMA. Exposure of myocytes to TNF-α, IL-1β, or TNF-α + IL-1β produced a concentration-dependent increase in intracellular cGMP that paralleled the depression of cardiac myocyte contractility (minimum P < 0.001). In addition, TNF-α, IL-1β, TNF-α + IL-1β, or HSS application to cardiac myocytes resulted in increased NO gas generation, which was inhibited byl-NMA (minimum P < 0.01). Furthermore, unstimulated cardiac myocytes were shown to harbor constitutive but not inducible NOS activity. These data suggest that the sequential generation of NO by a constitutive NOS and cGMP by guanylate cyclase represents an important mechanism of cardiac myocyte depression by TNF-α, IL-1β, TNF-α + IL-1β, and the myocardial depressant substance(s) of septic shock.

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Serrano-Gomez, Sergio, Gabriel Burgos-Angulo, Daniela Camila Niño-Vargas, María Eugenia Niño, María Eugenia Cárdenas, Estephania Chacón-Valenzuela, Diana Margarita McCosham, et al. "Predictive Value of Matrix Metalloproteinases and Their Inhibitors for Mortality in Septic Patients: A Cohort Study." Journal of Intensive Care Medicine 35, no. 1 (September 21, 2017): 95–103. http://dx.doi.org/10.1177/0885066617732284.

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Purpose: Over 170 biomarkers are being investigated regarding their prognostic and diagnostic accuracy in sepsis in order to find new tools to reduce morbidity and mortality. Matrix metalloproteinases (MMPs) and their inhibitors have been recently studied as promising new prognostic biomarkers in patients with sepsis. This study is aimed at determining the utility of several cutoff points of these biomarkers to predict mortality in patients with sepsis. Materials and Methods: A multicenter, prospective, analytic cohort study was performed in the metropolitan area of Bucaramanga, Colombia. A total of 289 patients with sepsis and septic shock were included. MMP-9, MMP-2, tissue inhibitor of metalloproteinase 1 (TIMP-1), TIMP-2, TIMP-1/MMP-9 ratio, and TIMP-2/MMP-2 ratio were determined in blood samples. Value ranges were correlated with mortality to estimate sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiving operating characteristic curve. Results: Sensitivity ranged from 33.3% (MMP-9/TIMP-1 ratio) to 60.6% (TIMP-1) and specificity varied from 38.8% (MMP-2/TIMP-2 ratio) to 58.5% (TIMP-1). As for predictive values, positive predictive value range was from 17.5% (MMP-9/TIMP-1 ratio) to 70.4% (MMP-2/TIMP-2 ratio), whereas negative predictive values were between 23.2% (MMP-2/TIMP-2 ratio) and 80.9% (TIMP-1). Finally, area under the curve scores ranged from 0.31 (MMP-9/TIMP-1 ratio) to 0.623 (TIMP-1). Conclusion: Although TIMP-1 showed higher sensitivity, specificity, and negative predictive value, with a representative population sample, we conclude that none of the evaluated biomarkers had significant predictive value for mortality.

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GRANT, I. S., and S. J. MACKENZIE. "Clinical observations on the use of phosphodiesterase inhibitors as second-line inotropes in septic shock." Clinical Intensive Care 8, no. 1 (February 1997): 10–13. http://dx.doi.org/10.3109/tcic.8.1.10.13.

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Erwin, Beth L., Michael A. Denaburg, Andrew B. Barker, Philip J. McArdle, Samuel T. Windham, and Charity J. Morgan. "Evaluation of Vasopressin for Septic Shock in Patients on Chronic Renin-Angiotensin-Aldosterone System Inhibitors." Critical Care Medicine 45, no. 12 (December 2017): e1226-e1232. http://dx.doi.org/10.1097/ccm.0000000000002729.

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Pedoto, Alessia, Apostolos K. Tassiopoulos, Albert Oler, Daniel J. McGraw, Stephen P. Hoffmann, Enrico M. Camporesi, and Tawfic S. Hakim. "Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide." Critical Care Medicine 26, no. 12 (December 1998): 2021–28. http://dx.doi.org/10.1097/00003246-199812000-00034.

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Masuda, Kazuya, and Tadamitsu Kishimoto. "A Potential Therapeutic Target RNA-binding Protein, Arid5a for the Treatment of Inflammatory Disease Associated with Aberrant Cytokine Expression." Current Pharmaceutical Design 24, no. 16 (August 29, 2018): 1766–71. http://dx.doi.org/10.2174/1381612824666180426103753.

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Background: Infection, tissue damage and aging can cause inflammation with high levels of inflammatory cytokines. Overproduction of inflammatory cytokines often leads to systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock. However, prominent therapeutic targets have not been found, although the incidence of sepsis is likely to increase annually. Our recent studies indicate that some RNA-binding proteins, which control gene expression of inflammatory cytokines at the post-transcriptional level, may play a critical role in inflammatory diseases such as sepsis. Results: 1) One of the RNA-binding proteins, AT-rich interactive domain-containing 5a (Arid5a) promotes cytokine production through control of mRNA half-lives of pro-inflammatory molecules such as IL-6, STAT3, T-bet, and OX40 in activated macrophages and T cells. Arid5a KO mice are refractory to endotoxin shock, bleomycininduced lung injury, and inflammatory autoimmune disease. 2) Chlorpromazine (CPZ), which is recognized as a psychotic drug, impairs post-transcriptional gene expression of Il6 in LPS-stimulated macrophages: CPZ inhibits the binding activity of Arid5a to the 3’UTR of Il6 mRNA, thereby destabilizing Il6 mRNA possibly through suppression of Arid5a expression. 3) CPZ has strong suppressive effects on cytokine production such as TNF-α in vivo. Mice with treatment of CPZ are resistant to lipopolysaccharide (LPS)-induced shock. Conclusion: Thus, Arid5a contributes to the activation of macrophages and T cells through positive control of mRNA half-lives of inflammatory cytokines and its related molecules, which might lead to cytokine storm. Interestingly, Arid5a was identified from an inhibitory effect of CPZ on IL-6 production in macrophages activated by LPS. Therefore, CPZ derivatives or Arid5a inhibitors may have a potential to suppress severe sepsis through control of post-transcriptional gene expression.

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Pullamsetti, Soni, Daniel Maring, Hossein Ghofrani, Konstantin Mayer, Norbert Weissmann, Bernhard Rosengarten, Martin Lehner, et al. "Effect of nitric oxide synthase (NOS) inhibition on macro- and microcirculation in a model of rat endotoxic shock." Thrombosis and Haemostasis 95, no. 04 (2006): 720–27. http://dx.doi.org/10.1160/th05-07-0518.

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SummaryTreatment of hemodynamic instability in septic shock often demands the administration of vasopressor agents, although these may have deleterious effects on microcirculatory homeostasis. Inhibition of nitric oxide synthase (NOS) has been suggested as an alternative therapeutic approach, as NO formation may be excessively increased in sepsis. To compare the effects of epinephrine titration, non-selective NOS inhibition by L-NMMA and selective inhibition of inducible NOS (iNOS) by 1400W on hemodynamics and on the regulation of microcirculation in a rat model of endotoxic shock, we intravenously injected endotoxin (LPS) or saline to male Wist ar rats and after 2 hours randomized LPS treated rats into four different groups that received either saline, norepinephrine, L-NMMA or 1400W (n=6 per group). Three hours after LPS administration, rats presented with severe systemic arterial hypotension (64 ± 3 vs. 115 ± 4 mmHg, p<0.001), unresponsiveness to volume treatment, lactate acidosis and a marked increase in plasmatic nitrite and nitrate levels (15 ±8 vs. 263 ± 47 µM, p<0.001). Measurement of the tissue oxygenation in the ileum mucosal layer by the Erlangen micro-lightguide spectrophotometer (EMPHO) technique demonstrated marked heterogeneity of hemoglobin saturation, with appearance of low oxygenated areas. Norepinephrine, usually stabilizing blood pressure (99 ±7 vs. 67 ±4 mmHg 60 min after infusion, p<0.01), increased lactate formation (7.9± 0.2 vs. 3.7 ± 0.5 mM, p<0.001) and drastically increased low oxygenated regions in the ileum mucosal layer. L-NMMA similarly increased blood pressure (92 ±6 vs. 67 ±4 mmHg 60 min after infusion, p<0.05), but did not enhance lactate acidosis. However, some further deterioration of mucosa oxygenation was again noted. 1400W forwarded stabilization of blood pressure (88 ± 5 vs. 67 ±4 mmHg 60 min after injection, p<0.05), reduced plasmatic nitrite and nitrate levels similar to L-NMMA, without an aggravation of lactate acidosis. In addition, mucosal oxygenation did not deteriorate in response to this agent. Thereby, we conclude that in a rat model of endotoxic shock selective iNOS inhibitors are superior to non-specific NOS inhibitors and in particular to norepinephrine for the treatment of macro-and microcirculatory abnormalities in experimental septic shock.

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Fauvel, Harold, Rémi Neuviere, Claude Chopin, Pierre Formstecher, and Philippe Marchetti. "Inhibitors of apoptosis display a cardioprotective effect in vivo in a rat model of septic shock." Biology of the Cell 91, no. 7 (September 1999): 558–558. http://dx.doi.org/10.1016/s0248-4900(99)90275-7.

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Sexe, Jordan, Chadwick Mayes, and Peter Tofts. "Euglycemic Diabetic Ketoacidosis in a Lung Cancer Patient Using Empagliflozin." Case Reports in Critical Care 2020 (July 1, 2020): 1–3. http://dx.doi.org/10.1155/2020/7437892.

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Diabetic ketoacidosis is a leading cause of morbidity and mortality in diabetic patients, and its diagnosis should be timely and accurate. SGLT2 inhibitors are a new class of antidiabetic medications that increase the renal excretion of glucose. It is thought that increased urinary excretion of glucose will mask hyperglycemia during DKA. This can lead to a delayed diagnosis of DKA and worsen outcomes. In this report, we detail a case of euglycemic DKA in a patient who presented to the Emergency Department meeting criteria for septic shock.

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Clayton, Jennifer K., and Jessica A. Starr. "Novel Approaches to the Treatment of Sepsis Syndrome." Journal of Pharmacy Practice 21, no. 5 (August 8, 2008): 371–79. http://dx.doi.org/10.1177/0897190008318233.

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Sepsis, severe sepsis, and septic shock are common diagnoses in intensive care units worldwide. In the United States, it is estimated that 750 000 cases of sepsis occur annually. This rate is expected to climb, with an additional 1 million cases per year expected by 2020. These infection-induced inflammatory syndromes ultimately lead to organ dysfunction, and a significantly high mortality rate. Recently, advances in knowledge of sepsis syndrome have led to progress in identifying potential treatment options beyond our current standards of care. Many health care facilities have implemented protocols to guide clinicians to use such standards: early goal-directed therapy and activated protein C therapy in qualifying patients. Nonetheless, debate continues to confuse identification of patient populations in whom corticosteroid therapy should be recommended. While the data describing studies of novel treatment approaches has been controversial in some cases, there have been promising results observed in others. Here we review several treatments that have recently gained attention in the medical literature: HMG-CoA reductase inhibitors (statins), selenium therapy, immunoglobulin therapy, and several agents currently in preclinical study.

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Zhou, Xin Mei, Man Li Xia, Min Wang, Ce Xu, and Qiang Xia. "Effect of nitric oxide synthase inhibitors on hemodynamic parameters and thoracic aorta tension in septic shock rats." Cell Biology International 32, no. 3 (March 2008): S21. http://dx.doi.org/10.1016/j.cellbi.2008.01.096.

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Yamaji, Kazuyo, Krishna Sarker, Koichi Kawahara, Satoshi Iino, Munekazu Yamakuchi, Kazuhiro Abeyama, Teruto Hashiguchi, and Ikuro Maruyama. "Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implications." Thrombosis and Haemostasis 89, no. 05 (2003): 875–84. http://dx.doi.org/10.1055/s-0037-1613475.

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SummaryAnandamide (AEA), an endogenous cannabinoid, is generated by macrophages during shock conditions, and is thought to be a causative mediator of septic shock. Thus, we hypothesized that AEA plays a crucial role in endothelial cell (EC) injury. Here, we demonstrate that AEA induces apoptosis in a time-and dose-dependent manner in human umbilical vein endothelial cells (HUVECs). AEA triggered phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38 mitogen activated protein kinase. AEA also showed a marked increase of interleukin 1β–converting enzyme (ICE)CED-3 family protease (caspase-3) activity. AEA-induced EC death was inhibited by a selective vanilloid receptor 1 (VR1) antagonist, capsazepine, and was enhanced by a VR1 agonist, capsaicin, indicating that AEA induces apoptosis in ECs via VR1. In conclusion, we propose that AEA may play a crucial role in EC injury under conditions of shock, and that the use of inhibitors of the AEA regulation system may have a therapeutic effect under these conditions.

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Hessler, Michael, Bernardo B. Pinto, Philip-Helge Arnemann, Tim-Gerald Kampmeier, Laura Seidel, Andrea Morelli, Hugo Van Aken, Martin Westphal, Sebastian Rehberg, and Christian Ertmer. "Differential Effects of Selective and Nonselective Potassium Channel Inhibitors in Ovine Endotoxemic Shock (Macrocirculation) and in a Rat Model of Septic Shock (Microcirculation)." SHOCK 51, no. 2 (February 2019): 247–55. http://dx.doi.org/10.1097/shk.0000000000001113.

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Journal articles on the topic 'Septic shock; Inhibitors'

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