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)

Dexamethasone has recently been introduced for the treatment of bronchopulmonary dysplasia (BPD). Whereas the short-term effect of dexamethasone has been documented in previous publications, studies on the long-term effect do not appear to exist in the literature. The aim of this retrospective study was to investigate the influence of dexamethasone on respiratory parameters, the long-term efficacy, and the side-effects. Dexamethasone was given to premature babies with BPD who could not be weaned from the respirator. Twelve infants were included in this study. The gestational ages ranged from 26 to 30 weeks and the birth weights ranged from 640 to 1410 g. Dexamethasone treatment was initiated at the age of 14 to 44 days. After 6 days of dexamethasone therapy, ventilation rates and FiO2 values improved significantly. All infants were successfully weaned from mechanical ventilation and extubated at 2 to 40 days after the start of dexamethasone therapy. The follow-up for the estimation of the long-term efficacy ranged from 3 to 18 months. Ten out of twelve patients had been weaned permanently from the ventilator; one 12-months-old infant is still respirator-dependent. One patient died at 8 months from BPD. In 5 out of 12 infants we observed a leukocytosis with neither clinical signs nor microbiological signs of an infection. Septicaemia developed in one case and one patient suffered from pneumonia. Arterial hypertension was observed in one infant during dexamethasone therapy. The results suggest that dexamethasone facilitates the weaning of preterm infants with BPD from the ventilator. This treatment may prevent some infants from long-term ventilation.
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PMID:[Dexamethasone therapy in bronchopulmonary dysplasia]. 249 83

Eight ventilator-dependent infants with bronchopulmonary dysplasia (BPD) were treated with dexamethasone (0.5 mg/kg/day). Therapy was initiated at 19.3 +/- 3.9 days of age, continued at the initial dose for 7 days, then tapered over 2 weeks. The clinical course of these infants with BPD was compared to that of 8 similar ventilator-dependent infants with uncomplicated hyaline membrane disease (HMD). At study entry, the BPD patients had significantly higher ventilator rates, peak inspiratory pressures, mean airway pressures, alveolar-arterial oxygen gradients and fraction of inspired oxygen (FiO2) values. After 7 days of dexamethasone therapy, ventilator rates, peak inspiratory pressures, mean airway pressures, FiO2 values and alveolar-arterial oxygen gradients improved significantly. At this time, ventilator rates, peak inspiratory pressures and FiO2 values were similar to those of patients with uncomplicated HMD. BPD patients were extubated after 6.5 +/- 2.4 days of therapy. The incidences of septicemia, rickets and retinopathy of prematurity were similar in the BPD and uncomplicated HMD patients. Most dexamethasone-treated patients developed arterial hypertension during the first 48 h of therapy. Blood pressures returned to normal within 7 days of stopping therapy. All BPD patients had cosyntropin responses tested 5.5 +/- 2.6 weeks after stopping therapy. Six were normal. Two had inadequate responses. At 1 year adjusted age, the dexamethasone-treated BPD infants and HMD infants had similar radiographic bone ages, similar growth patterns and similar scores on the Bayley infant development scale. Dexamethasone was useful in the treatment of early BPD. Used as short-term therapy, the drug had minimal complications and no long-term sequelae.
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PMID:Short-term dexamethasone therapy for bronchopulmonary dysplasia: acute effects and 1-year follow-up. 358 71

Increased morbidity in septic infections following splenectomy is a well-known phenomenon; despite antibiotic treatment the mortality rate associated with such infections is about 50%. Combined steroid-penicillin treatment of experimental pneumococcal sepsis was investigated in splenectomized Sprague-Dawley rats subjected to intravenous challenge with 200 colony-forming units (CFU) of pneumococci. Dexamethasone alone had no therapeutic effect. Benzylpenicillin alone was effective when given "early," i.e. 18 and 42 hours after challenge (0 of 10 animals killed), but not when given "late," i.e at 24 and 48 hours (10 of 14 killed). By contrast, even with "late" administration the combined treatment with dexamethasone and benzylpenicillin was effective against lethal pneumococcal sepsis (1 of 14 killed).
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PMID:Effect of steroids on the outcome of penicillin treatment in pneumococcal sepsis in splenectomized rats. 689 2

The benefits of nitric oxide synthase (NOS) inhibitors in the treatment of endotoxemia or sepsis presumably arise from inhibition of the type II (inducible) NOS. However, inasmuch as the effect of these inhibitors on NOS function in vivo is rarely assessed, NOS activity was evaluated in rats and mice by measuring changes in plasma nitrite and nitrate concentrations ([NOx]) after administration of lipopolysaccharide (LPS). In both species, [NOx] peaked at 20 hr, returning to base line by 48 to 72 hr. The ED50 values (dose that elicited a 50% inhibition of the LPS-dependent increase in [NOx] 6 hr after LPS administration) for L-NG-monomethylarginine acetate, L-NG-nitroarginine methyl ester and aminoguanidine (administered 3 hr after LPS) were 34, 21 and 19 mg/kg in the rat and 32, 5 and 4 mg/kg in the mouse. These compounds also decreased the survival of LPS-challenged animals, which in the case of L-NG-nitroarginine methyl ester was reversed by L-arginine. Dexamethasone (which prevents the induction of type II NOS) also inhibited the LPS-dependent increase in [NOx] with ED50 values of 0.05 mg/kg (rat) and 1 mg/kg (mouse), but did not lead to decreased survival. Thus, inhibition of the type I (neuronal) or type III (endothelial) NOS, rather than the type II isoform, may be a possible mechanism for the animal mortality. These models provide a simple and reproducible means for assessing the in vivo inhibition of type II NOS by various compounds.
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PMID:Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors. 753 50

To investigate the mechanism of sepsis-associated hyperbilirubinemia we have studied hepatocanalicular transport of organic anions in a rat model of endotoxemia. Rats were injected intravenously with lipopolysaccharides (LPS), and at different times after injection, canalicular transport of 2,4-dinitrophenyl-S-glutathione (GS-DNP), as a model organic anion, was measured in perfused livers and isolated hepatocytes. In isolated liver perfusion experiments the initial biliary GS-DNP secretion rate was found to be significantly decreased 18 h after injection with 2 mg/kg LPS. In isolated hepatocytes from these rats, GS-DNP efflux rate was also significantly decreased (193.0 +/- 67 and 448.3 +/- 53 nmol.min-1.g dry wt-1 in endotoxemic and normal hepatocytes, respectively). Inhibition of GS-DNP effluxin isolated endotoxemic hepatocytes was dose dependent and reached a maximum with 0.25 mg/kg LPS. Inhibition was maximal at 12 h after LPS injection. Transport activity gradually returned to normal in 4-5 days after endotoxemia was induced. Dexamethasone pretreatment partially reversed the inhibition of GS-DNP transport in isolated endotoxemic hepatocytes. The phorbol ester phorbol 12-myristate 13-acetate increased GS-DNP efflux by 73 +/- 16 and 24 +/- 8% in endotoxemic and control hepatocytes, respectively, but could not restore the transport activity of endotoxemic hepatocytes to control levels. These results show that canalicular organic anion transport is decreased in the endotoxemic liver; this may play a role in the frequently observed hyperbilirubinemia during sepsis.
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PMID:Impaired hepatocanalicular organic anion transport in endotoxemic rats. 757 54

With advances in neonatal intensive care survival of extremely low birth weight (< 1 kg) infants has increased significantly over the past decade. Dexamethasone is used increasingly for the prevention and treatment of chronic lung disease in these infants. The impact of dexamethasone therapy on the incidence or severity of retinopathy of prematurity (ROP) remains controversial. We conducted a retrospective study to evaluate the association between short-term dexamethasone treatment and severe ROP in extremely low birth weight infants. From October 1989 to December 1992, 309 very low birth weight infants were admitted to the neonatal intensive care unit. A total of 266 infants (86%) survived until hospital discharge. Of these, 90 weighed less than 1 kg. Thirty-eight of 90 infants received short-term dexamethasone therapy for chronic lung disease and the remaining 52 infants did not. Infants treated with dexamethasone and those not treated with dexamethasone were comparable in birth weight (820 vs 828 gm), gestational age (26.5 vs 26.9 weeks), inborn (11 vs 14), and occurrence of sepsis (13/38 vs 21/52). Infants treated with dexamethasone required longer periods of mechanical ventilation (44 +/- 23 vs 26 +/- 15 days, p < 0.001), had longer duration of supplemental oxygen (57 +/- 28 vs 29 +/- 23 days, p < 0.001), had higher incidence of patent ductus arteriosus (28/38 vs 18/52, p < 0.0003), and required surfactant therapy more often for respiratory distress syndrome (17/38 vs 11/52, p < 0.01), when compared with infants who did not receive dexamethasone. Severe ROP developed in 16 infants (stage III or higher); 12 of these were in the dexamethasone-treated group (p < 0.003). Thirteen infants required cryotherapy; nine were from the dexamethasone-treated group (p < 0.13). This study demonstrates an apparent association between the incidence of severe ROP and dexamethasone therapy. Prospective, randomized, controlled studies are needed to correct for differences in severity of cardiorespiratory illness to establish whether a causal role exists for steroid therapy in ROP. Until such studies are available, careful consideration must be given to indications, dosage, time of initiation, and duration of treatment with dexamethasone in extremely low birth weight infants.
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PMID:Severe retinopathy of prematurity in extremely low birth weight infants after short-term dexamethasone therapy. 766 64

In view of the immunosuppressive action of glucocorticoids (GCs), the activation of the hypothalamo-pituitary-adrenal axis in patients with sepsis or septic shock is paradoxical. At the same time, administration of GCs to these patients is not clearly beneficial. We investigated the role of GCs in severe illness by measuring the sensitivity of peripheral blood mononuclear leukocytes to GCs in a mitogen-stimulated lymphocyte proliferation assay. In addition, we studied the role of interleukin-2 and several other cytokines in this system. Cells from patients with sepsis or septic shock (n = 15) were more sensitive to the antiproliferative action of GCs than were cells from normal controls (IC50 6.7 +/- 2.1 nmol/L for patients vs. 19.5 +/- 2.5 nmol/L for controls; P < 0.01). This increased sensitivity of the peripheral mononuclear cells to dexamethasone during the period of sepsis normalized during the ensuing period of clinical recovery of these patients. Dexamethasone inhibited the production of interleukin-2 in the mitogen-stimulated cells. Addition of interleukin-2 antagonized the suppressive effects of dexamethasone in a dose-dependent manner, both in cells from controls and in cells from patients with sepsis. To a lesser extent, the combination of interleukin-1, interleukin-6, and tumor necrosis factor-alpha also counteracted the effects of dexamethasone. In conclusion, our results suggest that not only the activity of the hypothalamo-pituitary-adrenal axis but also the sensitivity to GCs is regulated during sepsis and septic shock. Generally there is an increased sensitivity to GCs, which might help to protect the organism as a whole through supportive effects on metabolism and vasculature. This hypersensitivity is counteracted, possibly at the site of inflammation, by high local concentrations of cytokines. This would enable an adequate local response of the immune system in the presence of elevated cortisol levels. In view of the increased sensitivity of peripheral leukocytes to GCs, treatment of these patients with high doses of GCs may not be beneficial or may even be harmful.
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PMID:Differential adaptation of glucocorticoid sensitivity of peripheral blood mononuclear leukocytes in patients with sepsis or septic shock. 777 26

Tumour necrosis factor alpha (TNF alpha) has been reported to play a key role in the pathogenesis of sepsis and chronic inflammatory diseases, including rheumatoid arthritis and atherosclerosis, suggesting that agents which inhibit TNF alpha production may have therapeutic utility for the treatment of such conditions. Production of TNF alpha by LPS (lipopolysaccharide)-stimulated murine, rat and human heparinized blood was investigated. LPS (1-100 micrograms/ml) caused a similar concentration- and time-dependent stimulation of TNF alpha production by rat and human blood, achieving levels of 750-5000 U/ml (L929 bioassay) at 6 h. In contrast, TNF alpha production by LPS-stimulated murine blood was poor and variable (0-150 U/ml). Dexamethasone and pentoxifylline caused a concentration-dependent inhibition of TNF alpha production by LPS-stimulated human and rat blood with IC50s of 0.26 +/- 0.05 and 73.0 +/- 26.4 microM for human and 5.7 +/- 1.8 nM and 20.6 +/- 8.0 microM for rat blood, respectively. Therefore, LPS-stimulated rat and human, but not murine, blood are suitable systems for the detection and evaluation of inhibitors of TNF alpha production.
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PMID:Production of TNF alpha by LPS-stimulated murine, rat and human blood and its pharmacological modulation. 831 28

Circulating endothelin-1 concentrations are elevated in animal models of sepsis. The major actions of endothelin-1 appear to be as a local autocrine and paracrine factor, rather than as a circulating hormone, and plasma concentrations may not reflect local tissue concentrations. We therefore measured tissue expression of mRNA encoding pre-pro-endothelin-1 by RNase protection assays, as an indicator of local production of ET-1 in an in vivo rat model of endotoxaemia. The effects of dexamethasone pre-treatment were also examined. There was a tissue-specific increase in pre-pro-endothelin-1 mRNA in endotoxaemia, apparent at 6h after endotoxin challenge in heart and lung. No significant changes in expression were seen in kidney or skeletal muscle. Dexamethasone pre-treatment significantly attenuated the rise in pre-pro-endothelin-1 mRNA in heart at 6h. Therefore, we have demonstrated tissue-specific differences in the effect of endotoxin upon pre-pro-endothelin-1 mRNA expression and in sensitivity to dexamethasone. This could account for some of the inter-tissue differences seen in local vascular response to endotoxin.
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PMID:Tissue expression of endothelin-1 mRNA in endotoxaemia. 857 67

Intravenous injection of Candida albicans into mice produced elevated serum tumor necrosis factor alpha (TNF-alpha) levels. We hypothesized that immunostimulants released in vivo from C. albicans during fungal sepsis might contribute to the elevated levels of TNF-alpha in serum. We tested this hypothesis in mice with C. albicans mannan (CAM). Increased serum TNF-alpha levels were observed following intravenous and intraperitoneal injections of CAM. Injection of CAM into mice resulted in increased serum TNF-alpha concentrations that reached 1,200 pg/ml of blood, compared with 2,400 microg/ml of blood following injection of 10 microg of endotoxin. The response to CAM was concentration dependent, requiring a minimum dose of 20 microg of CAM per g of body weight. Sera from mice were tested 30, 60, 90, and 120 min after intravenous injections with CAM. TNF-alpha concentrations were minimal 30 and 120 min after intravenous injection and maximal 60 and 90 min after CAM injection. The relative distribution of CAM in vivo in decreasing order was determined to be as follows: blood > liver > lung > spleen, 90 min following injection of a single 5-mg dose of CAM. CAM was confirmed as the stimulating substance by utilizing anti-CAM antibodies in vivo to block the response. Rabbit anti-mannan antibodies administered by intraperitoneal injection 24 h before CAM injection significantly suppressed (P < 0.05) the accumulation of TNF-alpha in the sera. Dexamethasone administered to mice before intravenous injection of mannan significantly reduced (40 to 90% reduction; P < 0.05) the concentrations of TNF-alpha in the sera of treated mice. Thus, when in vivo CAM clearance mechanisms are exceeded, sufficient CAM may become available to stimulate TNF-alpha production, making CAM an important part of pathogenesis in Candida sepsis.
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PMID:Intravenous injection of Candida-derived mannan results in elevated tumor necrosis factor alpha levels in serum. 889 Feb 7


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