Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phase I study to evaluate the use of i.p. infusion of recombinant interleukin-2 (rIL-2) was planned. The following dose levels were calculated: 0.1, 0.3, 1.0, 3.0 and 10 mg/m2/day for 14 days, but only the second levels were reached. In this trial the acute toxic effects at this dosage included cardiac ischemia, transient liver impairment and septic peritonitis. The maximum tolerated dose (MTD) was 0.3 mg/m2/day for 14 days. In addition, two patients developed peritoneal fibrosis. No objective responses were observed. Therefore, in order to explore the biological activity of low (nontoxic) doses, three patients (one untreated and two previously treated with rIL-2) were infused with 0.01 and 0.03 mg/m2/day for 7 days. Potentiation of cytolytic activities in peritoneal lymphocytes and activation of a lymphokine cascade in the ascitic fluid were observed at doses ranging from 0.03 mg/m2/day to 0.3 mg/m2/day. These findings in association with the toxic effects observed at the MTD suggest the use of the minimum effective dose for future locoregional immunotherapeutic protocols.
 ...
PMID:A phase I study of recombinant interleukin-2 intraperitoneal infusion in patients with neoplastic ascites: toxic effects and immunologic results. 203 10

The National Cancer Institute (NCI) Extramural IL2/LAK Working Group treated 93 patients with 114 cycles of high-dose intravenous (IV) interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells in three phase II trials. Thirty-six patients had metastatic melanoma, 35 had metastatic renal cell cancer, and 22 had colorectal cancer. All patients had a Karnofsky performance status greater than or equal to 80% and normal laboratory tests and organ function, and had received no more than one prior form of immunotherapy or chemotherapy. Objective responders were eligible to receive up to two additional courses of therapy at 12-week intervals. The most frequent toxicities were a capillary leak syndrome resulting in marked extravascular fluid shifts, and hypotension requiring treatment with large volumes of IV fluids and vasopressor agents. Laboratory and clinical evidence of hepatic and renal dysfunction were virtually universal. Intensive care-level support was routinely provided and the toxicity observations confirmed the need for this level of care. The life-threatening toxicities were cardiac and pulmonary. Five of the 27 patients who experienced significant respiratory compromise required intubation and mechanical ventilatory support. Twenty patients developed cardiac arrhythmias, the majority of which were supraventricular. There was a single episode of ventricular tachycardia requiring cardioversion. Four patients had transient cardiac ischemia, and an additional four had myocardial infarctions, one of which was fatal. With these exceptions, all toxicities were rapidly reversible. The occurrence of only a single therapy-related death and a very low incidence of other irreversible or life-threatening events is comparable to the level of toxicities often observed in other phase II trials. Although the intensity of this regimen limits this approach to a subset of cancer patients with excellent performance status and adequate organ function, because of the frequency and apparent durability of complete responses, this treatment warrants further investigation.
 ...
PMID:Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. 264 14

Previously, we have reported an increase in the cytokines interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) early after left lung allotransplantation in dogs. The purpose of this study was to develop a novel model of canine lung autotransplantation and to observe whether ischemia/reperfusion injury alone (in the absence of an allogenic stimulus) would result in this cytokine release as seen in the allograft. Thus, using this model, early changes in cellular and cytokine composition in the lung autograft were monitored through the use of bronchoalveolar lavage (BAL) and plasma. The effects of ischemia/reperfusion injury on lung histology and major histocompatibility class II (MHC II) antigen expression were also observed. Ten mongrel dogs were subjected to left lung autotransplantation. Lungs were stored cold for 4 h, with a warm ischemic time of 1 h. BAL, blood, and biopsy specimens were taken preoperatively and 1 h, 4 h, 24 h, and 1 wk postoperatively. The mean BAL IL-2 levels significantly rose from a preoperative value of 150 +/- 19 pg/ml to 246 +/- 67 pg/ml 4 h after transplantation (p < 0.05), decreasing to preoperative levels after 24 h (128 +/- 54 pg/ml). Plasma levels of IL-2 did not change from preoperative values. In contrast to IL-2, TNF-alpha and IFN-gamma did not change in either BAL or plasma of the autograft.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cytokine interleukin-2, tumor necrosis factor-alpha, and interferon-gamma release after ischemia/reperfusion injury in a novel lung autograft animal model. 759 35

Cardiac toxicity and hemodynamic alterations are frequently associated with high-dose interleukin-2 (IL-2) immunotherapy in cancer patients. Serious cardiac events including myocardial infarction, ischemia, and noninfectious myocarditis have been observed. We document two cases of unusually severe but reversible cardiac abnormalities related to IL-2 therapy: one patient with a profound form of global myocardial hypocontractility and a second patient with regional aneurysmal and dyskinetic changes of the left ventricle. These cases exhibit unique features not previously described in IL-2-treated patients. The possible pathophysiologic mechanisms underlying these global and regional forms of cardiomyopathy, including the production of secondary-messenger molecules such as nitric oxide and myocardial stunning, are discussed. Both patients remain disease free of their cancer (> 3 years since completing therapy), are without residual cardiac dysfunction or recurrent related symptoms, and have not experienced any additional cardiac events. The report demonstrates the complexity of the cardiac toxicities associated with IL-2-based immunotherapy and recognizes a need for treating physicians to be familiar with their management.
 ...
PMID:Severe reversible global and regional ventricular dysfunction associated with high-dose interleukin-2 immunotherapy. 857 67

Gut-origin sepsis is a serious medical complication of military injuries following hemorrhage. Splanchnic ischemia induces intestinal necrosis leading to systemic bacteremia. Rat and mouse models of hemorrhagic shock were used to investigate bacterial translocation from the gut. Orally administered ameliorative treatments using the cytokine interleukin-6 (IL-6) were able to reduce or eliminate sepsis following hemorrhage. To mimic battlefield wounds and hemorrhage, anesthetized mice were bled from the femoral artery, held at a mean arterial blood pressure of 35 mm Hg for 1 hour, and then resuscitated with shed blood and 2-fold volume lactated Ringer's solution. Anesthetized rats were bled from the carotid artery at a rate of 15 ml/kg at 1 ml/minute. Bacteriological cultures of livers and mesenteric lymph nodes from hemorrhaged animals given recombinant IL-6 had significantly fewer colonies per gram of tissue than saline-fed controls. 125I-labeled IL-6 remained in the gut for up to 6 hours giving regional protection, whereas labeled interleukin-2 was disseminated throughout the body in the same time. In vivo and vitro studies of IL-6 showed that long incubations with high doses of trypsin, chymotrypsin, or intestinal contents were necessary to inactivate the bioactivity of this cytokine. Electron microscopy showed that epithelial cells from hemorrhaged mice fed saline had sparse or missing villi and vacuolated cytoplasm. Epithelial cells from control mice or mice hemorrhaged and fed cytokine appeared completely normal. Oral administration of IL-6 on the battlefield may be an important treatment for the prevention of sepsis following hemorrhage.
 ...
PMID:Systemic sepsis following hemorrhagic shock: alleviation with oral interleukin-6. 915 11

Polymyositis (PM) and dermatomyositis (DM) are two major and distinct inflammatory myopathies. Cytokines, implicated in the immune process, have been recognized in the muscle tissue from PM and DM patients, but their functional in situ role has not been identified. We analyzed the expression of the signal transducer and activator of transcription 1 (STAT1), a molecule whose up-regulation indicates the interaction of cytokines, or growth factors, with their target receptors in muscle fibers and inflammatory infiltrates in PM and DM. An immunohistochemical analysis was performed using monoclonal antibodies to STAT1 in 57 muscle biopsies from 10 patients with DM, 10 with PM, and 37 controls. The profile of STAT1 up-regulation was also investigated in cultured muscle stimulated by interferon-gamma, epidermal growth factor, platelet-derived growth factor, and interleukin-2, using semiquantitative polymerase chain reaction and Western blot. High STAT1 expression was observed in many perifascicular atrophic muscle fibers from DM patients in 10/10 biopsies. In contrast, only a few muscle fibers undergoing necrosis were STAT1 positive in 2/10 patients with PM and in 2/37 controls. STAT1 reactivity was noted in most cells of the infiltrates in DM, PM, and controls. In vitro, STAT1 was stimulated by interferon-gamma but not by the other molecules studied. These results suggest that in DM, but not in PM, there is distinctive functional local cytokine activity able to increase STAT1 expression in muscle fibers. As interferon-gamma specifically activates STAT1 in vitro, this cytokine in conjunction with ischemia is probably involved in perifascicular muscle fiber pathology in DM.
 ...
PMID:Signal transducer and activator of transcription 1 in human muscle: implications in inflammatory myopathies. 921 34

The immunosuppressive effect of rapamycin is mediated by inhibition of interleukin-2-stimulated T cell proliferation. We report for the first time that rapamycin also inhibits growth factor-induced proliferation of cultured mouse proximal tubular (MPT; IC(50) ~1 ng/ml) cells and promotes apoptosis of these cells by impairing the survival effects of the same growth factors. On the basis of these in vitro data, we tested the hypothesis that rapamycin would impair recovery of renal function after ischemic acute renal failure induced in vivo by renal artery occlusion (RAO). Rats given daily injections of rapamycin or vehicle were subjected to RAO or sham surgery. Rapamycin had no effect on the glomerular filtration rate (GFR) of sham-operated animals. In rats subjected to RAO, GFR fell to comparable levels 1 day later in vehicle- and rapamycin-treated rats (0.25 +/- 0.08 and 0.12 +/- 0.05 ml. min(-1). 300 g(-1), respectively) (P = not significant). In vehicle-treated rats subjected to RAO, GFR increased to 0.61 +/- 0.08 ml. min(-1). 300 g(-1) on day 3 (P < 0.02 vs. day 1) and then rose further to 0.99 +/- 0.09 ml. min(-1). 300 g(-1) on day 4 (P < 0.02 vs. day 3). By contrast, GFR did not improve in rapamycin-treated rats subjected to RAO over the same time period. Rapamycin also increased apoptosis of tubular cells while markedly reducing their proliferative response after RAO. Furthermore, rapamycin inhibited activation of 70-kDa S6 protein kinase (p70(S6k)) in cultured MPT cells as well as in the renal tissue of rats subjected to RAO. We conclude that rapamycin severely impairs the recovery of renal function after ischemia-reperfusion injury. This effect appears to be due to the combined effects of increased tubular cell loss (via apoptosis) and profound inhibition of the regenerative response of tubular cells. These effects are likely mediated by inhibition of p70(S6k).
 ...
PMID:Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. 1155 17

Although high-dose interleukin-2 (IL-2, Proleukin), a highly toxic agent used in the treatment of renal cell carcinoma and melanoma, was initially associated with treatment-related mortality, it can, in the appropriate setting, be administered safely. High-dose IL-2 is associated with significant morbidity; however, the incidence and severity of toxicities have decreased as clinicians have gained experience with this agent and implemented toxicity prevention and management strategies. IL-2 toxicity can manifest in multiple organ systems, most significantly the heart, lungs, kidneys, and central nervous system. The most common manifestation of IL-2 toxicity is capillary leak syndrome, resulting in a hypovolemic state and fluid accumulation in the extravascular space. Capillary leak syndrome can contribute significantly to development of oliguria, ischemia, and confusion. Safe and effective administration of high-dose IL-2 consists of five key components: (1) administration by an experienced and knowledgeable health-care team, (2) adherence to strict patient-eligibility criteria, (3) implementation of standardized administration and patient assessment guidelines, (4) adherence to administration criteria, and (5) compliance with retreatment contraindications. This article reviews high-dose IL-2 toxicities and symptom management strategies and provides practical guidelines to facilitate the safe and effective administration of high-dose IL-2.
 ...
PMID:Managing toxicities of high-dose interleukin-2. 1246 35

Patients with refractory advanced or metastatic urothelial carcinoma derive only minor benefit from chemotherapy. Based on evidence that urothelial carcinoma may be associated with impaired immunological reactivity, we conducted a phase II trial of interleukin-2 (IL-2), a biologic response modifier, to assess its efficacy and toxicity in treating refractory advanced or metastatic urothelial carcinoma. Seventeen patients with urothelial carcinoma who had undergone no more than 1 cisplatin-containing chemotherapy regimen were treated with IL-2 at a dose of 3 x 10(6) IU/m(2)/day by continuous intravenous infusion for 4 consecutive days each week for 4 weeks. Cycles were to be repeated every 6 weeks until disease progression. Toxic effects could be assessed in all 17 patients and response in 13. The most common grade III and IV toxic effects included hypotension (13/17); anemia (6/17); thrombocytopenia (4/17); granulocytopenia (3/17); and, in 1 patient each, cardiac ischemia, bowel perforation, and an increase in creatinine level. One sudden death was assumed to be treatment related. Although we found no objective antitumor activity for IL-2, median patient survival was 10.5 months (95% confidence interval, 5.8 to 17.1 months), with a 15.9-month median survival for 3 patients with poor performance status and visceral metastases. Further clinical investigation of the biological effect of IL-2 in urothelial carcinoma may be warranted.
 ...
PMID:Treating refractory advanced or metastatic urothelial carcinoma with interleukin-2: a phase II study. 1268 23

Inflammation has been reported to play an important role in cardiac surgery under cardiopulmonary bypass due to systemic endotoxemia. In order to develop strategies against this injury in future we studied the combined effect of a number of inflammatory mediators in myocardial ischemia/reperfusion. Coronary sinus blood samples of ten patients undergoing coronary artery bypass graft surgery (CABG) were obtained at three time intervals (1) before onset of bypass (2) 30 min after cross clamp, and (3) 10 min after removal of cross clamp. The samples were subjected to evaluate levels of nitric oxide byproducts (nitrite and nitrate and citrulline), inflammatory cytokines (interleukin-2, interferon-gamma and interleukin-6), adhesion molecules, (CD62L and CD54), ratio of cell surface markers (CD4/CD8 and TCRalphabeta/gammadelta) cell activation markers (CD69 and HLA DR) and second messengers (protein kinase C, inositol 1,4,5 triphosphate and intracellular calcium levels). Ischemia and further reperfusion resulted in significant rise in nitrite and nitrate levels (p < 0.001), interleukin-6 (p < 0.01), CD62L (p < 0.001), CD69 (p < 0.05), protein kinase C (p < 0.001) and intracellular calcium (p < 0.001). A fall in CD4/CD8 ratio was observed on reperfusion. These changes during CABG show that ischemia/reperfusion leads to a release of an array of pro-inflammatory mediators of tissue injury, which could lead to pathophysiological changes. Hence the study suggests the need of some protective therapies against these inflammatory markers.
 ...
PMID:Release of pro-inflammatory mediators during myocardial ischemia/reperfusion in coronary artery bypass graft surgery. 1284 27


1 2 Next >>