Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To define the maximum tolerated dose and to study whether recombinant human interleukin-3 (rhIL-3) reduced chemotherapy-induced neutropenia and thrombocytopenia, 20 chemotherapy-naive patients with advanced ovarian cancer eligible for treatment with 6 cycles of carboplatin-cyclophosphamide every 4 weeks (day 1) were entered in a phase I/II open, single-center trial. Cohorts of five patients received during 7 days 1, 5, 10, or 15 micrograms/kg/d rhIL-3 (days 5 through 11) in cycles 1, 3, and 5 by continuous intravenous (IV) infusion or once daily subcutaneous (SC) administration. In control cycles 2, 4, and 6, no rhIL-3 was administered. rhIL-3 significantly increased the recovery of leukocyte, neutrophil, and platelet counts, especially at 5, 10, and 15 micrograms/kg rhIL-3. rhIL-3 also increased basophil, eosinophil, monocyte, and lymphocyte counts at this dose steps. Effects on reticulocytes were limited. No difference in efficacy between SC and IV rhIL-3 treatment was found. Chemotherapy postponement for insufficient bone marrow recovery was necessary in 22 of 45 control cycles versus 2 of 49 rhIL-3 cycles (P less than .001). Platelet transfusions were required in 7 of 45 control cycles versus 3 of 50 rhIL-3 cycles (P less than .5). rhIL-3 up to 10 micrograms/kg/d could be administered without severe side effects. At 15 micrograms/kg/d, rhIL-3 headache was dose-limiting. Other side effects were fever, flu-like symptoms, nausea, skin rash, flushing, facial erythema, and urticaria. Liver toxicity occurred in rhIL-3 and control cycles. rhIL-3 slightly increased tumor necrosis factor alpha, C-reactive protein, and serum amyloid A plasma levels, whereas no effect on IL-6 plasma levels was observed. rhIL-3 administered SC appears to be an interesting hematopoietic growth factor for reduction of chemotherapy-induced myelotoxicity.
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PMID:Effects of interleukin-3 after chemotherapy for advanced ovarian cancer. 151 36

The macrophage activator muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) was infused in liposomal form in 14 metastatic cancer patients (4 mg i.v. during 30 min twice weekly for 12 weeks). Clinical, pharmacokinetic and immunological parameters were studied before and 0.5, 2, 4, 24 and 72h after start of drug infusion in week 1, 4, 8 and 12. No tumor regressions were seen. Tumors progressed in 11 patients, in 4 of them within 2 months; 3 patients had stable disease. The intensity and frequency of side effects (fever and nausea) diminished from week 1 to 12. The rate of disappearance of total and free MTP-PE from blood was rapid and mean serum concentration-time curves remained unchanged throughout 12 study weeks. MTP-PE caused a marked increase of serum TNFa, IL-1 receptor antagonist (IL-1ra) and IL-6 in week 1, but not thereafter. In contrast, MTP-PE caused a persistent, 2-fold increase in serum neopterin and young forms of granulocytes (bands) during week 1 to 12. Before therapy, monocyte tumor cytotoxicity and in-vitro monocyte derived TNFa, IL-1 beta and IL-6 production were low in 9 patients (group L, < 15%) and high in 5 patients (group H, > 40%). Monocyte cytotoxicity and in-vitro cytokine production was transiently enhanced in week 1 in group L, it declined under therapy in group H. In conclusion, MTP-PE induced marked initial immunomodulation; the extent of the ex vivo monocyte cytokine and tumor cytotoxic response was dependent on pre-therapy cell activity. A decrease of the cytokine and IL-1ra response during prolonged therapy contrasted with a persistent increase of neopterin and juvenile blood granulocytes. The long lasting biologic effects may be relevant to direct future clinical studies with liposomal MTP-PE in an adjuvant setting.
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PMID:Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide. 806 81

To define the toxicity profile of recombinant human interleukin-6 (rhIL-6) and to study its effect on hematopoiesis, biochemical parameters and other cytokines, rhIL-6 was administered in a phase I-II study to 20 patients with breast carcinoma or nonsmall cell lung cancer. RhIL-6 doses were 0.5, 1.0, 2.5, 5.0, 10, and 20 micrograms/kg/d, with at least three patients per dose level. RhIL-6 was administered 24 hours by continuous intravenous infusion followed by subcutaneous (SC) administration for 6 days, partly on an outpatient basis. RhIL-6-related side effects were fever, headache, myalgia, and local erythema. Starting at 2.5 micrograms/kg/d, these side effects were compounded by nausea, reversible increase in liver enzymes, and anemia. Flu-like symptoms were controllable up to and including 10 micrograms rhIL-6/kg/d with acetaminophen. RhIL-6 increased platelet counts with a decrease in mean platelet volume and increased leukocytes caused by neutrophil, monocyte, and lymphocyte increase, with an increase in T cells and natural killer cells at 1.0 and 2.5 micrograms rhIL-6/kg/d. The reversible anemia was characterized by a decrease in serum iron, and an increase in ferritin and erythropoietin without reticulocytosis. RhIL-6 reduced total cholesterol levels and a dose-related increase of C-reactive protein and serum amyloid A plasma levels was observed. Serum IL-6 levels were increased, especially at 10 and 20 micrograms/kg/d, whereas no change in IL-1 beta and tumor necrosis factor alpha levels was observed. RhIL-6 can be administered with controllable side effects in this setting, up to and including a SC dose of 10 micrograms/kg/d on an outpatient basis, and has a promising stimulating effect on leukopoiesis and thrombopoiesis.
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PMID:Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. 806 39

Interleukin-1 (IL-1) has been shown to ameliorate the hematopoietic toxicities of antitumor chemotherapeutic agents in both mice and humans. However, IL-1 toxicity in humans is considerable and is similar to the systemic inflammatory toxicities induced by IL-3, IL-6, and other cytokines with pleiotropic biologic activities, eg, fever, nausea, malaise, and hypotension. We hypothesized that corticosteroids may reduce IL-1 toxicity without reducing IL-1 hematopoietic effects in vivo. C3H/HeJ mice (female, 6 weeks) were treated for 7 days subcutaneously with cortisone acetate (CA), (0.1, 0.25, or 0.5 mg/d/mouse), intraperitoneally with IL-1 (1 or 2 micrograms/d/mouse), or both. As expected, IL-1 increased white blood cell counts, splenic granulocyte-macrophage colony-forming units, and spleen cell number, and protected mice from lethal doses of carboplatin (200 mg/kg; Paraplatin, Bristol Laboratories, Evansville, IN) administered the day after completion of the 7 days of IL-1 administration. CA did not significantly block the hematopoietic effects of IL-1 or the ability of IL-1 to protect mice from the hematopoietic toxicity of carboplatin. IL-1 administered to mice at 8 micrograms/d/mouse for 5 days induced decreased activity, roughening of hair, diarrhea, pancytopenia, multiple metabolic abnormalities, and death in 60% of mice. IL-1 at the therapeutic doses (0.5 to 2 micrograms/d) was not toxic. CA in a dose-dependent manner blocked all of the above mentioned toxicities when administered 24 hours and 30 minutes before each IL-1 injection. CA also decreased IL-1-induced increase in plasma tumor necrosis factor levels at the time point examined.
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PMID:Corticosteroid modulation of interleukin-1 hematopoietic effects and toxicity in a murine system. 806 40

The use of OKT3 as an immunosuppressive agent is accompanied by increased cytokine production and constellation of side effects collectively termed cytokine release syndrome (CRS). Pentoxifylline (PTF) inhibits synthesis of some cytokines, and has been shown to attenuate CRS when administered before OKT3. In this double-blinded, placebo-controlled study, 46 renal allograft recipients were randomized to receive either PTF (800 mg q 8 hr for at least 24 h) p.o. or placebo, along with methylprednisolone (7 mg/kg), diphenhydramine, and acetaminophen, prior to beginning OKT3 as therapy for acute rejection. Patients were observed, and symptoms scored semiquantitatively. Despite the presence of therapeutic PTF levels (721 +/- 726 ng/ml), the frequency and severity of side effects (fever, chills, headache, neurocortical symptoms, dyspnea, nausea, vomiting, diarrhea) did not differ between treatment groups. Likewise PTF did not affect renal function or immunologic response to OKT3, with similar graft and patient survival in both groups. Plasma levels of TNF alpha, IFN gamma, IL-6, and IL-8 increased as predicted following OKT3 administration, without significant differences between PTF and placebo groups. In this controlled, multicenter trial, pretreatment with oral PTF was ineffective in attenuating OKT3-related CRS in renal allograft recipients.
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PMID:Pentoxifylline does not prevent the cytokine-induced first dose reaction following OKT3--a randomized, double-blind placebo-controlled study. 861 Mar 83

A phase II trial investigating the anti-tumour effects of recombinant human interleukin 6 (rhIL-6) in patients with metastatic renal cell cancer was carried out. RhIL-6 (150 microgram) was administered as a daily subcutaneous injection for 42 consecutive days on an outpatient basis. Forty-nine patients were studied, 12 with and 37 without previous immunotherapy. Forty patients were evaluable for response. A partial remission was noted in two patients, stable disease in 17 and progressive disease in 21. Toxicity was moderate and reversible and consisted mainly of fever, flu-like symptoms, nausea, weight loss and hepatotoxicity. Anaemia, leucocytosis and thrombocytosis and induction of acute phase protein synthesis were noted in most patients. In 15% of the patients anti-IL-6 antibodies developed, and were neutralising in only one patient. Baseline plasma IL-6 concentrations did not correlate with tumour behaviour before or after rhIL-6 treatment. In conclusion, rhIL-6 can be safely administered on an outpatient basis for prolonged period of time and has moderate, reversible toxicity. Its administration induces IL-6-antibody production in only a minority of patients. Antitmour effects of rhIL-6 in metastatic renal cancer are limited.
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PMID:Recombinant human interleukin 6 in metastatic renal cell cancer: a phase II trial. 861 81

To develop a T-cell-based therapy for carcinomas, the superantigen staphylococcal enterotoxin A (SEA) was supplied with tumor specificity by means of a recombinant fusion of the Fab fragment of the monoclonal antibody C242 recognizing human colorectal (CRC) and pancreatic carcinomas (PC). Using this Fab-SEA fusion protein (PNU-214565), potent cytotoxicity by activation of T cells can be obtained in the targeted area. Twenty-one patients with CRC and 3 with PC were treated with single, escalating doses of PNU-214565 to establish the maximum tolerated dose (MTD) and to define toxicities. The doses ranged from 0.01 ng/kg to 4.0 ng/kg with three patients at each dose level, except for the dose of 1.5 ng/kg with which six patients were treated because of dose-limiting toxicity. Adverse events (AE) were transient: 13 patients experienced mild to moderate fever. In one patient, a grade 3 fever was followed by a grade 2 hypotension. Other mild or moderate AEs were fatigue, nausea, vomiting, diarrhea, and abdominal pain. No significant hematological toxicity occurred. Immune activation was highly variable with strong activity in peripheral blood seen only in two patients at the dosage level 1.5 ng/kg. They showed pronounced elevations of interleukin-2 (IL-2), IL-6, tumor necrosis factor-alpha, and interferon-gamma, 3-5 hours after the start of infusion. In one patient, IL-2 and IL-6 increased substantially (2,925 U/mL and 32,000 U/mL) concomitantly with grade 3 fever and transient grade 2 neutropenia, grade 2 lymphopenia, and grade 2 monocytopenia. In conclusion, a single 3-hour infusion of PNU-214565 could be safely administered up to 4 ng/kg. MTD was not determined. Instead, a repeat-dose trial was initiated starting at 0.5 ng/kg, considered safe in this trial, with the objective of defining the MTD.
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PMID:Phase I study of single, escalating doses of a superantigen-antibody fusion protein (PNU-214565) in patients with advanced colorectal or pancreatic carcinoma. 1068 47

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide, which exhibits antitumor activity by the induction of intratumoral tumor necrosis factor alpha, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-gamma and nitric oxide synthase activity. ONO-4007 was given to 24 patients (13 males and 11 females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycle consisting of three weekly infusions at the same dose, followed by a rest period of 1 week. Cohorts of six patients received up to a maximum of four treatment cycles at increasing dose levels (75, 100, and 125 mg). The maximum tolerated dose was 125 mg, with grade 3 National Cancer Institute Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in two of six patients at this dose level. An additional six patients were treated at 100 mg, the dose below the maximum tolerated dose. Other toxicities included grade 2 National Cancer Institute Common Toxicity Criteria myalgia, nausea, and hypotension. The pharmacokinetics of ONO-4007 appeared to be independent of dose and showed linearity with respect to time. ONO-4007 has a low systemic clearance (approximately 1.3 ml/min) and a small volume of distribution (5-8 liters) with a long t1/2 of 74-95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor alpha and IL-6. No objective antitumor responses were observed. Seven patients maintained stable disease for at least two cycles, whereas five patients maintained stable disease for the full four-cycle duration of the study. Additional studies are required to determine the antitumor activity of ONO-4007.
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PMID:Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide. 1069 May 16

We report the case of a 24-year-old woman with systemic lupus erythematosus (SLE). The patient presented with cervical erythema and multiple arthralgia in December, 1996. Based on the high level of antinuclear antibody and the positivity for anti-double-stranded-DNA antibody, we diagnosed the patient as having SLE. Her symptoms improved and her condition was maintained following steroid treatment. In August 2000, the patient suddenly had headache, nausea, vertigo, cerebellar ataxia, fixation nystagmus, and intention tremor. She was negative for the anti-phospholipid antibody. The cerebrospinal fluid IgG index and the IL-6 level were high. MRI of the right cerebellar hemisphere showed an equal-signal-intensity region in the T 1-enhanced image, and a high-signal-intensity region with a diffuse undefined border in the T 2-enhanced image. The increased cerebral blood flow at the site corresponding to a cerebellar lesion detected by magnetic resonance imaging (MRI) was observed by brain single photon emission computed tomography (SPECT). The central nervous system (CNS) lupus was confirmed by the presence of a lesion in the cerebellum. The abnormalities detected in MRI and SPECT images of the brain disappeared immediately after the steroid pulse therapy, and symptoms such as ataxic gait were improved. This patient was diagnosed as having acute neuropsychiatric SLE with cerebellar symptoms that are rarely observed as a localized neural sign of SLE. The MRI and SPECT images suggested the presence of an inflammatory edematous lesion that was confined in the cerebellar hemisphere. This is considered to be due to the increase of vasopermeability.
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PMID:[A case with systemic lupus erythematosus presenting with reversible edematous lesion in cerebellum]. 1246 20

Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 mug m(-2). In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44-68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1-29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole-blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.
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PMID:A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer. 1456 10


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