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)

Combinations of interferon-alpha and interferon-gamma demonstrate synergistic antiviral and anti-proliferative activity in vitro. Therefore, we initiated a clinical study of combination interferon therapy in humans. Eighteen patients with metastatic solid tumors received daily intramuscular (IM) injections of recombinant interferon-alpha-A (IFN alfa-2a, Roferon-A; Hoffman-LaRoche, Nutley, NJ) and recombinant IFN-gamma (rIFN-gamma) for 6 weeks. The dose levels were 0.5, 1.0, 2.0, and 5.0 X 10(6) U/m2/d of each interferon. A minimum of two patients were entered sequentially at each dose level. Fever, chills, fatigue, and a greater than or equal to 50% drop in granulocyte counts were observed at all doses. Severity of symptoms corresponded to increasing dose levels. In contrast to the tachyphylaxis to these symptoms that usually develops in patients treated with the individual interferons, many patients on this study experienced persistent fever and worsening fatigue over 6 weeks. The maximum tolerated dose was 1 X 10(6) U/m2/d of each interferon. One patient with renal-cell carcinoma achieved a partial remission (duration, 3 months). Enzyme-linked immunoassay analysis in all four patients for whom complete data were available revealed that peak blood levels of IFN alfa-2a on day 22 were about tenfold higher than on day 1. Because of the possibility of cumulative toxicity, the recommended starting dose for further studies is 0.5 X 10(6) U/m2/d of each interferon, with escalation to 1.0 X 10(6) U/m2/d after 1 month if tolerance is acceptable. Phase II investigations to explore the antitumor efficacy of this regimen are planned.
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PMID:Phase I study of a combination of recombinant interferon-alpha and recombinant interferon-gamma in cancer patients. 309 4

We report a Phase I study in 39 cancer patients of the tolerance and biologic activity of 47 intravenous (i.v.), intramuscular (i.m.), and subcutaneous (s.c.) treatments with recombinant methional gamma interferon (IFN-gamma 4A) which most closely resembles the natural material produced by T lymphocytes. Patients were treated with IFN-gamma 4A 5 days a week for 2 weeks. After a 2-week rest period, patients were placed on the same dose of drug three times a week. The most common side effects--fever, chills, malaise, myalgias, and nausea and vomiting--were seen with all routes of administration. Reversible increases in hepatic transaminase and decrease in granulocytes counts were seen. The dose-limiting toxicities observed were malaise and orthostatic hypotension. The maximum tolerated dose was 500-1,000 micrograms/M2/day. The t1/2 of IFN-gamma 4A in the circulation was 20 min after i.v. injection. No blood levels were detected after i.m. or s.c. injection. Antibody against IFN-gamma 4A increased in three patients. A complete response was observed in one patient with pulmonary metastases from renal cell carcinoma.
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PMID:A phase I trial of recombinant human gamma interferon (IFN-gamma 4A) in patients with advanced malignancy. 313 13

In extensive preclinical testing, a CD3 x CD19 bispecific antibody (BsAb) induced killing of malignant B cells by resting T cells even in an autologous situation. In a 14 day clonogenic assay using a CD19+ pre-B cell line (REH), BsAb required repeated administration together with IL-2 to achieve a 5 log kill by resting peripheral blood T cells. Intravenously administered BsAb in an intrapatient dose escalation study of 3 patients with B cell non-Hodgkin's lymphoma showed limited toxicity (WHO grade II fever and chills) due to tumor necrosis factor-alpha (TNF-alpha) release by T cells. Pharmacokinetics with 2.5 mg BsAb showed peak levels of 200-300 micrograms/ml and a t1/2 of 10.5 h. The next patient, with chronic lymphocytic leukemia (CLL), received 0.6 mg BsAb/m2 as an i.v. infusion preceded by 1 MU IL-2/m2 s.c. Improved T cell activation was noted, as indicated by an increase in IFN-gamma, IL-6, IL-8, and IL-10, in addition to high TNF-alpha increases. TNF-alpha increases were highest on the first day. Toxicity remained restricted to grade II fever and chills, observed every day after the infusion of BsAb. No clear clinical effects were seen in this chemotherapy-resistant CLL patient with a high tumor burden. If subsequent patients also show limited toxicity, treatment of patients with a lower tumor load seems to be warranted to evaluate the efficacy of CD3 x CD19 BsAb therapy.
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PMID:Clinical experience with CD3 x CD19 bispecific antibodies in patients with B cell malignancies. 858 81

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.
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PMID:Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. 981 99

IFN-gamma is a potent immunomodulator, which has activity against melanoma in vitro and in murine models. However, preclinical data suggests that the optimal therapeutic and immunomodulatory dose may not be the maximally tolerated clinical dose. We conducted a Phase II/III trial in good prognosis patients with metastatic melanoma to determine whether a therapeutic and immunomodulatory dose-response curve of IFN-gamma could be identified, and whether the two could be correlated. Ninety-eight patients with metastatic melanoma were randomized to one of seven dose levels of IFN-gamma ranging from 0.01 to 0.90 mg/m2. All patients were required to have s.c., skin, soft tissue, or nodal disease, although visceral disease was also allowed, and no more than one prior chemotherapy regimen. Patients received IFN-gamma as a 1-h i.v. infusion three times per week for at least 8 weeks or until progressive disease. Ninety-five patients were eligible for toxicity evaluation; 81 were eligible for tumor response. Four patients responded to therapy (response rate, 5%) at three dose levels: two patients at 0.01 mg/m2 and one each at 0.5 and 0.9 mg/m2. The duration of response ranged from 5 to 58 weeks. Toxicities were typical of IFNs and included flu-like constitutional symptoms. No dose-response relationship was identified for efficacy. A dose-response relationship for toxicity was observed only for fever and chills (p = 0.035) and hepatic toxicity (p = 0.034). IFN-gamma has minimal activity in metastatic melanoma, and a therapeutic dose-response curve could not be identified. Although potent dose-dependent effects on immunomodulation were identified (J. M. Kirkwood, J. Bryant, J. H. Schiller, M. M. Oken, E. C. Borden, and T. L. Whiteside. Immunomodulatory function of interferon gamma in patients with metastatic melanoma: results of a phase IIB trial in subjects with metastatic melanoma: ECOG Study E4987, submitted for publication), this biological activity does not translate into therapeutic activity in the metastatic disease setting in this trial.
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PMID:Eastern cooperative group trial of interferon gamma in metastatic melanoma: an innovative study design. 981 86

Interferon (IFN)-alpha, IFN-beta, and IFN-gamma are currently available for the treatment of malignancies, viral infections (e.g., hepatitis C virus), multiple sclerosis (MS), and skin conditions. In addition to their therapeutic effects, IFNs commonly cause various side effects. Most common among the side effects of IFN are "flu-like" symptoms such as chills, fever, and muscle soreness. However, IFN can also cause significant neuropsychiatric side effects, particularly symptoms of depression. A literature search was conducted in order to summarize current information on (1) the frequency, characteristics, and risk factors of IFN-induced depression, (2) possible biochemical mechanisms associated with IFN-induced depression, and (3) the treatment strategies for IFN-induced depression. Review of the literature suggests that symptoms of depression induced by IFN therapy, in particular IFN-alpha therapy, are common and can limit the treatment utility, often necessitating discontinuation of IFN therapy or the use of psychopharmacologic agents. Depression is also a suspected side effect of therapy with IFN-beta and IFN-gamma; however, the association has not been as convincingly confirmed. Importantly, IFNs affect neurochemical pathways putatively involved in the etiology of depression. While these depressive side effects usually resolve after the completion of IFN therapy, they can persist or reappear with dose escalations. It is recommended that health care providers, patients and their families be informed about the potential risk of the psychiatric disturbances that can occur with IFN-alpha therapy. Screening and monitoring, ideally using symptom rating scales for depression, and early antidepressant treatment intervention appear necessary to optimize IFN therapy for the majority of patients.
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PMID:The phenomenology and treatment of interferon-induced depression. 1548 46

The objective of this study was to evaluate the safety and activity of the intratumoral administration of the immune costimulatory molecule, B7.1, encoded by a vector derived from the canarypox virus, ALVAC (ALVAC-B7.1), alone and with the intratumoral injection of ALVAC encoding the immune-stimulatory cytokine, interleukin 12 (ALVAC-IL-12). Fourteen patients with metastatic melanoma who had s.c. nodules received intratumoral injections on days 1, 4, 8, and 11. Nine patients were given escalating doses of up to 25 x 10(8) plaque-forming units of ALVAC-B7.1. Five patients were given 25 x 10(8) plaque-forming units of ALVAC-B7.1 combined with ALVAC-IL-12 50% tissue culture infective dose of 2 x 10(6). Toxicity was mild to moderate and consisted of inflammatory reactions at the injection site and fever, chills, myalgia, and fatigue. Higher levels of B7.1 mRNA were observed in ALVAC-B7.1-injected tumors compared with saline-injected control tumors. Higher levels of intratumoral vascular endothelial growth factor and IL-10, cytokines with immune suppressive activities, were also observed in ALVAC-B7.1- and ALVAC-IL-12-injected tumors compared with saline-injected controls. Serum levels of vascular endothelial growth factor increased at day 18 and returned to baseline at day 43. All patients developed antibody to ALVAC. Intratumoral IL-12 and IFN-gamma mRNA decreased. Changes in serum IL-12 and IFN-gamma levels were not observed. Tumor regressions were not observed. The intratumoral injections of ALVAC-B7.1 and ALVAC-IL-12 were well tolerated at these dose levels and at this schedule and resulted in measurable biological response. This response included the production of factors that may suppress the antitumor immunologic activity of these vectors.
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PMID:Phase I study of the intratumoral administration of recombinant canarypox viruses expressing B7.1 and interleukin 12 in patients with metastatic melanoma. 1593 Mar 53

Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease with significant morbidity and mortality. An epidemic in 2003 affected 8,098 patients in 29 countries with 774 deaths. The aetiological agent is a new coronavirus spread by droplet transmission. Clinical and general laboratory manifestations included fever, chills, rigor, myalgia, malaise, diarrhoea, cough, dyspnoea, pneumonia, lymphopenia, neutrophilia, thrombocytopenia, and elevated serum lactate dehydrogenase (LD), alanine aminotransferase (ALT) and creatine kinase (CK) activities. Treatment has been empirical; initial potent antibiotic cover, followed by simultaneous ribavirin and corticosteroids, with or without pulse high-dose methylprednisolone, have been used. The postulated disease progression comprises (1) active viral infection, (2) hyperactive immune response, and (3) recovery or pulmonary destruction and death. We investigated serum LD isoenzymes and blood lymphocyte subsets of SARS patients, and found LD1 activity as the best biochemical prognostic indicator for death, while CD3+, CD4+, CD8+ and natural killer cell counts were promising predictors for intensive care unit (ICU) admission. Plasma cytokine and chemokine profiles showed markedly elevated Th1 cytokine interferon (IFN)-gamma, inflammatory cytokines interleukin (IL)-1beta, IL-6 and IL-12, neutrophil chemokine IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-gamma-inducible protein-10 (IP-10) for at least two weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumor necrosis factor (TNF)-alpha and anti-inflammatory cytokine IL-10. Corticosteroid reduced IL-8, MCP-1 and IP-10 concentrations from 5-8 days after treatment. Measurement of biochemical markers of bone metabolism demonstrated significant but transient increase in bone resorption from Day 28-44 after onset of fever, when pulse steroid was most frequently given. With tapering down of steroid therapy, there was a decrease in bone resorption marker together with an increase in bone formation markers round Day 50, suggesting that some of the bone loss might be reversed. Our research studies on the chemical pathology and clinical immunology of SARS should have implications for the pathophysiology and therapy of this potentially lethal infection.
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PMID:Severe acute respiratory syndrome: clinical and laboratory manifestations. 1845 12

The aim of this preliminary study was to investigate the plasma cytokine profiles in a group of patients suffering from Plasmodium vivax malaria during the peak of its transmission season. Plasma samples of 173 P. vivax patients and 34 healthy individuals were analyzed for IFN-gamma, TNF-alpha, IL-10 and IP-10 levels by ELISA. Levels of both pro- and anti-inflammatory cytokines were significantly higher in P. vivax patients compared to controls. Children with P. vivax infection had significantly higher levels of IFN-gamma than adults (P=0.017). Asexual parasitaemia versus TNF-alpha (r=-0.31, P=0.01), IL-10 (r=-0.30, P=0.015) and gametocytaemia versus IFN-gamma (r=-0.26; P=0.034) levels showed significant negative correlation in children compared to adults. The median concentrations of IFN-gamma (P=0.001), IL-10 (P=0.032) and IP-10 (P</=0.05) were higher in children reported with chills and rigors, whereas in adults only IFN-gamma levels was higher (P<0.0001). The median plasma concentrations of IFN- gamma (P=0.02), IL-10 (P<0.0001) and IP-10 (P=0.068) were higher in patients with mild anaemia compared to non-anaemic patients. The results indicated that both pro- and anti-inflammatory cytokine responses are associated with clinical signs of mild anaemia and paroxysm during symptomatic P. vivax malaria in Central India.
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PMID:A preliminary study on pro- and anti-inflammatory cytokine profiles in Plasmodium vivax malaria patients from central zone of India. 1995 46