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)

Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.
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PMID:A Southwest Oncology Group Phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer. 151 22

We demonstrated the clinical effectiveness of recombinant interferon-gamma (rIFN gamma) (Biogen) in 18 patients with Philadelphia-positive chronic myeloid leukemia. Sequential cytogenetic studies and molecular analyses of the breakpoint cluster region and for immunoglobulin and T cell rearrangements were performed every 3-4 months. In 13 patients who received treatment for a minimum of 3 months, the majority were treated with 1.5 mg/m2, t.i.w., i.v. Nonhematologic effects--particularly chills, rigors, myalgia, fatigue, headaches, and nausea--were significant. Complete or partial hematologic responses were observed in six patients, two of whom had approximately 20% normal metaphases after an average of 74 weeks of treatment. However, reversion to 100% Ph+ cells occurred 30 weeks later. In these two patients, in whom normal metaphases were found, no changes were observed in the presence of rearrangements of the breakpoint cluster region. In addition, the marrows remained hypercellular, and the leukocyte alkaline phosphatase score and B12 levels remained abnormal. No immunoglobulin or T cell beta-chain gene rearrangements were found. These data indicate the clinical effectiveness of rIFN gamma in some patients with chronic myeloid leukemia, although the fundamental nature of the disease is unaltered by this form of treatment.
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PMID:Recombinant gamma-interferon has activity in chronic myeloid leukemia. 215 24

A phase I study of the effects of intravenous administration of interferon-gamma on 31 patients was performed. The effects of dose, schedule, and chronic administration were studied. In the first phase of the study, a dose range of 0.01-500 MU/m2 (0.0002-25 mg/m2) was tested and we found the maximum tolerated dose to be 400 MU/m2; the dose-limiting toxicity with this preparation was hypotension. In the second phase, three different schedules of administration were tested. There were no significant differences in toxicity between a 20 min, a 4 h, or a 24 h infusion of 60 MU/m2 (3 mg/m2). In the third phase, patients received chronic administration of either 1 or 30 MU/m2. Patients given 30 MU/m2 twice a week for 4 weeks showed more symptoms--fever, nausea, and orthostasis--than those treated with 1 MU/m2. No significant changes were seen in natural killer cell activity, antibody-dependent complement cytotoxicity, or monocyte cytotoxicity at any dose. Maximal stimulation of 2',5'-oligodenylate synthetase occurred at low doses (12 MU/m2). Depressed bone marrow colony formation for CFU-GM, BFU-E, and CFU-GEMM in vivo was noted. No objective antitumor responses were noted. This preparation of recombinant interferon-gamma can be given in doses as high as 400 MU/m2. Chronic administration would appear to be limited to 30 MU/m2. However, lower doses may give maximal biologic responses. These studies provide further information on the biologic effects of a wide dose range and a variety of schedules of recombinant interferon-gamma.
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PMID:Phase I studies of recombinant interferon-gamma. 216 May 21

A Phase I study of recombinant interferon-gamma (rIFN-gamma) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-gamma. rIFN-gamma was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2-4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7-12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1-1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-gamma is given at doses at or near this MTD.
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PMID:A phase I trial of recombinant human interferon-gamma in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS). 254 86

Based upon the in vitro synergistic activity of interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma) observed in melanoma cells, we initiated a Phase II trial using the combination to determine the clinical antitumor efficacy in patients with advanced disease. Fifteen patients with metastatic malignant melanoma were given 2,000 micrograms of recombinant IFN-gamma (rIFN-gamma) (Biogen) intravenously (i.v.) over 10 min, followed by a 10 min i.v. injection of 30 million units of recombinant IFN-beta (rIFN-beta ser) (Triton) 3 x/week. Six patients had skin, soft tissue, nodal, or subcutaneous metastases, 6 had visceral disease only, and 3 had both. Seven patients had received prior treatment, including chemotherapy (6), radiotherapy (3), and/or immunotherapy (3). Side effects included typical IFN constitutional symptoms such as anorexia, fatigue, nausea, and myalgias, but were not dose limiting. The mean drop in the white blood cell count (WBC) following 1 month of therapy, compared to baseline, was 3.3 x 10(3)/mm2 (p = 0.002); the mean increase in SGOT was 24.1 U/l (p less than 0.001). One patient had a dose reduction for Grade III anorexia and fatigue which did not resolve with repeated treatment. One patient with liver metastases had radiographical and clinical stabilization of his disease for 1 year. No responses were seen. The median time to progression was 6 weeks. Two patients' tumors were evaluable in the human tumor colony forming assay (HTCFA) and were markedly sensitive to the antiproliferative effects of IFN combinations. Both patients, however, failed to respond clinically.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phase II trial of a combination of interferon-beta ser and interferon-gamma in patients with advanced malignant melanoma. 314 69

Recombinant interferon-gamma was given to patients with tumours by a six-hour intravenous infusion using a portable mini-pump, to assess the side-effects of the drug. At present, 11 patients have been treated; 2 adenocarcinoma of the ovary, 3 squamous carcinoma of the bronchus, 1 adenocarcinoma of the breast, 1 adenocarcinoma of the stomach, 1 Hodgkin's lymphoma, 1 case of two primaries, adenocarcinoma of the breast and ovary, and 1 adenocarcinoma of unknown origin. Two patients received 1 X 10(6) units/m2/infusion, four received 3 X 10(6) U/m2/inf., three received 6 X 10(6) U/m2/inf. and two received 9 X 10(6) U/m2/inf. Two further dose levels will be used in the future; 27 and 51 X 10(6) U/m2/inf. Three 6-hour infusions a week were given for a four week period. The major side-effects of gamma-interferon were dose-related pyrexia with rigors to which there was no tachyphylaxis, acute and chronic tiredness, nausea with or without vomiting, headache, backache and myalgia. There was also a dose-dependent immediate but mild and transient decrease in the total white cell count. All effects have been transient, and none have been severe. We have also noticed that intravenous infusions by mini-pumps are tolerated far better by the patients than conventional drip systems, and we feel mini-pumps are the ideal way to give intravenous infusions.
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PMID:A phase 1 study of recombinant interferon-gamma given intravenously by portable mini-pump: a preliminary report. 624 30

The combination of chemotherapy and immunotherapy seems to improve response rate in metastatic melanoma. We investigated the effects on toxicity and immunological effects of a single dose of dacarbacin (DTIC; 850 mg/m2) or cisplatin (CDDP; 100 mg/m2) added to subsequent immunotherapy with interferon-alpha (IFN-alpha) and interleukin-2 (IL-2). Twelve patients, who did not respond to IFN-alpha/IL-2 alone were studied. Six received DTIC and IFN-alpha/IL-2, and six received CDDP and IFN-alpha/IL-2. DTIC did not add significant toxicity except for nausea. Significant thrombocytopenia was observed in two patients after CDDP. Although CDDP led to grade 3 nephrotoxicity in two patients, the IL-2-induced fluid retention was less severe than with IFN-alpha/IL-2 alone. Pharmacokinetics of IL-2 were not altered by DTIC, but higher IL-2 serum levels were found in patients with grade 3 nephrotoxicity after CDDP. The IL-2-related induction of secondary mediators (interferon-gamma, tumour necrosis factor-alpha, soluble CD25) was not impaired by chemotherapy and the induction of neopterin was significantly higher after addition of CDDP. One partial response was observed after addition of DTIC to IFN-alpha/IL-2, and one after addition of CDDP. The addition of a single dose of DTIC or CDDP to IFN-alpha/IL-2 is fairly well tolerated and does not abolish induction of secondary mediators. Randomized trials are necessary to test the clinical efficacy.
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PMID:Addition of dacarbazine or cisplatin to interferon-alpha/interleukin-2 in metastatic melanoma: toxicity and immunological effects. 749 66

We report a case of a patient with systemic mastocytosis who was treated with interferon-gamma. Because of severe diarrhoea, nausea and weight loss due to mast cell infiltration of the gastric mucosa the patient received 150 micrograms d-1 interferon-gamma subcutaneously for 10 months. During therapy, the plasma concentrations of IL-3, IL-4 and GM-CSF, which seem to play a role in mast cell growth and differentiation were monitored. The patient had good symptomatic relief and the initially very high eosinophil counts in the peripheral blood showed a partial reduction. However, after 4 months of therapy the patient relapsed. In serum obtained after the relapse, but not in stored serum from the beginning of the therapy, neutralizing antibodies against interferon-gamma were found. Therefore an initial response to the therapy and a secondary failure mediated by treatment-induced antibodies against recombinant interferon-gamma might be suggested. Interferon-gamma may be a well tolerated therapeutic option in systemic mastocytosis. However, treatment-induced neutralizing antibodies against recombinant interferon-gamma should be considered if secondary treatment failure occurs.
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PMID:Treatment of systemic mastocytosis with interferon-gamma: failure after appearance of anti-IFN-gamma antibodies. 758 19

A Phase I trial was conducted to investigate the clinical toxicity, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AMs), peripheral blood neutrophils, and monocytes after subcutaneous injection of recombinant interferon-gamma (rIFN-gamma). Six patients with lung cancer received rIFN-gamma subcutaneously as single doses of 0.2, 0.6, and 1.8 mg. Bronchoalveolar lavage was performed three times: 21 h before as well as 6-7 and 27 h after injection. Serum samples were taken five times during the 27-h follow-up. IFN concentrations were measured from alveolar epithelial lining fluid (ELF) and serum by using an antiviral bioassay. IFN-gamma was not detectable in ELF after subcutaneous injection. AMs did not effect an increase in CL responses to N-formyl-methionyl-leucyl-phenylalanine or to phosphate-buffered saline. Circulating IFN-gamma was detectable at 3-12 h after an injection of 1.8 mg of rIFN-gamma, the highest dose given. CL responses of peripheral blood monocytes increased in all patients after injection, whereas the responses of neutrophils were less clear-cut. All patients developed systemic side effects such as transient fever, nausea, headaches, and flu-like symptoms. The findings suggest that rIFN-gamma passes poorly from the blood to the pulmonary alveoli. On the basis of this and our previous findings of increased CL responses in AMs and measurable IFN concentrations in ELF after inhalation of rIFN-gamma, we recommend inhalation rather than the parenteral route of IFN-gamma for the treatment of respiratory diseases.
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PMID:Subcutaneously administered recombinant interferon-gamma in humans: pharmacokinetics and effects on chemiluminescence responses of alveolar macrophages, blood neutrophils, and monocytes. 806 1

Preclinical data have shown a synergism between 5-fluorouracil and interferon-gamma against human colon carcinoma cell lines. We conducted a phase II trial of this combination in 34 patients with metastatic colorectal cancer. 5-Fluorouracil was administered as an intravenous bolus of 500 mg/m2 weekly and interferon-gamma subcutaneous injection at a dose of 200 micrograms (6 x 10(6) IU) 3 times a week. Thirty-two patients were evaluable for response. There was one complete and two partial responses (response rate 9.0%, 95% CI 1.98-25.02%). Eleven patients (34%) had stable disease. Common toxicities included fever 81%, nausea/vomiting 19%, diarrhea 16%, flu-like syndrome 16%, malaise 12.5% and leukopenia 12.5%. These results indicate that the above combination of 5-fluorouracil and interferon-gamma has an unimpressive activity in patients with advanced colorectal carcinoma. Toxicity was very tolerable.
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PMID:Phase II study of 5-fluorouracil and interferon-gamma in patients with metastatic colorectal cancer. A Hellenic Cooperative Oncology Group Study. 860 43


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