Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011991 (diarrhea)
 57,543 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Measurement of disease activity in patients with inflammatory bowel disease is difficult. The best available methods are complex and time consuming, but it may be possible to use tumour necrosis factor alpha (TNF alpha) concentration in stool as a marker of disease activity. We measured TNF alpha concentrations in stool samples from normal children, infants with diarrhoea, and children with inflammatory bowel disease in active and inactive phases of the disease. In 10 normal children and 14 children with diarrhoea, median stool TNF alpha concentrations were 58 and 45 pg/g stool, respectively. Compared with diarrhoeal controls, stool TNF alpha concentrations were significantly increased in children with active Crohn's disease (n = 13, median 994 pg/g, p less than 0.0002) and active ulcerative colitis (n = 4, range 276-5982 pg/g, p less than 0.003). In patients with inactive disease, either as a result of surgery or treatment with steroids, the concentration of stool TNF alpha fell to those of controls. Measurement of stool TNF alpha concentrations may provide a simple way to monitor disease activity in inflammatory bowel disease.
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PMID:Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. 135 31

Polymorphoneutrophil leucocytes (PMNLs) are implicated in the pathogenesis of diarrhea-associated hemolytic uremic syndrome (D+ HUS). We investigated mechanisms of PMNL involvement by measuring tumor necrosis factor alpha (TNF alpha) and the novel cytokine, interleukin-8 (IL-8), a potent activator of neutrophils, together with alpha 1- antitrypsin-complexed elastase (alpha 1-AT-E) as a marker of neutrophil degranulation, and anti-neutrophil cytoplasmic antibodies (ANCA). IL-8 was not detected in the 17 normal children, but was significantly elevated in 20 of 25 D+ HUS children (P less than 0.005), and in three of nine children with non-diarrhea-associated (D-) HUS. Sequential data showed that IL-8 peaked transiently in the circulation, reaching a maximum just before a more protracted burst of alpha 1-AT-E. The IL-8 levels correlated significantly with circulating alpha 1-AT-E concentrations (r = 0.50, P less than 0.05). In D+ HUS IL-8 levels also correlated with the PMNL count (r = 0.63, P less than 0.005), and the highest values were seen in those children who died in the acute phase of the disease. TNF alpha was raised in only 1 of 16 D+ HUS children and in no patients were ANCA detected. The data suggest that PMNLs in HUS are recruited by IL-8, that this cytokine plays a key role in the PMNL activation which occurs, and that agents which suppress this recruitment and activation might play a therapeutic role in this disorder.
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PMID:Interleukin-8 and polymorphoneutrophil leucocyte activation in hemolytic uremic syndrome of childhood. 145 86

We have used an antihuman tumor necrosis factor monoclonal antibody, CB006 (murine IgG1), to prevent the OKT3-induced acute clinical syndrome. This syndrome is due to the massive, although transient release in the circulation of various cytokines (TNF, interferon gamma, interleukin 2, interleukin 6) and represents one important side effect linked to in vivo use of OKT3. Fourteen kidney allograft recipients undergoing prophylactic OKT3 therapy were treated with CB006 in a single i.v. injection of either 0.4 mg/kg (group I, 7 patients) or 2 mg/kg (group II, 7 patients), 1 hr before the first OKT3 administration. Nineteen consecutive patients formed a historical control group. None of the CB006-pretreated patients showed any of the common, severe OKT3-associated symptoms (hypotension, respiratory distress, or neurotoxicity), which were observed in 10% of the historical controls. In addition, CB006-treated patients showed a lower frequency of pyrexia (> or = 39 degrees C) and gastrointestinal symptoms. None of the CB006-treated patients presented severe vomiting or diarrhea, defined as repeated episodes inducing significant fluid and electrolyte loss. Two out of the 7 patients in group I and group II had mild transitory diarrhea. Mild single vomiting episodes occurred in 2 group I patients and 3 group II patients. At variance in all controls, gastrointestinal symptoms were long lasting and associated with major prostration due to electrolyte and fluid loss. Importantly, CB006-treated patients who presented mild symptoms had detectable bioactive circulating TNF, showing incomplete inactivation of OKT3-induced TNF by CB006. CB006 was perfectly well tolerated, did not induce xenosensitization, and did not affect the biological or clinical effectiveness of OKT3.
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PMID:Evidence that antihuman tumor necrosis factor monoclonal antibody prevents OKT3-induced acute syndrome. 146 94

In keeping with the in vitro mitogenic properties of anti-CD3 MoAbs, the first injections of anti-CD3 are invariably responsible for an in vivo cellular activation. This activation induces a massive cytokine release in the circulation (TNF, IFN gamma, IL-2, IL-6, and IL-3). Paralleling this release, a severe clinical reaction occurs in OKT3-treated patients and in 145 2C11-treated mice. Corticosteroids both in vitro and in vivo inhibit the production of several cytokines involved in the anti-CD3 reaction. A single 1 mg hydrocortisone dose was administered to 145 2C11-treated mice according to different kinetics schedules. When given 1 hr prior to the anti-CD3 MoAb, hydrocortisone exerted a beneficial effect on the mouse physical reaction. Hypothermia was totally abrogated at the 4-hr time point. Diarrhea decreased by 50%. Hypomotility improved although not significantly. This improvement correlated with a major modification in the anti-CD3 pattern of cytokine release. At the 90-min blood withdrawal time point cytokine serum levels showed a 100% decrease for IFN gamma, an 88% decrease for IL-6, and 85% decrease for IL-2, and a 75% decrease for TNF. At 4 hr IL-2 serum levels were diminished by 65%; IL-6, IL-3, and IFN gamma serum levels were comparable to controls; and, interestingly, TNF was still detected, whereas it has already disappeared when 145 2C11 was administered alone. Importantly, when given more than 1 hr prior to anti-CD3 injection, corticosteroids were ineffective. To conclude, high doses of corticosteroids must be given with a precise kinetics--i.e. 1 hr prior to anti-CD3 MoAb--to achieve their maximal beneficial effect in the prevention of the anti-CD3 reaction.
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PMID:Reduction of morbidity and cytokine release in anti-CD3 MoAb-treated mice by corticosteroids. 169 10

The small intestine is a major target in HIV infection. Chronic diarrhoeal disease associated with malabsorption is the principal clinical manifestation of such infection. Reduced intestinal immunity and opportunistic enteric infections play a major role in clinical disease, but an enteropathy induced by HIV per se has also been implicated. The immunopathology of reduced intestinal immunity and its progression during HIV infection is poorly understood. HIV genome and proteins have been detected reproducibly in cells of the lamina propria resembling macrophages, but direct epithelial infection with HIV is controversial. Another factor which may contribute to diarrhoea is autonomic neuropathy within the jejunum. Small intestinal disease causes malabsorption of fat and disaccharides and may contribute to the weight loss seen in advancing HIV infection. However, malnutrition seen in HIV infection is multifactorial and may occur as a constitutional sign of infection in the absence of overt intestinal disease. Reduced food intake does not appear to be a causative factor in the weight loss in constitutionally well stage IV patients and there is some evidence that release of cytokines (TNF alpha/cachectin) into plasma or locally into tissue may mediate such events. The response of HIV-infected individuals to nutritional support is variable, but it is becoming increasingly apparent that the response is limited by the presence of severe systemic infection. However, aggressive nutrition is an important therapeutic mode which should be offered to all HIV-infected patients.
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PMID:Malabsorption, malnutrition and HIV disease. 228 81

The effects of recombinant human Tumor Necrosis Factor (rHu-TNF, PT-050), an antitumor agent, on the cardiovascular, gastrointestinal, renal and blood functions were examined in experimental animals. 1. PT-050 at 10(5) U/kg i.v. did not affect blood pressure and blood flow in anesthetized dogs. However, these were decreased 2-3 h after i.v. injection of 10(6) U/kg. A sustained decrease in blood pressure was seen in conscious dogs. PT-050 decreased systolic blood pressure and increased heart rate with a peak at 5-7 h after administration of 10 micrograms/kg (2.55 x 10(4) U/kg) i.v. and 10(5) U/kg s.c. PT-050 was without effect on perfusion volume in rabbit ear vessel preparations. 2. PT-050 enhanced gastric emptying in rats and intestinal charcoal meal propulsion in mice at 10(6) and 10(7) U/kg s.c., respectively. It decreased gastric juice volume and acid content with an increase of gastric juice pH in pyrolus ligated rats at 10(6) U/kg s.c. 3. PT-050 caused diarrhea at 10(5) U/kg i.v. in mice, while at 10(7) U/kg s.c., it did not exert the effect. 4. PT-050 increased urine volume and Na+ excretion at 3 x 10(3) U/kg i.v. and 10(5) U/kg s.c. in saline-loaded rats. 5. PT-050 decreased platelet counts at 10(5) U/kg i.v., depressed platelet aggregation responses to collagen and ADP at 10(6) U/kg i.v., and prolonged APTT and PT at 3 x 10(5) U/kg i.v. in rats, although it neither affected platelet aggregation nor blood coagulation in vitro. PT-050 neither affected platelet counts at 10(5) U/kg s.c., nor platelet aggregation at 10(7) U/kg s.c.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:General pharmacology of recombinant human tumor necrosis factor. 1st communication: effects on cardiovascular, gastrointestinal, renal and blood functions. 233 64

This study was conducted to determine if macrophage elaborated monokines in general, and human recombinant tumor necrosis factor (hrTNF alpha) in particular alter glucose metabolism in a manner analogous to that observed in endotoxin-treated animals. Endotoxin-tolerant rats were infused for 3 hr with saline, E. coli endotoxin (100 micrograms/l weight) or monokines contained in conditioned media from endotoxin-stimulated RAW 264.7 cells (1 microgram/ml). Compared to saline- and endotoxin-infused rats, animals receiving the monokine mixture had no change in mean arterial blood pressure or heart rate but exhibited overt signs of morbidity including stupor and diarrhea. Monokine-infused rats remained euglycemic but had elevated lactate concentrations and a 15-30% increase in glucose rate of appearance (Ra). Nontolerant rats received a 3 hr infusion of saline, hrTNF alpha (15 micrograms/100 g), or heat-treated hrTNF alpha. HrTNF alpha infusion increased glucose Ra about 25% compared to the two control groups but did so without producing signs of morbidity seen in the monokine infused animals. Serum TNF levels were 6-fold higher in rats infused with the monokine mixture compared to animals infused with hrTNF alpha, and this reflected the different levels of TNF contained in the monokine mixture and hrTNF alpha infusates. Plasma insulin, glucagon, and catecholamine concentrations were increased in rats infused with either the monokine mixture or hrTNF alpha, but the increases were more pronounced in rats receiving the monokine mixture. The results demonstrate that monokines and hrTNF alpha increase glucose production in vivo, and that the effect may be mediated by endocrine changes known to influence glucose homeostasis.
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PMID:Glucose kinetics in rats infused with endotoxin-induced monokines or tumor necrosis factor. 337 Jul 60

A phase I and pharmacokinetic study of recombinant tumor necrosis factor (rH-TNF Asahi) was carried out in 29 patients, who received a total of 72 courses with doses ranging from 1 to 48 X 10(4) units/m2. Drug was given as 1-h i.v. infusions. Acute toxicities, taking the form of fever, chills, tachycardia, hypertension, peripheral cyanosis, nausea and vomiting, headache, chest tightness, low back pain, diarrhea and shortness of breath were seen, but were not dose-limiting or dose-related. Some early rise in SGOT, without any change in serum bilirubin, was noted at the highest doses. Eosinophilia, monocytosis, mild hypocalcemia and an increase in fibrin degradation products were seen in a few patients. The dose-limiting toxicity was hypotension, which occurred after the end of the drug infusion and was seen in all 5 patients treated at the highest dose. There was no mortality or long-term morbidity. There were no responses. Pharmacokinetic studies indicated a rapid plasma clearance and a short plasma half-life, generally less than 0.5 h.
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PMID:Phase I clinical trial of recombinant human tumor necrosis factor. 366 33

Antitumor effects of i.v. injected human recombinant tumor necrosis factor (rTNF) against solid Meth A tumors in mice appeared to be critically dependent on the dose and were limited by its toxicity. Extensive necrosis and complete cures were only induced by doses having untoward effects, such as diarrhea, hypothermia, ruffled fur, and lethargy. Murine tumor necrosis serum (TNS, 0.5 ml) had about the same antitumor potential and induced all side effects except diarrhea. More extensive necrosis and approximate doubling of the incidence of complete regression in the absence of gross side effects were observed upon administration of a low dose of rTNF combined with detoxified endotoxin, nontoxic poly A:U, or submicrogram doses of toxic endotoxin. The separate constituents had little antitumor effects, if any at all. Increasing the dose of toxic endotoxin resulted in a further potentiation of necrosis, overt toxicity, but no cures. Muramyl dipeptide and interferon alpha/beta did not potentiate effects of rTNF. In vitro growth of Meth A cells was not inhibited by toxic endotoxin, rTNF or the combination, although TNS was highly inhibitory. Data show that therapeutic effects of rTNF and its synergy with endotoxin are not due to direct effects on the tumor cells and that the extent of prompt in vivo tumor necrosis does not predict the course of tumor growth. Therapeutic effects of both TNS and toxic endotoxin probably involve a synergy between low levels of TNF and other factors/effects induced by endotoxin. Detoxified endotoxin and poly A:U probably induce the latter effects and little or no TNF, so explaining the absence of side effects, their weak antitumor potential, and their powerful synergistic action with rTNF. A role for interferon alpha/beta as an induced synergistic factor is not likely. Muramyl dipeptide and TNF might share properties needed for synergy with endotoxins.
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PMID:Synergistic action of human recombinant tumor necrosis factor with endotoxins or nontoxic poly A:U against solid Meth A tumors in mice. 382 51

The hyper-IgD syndrome is a rare entity characterized by early onset of attacks of periodic fever. All patients have an elevated serum IgD (> 100 U/ml). Symptoms during attacks include joint involvements (arthralgias/arthritis), abdominal complaints (vomiting, pain, diarrhoea), skin lesions, swollen lymph nodes, and headache. In 1992 an International hyper-IgD study group was established, and to date the diagnosis has been made in 60, mainly European patients; 14 come from France. The disorder occurs in families and is transmitted by autosomal recessive inheritance. Linkage studies indicate that the gene encoding for familial Mediterranean fever is different from the gene for the hyper-IgD syndrome. In children the hyper-IgD syndrome should be distinguished from two other periodic febrile disorders. CINCA (chronic inflammatory, neurological, cutaneous and articular syndrome) and FAPA (periodic fever, adenopathies, pharyngitis, and aphtous stomatitis) share some symptoms with the hyper-IgD syndrome but in these syndromes serum IgD is normal. The pathogenesis remains to be elucidated but during attacks all patients have an acute-phase response with elevated C-reactive protein concentrations. During the febrile episodes, the inflammatory cytokines such as IL-6 TNF alpha, IFN gamma are increased together with natural occurring inhibitors such as IL-1ra and sTNFr. There is no therapy for the syndrome and patients will experience attacks during their entire life although frequency and severity tend to diminish with age.
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PMID:[Hyperimmunoglobulin D syndrome]. 756 50


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