Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085593 (chills)
 4,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemistry, biological activity, and pharmacokinetics of gamma-interferon and recombinant interferon gamma are reviewed, and the agent's clinical efficacy, adverse effects, and dosage and administration for the treatment of chronic granulomatous disease (CGD) and other disorders are described. Endogenous gamma-interferon is a 166-amino-acid protein encoded by a single gene on chromosome 12. Recombinant human interferon gamma is purified from Escherichia coli as a monomer containing 139 amino acids. Gamma-interferon has antiviral, immunomodulatory, and antiproliferative activity. Serum concentrations of recombinant interferon gamma increase in proportion to the dose. Clearance after i.m. or s.c. administration fits a two-compartment model. The half-life is 3.5-7.5 hours, and bioavailability is 89%. Evidence that recombinant interferon gamma can enhance phagocytic oxidative metabolism led to its evaluation for use in the treatment of CGD. Clinical studies showed that the agent decreases the frequency of serious infections in patients with CGD. Recombinant interferon gamma has shown only limited success in the treatment of metastatic renal cell carcinoma (RCC), both as a single agent and in combination with recombinant interferon alfa. Similarly, although interferons appear to be able to change cytogenetic abnormalities in some patients with Philadelphia chromosome-positive chronic myelogenous leukemia, therapy with recombinant interferon gamma has led to minimal success. However, the agent has produced some encouraging results in atopic dermatitis. The adverse effects of recombinant interferon gamma in patients with CGD usually consist only of fever, chills, headache, and erythema. The recommended dosage in CGD-afflicted children whose body surface area is greater than 0.5 sq m is 50 micrograms/sq m given by s.c. injection three times a week for life. Recombinant interferon gamma has given new hope to patients with CGD. Although the drug is very expensive, the cost may be offset by fewer hospitalizations to treat infection.
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PMID:Recombinant interferon gamma for treatment of chronic granulomatous disease and other disorders. 134 90

Chronic granulomatous disease is a group of rare x-linked or autosomal genetic disorders of the phagocytic NADPH oxidase system involved in host defence against various microorganisms. It is manifested by a common phenotype consisting of recurrent serious, life-threatening infection and granuloma formation. Following the finding that interferon gamma-1b (IFN gamma-1b) can potentiate phagocyte activity in some other disease states as well as restoring defective phagocyte NADPH oxidase system activity in at least some patients with chronic granulomatous disease, a large-scale placebo-controlled trial was undertaken with IFN gamma-1b in patients with chronic granulomatous disease. Long term treatment with a therapeutic dosage of IFN gamma-1b produced a significant reduction in the incidence of serious clinical events necessitating hospitalisation. The relative risk of serious infection and the number of days in hospital were each reduced by about two-thirds, and the mean duration of hospital stay by about one-third in those who did experience infection. The greatest therapeutic benefit was found in patients aged less than 10 years, but all patients were improved regardless of age, sex, use of prophylactic antibiotics or genetic pattern of inheritance. The drug was well tolerated with the commonest adverse effects (e.g. fever, headache, chills, injection site erythema) usually being mild, transient, and relieved by symptomatic treatment. IFN gamma-1b therefore provides an effective and well tolerated therapy for patients with chronic granulomatous disease, offering an important clinical advance in the treatment of this rare genetic disorder by improving the prognosis of its serious and life-threatening infectious sequelae.
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PMID:Interferon gamma-1b. A review of its pharmacology and therapeutic potential in chronic granulomatous disease. 137 55

The purpose of this phase I study was to evaluate the toxicity and biological activity of autologous blood-derived macrophages activated ex-vivo with recombinant human interferon gamma (rhuIFN gamma) [monokine-activated killer (MAK) cells] and administered intravenously to 11 lung cancer patients once a week for 6 consecutive weeks. Peripheral blood monocytes were collected by leukapheresis and then purified by counterflow elutriation. The MAK cells were generated by culturing the purified monocytes in Teflon bags for 7 days and adding rhuIFN gamma to the cultured cells for the last 18 h. These MAK cells expressed differentiation-associated surface antigen MAX1, and were cytotoxic in vitro against tumour cell line U937. The MAK cells were infused at dose levels from 1 x 10(7) to 5 x 10(8) on an intrapatient dose-escalating schedule. No severe adverse side-effects occurred. Toxicity was mild to moderate [primarly fever (75%) and chills (32%)], non-dose-dependent, and non-cumulative. No consistent change in haemostatic function, or liver or renal function was observed. Dose-limiting toxicity was not reached at 5 x 10(8) cells (optimal dose reproduced for each patient). The maximum tolerated dose was not determined. The immunomodulatory activity of i.v. infused MAK cells was demonstrated both in vivo by significant increases in granulocyte count and neopterin level in the patients' peripheral blood post-infusion and in vitro by secretory products (IL-1. TNF alpha, neopterin, and thromboplastin-like substance) in the culture supernatants. The in vivo traffic patterns of autologous MAK cells labelled ex-vivo with 111In oxine were studied in 7 patients. Gamma imaging showed an immediate but transient lung uptake (less than 24 h), and a progressive uptake of radioactivity in the liver and spleen was seen from 6 h to 72 h post-infusion. Our results indicate that the preparation of high numbers of autologous, blood-derived MAK cells is a feasible procedure, and their transfusion is safe for patients. This immunotherapeutic approach seems to be encouraging from the point of view of establishing an adjuvant therapeutic modality in cancer patients with minimal residual disease.
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PMID:Phase I trial of intravenous infusion of ex-vivo-activated autologous blood-derived macrophages in patients with non-small-cell lung cancer: toxicity and immunomodulatory effects. 165 Nov 60

Interleukin-2 (IL-2)-based immunotherapy regimens are accompanied by dose-limiting toxicity consisting of fever, tachycardia, chills and capillary leak syndrome. We hypothesized that the toxicity was caused by the induction and release of endogenous cytokines such as tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). We measured the serum levels of TNF alpha and IFN gamma in IL-2-treated melanoma patients and attempted a correlation with clinical toxicity. A total of 23 patients received either 6 x 10(6) IU or 12 x 10(6) IU Cetus IL-2/m2 by i.v. bolus daily for 5 consecutive days on weeks 1, 3 and 5. Serum TNF alpha and IFN gamma levels were measured by enzyme-linked immunosorbent assay. Clinical toxicity was scored each day by objective measurements of hypotension, tachycardia, fever and chills/rigors. Clinical toxicity and IFN gamma levels correlated nicely, peaking on the 5th day of each treatment cycle. The kinetics and magnitude of TNF alpha production, however, were not predictable and did not correlate with either IFN gamma or toxicity. Some patients had modest increases in TNF alpha production while others had markedly increased levels during the second and third treatment weeks. Remarkably, these high levels persisted during nontreatment weeks and after completion of therapy. This clinical study demonstrates novel kinetics for immunoreactive TNF alpha in IL-2 cancer patients, which do not correlate well with toxicity.
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PMID:Production of tumor necrosis factor alpha and interferon gamma in interleukin-2-treated melanoma patients: correlation with clinical toxicity. 176 Aug 11

Human blood monocytes (Mo) and monocyte-derived macrophages (M phi) are known to be potent antitumor cytotoxic effector cells through activation with recombinant human interferon gamma (rIFN-gamma), bacterial muramyldipeptide or the synthetic derivative muramyltripeptide phosphatidylethanolamine entrapped in liposomes (L-MTP-PE). Large-scale generation of ex vivo activated Mo from the blood of cancer patients proved feasible. We report our experience with a fixed rotor speed counterflow centrifugation elutration (CEE) procedure using the newly available Beckman high capacity JE-5.0 rotor system that reproducibly isolates up to 1.0-1.5 x 10(9) Mo with greater than 90% purity, in suspension and functionally intact derived from peripheral blood mononuclear cell-enriched suspensions obtained by leukapheresis (LP) from healthy volunteers and cancer patients. The semiclosed, easy to handle CCE system, was adapted to a sterile technique that permitted clinical trials in adoptive monocyte immunotherapy. Freshly isolated Mo did not lose morphological or functional integrity and had no spontaneous activation. Their abilities to become activated to the cytotoxic state after 18-h stimulation with 500 U/ml rIFN-gamma or 1 microgram/ml L-MTP-PE and to differentiate into matured M phi in vitro were not altered. The system was therefore used to isolate large numbers of Mo for a phase I clinical trial of intraperitoneal immunotherapy with L-MTP-PE activated autologous Mo in nine patients with peritoneal carcinomatosis. Each patient received weekly Mo infusions (n = 5) with an intrapatient dose escalation schedule (from 10(7) to 10(9) Mo). Toxicities were mild including fever, chills and abdominal pain. There was no treatment-induced thromboembolic event or capillary leak syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Apheresis-elutriation program for adoptive immunotherapy with autologous activated monocytes in cancer patients. 186 56

A total of 29 patients with advanced malignancy were treated with recombinant interferon gamma (rIFN gamma, specific activity = 2.10(7) units/mg, purity greater than 95%) given by intravenous bolus at doses escalating from 0.01 mg/m2 to 5 mg/m2 (2 x 10(5) - 10(8) IU/m2) in nine successive steps (at least 3 patients/step). Injections of rIFN gamma were repeated every 72 h for 15 days. Toxicity was evaluated according to the WHO scale. Fever and chills occurred in all patients treated without clear dose effect. Nausea and vomiting appeared at the fifth dose level and their frequency seemed to be dose-related. Cardiovascular side-effects (first-degree atrioventricular reversible block) were observed at the 2 mg/m2 and 5 mg/m2 levels (3 patients). Hematological toxicities were mild (2 grade 1 and 1 grade II cases of granulocytopenia). Minor biological modifications included a transitory rise in hepatic enzymes (12 patients), which correlated with the presence of liver metastasis. Hypocholesterolemia was observed in 18 patients. The appearance of antibodies against rIFN gamma was not detected. One partial clinical response was observed in a patient receiving 2 mg/m2. During rIFN gamma therapy this patient had the highest scores in this series for peripheral T lymphocytes with an activated phenotype (HLA DR+, TAC+) = 15% and for natural killer (NK) cells (NKH1, Leu19+) = 17%. rIFN gamma appears as a well-tolerated and promising therapeutic agent with toxicities and mode of action probably distinct from IFN alpha and beta.
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PMID:A phase I trial with recombinant interferon gamma (Roussel UCLAF) in advanced cancer patients. 212 85

A clinical trial was conducted to determine the tolerance and toxicity of recombinant tumor necrosis factor (rTNF) and recombinant interferon gamma (rIFN-gamma) when administered concurrently by continuous intravenous infusion to 11 patients with the AIDS-related complex (ARC). In addition, HIV culture, p24 antigen levels, and CD4 positive lymphocytes were monitored to obtain preliminary evidence of antiviral and immunologic effects. Two 5-day treatment cycles were separated by a 9-day washout period. Two patients were entered at each dosage level and each patient received the two 5-day treatment cycles at two sequential dose levels ranging from 1 to 25 micrograms/m2. Two patients did not complete their second treatment cycle--one due to the development of a rash, the second due to central venous catheter discomfort. The occurrence of phlebitis with peripheral vein administration of these agents necessitated administration via central venous catheter. With the exception of a single patient who developed severe headache at the 25 micrograms/m2 dose, severe clinical toxicities were not observed. Fever, chills, headache, and myalgias were the most significant clinical toxicities observed and all were dose dependent. The percentage fall in total granulocytes was dose dependent and ranged from 17% at the 1 microgram/mm2 dose to 48% at both the 15 and 25 micrograms/mm2 dose levels. The mean nadir granulocyte count was 1694/mm3. No significant renal or hepatic toxicity was observed. Of 22 treatment cycles the CD4 cell number was increased in 11, unchanged in 7, and decreased in 4. The mean CD4 cell number did not change significantly (176 +/- 143/mm3 pretherapy versus 279 +/- 305/mm3 posttherapy).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A phase I/II study of recombinant tumor necrosis factor and recombinant interferon gamma in patients with AIDS-related complex. 256 51

A phase I-II study of human recombinant interferon gamma (rIFN-gamma) was conducted in patients with various advanced cancer refractory to standard chemotherapies. In the phase I study, seven patients received 14 courses of escalating doses ranging from 2 X 10(6)U/m2 to 64 X 10(6)U/m2 by 1-hour intravenous infusion for 5 consecutive days. The toxicities were high fever with chills, anorexia, occasional nausea and vomiting, elevation of serum GOT, and dose-related leukopenia and neurotoxic symptoms such as heavy fatigue with somnolence or lethargy, both of which were reversible. The pharmacokinetics showed that the peak levels of serum rIFN-gamma activity were dose-related but decreased rapidly to below measurable levels within 6 hours after infusion in patients receiving less than 12 X 10(6)U/m2. Considering these data, the dosage of rIFN-gamma 6 X 10(6) U/m2 by daily intramuscular injection for more than 4 weeks was selected for the early phase II study. There was no partial response out of 11 evaluable patients but a stable condition was observed in 2 cases of renal cell carcinoma and one case each of breast cancer and ovarian cancer. All toxicities seen were similar to those observed in the phase I study, but no tachyphylaxis developed with continued dosage. The antitumor effect of rIFN-gamma remains to be evaluated in a further study employing higher doses.
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PMID:[Phase I-II study of recombinant interferon gamma]. 298 59

Fifteen patients with advanced malignancy were treated with recombinant interferon gamma (rIFN-gamma) (specific activity approximately 2 X 10(7) units/mg, purity greater than 99%) given by 1-hour iv infusion three times a week for 6 weeks, at fixed dose levels of 0.1, 0.5, 1.0, or 2.0 mg/m2/day. The common side effects were constitutional symptoms, including fever, chills, myalgias, and headache, but these were less severe than those observed following daily 6-hour iv infusions. Significant changes in blood cell counts and routine serum chemistries were not observed, but there was a dose-dependent increase in serum triglyceride levels. The maximum safely tolerated dose achieved was 1.0 mg/m2/day. Peak serum interferon levels occurred at the midpoint of the infusion and were dose-dependent. rIFN-gamma was rapidly cleared from serum and no detectable activity was found 2 hours after the infusion. Two patients, both with B-cell malignancies, showed objective evidence of tumor regression during the treatment. Treatment was associated with an increase in serum levels of beta 2-microglobulin and the H2O2 secretory capacity of peripheral blood monocytes. We conclude that rIFN-gamma administered by short iv infusion can induce biological activities and causes less toxicity than when given by prolonged iv infusion.
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PMID:Phase I trial of recombinant interferon gamma by 1-hour i.v. infusion. 308 30

A phase I and II evaluation of 42 patients with advanced renal cell carcinoma treated with recombinant interferon gamma was done. Patients were treated with either a daily 2-hour infusion or 24-hour infusion for 7 days every 3 weeks for at least 2 cycles. Patients who demonstrated stable disease or improvement on therapy then were continued on a maintenance program of 5 days of recombinant interferon gamma administered every 3 to 4 weeks. The initial starting dose was 10 mcg. per m.2 per day with escalations to 30, 100, 300, 1,000 and 3,000 mcg. per m.2. Dose-limiting toxicity occurred at 1,000 to 3,000 mcg. per m.2, and included leukopenia, chills, fevers, rigors and hepatotoxicity as manifested by elevation in the transaminase and bilirubin levels. Tumor responses were seen initially at the 300 mcg. per m.2 dose level. Over-all, of 41 patients evaluable for therapeutic effectiveness 1 demonstrated a complete response 6 months in duration and 3 demonstrated partial responses 2, 9 and 13 months in duration. However, 6 patients demonstrated organ site responsiveness, including resolution of pulmonary lesions (2 complete and 1 partial responses), lymphadenopathy (1 complete and 1 partial responses), a pleural-based lesion in 1 patient with a partial response and complete resolution of hepatic metastases in 1 patient. We conclude that recombinant interferon gamma at a dose of 1,000 to 3,000 mcg. per m.2 for 7 days and repeated every 2 to 3 weeks had demonstrable anticancer activity in patients with metastatic renal carcinoma.
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PMID:Phase I/II study of recombinant interferon gamma in advanced renal cell carcinoma. 312 14


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