Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The wider availability of recombinant human growth hormone and insulin-like growth factor-I has resulted in an investigation into the potential benefits of the pharmacological administration of these anabolic peptides in a variety of clinical conditions, characterized by an increase in catabolic rate. The initial studies were small, often uncontrolled open investigations, but investigators have more recently concentrated on larger, controlled multi-centre trials. Studies to date have included patients with cardiac failure, sepsis, burns, cancer cachexia, end-stage renal failure, trauma and AIDS, and those prior to or following major surgery. The authors have in general cautiously interpreted positive effects of treatment with growth hormone and insulin-like growth factor-I, either alone or in combination, on net protein balance, body composition, well-being and performance. Two large, randomized, placebo-controlled European multi-centre studies have recently detailed the effects of growth hormone treatment in critically ill intensive care patients. Major increases in mortality and morbidity were associated with growth hormone treatment. The mechanism(s) accounting for the increased mortality remain poorly understood. These negative findings have led to a decrease in the clinical use of growth hormone and in research activity in the area of anabolic treatment in human illness.
 ...
PMID:Treatment with growth hormone and insulin-like growth factor-I in critical illness. 1180 May 16

Patients suffering severe burns have an accelerated catabolism with a highly negative nitrogen balance that may worsen their prognosis. Somatropin treatment has been shown to improve this balance in different hypercatabolic situations. Moreover, in children with extensive burns it also reduces the healing time of the skin graft donor site and shortens the hospital stay. In the existing literature there are no controlled prospective clinical trials in adult patients that confirm these data. Our aim was to demonstrate the efficacy of recombinant growth hormone (somatropin) in reducing the healing time of the skin graft donor sites and the length of stay in the burn unit in adult patients with severe burns. A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 adult patients with severe burns (more than 40% of the total body surface burned or more than 15% full-thickness burns). Patients received placebo (n = 11) or somatropin (n = 13) at a dosage of 0.15 mg/kg/day divided into two equal doses (every 12 hours) via intramuscular injection. Treatment was initiated the day the first autograft was performed and terminated the day the patient was discharged from the burn unit. The mean number (+/- SD) of skin grafts per patient was similar between the two groups (4.2 +/- 1.8 vs 3.4 +/- 1.8 in the placebo and somatropin groups, respectively). No reduction in the healing time of the skin graft donor site was observed in the somatropin group compared to the placebo group. Likewise, the time admitted to the burn unit was not significantly different, either in the absolute number of days (36.2 +/- 19.7 vs 30.1 +/- 16.8 days in the placebo and somatropin groups, respectively) or in relation to the percentage of the total body surface burned or the body surface with full-thickness burns. Growth hormone and insulin-like growth factor I (IGF-I) levels were three and five times higher, respectively, in the somatropin group than in the placebo group. Ten of the patients treated with somatropin experienced hyperglycemia, and seven of them required insulin treatment. No other adverse side effect was observed. One patient in the placebo group died as a result of sepsis and multiple organ failure. Somatropin, with the treatment regimen and dosage used in these studies, did not reduce the healing time of the skin graft donor sites or the length of hospitalization in the burn unit in adult patients with severe burns.
 ...
PMID:Effects of human recombinant growth hormone on donor-site healing in burned adults. 1189 25

During sepsis, growth hormone (GH) resistance contributes to the catabolism of muscle protein. To determine the role of tumor necrosis factor (TNF) as a mediator of GH resistance, we examined the effects of a TNF antagonist [TNF-binding protein (TNFbp)] on the GH/insulin-like growth factor (IGF) I system during abdominal sepsis. To investigate potential mechanisms, the effects of TNF on the IGF-I response to GH and GH signaling were examined in cultured rat hepatocytes (CWSV-1). Three groups of rats were studied: Control, Sepsis, and Sepsis + TNFbp. Liver, gastrocnemius, and plasma were collected on day 5. In gastrocnemius, neither sepsis nor TNFbp altered the abundance of IGF-I mRNA. However, septic rats demonstrated an increase in circulating GH and a reduction in plasma IGF-I concentrations that was ameliorated by pretreatment with TNFbp. Liver from septic rats demonstrated a 50% reduction in GH receptor (GHR) and IGF-I mRNA on day 5 that was attenuated by TNFbp. However, the abundance of GHR protein was not different in liver from Control, Sepsis, or Sepsis + TNFbp rats. Consequently, a decreased amount of hepatic GHR does not explain the GH-resistant septic state. In CWSV-1 hepatocytes, TNF-alpha had no effect on GHR protein level but inhibited the induction of IGF-I mRNA by GH. Nuclear protein from TNF-treated hepatocytes demonstrated similar levels of phosphorylated signal transducer and activator of transcription-5 (STAT5) and DNA binding relative to controls 5 min after GH treatment. However, both of these parameters were decreased (vs. control) in TNF-treated cells 60 min after GH treatment. Collectively, these results suggest that TNF mediates hepatic GH resistance during sepsis by inhibiting the duration of signaling via the janus kinase-2/STAT5 pathway.
 ...
PMID:Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis. 1216 40

Sepsis, excessive inflammation, multiple organ failure and weakness prolong the need for intensive care in critically ill patients. Furthermore, the risk of death is high in the prolonged critically ill patient (20% after two weeks and 30% after 3 weeks). In prolonged critical illness, protein hypercatabolism and relative preservation of adipose tissue with fatty infiltration of vital organ systems is present. In view of the crucial role of the hypothalamus-pituitary axis for metabolic homeostasis, we have studied this endocrine organ in the context of critical illness. The initial "adaptive" neuroendocrine response to critical illness illness consists primarily of activated anterior pituitary function. In the chronic phase of critical illness, a uniformly reduced pulsatile secretion of anterior pituitary hormones has been observed, whereby impaired function of target organs. A reduced availability of thyrotropin (TSH)-releasing hormone (TRH), gonadotropin (LH)-releasing hormone (GnRH), the endogenous ligand of the growth hormone (GH)-releasing peptide (GHRP) receptor (ghrelin) and, in very long-stay critically ill men also of GH-releasing hormone (GHRH), inferrentially appears involved. Pulsatile secretion of GH, TSH and LH can be re-amplified by relevant combinations of releasing factors which also substantially increases circulating levels of insulin-like growth factor (IGF)-I, GH-dependent IGF-binding proteins, thyroxine (T4), triiodothyronine (T3) and testosterone. Anabolism is only evoked when GH-secretagogues, TRH and GnRH are administered together whereas the effect of single hormone treatment is minor and accompanied by side effects. A remarkable observation was that a high serum concentration of IGF-binding protein 1 predicts death in the ICU. This observation challenged the classical dogma of adaptive hyperglycemia during critical illness. In a large prospective randomized clinical study (1548 patients), we showed that ICU mortality was reduced by 42% with strict normalization of glycemia using exogenous insulin infusion (N Engl J Med 2001). This was due to prevention of typical ICU complications such as sepsis, multiple organ failure and need for prolonged invasive organ support and intensive care. We conclude that the new concept of reduced stimulation of pituitary function in prolonged critically ill patients opens new therapeutic perspectives to reverse the paradoxical 'wasting syndrome' but that maintenance of strict normoglycemia with insulin is crucial to also increase the chances of survival of these patients.
 ...
PMID:Endocrinology in intensive care medicine: new insights and therapeutic consequences. 1223 41

The effect of sepsis on the rate of protein synthesis in the heart is poorly described. We have investigated changes in protein synthesis in the ventricles of the heart over time after cecal ligation and puncture (CLP) in rats in comparison with sham-operated and unoperated animals (ad libitum). All operated animals were starved from the time of surgery to the time of sacrifice. When operated animals were compared with ad libitum animals, ventricular weight and ventricular protein, and DNA and RNA contents were unchanged at 24 h, but were invariably reduced at 72 and 96 h. Fractional rate of protein synthesis (FSR), RNA activity, and cellular efficiency were reduced at 24 h and further reduced at 72 and 96 h. There were no differences, however, between septic and sham-operated animals. Eighteen hours after CLP, additional groups of rats were infused intravenously with 0.9% sodium chloride, parenteral nutrition (PN), or PN with glutamine, and were given a single dose of 400 microg recombinant human growth hormone (rhGH) or an equal volume of 0.9% sodium chloride. FSR was higher in animals given PN when compared with those given 0.9% sodium chloride only, and did not differ from FSR measured in unoperated animals. There was no additional benefit from the acute administration of either glutamine-enriched PN or rhGH. These results indicate that ventricular protein synthesis is markedly reduced by surgery and starvation, but that superimposed sepsis does not further influence these changes. PN can prevent the fall in cardiac protein synthesis associated with starvation, surgery, and sepsis, but neither glutamine nor rhGH produced any additional benefit.
 ...
PMID:Influence of starvation, surgery, and sepsis on cardiac protein synthesis in rats: effects of parenteral nutrition, glutamine, and growth hormone. 1235 29

The catabolic response to sepsis, severe injury, and burn is characterized by whole-body protein loss, mainly reflecting increased breakdown of muscle proteins, in particular myofibrillar proteins. Glucocorticoids and various proinflammatory cytokines are important regulators of muscle proteolysis in stressed patients. There is evidence that breakdown of proteins by the ubiquitin-proteasome pathway plays an important role in muscle cachexia, although other mechanisms may participate, such as calcium- and calpain-dependent release of myofilaments from the sarcomere. Three types of treatments have been used to reduce or prevent the catabolic response to injury and sepsis: 1). nutritional, 2). hormonal, and 3). pharmacologic. With regard to nutrition support, it is generally believed that enteral feeding is superior to parenteral feeding and that early feeding is better than late feeding. Although "immune-enhancing" enteral nutrition has been shown in several recent studies to improve outcome in critically ill patients, the specific effects of these treatments on the catabolic response in muscle are not known. In addition to nutrition support, various hormones, including insulin, growth hormone, and insulin-like growth factor-1, may blunt the catabolic response in patients with stress. Experimental studies have indicated that other treatments may become available in the future, including cytokine antibodies, calcium antagonists, and induction of heat shock response. Methods to prevent or reduce the catabolic response to stress are important considering the significant clinical consequences of muscle cachexia.
 ...
PMID:Catabolic response to stress and potential benefits of nutrition support. 1243 20

We investigated the combined effect of glutamine (GLN) and growth hormone (GH) on bacterial translocation (BT) in sepsis. After single intraperitoneal injection of lipopolysaccharide (10 mg/kg), 48 rats were divided randomly into four groups of 12 animals each: the control group received chow orally; the GLN group received chow plus 10% GLN; GH group received chow plus GH; and the GLN/GH group received chow, 10% GLN, and GH. Twenty-four and 96 hr later, rats were sacrificed. Portal blood culture, bacterial colony counts of cultured mesenteric lymph nodes, mucosal thickness, malondialdehyde (MDA), and glutathione (GSH) levels in the gut mucosa were measured. There was no significant change of the rate of portal blood culture between all treatment groups at 24 and 96 hr. At 24 hr, the rats receiving combined treatment of GLN and GH showed lower bacterial colony counts and mucosal MDA levels than the control rats, and higher mucosal GSH levels than the control and GLN-treated rats. At 96 hr, rats treated with both GLN and GH exhibited lower bacterial colony counts and mucosal MDA levels, and higher mucosal thickness and GSH levels than control, GLN, or GH-treated rats. This study suggests that the combination of GLN and GH may synergistically reduce BT over time in sepsis.
 ...
PMID:Combined administration of glutamine and growth hormone synergistically reduces bacterial translocation in sepsis. 1258 81

The pharmacotherapy of burn care has evolved from the first topical antibiotics instituted > 30 years ago. These have helped greatly to reduce the incidence of burn wound sepsis, but a better understanding of the principles of burn care has resulted in earlier burn wound excision and complete coverage with autograft, cadaver skin, synthetic dressings, and amnion. This has markedly reduced septic complications and ameliorated the hypermetabolic response to burn injury. The hypermetabolic response, which is mediated by hugely increased levels of circulating catecholamines, prostaglandins, glucagon and cortisol, causes profound skeletal muscle catabolism, immune deficiency, peripheral lipolysis, reduced bone mineralisation, reduced linear growth, and increased energy expenditure. Supportive therapy and pharmacological manipulation, acutely and during rehabilitation, with growth hormone, insulin and related proteins, oxandrolone and propranolol can ameliorate the hypermetabolic response, improving survival and long-term outcome. Despite judicious use of topical and systemic antibiotics, opportunistic nosocomial bacterial resistance threatens to annul the improved survival of patients with severe burns. Patterns of emerging resistance encountered in burn units need to be considered, in light of a decreasing antibiotic armamentarium. A holistic approach to pharmacotherapy of severely burned patients including current practice in antimicrobial control, analgesia, sedation, and anxiety management is required. Current therapy of frequently encountered problems, such as post-burn pruritus, prophylaxis of deep venous thrombosis and peptic ulceration, and pharmacological manipulation of inhalation injury in the burned patient is described. Current pharmacotherapy to ameliorate psychosocial problems associated with burns such as acute stress disorder, depression and post traumatic stress disorder are discussed. Better analgesics, newer antibiotics and immune stimulating drugs are required to reduce mortality and morbidity in large burns.
 ...
PMID:Current pharmacotherapy for the treatment of severe burns. 1261 89

Severe burn incites metabolic disturbances which last up to one year post injury. Persistent profound catabolism after severe burn hampers rehabilitative efforts delaying meaningful return of individuals to society. The simplest effective anabolic strategies for severe burn injuries are early excision and grafting of the burn wound, prompt treament of sepsis, maintenance of environmental temperature at 30-32 inverted exclamation mark C, continuous enteral feeding of a high carbohydrate, high protein diet, early institution of vigorous resistive and aerobic resistive exercise programs. To further minimize erosion of lean body mass administration of recombinant human growth hormone, insulin, oxandrolone or propranolol are all reasonable approaches. Exogenous continuous low dose insulin infusion, beta blockade with propranolol and the use of the synthetic testosterone analog, oxandrolone are the most cost effective and least toxic pharmaco therapies to date.
 ...
PMID:Nutritional and pharmacological support of the metabolic response to injury. 1276 18

Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta inhibit the GH-stimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-alpha synthesis. The goal of our study was to investigate whether inhibition of TNF-alpha production by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I (-45% at 12 h; P<0.01 vs time 0) and its liver mRNA (-67% at 12 h; P<0.01 vs time 0) while it induced circulating TNF-alpha and IL-1beta and their hepatic expression (P<0.01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-alpha (-98% at 90 min; P<0.001 vs LPS alone) and to a lesser extent in serum IL-1beta (-44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-alpha induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-alpha, in particular IL-1beta or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.
 ...
PMID:Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I. 1284 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>