piperidines and Shock--Septic

Anti-melanoma differentiation-associated gene 5 juvenile dermatomyositis (anti-MDA5 JDM) is associated with high risk of developing rapidly progressive interstitial lung disease (RP-ILD). Here we report an 11-year-old girl with anti-MDA5 JDM and RP-ILD which led to a fatal outcome, further aggravated by SARS-CoV-2 infection. She was referred to our hospital after being diagnosed with anti-MDA5 JDM and respiratory failure due to RP-ILD. On admission, fibrobronchoscopy with bronchoalveolar lavage (BAL) revealed

Topics: Adenosine Monophosphate; Alanine; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Antiviral Agents; Autoantibodies; Bronchoscopy; Child; COVID-19; COVID-19 Nucleic Acid Testing; Cyclophosphamide; Dermatomyositis; Disease Progression; Fatal Outcome; Female; Humans; Hydroxychloroquine; Immunocompromised Host; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung; Lung Diseases, Interstitial; Lymphohistiocytosis, Hemophagocytic; Mediastinal Emphysema; Methylprednisolone; Piperidines; Pneumonia, Pneumocystis; Pneumothorax; Pyrimidines; Respiratory Insufficiency; Shock, Septic; Subcutaneous Emphysema; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination

Rheumatoid arthritis is a chronic inflammatory disease of joints. Dysoxylum binectariferum Hook.f (Family: Meliaceae) is a Indian medicinal plant which is traditionally being used to heal inflammation of joints.. This work was aimed to carry out chemical standardization, in-vitro/in-vivo validation, oral pharmacokinetics and formulation development of anti-arthritic botanical lead, the rohitukine-enriched fraction of D. binectariferum.. The rohitukine-enriched fraction of D. binectariferum was standardized using four chemical markers and was checked for microbial load, heavy metal content, aflatoxins and pesticides. Its in-vitro inhibitory effect on the lipopolysaccharide (LPS) induced production of pro-inflammatory cytokines TNF-α and IL-6 was studied in THP-1 cells. The in-vivo anti-arthritic activity was investigated in collagen-induced arthritis model in DBA/1J mice. The sustained release capsule formulation was developed and characterized for physicochemical and pharmacokinetic properties.. Rohitukine and schumaniofioside A were found to be major chemical constituents of the botanical lead. The rohitukine-enriched fraction of D. binectariferum significantly reduced the production of both pro-inflammatory cytokines TNF-α and IL-6 (>50% inhibition at 3.12 μg/mL) in THP-1 cells. In LPS-treated wild-type mice model, the rohitukine-enriched fraction at 200 mg/kg (PO, QD) completely reduced serum TNF-α levels. In transgenic mice model (collagen-induced arthritis in DBA/1J mice), rohitukine-enriched fraction at 100 mg/kg (PO, QD) dose has resulted in >75% reduction of TNF-α/IL-6 serum levels, 68% reduction in anti-mouse type II collagen IgG1 antibody levels, decreased joint proteoglycan loss and reduced paw edema in DBA/1J mice. The sustained release capsule formulation of rohitukine-enriched fraction showed sustained-release of rohitukine over the period of 24 h, and resulted in an improved plasma-exposure of rohitukine in SD rats.. The data presented herein demonstrated anti-arthritic potential of rohitukine-enriched fraction of D. binectariferum and this study will serve as the benchmark for further research on this botanical lead and developed sustained release capsule formulation.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Chromones; Cytokines; Delayed-Action Preparations; Female; Foot Joints; Humans; Male; Meliaceae; Mice, Inbred BALB C; Mice, Inbred DBA; Piperidines; Plant Extracts; Plant Leaves; Rats, Sprague-Dawley; Shock, Septic; THP-1 Cells; Tumor Necrosis Factor-alpha

Tofacitinib, a janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis (RA). Septic arthritis (SA) and sepsis caused by Staphylococcus aureus (S. aureus), for which RA patients are at risk, are infections with high mortality. The aim of this study was to investigate the effect of tofacitinib on S. aureus infections using mouse models. In vitro tofacitinib treated mouse splenocytes were stimulated with S. aureus derived stimuli. Mice pre-treated with tofacitinib were inoculated intravenously with either arthritogenic- or septic doses of S. aureus. Arthritis severity and mortality were compared between groups. Additionally, pre-treated mice were challenged with staphylococcal toxin TSST-1 to induce shock. Tofacitinib inhibited splenocyte proliferation and IFN-γ production in response to TSST-1 and dead S. aureus. In SA, tofacitinib treatment aggravated arthritis with more severe bone erosions. However, in sepsis, treated mice displayed significantly prolonged survival compared to controls. Similarly, in staphylococcal enterotoxin-induced shock tofacitinib pre-treatment, but not late treatment dramatically reduced mortality, which was accompanied by decreased levels of TNF-α and IFN-γ. Our findings show that tofacitinib treatment increase susceptibility of SA in mice, but has a positive effect on survival in S. aureus-induced sepsis and a strong protective effect in toxin-induced shock.

Topics: Animals; Arthritis, Infectious; Cytokines; Disease Progression; Drug Administration Schedule; Female; Immunosuppressive Agents; Janus Kinases; Mice; Mice, Inbred BALB C; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sepsis; Shock, Septic; Spleen; Staphylococcal Infections; Staphylococcus aureus; T-Lymphocytes

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Delayed Diagnosis; Disease Susceptibility; Disseminated Intravascular Coagulation; Fatal Outcome; Humans; Immunocompromised Host; Lymphoma, Mantle-Cell; Male; Meningitis, Bacterial; Neoplasm Proteins; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Risk Factors; Shock, Septic

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medical use. Piperine exhibits anti-inflammatory activity; however, the underlying mechanism remains unknown. We examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses. Administration of piperine inhibited LPS-induced endotoxin shock, leukocyte accumulation and the production of tumor necrosis factor-alpha (TNF-alpha), but not of interleukin (IL)-1beta and IL-6. In peritoneal macrophages, piperine inhibited LPS/poly (I:C)/CpG-ODN-induced TNF-alpha production. Piperine also inhibited LPS-induced endotoxin shock in TNF-alpha knockout (KO) mice. To clarify the inhibitory mechanism of LPS-induced endotoxin shock, type 1 interferon (IFN) mRNA expression was determined. Piperine inhibited LPS-induced expression of type 1 IFN mRNA. Piperine inhibited the levels of interferon regulatory factor (IRF)-1 and IRF-7 mRNA, and the phosphorylation and nuclear translocation of IRF-3. Piperine also reduced activation of signal transducer and activator of transcription (STAT)-1. In addition, activation of STAT-1 was inhibited in IFN-alpha/beta-treated cells by piperine. These results suggest that piperine inhibits LPS-induced endotoxin shock through inhibition of type 1 IFN production.

Topics: Alkaloids; Animals; Benzodioxoles; Female; Gene Knockout Techniques; Inflammation; Interferon Type I; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides; Shock, Septic; STAT1 Transcription Factor; Tumor Necrosis Factor-alpha

1. Our study was undertaken to investigate whether bacterial endotoxin/lipopolysaccharide (LPS) affects the neurogenic vasopressor response in rats in vivo by presynaptic mechanisms and, if so, to characterize the type of presynaptic receptor(s) operating in the initial phase of septic shock. 2. In pithed and vagotomized rats treated with pancuronium, electrical stimulation (ES) (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibers or intravenous bolus injection of noradrenaline (NA) (1-3 nmol x kg(-1)) increased the diastolic blood pressure (DBP) by about 30 mmHg. Administration of LPS (0.4 and 4 mg x kg(-1)) under continuous infusion of vasopressin inhibited the neurogenic vasopressor response by 25 and 50%, respectively. LPS did not affect the increase in DBP induced by exogenous NA. 3. The LPS-induced inhibition of the neurogenic vasopressor response was counteracted by the cannabinoid CB(1) receptor antagonist SR 141716A (0.1 micromol x kg(-1)), but not by the CB(2) receptor antagonist SR 144528 (3 micromol x kg(-1)), the vanilloid VR1 receptor antagonist capsazepine (1 micromol x kg(-1)) or the histamine H(3) receptor antagonist clobenpropit (0.1 micromol x kg(-1)). The four antagonists by themselves did not affect the increase in DBP induced by ES or by injection of NA in rats not exposed to LPS. 4. We conclude that in the initial phase of septic shock, the activation of presynaptic CB(1) receptors by endogenously formed cannabinoids contributes to the inhibition of the neurogenic vasopressor response.

Topics: Animals; Autonomic Fibers, Postganglionic; Autonomic Fibers, Preganglionic; Blood Pressure; Camphanes; Capsaicin; Decerebrate State; Disease Models, Animal; Electric Stimulation; Germany; Imidazoles; Infusions, Intravenous; Lipopolysaccharides; Male; Norepinephrine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Presynaptic; Rimonabant; Shock, Septic; Solvents; Thiourea; Vagotomy; Vasomotor System; Vasopressins

1. The effects of the selective and potent novel platelet-activating factor (PAF) antagonist, UR-12633 (1-(3,3-diphenylpropionyl)-4-(3-pyridylcyanomethyl)piperidin e) on several markers of endotoxic shock syndrome were evaluated in rats and mice. 2. UR-12633, administered 60 min after E. coli lipopolysaccharide (LPS), reversed the LPS-induced sustained hypotension in rats at doses of 0.01 to 1 mg kg-1, i.v. The reference compound WEB-2086 (1 mg kg-1) also reversed the LPS-induced hypotension. UR-12633 (1 mg kg-1), administered 10 min before LPS, almost fully inhibited sustained hypotension. The immediate hypotension (within 1 min) caused by LPS was not prevented by either UR-12633 or WEB-2086. 3. Pretreatment with 10 mg kg-1, i.v. of either UR-12633 or WEB-2086 inhibited the increase in disseminated intravascular coagulation markers, such as activated partial thromboplastin time (55 and 74% inhibition, respectively), and prothrombin time (22 and 72% inhibition) and prevented the decrease in plasma fibrinogen content (100 and 29% inhibition). 4. Increases in acid phosphatase (ACP) plasma activity, a marker of lysosomal activation, and in lactate dehydrogenase (LDH), a marker of tissue damage, were inhibited by pretreatment with 10 mg kg-1, i.v. of either UR-12633 or WEB-2086 (100% and 69% inhibition, ACP; 62 and 48% inhibition, LDH). Hyperglycaemia (71 and 46%) and hyperlactacidaemia (92 and 56%) were also inhibited. 5. UR-12633, but not WEB-2086, inhibited the LPS-induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the increase in Evans blue dye extravasation. 6. In a series of nine reference compounds and UR-12633, we found a high correlation (P < 0.001) between PAF antagonist activity, measured as the inhibition of PAF-induced rabbit platelet aggregation or PAF-induced mortality in mice and the inhibition of LPS-induced mortality. 7. In spite of the multifactorial nature of endotoxic shock, in which many mediators may be involved, the new potent PAF antagonist, UR-12633, proved effective in protecting against changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents.

Topics: Analysis of Variance; Animals; Azepines; Blood Pressure; Cell Membrane; Disease Models, Animal; Escherichia coli; Hypotension; Lipopolysaccharides; Male; Mice; Piperidines; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Sprague-Dawley; Shock, Septic; Triazoles

1. We investigated the effects of the selective endothelin (ET)A receptor antagonist BQ-485 and the selective ETB receptor antagonist BQ-788 on circulatory failure, multiple organ dysfunction syndrome (MODS) and the alterations in acid base balance caused by endotoxaemia in the anaesthetized rat. 2. Male Wistar rats were anaesthetized (thiopentone sodium; 120 mg kg-1, i.p.) and received a continuous infusion of vehicle (saline, 0.6 ml kg-1h-1, i.v.), BQ-485 (10 nmol kg-1 min-1, i.v.) or BQ-788 (10 nmol kg-1 min-1, i.v.). Fifteen min later, animals received a bolus injection of either saline (0.9% NaCl, 1 ml kg-1, i.v.) or E. coli lipopolysaccharide (LPS, 10 mg kg-1, i.v.). 3. Injection of LPS resulted in a fall in blood pressure from 115 +/- 4 mmHg (time 0) to 82 +/- 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the pressor responses to noradrenaline (NA, 1 microgram kg-1, i.v.). Infusion of BQ-788 attenuated the delayed hypotension (at 360 min: 100 +/- 4 mmHg, n = 7; P < 0.05) and significantly enhanced the pressor responses elicited by NA (at 60 to 240 min). In contrast, treatment of LPS-rats with BQ-485 augmented the hypotension (at 360 min), but did not affect the vascular hyporeactivity elicited by endotoxaemia. 4. Endotoxaemia for 360 min resulted in rises in the serum levels of urea and creatinine (indicators of renal failure), glutamate-oxalate-transferase (GOT) and glutamate-pyruvate-transferase (GPT) (indicators of hepatocellular injury), and bilirubin and gamma-glutamyl transferase (gamma GT) (indicators of liver failure) as well as nitrite (indicator of the induction of nitric oxide synthase; iNOS). Treatment of LPS-rats with BQ-788, but not with BQ-485, attenuated the degree of liver injury and failure, while neither BQ-788 nor BQ-485 affected the acute renal failure or the induction of iNOS caused by endotoxin. 5. Endotoxaemia also caused (within 15 min) an acute metabolic acidosis (falls in pH, HCO3-and base excess) which was compensated by hyperventilation (fall in PaCO2). Treatment of LPS-rats with BQ-788 or BQ-485 did not affect the metabolic acidosis caused by LPS. 6. Thus, the selective ETB receptor antagonist BQ-788 attenuated (i) the delayed hypotension, (ii) the vascular hyporeactivity to NA as well as (iii) the degree of hepatocellular injury and dysfunction caused by endotoxin in the anaesthetized rat. In contrast, the selective ETA receptor antagonist did neither attenuate the circulatory failure nor the liver or rena

Topics: Alanine Transaminase; Analysis of Variance; Animals; Aspartate Aminotransferases; Azepines; Blood Pressure; Creatinine; Endotoxemia; Escherichia coli; Heart Rate; Hypotension; Lipopolysaccharides; Male; Nitric Oxide; Oligopeptides; Piperidines; Rats; Rats, Wistar; Shock, Septic; Urea

In anesthetized piglets the influence of an LD100 of Escherichia coli endotoxin (0.5 mg/kg IV, bolus injection) on several hemodynamic parameters and on survival time was studied. Endotoxin provoked a pronounced decrease in arterial pressure and cardiac output and an increase in portal venous and pulmonary arterial pressure and heart rate. Total peripheral and mesenteric vascular resistances displayed an initial increase followed by a sustained decrease, whereas pulmonary vascular resistance revealed a pronounced biphasic increase. All pigs died within 210 min following endotoxin administration. Pretreatment with the 5-HT2-antagonists R 41468 and R 50970 and with the prostanoid-synthesis inhibitor flurbiprofen induced a significant attenuation of the increase in pulmonary vascular resistance and beneficial effects on survival. Best survival results were obtained with prednisolone sodium succinate, although these results can only partly be ascribed to beneficial hemodynamic effects. The experiments with the opiate antagonists, however, point to detrimental effects.

Topics: Adrenal Cortex Hormones; Anesthesia; Animals; Bacterial Toxins; Blood Pressure; Cardiac Output; Enterotoxins; Escherichia coli Proteins; Flurbiprofen; Heart Rate; Hemodynamics; Ketanserin; Narcotic Antagonists; Piperidines; Prednisone; Pulmonary Circulation; Serotonin Antagonists; Shock, Septic; Swine; Time Factors; Vascular Resistance

A septic shock state was induced in cats by intravenous infusion of live Escherichia coli bacteria. Cats pretreated with an unspecific 5-HT blocker, dihydroergotamine (DHE), or with a specific 5-HT blocker, ketanserin, were compared with a series receiving bacteria without pretreatment. DHE pretreatment prevented the reduction in systemic arterial blood pressure found in the other series during the 2-hour period of septic shock. Pretreatment could not influence the increased vascular resistance in the pulmonary vascular bed or the early increase in pulmonary arterial blood pressure. Peripheral blood flow distribution was studied using radioactive labelled microspheres. Compared to bacteremia without pretreatment, the 5-HT blockers increased CNS blood flow and ketanserin also prevented the reduction in pancreatic blood flow. Gastric blood flow and gastric mucosal blood flow remained unchanged in all series as did the small intestinal total blood flow. Small intestinal mucosal blood flow, however, was reduced after 2 h of bacteremia. Microscopy revealed no gastric epithelial damage while the jejunal mucosa was characteristically damaged. There was no correlation between the changes in the small intestinal blood flow and the degree of mucosal damage, however, supporting the countercurrent theory for the pathogenesis of these lesions.

Topics: Animals; Blood Pressure; Cardiovascular System; Cats; Dihydroergotamine; Escherichia coli Infections; Gastric Mucosa; Intestinal Mucosa; Ketanserin; Piperidines; Regional Blood Flow; Sepsis; Shock, Septic; Vascular Resistance

A standardized septic shock was induced in cats by intravenous infusion of a live E. coli bacteria strain. The bacterial infusion induced a rapid haemodynamic response characterized mainly by a pulmonary arterial hypertension and a late phase characterized by systemic hypotension and hypodynamic circulation. Systemic arterial, pulmonary arterial, portal venous, left atrial pressures, max inspiratory-expiratory pressure difference in the trachea, aortic and intestinal blood flows were monitored. Arterial blood samples were taken for recording the number of circulating platelets and white blood cells and for determining the acid-base balance. The effect of pretreatment with ketanserin, a specific 5-hydroxytryptamine2 (5-HT2)-receptor blocker on these haemodynamic reactions was studied. In short term experiments on non-bacteriaemic control cats, ketanserin prevented the pulmonary hypertension induced by intravenous 5-HT infusions but not the increase in intestinal blood flow. Ketanserin induced a reduction of total peripheral (including intestinal) vascular resistance to blood flow but had no effect on aortic blood flow. After infusion of bacteria, ketanserin pretreated cats were more hypotensive due to a relative peripheral dilatation of the resistance vessels. Ketanserin pretreatment had no effect on the pulmonary vascular reactions, the tracheal pressure difference or the number of circulating platelets or white blood cells. Thus, except for a more pronounced hypotension early after bacterial infusion, ketanserin pretreatment did not influence the haemodynamic response. It is concluded that 5-HT is not of significant importance in the pathogenesis of the haemodynamic reactions following experimental bacteraemia.

Topics: Animals; Blood Pressure; Cats; Escherichia coli Infections; Hemodynamics; Intestines; Ketanserin; Lung; Piperidines; Premedication; Regional Blood Flow; Shock, Septic; Time Factors; Vascular Resistance

The well-documented acute cardiodynamic changes in canine endotoxemia were significantly altered by pretreatment with either a newly synthesized serotonin receptor antagonist (ketanserin) or with a prostaglandin synthetase inhibitor (indomethacin). Ketanserin, but not indomethacin, significantly attenuated the endotoxin-induced pulmonary hypertension and vasoconstriction but had no effect on the typical systemic hemodynamic changes. In sharp contrast, indomethacin significantly attenuated systemic hypotension and enhanced peripheral vascular resistance. Neither drug influenced the typical acute fall in cardiac output or the capillary permeability edema; neither drug attenuated the metabolic acidosis of endotoxemia. These results imply that, although serotonin and the prostaglandins each participate in a unique manner in the pathophysiology of experimentally induced endotoxic shock, neither autacoid appeared singularly responsible for the hemodynamic and metabolic alterations consistently observed.

Topics: Animals; Dogs; Hemodynamics; Indomethacin; Ketanserin; Oxygen; Piperidines; Prostaglandins; Pulmonary Circulation; Serotonin; Serotonin Antagonists; Shock, Septic

Pulmonary hypertension secondary to sepsis is due, in part, to release of serotonin from platelets. This study examines the effects of ketanserin, a new, highly specific serotonin antagonist, on platelet aggregation and the cardiovascular changes associated with bacterial endotoxemia in dogs. Ketanserin markedly inhibits in vitro platelet aggregation induced by mixing serotonin and epinephrine. When ketanserin is administered to animals before endotoxin infusion, cardiac output is greater and mean pulmonary artery pressure (MPAP), pulmonary and systemic vascular resistance (PVR and SVR) and arteriovenous oxygen content difference [C(a-v)O2] are less than in animals not receiving ketanserin. Similar results for PVR, SVR, and C(a-v)O2 are obtained when ketanserin is administered after endotoxin infusion. The data indicate that ketanserin inhibits serotonin-induced platelet aggregation and modifies many cardiovascular changes associated with bacterial endotoxemia.

Topics: Animals; Dogs; Epinephrine; Hemodynamics; Hypertension, Pulmonary; Ketanserin; Male; Oxygen; Piperidines; Platelet Aggregation; Serotonin; Serotonin Antagonists; Shock, Septic

Topics: Animals; Atropine; Blood Circulation; Blood Pressure; Blood Pressure Determination; Chloralose; Cyproheptadine; Diphenhydramine; Dogs; Endotoxins; Hemorrhage; Histamine H1 Antagonists; Histamine Release; Humans; Hypertension; Hypertension, Portal; Isoproterenol; Morphine; p-Methoxy-N-methylphenethylamine; Pharmacology; Phenothiazines; Phenoxybenzamine; Piperidines; Research; Reserpine; Shigella; Shock, Septic; Splenic Artery; Sympatholytics; Vasodilator Agents