Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anisodamine, an anticholinergic drug, is widely used in China for treatment of infants with septic shock and has been reported to inhibit thromboxane synthesis in cultured cells. Thromboxane A2 plays an important role in the early pulmonary hypertension in sepsis; however, the role of thromboxane A2 later in sepsis is unclear. We tested the hypothesis that thromboxane A2 synthesis inhibition with dazmegrel, and cholinergic blockade with anisodamine, would attenuate the later phase of pulmonary hypertension induced by 4 h of group B streptococcus (GBS) infusion. 1 mg/kg of dazmegrel reversed the pulmonary hypertension and slightly increased cardiac output; these hemodynamic improvements persisted for 30-60 min. Plasma thromboxane B2 levels returned toward pre-GBS baseline values after dazmegrel treatment. Thus, thromboxane A2 is still a major mediator of pulmonary hypertension in piglets after 4 h of continuous GBS infusion. 0.5 mg/kg of anisodamine had no significant hemodynamic effect. 2 and 4 mg/kg of anisodamine each caused transient, dose-related decreases in systemic artery pressure; cardiac output also fell after the highest anisodamine dose. Pulmonary hypertension was not alleviated by anisodamine. All hemodynamic changes induced by anisodamine were short-lived and returned to preanisodamine values within 10 min. Anisodamine did not ameliorate thromboxane-mediated pulmonary hypertension in this animal model, and therefore may not inhibit thromboxane synthesis in vivo. The results of this study do not support the use of anticholinergic therapy to improve hemodynamics in GBS sepsis, but do suggest that thromboxane synthesis inhibition may be a clinically useful therapy in advanced GBS sepsis.
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PMID:Delayed thromboxane synthesis inhibition, but not cholinergic blockade, reverses group B streptococcus-induced pulmonary hypertension. 130 45

Isoproterenol, dobutamine, dopamine, and nitroprusside are four vasoactive drugs used to decrease pulmonary arterial pressure and increase cardiac output in newborns, infants, and children with sepsis. Thromboxane A2 likely produces some of the hemodynamic changes in sepsis, and U46619, a thromboxane A2 mimetic, produces similar changes in lambs. We studied the hemodynamic effects of these four vasoactive drugs in 10 spontaneously breathing newborn lambs during an infusion of U46619. After baseline hemodynamic measurements, U46619 (1-2 micrograms/kg/min) was infused to increase pulmonary arterial pressure and to decrease cardiac output. Then, either isoproterenol (0.05-1.0 micrograms/kg/min), dobutamine (5-20 micrograms/kg/min), dopamine (3-30 micrograms/kg/min), or nitroprusside (0.5-10.0 micrograms/kg/min) was infused. Every 10 min, measurements were repeated and the dose increased. U46619 significantly increased pulmonary arterial pressure by 182% and decreased cardiac output by 25% (p less than 0.05). Isoproterenol decreased pulmonary arterial pressure by 30% (p less than 0.05) and increased cardiac output by 25% (p less than 0.05) at low doses, and increased cardiac output by 115% at the maximum dose (p less than 0.05). Dobutamine decreased pulmonary arterial pressure by 11% (p less than 0.05) at low doses, and increased cardiac output by 28% (p less than 0.05) at low doses, and increased cardiac output by 71% at the maximum dose (p less than 0.05). Dopamine did not decrease pulmonary arterial pressure or increase cardiac output. Nitroprusside decreased pulmonary arterial pressure by 11% at the maximum dose (p less than 0.05). Isoproterenol and dobutamine may be more useful than dopamine and nitroprusside in the management of pulmonary hypertension and decreased cardiac output during sepsis.
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PMID:Effects of vasoactive drugs on thromboxane A2 mimetic-induced pulmonary hypertension in newborn lambs. 201 53

Persistent pulmonary hypertension of the newborn (PPHN), initially described by Gersony et al as persistent foetal circulation (PFC syndrome), results from a flawed transition from foetal to extrauterine pulmonary circulation. It is characterised by the maintenance of a high pulmonary vascular resistance and right-to-left shunting through the ductus arteriosus and foramen ovale. Infants with a wide variety of underlying clinical conditions develop PPHN. According to Rudolph three main anatomic types of PPHN can be identified: normal pulmonary vascular development increased pulmonary vascular smooth muscle development decreased cross-sectional area of pulmonary vascular bed. It is important to realize that several pathophysiologic mechanisms may coexist and interact. Besides metabolic and respiratory acidosis, hypercapnia and hypoxaemia some other factors induce pulmonary vasoconstriction. Thromboxane, leukotrienes and prostaglandins play a decisive role. Since PPHN can be associated with a broad spectrum of clinical conditions, a specific clinical picture is lacking. The baby is usually term or post-term, cyanotic immediately after birth or some hours later. Birth asphyxia, hyperviscosity, sepsis and aspiration of meconium have been recognized as predisposing factors. The diagnosis can be confirmed by echocardiography. Contrast echo will indicate right-to-left shunting with normal anatomy. Currently hyperventilation, tolazolin, chlorpromazin and dopamine/dobutamine have been advocated as central foci for clinical therapy. Recently prostacyclin was introduced as a specific pulmonary vasodilatator.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Persistent pulmonary hypertension of newborn. The PFC syndrome]. 229 36

Thromboxane A2 may play a major role in circulatory shock. In some species, thromboxane synthetase inhibitors have a beneficial effect on shock induced by endotoxin, trauma, sepsis and administration of arachidonate. In some shock models, however, results with thromboxane synthetase inhibitors have been conflicting. The effect of UK-38,485, a selective thromboxane inhibitor, was evaluated in ponies injected with endotoxin intraperitoneally. Four groups of ponies were used to compare the effects of endotoxin alone, UK-38,485 alone, treatment with UK-38,485 before endotoxin challenge and treatment with UK-38,485 after endotoxin challenge. Haematological, metabolic, eicosanoid and clinical responses in each group were evaluated. The results indicated that UK-38,485 is an effective inhibitor of thromboxane A2 generation following endotoxin challenge. Prostacyclin values were elevated compared with baseline in ponies administered UK-38,485 and endotoxin. However, prostacyclin values were not significantly different from those of ponies receiving endotoxin alone. Furthermore, UK-38,485 failed to attenuate the haematological, metabolic and clinical manifestations commonly seen in the pony after endotoxin challenge.
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PMID:Effects of a specific thromboxane synthetase inhibitor in equine endotoxaemia. 331 81

The effects of Pseudomonas aeruginosa cytotoxin on the pulmonary microvasculature were studied in blood-free, perfused, isolated rabbit lungs. Cytotoxin was administered to the recirculating Krebs Henseleit albumin (1%) buffer during two consecutive 30-min-perfusion phases (phases 1 and 2) at a concentration of 13 micrograms/ml, followed by a third perfusion phase (phase 3) without toxin. After perfusion phases 2 and 3, the capillary filtration coefficient (Kf,c) and vascular compliance were determined gravimetrically from two-step microvascular pressure increments under zero-flow conditions. Cytotoxin caused a continuous release of K+ and lactate dehydrogenase, which started within the first 5 min and amounted to about 50% of the total lung cellular K+ and 5 to 7% of the total lactate dehydrogenase by the end of the experiment. The toxin caused the continuous generation of prostaglandin I2, which was detectable in the perfusates of all perfusion phases at maximum values five times above the control values and which was measured in the bronchoalveolar lavage fluid at the end of the experiment. Thromboxane generation in toxin-treated lungs did not significantly exceed that of control lungs or of lungs with mechanically induced edema. Cytotoxin caused a gradual increase in pulmonary vascular resistance, to maximum values 2.5 times above the control, starting within 1 min; the increase was partially reversible after washout of the toxin. After a lag period of 20 to 30 min, the lungs gained weight, amounting to a mean gain of 9.1 g at the end of the experiments. After perfusion phases 2 and 3, an almost fourfold increase in Kf,c, which was not reversible after washout of the toxin, was measured, whereas the values of vascular compliance were not altered. We conclude that pseudomonal cytotoxin may be an important factor in the pathogenesis of prolonged microvascular injury, encountered in states of P. aeruginosa sepsis or acute lung failure with secondarily acquired P. aeruginosa pneumonia.
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PMID:Pulmonary microvascular injury induced by Pseudomonas aeruginosa cytotoxin in isolated rabbit lungs. 351 62

Thromboxane A2 has been implicated as a mediator of cardiorespiratory dysfunction in sepsis. This study evaluated whether or not thromboxane A2 was necessary or sufficient for these adverse effects to occur during bacteremia. Fourteen adult swine under barbiturate anesthesia and breathing room air were monitored with arterial and pulmonary artery catheters. Animals were studied for 4 hours in three groups: group I, graded infusion of 10(9)/ml Aeromonas hydrophila; group II, Aeromonas hydrophila infusion plus SQ 29,548 (thromboxane A2 antagonist); and group III, U46619 (thromboxane A2 agonist) infusion in normal swine to pulmonary artery pressures observed in group I. Hemodynamic parameters, arterial and mixed venous blood gases, and plasma thromboxane B2 and prostaglandin 6-keto-F1 were measured. At sacrifice after 4 hours, wet-to-dry lung weights were calculated. Results indicated that thromboxane A2 was necessary and sufficient for the development of pulmonary hypertension and impaired alveolar-capillary oxygen diffusion in graded bacteremia. It was necessary but not sufficient for increased lung water to occur and sufficient but not necessary for decreased cardiac index and stroke volume index. Thromboxane A2 was neither sufficient nor necessary to the pathophysiology of systemic hypotension during graded bacteremia. Plasma prostaglandin 6-keto-F1 levels were increased in hypotensive animals with sepsis, suggesting its involvement in hypotension during sepsis.
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PMID:Thromboxane A2 mediates hemodynamic and respiratory dysfunction in graded bacteremia. 352 3

The lung is very susceptible to sepsis or endotoxin injury in the trauma patient. We studied the effect of an episode of hemorrhagic shock and resuscitation on the prostaglandin-induced pulmonary hypertension and leukocyte-induced increased permeability phase of endotoxin lung injury. Eight unanesthetized sheep with chronic lung lymph fistula were bled 50% of blood volume for 2 hr, then resuscitated. Thromboxane, TxA2, levels increased from 0.1 to 0.6 ng/ml during shock, while blood white cell count decreased. Both parameters returned to baseline while lung lymph flow increased twofold during resuscitation with lymph being protein-poor, indicating no increase in permeability. Lung water was not increased but some pulmonary leukostasis was evident histologically after resuscitation. We then studied the effect of this process on all immediate endotoxin insult. Seven unanesthetized sheep were given 0.7 microgram/kg E. coli endotoxin alone, and again after shock and resuscitation, in paired studies performed 3 days apart. There was no difference in either the early pulmonary hypertension or the later increased permeability phase of endotoxin lung injury when comparing the paired studies, as measured by lymph flow and protein flux. Hemorrhagic shock, despite producing a transient increase in thromboxane and pulmonary leukocyte sequestration, does not accentuate the lung injury of endotoxin if the shock state is adequately resuscitated.
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PMID:Effect of hemorrhagic shock on endotoxin-induced pulmonary hypertension and increased vascular permeability in unanesthetized sheep. 636 38

Thromboxane (TX) has been reported to cause mortality in endotoxin or septic shock. Cyclooxygenase inhibition improves survival in gram-negative or gram-positive shock. The exact level in the prostaglandin system of which the protection occurs is unknown. This study was designed to compare the effects of a cyclooxygenase inhibitor (indomethacin, IND) to a thromboxane synthetase inhibitor (IMI) on survival and on the production of Tx and prostacyclin (PGI2) in a clinically relevant rat gram-negative sepsis model. Three groups were studied: 1) control (N = 35) animals received E coli only; 2) IND (N = 35) treated animals received 3 mg/kg IP; 3) IMI (N = 35) treated animals received 30 mg/kg IP. All drugs were given 1 h after an IP injection of E coli (LD70) organisms. In this model only IND significantly improved survival. IND and IMI significantly blocked the production of Tx seen in septic shock. IND blocked PGI2 production whereas IMI increased the production. These results show that Tx may not be important in the irreversible stages of shock. Shunting prostaglandin production to PGI2 with thromboxane synthetase inhibitors needs to be considered when using this group of compounds. The mechanism of protection by IND remains unknown.
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PMID:Thromboxane synthetase inhibitors in septic shock. 668 24

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.
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PMID:Delayed thromboxane or tumor necrosis factor-alpha, but not leukotriene inhibition, attenuates prolonged pulmonary hypertension in endotoxemia. 766 5

Early-onset neonatal group B beta-hemolytic streptococcus (GBS) infection exhibits pathophysiologic characteristics of a toxic shock syndrome, in which a cascade of inflammatory mediators are involved. Thromboxane A2 (TXA2) is thought to play an important role as a mediator of the pulmonary response to GBS toxin, because high lung lymph concentrations of a TXA2 metabolite have been observed after GBS toxin injections in sheep. The aim of this study was to evaluate the effects of a selective antagonist of the TXA2-prostaglandin endoperoxide receptor (SQ 29,548). Six unanesthetized young lambs, each serving as its own control, were given SQ 29,548 or vehicle control followed by GBS toxin challenge. Hemodynamic and lung function (lung mechanics, lung volume, ventilation) responses were followed for 5 h. When compared with the control studies, treatment with SQ 29,548 significantly altered the response to GBS toxin. SQ 29,548 reduced the increase in pulmonary and systemic vascular resistance, improved cardiac output and stroke volume, improved dynamic lung compliance but not airway resistance, and improved oxygenation. The attenuating effect of SQ 29,548 was most pronounced during the first phase of toxin response (15-90 min after toxin infusion), but significant treatment effects were also seen during the second phase (120-300 min after toxin infusion). This study demonstrates that TXA2 is an important mediator of the response to GBS toxin and is responsible for hemodynamic and lung function changes. Thromboxane receptor blockade may offer a potential therapeutic approach to infants with severe early-onset GBS sepsis.
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PMID:Thromboxane receptor blockade (SQ 29,548) in group B streptococcal toxin challenge in young lambs. 806 40


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