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)

Local immunosuppression is based on the rationale that one can simultaneously prevent rejection and reduce systemic side effects by administering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n = 11) and 0.75 (n = 8) mg/kg/day and by continuous iv infusion at 0.5 (n = 12) and 0.75 (n = 6) mg/kg/day. Mean +/- SD elimination half-life was 0.6 +/- 0.1 hr, and the transplanted kidney removed as much as 55-88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0. 5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days; P = 0.04) but not iv (MST = 9 days; P = 0. 09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days; P = 0.04) and systemic (MST = 11 days; P = 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. DSG significantly suppressed vascular rejection at both doses when administered locally and systemically, dose-dependently affected the severity of tubulointerstitial rejection and graft edema, and was not nephrotoxic. Our autotransplant pharmacokinetic data overestimated the allografted kidney's ability to extract DSG during local infusion of slightly lower, but immunosuppressive, doses, so that death from systemic toxicity was not prevented and a direct survival benefit of ia vs iv therapy was not realized. Local DSG administration might be combined with other immunosuppressants to therapeutic advantage.
 ...
PMID:Pharmacokinetics and pharmacodynamics of 15-deoxyspergualin in a canine renal allograft model of local immunosuppression. 929 81

Loss of lean body mass is common in patients with acute or chronic renal failure but the mechanisms causing this loss are only beginning to be understood. One mechanism involves an inability of uremic patients to activate the critical metabolic responses that maintain protein balance when dietary protein is limited. Metabolic responses to dietary protein restriction include a sharp reduction in the degradation of essential amino acids and protein; changes in protein synthesis are less reliable. If uremia prevents suppression of essential amino acid or protein degradation when dietary protein is reduced by anorexia, negative nitrogen balance and loss of lean body mass will ensue. One complication of uremia, metabolic acidosis, stimulates the degradation of branched-chain amino acids and proteins and therefore blocks the ability of the patient to respond to a low-protein diet. The mechanisms require glucocorticoids and involve increased activity of branched-chain keto acid dehydrogenase and the ubiquitin-proteasome proteolytic pathway; there also is increased transcription of genes encoding components of enzymes involved in the pathways. Besides acidosis, a low insulin concentration and cytokines activate the ubiquitin-proteasome proteolytic pathway. Understanding how proteolysis is activated, including how these genes are stimulated, is important because the same pathways are activated in diabetes, cancer, sepsis, burns, starvation, and muscle denervation. Activation of the ubiquitin-proteasome pathway leads to reduced lean body mass.
 ...
PMID:Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease. 949 77

Sequential chemotherapy with methotrexate and 5-fluorouracil (MTX/5-FU) for advanced gastric cancer was given 29 patients. The procedure consisted of weekly MTX 100 mg/m2 (i.v.) followed three hours later by 5-FU 600 mg/m2 (i.v.) with leucovorin rescue on each of the following two days. Nine of 28 patients (32.1%) showed partial response to this treatment. Response rates were 28.6% in the 21 cases with poorly differentiated adenocarcinoma and 42.9% in the 7 cases with well- or moderately-differentiated adenocarcinoma. This procedure was especially effective for primary lesions (PR 9/20: 45%) and lymphnode metastases (CR 4 + PR 4, 8/17: 47.1%). Side effects were mild leukopenia and G-I symptoms such as nausea, diarrhea and loss of appetite, except in 1 patient who died of severe myelosuppression with sepsis. We concluded that sequential MTX/5-FU therapy is fairly effective and the adjuvant chemotherapy of choice for advanced or recurrent gastric cancer with not only poorly differentiated adenocarcinoma but also well- or moderately-differentiated adenocarcinoma.
 ...
PMID:[Sequential chemotherapy with methotrexate and 5-fluorouracil for advanced gastric cancer]. 953 Mar 60

The production of pro-inflammatory cytokines, such as interleukins 1 and 6 and tumour necrosis factors, occurs rapidly following trauma or invasion of the body by pathogenic organisms. The cytokines mediate the wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting, acute phase protein production and immunomodulation. In part, the symptoms result from a co-ordinated response, in which the immune system is activated and nutrients released, from endogenous sources, to provide substrate for the immune system. Although the cytokine mediated response is an essential part of the response to trauma and infection, excessive production of pro-inflammatory cytokines, or production of cytokines in the wrong biological context, are associated with mortality and pathology in a wide range of diseases, such as malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS. Cytokine biology can be modulated by antiinflammatory drugs, recombinant cytokine receptor antagonists and nutrients. Among the nutrients, fats have a large potential for modulating cytokine biology. A number of trials have demonstrated the anti-inflammatory effects of fish oils, which are rich in n-3 polyunsaturated fatty acids, in rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma. Animal studies, conducted by ourselves and others, indicate that a range of fats can modulate pro-inflammatory cytokine production and actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1 production and tissue responsiveness to cytokines, fats rich in n-3 polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids decrease tissue responsiveness to cytokines and IL6 production is enhanced by total unsaturated fatty acid intake. There are a large number of potential cellular mechanisms which may mediate the effects observed. The majority relate to the ability of fats to alter the composition of membrane phospholipids. As a consequence of alterations in phospholipid composition, membrane fluidity may change, altering binding of cytokines to receptors and G protein activity. The nature of substrate for various signalling pathways associated with cytokine production and actions may also be changed. Consequently, alterations in eicosanoid production and activation of protein kinase C may occur. We have examined a number of these potential mechanisms in peritoneal macrophages of rats fed fats with a wide range of fatty acid composition. We have found that the total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal macrophages relates in a positive curvilinear fashion with dietary linoleic acid intake; that TNF induced IL1 and IL6 production relate in a positive curvilinear fashion to linoleic acid intake; that leukotriene B4 production relates positively with dietary linoleic acid intake over a range of moderate intakes and is suppressed at high intakes, while PGE2 production is enhanced. There was no clear relationship between linoleic acid intake and membrane fluidity, however fluidity was influenced in a complex manner by the type of fat in the diet, the period over which the fat was fed and the presence of absence of TNF stimulation. None of the proposed mechanisms, acting alone, can explain the positive effect of dietary linoleic acid intake on pro-inflammatory cytokine production. However each may be involved, in part, in the modulatory effects observed.
 ...
PMID:Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids. 955 30

Forty-three patients with myelodysplastic syndromes (MDS) received treatment with oral etoposide 50 mg/day for 21 consecutive days every 4 weeks. Eighteen patients (42%) experienced hematological responses, including 12 of 17 (70%) patients with chronic myelomonocytic leukemia (CMML). Three of five CMML patients who failed treatment with hydroxyurea experienced major hematological responses with oral etoposide. Median response duration exceeded 9 months (range: 4-49 + months), and one patient remains in an unmaintained complete remission for 4 years. Toxicity included nausea/vomiting in five patients, fever (four patients), infection (three patients), mucositis (two patients), and anorexia (two patients). Two patients had grade 4 neutropenia with sepsis necessitating treatment withdrawal. We conclude that low-dose oral etoposide has remitting activity in MDS and is an effective treatment alternative for patients with CMML.
 ...
PMID:Treatment with low-dose oral etoposide in patients with myelodysplastic syndromes. 958 73

During infection and injury a series of metabolic events are activated that leads to a state of negative nitrogen balance and significant loss of lean body mass. This process is characterized by marked anorexia, net whole body protein breakdown, and liver anabolism. This host response initially is beneficial to the body because it helps it to fight disease and enhance healing. However, if such imbalance is maintained for long periods, it will invariably produce significant loss of lean body mass that may lead to a series of untoward clinical events. The role of the proximate cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) as well as glucocorticoids as important mediators of many pathophysiological manifestations of infection and injury has been studied extensively. However, the involvement of other mediators, at least in skeletal muscle proteolysis during sepsis has been hypothesized, because blockade of glucocorticoids, TNF, IL-1, and IL-6 reduces but does not normalize protein breakdown rates nor does the direct application of these mediators to skeletal muscle in vitro enhance proteolysis. Furthermore other studies have suggested that the lymphokine, interferon-gamma (IFN-gamma, type II interferon or immune interferon), produces fever and enhances thermogenesis, body weight loss, and skeletal muscle depletion in rodents in a manner similar to that seen with TNF and IL-1. Cytokines appear to be major components of the host metabolic response during infection and injury. However, neither all the cytokines involved nor the exact mechanisms underlying their metabolic effects are completely understood. The regulation of muscle protein synthesis and breakdown, which largely determines the development of cachexia, appears to depend on the delicate balance between a number of regulatory substances including cytokines, glucocorticoids, catecholamines, insulin, and insulin-like growth factors.
 ...
PMID:The role of cytokines in the catabolic consequences of infection and injury. 1008 3

From October 1995 to June 1997, 19 chemotherapy-naive patients with pathology-proven locally advanced or metastatic biliary tract carcinomas (BTC) were enrolled. The regimen consisted of 5-fluorouracil (5-FU) 2600 mg/m2 and leucovorin (LV) 150 mg by weekly 24 h infusion for 6 weeks and followed by a 2 week break. The treatment was terminated if disease progressed, the patient refused or unacceptable toxicity occurred. All patients required a Port-A catheter insertion and were treated at outpatient clinics by portable infusion pumps. There were 12 males and seven females with a median age of 62 years (range 45-77). The primary tumor sites were nine intrahepatic cholangiocarcinomas (CC), three perihilar CC, one distal BTC and six gallbladder cancers. A total of 179 chemotherapy sessions were given with a mean of 9.5 (range 2-18). Eighteen patients were evaluable for response. The response rates were: 33% (six of 18) partial response (PR), 39% (seven of 18) stable disease (SD) and 28% (five of 18) progressive disease (PD). All of the patients were evaluable for toxicity. The most common toxicities were mild fatigue (nine of 19, 47%), loss of appetite (nine of 19, 47%), skin hyperpigmentation (five of 19, 26%) and diarrhea (two of 19, 11%). Only one patient had grade IV myelotoxicity with sepsis but without treatment-related death. The median time to progression was 4 months. The overall median survival time was 7.0 months. The median survival time of the PR was not reached, SD was 8.0 months and PD 3.5 months. In conclusion, weekly high-dose 5-FU with LV by 24 h infusion in an outpatient setting for patients with BTC is effective, only mildly toxic and deserves further study.
 ...
PMID:Weekly 24 h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract carcinomas. 966 May 35

The pro-inflammatory cytokines and oxidant molecules produced during the inflammatory response, which follows infection and injury, may be beneficial, or detrimental to the patient, depending on the amounts and contexts in which they are produced. Aberrant or excessive production has been implicated in inflammatory disease, and sepsis. The upregulation of cytokine production by NF kappa B and NFIL-6 activation by oxidants increases the likelihood of cytokine-induced mortality and morbidity. Complex systems exist for the control of cytokine production and oxidant actions. The former include the hormones of the hypothalamo-pituitary-adrenal axis, acute phase proteins, and endogenous inhibitors of interleukin (IL)-1 and tumor necrosis factor (TNF). The latter include endogenously synthesized antioxidants, such as glutathione and dietary antioxidants, such as tocopherols, ascorbates and cachectins. Nutrients change cytokine production and potency by influencing tissue concentrations of many of the molecules involved in cytokine biology. Monounsaturated fatty acids and omega-3 polyunsaturated fatty acids (PUFAs) suppress TNF and IL-1 production and actions, while n-6 PUFAs exert the opposite effect. Changes in eicosanoid production are more likely to underlie this effect than alterations in membrane fluidity. Low antioxidant intake results in enhanced cytokine production and effects. The anorexia that follows infection and injury, may be purposeful to permit release of substrate from endogenous sources to support and control the inflammatory process. Therefore, prior as well as concurrent nutrient intake are of importance in determining the outcome of the inflammatory response.
 ...
PMID:Nutritional modulation of cytokine biology. 968 68

Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) have been implicated as key mediators in inflammation, morbidity, and mortality associated with sepsis. We examined the role of IL-6 and TNF-alpha signaling on hypothermia, fever, cachexia, anorexia, and survival during sepsis induced by cecal ligation and puncture (CLP) in male and female gene knockout mice. Male wild-type mice developed an initial hypothermia and subsequent fever during sepsis. Male IL-6 knockout mice did not develop fever; rather, they maintained a profound hypothermia during sepsis. Male TNF p55/p75 receptor (TNFR) knockout mice had attenuated hypothermia, but developed a virtually identical fever as wild-type mice. Cachexia did not differ between male wild-type and IL-6 or TNFR knockout mice, whereas anorexia was prolonged in IL-6 knockout mice. Due to the rapid lethality of sepsis in female mice, survival was the only variable we were able to statistically compare among female genotypes. Female wild-type mice had significantly decreased survival compared with male wild-type mice. Survival was significantly enhanced in male and female TNFR knockout mice compared with their wild-type controls. Lack of IL-6 did not affect male or female lethality. These data support the hypothesis that IL-6 is a key mediator of fever and food intake, whereas TNF is responsible for the initial hypothermia and lethality of sepsis in both sexes of mice. The enhanced lethality of CLP-treated female mice supports a role for sex steroids during sepsis.
 ...
PMID:Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. 968 88

A case of intestinal perforation associated with SLE is presented. A 54-year-old woman was diagnosed as having SLE twenty-five years ago when she had facial erythema, photosensitivity, oral aphtha, polyarthraliga, leukopenia, positive LE cell and positive antinuclear antibody. She had been treated with prednisolone and admitted to Kushiro City General Hospital because of one month history of fever and anorexia in February 1996. Laboratory findings did not reveal activity of SLE, and a diagnosis of urinary tract infection was made based on the findings of urinalysis. After severe diarrhea, disseminated intravascular coagulation (DIC) developed. A rectal perforation was revealed by endoscopic and radiological examination. An emergency laparotomy revealed necrosis of the rectum and sigmoidostomy was performed. The biopsied specimen of the rectum were diagnosed as gangrene of ischemic colitis histologically. Because of a penetration to the urinary bladder, an ureterocutaneostomy was performed. She died of sepsis and DIC on the 127th day of admission. Only 11 cases of intestinal perforation associated with SLE have been reported in Japan, and the association of vasculitis has been considered. In the present case, the prolonged use of prednisolone might cause the necrotizing ischemic colitis.
 ...
PMID:[A case of systemic lupus erythematosus developed with intestinal perforation]. 972 61


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